302858 Taylor & Francis Informa SBI

GOLDSTEIN • WYLLIE
CARSON • KIRBY

E
TEXTBOOK OF

RECTILE
DYSFUNCTION
S ECOND E DITION
Erectile Dysfunction
Textbook of

Editors
CULLEY C CARSON III
ROGER S KIRBY
IRWIN GOLDSTEIN
Second
Edition MICHAEL G WYLLIE
Textbook of Erectile Dysfunction
Textbook of Erectile Dysfunction
Second Edition

Edited by

Culley C Carson III MD

Division of Urology
University of North Carolina at Chapel Hill
Chapel Hill, NC
USA

Roger S Kirby MA MD FRCS(Urol) FEBU

Director
The Prostate Centre
London
UK

Irwin Goldstein MD
Director
San Diego Sexual Medicine
Alvarado Hospital
San Diego, CA
USA
and

Michael G Wyllie
Urodoc Ltd
Kent
UK
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Textbook of erectile dysfunction / edited by Culley C. Carson III . . . [et al.]. – 2nd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-84184-646-0 (hb : alk. paper) 1. Impotence. 2. Penis–Diseases. I.
Carson, Culley C.
[DNLM: 1. Erectile Dysfunction–diagnosis. 2. Erectile Dysfunction–therapy. 3.
Penile Diseases–diagnosis. 4. Penile Diseases–therapy. WJ 709 T355 2009]
RC889.T49 2009
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Dedicated to my parents Culley
and Dorothy Carson and my
wife Mary Jo Carson
Contents
List of contributors xi
Preface xix
Culley C Carson III, Roger S Kirby, Irwin Goldstein, and Michael G Wyllie

SECTION 1: BASIC SCIENCE

1. The history of erectile dysfunction 1
Sachin Agrawal and William D Dunsmuir
2. The history of the International Society for Sexual Medicine 11
Ronald W Lewis and Gorm Wagner
3. Epidemiology of erectile dysfunction 17
Peter Boyle
4. Anatomy of erectile function 25
William O Brant, Anthony J Bella, and Tom F Lue
5. Microscopic anatomy of erectile function 28
Anthony J Bella, William O Brant, and Tom F Lue
6. Vascular physiology of erectile function 35
Noel N Kim
7. Central nervous system control of sexual function in males and females 42
Lesley Marson
8. Ejaculatory physiology 54
Levent Gurkan, Austin DeRosa, and Wayne JG Hellstrom
9. Endocrinology of male sexual function 61
Mario Maggi, Giovanni Corona, and Gianni Forti
10. Pathophysiology of erectile dysfunction: molecular basis 72
Biljana Musicki and Arthur L Burnett
11. Neurotransmitters in the corpus cavernosum: nitric oxide and beyond 83
Anthony J Bella, William O Brant, Gerald B Brock, and Tom F Lue
12. Receptor pharmacology related to erectile dysfunction 91
Christian Gratzke, Tamer Abouschwareb, George J Christ, and Karl-Erik Andersson
13. Environmental erectile dysfunction 106
Arthur L Burnett
14. Erectile dysfunction and treatment of carcinoma of the prostate 112
Culley C Carson III

SECTION 2: RISK FACTORS AND CLINICAL EVALUATION

15. Vascular risk factors and erectile dysfunction 120
Graham Jackson and Alethea Cooper
16. Mediterranean diet and erectile dysfunction 126
Dario Giugliano, Myriam Ciotola, Francesco Giugliano, Massimo D’Armiento,
and Katherine Esposito
17. Pharmacological risk factors for altered male sexual function 134
Michael G Wyllie
18. Male sexual dysfunction and the prostate 142
Michael G Wyllie
vii
viii Contents

19. Basic assessment of the patient with erectile dysfunction 148

Roger S Kirby and Michael G Kirby
20. The contemporary role of penile duplex scanning in sexual dysfunction 159
Gerald Brock and Anthony Bella
21. Imaging in erectile dysfunction 165
David Rickards
22. Neurophysiologic testing in erectile dysfunction 168
Yoram Vardi and Ilan Gruenwald
23. Biopsy of the corpus cavernosum 176
Eric Wespes
24. Endocrine evaluation of male sexual function 179
Sanjay N Mediwala and Glenn R Cunningham
25. The biopsychosocial evaluation of erectile dysfunction 184
Stanley E Althof and Rachel Needle
26. Erectile dysfunction: the couple contex 190
William A Fisher, Alexandra McIntyre-Smith, and Michael Sand
27. Primary care evaluation and treatment of erectile dysfunction: American perspective 201
Richard Sadovsky and Martin Miner

SECTION 3: TREATMENT OF SEXUAL DYSFUNCTION

28. Phosphodiesterase type 5 inhibitors: molecular basis for pharmacological effects 213
Sharron H Francis and Jackie D Corbin
29. Phosphodiesterase type 5 inhibitors: non-erectile dysfunction cardiovascular effects 221
Charalambos Vlachopoulos, Nikolaos Ioakeimidis, Konstantinos Rokkas, and Christodoulos Stefanadis
30. Sildenafil: first in the therapeutic class of phosphodiesterase type 5 inhibitors 231
Culley C Carson III
31. Tadalafil: long-acting phosphodiesterase type 5 inhibitor 237
Anthony J Bella and Gerald B Brock
32. Vardenafil: a biochemically potent phosphodiesterase type 5 inhibitor 248
Sharron H Francis and Jackie D Corbin
33. The Princeton Guidelines for treatment 257
Graham Jackson
34. Phosphodiesterase type 5 inhibitors: safety and adverse events 262
Konstantinos Hatzimouratidis and Dimitrios Hatzichristou
35. Diagnosis and treatment of hypogonadism 271
Mathew Oommen, Levent Gurkan, Allen D Seftel, and Wayne JG Hellstrom
36. Central nervous system agents for the treatment of erectile dysfunction 276
Julita Mir and Ricardo Munárriz
37. Intracavernosal therapy for erectile dysfunction 281
Carsten Maik Naumann, Moritz Franz Hamann, Sascha Kaufmann, Amr Al-Najar,
Christof van der Horst, and Klaus-Peter Jünemann
38. Invicorp in erectile dysfunction 286
Michael G Wyllie and W Wallace Dinsmore
39. Vacuum systems for erectile dysfunction 291
Audrey C Rhee and Ronald W Lewis
40. Integrated sex therapy: a psychosocial–cultural perspective integrating behavioral, cognitive,
and medical approaches 298
Michael A Perelman
 Contents ix

41. Gene therapy in erectile dysfunction: an update 306

Tamer Aboushwareb, Christian Gratzke, Karl-Erik Andersson, and George J Christ
42. Stem and endothelial progenitor cells in erectile biology: future therapeutic applications and
potential biomarker for erectile dysfunction 314
Trinity J Bivalacqua, Travis D Strong, Hunter C Champion, and Arthur L Burnett
43. Mechanical, malleable, and soft semi-rigid penile implants for erectile dysfunction 323
John J Mulcahy
44. Inflatable penile prostheses in erectile dysfunction (including penile shaft re-modeling in
Peyronie’s disease) 329
Daniel Yachia
45. Inflatable penile prostheses 338
Culley C Carson III
46. Design, development, and use of questionnaires and surveys in the evaluation and management of
sexual dysfunction: erectile dysfunction 347
Glen W Barrisford and Michael P O’Leary
47. Assessment of male ejaculatory disorders 353
Raymond C Rosen, Stanley E Althof, and Tara Symonds
48. Clinical trial design for erectile dysfunction 360
Michael G Wyllie
49. Sexual function in congenital anomalies 367
CRJ Woodhouse
50. Veno-occlusive impotence and erectile dysfunction: treatment and outcomes 382
Aksam A Yassin and Farid Saad
51. Penile fracture: evaluation and management 392
Osama KZ Shaeer and Kamal ZM Shaeer

SECTION 4: SPECIAL PROBLEMS

52. Risks, complications, and outcomes of penile lengthening and augmentation procedures 398
Hunter Wessells and Jack W McAninch
53. Peyronie’s disease: evaluation and review of non-surgical therapy 405
Frederick L Taylor and Laurence A Levine
54. Surgical treatment of Peyronie’s disease 413
Culley C Carson III
55. Priapism 420
Rajeev Kumar and Ajay Nehra
56. Phosphodiesterase type 5 inhibitor therapy for priapism 428
Trinity J Bivalacqua, Biljana Musicki, Hunter C Champion, and Arthur L Burnett
57. Augmentation of phosphodiesterase type 5 inhibitor response with testosterone 434
Antonio Aversa
58. Phosphodiesterase type 5 inhibitors for the treatment of women’s sexual function 443
Salvatore Caruso, Agnello Carmela, and Lucia Di Mari
59. Erectile dysfunction and diabetes 449
Suks Minhas, Ian Eardley, and Michael G Kirby
60. Chronic renal failure and sexual dysfunction 457
Culley C Carson III and Aaron C Lentz
61. Evaluation of ejaculatory disorders 468
Jason M Greenfield and Craig F Donatucci
x Contents

62. Medical treatment of ejaculatory dysfunction 474

Chris G McMahon
63. Topical agents for the treatment of premature ejaculation 495
Michael G Wyllie
64. Potency-preserving surgery: radical prostatectomy and other pelvic surgery 503
Paolo Gontero and Roger S Kirby
65. Rehabilitation of sexual function following prostatectomy 512
Francesco Montorsi and Alberto Briganti
66. Sexual dysfunction and prostate cancer therapy 521
John M Fitzpatrick, Roger S Kirby, Robert J Krane, Jan Adolfsson, Don WW Newling, and
Irwin Goldstein
67. Gender reassignment surgery 526
Michael Sohn and Klaus Exner

Index 533
List of Contributors
Tamer Abouschwareb Anthony J Bella MD FRCS(C)
Wake Forest Institute for Regenerative Medicine Assistant Professor and Director of Basic Urologic Research
Wake Forest University School of Medicine Division of Urology
Winston Salem, NC Department of Surgery
USA and Associate Scientist, Neuroscience
Ottawa Health Research Institute
University of Ottawa
Jan Adolfsson
Ottawa, ON
Associate Professor of Urology
Canada
Karolinska Institute
Department of Urology
Huddinge University Hospital Trinity J Bivalacqua MD PhD
Huddinge James Buchanan Brady Urological Institute
Sweden Department of Urology
Johns Hopkins Hospital
Baltimore, MD
Sachin Agrawal MRCS
USA
Urology Registrar
Department of Urology
St Peters Hospital Peter Boyle
Chertsey Division of Epidemiology and Biostatistics
UK European Institute of Oncology
Milan
Italy
Stanley E Althof PhD
Professor of Psychology
Case Western Reserve University School of Medicine William O Brant MD
Cleveland, OH Division of Urology
Voluntary Professor of Psychology University of Utah
University of Miami Miller Medical School Salt Lake City, UT
and Executive Director USA
Center for Marital and Sexual Health of South Florida
West Palm Beach, FL
Alberto Briganti MD
USA
Department of Urology
University Vita Salute San Raffaele
Karl-Erik Andersson MD PhD Milan
Wake Forest Institute for Regenerative Medicine Italy
Wake Forest University School of Medicine
Winston Salem, NC
Gerald B Brock MD FRCSC
USA
Professor of Urology
Department of Surgery
Antonio Aversa MD PhD Division of Urology
Senior Researcher University of Western Ontario
Department of Medical Pathophysiology London, ON
Sapienza University of Rome Canada
Rome
Italy
Arthur L Burnett MD FACS
Patrick C. Walsh Professor of Urology
Glen W Barrisford The James Buchanan Brady Urological Institute
Division of Urology Department of Urology
National Naval Medical Center Johns Hopkins Medical Institutions
Bethesda, MD Baltimore, MD
USA USA

xi
xii Contributors

Agnello Carmela MD Glenn R Cunningham MD

Research Group for Sexology Professor of Medicine
Department of Microbiological and Gynaecological Professor of Molecular and Cellular Biology
Science Baylor College of Medicine
University of Catania and Medical Director
Catania St Luke’s–Baylor Diabetes Program
Italy St Luke’s Episcopal Hospital
Houston, TX
Culley C Carson III MD USA
Division of Urology
University of North Carolina at Chapel Hill
Chapel Hill, NC Massimo D’Armiento
USA Division of Urology
Department of Geriatrics and Metabolic Diseases
Salvatore Caruso MD University of Naples SUN
Research Group for Sexology Naples
Department of Microbiological and Italy
Gynaecological Science
University of Catania Austin DeRosa
Catania Medical Student
Italy School of Medicine
Hunter C Champion MD PhD Tulane University Health Sciences Center
Division of Cardiology New Orleans, LA
Department of Medicine USA
Johns Hopkins Hospital
Baltimore, MD Lucia Di Mari MD
USA Research Group for Sexology
Department of Microbiological and Gynaecological
George J Christ Science
Wake Forest Institute for Regenerative Medicine University of Catania
Wake Forest University School of Medicine Catania
Winston Salem, NC Italy
USA

Myriam Ciotola W Wallace Dinsmore MBBCh MD FRCP FRCPI FRCP(Ed)

Division of Metabolic Diseases Department of Genito-Urinary Medicine
University of Naples SUN Royal Victoria Hospital
Naples Belfast
Italy UK

Alethea Cooper
Health Psychologist Craig F Donatucci MD
Guy’s and St Thomas’ NHS Foundation Trust Department of Surgery/Division of Urology
London Duke University Medical Center
UK Durham, NC
USA
Jackie D Corbin PhD
Department of Molecular Physiology and Biophysics William D Dunsmuir MS FRCS(Urol)
Vanderbilt University School of Medicine Consultant Urologist
Nashville, TN Department of Urology
USA St Peters Hospital
Giovanni Corona Chertsey
Andrology Unit UK
Department of Clinical Physiopathology
University of Florence Ian Eardley
Florence Consultant Urologist
and Endocrinology Unit Department of Urology
Maggiore-Bellaria Hospital St James’ University Hospital
Bologna Leeds
Italy UK
 Contributors xiii

Katherine Esposito Paolo Gontero

Division of Metabolic Diseases Senior Lecturer in Urology
University of Naples SUN University of Turin
Naples Turin
Italy Italy

Klaus Exner Christian Gratzke

Department of Plastic and Reconstructive Surgery Wake Forest Institute for Regenerative Medicine
Marcus-Hospital Wake Forest University School of Medicine
Frankfurt Winston Salem, NC
Germany USA

Jason M Greenfield MD
William A Fisher PhD
Department of Surgery/Division of Urology
Department of Psychology
Duke University Medical Center
and Department of Obstetrics and Gynaecology
Durham, NC
University of Western Ontario
USA
London, ON
Canada
Ilan Gruenwald
Neuro-urology Unit
John M Fitzpatrick Rambam Health Care Campus
Professor of Surgery and Consultant Urologist and Technion Faculty of Medicine
Mater Misericordiae Hospital Haifa
and University College Dublin Israel
Dublin
Ireland Levent Gurkan MD
Research Fellow
Gianni Forti Department of Urology
Andrology Unit Section of Andrology
Department of Clinical Physiopathology Tulane University Health Sciences Center
University of Florence New Orleans, LA
Florence USA
Italy
Moritz Franz Hamann MD
Sharron H Francis PhD Department of Urology and Pediatric Urology
Department of Molecular Physiology and Biophysics University Hospital Schleswig-Holstein
Vanderbilt University School of Medicine Kiel
Nashville, TN Germany
USA
Dimitrios Hatzichristou MD PhD
Center for Sexual and Reproductive Health
Dario Giugliano
Second Department of Urology
Division of Metabolic Diseases
Papageorgiou General Hospital
University of Naples SUN
Aristotle University of Thessaloniki
Naples
Greece
Italy
Konstantinos Hatzimouratidis MD PhD
Francesco Giugliano Center for Sexual and Reproductive Health
Division of Urology Second Department of Urology
Department of Geriatrics and Metabolic Diseases Papageorgiou General Hospital
University of Naples SUN Aristotle University of Thessaloniki
Naples Greece
Italy
Wayne JG Hellstrom MD FACS
Irwin Goldstein MD Professor of Urology
Director Chief
San Diego Sexual Medicine Section of Andrology
Alvarado Hospital Tulane University Medical Center
San Diego, CA New Orleans, LA
USA USA
xiv Contributors

Nikolaos Ioakeimidis MD Aaron C Lentz MD

Cardiovascular Diseases and Sexual Health Unit Resident in Urologic Surgery
First Department of Cardiology Department of Surgery/Division of Urology
Athens Medical School University of North Carolina at Chapel Hill
Hippokration Hospital Chapel Hill, NC
Athens USA
Greece
Laurence A Levine MD
Professor of Urology
Graham Jackson FRCP FACC FESC Department of Urology
Consultant Cardiologist Rush University Medical Center
Guy’s and St Thomas’ NHS Foundation Trust Chicago, IL
London USA
UK
Ronald W Lewis
Professor of Surgery (Urology) and Physiology
Klaus-Peter Jünemann MD
Chief of Urology
Professor of Urology
Medical College of Georgia
Department of Urology and Pediatric Urology
Augusta, GA
University Hospital Schleswig-Holstein
USA
Kiel
Germany Tom F Lue MD FACS
Professor and Vice Chair
Sascha Kaufmann MD Department of Urology
Department of Urology and Pediatric Urology University of California, San Francisco
University Hospital Schleswig-Holstein San Francisco, CA
Kiel USA
Germany Mario Maggi
Andrology Unit
Noel N Kim PhD Department of Clinical Physiopathology
Alagin Research LLC University of Florence
and Institute for Sexual Medicine Florence
San Diego, CA Italy
USA
Lesley Marson PhD
Department of Surgery, Division of Urology
Roger S Kirby MA MD FRCS(Urol) FEBU School of Medicine
Director University of North Carolina at Chapel Hill
The Prostate Centre Chapel Hill, NC
London USA
UK
Jack W McAninch MD FACS
Professor and Vice Chairman
Michael G Kirby
Department of Urology
Visiting Professor
University of California
University of Hertfordshire and the Prostate Centre
San Francisco General Hospital
London
San Francisco, CA
UK
USA

Robert J Krane Alexandra McIntyre-Smith MA

Department of Urology Department of Psychology
Boston University School of Medicine University of Western Ontario
Boston University Medical Center London, ON
Boston, MA Canada
USA
Chris G McMahon MBBS FAChSHM
Associate Professor
Rajeev Kumar MCh Faculty of Health Sciences
Assistant Professor of Urology University of Sydney
All India Institute of Medical Sciences Australian Center for Sexual Health
New Delhi Sydney, NSW
India Australia
 Contributors xv

Sanjay N Mediwala MD Carsten Maik Naumann MD

Clinical Fellow Department of Urology and Pediatric Urology
Division of Endocrinology University Hospital Schleswig-Holstein
Baylor College of Medicine Kiel
Houston, TX Germany
USA
Rachel Needle PsyD
Martin Miner MD Postdoctoral Fellow
Co-Director Men’s Health Center Center for Marital and Sexual Health of South Florida
The Miriam Hospital West Palm Beach, FL
and Associate Clinical Professor of Family Medicine USA
The Warren Alpert School of Medicine
Brown University School of Medicine Ajay Nehra MD FACS
Providence, RI Professor of Urology
USA Mayo Clinic
Rochester, MN
Suks Minhas
USA
Consultant Urologist and Andrologist
Honorary Senior Lecturer
Institute of Urology and Middlesex Hospital Don WW Newling
University College Hospital Department of Urology
London Academic Hospital
UK Vrije Universiteit
Amsterdam
Julita Mir MD The Netherlands
Department of Medicine
Boston University School of Medicine Michael P O’Leary
Boston, MA Division of Urology
USA Brigham and Women’s Hospital
Harvard Medical School
Francesco Montorsi MD Boston, MA
Department of Urology USA
University Vita Salute San Raffaele
Milan Mathew Oommen MD
Italy Fellow
Department of Urology
John J Mulcahy MD PhD FACS Tulane University Medical Center
Clinical Professor of Surgery (Urology) New Orleans, LA
University of Arizona USA
Tucson, AZ
USA
Michael A Perelman PhD
Ricardo Munárriz MD Director, Human Sexuality Program
Associate Professor of Urology Clinical Associate Professor of Psychiatry,
Director, Center for Sexual Medicine Reproductive Medicine and Urology
Boston University School of Medicine The New York Presbyterian Hospital
Boston, MA Weill Medical College of Cornell University
USA New York, NY
USA
Biljana Musicki PhD
Department of Urology Audrey C Rhee MD
Johns Hopkins Hospital Resident in Urology
Johns Hopkins University School of Medicine Medical College of Georgia
Baltimore, MD Augusta, GA
USA USA

Amr Al-Najar MD David Rickards

Department of Urology and Pediatric Urology Consultant Uroradiologist
University Hospital Schleswig-Holstein University College Hospital
Kiel London
Germany UK
xvi Contributors

Konstantinos Rokkas MD Michael Sohn

Cardiovascular Diseases and Sexual Health Unit Department of Urology
First Department of Cardiology Marcus-Hospital
Athens Medical School Frankfurt
Hippokration Hospital Germany
Athens
Greece Christodoulos Stefanadis MD
Cardiovascular Diseases and Sexual Health Unit
Raymond C Rosen PhD First Department of Cardiology
Chief Scientist Athens Medical School
New England Research Institutes Hippokration Hospital
Watertown, MA Athens
USA Greece
Farid Saad
Travis D Strong BS
Scientific Affairs, Men’s Healthcare
James Buchanan Brady Urological Institute
Bayer Schering Pharma AG
Department of Urology
Professor, Research Department
Johns Hopkins Hospital
Gulf Medical University
Baltimore, MD
Ajman
USA
United Arab Emirates
and Men’s Health Reproduction Study Center
Hang Tuah University Tara Symonds PhD
Surabaya Global Outcomes Research
Indonesia Pfizer Ltd
Kent
Richard Sadovsky MD UK
Associate Professor of Family Practice
State University of New York Frederick L Taylor MD
Health Science Center at Brooklyn Resident in Urology
Brooklyn, NY Department of Urology
USA Rush University Medical Center
Chicago, IL
Michael Sand PhD MPH USA
Adjunct Senior Scientist
New England Research Institutes Christof van der Horst MD
Watertown, MA Department of Urology and Pediatric Urology
USA University Hospital Schleswig-Holstein
Kiel
Allen D Seftel MD Germany
Professor of Urology
Case Medical Center/University Hospitals of Cleveland
Yoram Vardi
Chief
Neuro-urology Unit
Section of Urology
Rambam Health Care Campus
Louis Stokes Cleveland VA Medical Center
and Technion Faculty of Medicine
Cleveland, OH
Haifa
USA
Israel
Kamal ZM Shaeer MD
Department of Andrology Charalambos Vlachopoulos MD
Faculty of Medicine Cardiovascular Diseases and Sexual Health Unit
Cairo University First Department of Cardiology
Cairo Athens Medical School
Egypt Hippokration Hospital
Athens
Osama KZ Shaeer MD Greece
Department of Andrology
Faculty of Medicine Gorm Wagner MD PhD
Cairo University Institute of Preventive Medicine
Cairo Copenhagen
Egypt Denmark
 Contributors xvii

Eric Wespes MD PhD Michael G Wyllie

Department of Urology Urodoc Ltd
CHU de Charleroi Kent
Charleroi UK
Belgium
Daniel Yachia MD
Professor of Urology (Emeritus)
Hunter Wessells MD Rappaport Faculty of Medicine
Professor and Chair Technion – Israel Institute of Technology
Department of Urology Haifa
Nelson Chair in Urology and Head, Department of Urology (Emeritus)
University of Washington Hillel Yaffe Medical Center
School of Medicine Hadera
and Chief of Urology Israel
Harborview Medical Center
Seattle, WA Aksam A Yassin MD PhD EdD FEBU
USA Professor of Urology and Human Sexuality
Chairman
Institute of Urology and Andrology
CRJ Woodhouse MB FRCS FEBU Segeberger Kliniken
Professor of Adolescent Urology Norderstedt-Hamburg
The Institute of Urology Germany
and Honorary Consultant Urologist and Department of Urology
The Hospital for Children Gulf Medical College School of Medicine
London Ajman
UK United Arab Emirates
Preface
While the last decade has seen enormous changes in the by extension, sexual dysfunction in both men and women.
understanding and treatment of sexual dysfunction and That landscape continues today and the management of
erectile dysfunction, the problem of sexual dysfunction sexual dysfunction has enlarged from strict erectile problems
has been described since the ancients. Indeed Greek cup to include premature ejaculation, hypogonadism, and female
paintings, the Old Testament, Hindus, and ancient Chinese sexual dysfunction.
have all described sexual problems. Treatments from surgery, This second edition of The Textbook of Erectile Dysfunction
herbs, spices, and potions have all been suggested as remedies. marks many of those advances. While the first edition included
The more modern song describing ‘Love Potion Number 9’ only moderate discussion of the medical treatment of sexual
and the search for ‘Spanish Fly’ both detail these remedies dysfunction and its causes, this edition moves into a higher
and their promise of resolution of sexual and erectile level of discussion with subjects such as the basic science
dysfunction. approach to erection and sexual investigation, a more refined
Beginning with Kinsey in 1948 and through Masters review of the PDE-5 inhibitors including newer agents, and a
and Johnson in the 1960s, the epidemiology and behavioral discussion of central nervous system agents, their advantages,
treatment model has flourished before specific tested medical and disadvantages. There is also a complete discussion of the
methods had been developed. Simultaneously, surgeons surgical approach to sexual problems including priapism,
attempted to recreate the os penis of lower animal forms Peyronie’s disease, and penile implants. The authors of these
with surgical procedures beginning with transplanted rib chapters are chosen from among the world’s experts in this
cartilage and proceeding through latex to the currently used growing field and are each uniquely qualified for reporting on
silicone elastomer. It has been just three decades since the their area of interest. This edition provides a single source for
first functional, safe, and satisfactory penile implant has been up-to-date information on sexual dysfunction from history to
introduced. basic science to treatment options.
The true revolution in treatment and patient acceptance, The editors would like to express their sincere appreciation
however, began with the marketing of the first phosphodi- to all the contributors for their time, efforts, and expertise.
esterase type 5 inhibitor (PDE-5), sildenafil, in 1998. This Without these efforts this textbook could not have become a
revolution was not only scientific and medical, but also reality. We would also like to acknowledge the assistance of
societal. Once these PDE-5 inhibitors were available, the the editorial staff who have taken difficult manuscripts
international acceptance of the diagnosis and treatment of and transformed them into complete, understandable, and
erectile dysfunction assumed titanic proportions. Subjects readable chapters.
confined to the back rooms were suddenly dinner party
conversation and the media were rife with reports, debates, C Carson, R Kirby, I Goldstein, M Wyllie
and discussion of the treatment of erectile dysfunction and, October 2008

xix
1 The history of erectile dysfunction
Sachin Agrawal and William D Dunsmuir

Introduction caused impotence. In this bizarre case, the court ruled that the
doctor ‘oversee’ the defendant’s attempts at self-restraint to
Throughout antiquity, erectile function has symbolized virility assess the condition’s curability. The law subsequently
and manhood. Erections are special to the human male, since changed, introducing the term ‘naturally impotent’ into the
in most animals copulation is quick. In the rat, erection and statute, making cause immaterial. To this day, impotence
ejaculation are almost simultaneous reflex events. In the dog, remains grounds for annulment.
copulation lasts around 20 seconds. Even the African ostrich, Since ancient times, the fear of humiliation and conceal-
renowned for his ostentatious courtship displays, completes ment has colored the literature. In Satyricon by Petronius,
the act within a minute.1 Throughout nature, strategies have Encolpius was damned to impotence for desecrating the
evolved to facilitate penetration. Mammals like the walrus, rites of Priapus (the god of fertility). Having been rendered
whale, and orangutan have ossified penile shafts. This os penis, impotent, he was then humiliated by being forced into a pub-
os priapi, or baculum measures up to 3.5 m. However, for some lic orgy with the priestess Quartilla.5 Exposing the afflicted
species, survival does not depend on speed. Indeed, the pro- has forever been of public interest. Take the 19th century
traction of sex has evolved perhaps solely in humans. Erectile English writer and reformer, John Ruskin: his marriage was
dysfunction has been ever-present, with modern medical publicly dissolved on grounds of non-consummation. Ruskin
practice evolving through observation, experimentation, and suffered a mental breakdown and retreated into isolation.6
refinement of ancient remedies. This chapter examines its As with so many men, the loss of potency led to the loss of
impact, tracing its history from antiquity to the present day. self-worth. Indeed, the presumed impotence and inability of
the last Spanish Hapsburg, Don Carlos II (1661–1700), to
provide an heir led to the War of Spanish Succession. It is not
The impact of impotence through surprising that so much time and energy has been spent in
finding a cure.
the ages
Impotence has influenced society in two ways: through its
association with humiliation and through its influence on Aphrodisiacs and antiquity
the validity of marriage. ‘Non-consummation’ claims were
frequently used for annulment, these often leveled at the male. Aphrodisiacs derive their name from Aphrodite, the Greek
Furthermore, humiliation was a powerful form of social control. goddess of love. Since antiquity they have increased sexual drive
Many men were ridiculed and destroyed by the public exposure and pleasure, with many purported to help erectile function.
of their impotence. By the 16th century, ecclesiastic trials were Some may have originated by correcting nutritional deficien-
widespread. Juries comprising theologians, physicians, and cies and improving health. Oysters are rich in zinc, rhinoceros
midwives demanded that the accused ‘prove himself ’. Galleries horn contains calcium and amino acids, and chocolate has
delighted at these civic displays of voyeurism, with trial reports magnesium and phenylethylamine. Other aphrodisiacs resem-
distributed in the thousands. So great was public exhilaration bled sexual organs, such as the mandrake and the penis or
and fear generated that these courts bestowed tremendous oysters and the ovaries. The majority heightened physical and
power to the medieval Church (Figure 1.1).2 Only the struggle sexual awareness, indirectly affecting erectile function. Many
for power between the Church and State in France (around bizarre remedies exist, including bear’s gall bladder, shark’s
1677) led to abolition of these shameful rituals.3 However, fin, powdered lizard, snake’s blood, fermented leeches (mas-
the relationship between law, the Church and the medical saged into the penis), and the skin and glands of the Bufo toad
professions remained unclear. In 1896, the Illinois Supreme (which contains bufotenine, a hallucinogenic known as chan
Court annulled a marriage on the basis of impotence, with a su in Chinese medicine).7 Man’s desire has also led to many
doctor being called to give evidence.4 This raised an ethical species of animals being added to the endangered list: powdered
dilemma regarding the professional code of confidence. The rhinoceros horn can cost $27,000 per pound,8 and in Asia dried
doctor eventually testified that excessive masturbation had tiger penis soup costs $350.9

1
2 Textbook of Erectile Dysfunction

of action. Yohimbine, an alpha-2-adrenergic receptor anta-

gonist, is the main alkaloid from the bark of the west African
tree Pausinystalia yohimbe. These receptors are found in the
abdomen, pelvis, and sex organs and are docked with epi-
nephrine. In a normal erection, nerve impulses displace this
epinephrine, and yohimbine displaces epinephrine by inter-
fering with this docking. Higher doses cause a rapid heart rate,
high blood pressure, anxiety, and over-stimulation. Yohimbine
acts as a dual aphrodisiac: it directly affects erections and it
heightens arousal. Unfortunately this epinephrine release is a
double-edged sword, since higher doses cause a blood shift
away from genitalia, making an erection almost impossible.
Cocaine and amphetamines also exhibit this feature and can
lead to penile shrinkage. Recent reviews suggest yohimbine
allows satisfactory erections in 30% of patients versus 14%
with placebo.12 Ambergris, a rare fat-like substance from
whales, is cited in Arabic folklore as a powerful aphrodisiac. In
rats it increases testosterone and copulatory behavior.13
Opium poppies have been found to contain papaverine; its
mechanism is not fully understood, but it is thought to inhibit
phosphodiesterase.
In India, urological ailments were first described around
3000 BC (the Vedic period), peaking during the 9th century BC.
Ayurvedic medicine was outlined in the six volumes of
the Charaka Samitha. Susrata described systemic surgery in
the Susrata Samitha, a text that was translated into Arabic
and Latin, later forming part of European medicine as
described by Hunter.14 Both of these works described uro-
logical conditions, and Susrata Samitha described several
Figure 1.1 Medieval Church Court trial. (Reproduced courtesy surgical instruments. Ayurveda described erectile dysfunction
of Wilma Cluness.) as treatable throughout all ages. The treatment, vaji karana,
involved physical, psychological, and herbal preparations.
Susrata Samitha states that this treatment ‘makes a man
sexually strong as a horse (vaji) and enables him to cheerfully
The Spanish fly was probably the most dangerous aphro- satisfy the heat and amorous ardors of young maidens’.15
disiac; it was used by the Romans and mentioned in the In ancient Egyptian texts, the Book of the Dead mentions
15th century Arabic text The Perfumed Garden for the Soul ’s Nymphaea caerulea (the blue lotus) being used as a sexual
Delectation.10 Made from dried beetle, it was actually poison- adjunct and hallucinogenic in religious rituals.16 It contains
ous, containing as it did cantharadin. It acted by irritating the apomorphine (a centrally acting dopamine agonist that
urogenital tract, causing vasodilatation. Side-effects included causes smooth muscle relaxation) and aporphine (which is
infections, scarring, priaprism, and even death. hydroxylated to apomorphine in the body). In studies, apo-
Alcohol is amongst the oldest aphrodisiacs. The Romans morphine hydrochloride is more effective than placebo but
believed it increased libido, so much so that they forbade clearly less effective than phosphodiesterase type 5 (PDE-5)
women from drinking it. Absinthe was considered a stimulant, inhibitors.17 In the UK apomorphine hydrochloride was
extracted from wormwood; it contained thujol and thujon discontinued in 2005 for commercial reasons, and it will
essential oils and other toxic compounds. It can cause blind- probably be confined to history. In the Ebers papyrus (pre-
ness and neurological problems and has been banned in its scription 663), weakness of the penis, was called ‘grapo’
original form in most of Europe since the early years of the and 37 drugs, including honey, were recommended in its
20th century. treatment.18
Aphrodisiacs, including alcohol, amphetamines, and mari-
juana, increase libido and heighten sexual pleasure when used
in low doses by reducing anxiety, by neuro-modulation, or by
their hallucinogenic effects. Marijuana use was mentioned in Antiquity to Enlightenment
Garcia de Orta’s Colloquies on the Simples and Drugs of India.11
Recently, cocaine has been the aphrodisiac of choice. It reduces In ancient times, agriculture, animal husbandry, and human
norepinephrine reuptake within the brain, prolonging nor- fertility were linked by religious ritual. The gods of harvest
epinephrine effects in the synapses. were worshiped with phallic icons, and impotent men turned
While many remedies have been lost, some, including plant- to the priesthood. Ancient Greeks prayed to Aphrodite,
based aphrodisiacs such as ginseng and yohimbine, remain and the Bible describes impotence as divine retribution.
popular. Many now have scientifically proven mechanisms In Genesis, God rendered Abimelech impotent for sleeping
 The history of erectile dysfunction 3

with Abraham’s wife.19 Folklore said that God allowed the

devil power over the genitals. In medieval times, people
believed that if a witch tied a knot in a strip of leather, it
empowered the devil to strike a man impotent.20 We can
only guess how many women were persecuted for men’s
sexual failings.
Hippocrates (460–370 BC) stated that ‘pneuma’ (air) and
‘vital spirits’ flowing into the penis generated erections and
that impotence was caused by imbalances between the humors
(blood, phlegm, yellow bile, and black bile) and the elements
(earth, air, fire, and water). He believed that sexual excess
reduced potency (a theme explored many times since) and
that fine cords facilitated erection, rather like a system of
‘pulleys’ connecting the penis and testis. Damage to these
fine cords, as occurred with castration, profoundly affected
erectile capability.21 Hippocrates’ teachings pervaded Western Figure 1.2 Eunuchs were sexually active in the ancient Roman
medicine until the Renaissance, when increased anatomical harems. (Reproduced courtesy of Paula Day.)
and scientific knowledge challenged ‘classical’ models. Leonardo
da Vinci (1452–1519) observed that men executed by hanging
developed reflex erections. Examining these, he found that
they contained blood, not air.3 In 1677, Reiner de Graaf dem- However, the notion that castration ensured impotence was
onstrated that injecting water into the internal iliac artery far from true. The females of the Roman harems found
generated erections in human cadavers.22 In 1573, Varilo eunuchs made novel playmates, their sexual prowess often
stated that the ischiocavernosus and bulbospongiosus (or intact with guaranteed contraception (Figure 1.2). Addition-
bulbocavernosus) muscles impeded venous return by con- ally, early Christian choristers, gelded in their youth to
stricting the root of the penis. Eckhard, in 1863, electrically ensure their voices were retained, frequently lived sexually
stimulated pelvic nerves (the nervi erigentes) in a dog, induc- active lives. Indeed, Italian literature is replete with stories
ing tumescence, thus demonstrating a neurovascular compo- of castrati and their sexual cavorting. Castration still occurs
nent.23 During the Victorian period (1837–1901), impotence in India, the Middle East, and China, with its effect on
was widely debated (see below), and treatments included qui- potency now more clearly understood. The Hijaras are an
nine, opium, digitalis, and cold salt water sponging as well as Indian sect of males, convinced (or coerced) into castration.
more drastic measures such as scarification of the perineum, They function as transvestite male prostitutes, many potent,
blood-letting, and the passage of a mercury-covered boogie who indulge in sexual paraphilia.26 Castration for sex crimes
into the urethra.9,24 was practiced until recently in Europe. Heim reported that
31% of such men remained potent following emasculation
and that rapists were more likely to be sexually active than
homosexuals or pedophiles.27 In prostate cancer, 19% of
The 19th to mid-20th centuries men who undergo surgical or chemical castration will
remain potent.28 Clearly, castration does not always result
During the 19th century three schools of thought developed
in impotence.
regarding the endocrinology, psychology, and pathology of
However, the influence of the testes on sexual behavior
erectile dysfunction. How these schools evolved, clashed, and
is more complex. Even ancient civilizations realized that it
fused is explored here.
influenced potency and libido, with testicles frequently pro-
posed as an impotence cure. Susruta (around 500 BC) advo-
cated the ingestion of testicular tissue to treat impotence.25
The endocrine debate In 1889, Brown-Séquard reported himself ‘rejuvenated and
The association between the testis, male behavior, potency, cured of impotence’ following self-injection of aqueous
and fertility has probably been recognized since castration canine testicular extract.29 Berthold (in 1849) demonstrated
started. Neolithic tribes in Asia Minor castrated animals for a clear androgenic role for the testes. He castrated roosters,
domestication as early as 4000 BC. In humans, castration prob- causing regression of the comb and wattle, but showed that
ably originated in Babylon in the second millennium BC, to transplanting testes back into the abdominal cavity prevented
safeguard against adultery.25 Castration was also practiced for this.30 Defining testicular function caused confusion for the
other reasons. The Christian priesthood (ca 3rd century AD) next 100 years. The problem was twofold: crude methodo-
practiced voluntary castration to help self-imposed religious logy and man’s desperation led to many erroneous practices.
celibacy. Many civilizations regularly castrated slaves to sup- For example, despite Astley Cooper’s sound scientific work
press rebellion. Castration was widespread in the eastern (published in 1823) showing that spermatogenesis and tes-
Roman Empire, where its critical timing and effects on potency ticular function were unaffected by ligation of the vasa,31
were understood. Boys castrated before puberty were recog- Ancel and Bouin (in 1904) reported different results for the
nizably ‘eunchnoid’, usually with docile personalities. Castrati same experiments, claiming that ligation of the vas deferens
were also infertile, making ideal guardians for the harems. caused sperm cell atrophy with concomitant Leydig cell
4 Textbook of Erectile Dysfunction

Leydig cell The lack of efficacy of both methods, on both prostatic

hyperplasia shrinkage and erectile function, were documented long before
‘rejuvenating’ operations became fashionable.41 Clearly, the
profession was in a mess.
Scientific studies gradually clarified male genitourinary
and reproductive physiology.42 In 1934, WE Lower cleverly
demonstrated pituitary gonadotrophic control of the testes.
By creating a peritoneal anastomosis between two rabbits
(coelenteral fusion), he developed an experimental model
where he selectively ablated the endocrine system at different
levels, conclusively showing that prostatic, erectile, and testi-
cular function were under pituitary control (Figure 1.6).43
Furthermore, in 1931, Butenandt44 succeeded in isolating
15 mg of androsterone from 25,000 liters of policemen’s urine.
The synthesis of testosterone from cholesterol followed,
performed by Ruzicka45 in 1935. Both men shared the 1939
Nobel Prize for chemistry, spawning an industry around
Sperm the development and consumption of anabolic androgenic
cell steroids, legally and illegally. This industry’s expansion enabled
atrophy a greater understanding of how endocrine agents affect erec-
tile and sexual function. Factors included dose, administration
and circumstances but, in general, hormone supplementation
Figure 1.3 Sperm cell atrophy and Leydig cell hyperplasia, as
rarely improves erectile function.21 The overall role of andro-
described in C R Soc Biol (Paris) 1904; 56: 281–2.32
gens in erectile function is still poorly understood, but in
the early 20th century, this only added to the confusion
caused by the other two great controversies, the organic and
psychogenic debates.

hyperplasia and suggesting that ligation might increase endo-

genous male hormone production, benefiting potency and
health (Figure 1.3).32 The ‘organic’ versus ‘psychogenic’ debate
The excitement generated from these findings led many During the late 19th and early 20th centuries, proponents
doctors to propose this as an impotence cure. In 1917, of the ‘organic’ and ‘psychogenic’ schools frequently clashed
the Austrian surgeon and physiologist Professor Steinach in acrimonious debate. Sigmund Freud founded the discipline
(1861–1944) seemingly provided evidence of marked ‘rejuve- of psychoanalysis in the late 19th century. His followers
nation’ in aging rams after vasoligation. Encouraged, he explained impotence in terms of regression of unresolved
applied this principle to humans, performing numerous conflicts. Freud believed that healthy psychological develop-
procedures on impotent men. Sigmund Freud and William ment required the experience of an Oedipus complex during
Yeats are thought to be amongst them.33 More alarming infant sexual development – the erotic attachment of a
were the techniques of Voronoff (1866–1951)34 in France and child to the parent of opposite sex, coinciding with hostility
Lespinasse35 in Chicago (Figure 1.4). They transplanted towards the other parent. In later adult life, transference
testicular grafts from apes directly into the human testis or of these feelings to a new sexual partner could result in
the subtunical space (Figure 1.5). In 1918, Dr Leo Stanley, a inner conflict and erectile dysfunction. Many psychiatrists
Californian prison physician, reported improving impotence. championed psychoanalysis, but treatment was realistically
He used pressurized syringes to implant strips of testicles available only to the rich. For most men seeking medical
from goats, rams, deer, and even dead inmates’ testicles. help, the general advice was ‘resensitization’ through long
The testicles were implanted under the abdominal skin of periods of abstinence. Excessive masturbation was cited by
1000 inmates.9,36 Despite initial claims, these techniques did many doctors as a cause, creating great anxiety among the
not restore the ‘fountain of youth’ or cure impotence. In youth, who feared they would ‘fail’ in later life.46 In 1927,
the 1930s, many clinicians challenged the credibility of the psychoanalysts that reported repressed sexuality caused
‘rejuvenists’.37 In 1934, TE Hammond gave one of the most over 95% of cases of impotence47 and designed special
eloquent and ferocious challenges in the British Journal of anti-masturbatory devices (Figure 1.7). In 1934, New York
Urology.38 He reviewed his own series of castrati, men who psychiatrists effectively declared ‘open war’ with urologists. In
had lost both testes through accident or tuberculosis. He a statement, they urged general practitioners not to refer
reported that they were potent and questioned the role of patients to urologists, and fuelled a bitter debate that raged
the testicles in erectile physiology. Furthermore, in the early in the medical literature. Psychiatrists accused urologists
20th century, castration and vasoligation were used to treat of charlatanism, and urologists defended their practice with
symptoms of prostate enlargement. Naturally, proponents elaborate descriptions of the pathology they claimed to
stressed that impotence was an infrequent complication.39,40 observe.48
 The history of erectile dysfunction 5

(a) (b)

(c) (d)

Figure 1.4 (a) Voronoff with his monkey. (Reproduced from Chadwick AJ, Mann WN, eds. Hippocratic Writings. London: Penguin,
1987, with permission.) (b) Voronoff performs testicular transplantation from a monkey to man. (c, d) As witnessed by his countenance,
an elderly man is markedly rejuvenated following testicular transplantation. (Reproduced from Voronoff S. Rejuvenation by Grafting.
London: George Allen and Unwin, 1925, with permission.)

Thomas Curling’s classic publication in 1878 summarized urethral structure in patients with erectile failure. Wolbarst
factors thought to be important.49 He described numerous reviewed 300 cases of impotence and claimed that 87%
pathologies, venereal disease in particular, and was probably of patients had pathological posterior urethral changes.50
amongst the first to connect impotence, diabetes, and Pey- Max Huhner eloquently summarized its significance in
ronnie’s disease. More importantly, he described the cysto- 1936, mounting a sterling defense of urological practice.51
scopic appearances of the verumontanum. Many urologists Huhner described perpetual prostatic ‘irritation’ caused
frequently observed inflamed swellings of this posterior by these urethral swellings, resulting in a constant desire for
6 Textbook of Erectile Dysfunction

(a) (b)

(c)

Figure 1.5 (a, b) Direct grafting into the tunica albuginea. (c) Grafting into the subtunical space. (Reproduced from Voronoff S.
Rejuvenation by Grafting. London: George Allen and Unwin, 1925, with permission.)

sexual excess. Men would indulge too frequently in coitus or and desensitization (by whatever method) helped but a
masturbation and desensitize their erectile centers, causing few people. More practical devices such as suction pumps
impotence (Figure 1.8).51 Common urological treatments and penile supports (scaffolds) were introduced in the
included cauterization of the posterior prostatic urethra 20th century (Figure 1.10). Many were patented, and some
along with the urethral instillation of cantharides.51 Psychia- sold by the thousand.53 Various surgical techniques were
trists including Hammond52 and urologists like Curling49 tried. Wooten,54 in 1902, advocated dorsal vein ligation to
attempted to resensitize erectile centers. They applied faradic retard outward penile blood flow. Lilienthal championed
electrical current to the penis, prostatic urethra, and spinal this in the 1930s.51 Further attempts to impede outflow
cord (Figure 1.9). included ischiocavernosal muscle plication by Lowsley
Most treatments were disappointing. Psychoanalysis, aphro- and Bray (1936)55 (Figure 1.11). Despite claims of great
disiacs, vasoligation, testicular grafting, forced abstinence, success, this last-named procedure has passed into obscurity,
 The history of erectile dysfunction 7

Two rabbits fused by peritoneal anastomosis

Sensory center:
sexual desire
Erection center:
sensitization

Rabbit 1: castrated Rabbit 2: hypophysectomized

Prostate

Verumontanum

Figure 1.8 Perpetual prostatic irritation resulting in desentization

of the erectile centers. (Adapted from J Urol 1936; 36: 770–84,
Testicular function maintained in rabbit 2
with permission.)

Figure 1.6 The ingenious coelenteral fusion model of WE

Lower.43

+ –

Figure 1.9 Faradic electrical desensitization of the

verumontanum.

Figure 1.7 Anti-masturbatory device.

though dorsal vein ligation has drifted in and out of fashion

ever since.

Plastics, prosthetics, pumps and pills

During the Second World War, many pilots and soldiers
lost genitalia through burns and land mines. This saw plastic
surgical penile reconstruction develop in the post-war period.
Gills and Borgoras were the pioneers, the latter using rib car-
tilage in 1936 to allow successful micturition and intercourse.56 Figure 1.10 Penile scaffold.
8 Textbook of Erectile Dysfunction

(a) (b)

(c)

Figure 1.11 (a, b) Ischiocavernosal muscle plication of Lowsley and Bray. (c) Plication is complete. (Reproduced from Zentralbl
Chir 1936; 63: 1271–6, with permission.)

In 1948 Bergman fashioned a new penis over an autografted The post-war period was also a time of changing attitudes.
rib cartilage (Figure 1.12).57 These techniques were extended Male sexual dysfunction had previously been taboo and free
to treat impotence, but had limited success, owing to eventual discussion had been repressed. Lesley Hall remarked that even
cartilage reabsorption. However, they heralded prosthetic sad heroes of 20th-century literary works – Hemingway’s Jake
implant surgery. In 1964, Loeffler reported the insertion of Barnes in The Sun Also Rises and DH Lawrence’s Clifford
acrylic rods into the penis to treat impotence.58 Beheri inde- Chatterley in Lady Chatterley’s Lover sustained impotence as
pendently performed 700 cases in Egypt in 1966.59 The original unfortunate victims of war.6 People were uncomfortable
technique described the rods being placed between the tunica identifying with men who had lost their ‘manliness’. The Kinsey
and Buck’s fascia, but they were later placed intracavernosally Report (1948) highlighted the widespread prevalence of this
because the initial technique caused pain. Subsequently, problem.60 Attitudes changed slowly, but openness evolved,
numerous and more sophisticated devices have been designed with more men seeking help.
and are commonly used, including newer self-erectable The 1960s and 1970s heralded the arrival of Masters
prostheses. and Johnson61 and Helen Kaplan62 and a renaissance of
 The history of erectile dysfunction 9

‘new sexual therapies’. In 1982, Virag63 and Brindley64 intro-

duced the effective intracavernosal agents, papaverine and
phentolamine, respectively. In the 1970s, Geddings Osbon
created the ErecAid, noting that vacuum devices could cause
an erection. The prototype was based on a bicycle pump;
currently a number of models are available, providing good
results.9 Prostaglandins and other agents have recently been
added to the therapeutic armory. The development of erectile
tissue-specific PDE-5 inhibitors has made effective oral agents
a reality. Sildenafil citrate, the first PDE-5 inhibitor, was
released by Pfizer in 1998; it originated as a drug for heart
failure but was observed to cause erections. Newer PDE-5
inhibitors, such as vardenafil and taldenafil, have subsequently
been introduced.
The history of erectile dysfunction is ongoing and new
chapters are being written, with newer therapies replacing
older ones. Increasingly, surgeons, physicians, and psycho-
logists work together in multidisciplinary teams to tackle the
multifactorial nature of erectile dysfunction. A great deal has
been achieved since the days when men prayed to Aphrodite
for deliverance. Many causes have been identified and defined.
Figure 1.12 Autograft of rib cartilage. (Reproduced from JAMA However, for those affected, the feeling of destruction remains,
1948; 59: 1174–80, with permission.) with solutions still imperfect and limited.

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J Urol 1934; 31: 391–6. sum Koitus fähigen Penis (pentiplastica totallis). Zentralbl Chir
44. Butenandt A, Tscherning K. Über Androsteron, ein krystallisiertes 1936; 63: 1271–6. [in German]
männliches Sexualhormon I. Isoliereng und Reindarstellung aus 57. Bergaman RT, Howard AH, Barnes RW. Plastic reconstruction of
Männerharn [Androsterone, a crystalline male sex hormone I. the penis. JAMA 1948; 59: 1174–80.
Isolation and purification of urine]. Z Physiol Chem 1934; 229: 58. Loeffler RA, Sayegh ES, Lash H. The artificial os penis. Plast Reconstr
167–84. [in German] Surg 1964; 34: 71–4.
45. Ruzicka L, Wettstein A. Über die krystalliche Herstellung des 59. Beheri GE. Surgical treatment of impotence. Plast Reconst Surg
Testikelhormons, Testeron (Androsten-3-on-17-ol) [The crystalline 1966; 38: 92–7.
production of the testicle hormone, testosterone (Androsten-3-on- 60. Kinsey AC, Pomeroy WB, Martin CE, et al. Sexual Behaviour in the
17-ol)]. Helv Chim Acta 1935; 18: 986–94. [in German] Human Male. Philadelphia: Saunders, 1948: 120–67.
46. Hammond WA. Some remarks on sexual excess in adult life as a 61. Masters WH, Johnson VE. Human Sexual Inadequacy. London:
cause of impotence. Va Med Mon 1883; 10: 145–50. Churchill, 1970: 3–97.
47. Stekel W. Impotence in the male. New York: Liveright, 1927: 62. Kaplan H. The New Sex Therapy. New York: Brunner/Mazel,
100–25. 1974: 10–27.
48. Ballenger EG, Elder OF, McDonald PH. Impotence. J Urol 1936; 63. Virag R. Intracavernous injection of papaverine for erectile failure.
36: 250–4. Lancet 1982; 2: 938.
49. Curling TB. Functional disorders of the testicle: impotency. In: 64. Brindley GS. Cavernosal alpha-blockade: a new technique for
Disease of the testis, spermatic cord and scrotum. London: investigating and treating erectile impotence. Br J Pyschiatry 1983;
Churchill, 1878: 429–65. 143: 332–7.
2 The history of the International Society
for Sexual Medicine
Ronald W Lewis and Gorm Wagner

Biennial meetings and structure • Measurement of bulbocavernosal latency test

• Early effects of oral atropine, alpha-blockers, and beta-
of the organization blockers on human penile erection
• Techniques and pitfalls of phallography (which would
The founding of the International Society for Sexual Medicine
become cavernosography)
can be traced back to a couple of meetings that were held in
• Anatomic basis of the corpora cavernosa
1978 and 1980. Dr Adrian Zorgniotti, a urologist with a vision
• Pudendal arteriography
for the future for sexual medicine, became aware of some
• Microvascular surgery techniques
unique reports on the work of a vascular surgeon, Vaclav
• The results of treatment of other vascular disease in the
Michal (Prague, Czechoslovakia), regarding his success stories
pelvis as it relates to postoperative sexual dysfunction
on restoration of erectile function in patients having pelvic
• A very unusual case of a congenital shunt between the
vascular reconstruction. These surgeries had led him to pro-
corpora cavernosa and the glans of the penis
pose revascularization of the corpora cavernosa directly by
• Some of the early problems with surgery for arterial
anastomosis of the inferior epigastric artery to the corpus
vascularization
tissue.1 Zorgniotti, along with his colleague Dr Guiseppe Rossi,
• A discussion of the drainage system of the penis and how
decided to host a meeting at their home institution, Cabrini
that might be involved with erection
Medical Center, in New York City, in the fall of 1978. Two other
• Complications of the then current vascular surgery.
groups were also invited to be a focus of the meeting. Dr Jean
François Ginestié (Montpelier, France) was the main presenter
for two radiologists who had developed exquisite internal Zorgniotti and Wagner planned a closed symposium at the
pudendal arteriography studies; and Gorm Wagner (Copen- meeting in Monaco, inviting key physicians and surgeons
hagen, Denmark) was the presenter for a multidisciplinary involved in cutting-edge research in the field of ED in order
group involved in unique diagnostic tests for erectile dys- to develop agendas for intensified research in this field,
function (ED). The interest was so keen after this meeting possible co-operative research protocols, and areas for future
that it was decided to reassemble after 2 years to see where the meetings. At the close of the meeting in Monaco, Wagner
science would go. Some of the presentations at this meeting invited the next meeting to be held in Copenhagen 2 years
led to the publication of a book, Vascular Impotence: Proceed- later.
ings of the First International Conference on Corpus Cavernosum In their frequent correspondence, Wagner and Zorgniotti
Revascularization.2 continued discussing a name for this developing group. They
The second meeting, entitled The Second International had truly become the nucleus for these international meetings
Meeting on Corpus Cavernosum Revascularization, took place and at the 1982 meeting in Copenhagen, Denmark, the
in October 1980 in Monaco. At this meeting the group of group decided on a name for the organization: The Interna-
international physicians and scientists focused on alternatives tional Society for Impotence Research (ISIR). The meeting
to vascular surgery for ED. A series of articles that focus on the in Copenhagen was still labeled as the Third International
meetings of this society is being prepared by the authors of Symposium on Corpus Cavernosum Revascularization.
this book chapter. The first such article, dealing with the It was at the Copenhagen meeting that the idea of an inter-
details of these first two meetings, called ‘The Beginnings’, will national biennial meeting was solidified, and it was decided
be published in the Journal of Sexual Medicine.3 The breath of that the 1984 meeting would be held in Paris, France. It was to
developing science in this field can be found in the subjects be hosted by Dr Ronald Virag, a vascular surgeon who had
discussed at these meetings, which included: been very active in developing unique techniques for corpus
cavernosum revascularization, which he had initially presented
• Doppler evaluations of penile arteries at the meeting in Monaco. He was the first to call this biennial
• Unique blood flow measurement by clearance method in meeting the World Meeting on Impotence, and hence his
the human corpora cavernosa meeting was the first with such a title. He also published a book
• Incorporation of visual sex stimulation in the evaluation after the meeting with papers requested and received that rep-
of ED resented data presented at the meeting.4

11
12 Textbook of Erectile Dysfunction

Table 2.1 Biennial Meetings of the Society Table 2.2 Officers of the Society

Symposia on Corpus Cavernosum Revascularization Presidents

Year Place Major host Vaclav Michal 1978–1986

1978 New York Adrian Zorgniotti Adrian Zorgniotti 1986–1988
1980 Monaco Adrian Zorgniotti and Gorm Gorm Wagner 1988–1994
Wagner Robert Krane 1994–1998
1982 Copenhagen Gorm Wagner Ronald Lewis 1998–2000
Symposia on Corpus Cavernosum Revascularization Sydney Glina 2000–2002
World Meetings on Impotence Research Jacques Buvat 2002–2004
Year Place Major host Ganesan Adaikan 2004–2006
Ira Sharlip 2006–2008
1984 Paris Ronald Virag
1986 Prague Vaclav Michal Presidents-elect
1988 Boston Robert Krane and Irwin Goldstein Ronald Lewis 1996–1998
1990 Rio de Janeiro Pedro Puech-Leao and Sydney Sydney Glina 1998–2000
Glina
Jacques Buvat 2000–2002
1992 Milan Eduardo Austoni
Ganesan Adaikan 2002–2004
1994 Singapore Ganesan Adaikan
Ira Sharlip 2004–2006
1996 San Francisco Tom Lue
John Dean 2006–2008
1998 Amsterdam Eric Meuleman
2000 Perth Carolyn Earle and Bronwyn Secretary–treasurers
Stuckey Ronald Lewis 1992–1996
World Conferences of the ISSIR or ISSM Jacques Buvat 1996–2000

Year Place Major host Secretaries

2002 Montreal Jeremy Heaton Ira Sharlip 2000–2004

2004 Buenos Aires Edgardo Becher Edgardo Becher 2004–2008
2006 Cairo Khaled Dabees Treasurer

Eric Meuleman 2000–2006

Luca Incrocci 2006–2008
The fifth meeting was held in Prague, Czechoslovakia, in
1986 in honor of Dr Michal. It would be the Fifth Symposium
on Corpus Cavernosum Revascularization and the Second
World Meeting on Impotence. Injection therapy was high- the officers were more clearly defined. The office of secretary–
lighted, both at the Paris meeting and at the Prague meeting, treasurer was established at this meeting, originally for a term of
with a new agent – prostaglandin E1 – and this received atten- 6 years but this was later changed to a 4-year term; Dr Ronald
tion at the Prague meeting from Singapore, Japan, and Vienna. Lewis was elected as the first secretary–treasurer. At the 1994
Thus, one of the main functions of this society was estab- meeting in Singapore, Dr Robert Krane from Boston was
lished – a biennial international meeting at which to share elected president. Dr Krane was one of the major people (along
scientific advances in the field. Table 2.1 lists all of the meetings with his young colleague, Irwin Goldstein) responsible for the
of the Society from 1978. first meeting of this organization in the USA in 1988 – he
It is interesting to point out there are only three current worked to develop the ISIR as a parent organization for the
members of this society who have attended all of the biennial developing regional organizations, including the European
meetings since 1978 and that each of them has served this Society for Impotence Research, founded in 1995 (the future
society as president: Gorm Wagner (Copenhagen) – president European Society for Sexual and Impotence Research, and then
from 1988 to 1992; Ronald Lewis (beginning attendance from the European Society for Sexual Medicine), the Society for
New Orleans, Louisiana; then Rochester, Minnesota; now the Study of Impotence, founded in 1994 (to become the
Augusta, Georgia) – president from 1998 to 2000; and Ira Society of Sexual Research of North America and then the
Sharlip (San Francisco, California with a brief stint in New Society of Sexual Medicine of North America), the South and
Orleans, Louisiana) – president from 2006 to 2008. Table 2.2 Central American Society founded in 1990, which joined ISIR
lists the presidents, secretaries, and treasurers of the Society. in 1997 (SLAI – Sociedad LatinoAmericana para el Estudio de
Highlights of growth of the organization include the follow- la Impotencia, later to become the Latin American Society
ing milestones. At the 1992 meeting the first official by-laws for Sexual Medicine); and he worked towards limited affilia-
of the organization were adopted and the terms of office for tions with the Asian Pacific Society for Impotence Research,
 The history of the International Society for Sexual Medicine 13

founded in 1987, and the developing African Society for Impo- physiology; and Dr Clinton Webb, a prominent smooth mus-
tence Research, founded in 1997. cle physiologist. At the 2003 fourth biennial meeting of the
There was a sharing of profits from the 1994 meeting in African Society of Sexual and Impotence Research, the meet-
Singapore (hosted by Dr Ganesan Adaikan) with ISIR. At the ing was preceded by a full-day ISSIR meeting that covered
meeting in 1996 in San Francisco, California (hosted by Tom three topics: education, priapism, and the influence of life-
Lue and his group from the University of California, San style on ED.
Francisco) the first papers on a possible emerging new oral At the 2004 meeting in Buenos Aires, the society officially
therapy for ED were presented. The group from San Francisco changed its name to the International Society for Sexual
presented to ISIR a portion of the profits for the specific Medicine (ISSM), following the lead of two of its affiliates,
purpose of sponsoring a new award – the Tanagho Prize (see which had earlier changed their names to the European Society
below). of Sexual Medicine and the Society of Sexual Medicine of
At the 1998 meeting held in Amsterdam in the Netherlands, North America.
a professional organization assisted Dr Eric Meuleman in the
arrangements for the meeting. The leaders of the society were
so impressed that Status Plus of the Netherlands became the Publications and communications
official business office of the society. The Dutch group hosting
the 1998 meeting made a donation of $75,000 to the Adrian The second major function of the international society has
Zorgniotti Research Fund of the ISIR. been the publication of a journal, which began in 1989, just
Dr Lewis, while he was secretary of the organization from 11 years after the first meeting in New York. The first editors
1992 to 1994, suggested that the office of president-elect be were Drs Gorm Wagner and Bill Furlow (Mayo Clinic,
established and that the term of the president be limited to a Rochester, Minnesota). They served as co-editors-in-chief
2-year stint from one biennial meeting to another. The office from 1989 to 1992. In 1992, Furlow resigned as editor-in-chief
of secretary was also changed to a 4-year term. The by-laws and was replaced by Dr Arnold Melman as the new co-editor-
were changed to reflect these changes, which allowed more of in-chief, along with Wagner, until 2002, leaving the journal
the developing leaders in the field to serve the Society as with an impact factor of 2.7. The journal, entitled at first The
president. During his term as secretary–treasurer, Jacques International Journal of Impotence Research, started as a four-
Buvat consolidated the bank accounts of the organization times-a-year publication, published and owned by Smith–
under our registered name, as ISIR, in 1998. Gordon and Co of London, UK. In 1995, the journal was
At the meeting in 2000, hosted in Perth, Australia (chaired purchased from that company by Stockton Press. Stockton
by Carolyn Earle and Dr Bronwyn Stuckey), the first sessions Press was merged with Nature Publications Group in 2000 and
on female sexual dysfunction were made part of the program. thus the journal came into the ownership of this publisher. In
In an effort to solidify this for the future, the name of the orga- 2003 Irwin Goldstein assumed the office of editor-in-chief of
nization was changed to the International Society for Sexual the journal, after the newly appointed Publication Committee
and Impotence Research (ISSIR), a bridging name between headed by John Pryor of London interviewed a strong slate rep-
the old and the final new name. resented by this candidate and three others for the position.
For the 2002 meeting a professional congress organizer was In 2003, it was decided by the leadership of the ISSIR that
directly contracted by the ISSIR executive at the suggestion of the journal would be better suited for ownership by the Society.
the local organizer, Dr Jeremy Heaton. As a result, the largest An attempt was made to enquire about sale of the current
ever contribution to the treasury from a biennial meeting of International Journal of Impotence Research to the ISSIR but
the ISSIR was made. However, it was decided that our own Nature Publishing Group was not interested in this offer. The
business office would be more efficient at running future ISSIR then entered into a contract with Blackwell Publishing
scientific biennial meetings, and thus the 2004 meeting, held House to publish a new journal, to be called the Journal of
in Buenos Aires, Argentina and hosted by Dr Eduardo Becher, Sexual Medicine. ISSIR would retain ownership of this journal
was run by Status Plus, our business office in the Netherlands. and Blackwell would be the publishing partner. The entire
During Jacques Buvat’s term as president and Ira Sharlip’s editorial team of the International Journal of Impotence
term as secretary, an industrial partnership board was created. Research moved to the new journal, which became the official
The members of the industrial advisory board made signifi- journal of the ISSIR and subsequently the ISSM and all of the
cant financial contributions as unrestricted funds to the five regional affiliates. In addition, in 2006 the journal became
international Society, with the purpose that these funds be the official journal of the International Society for the Study
distributed among the four regional affiliates that participated of Women’s Sexual Health. It has become the dominant jour-
in the plan. The European Society of Sexual Medicine decided nal in sexual medicine, a monthly journal from 2008; it has
to remain independent of this plan. In 2001 the ISSIR pre- a recently announced first impact factor of 4.676. This was
sented a special symposium during the European Society for impressive from a three-volume start in 2003 to a six-volume
Sexual and Impotence Research meeting in Rome, Italy, in journal for the years 2004–2007. In 2008 the journal became a
order to show solidarity with its affiliated organizations. The monthly publication. This factor placed the journal fourth in
title of the symposium was ‘Molecular Mechanisms of Erec- terms of impact factor for all urological and related journals,
tile Function’. The speakers were Dr Robert Furchgott, the with the Journal of the American Society of Nephrology, Euro-
1998 Noble Prize recipient, who discovered that the nitric pean Urology, and Kidney International as the only such jour-
oxide molecule is a messenger for vital functions in the body; nals ahead of it; the highest impact factor for journals in the
Dr Donald Maurice, a key researcher in phosphodiesterase andrology category were 2.183 and 2.137. In addition to Irwin
14 Textbook of Erectile Dysfunction

Goldstein, there are nine associate editors: Gloria Buchmann

Table 2.3 Jean François Ginestié Prize winners
from New Brunswick, New Jersey; Ian Eardley from Leeds,
UK; Annamaria Giraldi from Copenhagen, Denmark; Wayne 1984 Herbert Newman, USA
Hellstrom from New Orleans, Louisiana; Mario Maggi from
1986 P Ganesh Adaikan, Singapore
Florence, Italy; Chris McMahon from Sydney, Australia; James
Pfaus from Montreal, Canada; Caroline Pukall from Kingston, 1988 William D. Steers, USA
Canada; and Ira Sharlip from San Francisco, California. 1990 KM Azodzei, USA
In August 1998, Jacques Buvat, editor, presented the first 1992 Geng-Long Hsu, Taiwan
issue of the ‘Newsbulletin’ of the ISIR. This was to serve as a 1994 Gerald Brock, Canada
newsy communication of the happenings and events of the
1996 Kwangsung Park, USA
parent ISIR as well as the affiliates, with information con-
cerning the officers of those organizations and summaries of 1998 Gyung-Woo Jung, Korea
meetings regarding sexual medicine. As an example of the 2000 Annamaria Giraldi, Denmark
latter function the first issue contained a take-home message Kanhan Chitaley, USA
of sexual medicine issues presented at the 93rd Annual Meet-
2002 John Mulhall, USA
ing of the American Urological Association in San Diego,
California in 1998, prepared by Tom Lue. Luca Incrocci, who Trinity J Bivalacqua, USA
joined the editorial committee of the ‘Newsbulletin’ in the 2004 B Musicky, USA
May 2000 issue (issue 3), and who assumed the title of associate 2006 T Mostafa, Egypt
editor in June 2001, became the new editor-in-chief of the
‘Newsbulletin’ with issue 9, in October 2002. Dr Hussein
began to report on summaries of activities of discussions on
ISSIR list in the April 2002 issue. Issue 12, in December 2003, Table 2.4 Newman–Zorgniotti Prize winners
marked the Netherlands publication of this communication.
In 2000, the new president of the ISSIR, Dr Sydney Glina, 1988 C Persson and KP Junemann, Germany
established a website committee. Jacques Buvat was named 1990 Christian Steif, Germany
chairman of this committee. Alexandre Gilbert, the new web 1992 no award
administrator, presented the new design of the website in
1994 S Krishnamurti, India
issue 7 of the ‘Newsbulletin’ in December 2001. Dr Gregory
Broderick became chairman of the website committee in the 1996 no award
fall of 2002. At the biennial meeting of the ISSIR (during 1998 Michael J Metro, USA
which the Society became the ISSM) in Buenos Aires, the 2000 Kwangsung Park, Korea
website committee and the ‘Newsbulletin’ committee were 2002 Clifford Bleustein, USA
combined into a single communications committee to be co-
2004 P Teloken, Brazil (male sexual dysfunction)
chaired by Jacques Buvat and Luca Incrocci. Ridwan Shabsigh, USA (female sexual
During Jacques Buvat’s term as president of the ISSM he dysfunction)
had the vision to create a standards committee. This commit-
2006 AL Burnett, USA
tee, under the leadership or Dr Hartmut Porst of Germany
and the co-chairman of the standards committee Jacques
Buvat, took on the herculean task of developing a book as a
work-product of this committee’s efforts to update current Table 2.5 Tanagho Prize winners
knowledge and present standards in the field of sexual medi-
cine for both sexes. This 28-chapter volume was published in 1998 Hong-Zhan Wang, USA
2006 and represents ‘a focused consonance between clinical 2000 Yosikauzu Sato, Japan
problems and contemporary scientific literature’, in the words 2002 Biljana Musicky, USA
of Ira Sharlip, the president of the ISSM in the year that the
2004 K Park, Korea
volume was published.5
2006 B Shrilatha, Singapore

Scientific awards and research

The ISIR recognized that it should award cutting-edge research • The Zorgniotti–Newman Prize of US$1000 was first
with awards at the biennial meetings. Tables 2.3, 2.4, 2.5, awarded in 1988. It is funded by the Zorgniotti Research
and 2.6 list the recipients of these awards over the years. At Fund, itself funded by voluntary donations of ISIR mem-
present the ISSM has four permanent prizes. bers as well as by a donation from the Dutch organizers of
the eight biennial ISIR Meeting, from the profits of this
• The Jean François Ginestié Prize of US$2500 was first congress. It honors two other famous pioneers in the field
awarded in 1984. It is funded by the family of Dr Ginestié, of ED, both founders of the ISIR, and is awarded for the
a French pioneer in the field of ED (who performed the best clinical paper.
first arteriographies of the pudendal arteries). This prize is • The Tanagho Prize of US$1000 was first awarded in 1998.
awarded for the best paper on basic science. It is funded by the Tanagho Fund, made up of the benefits
 The history of the International Society for Sexual Medicine 15

Table 2.6 ISIR Poster Prize winners Table 2.7 Female Sexual Dysfunction Prize winners

1990 JA Moreno, USA 2002 Kathleen Connell, USA

1992 RS Pickard, UK 2004 S Ückert, Germany
1994 J Bernabi, France 2006 no award
1996 Hunter Wessels, USA
1998 Yi Tang, France
2000 MA Khan, UK • Dr Xiaogang Jiang, University Hospital, Copenhagen,
2002 Michael Di Santo, USA Denmark – Uninterrupted 24-hour registration of corpus
2004 S Ückert, Germany (basic science, female)
cavernosum electromyography with a portable recording
system.
K Park, South Korea (basic science, male)
R Shabsigh, USA (clinical, female) Another six awards were given in 2002:
P Teloken, Brazil (clinical, male)
• Dr Derek Bochinski, University of California, San
of the San Francisco ISIR Meeting (1996). It awarded for Francisco – Comparison of the effect of three combina-
the best innovative research. tions in the nerve freezing ED rat model
• The Poster Prize of US$1000 was first awarded in 1990 and • Dr Kelvin P Davies, Albert Einstein College of Medicine,
is awarded for the best poster. Bronx, New York – Changes in global gene expression
accompanying ED in diabetics
A female sexual dysfunction prize was announced at the 2002 • Dr Jas Kalsi, Wolfson Institute for Biomedical Research,
biennial meeting in Montreal, Canada (Table 2.7). London, UK – Effect of nitric oxide-independent vasore-
At the meeting in Amsterdam in 1998, the ISIR presented laxant agents on cavernosal smooth muscle
the first pre-conference symposium. At the same meeting • Dr Steven R. King, Baylor College of Medicine, Houston,
Pfizer Inc made a $50,000 unrestricted educational grant to Texas – Steroidogenic acute regulatory protein’s role in
support young investigators in the field. This was to be divided libido
into five $10,000 grants and to be administered by a panel that • Dr Guiting Lin, University of California, San Francisco,
reviewed submitted grant applications, chaired by Dr Robert California – Embryonic stem cells therapy for neuro-
Krane. There were four grant awards announced at the 2000 genic ED
meeting in Perth, Australia: • Dr Ricardo M Munarriz, University School of Medicine,
Boston, Massachusetts – Is PDE-5 expression, phosphory-
• Dr Trinity Bivalacqua, Tulane University, New Orleans, lation, or activity regulated by steroid hormones in the
Louisiana – Gene transfer of eNOS and nNOS penile corpus cavernosum smooth muscle?
• Dr Yutian Dai, Medical College of Georgia, Augusta –
Effects of RHO kinase inhibition The first International Consultation on ED was organized by
• Dr Kwangsung Park, Chonnan Medical University, Kwanjiu, Dr Saad Khoury and convened in July 1999 in Paris, under
Korea – Effect of hyperglycemia on vaginal function the co-sponsorship of the World Health Organization and
• Dr John Mulhall, Loyola University, Maywood, Illinois – the Union Internationale Contre le Cancer. This consultation
Analysis of ED as a predictor of coronary arterial disease. was chaired by A Jardin and co-chaired by G Wagner. Its
There were six awards in 2001: mission was to develop recommendations for the diagnostic
evaluation and management of ED. Recommendations for
• Dr Hunter C Champion, The Johns Hopkins Hospital, that meeting were based on a thorough review of the available
Baltimore, Maryland – Role of arginase in aging-associated literature and the subjective opinion of 128 recognized global
ED: influence of in vivo gene transfer multidisciplinary experts representing 29 countries and serving
• Dr Taben M. Hale, Queen’s University, Kingston, Ontario, on 18 committees. This meeting was co-sponsored by ISIR and
Canada – Development of a new therapeutic strategy in the Société Internationale d’Urologie. A book was produced
sexual dysfunction: pharmacologically targeting vascular from this effort.6 This meeting led to the second consultation
remodeling held in Paris in 2003, again co-sponsored by ISSM and
• Dr Noel N Kim, Boston University School of Medicine, expanded to cover sexual disorders in both men and women.
Boston, Massachusetts – Does chronic phosphodiesterase A second book was published in 2004.7
type 5 (PDE-5) inhibition increase PDE-5 activity and
attenuate penile erectile function?
• Dr Jonathan Man, Guy’s and St Thomas’ Hospitals, London, Summary
UK – Is ED, per se, characterized by generalised increased
oxidative stress and endothelial dysfunction? The organization that was to become the International Society
• Dr Mahadevan Rajasekaran, UCSD Medical Center, San for Sexual Medicine had its beginnings less than 30 years ago
Diego, California – Role of RHO-kinase pathway in and its first focus was possible revascularization surgery for
hypertension-related male ED? ED. This organization blossomed at a time when the majority
16 Textbook of Erectile Dysfunction

of sexual medicine was considered to be in the province of The sharing of information on a biennial basis led to the
psychological problems. Not long after the first meeting in wish to establish a journal to be able to disseminate higher
1978, other scientific, diagnostic, and therapeutic elements of science that was occurring in sexual medicine. However, the
sexual medicine were placed under more scientific scrutiny. field of education was not confined to members of the Society;
The early founders of the organizations were particularly rather, a new effort was made to educate other healthcare
interested in looking at anatomical and physiological pro- practitioners about sexual medicine; in addition, an effort to
cesses that explain normal sexual function as well as patho- help educate the general public in matters of sexual medicine
logical dysfunction. This focus led to the decision to have became even a greater focus for the organization.
biennial meetings to share cutting-edge findings in the field of The Society has continued to be a truly international orga-
sexual medicine. As molecular biology techniques were used nization that brings together investigators in various disci-
to explain other disease processes, the group of scientists who plines across the world to define more clearly the biology of
made up this organization easily moved into this more intense sexual medicine. Long-term friendships are forged and scien-
scientific evaluation. Not only was the scrutiny afforded to tific enquiry is not only encouraged, but has become the life-
problems of ED, but the members of the organization rapidly blood of the organization. The attempt of this chapter is to
realized and expanded into all fields of sexual medicine, so place a historical perspective on how the organization has
that the organization became the International Society of changed and to introduce some of the key players that have
Sexual Medicine. helped nurture and develop it.

REFERENCES

1. Michal V, Viramar R, Pospichal J, Hejhal L. Arterial epigastrico- 4. Virag R, Virag-Lappas H, eds. Proceedings of the First World Meeting
cavernous anastomosis for the treatment of sexual impotence. on Impotence. Les Editions du CERI: Paris, France, 1984.
World J Surg 1997; 1: 515–19. 5. Porst H, Buvat J, eds. Standard Practice in Sexual Medicine. Oxford:
2. Zorgniotti AW, Rossi G, eds. Vasculogenic Impotence: Proceed- Blackwell, 2006.
ings of the First International Conference on Corpus Caverno- 6. Jardin A, Wagner G, Khoury S, et al. Erectile Dysfunction. Plymouth,
sum Revascularization. Springfield, Illinois: Charles C Thomas, UK: Plymouth Distributors, 1999.
1980. 7. Lue TF, Basson R, Rosen R, et al., eds. Sexual Medicine: Sexual Dys-
3. Lewis R, Wagner G. History of the International Society of Sexual functions in Men and Women. Paris, France: Health Publications,
Medicine (ISSM) – the beginnings. J Sex Med 2008; 5: 740–5. 2004.
3 Epidemiology of erectile dysfunction
Peter Boyle

Introduction psychological community and the medical community and it

was only after the two groups began serious interaction that
There is a centuries-old tradition that ‘impotence’ is a conse- true progress was made. Neither group would admit the
quence of witchcraft or satanic magic.1 In European culture, importance of issues in the other’s domain as a cause of
the issue is of masculinity with the capacity for a strong erec- this problem: surgeons pronounced that 80–90% of impo-
tion symbolic of the strong man. Bancroft2 reviews the history tence is caused by physical, not psychological, problems,6
of impotence and the historical literature. The frequency of whereas sex therapists have to come to terms with the fact that
impotence has not been well investigated until recently and many men with erectile dysfunction, possibly as many as 50%,
one of the major difficulties is the sensitivity of the informa- have physical abnormalities that contribute to their erectile
tion, with respondents tending to give unreliable replies.3 For problems.1
example, Marsey et al.4 investigated the occurrence of impo- The epidemiology of ED is so poorly understood that to
tence in a large cohort of men who had undergone vasectomy, entitle a chapter ‘Epidemiology of erectile dysfunction’, giving
together with an equally large control group. Hidden among the indication that there was some certainty about any state-
questions about many aspects of health and well-being were ments, is a little presumptuous. In this chapter, the author
questions about impotence. These produced incidence esti- discusses some of the epidemiological data available, puts it
mates of approximately 17 new cases per 100,000 man-years.4 in some perspective and outlines the basic requirements
This is slightly lower than the incidence rate of bladder cancer necessary to understand more completely the epidemiological
in the same community and difficult to believe. The epide- picture.
miological investigation of impotence has also been held
back by the lack of a clear and common definition of the
condition.
Impotence is the persistent failure to develop and maintain Erections and the causes
erections of sufficient rigidity for penetrative sexual inter- of dysfunction
course. The disorder is common enough, from all accounts,
but there are few reliable data available about the population Sexual arousal is a function of great evolutionary antiquity
prevalence. Many patients, and even their doctors, are still and is often best understood by specialists in research on
very reluctant to discuss such problems and, consequently, a human nature, such as sociobiologists. Sexual arousal in
large proportion of both the public and the medical profession men is, in some important respects, quite different from
are ignorant about available treatment options.5 sexual arousal in women, particularly with regard to the
The general terminology used to describe this condition stimuli and experiences that are optimally exciting.7 Sexual
has been moving away from the highly emotive term impo- arousal to erotic stimuli diminishes as initially highly exciting
tence towards a more widely descriptive term erectile dys- stimuli lose their ability to create arousal with habituation.
function (ED). Today it is recognized that the causes of ED This has also been shown in laboratory animals, where the
are frequently multiple, with psychological, neurological, male quickly tires of the same partner but whereby rates of
endocrinological, vascular, traumatic and iatrogenic compo- intercourse are quickly restored if a fresh partner is found.8
nents described. Very little high-quality epidemiological Farm animals, such as bulls and rams, have a marked prefer-
investigation of ED has been undertaken and completed, so ence for novel females: for example, rams introduced to the
that the relative importance of each of these groups of causes same partner have a much longer time to ejaculation (around
to the overall burden of impotence in the community is 17 minutes) compared with rams introduced to different
unknown at present. There are incomplete indications of a partners at the same rate (around 2 minutes).9 Thus, it could
precise role of environmental or lifestyle factors in the develop- be possible that factors such as habituation could play a
ment of impotence, although smoking, hypertension, hyper- part in the development of ED although there are physio-
lipidemia, diabetes mellitus and the presence of vascular logical mechanisms as well as psychological mechanisms that
disease have been proposed as potential risk factors.5 Research must be kept in mind in the potential etiology of erectile
on ED proceeded for many years in parallel among the dysfunction.

17
18 Textbook of Erectile Dysfunction

In simple terms, erection of the penis depends on the Basic epidemiological considerations
adequate filling of the paired corpora cavernosa with blood at
systolic pressure (or even slightly above).5 Erection occurs The most useful definition of epidemiology is that it is
when the tonically contracted cavernosal and helicine arteries the scientific study of the distribution and determinants of
relax, increasing blood flow to the lacunar spaces and result- disease in humans.14 From this evolve the two components
ing in engorgement of the penis. Relaxation of the trabecular of descriptive epidemiology – the description of disease
smooth muscle of the corpora cavernosa is mediated by incidence, mortality and prevalence by persons, place and
acetylcholine, which acts on endothelial cells causing them in time – and analytical epidemiology – the search for determi-
turn to release a further non-adrenergic non-cholinergic carrier nants of disease risk that may serve to increase prospects for
of the relaxation signal. The strongest suspect for this second prevention.
carrier is currently nitric oxide, although other candidates, par- Determination of disease frequency, the first step towards
ticularly vasoactive intestinal polypeptide, cannot be entirely geographical and temporal comparisons, relies on a definition
ruled out at present.10 (or at least on a working epidemiological definition) of the
Thus, the search for etiological factors in erectile dysfunc- disease or condition under investigation. ED shares with the
tion has certain clues to begin with: factors that interfere with other common urological condition of benign prostatic hyper-
the filling of the corpora cavernosa, with the blood flow to the plasia (BPH)15 the absence of a unifying definition of which
lacunar spaces, or with the production and regulation of nitric the sensitivity and specificity can be determined. This is a fun-
oxide (or other carriers of the relaxation signal) are prime damental problem that requires resolution. It should also be a
suspects for any etiological investigation. priority to establish a system of classification, after determina-
Erectile dysfunction is not always, however, the failure of tion of the severity and ‘cause’ of erectile dysfunction.
some mechanical or biochemical process: sexual function Many questionnaires have been developed in the hope of
cannot be considered on its own without bearing in mind the achieving this (among other goals),16 although many have suf-
concept of sexuality. The human sexual response is a complex, fered from being too long and fussy with detail. Recently, two
multifaceted phenomenon that is not completely, or nearly, questionnaire-based symptom scales have been developed17,18
understood by anyone at present. Problems with potency are that employ modern concepts of psychometric methodology
frequently multi-factorial in origin. and that attempt to overcome the inherent difficulties experi-
In nervous or anxious men, increased sympathetic tone and enced with earlier attempts. The brief Sexual Function Index
raised circulating catecholamine concentrations may interfere (SFI)17 covers the domains of sexual drive, erection, ejacula-
with the mechanisms of smooth muscle relaxation underlying tion, perceptions of problems in each of these areas and overall
erection. Psychogenic impotence is self-perpetuating: each satisfaction in a total of nine questions. The International
failure increases the associated anxiety levels and frequently Index of Erectile Dysfunction (IIEF)18 has been developed and
can lead to the continual failure to have erections. This is the covers in 15 questions the domains of erectile function, orgas-
commonest cause of intermittent erectile dysfunction in mic function, sexual desire, intercourse satisfaction and overall
young men, although it is usually secondary to organic dys- satisfaction. The similarity of these two instruments, both
function from middle age onwards.11 developed on the basis of detailed statistical analysis, is very
Free serum testosterone concentrations fall progressively reassuring. Time is necessary to observe which comes into the
with age, while erectile dysfunction increases in frequency. forefront of international usage, although the shorter version
Falling testosterone levels are associated with a loss of libido of O’Leary and his colleagues17 has its attractions, if all other
and reduced frequency of erections,5 although the straight- things are equal (i.e. if the questionnaires perform similarly).
forward restoration of circulating androgen levels often does A particular problem surrounds the probability of a man
not restore sexual function. This underlines, once again, the declaring his impotence and, to a large extent, this can be
complex nature of male sexual function and the interplay with influenced by aspects of sexuality. There will be couples
sexuality. who accept the reduction in sexual activity and potency as a
Although endocrinological impotence frequently is a con- natural consequence of aging (and many may, in fact, be
sequence of poorly understood processes, neurogenic impo- pleased and relieved). In similar circumstances, others will
tence often can have a precise cause attributed. Several be extremely concerned and upset. Such facets of sexuality
neurological disorders can impair erectile function, although will have a strong influence on who comes to the doctor or
it is unusual – but not completely unknown – for impaired who admits to the interviewer that they have erectile dys-
erectile function to be the sole manifestation of diseases or function. Frequency of self-reports is not to be trusted and
disorders of the nervous system. Peripheral neuropathies, consequently will bias any epidemiological study that would
most frequently associated with alcoholism or diabetes, are investigate the etiology of the phenomenon. Solstad and
associated with impotence. Hertoft19 interviewed 100 men who had previously completed
Probably the most important causes of erectile dysfunction a questionnaire regarding erectile dysfunction: whereas less
are impaired blood flow to the penis or excessive leakage from than 4% of all men who completed the questionnaire (16 of
the penis; frequently, both are present. In older men, reduced 439) reported erectile dysfunction, among the 100 men from
blood flow into the penis due to atherosclerotic lesions of the the initial sample who were subsequently interviewed, nearly
internal iliac, pudendal and cavernosal arteries is the most 40% reported some kind of sexual dysfunction. Interestingly,
common cause.11,12 With large increases taking place in the only 7% found their problems abnormal for their age and
aging population,13 vascular impotence will take on ever- only 5% indicated that they would seek treatment for their
increasing importance in urological practice. problems.19
 Epidemiology of erectile dysfunction 19

Descriptive epidemiology of and is potentially biased, for reasons associated with the
discussion in the previous section.
erectile dysfunction Diokno and colleagues included questions about sexual
activity and its correlates in a clinic examination, whose
The reported frequency of erectile problems in completely
participants were identified by a household survey of a pro-
unrepresentative samples is very similar. For example,
bability sample of Washtenaw County, Michigan, USA. Men
Sanders20,21 reports an analysis of responses to two surveys
were aged 60 years and over and were questioned with regard
published in Woman magazine: 7% of men reported them-
to medical, epidemiological and social aspects of aging.29
selves to have erectile problems compared with 8% of women
Of married men, 73.8% reported that they were sexually active
who made the same report. Frank et al.22 studied 100 married
(whereas the corresponding figure for married women was
couples and reported that 7% had difficulty in getting an
55.8%), with levels decreasing with age. Overall, 35.3% of men
erection; the same figure (in a study of 58 men) was reported
included in this sample reported that they were impotent.
by Nettelbladt and Uddenberg.23 Even although the figures are
Feldman and his colleagues conducted the most useful and
all so similar, this may just reflect the effects of the same major
comprehensive study of the epidemiology of impotence until
biases that have been outlined above.
the present time.30 The study sample consisted of respondents
Many of these (and similar previous) reports on the fre-
to the Massachusetts Male Aging Study (MMAS): this was a
quency of erectile dysfunction are of very limited value, being
cross-sectional, random sample survey of health status and
based on poor epidemiological methodology and likely to be
related issues in men aged between 40 and 70 years. The MMAS
biased in directions that are frequently difficult for the reader
was conducted between 1987 and 1989 in 11 randomly selected
to determine; these should be discarded immediately. Even in
towns in the Boston area of Massachusetts, USA. Of 1709
many recent reports, the methods for obtaining study popula-
respondees, 1209 men provided complete responses and consti-
tions have differed, the definitions of impotence have varied
tute the sample on which the findings were based. Although
widely from study to study, and stratified information of
the 419 men excluded did not differ from the study sample
prevalence by age has frequently been omitted completely or
with respect to all essential variables, a 2/3 non-response rate
has been unreliable owing to the small numbers of subjects in
to sexual questions should be a cause for some hard cynical
each of the age classes. These are catastrophic failures from the
questioning. A total of 291 men did not respond because they
point of view of comparison of rates. However, some limited
had no sexual partner, and this could bias the prevalence
data are available regarding the occurrence of ED.
downward. Discriminant analysis was employed to create an
Among 1180 men attending a medical outpatient clinic,
impotence scale of nil, minimal, moderate and complete impo-
Slag et al.24 observed that 34% reported impotence to their
tence, which was accorded to each individual in the survey.30
interviewers. These were attendees at a medical outpatient
Between the fifth and seventh decades, the probability
clinic and may differ from the general population in having
of complete impotence almost tripled, from 5.1% to 15%
over-representation of diabetes, hypertension and other
(Figure 3.1); 60% of men were potent in their fifth decade,
vascular diseases.
whereas only 33% were potent at 70 years.30
Erectile dysfunction is the most common presenting
Of 1680 men who participated in the (free) Prostate
symptom among men attending sexual problem clinics. For
Cancer Awareness Week and who were invited to complete a
example, in Edinburgh, over a 3-year period, over one-half of
self-administered questionnaire containing questions on
all men presenting at this clinic reported erectile dysfunction
urinary symptoms, impotence, quality of life and age, 1517
as their main complaint. The next most common complaint
answered the questionnaire, a response rate of 90.3%.31 A total
was premature ejaculation,25 which was reported by 13% of
the men. Of these men, over one-half (52%) had some other
55
condition that contributed to their erectile dysfunction: 32%
arterial, 21% neurological, 29% urological and 19% diabetes 50
mellitus.25 In a similar clinic in Singapore, 72.5% of men 45
attending the Sexual Dysfunction Clinic at Toa Payoh Hospital
Percentage with impotence

40
had erectile dysfunction due to organic causes with the
remaining 27.5% of patients having erectile dysfunction due 35
to psychogenic causes.26 Of the patients with organic impo- 30
tence, in 81% of cases this could be attributed to the effects of 25
diabetes and vascular disease.27
20
In a small study (212 family practice patients) with a young
mean age (37 years), 27% of men, on detailed questioning, 15
reported being impotent.27 The small sample and the young 10
average age argue strongly against the representativeness of
5
these findings to a community, however.
Morley28 determined the prevalence of impotence to be
40–44 45–49 50–54 55–59 60–64 65–69 70–74
27% in men of more than 50 years of age undergoing a general Age group
health screening. In terms of size of the sample and the mean
age of the men, this sample is better than most. However, it is Figure 3.1 Probability of complete or moderate impotence in
still hindered by the lack of definition of the term impotence Massachusetts Male Aging Survey.30
20 Textbook of Erectile Dysfunction

of 129 men (7.7%) had not had any erections during the the non-smokers (8.5%) were comparable to the general
previous 12 months. Of subjects who reported that they had sample (9.4%). Feldman et al.30 also found that drug effects
experienced erections during the previous 12 months, 12.4% were exacerbated by current smoking, which increased the
had had erections on less than one occasion in five when age-adjusted probability of complete impotence in those
sexually stimulated during the last month. There was a strik- taking cardiac medication (from 14 to 41%), using antihyper-
ing association between the frequency of varying degrees of tensive medications (from 7.5 to 21%) and using vasodilators
impotence and age. (from 21 to 52%). However, in this study an overall effect of
Sexual function was assessed in the prospective Olmsted current smoking was not noted,30 with complete impotence
County Study of Urinary Symptoms and Health Status Among present in 11% of smokers and 9.3% of non-smokers. Among
Men, involving a random sample of men living there.32 The current smokers, the probability of impotence demonstrated
prevalence of sexual problems and erectile dysfunction no dose dependency with current smoking or lifetime cigarette
increased with age. Comparison of men aged 70–79 years with consumption.
men aged 40–49 years indicated that older men were more Diabetes is widely recognized to be associated with impo-
worried about sexual function (46.6% vs 24.9%), had worsened tence. A review of seven prevalence surveys found rates of erec-
performance compared with a year ago (30.1% vs 10.4%), tile dysfunction ranging from 35% to 59% among diabetics.45
expressed extreme dissatisfaction with sexual performance The association with increasing prevalence with age is also
(10.7% vs 1.7%), had an absence of sexual drive (25.9% vs found. For example, Figure 3.2 contrasts the prevalence of
0.6%) and reported complete erectile dysfunction when sexu- erectile dysfunction in diabetic and non-diabetic men,1 and
ally stimulated (27.4% vs 0.3%).32 Age did not appear to be clearly demonstrates the differences between diabetic and
an independent determinant of this dissatisfaction; rather, non-diabetic men in terms of prevalence of erectile dysfunc-
this could be accounted for primarily by the age-related tion as well as the striking association with age in both groups.
increase in erectile dysfunction, decreased libido and their Similar prevalences have been reported recently46,47 and, addi-
interaction. tionally, erectile dysfunction in diabetic men has been associ-
Prior to Jonler et al.31 and Feldman et al.,30 Kinsey et al.33 had ated with the presence of severe diabetic retinopathy, a history
found impotence to be an age-dependent disorder with a pre- of peripheral neuropathy, amputation, cardiovascular disease,
valence of 1.9% at 40 years and 25% at age 65.33 All three studies a higher glycosylated hemoglobin, use of antihypertensive
share the common feature of being based on selected popula- drugs and a higher body mass index.46 It would appear that
tion subgroups. The trends with age, and the high prevalences tighter glycemic control and careful selection of antihyperten-
at older ages, are comfortingly similar, not only to themselves sive medication could prove beneficial in the avoidance of
but also compared with other surveys of this area.22,34–38 erectile dysfunction in diabetic patients.46
Despite the methodological inadequacies in each of these In the MMAS, the age-adjusted probability of complete
studies, to some degree or another, it is clear that impotence impotence was three times higher in men who reported
is a very common condition in men and one in which the having treated diabetes than in those without diabetes. In
prevalence is strongly linked to aging. The prevalence prob- studies of diabetic patients, there have been consistent findings
ably now exceeds 2% in the fifth decade, rising to 25–30% by of high prevalences of impotence, with estimates ranging
the middle of the seventh decade, as estimated by Furlow in between one-third and one-half and, occasionally, up to three-
1985.39 Good data are still required, particularly by ethnic quarters.48,49 It has been reported that impotence in diabetics
group and at older ages. No data are available for impotence increases from 15% at age 30–34 to 55% at age 60 years.50
among men aged 75 or over, of whom substantially over one- It has been reported that impotence occurs at an earlier age in
half may be affected.5

60
Percentage prevalence of erectile dysfunction

Determinants of erectile dysfunction

in men 50

Until the early 1980s, it was commonly held that psychogenic

40
causes were the etiology in up to 90% of cases of erectile
dysfunction.40–42 Current thinking favors arterial changes as the
key factor in the largest proportion of impotence,5,12,24,43 with 30
alterations in the flow of blood to and from the penis the single
most important cause. Some studies have indicated that there 20
may be evidence of a role for certain cardiovascular risk factors
in determining the risk of impotence, including tobacco,
10
hypertension, diabetes mellitus and hyperlipidemia.
Cigarette smoking has been implicated as an independent
risk factor for (vascular) impotence.44 In the MMAS, among 0
20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59
subjects with treated heart disease the age-adjusted probabi-
Age (years)
lity of complete impotence was 56% for current smokers,
compared with 21% in current non-smokers.30 Among treated Figure 3.2 Prevalence of erectile dysfunction in diabetic (right
hypertensives, those who currently smoked cigarettes had an columns) and non-diabetic (left columns) men. Data have been
elevated probability of complete impotence (20%), whereas abstracted from reference 1.
 Epidemiology of erectile dysfunction 21

men with diabetes than in men in general, both in type I and 1.03). Men with total cholesterol over 6.21 mmol/liter
type II diabetes.51,52 (240 mg/dl) had 1.83 times the risk (95% CI 1.00, 3.37) of
Vascular disease is the aspect of diabetes most widely held that of men with less than 4.65 mmol/liter (180 mg/dl). These
to be responsible for associated impotence. The association of differences remained essentially unchanged after adjustment
impotence with vascular disease appears to be quite consistently for potential confounding factors (Figure 3.3).60
reported. Impairment in the hemodynamics of erection has Feldman et al.30 reported that the probability of impo-
been demonstrated in men with a number of vascular diseases: tence varied inversely with HDL-C. For younger men, aged
in a group of men aged 31–86 with myocardial infarction, 40–55 years, the age-adjusted probability of moderate impo-
64% were impotent,53 and 57% of men in a study of coronary tence increased from 6.7% to 25% as HDL-C decreased from
bypass surgery were found to be impotent.54 Similar excesses 90 to 30 mg/dl. In older subjects, aged 56–70 years, the prob-
of impotence have been demonstrated in men with peripheral ability of complete impotence increased from near zero to
vascular disease55 and cerebrovascular accidents.56 It has also 16% as HDL-C decreased from 90 to 30 mg/dl. No association
been reported that impotence was increased among patients with total cholesterol was found in this study.30
with arthritis,57 although Feldman noted that the same asso- Impotence is often reported following radical prostatec-
ciation in the MMAS study was confined to smokers.30 tomy, although preservation of the neurovascular bundles
The effect on sexual function of lifestyle factors related to helps to reduce the frequency of the condition. Quinlan et al.61
cardiovascular disorders such as alcohol consumption has reported 600 radical retropubic prostatectomies from the
been reported to be either slight30 or unclear.58,59 There is no Johns Hopkins Hospital of which 503 men were potent pre-
consistent evidence suggesting that obesity per se is associated operatively.61 Three factors were found to be related to the
with impotence.30,58,59 A high level of total cholesterol or low return of sexual function postoperatively, namely age, clinical
level of high-density-lipoprotein cholesterol (HDL-C) may stage of the tumor and surgical approach – i.e. whether the
result in arteriosclerosis and induce erectile dysfunction by neurovascular bundles were preserved or excised. In young
arterial insufficiency. Wei et al.60 reported the relation between men, aged less than 50 years, potency was similar in patients
serum cholesterol and erectile dysfunction among blood who had both neurovascular bundles preserved (90%) and
samples obtained from the Cooper Clinic in Dallas, Texas, in those who had one neurovascular bundle widely excised
USA. The study included a total of 3250 men aged 26–83 years (91%). In men over 50 years, sexual function was better in
(mean age reported to be 51 years) without erectile dysfunc- men who had both bundles preserved than in men in whom
tion at the first visit and who had a further clinic visit between one neurovascular bundle was widely excised (p < 0.05). When
6 and 48 months following.60 Erectile dysfunction was reported the relative risk of impotence was adjusted for age, the risk
by 71 men (2.2%) during this period and every mmol/liter of postoperative impotence was twofold greater if there was
increase in total cholesterol was associated with 1.32 times the capsular penetration or seminal vesicle invasion, or if one
risk of erectile dysfunction (95% confidence interval [CI] neurovascular bundle was excised (p < 0.05). In contrast, the
1.04, 1.68). Men with an HDL-C measurement over 1.55 proportion of men who stated that they were impotent follow-
mmol/liter (60 mg/dl) had 0.30 times the risk (95% CI 0.09, ing transurethral resection of the prostate (TURP) for BPH
(24%) was essentially similar to the preoperative impotence
rate (22%).62 Previous anecdotal reports of an association
3.4 between TURP and erectile dysfunction may have arisen
3.2
because of patients’ confusion in equating retrograde ejacula-
tion with erectile dysfunction.63
3.0
Of 40 patients with aorto-iliac occlusive disease (AIOD)
2.8
scheduled for surgery, 31 were given questionnaires and penile
2.6
dynamic color Doppler ultrasonography.64 Five of the 31
2.4
who volunteered were found to be potent (16%) and the
Adjusted odds ratio

2.2
remaining 26 (84%) were found to have erectile dysfunction.
2.0
This was found to be entirely arteriogenic in 8% of cases,
1.8
purely venogenic in 23% of cases and a combination of arte-
1.6
riogenic and venogenic in 53%. Following surgery, 20 patients
1.4
returned for evaluation and erectile function was found to
1.2 have improved in seven patients. Of these patients, six (of
1.0 nine) had undergone endarterectomy and one (of 11) had
0.8 undergone reconstruction.64
0.6 The association between impotence and taking medication
0.4 is still controversial in many instances, as many of these
0.2 associations have been based on case reports and personal
0 case series. Morley28 noted that 16 of the 200 most widely
<180 180–240 >240 <30 30–60 >60
prescribed drugs in the United States were associated with
Total cholesterol (mg/dl) HDL cholesterol (mg/dl)
impotence and that 1/4 men in a medical outpatient popula-
Figure 3.3 Relative (and 95% confidence interval) risk of tion were reported to have drug-induced erectile dysfunc-
erectile dysfunction by levels of total cholesterol and high- tion.24 The frequency of erectile dysfunction was found to be
density-lipoprotein (HDL) cholesterol. Data abstracted from slightly elevated in men receiving finasteride, a 5-alpha-
reference 60. reductase inhibitor used in the treatment of BPH.65,66 Erectile
22 Textbook of Erectile Dysfunction

dysfunction has been associated with a wide range of antihy- methodological failings in the available studies, the prevalence
pertensive preparations, including diuretics, sympatholytics, of the disease in aging men is very high. The etiology of
beta-adrenoceptor-blocking agents and vasodilators.67,68 Unfor- erectile dysfunction is classified into several major subhead-
tunately, many of these reports are from studies where the ings; whereas psychogenic impotence was held, only 20 years
presence of impotence was not ascertained before the trial ago, to account for over 80% of cases, today it is widely
began and, in most of the studies, it is difficult to separate accepted that the commonest cause, and the explanation for
the effect of the treatment from the effect of the disease. The the majority of cases, is the vascular changes commonly found
one exception appears to be doxazosin, an alpha-adrenergic in aging men. In particular, erectile dysfunction appears to
receptor blocker used in the treatment of hypertension and be common in diabetic patients and in men with clearly
BPH, which was shown in a four-arm study to enhance sexual defined, serious vascular disease. A number of risk factors for
function.69 vascular disease appear to be related to the risk of impotence,
Psychological factors directly involved in the development including cigarette smoking and serum cholesterol levels,
of impotence have been very poorly studied from the etio- particularly HDL-C. Erectile function also appears to be very
logical point of view. It has not been common practice to sensitive to unrelated drug therapy effects.
include psychological assessments in prospective studies and, Smoking is the largest single source of preventable mortality
in retrospective surveys, it is difficult to avoid the effect similar worldwide today. Smokers have great difficulty in stopping
to confounding by indication, wherein men who become the habit, although it is very tempting to speculate that if it
impotent then become depressed and exhibit other psycho- could be demonstrated that smoking cessation reduced the
logical traits. probability of becoming impotent, then men might be more
motivated to give up this noxious habit and improve the
expected duration as well as the quality of their lives.
Acknowledgments There are a number of priorities in epidemiological research
on erectile dysfunction. First, it is necessary to develop stan-
This work was conducted within the framework of support dard instruments to determine with certain sensitivity and
from the Associazione Italiana per la Ricerca sul Cancro. specificity the presence, frequency and nature of erectile dys-
function in men; there have been important developments in
this field in the recent past. Subsequently, this should be used
Conclusions and recommendations to determine variations in the occurrence of erectile dysfunc-
tion, be it internationally, temporally or in special groups of the
With the 20th century has come a wide range of diseases of population; this is now ongoing. There is an urgent need to
affluence and aging, including appendicitis, myocardial have a better understanding of the etiology of erectile dys-
infarction, osteoporosis and old age. Prior to age 40, impo- function: risk factors need to be identified more clearly so that
tence is a relatively uncommon disorder but the prevalence prevention possibilities can be investigated. In this line, it
rises in such a way that the majority of men over 70 years of would be interesting and useful to have urgent information
age may suffer from erectile dysfunction. Although 100 years on whether the cessation of cigarette smoking or lowering
ago this was of little consequence in public health terms, today HDL-C levels could lead to a reduction in the probability of
life expectancy approaches 80 years in the most developed developing impotence. A positive effect of cholesterol-lowering
countries. Although ED does not kill, it is a major contributor drugs on nocturnal penile tumescence has been observed and,
to a reduced quality of life and to the consequent psychologi- given the association now developing between cardiovascular
cal sequelae of many aging men. disease and decreased nocturnal penile tumescence,70 this
The epidemiology of erectile dysfunction is very poorly could lead to the prioritization of this research line as one
researched and incompletely understood, although several important way forward towards prevention. However, this
aspects of the epidemiology are clear, at least in qualitative line of etiological and preventive research appears to have
terms. Most importantly, despite the presence of all possible stalled and is developing only very slowly at present.

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JP (eds) Impotence: an integrated approach to clinical practice. 45. Fairbairn CG, McCulloch DK, Wu FC. The effects of diabetes on
Edinburgh: Churchill Livingstone, 1993. male sexual function. Baillières Clin Endocrinol Metab 1982; 11:
17. O’Leary MP, Fowler FJ, Lenderking WR, et al. A brief sexual func- 749–84.
tion inventory for urology. Urology 1995; 46: 697–706. 46. Klein R, Klein BE, Lee KE, et al. Prevalence of self-reported erectile
18. Rosen RC, Riley A, Wagner G, et al. The International Index of dysfunction in people with long-term IDDM. Diabetes Care 1996;
Erectile Dysfunction (IIEF): a multidimensional scale for the assess- 19: 135–41.
ment of erectile dysfunction. Urology 1997; 49: 822–30. 47. Brunner GA, Pieber TR, Schattenberg S, et al. Erectile dysfunction
19. Solstad K, Hertoft P. Frequency of sexual problems and sexual in patients with type I diabetes mellitus. Wien Med Wochenschr
dysfunction in middle-aged Danish men. Arch Sex Behav 1993; 1995; 145: 584–6.
22: 51–8. 48. Zemel P. Sexual dysfunction in the diabetic patient with hyperten-
20. Sanders D. The Woman book of love and sex. London: Sphere, sion. Am J Cardiol 1988; 61: 27H–33.
1985. 49. Rubin, A et al. Impotence and diabetes mellitus. JAMA 1958;
21. Sanders D. The Woman report on men. London: Sphere, 1987. 168: 496.
22. Frank E, Anderson C, Rubinstein D. Frequency of sexual dysfunc- 50. Smith AD. Causes and classification of impotence. Urol Clin North
tion in ‘normal’ couples. New Engl J Med 1978; 299: 111–15. Am 1981; 8: 79–89.
23. Nettelbladt P, Uddenberg N. Sexual dysfunction and sexual 51. Whitehead ED, Klyde BJ. Diabetes-related impotence in the elderly.
satisfaction in 58 married Swedish men. J Psychosom Res 1979; Clin Geriatr Med 1990; 6: 771–95.
23: 91–100. 52. McCulloch DK, Campbell IW, Wu FC, et al. The prevalence of
24. Slag MF, Morley JE, Elson MK, et al. Impotence in medical clinic diabetic impotence. Diabetologia 1980; 18: 279–83.
outpatients. JAMA 1983; 249: 1736–42. 53. Wabrek AJ, Burchell RC. Male sexual dysfunction associated with
25. Warner P, Bancroft J and members of the Edinburgh Human Sexu- coronary heart disease. Arch Sex Behav 1980; 9: 69–75.
ality Group. A Regional Service for Sexual Problems: a three-year 54. Gundle MJ, Reeves BR, Tate S, et al. Psychological outcome
study. J Sex Marital Ther 1987; 2: 115–25. after aortocoronary artery surgery. Am J Psychiatry 1980; 137:
26. Lim PH, Ng FC. Erectile dysfunction in Singapore men: presenta- 1591–4.
tion, treatment and results. Ann Acad Med Singapore 1992; 21: 55. Ruzbarski V, Michal V. Morphologic changes in the arterial bed of
248–53. the penis with ageing: relationship to the pathogenesis of impo-
27. Schein M, Zyzanski SJ, Levine S, et al. The frequency of sexual tence. Invest Urol 1977; 15: 194–9.
problems among family practice patients. Fam Pract Res J 1988; 7: 56. Agarwal A, Jain DC. Male sexual dysfunction after stroke. J Assoc
122–34. Physicians India 1989; 37: 505–7.
28. Morley JE. Impotence in older men. Hosp Pract 1988; 23: 139–42. 57. Blake DJ, Maisak R, Koplan A, et al. Sexual function among patients
29. Diokno AC, Brown MB, Herzog AR. Sexual function in the elderly. with arthritis. Clin Rheumatol 1988; 7: 50–60.
Arch Intern Med 1990; 150: 197–200. 58. Kosch SG, Curry RW, Kuritzky L. Evaluation and treatment of
30. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence impotence: a pragmatic approach addressing organic and psycho-
and its medical and psychological correlates: results of the genic components. Fam Pract Res J 1988; 7: 162–74.
Massachusetts Male Aging Study. J Urol 1994; 151: 54–61. 59. Fried LP, Moore RD, Parson TA. Long-term effects of cigarette
31. Jonler M, Moon T, Brannan W, et al. The effect of age, ethnicity smoking and moderate alcohol consumption on coronary
and geographical location on impotence and quality of life. Br J artery diameter. Mechanism of coronary artery disease indepen-
Urol 1995; 75: 651–5. dent of atherosclerosis or thrombosis? Am J Med 1986; 80:
32. Panser LA, Rhodes T, Girman CJ, et al. Sexual function of men 37–44.
ages 40 to 70 years: the Olmsted County Study of urinary symp- 60. Wei M, Macera CA, Davis DR, et al. Total cholesterol and high
toms and health status among men. J Am Geriatr Soc 1995; 43: density lipoprotein cholesterol as important predictors of erectile
1107–11. dysfunction. Am J Epidemiol 1994; 140: 930–7.
33. Kinsey AC, Pomeroy W, Martin CE. Age and sexual outlet. In: 61. Quinlan DM, Epstein JL, Carter BS, Walsh PC. Sexual function
Kinsey AC, Pomeroy W, Martin CE (eds) Sexual behaviour in the following radical prostatectomy: influence of preservation of
human male. Philadelphia: Saunders, 1948. neurovascular bundles. J Urol 1991; 145: 998–1002.
34. Pearlman CK, Kobashi LJ. Frequency of intercourse in men. J Urol 62. Doll HA, Black NA, McPherson K, et al. Mortality, morbidity and
1972; 107: 298–301. complications following transurethral resection of the prostate for
35. Morley JE. Impotence. Am J Med 1986; 80: 897–905. benign prostatic hyperplasia. J Urol 1992; 147: 1566–73.
36. Pfeiffer E, Davis GC. Determinants of sexual behaviour in middle 63. Soderdahl DW, Knight RW, Hansberry KL. Erectile dysfunction
and old age. J Am Geriatr Soc 1972; 20: 151–8. following transurethral resection of the prostate. J Urol 1996; 156:
37. Mulligan T, Retchin SM, Chinchilli VM, Bettinger CB. The role of 1354–6.
ageing and chronic disease in sexual dysfunction. J Am Geriatr Soc 64. Cormio L, Edgren J, Lepantalo M, et al. Aortofemoral surgery and
1988; 36: 520–4. sexual function. Eur J Vasc Endovasc Surg 1996; 11: 453–7.
38. Keil JE, Sutherland SE, Knapp RG, et al. Self-reported sexual func- 65. Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of finas-
tioning in elderly blacks and whites: the Charleston heart study teride in men with benign prostatic hyperplasia. New Engl J Med
experience. J Aging Health 1992; 4: 112. 1992; 327: 1185–91.
39. Furlow WL. Prevalence of impotence in the United States. Med 66. Finasteride Study Group. Finasteride (MK-906) in the treatment of
Aspects Hum Sex 1985; 19: 13–16. benign prostatic hyperplasia. Prostate 1993; 22: 291–9.
24 Textbook of Erectile Dysfunction

67. Segraves RT, Madsen R, Corter CS. Erectile dysfunction associated 69. Treatment of Mild Hypertension Research Group. A randomized,
with pharmaceutical agents. In: Segraves RT, Schoenber HW (eds) placebo-controlled, trial of a nutritional–hygienic regime along
Diagnosis and treatment of erectile disturbances. A guide for clini- with various drug monotherapies. Arch Intern Med 1991; 151:
cians. New York: Plenum Press, 1985: 22–63. 1413–23.
68. Wein AJ, van Arsdalen KN. Drug-induced male sexual dysfunc- 70. Rosen RC, Weiner DN. Cardiovascular disease and sleep-related
tion. Urol Clin North Am 1988; 15: 23–31. erections. J Psychosom Res 1997; 42: 517–30.
4 Anatomy of erectile function
William O Brant, Anthony J Bella, and Tom F Lue

Introduction tunica albigunea consists of two layers, the outer of which is

oriented longitudinally whereas the inner layer consists of
The penis is essentially a tripartite structure, with bilateral circular fibers. The inner layer contains struts that course the
corpora cavernosa and the midline ventral corpus spongiosum cavernosal space and serve to augment the support provided
and glans, all three of which are surrounded by loose subcuta- by the intracavernosal septum. The corpus spongiosum lacks
neous tissue and skin that can be moved freely over the erect both the outer layer as well as the struts.
organ (Figure 4.1). The cavernosa function as the main erectile There is variability in the thickness and strength of the
bodies, while the spongiosum contains the urethra. The length tunica albigunea in various locations. Thickness ranges from
of the penis is highly variable, especially in the flaccid state, approximately 0.8 mm at the five o’clock and seven o’clock
since it is dependent on the degree of contraction of the positions (just lateral to the corpus spongiosum) to 2.2 mm at
cavernosal smooth muscle tissue. There is considerably less the one o’clock and eleven o’clock positions.2
variation in length of the fully erect penis, with one study
demonstrating a good correspondence between erect length
and stretched penile length, as measured from the pubopenile Corpora cavernosa
junction to the meatus.1 This length was found to be an average
of 12.4 cm. The paired corpora cavernosa originate separately underneath
the ischiopubic rami, then merge as they pass under the pubic
arch. The septum between them is incomplete in humans,
Skin and fascia although complete in some other species. They are supported
by several fibrous structures, including the surrounding
Penile skin is continuous with that of the lower abdominal tunica albigunea, the intracavernous struts radiating from the
wall and continues over the glans penis; there it folds back on inner layer of the tunica albigunea, and perineural, periarte-
itself and attaches at the coronal sulcus. The folded portion is rial fibrous sheaths. The spongy inner portion of the corpora
known as the prepuce. consists mainly of interconnected sinusoids separated by
There are two fascial layers. The more superficial is the smooth muscle trabeculae, which are surrounded by collagen
dartos fascia, continuous with Scarpa’s fascia of the abdomen. and elastic fibers. These sinusoids are larger centrally and
It continues caudally as the dartos fascial layer of the scrotum smaller towards the periphery. The corpus spongiosum and
and Colles’ fascia in the perineum. The deeper fascial layer is its distal termination in the glans penis is similar in internal
Buck’s fascia, which covers the corpora cavernosa and the structure to the corpora cavernosa except that the sinusoids
corpus spongiosum in separate compartments, including are larger, there is a lack of outer layer of the tunica albigunea,
coverage of the deep dorsal vein as well as the dorsal neuro- and the tunica albigunea is absent in the glans.
vascular bundles. Buck’s fascia attaches to the perineal mem-
brane proximally and to the coronal sulcus distally, where it
fuses with the tips of the corpora. The fundiform and sus- Associated musculature
pensory ligaments attach to the pubic symphysis and Buck’s
fascia, and allow the erect penis to achieve a horizontal or The paired ischiocavernosus muscles originate from the ischial
greater angle. tuberosity, cover the proximal corpora, and insert into the
inferiomedial surface of the corpora. These muscles are inner-
vated by the perineal branch of the pudendal nerve and allow
Tunica albigunea the corpora cavernosa to obtain much higher intracorporal
pressures than would be possible with arterial pressure alone.
The corpora are surrounded by tunica albigunea, a strong The bulbospongiosal muscle originates at the central perineal
structure of heterogeneous thickness and anatomy, the pur- tendon, covers the urethral bulb and corpus spongiosum, and
pose of which is to both provide rigidity of the erectile bodies inserts into the midline. This muscle is innervated by a branch
as well as to function in the veno-occlusive mechanism. The of the perineal nerve and assists in the ejaculation of semen.

25
26 Textbook of Erectile Dysfunction

Superficial and deep dorsal vein

Dorsal artery
Fascicles of dorsal nerve
Subtunical space
Skin
Cavernosal artery
Superficial
(dartos) fascia Erectile tissue
Tunica albuginea:
Deep (Buck’s)
Outer longitudinal layer
fascia
Inner circular layer
Corpus spongiosum

Figure 4.1 Cross-sectional anatomy of the penis. With permission from the American Urological Association AUA Update Series,
volume 13, lesson 2; 1994.6

Penile vascular anatomy dorsal vein, laterally to the circumflex vein, and ventrally
to the periurethral vein. Beginning at the coronal sulcus,
The main source of blood supply to the penis is usually the prominent deep dorsal vein is the main venous drain-
through the internal pudendal artery, a branch of the internal age of the glans penis, corpus spongiosum, and distal
iliac artery (Figure 4.2). In many instances, however, accessory two-thirds of the corpora cavernosa. Usually, a single vein,
arteries arise from the external iliac, obturator, vesical, or but sometimes more than one deep dorsal vein, runs
femoral arteries, and they may occasionally become the upward behind the symphysis pubis to join the peripro-
dominant or only arterial supply to the corpus cavernosum.3 static venous plexus.
Damage to these accessory arteries during radical prostatec- 3. Emissary veins from the infrapubic penis drain the
tomy or cystectomy may result in vasculogenic erectile dys- proximal corpora cavernosa and join to form cavernous
function (ED) after surgery.4,5 The internal pudendal artery and crural veins. These veins join the periurethral veins
becomes the common penile artery after giving off a branch to from the urethral bulb to form the internal pudendal
the perineum. The three branches of the penile artery are the veins.
dorsal, bulbourethral, and cavernous arteries. The cavernous
artery is responsible for tumescence of the corpus cavernosum
and the dorsal artery for engorgement of the glans penis during
erection. The bulbourethral artery supplies the bulb and corpus Lymphatics
spongiosum. The cavernous artery enters the corpus caverno-
sum at the hilum of the penis, where the two crura merge. Lymphatics of the prepuce and penile shaft converge dorsally,
Distally, the three branches join to form a vascular ring near and then drain into both right- and left-sided superficial ingui-
the glans. Along its course, the cavernous artery gives off many nal lymph nodes via channels alongside superficial external
helicine arteries, which supply the trabecular erectile tissue pudendal vessels. Lymphatics of the glans and penile urethra
and the sinusoids. These helicine arteries are contracted and pass deep to Buck’s fascia and drain into both superficial and
tortuous in the flaccid state and become dilated and straight deep inguinal nodes.
during erection.
The venous drainage from the three corpora originates in
tiny venules leading from the peripheral sinusoids immedi-
ately beneath the tunica albuginea (see Figure 4.2). These Innervation
venules travel in the trabeculae between the tunica and the
peripheral sinusoids to form the subtunical venular plexus The penis is supplied by both somatic and autonomic nerves.
before exiting as the emissary veins. Outside the tunica albug- The somatic dorsal nerves provide sensory innervation (as
inea, the venous drainage is as follows: well as provide some degree of autonomic function) for the
penile skin and glans, and approximately follow the course of
1. The skin and subcutaneous tissue drain through multiple the dorsal penile arteries, eventually becoming the pudendal
superficial veins that run subcutaneously and unite nerve (after joining with other nerves) and entering the spinal
near the root of the penis to form a single (or paired) cord via S2–S4 nerve roots. Sympathetic autonomic fibers
superficial dorsal vein, which in turn drains into the derive from the hypogastric plexus and join parasympathetic
saphenous veins. Occasionally, the superficial dorsal vein autonomic fibers from S2–S4 in the pelvic plexus. Cavernous
may also drain a portion of the corpora cavernosa. nerves represent the penile branches of the pelvic plexus that
2. In the pendulous penis, emissary veins from the corpus ramify once they have pierced the corporal bodies, and thus
cavernosum and spongiosum drain dorsally to the deep contain both sympathetic and parasympathetic fibers.
 Anatomy of erectile function 27

Internal pudendal artery Periprostatic Internal pudendal vein

piexus
Deep dorsal vein
Circumflex vein Cavernous vein

Cavernous
artery Bulbar vein
Bulbourethral Bulbourethral vein
artery
Circumflex artery
Dorsal artery Subtunical venous plexus
Retrocoronal
venous plexus

(a) (b)

Internal iliac vein

External
iliac vein

Internal
pudendal vein
Periprostatic plexus
Saphenous vein Crural vein
Superficial Cavernous vein
dorsal vein
Deep dorsal vein

Circumflex vein
Subtunical plexus

Emissary vein

Bulbourethral vein

(c)

Figure 4.2 Arterial and venous anatomy of the penis. (a) penile arterial supply; (b) penile venous drainage; (c) cross-sectional penile
and related pelvic venous drainage. With permission from Mulcahy JJ, ed. Male Sexual Function, 2nd edn. New Jersey: Humana,
2006.7

REFERENCES

1. Wessells H, Lue TF, McAninch JW. Penile length in the flaccid and 5. Kim ED, Blackburn D, McVary KT. Post-radical prostatectomy
erect states: guidelines for penile augmentation. J Urol 1996; 156: penile blood flow: assessment with color flow Doppler ultrasound.
995–7. J Urol 1994; 152: 2276–9.
2. Hsu GL, Brock G, Martinez-Pineiro L, et al. Anatomy and strength 6. Devine CJ, Jr, Angermeier KW. Anatomy of the penis and male
of the tunica albuginea: its relevance to penile prosthesis extrusion. perineum. Part 1. AUA Update Series, volume 13, lesson 2.
J Urol 1994; 151: 1205–8. Linthicum, MD: American Urological Association, 1994.
3. Breza J, Aboseif SR, Orvis BR, et al. Detailed anatomy of penile 7. Brant WO, Bella AJ, Garcia MM, Lue TF. Vascular surgery for erec-
neurovascular structures: surgical significance. J Urol 1989; 141: tile dysfunction. In: Mulcahy JJ, ed. Male Sexual Function. 2nd
437–43. edn. New Jersey: Humana, 2006; 419–34.
4. Aboseif S, Shinohara K, Breza J, et al. Role of penile vascular injury
in erectile dysfunction after radical prostatectomy. Br J Urol 1994;
73: 75–82.
5 Microscopic anatomy of erectile function
Anthony J Bella, William O Brant, and Tom F Lue

Introduction 150% of ‘resting’ length.4 Elastin content is also a key deter-

minant of stretched penile length.
Penile erection is dependent upon successful integration of The presence or absence of both tunical layers, the thick-
gross and microscopic aspects of neurovascular function, ness of the tunica itself and of the intracavernous pillars varies
culminating in the hemodynamic changes of tumescence. throughout the course of the penis, as does the histological
Recent progress in the understanding of physiologic mecha- composition, reflecting the relationship between anatomical
nisms responsible for erectile function has been accompanied ‘design’ and function. The strength and thickness of this layer
by the identification and characterization of key penile ultra- correlates with location, with the thinnest portion noted to be
structural components that are able to respond to various between the 5 o’clock and 7 o’clock positions.5 This coincides
stimuli or provide a physical framework for increased blood with the absence of the outer longitudinal layer at the ventral
flow to the corpora cavernosa and veno-occlusive trapping groove over the urethra; extrusion of penile prosthesis is most
that restricts outflow. In this chapter, the microscopic anat- common at this location.6 As the crura diverge proximally,
omy of the tunical fibroelastic skeleton of the penis, corpora circular fibers provide sole support. A higher elastin-to-collagen
cavernosa (supportive and smooth muscle components), and ratio, as well as the absence of the outer layer and struts, for
penile innervation and blood supply are reviewed in the the tunica overlying the corpus spongiosum ensures a low-
context of the erectile process. pressure structure during erection.7
The average thickness of the tunica is also seen to relate
to the stress forces applied to this structure prior to penetra-
tion (i.e. during rigid erection). The 0.8 ± 0.1mm thickness
Tunica albuginea between the 6 o’clock and 7 o’clock positions has associated
The primary function of the tunica albuginea is to afford forces of 1.6 ± 0.2 × 107 Newtons (N)/m2, there is 1.2 ± 0.2 mm
rigidity, flexibility, and tissue strength to the penis.1 It is a thickness at the 9 o’clock position, with 3.0 ± 0.3 × 107 N/m2,
bilayered covering of the corpora cavernosa with multiple and 2.2 ± 0.4 mm thickness at the 11 o’clock position, with
sublayers (Figure 5.1). The inner-layer bundles of the corpora 4.5 ± 0.5 × 107 N/m2 (mirror-image measures are nearly
cavernosa are circular, and serve to support and contain identical).5
the cavernous tissue. Furthermore, intracavernosal pillars In addition to providing a supportive framework to the
radiate from the inner layer into the corpora, acting as struts paired corpora, the tunica albuginea is essential to venous
to augment the penile septum and provide support to the trapping, and pathophysiological changes such as those seen
erectile tissues. The outer longitudinally oriented layer is with Peyronie’s disease may compromise this function and
composed of connective tissue bundles that extend from the lead to venous leak. The emissary veins, as described in
glans penis to the proximal crura, inserting on the inferior Chapter 4, travel between the inner and outer layers of the
pubic rami.2 tunica for short distances, and often pierce the outer bundles
The tunica itself is composed of elastic fibers that form an in an oblique manner (Figure 5.3).8 The outer longitudinal layer
irregular, latticed network on which the collagen fibers rest serves as a backboard, resulting in compression of the emis-
(Figure 5.2). This ultrastructural arrangement provides strength sary veins during penile engorgement and limiting the amount
and allows the tissue to return to its baseline configuration of penile blood that is able to drain away from the corpora
after the corporal expansion during erection. Key to this func- (Figures 5.4 and 5.5). The end-result is maintenance of an
tion is the composition and distribution of component fibers; erect penis. Inadequate venous occlusion may result in erectile
the tunica albuginea is primarily composed of type I, but also dysfunction (ED) via the following mechanisms:2
of type III, fibrillar collagen in organized arrays, throughout
which are interspersed elastin fibers.3 Both fiber types are • degenerative tunical changes secondary to Peyronie’s dis-
essential for normal function: the steel-like tensile strength of ease, aging, or diabetes, or secondary to traumatic injury
collagen is unyielding and resists uncontrolled deformity at impairing subtunical and emissary vein compression;
high pressure, while elastin content allows for tunical expan- • alteration in the fibroelastic components of the cavernous
sion because these fibers are able to stretch to approximately smooth muscle, trabeculae, or endothelium;

28
 Microscopic anatomy of erectile function 29

Figure 5.3 Emissary vein with subtunical venous plexus

(human penile cast). The cast was made by injecting blue
material into the corpus cavernosum and yellow material into
the deep dorsal vein. Skin and tunica albuginea were digested
away. Reproduced with permission from reference 2.

Corpora cavernosa ultrastructure,

the corpus spongiosum and the
glans penis
Figure 5.1 Structure of the tunica albuginea. The spongy corpora cavernosa are paired cylinders contained
within the supportive envelope of the tunica albuginea; located
on the dorsal aspect of the penis, the proximal ends (crura)
originate at the undersurface of the puboischial rami as two
separate structures and merge under the pubic arch, continu-
ing as a unit to the glans. Support for the corpora is provided
by a fibrous skeleton that includes the tunica albuginea, the
intracavernous pillars, the intracavernous fibrous network,
and the periarterial and perineural fibrous sheath.2 The midline
corporal septum is incomplete, allowing blood to flow from
one side to the other.
As with the tunica, cavernosal design reflects a functional
need for rigidity, strength, and flexibility. It has been sug-
gested that the intracavernous fibrous framework adds
strength to the tunica albuginea. Within the tunica are the
interconnected sinusoids separated by smooth muscle trabe-
culae and surrounded by collagen (predominantly types I
and IV), elastin, fibroblasts, and loose areolar tissue.9,10
Figure 5.2 Human tunica albuginea, demonstrating interwoven Smooth muscle predominates, accounting for 45% of corpo-
elastic fibers and fine collagen fibers. Reproduced with ral volume.11 Alterations of the cytoskeleton either for tissue
permission from reference 2. type components or for relative quantities may be respon-
sible for changes in penile morphology in flaccid and erect
states. For example, loss of compliance of the penile sinusoids
• inadequate cavernous smooth muscle relaxation; has been observed as a by-product of aging, and is associated
• acquired venous shunts; or with increased deposition of collagen; hypercholesterolemia-
• congenital anomalous large venous channels.1 induced dysregulation of collagen may also cause loss of
compliance.12
Inherent differences for the arterial system ensure that occlu- Terminal branches of the cavernous nerves and helicine
sion by the tunica albuginea does not occur during tumes- arteries are intimately associated with corporal smooth muscle;
cence; the cavernous artery and branches of the dorsal artery sinusoids are larger in the center and become progressively
traverse the outer layer in a more direct (perpendicular) smaller towards the periphery.2 Blood slowly diffuses from the
manner and are instead surrounded by a periarterial fibrous central to the peripheral sinusoids in the flaccid state, and the
sheath, limiting occlusive ability.3 blood gas levels are similar to those of venous blood. During
30 Textbook of Erectile Dysfunction

(a) (b)

Figure 5.4 (a) Microscopic changes during penile erection. In the flaccid state, the arteries, arterioles and sinusoids are contracted.
The inter-sinusoidal and subtunical venular plexuses are open, allowing free flow to the emissary veins. (b) Scanning electron
micrograph of canine subtunical venous plexus cast in flaccid state. Part (b) reproduced with permission from reference 2.

(a) (b)

Figure 5.5 (a) In the erect state, the muscles of the sinusoidal wall and the arterioles relax, allowing maximal flow to the compliant
sinusoidal spaces. Most of the venules are compressed between the expanding sinusoids. The larger intermediary venules are
sandwiched and flattened by distended sinusoids and the tunica albuginea; this effectively reduces the venous flow to a minimum.
(b) Scanning electron micrograph of canine subtunical venous plexus cast in erect state. Part (b) reproduced with permission from
reference 2.

erection, the oxygen tension approximates that of arterial of the tunica is absent. Intraspongiosal pressures reach only
blood due to the rapid entry of arterial blood to the central one-half to one-third of those of the cavernosa, owing to the
and peripheral sinusoids.13 less constraining tunical layer, resulting in lesser venous
Corporal geometry is a key characteristic that allows erec- occlusion.12 The glans itself has no tunical covering, but is able
tions to occur.14 Midline septal fibers stretch tautly between to engorge, owing to the presence of continued arterial inflow
the dorsal and ventral corporal aspects, creating a functional and venous outflow during erection (a functional arterio-
‘I-beam’, resulting in anteroposterior rigidity.7 Relative indis- venous fistula).2 Partial compression of the deep dorsal and
pensability of the paired lateral columns adds to stability circumflex veins between Buck’s fascia and the engorged
during erection, while intrasinusoidal pressures within the corpora cavernosa also contribute to glanular tumescence.
corpora distend the tunica albuginea to its maximal capacity.2 During the rigid erection phase, spongiosal and penile veins
The tunica itself resists out-of-column deformities. are externally compressed by the ischiocavernosus and bulbo-
The structure of the corpus spongiosum is similar to that of cavernosus muscles, further increasing engorgement and
the corpora except that sinusoids are larger and the outer layer pressure in the glans and spongiosum.
 Microscopic anatomy of erectile function 31

Cavernous smooth muscle

In the flaccid state, cavernous (or corporal) smooth muscle
is tonically contracted with a partial pressure of oxygen mea-
suring approximately 35 mmHg.13 Blood flow to the penis is
approximately 5 ml per minute.15 With sexual stimulation and
the release of neurotransmitters from the cavernous nerve
terminals (see Chapter 11) smooth muscle relaxation occurs,
and the end-result is an erect penis. Modulation of the caver-
nous smooth muscle tone is a complex process regulated by a
myriad of intracellular events and extracellular signals, and
therefore it is not surprising that the ultrastructure reflects
these physiologic functions.
Cavernous smooth muscle cells are composed of thin,
intermediate, and thick filaments, which are primarily com-
posed of, respectively, actin, desmin or vimentin, and myosin.3
In humans, two types of electrical activity have been reported
for the corpus cavernosum: spontaneous and activity-
induced.16 Further, DiSanto and associates have reported
overall composition to be in between that of aortic (tonic) and
bladder smooth muscle (phasic).17
Figure 5.6 Somatic and autonomic innervation of the penis.
Smooth muscle contraction and relaxation is primarily
regulated by sarcoplasma free calcium. Each of the filament
types has a specific role, but the primary mechanism is the
interaction between actin and myosin. Contractile tone is spinal cord; S3 is the primary source of erectogenic fibers.22
conferred by cross-bridges linking regulatory myosin light The cavernous nerves project from the pelvic plexus, leaving
chain globular heads and actin; tone is maintained with mini- the pelvis between the transverse perineal muscles and mem-
mal expenditure of energy.18 Relaxation occurs as cytosolic braneous urethra. Cadaveric dissection has identified medial
calcium is lowered. and lateral branches, which accompany the urethra and pierce
Smooth muscle fibers damaged by vasculogenic or neuro- the urogenital diaphragm 4 mm and 7 mm laterally to the
genic causes of impotence demonstrate similar ultrastructural sphincter, respectively, as well as multiple communications
changes, suggesting a variety of pathological mechanisms with between the cavernous and dorsal nerves.23 Since cavernous
common end-points.19 Patients undergoing implantation of a nerve damage during extirpative surgeries for prostate, blad-
penile prosthesis for ED of varying etiologies have been shown der, and rectal cancer commonly causes neurogenic ED, it is
to have a decreased number of smooth muscle cells and sinu- essential to understand their anatomic course. Preservation
soidal endothelial changes.2 The decreased oxygen tension of and minimal disruption of these nerves is paramount, because
arteriogenic ED may diminish trabecular smooth muscle con- they represent the final pathway for vasodilatory and vaso-
tent, leading to venous leakage. Hypercholesterolemic rabbits constrictive input to the cavernous smooth muscle; cavernous
demonstrate early atherosclerotic changes and significant nerve injury may also occur secondary to pelvic fracture, with
smooth muscle degeneration with loss of cell-to-cell contact.20 ED the end-result of direct nerve trauma, vascular insuffi-
Diabetes may compromise contractility, reduce cavernous ciency, or a combination of both.3 The cavernous nerve itself
smooth muscle content, thicken the basal lamina, increase divides into a lesser branch (supplying the corpus spongiosum
collagen, and cause the loss of endothelial cells.2 Cavernous erectile tissue and penile urethra) and a major branch (enabling
nerve injury at the time of radical prostatectomy may also penile erection). The major branch courses along the prosta-
decrease levels of cavernous smooth muscle while increasing tovesicular artery and veins as part of the neurovascular bundle
collagen content, compromising the erectile process.21 of the prostate.23,24 Key surgical landmarks are as follows.23,24

• After passing the tip of the seminal vesicle, the cavernous

Functional neuroanatomy nerve continues along the posterolateral aspect of the pros-
tate at the five o’clock and seven o’clock positions within
Penile innervation is both autonomic (sympathetic and para- the endopelvic fascia.
sympathetic) and somatic (sensory and motor). The cavernous • At the level of the prostatic apex and membranous urethra,
nerves are the primary influence on the neurovascular events the nerves are located at the three o’clock and nine o’clock
during erection and detumesence; they originate from neurons positions.
in the spinal cord and peripheral ganglia, and they consist of • Distally, some fibers penetrate the tunica albuginea of
sympathetic and parasympathetic fibers (Figure 5.6). Somatic the corpus spongiosum while the remaining fibers proceed
nerves fulfill sensory roles and contract the bulbocavernosus more anteriorly at the eleven o’clock and one o’clock
and ischiocavernosus musculature. positions. These enter the penile crura along with terminal
Parasympathetic fibers originate from the second, third, branches of the pudendal artery and exiting cavernous
and fourth sacral vertebral segments (S2, S3, and S4) of the veins.
32 Textbook of Erectile Dysfunction

Sympathetic preganglionic cavernous nerve fibers are prima- Intercellular communication

rily responsible for detumescence; these fibers arise from
preganglionic neurons in intermediolateral gray matter from Histological studies of the cavernosal tissues have demon-
the eleventh thoracic (T11) to the second lumbar (L2) spinal strated that autonomic innervation consists of widely spaced
cord segments. Variability in cavernous nerve composition nerve fibers. However, the process of penile erection and
(i.e. in the ratio of parasympathetic to sympathetic fibers), as detumescence requires a co-ordinating mechanism among
well as in sympathetic fiber origin (from as high as the ninth the cavernous smooth muscle fibers that allows synchronized
thoracic cord segment to as low as the fourth lumbar cord relaxation and contraction; electromyography confirms that
segment), has been described.7,25 These preganglionic fibers activity in the cavernous tissue of patients with normal erectile
most commonly arise from the tenth thoracic to the second function is synchronous.29,30
lumbar segments, passing to the paravertebral sympathetic Transport channels termed ‘gap junctions’ are present in
chain ganglia where synaptic connections with ganglion the membranes of adjacent cavernous smooth muscle cells,
cells are formed. Postganglionic fibers originating in the sacral allowing exchange of ions such as calcium and second messen-
and caudal lumbar ganglia proceed to the urogenital tract ger molecules.31 Electron microscopy demonstrates prominent
via the cavernous nerves as well as via the pelvic and puden- gap junctions, which are formed by a hemichannel hexamer
dal nerves. A second pathway for sympathetic preganglionic of connexin proteins, creating pore-like aqueous intercellular
fibers occurs without lumbar synaptic contacts; fibers leave channels.2,3 The major component of gap junctions is
the chain ganglia and pass along the lumbar splanchnic nerves connexin-43, a membrane-sparing protein of less than 0.25 µm
to prevertebral ganglia in the superior hypogastric plexus that has been identified between smooth muscle cells of human
(overlying the great vessels at the third lumbar to first sacral corpus cavernosum and that facilitates the transmission of
vertebrae).3 The superior hypogastric plexus (or presacral electrical or chemical signals.32 Cell-to-cell myocyte commu-
nerve) divides into the left and right hypogastric nerves, nication does not occur via individualized innervation, rather
descending to the inferior hypogastric (or pelvic) plexus. In via gap junction links that allow synchronized smooth muscle
addition to their role in the erectile process, sympathetic tone. These connections have been shown to modulate nitric-
fibers from T11–L2 are also responsible for contraction oxide-induced cavernous smooth muscle relaxation, as well as
of internal accessory organs (prostate smooth muscle, semi- alpha-1-adrenergic- and enthothelin-1-induced contractility.
nal vesicle, and bulbourethral gland), ducts (ejaculatory Although their pathophysiological impact is not fully eluci-
ducts, vasa deferentia, ductus epididymis, ductuli efferentes), dated, connexin-43 expression in cavernous tissues excised
closure of the internal urethral sphincter, and ejaculatory from men with organic erectile dysfunction demonstrates
emission.2,3,7 significant heterogeneity.3 For example, in men with severe
Sensory (somatic) function of the glans is unique, in that arterial disease, a loss or reduction of membrane contact has
80–90% of afferent glans terminals are unmyelinated C or been demonstrated as the presence of collagen fibers between
myelinated A-δ fiber-free nerve endings.26 Sensory pathways cellular membranes alters the co-ordinated smooth muscle
also originate at receptors found within the penile skin, ure- response to erectile stimulus.33
thra and corpus cavernosum, with nerve fibers from these
receptors converging to form bundles of the dorsal nerve of
the penis. The dorsal nerve joins other nerves to become the Arterial microanatomy of the penis
internal pudendal nerve, entering the spinal cord at the dorsal
roots of S2–S4 to terminate in the central gray region of the The majority of the arterial supply to the erectile tissue is via
lumbosacral segment.2 Spinothalamic and spinoreticular path- the cavernosal artery, which itself is a branch of the internal
ways to the thalamus and sensory cortex convey messages of pudendal artery (the terminal branch of the hypogastric
pain, temperature, and touch via the dorsal and pudendal artery) (Figure 5.7). The cavernosal artery extends through
nerves. Afferent input from the skin and glans is also the the cavernosal bodies after entering at the inferomedial aspect
mechanism responsible for reflexogenic erections. It is impor- of the hilum of the penis where the crura merge, piercing the
tant to note that the dorsal nerve of the penis is not purely tunica. At the base of the penis the cavernosal arteries are close
somatic, but also contains nerve bundles demonstrating nitric to the septum, whereas distally they are centrally located in
oxide synthase, which is indicative of autonomic function, each cavernosal body. Two types of branches occur: outer
therefore providing evidence for a dual role (erectile and capillaries, which provide nutrition during flaccidity, supply-
ejaculatory function).27 ing the nerve fibers and smooth muscle; and multiple helicine
The center of somatomotor penile innervation is Onuf’s branches, which supply the erectile tissue, opening directly
nucleus in S2–S4. The motor pathway to the penis traverses into the cavernous spaces without entering capillaries and
the sacral nerves to the pudendal nerve, innervating the bulbo- then emptying into postcavernous venules (Figure 5.8). The
cavernosus muscle (rhythmic contraction of ejaculation) and helicine arteries appear tortuous and contracted when the
ischiocavernosus muscle (contraction results in the rigid penis is flaccid, becoming straight and larger in caliber during
erection phase) via the perineal branch. The pudendal nerve erection. The corkscrew-like shape ensures that flow is not
leaves the pelvis via the greater sciatic foramen on the medial compromised, allowing for elongation and dilatation. These
aspect of the internal pudendal artery; it continues as the arteries are surrounded by multiple layers of smooth muscle,
dorsal nerve of the penis along the dorsal artery, terminating which remains contracted during the non-erect state (allow-
at the glans.28 ing only small quantities of blood into the lacunar spaces).2,3,7
 Microscopic anatomy of erectile function 33

perineum into the dorsal artery of the penis and the

bulbourethral artery. These vessels form a vascular ring near
the glans; the paired dorsal arteries course within the neuro-
vascular bundles at the eleven o’clock and one o’clock posi-
tions, lateral to the dorsal vein and medial to the dorsal nerves.
The dorsal arteries supply the more superficial components of
the penis; they supply the spongiosum distally via circumflex
branches; they provide frenular branches; and they may con-
tribute to the blood supply of the erectile bodies.2 They are
also responsible for glans engorgement during erection. The
bulbourethral artery continues as the urethral artery after its
bulbar offshoot, coursing along the ventral surface of the cor-
pus spongiosum beneath the tunica albuginea. Of note, given
the blood supply to the glans, it can be completely separated
from the corpora cavernosa during surgery without compro-
mising vascularization.
Decreased perfusion pressure and arterial flow to sinusoi-
dal spaces may occur, owing to atherosclerotic or traumatic
arterial occlusive disease of the hypogastric–cavernous–
Figure 5.7 Arterial supply of the penis. helicine arterial tree; clinically, arterial disease may manifest
itself as an increased time to maximal erection or as decreased
rigidity. As the number of vascular risk factors increases (e.g.
hypertension, hyperlipidemia, diabetes, and cigarette smoking),
the occurrence of atherosclerotic lesions of the internal
pudendal, common penile, and cavernous arteries increases
significantly.36 On the other hand, a focal stenosis of the com-
mon penile or caverous artery is most often seen in young
patients who have sustained blunt perineal or pelvic trauma.37
Thus, both generalized and focal arterial disease may manifest
itself as erectile dysfunction.

Conclusion
The microanatomy of erectile function reflects the physio-
logical changes necessary for the human penis to attain an
erect state. Erection is dependent upon intact innervation and
arterial supply, as well as on a normal cavernous smooth muscle
response to stimuli and an efficient veno-occlusive trapping
mechanism. During erection, the relaxation of smooth muscle
in the cavernous trabeculae and arterial walls facilitates the
complex cascade responsible for penile rigidity:12

1. Increased penile blood flow caused by dilation of arterioles

and arteries.
Figure 5.8 Venous drainage of the penis. 2. Expansion of sinusoids and resultant trapping of blood.
3. Compression of subtunical venous plexuses between
the tunica albuginea and peripheral sinusoids, reducing
venous outflow.
It is not uncommon for the erectile tissue to be primarily 4. Tunica albuginea expansion, further decreasing venous
supplied by accessory arteries, such as the accessory pudendal outflow as emissary veins are occluded between inner
artery. In fact, the dominant blood supply to the corpora circular and outer longitudinal layers.
may arise from the external iliac, obturator, vesical or femoral 5. Intracavernous pressure increase to approximately
arteries, or even derive exclusively from a single (unilateral) 100 mmHg (full erection phase).
cavernous or accessory pudendal artery.34 Careful preservation 6. Ischiocavernous muscle contraction, which further
during radical prostatectomy is suggested for the accessory increases intracavernous pressures to several hundred
pudendal vessels, as this maneuver has been shown to protect, mmHg (rigid erection phase).
and hasten the recovery of, sexual function.35
In addition to the cavernosal artery, the common penile Detumescence occurs as gradual smooth muscle contraction
branch of the internal pudendal artery branches in the anterior against a closed venous system causes a transient increase in
34 Textbook of Erectile Dysfunction

intracavernous pressure, followed by a slow pressure decrease Whether isolated to a single element of penile microscopic
as venous channels open with a resumption of basal arterial anatomy or occurring on more than one tissue level, pathologic
flow, and, finally, a rapid pressure decrease with fully restored structural changes may compromise the physiologic processes
capacity for venous outflow. that lead to penile erection, and so result in erectile dysfunction.

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structure of the human tunica albuginea: anatomical and ultra- the norm for radical prostatectomy patients. J Sex Med 2007; 4:
structural levels. Int J Impot Res 1992; 4: 117–29. 538–43.
2. Lue TF. Physiology of penile erection and pathophysiology of erec- 22. Lue TF, Zeineh SJ, Schmidt RA, Tanagho EA. Neuroanatomy of
tile dysfunction. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, penile erection: its relevance to iatrogenic impotence. J Urol 1984;
Peters CA, eds. Campbell–Walsh Urology, 9th edn. Philadelphia: 131: 273–80.
Saunders Elsevier, 2007: 718–49. 23. Paick JS, Donatucci CF, Lue TF. Anatomy of cavernous nerves
3. Milhoua P, Lowe D, Melman A. Normal anatomy and physiology. distal to prostate: microdissection study in adult male cadavers.
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4. Brock G, Hsu GL, Nunes L, von Heyden B, Lue TF. The anatomy localization of the autonomic nerves from the pelvic plexus to the
of the tunica albuginea in the normal penis and Peyronie’s disease. corpora cavernosa: a detailed anatomical study of the adult male
J Urol 1997; 157: 276–81. pelvis. J Urol 1985; 133: 207–12.
5. Hsu GL, Brock G, von Heyden B, et al. The distribution of 25. de Groat WC, Steers WD. Neuroanatomy and neurophysiology of
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73: 566–71. porary management of impotence and infertility. Williams and
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J Urol 1994; 151: 1205–8. pathic sensibility of the human glans penis. Brain Res 1986; 371:
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Rosen R, et al., eds. Sexual Medicine: Sexual Dysfunctions in Men localization of nitric oxide synthase in the autonomic innervation
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8. Lue TF. Erectile dysfunction. N Engl J Med 2000; 342: 1802–13. 28. Yang CC, Bradley WE. Peripheral distribution of the human dorsal
9. Luangkhot R, Rutchik S, Agarwal V, et al. Collagen alterations in nerve of the penis. J Urol 1998; 159: 1912–17.
the corpus cavernosum of men with sexual dysfunction. J Urol 29. Christ GJ, Moreno AP, Parker ME, et al. Intercellular communica-
1992; 148: 467–71. tion through gap junctions: a potential role in pharmacomechani-
10. Goldstein AM, Padma-Nathan H. The microarchitecture of the cal coupling and syncytial tissue contraction in vascular smooth
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J Urol 1990; 144: 1144–6. 49: PL195–200.
11. Wespes E, Goes PM, Schiffman S, Depierreux M, Vander Haeghen 30. Steif CG, Djamilian M, Anton P, et al. Single potential analysis
JJ. Computerized analysis of smooth muscle fibers in potent and of cavernous electrical activity in impotent patients: a possible
impotent patients. J Urol 1991; 146: 1015–17. diagnostic method for autonomic cavernous dysfunction and
12. Nitahara KS, Lue TF. Microscopic anatomy of the penis. In: cavernous smooth muscle degeneration. J Urol 1992; 148:
Carson C, Kirby R, Goldstein I, eds. Textbook of Erectile Dysfunc- 1437–40.
tion. ISIS Medical Media: Oxford, 1999: 31–41. 31. Christ GJ, Moreno AP, Melman A, Spray DC. Gap junction
13. Sattar AA, Salpigides G, Vander Haeghan JJ, Schulman CC, Wespes E. mediated intercellular diffusion of Ca2+ in cultured human
Cavernous oxygen tension and smooth muscle fibers: relation and corporal smooth muscle cells. Am J Physiol 1992; 263:
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14. Luo H, Goldstein I, Udelson D. A three-dimensional theoretical 32. Campos de Calvalho AC, Roy C, Moreno AP, et al. Gap junctions
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Neurol 1992; 12: 87–97. penile ultrastructure with clinical arterial evaluation. J Urol 1989;
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electromyogram: spontaneous and evoked electrical activities. J 34. Droupy S, Benoit G, Giuliano F, Jardin A. Penile arteries in
Urol 1995; 153: 653–64. humans. Origins–distribution–variations. Surg Radiol Anat 1997;
17. DiSanto ME, Wang Z, Menon C, et al. Expression of myosin iso- 19: 161–7.
forms in smooth muscle cells in the corpus cavernosum penis. Am 35. Secin FP, Touijer K, Mulhall J, Guillonneau B. Anatomy and pres-
J Physiol 1998; 275: C976–87. ervation of accessory pudendal arteries in laparoscopic radical
18. Hai CM, Murphy RA. Crossbridge phosphorylation and regulation of prostatectomy. Eur Urol 2007; 51: 1229–35.
the latch state in smooth muscle. Am J Physiol 1998; 255: C86–94. 36. Shabsigh R, Fishman IJ, Schum C, Dunn JK. Cigarette smoking and
19. Mersdorf A, Goldsmith PC, Deiderichs W, et al. Ultrastructural other vascular risk factors in vasculogenic impotence. Urology
changes in impotent penile tissue: a comparison of 65 patients. 1991; 38: 227–31.
J Urol 1991; 145: 749–58. 37. Levine FJ, Greenfield AJ, Goldstein I. Arteriographically deter-
20. Junemann KP, Aufenanger J, Konrad T, et al. The effect of impaired mined occlusive disease within the hypogastric-cavernous bed in
lipid metabolism on the smooth muscle cells of rabbits. Urol Res impotent patients following blunt perineal and pelvic trauma. J
1991; 19: 271–5. Urol 1990; 144: 1147–53.
6 Vascular physiology of erectile function
Noel N Kim

Introduction Thus, changes in smooth muscle tone are crucial for regu-
lating erectile function. In that regard, continuing research to
The previous chapters on penile anatomy emphasize the elucidate the myriad of mechanisms that regulates vascular
importance of the vasculature in mediating erectile function. smooth muscle cell (VSMC) contractility is essential to under-
The penile corpora cavernosa are highly specialized vascular standing erectile physiology. The basic paradigm of smooth
structures that are uniquely suited to their function of becom- muscle, endothelium, and nerve interactions to influence
ing engorged during sexual arousal. In addition, the network vascular reactivity is universally acknowledged, but warrants
of resistance arterioles that carry blood to the corpora caver- more detailed consideration within the context of genital
nosa plays an equally important role in determining the state tissues. This chapter describes the basic mechanisms that
of penile engorgement. In the non-aroused, flaccid state, the regulate VSMC contractility, including additional consider-
arterial and trabecular smooth muscle remain constricted, ation of non-contractile responses in VSMCs. However, dis-
and the hemodynamic environment of the corpora cavernosa cussion of specific neurotransmitters, receptor pharmacology,
is similar to the venous circulation in terms of pressure, flow, and regulation of extracellular matrix by smooth muscle have
and oxygen tension. There is low resistance to the drainage of been omitted, since these are addressed elsewhere in this book.
blood from the cavernosal bodies, and this contributes to the While much of the information specific to genital tissue
maintenance of penile flaccidity. vascular physiology is derived from studies on penile corpus
The onset and maintenance of penile tumescence is initiated cavernosum, findings from cardiovascular research will also
by central psychogenic or peripheral reflexogenic sensory be presented to gain further insight into VSMC function.
stimuli (or both), as described in greater detail in the following
chapters. Both central and peripheral pathways stimulate
sacral parasympathetic efferent nerve fibers, which ultimately
cause the relaxation of the vascular smooth muscle in the Endothelium: an active regulator of
resistance arterial bed and the trabeculae of the corpora vascular function
cavernosa. These events result in a higher rate of blood flow
into the penis, and greatly increase the compliance of the The endothelium consists of a monolayer of cells that forms a
cavernosal bodies, enabling expansion and accommodation of continuous surface, lining the vascular compartment through-
the increased blood volume within the cavernosal lacunae. out the body. The total mass of the endothelium has been
The increased blood flow also potentiates local vasodilation estimated to be 500 g in the average adult human, the majority
through endothelial shear stress-induced responses. During of which is contained in the pulmonary vasculature.1 Much
this early filling phase, the hemodynamic environment within like skin, the endothelium may be considered a single organ
the erectile tissues transitions into an arterial system with with multiple functions and differential responses that are
respect to blood flow and oxygen tension. However, blood dependent upon both the systemic and local environments.
pressure remains low. Among other functions, a healthy endothelium serves to
The rapid volume expansion of the erectile tissue leads to provide an anti-thrombotic, anti-inflammatory, and anti-
engagement of the veno-occlusive mechanism, reducing the atherogenic surface while also regulating vascular tone and
outflow of blood. The restriction of blood drainage is accom- permeability. The importance of endothelial regulation can
plished by elongation and compression of the subtunical be better appreciated by considering pathological states that
venules that are located between the corpora cavernosa and have in common dysfunctional endothelium. Endothelium-
the tunica albuginea. Veno-occlusion enables the trapping of dependent relaxation of blood vessels has been shown to be
blood within the cavernosal sinusoids and causes the intra- compromised in animal models of atherosclerosis, hyperten-
cavernosal pressure to rise to systemic arterial levels. As the sion, diabetes, aging, smoking, and renal failure.1–4 Thus, dis-
pressure gradient between the systemic arterial circulation eased or damaged endothelium has been proposed to be a
and the intracavernosal vascular compartment is dissipated, major contributor to vascular insufficiency of genital tissues.
blood flow decreases. Altogether, these events act in concert to The endothelium produces many vasoactive compounds
achieve and maintain full tumescence and rigidity. that can influence the contractile, trophic, or synthetic function

35
36 Textbook of Erectile Dysfunction

of vascular smooth muscle cells. Factors that cause relaxation trabecular bundle is limited to several cell layers. Given this
include nitric oxide (NO), carbon monoxide, endothelium- arrangement, intercellular communication, for the purpose of
derived hyperpolarizing factor, prostacyclin and endothelin regulating smooth muscle tone in a co-ordinated fashion, can
(through ETB receptors). Factors that cause contraction be accomplished by two general mechanisms:
include endoperoxides, thromboxane A2, superoxide anions,
and endothelin (through ETA receptors). One of the more • extracellular diffusion of vasoactive and trophic factors
novel mechanisms of regulating endothelial signaling involves released by endothelium, nerves and smooth muscle (para-
changes in the number of caveolae on the surface of endo- crine and autocrine regulation); and
thelial cells. Caveolae are invaginated microdomains of plasma • intracellular diffusion of second messengers from stimu-
membrane that are rich in endothelial NO synthase and con- lated cells into adjacent cells by means of gap junctions.
tain the family of transmembrane structural proteins known
as caveolins, as well as cholesterol, sphingolipids, and glycosyl These mechanisms are not mutually exclusive and it is likely
phosphatidyl inositol-linked proteins. In addition, caveolae that they act in complementary fashion to propagate regula-
contain numerous other signaling proteins, such as receptors tory signals.
with seven-transmembrane domains, G proteins, adenylyl Extracellular diffusion of regulatory substances requires
cyclase, phospholipase C, protein kinase C, calcium pumps, sufficient concentrations to be secreted near a population of
and calcium channels. Thus, these specialized signaling regions effector cells. The magnitude of the response is determined by
have been termed transductosomes.5 the number of cells directly stimulated by the secreted sub-
stance. In contrast, intracellular propagation of signals across
multiple cells through gap junctions does not require each
Multiple functions of vascular responding cell to be activated by the initial stimulus. A single
cell may be stimulated by a secreted substance and generate
smooth muscle second messengers that can diffuse into neighboring cells. In
this mechanism, the magnitude of response is directly pro-
As a major constituent and primary effector of the vascular
portional to the number of cells activated by the spread of
structures in the genitals, the VSMC is highly adaptable and
intracellular messengers, rather than the number of cells
multi-functional. The two primary functions of VSMCs are
directly stimulated by the secreted substance.
contraction and synthesis or maintenance of extracellular
The structure and function of gap junctions in the vascula-
matrix. In cell culture experiments, VSMCs have been charac-
ture have been studied for the past several decades. VSMCs
terized as having either ‘contractile’ or ‘synthetic’ functional
and endothelial cells are known to form functional syncytia by
phenotypes. However, these two categories are considered to
virtue of junctional plaques in their plasma membranes.9,10
be extremes that are manifested under in vitro conditions,
These plaques contain hundreds to thousands of gap junction
and it is likely that a range of intermediary phenotypes exist
complexes. The diameters of plaques between VSMCs range
in any given tissue in vivo. Increasingly, protein and gene
from 0.2 µm to 0.5 µm, whereas those between endothelial
expression studies are illustrating the ability of VSMCs to alter
cells have been observed to be up to twice as large.9 The area of
their cellular phenotypes in response to changes in their
each junctional plaque may be important in determining the
environment.6,7 In addition, studies by developmental biolo-
rate of signal propagation. Each gap junction channel is
gists indicate that VSMCs in different vascular beds may arise
formed by the docking of two hemi-channels, each hemi-
from varying cellular lineages (multiple sources of progenitor
channel being contributed by an opposing cell. Hemi-chan-
cells) and can be recruited from different locations in the
nels are hexameric structures formed from connexins, a large
developing embryo.8 Furthermore, comparative studies have
family of proteins derived from multiple genes.11 VSMCs have
led investigators to speculate that lineage-specific differences
been shown to express connexin (Cx) 40 and Cx43, whereas
in VSMC growth and transcriptional responses may persist
endothelial cells express Cx37 in addition to Cx40 and Cx43.9
beyond the early developmental period and into the adult
Cx proteins apparently have relatively short half-lives with esti-
organism.8 It remains unclear as to what extent the observed
mated cycling times of 1–5 hours.10 This suggests that junctional
heterogeneity of VSMCs is due to adaptation in altered cellu-
plaques are highly dynamic structures that may have the ability
lar environments as opposed to differences in lineage. The
to attenuate or potentiate smooth muscle responses.
apparent mosaic nature of smooth muscle throughout the
While the role of most connexins has not been studied in
body may account for some of the diversity in responses found
genital tissues, the expression of Cx43 has been confirmed in
in different vascular tissues in health and disease. Nevertheless,
smooth muscle and endothelial cells derived from human
most VSMCs in peripheral blood vessels are derived from the
penile corpus cavernosum.9,10 Furthermore, functional and
mesoderm and exhibit a set of common characteristics.
pharmacological studies suggest that they play an important
role in signal propagation.12 In studies using non-genital
tissues, junctional plaques between endothelial and smooth
Co-ordinated regulation of vascular muscle cells have been observed.13,14 However, the presence of
smooth muscle cells these ‘myoendothelial’ gap junctions has not been studied in
genital tissues and their significance remains unclear. Thus,
Most VSMCs in blood vessels and in cavernosal tissues are gap junctions enable smooth muscle and endothelial cells to
not adjacent to, or in direct contact with, an endothelial cell form a continuous network of functional units. These cellular
or nerve terminus. However, the thickness of any arteriole or networks can rapidly co-ordinate the response to various
 Vascular physiology of erectile function 37

stimuli that may not be homogeneously distributed through- oriented in opposite directions on either side of the M-line
out the tissue. within the sarcomere. Actin filaments are composed of two
long strands of globular actin that intertwine into a double
helical arrangement. While troponins are absent in smooth
Mechanism of smooth muscle, other regulatory proteins such as caldesmon and
calponin are known to be associated with actin. The potential
muscle contraction roles of these proteins are discussed below, after a brief
Generation of force by VSMCs is ultimately determined by presentation of the cross-bridge cycle.
the interaction between myosin cross-bridges and actin
filaments.15–17 Numerous dense bodies consisting of alpha- The cross-bridge cycle and the central role of calcium
actinin are distributed throughout the smooth muscle cell,
The contractile response of the smooth muscle cell is tightly
either in the cytoplasm or associated with the plasma mem-
associated with the intracellular concentration of free calcium.
brane. Analogous to the Z-disk structures in striated muscle,
However, intracellular calcium regulates the contractile appa-
dense bodies provide points of anchorage for actin filaments
ratus in an indirect manner through the regulatory protein
and are themselves stabilized by a network of intermediate
calmodulin, which has the capacity to bind four calcium
filaments that are composed of desmin and vimentin. Unlike
ions. Calcium-bound calmodulin undergoes a conformational
striated muscle, the molecular contractile units of interdigi-
change and thereby increases its affinity for myosin light chain
tating actin (thin) filaments and myosin (thick) filaments are
kinase (MLCK) and activates it. Calmodulin-activated MLCK
not regularly aligned with one another and can be oriented in
then phosphorylates the serine-19 residue of MLC20. In the
multiple directions.
presence of ATP, this phosphorylation enables actin to activate
Smooth muscle myosin is a large hexameric protein, con-
the myosin ATPase and initiates cross-bridge cycling. Crystal
sisting of two heavy chains and four light chains. The heavy
structure studies of myosin complexed to analogs of ATP and
chains are identical and have both globular and linear domains.
the ATP–ADP transition state suggest that a single power stroke
The linear domains contain the C-termini and form coiled-
can achieve approximately 10 nm of linear displacement.19
coil structures that result in the ‘tail’ of the myosin molecule,
Beginning with a state in which myosin cross-bridges are
while the globular domains contain the N-termini and possess
bound to actin with high affinity in the absence of ATP, one
actin-binding sites and ATP catalytic activity (ATPase). These
complete cycle consists of the following events (Figure 6.2):
globular heads of the myosin molecule form the cross-bridges
of the contractile apparatus. The four light chains in myosin 1. Phosphorylation of MLC20 by calcium–calmodulin–
consist of two essential light chains that have a molecular MLCK complex activates myosin ATPase
weight of 17 kD each (ELC17) and two regulatory light chains 2. ATP binds the globular head of myosin and causes it to
that have a molecular weight of 20 kD each (MLC20). One dissociate from the actin filament, changing the cross-
essential and one regulatory light chain is associated with each bridge angle to prepare for the power stroke
globular head in myosin. In smooth muscle, myosin mole- 3. In this dissociated state, myosin hydrolyzes ATP and
cules self-associate into a side-polar arrangement in which the rebinds with actin in a low affinity state
globular heads protrude in a linear array on two opposing 4. Release of the hydrolyzed inorganic phosphate increases
sides of the thick filament.18 On any given side, the globular the affinity of myosin for actin and generates the power
heads are oriented in the same direction, but anti-parallel to stroke of the globular myosin head, shortening the
those on the opposite side (Figure 6.1). contractile apparatus
This is in contrast to skeletal muscle myosin, which has a 5. Dissociation of ADP from myosin enables another
bipolar helical arrangement, in which the globular heads pro- molecule of ATP to bind the myosin cross-bridge and
trude in a helical pattern around the thick filament and are continue onto a second cycle.
This series of events continues until MLC20 is dephosphory-
Side polar Bipolar helical lated by myosin light chain phosphatase (MLCP). Assuming
(smooth muscle) (striated muscle) that energy stores are not limiting, maintenance of high intra-
cellular calcium concentrations ensures that MLCK remains
active and perpetuates cross-bridge cycling.

Molecules regulating the contractile apparatus

Myosin light chain phosphatase and Rho-kinase
At any given level of intracellular calcium, the contractile
apparatus may become further sensitized by the inhibition
of MLCP, such that the rate of myosin dephosphorylation
(inactivation) is reduced and the action of MLCK becomes
more efficient. Thus, modulation of MLCP activity is thought
to be important for regulating smooth muscle contraction.
MLCP is a holoenzyme consisting of a type 1 phosphatase
Figure 6.1 Structure of myosin. (PP1c-delta), a myosin-targeting subunit (MYPT-1 – also
38 Textbook of Erectile Dysfunction

Actin
Calcium–CaM
ADP
MLCP MLC20 MLCK

Myosin ELC

ADP
ADP
High-
affinity P P

ATP
Pi Power
stroke

ADP-P
Low- ATP
affinity P P

ADP-P
Calponin
MLCP ? Latch
Pi (High-affinity,
slow-release)

Figure 6.2 Mechanism of smooth muscle contraction. MLCP, myosin light chain phosphatase; MLCK, myosin light chain kinase;
ELC, essential light chain (of myosin); MLC20, myosin light chain with a molecular weight of 20 kD; CaM, calmodulin, Pi, inorganic
phosphate.

called myosin binding subunit, MBS), and a 20 kD subunit of actin-associated molecules remains controversial, ignoring
unknown function.20,21 The activity of MLCP can be modu- these potential regulatory mechanisms reduces our under-
lated by a variety of factors. Two of the better-recognized standing of the contractile apparatus to an oversimplification.
mechanisms involve both direct and indirect effects of Rho– Both caldesmon and calponin have the ability to bind actin
Rho-kinase pathway. Rho proteins are small GTPases classified and myosin and can inhibit myosin ATPase activity to suppress
as a subgroup of the Ras superfamily; they can be activated development of smooth muscle tone.16,27 Studies examining
by the binding of agonists to G protein-coupled receptors.22 protein interactions also suggest that calponin may facilitate
Activated Rho can in turn activate Rho-kinase, a serine– agonist-induced signal transduction by facilitating protein
threonine kinase. Rho-kinase can then phosphorylate multi- kinase C activation in the plasma membrane.27 Furthermore,
ple substrates including MYPT1, the 17 kD protein kinase calponin may mediate the targeting of extracellular regulated
C-potentiated inhibitor protein (CPI-17), and MLC20.22 Phos- kinase and protein kinase C to the plasma membrane. Lastly,
phorylation of MYPT-1 and CPI-17 results in the inhibition tropomyosin is intimately associated with actin filaments,
of PP1c-delta phosphatase activity, whereas phosphorylation forming a continuous strand made of coiled coil monomers.
of MLC20 would stimulate activation of myosin. The RhoA– In the absence of troponins, smooth muscle tropomyosin
Rho-kinase pathway and its effects on MLCP have been shown appears to participate in co-operative interactions between
to play an important role in regulating smooth muscle con- actin and myosin, as well as with caldesmon. Thus, through
tractility in both male and female genital smooth muscle.23–26 changes in their associations between actin and myosin and
The presence of CPI-17 protein has been detected in human other key signaling molecules, calponin, caldesmon, and tro-
and rabbit penile corpus cavernosum,23 but its functional sig- pomyosin may regulate cross-bridge cycling and VSMC tone
nificance remains to be determined. in a manner that could not be accomplished by calcium
alone.
Actin-associated proteins
In as much as myosin may be considered the molecular motor Latch: a unique characteristic of vascular smooth
that mediates contraction, experimental evidence suggests muscle cell contraction
that cross-bridge cycling rates and tension development in A hallmark of smooth muscle function is its ability to maintain
smooth muscle are not necessarily proportional to MLC20 tension for prolonged periods without a correspondingly high
phosphorylation.16,27 These discrepancies are partially attribut- consumption of energy. Thus, the rate of ATP hydrolysis is
able to the presence of other proteins associated with actin not proportional to the number of myosin heads engaged in
that may regulate myosin–actin interactions. Included in this generating force. This efficiency in maintenance of tone has
list of proteins are caldesmon, calponin, and tropomyosin. been termed the latch state, and is critical for sustaining the
While much of the experimental evidence regarding these ‘basal’ non-aroused state in genital tissues, which requires the
 Vascular physiology of erectile function 39

smooth muscle to remain contracted for most of the time. Signal transduction pathways
The mechanism by which VSMCs can achieve latch remains
unknown. However, decreased MLC20 phosphorylation and regulating vascular smooth muscle
low myosin ATPase activity have been associated with latch.15 cell tone
In addition, after attaining the latch state, mammalian smooth
muscle is not able to redevelop force when cross-bridges are sub- Pathways that regulate smooth muscle contractility ultimately
jected to a quick release by the addition of ATP in the absence of influence intracellular calcium levels or alter the calcium
calcium. These data suggest that the latch state results from a sensitivity of the contractile proteins (Figures 6.3 and 6.4).
decrease in the rate of cross-bridge detachment from the actin Thus, vasoactive substances, via pharmacomechanical coupling
filament. Under normal physiological conditions, ATP availabi- (contraction or relaxation in the absence of membrane potential
lity is not restricted and any dephosphorylated myosin bound to changes), or changes in cell membrane potential, via electro-
actin in the high-affinity state would quickly bind ATP and dis- mechanical coupling, can change intracellular calcium con-
sociate from the actin filament. Thus, this mechanism could not centrations, which regulate the contractile apparatus, as
account for a slow rate of cross-bridge detachment. For these described previously. However, intracellular calcium concentra-
reasons, it has been proposed that dephosphorylated myosin tions need not change for contraction or relaxation to occur if
remains bound to actin in the high-affinity state while still the sensitivity of the contractile apparatus to calcium is
binding ADP. This type of interaction could also facilitate co- changed. This additional mode of calcium-independent regu-
operative attachment of non-phosphorylated myosin to actin to lation can result in sensitization through inactivation of MLCP
help to stabilize the latch state. Recently, it has been proposed or desensitization through the inactivation of MLCK. Both
that calponin participates in the latch state by simultaneously phosphatase and kinase activity can be inhibited by phospho-
binding actin and myosin to stabilize cross-bridge interactions rylation events (e.g. phosphorylation of MLCP by Rho-kinase).
and slow the rate of detachment.28 In general, most vasoactive substances exert their effects

Contractile
agonist
Calcium
ROC
Calcium PIP2 L-Type calcium
channel Sodium
SOC alphaq PLC-
DAG Calcium
Gq beta
Calcium
Calcium MLCK-like NSCC
IP3
kinase? Sodium
Calcium
CaM SERCA Depol.
PLmb PKC
(inhibited) IP3R
Calcium
Calcium
SER
CaM
ERK
MLCK L-type
MLCK
Calcium calcium
channel
PIP3
AM-P Contraction

PI3K-
AM PIP2
G gamma
Calcium
Beta-
alpha
Contractile MLCP MLCP-P alpha
Rh
agonist o (inactive)
Rho-kinase G

Contractile
agonist

Figure 6.3 Signal transduction pathways regulating smooth muscle contraction. Gray arrows indicate association, binding, or
activation, whereas the clear arrow from “Rho-kinase“ indicates inhibitory regulation. Indirect or putative interactions are indicated
by dashed arrows. Alpha, alpha subunit of GTP-binding protein; alphaq, alpha subunit of Gq; beta-gamma, beta and gamma subunits
of GTP-binding protein; AM, actin-myosin contractile apparatus; CaM, calmodulin; DAG, 1,2-diacylglycerol; ERK, extracellular
regulated kinase; Gi GTP-binding protein; Gq, q family of GTP-binding proteins; IP3, inositol 1,4,5-trisphosphate; IP3R, IP3 receptor;
MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; NSCC, non-specific cation channel; PIP2, phosphatidylinositol
4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLC-beta,
phospholipase C-beta; PLmb, phospholamban; ROC, receptor-operated channel; SOC, store-operated channel; SER, smooth
endoplasmic reticulum; SERCA, SER calcium ATPase.
40 Textbook of Erectile Dysfunction

Calcium NO
Vasodilatory Potassium
agonists
BKca
Adenylyl Calcium Potass
CO NO ium
cyclase ATPase
alphas
Gs KATP
ATP Calcium
Potassium
Guanylyl Hyp
GTP cAMP erp Potassiu
cyclase olar m
izat
ion
cGKI cAK
GTP Potassium
cAK

cGMP cGKI
HSP20
Calcium Lower
affinity
PLmb for CaM Desensitization
(inactive) MLCK
MLCK-P
SERCA P (inactive) CaMK II

High calcium AM-P

SER Calcium

AM
P P Relaxation
cGMP MLCP
cGMP–cGKI beta–IP3R–IRAG
complex cGKI
(inactive IP3R)

Figure 6.4 Signal transduction pathways regulating smooth muscle relaxation. Gray arrows indicate association, binding, or
activation, whereas the clear arrow from “cAK” to “MLCK“ indicates inhibitory regulation. Indirect or putative interactions are
indicated by dashed arrows. Alphas, alpha subunit of Gs protein; AM, actin-myosin contractile apparatus; BKCa, calcium-activated
maxi-potassium channel; cAK, cAMP-dependent protein kinase; cGK, CaMK, calmodulin-dependent kinase; cGKI, cGMP-dependent
protein kinase type 1; cGKI-beta, beta isoform of cGKI; cGMP-dependent protein kinase; CO, carbon monoxide; HSP20, 20 kilodalton
heat shock protein; IP3R, IP3 receptor; IRAG, IP3R-associated cGK substrate; KATP, ATP-dependent potassium channel; MLCK, myosin
light chain kinase; MLCP, myosin light chain phosphatase; NO, nitric oxide; PLmb, phospholamban; SER, smooth endoplasmic
reticulum; SERCA, SER calcium ATPase.

through intracellular signaling mechanisms that involve at In addition to growth factors and cytokines, vasoactive factors
least some aspect of pharmacomechanical coupling. While an have also been shown to have trophic effects in the vascula-
exhaustive review detailing the pharmacology of each vaso- ture, suggesting that many of the same intracellular mediators
active substance or class of receptors is beyond the scope of that cause contraction or relaxation are also involved in
this chapter, key pathways that regulate smooth muscle tone trophic responses in VSMCs.
are summarized in Figures 6.3 and 6.4. While the intracellular integration of various stimuli and
co-ordination of responses is poorly understood, it is likely
that the net response of any given VSMC is dependent upon
the overall gene expression profile. Synthetic VSMCs are pri-
Non-contractile responses in vascular marily characterized by a significantly decreased expression of
smooth muscle cells contractile proteins. Thus, activation of pathways that may
have mediated tonic responses in contractile VSMCs may
Changes in VSMC growth and extracellular matrix production modulate cell growth or matrix production in a synthetic
can have a profound impact on the function of genital tissues. VSMC.29
The extracellular matrix itself is a dynamic structure that plays Many growth factors stimulate cell surface receptors with
an important role in modulating cell morphology, movement, intrinsic tyrosine kinase activity in their cytoplasmic domains.
growth, differentiation, and survival by regulating cell adhe- This tyrosine kinase activity is considered essential for regu-
sion, cytoskeletal machinery, and intracellular signaling. It is lating cell growth. Several of these receptors have been linked
possible that VSMCs may transform from primarily contractile with the activation of phospholipase C (PLC)-gamma. Also,
cells into primarily synthetic cells (or vice versa) in response phospholipase D may be more important for mediating
to changes in their environment (e.g. chronic disease states trophic responses than contractile responses. Some variations
or acute injury). Alternatively, there may be an inherently in responses to growth factors and vasoactive substances may
heterogeneous population of VSMCs in a given vascular tissue. be due to the different mechanisms of activation for different
 Vascular physiology of erectile function 41

PLC isoforms. In addition to preferential activation of PLC- plasma membrane receptor and shuttling protein between the
gamma by tyrosine kinases, the beta-1 and beta-3 isoforms of cell surface and the nucleus.31
PLC are activated by the alpha-q subunit of Gq, whereas the
beta-2 and beta-3 isoforms can be activated by the beta- Summary and perspective
gamma subunits of Gi. PLC activity gives rise to the formation
of diacylglycerol and stimulation of protein kinase C. Protein Although an impressive amount of knowledge has been
kinase C activation has been shown to have both proliferative accumulated regarding smooth muscle biology and vascular
and anti-proliferative effects to platelet-derived growth factor, physiology, it is important to keep in mind that many questions
epidermal growth factor, and angiotensin II.30 While the rea- still remain and are being actively investigated. While a central
sons for these variable responses remain unclear, it must be and enduring question has been how calcium can elicit dif-
stressed that multiple isoforms of protein kinase C exist and ferent responses within a given cell, it is becoming more
that each isoform has numerous substrates. apparent that unique spatial and temporal differences in intra-
Aside from its effects on the contractile apparatus and ion cellular calcium flux play an important role in this regulation.
channels, protein kinase C has also been shown to modulate Mechanistic questions still remain, even in the well-established
DNA synthesis, potentially through the phosphorylation of field of contractile proteins. For example, the disassembly of
transcription factors.30 Among the most intriguing of these is the contractile apparatus within VSMCs transitioning from
nucleolin, a multi-functional protein located primarily in the contractile to synthetic phenotypes is not clearly understood.
nucleolus. In addition to its activities as a regulator of ribo- Future studies in genital tissue physiology will benefit from
somal DNA transcription and ribosomal assembly, nucleolin the application of knowledge gained from the fields of smooth
has been shown to regulate DNA decondensation and act as a muscle and vascular biology.

REFERENCES

1. Triggle CR, Hollenberg M, Anderson TJ, et al. The endothelium in 17. Somlyo AP, Somlyo AV, Kitazawa T, et al. Ultrastructure, function
health and disease: a target for therapeutic intervention. J Smooth and composition of smooth muscle. Ann Biomed Eng 1983; 11:
Muscle Res 2003; 39: 249–67. 579–88.
2. Frohlich ED. Fibrosis and ischemia: the real risks in hypertensive 18. Xu JQ, Harder BA Uman P, et al. Myosin filament structure in
heart disease. Am J Hypertens 2001; 14: 194S–199S. vertebrate smooth muscle. J Cell Biol 1996; 134: 53–66.
3. De Vriese AS, Verbeuren TJ, Van de Voorde J, et al. Endothelial 19. Dominguez R, Freyzon Y, Trybus KM, et al. Crystal structure of a
dysfunction in diabetes. Br J Pharmacol 2000; 130: 963–74. vertebrate smooth muscle myosin motor domain and its complex
4. Matz RL, Schott C, Stoclet JC, et al. Age-related endothelial dys- with the essential light chain: visualization of the pre-power stroke
function with respect to nitric oxide, endothelium-derived hyper- state. Cell 1998; 84: 559–71.
polarizing factor and cyclooxygenase products. Physiol Res 2000; 20. Ito M, Nakano T, Erdodi F, et al. Myosin phosphatase: structure,
49: 11–18. regulation and function. Mol Cell Biochem 2004; 259: 197–209.
5. Darblade B, Caillaud D, Poirot M, et al. Alteration of plasmalem- 21. Huang QQ, Fisher SA, Brozovich FV. Unzipping the role of myosin
mal caveolae mimics endothelial dysfunction observed in ather- light chain phosphatase in smooth muscle cell relaxation. J Biol
omatous rabbit aorta. Cardiovasc Res 2001; 50: 566–76. Chem 2004; 279: 597–603.
6. Manabe I, Nagai R. Regulation of smooth muscle phenotype. Curr 22. Fukata Y, Amano Mutsuki, Kaibuchi K. Rho-Rho-kinase pathway
Atheroscler Rep 2003; 5: 214–22. in smooth muscle contraction and cytoskeletal reorganization of
7. Shanahan CM, Weissberg PL. Smooth muscle cell heterogeneity: non-muscle cells. Trends Pharmacol Sci 2001; 22: 32–9.
patterns of gene expression in vascular smooth muscle cells in vitro 23. Wang H, Eto M, Steers WD, et al. RhoA-mediated Ca2+ sensitiza-
and in vivo. Arterioscler Thromb Vasc Biol 1998; 18: 333–8. tion in erectile function. J Biol Chem 2002; 277: 30614–21.
8. Majesky MW. Vascular smooth muscle diversity: insights from 24. Chitaley K, Wingard CJ, Webb RC, et al. Antagonism of Rho-kinase
developmental biology. Curr Atheroscler Rep 2003; 5: 208–13. stimulates rat penile erection via a nitric oxide-independent path-
9. Christ GJ, Spray DC, El–Sabban M, et al. Gap junctions in way. Nat Med 2001; 7: 119–22.
vascular tissues — evaluating the role of intercellular communica- 25. Park JK, Lee SO, Kim YG, et al. Role of rho-kinase activity in angio-
tion in the modulation of vasomotor tone. Circ Res 1996; 79: tensin II-induced contraction of rabbit clitoral cavernosum smooth
631–46. muscle. Int J Impot Res 2002; 14: 472–7.
10. Brink PR. Gap junctions in vascular smooth muscle. Acta Physiol 26. Cellek S. The Rho-kinase inhibitor Y-27632 and the soluble guany-
Scand 1998; 164: 349–56. lyl cyclase activator BAY41-2272 relax rabbit vaginal wall and
11. Sohl G, Willecke K. Gap junctions and the connexin protein clitoral corpus cavernosum. Br J Pharmacol 2003; 138: 287–90.
family. Cardiovasc Res 2004; 624: 228–32. 27. Morgan KG, Gangopadhyay SS. Cross-bridge regulation by thin
12. Christ GJ, Zhao W, Moss J, et al. Gap junctions modulate tissue filament-associated proteins. J Appl Physiol 2001; 91: 953–62.
contractility and α1-adrenergic agonist efficacy in isolated rat 28. Szymanski PT. Calponin (CaP) as a latch-bridge protein – a new
aorta. J Pharmacol Exp Ther 1993; 266: 1054–65. concept in regulation of contractility in smooth muscles. J Muscle
13. Beny JL, Pacicca C. Bidirectional electrical communication Res Cell Motil 2004; 25: 7–19.
between smooth muscle and endothelial cells in the pig coronary 29. Komalavilas P, Shah PK, Jo H, et al. Activation of mitogen-
artery. Am J Physiol 1994; 266: H1465–72. activated protein kinase pathways by cyclic GMP and cyclic GMP-
14. Sandow SL, Hill CE. Incidence of myoendothelial gap junctions in dependent protein kinase in contractile vascular smooth muscle
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15. Somlyo AP, Somlyo AV. Signal transduction and regulation in Physiol 1994; 267: C659–78.
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Physiol Pharmacol 1994; 72: 919–36. 1911–22.
7 Central nervous system control of sexual
function in males and females
Lesley Marson

Introduction primarily under inhibitory control from the brainstem

(Figure 7.1). This framework still stands today and can also be
Several reviews that focus on the behavioral and neuroendo- applied to female sexual reflexes.6,18
crine aspects of sexual function have been published.1–4 The While some recent valuable insights using imaging tech-
emphasis of this chapter is on the brain and spinal control of niques have been gained from studies in humans, much of
erectile and ejaculatory reflexes in males, and it gives a brief what we know about the anatomy and physiology and the
overview of sexual function in females. For more information pharmacological control of the CNS pathways that regulate
on female sexual function refer to selected reviews.5–10 The sexual function has relied on animal models. These findings
focus here is on neuroanatomical and neurophysiological indicate that multiple factors interact at supraspinal levels to
studies, primarily performed in the rat. Much progress of the influence the excitability of spinal reflexes. Sexual responses
central nervous system (CNS) neurobiology and neurophar- are under both voluntary and involuntary control, and signifi-
macological control of erectile and ejaculatory function has cant changes occur during sexual maturity, which depends on
been made over the past few decades primarily using rodent type and level of gonadal steroid hormones.
animal models in which many of the autonomic and somatic
changes seen during sexual reflexes are similar to that reported
in humans.11–14 Models of erection and ejaculation
Initial studies attempting to understand the CNS organiza-
tion of erectile and ejaculatory process were based on the Study of sexual behavior and reflexes has necessitated the
results of fairly large lesions studies done in the 1960s, and the development of several models that exemplify various aspects
resultant effects of these lesions on sexual behavior. With of sexual reflexes. Undoubtedly the most complete way of
the development of more sophisticated techniques an effort has examining sexual responses is to monitor sexual activity
been made to identify and characterize neurons and their path- during sexual behavior or intercourse. Many laboratories use
ways that are involved in various aspects of sexual behavior. this approach to examine putative neurotransmitters and the
Around 40 years ago, Frank Beach proposed a general frame- role of selected brain regions in regulating sexual behavior. In
work for the central nervous organization of sexual function, addition to monitoring mounts, intromissions, ejaculations,
which was based on his concepts and published research at and lordosis, aspects of motivational behavior, aggression,
that time (Figure 7.1).15 Beach proposed that hormonal and and reward systems can be assessed.
sensory inputs regulating sexual behavior were integrated in This chapter focuses on more reflex aspects of sexual func-
the forebrain. Forebrain nuclei relayed through the brainstem tion (i.e. the neurophysiology and neuroanatomy of genital
to the spinal cord and thus controlled the lower genital reflexes) and in doing so outlines the CNS regions involved in
reflexes. The higher brain regions could initiate sexual beha- the actual processing of these reflexes. Neurophysiological
vior. Evidence for excitatory influences on sexual reflexes are and neuroanatomical techniques often require surgical inter-
evident from nocturnal erections and psychogenic erections. ventions or anesthetic to monitor the autonomic and somatic
Beach also proposed that genital reflexes, such as erection and components of sexual reflexes. Thus complete parallelism
ejaculation, could be produced in response to genital stimula- with sexual behavior, especially in humans, cannot necessarily
tion even if the connections from the brain were severed from be confirmed. However, data gained from these types of
the spinal cord. Thus, peripheral genital stimulation enhances studies have not only supported observations obtained from
excitability within the spinal cord. The brain perceives and behavioral studies, but have also been paramount in discover-
modulates sexual function but the spinal cord contains the ing many of the neurobiological mechanisms that have aided
neural circuits for erection, ejaculation, and climax. Evidence understanding human sexual function and dysfunction.
supporting this hypothesis came from spinal cord injured
patients, in whom genital stimulation could still produce
erections, and from spinalized experimental animals in which Ex copula reflexes
genital stimulation more easily produced sexual reflexes.11,15–17 Hart1,19 and Sachs20,21 described a preparation for eliciting
These studies also implied that spinal sexual reflexes were penile reflexes in awake male rats. The rats are lightly restrained

42
 Central nervous system control of sexual function in males and females 43

Higher sensory BC EMG

inputs

Hormonal 10 s
Forebrain
inputs IC EMG

400
Brainstem
ICP
300
200
100
Genital Sexual motor
Spinal cord 0
stimulation output Mechanical mmHg
stimulation

Figure 7.1 Schematic drawing of the hierarchical control

of sexual reflexes. Higher sensory inputs are integrated with Figure 7.2 Recording of the urethrogenital (UG) reflex, demon-
hormonal inputs in the forebrain, which then relays informa- strating the synchrony of penile muscle activity and penile
tion through the brainstem to the spinal cord. The brainstem erections, recorded as intracavernosal pressure (ICP). The UG
provides primarily an inhibitory input to the spinal cord reflex was elicited in the spinalized anesthetized rat by mechan-
circuits regulating sexual reflexes. Genital stimulation can ical stimulation of the urethral bulb with a fine catheter at the
also initiate motor output by activating spinal cord systems period indicated by the bar (mechanical stimulation). This
directly. resulted in rhythmic busting of the muscles. The UG reflex was
elicited at the termination of the stimulus. Electromyographic
in a supine position and the penile sheath retracted. This (EMG) recordings were from the bulbospongiosus (BC) and
elicits, within a few minutes, clusters of penile reflexes, inclu- ischiocavernosus (IC) muscles. Both recordings were rectified
and integrated with a 200 ms time constant. ICP showed large
ding erection of the penile body and glans. This response is
increases coincident with penile muscle contractions and erec-
greatly facilitated by spinal transection, indicative of a descend- tions. Modified from reference 13 with permission.
ing inhibition of sexual reflexes.
Neurophysiologic recordings in humans have shown
concomitant rhythmic contractions of the perineal muscles
Intracavernous pressure
with ejaculation, together with the sensation of orgasm/
Intracavernous pressure recordings have been used as an index climax.1,24,27–29 Ischiocavernosus and bulbospongiosus muscle
of penile erection, and valuable information on drug therapies recordings have also been monitored during copulation in
to enhance erections has been gained using this model.22,23 male rats, and these muscles fired in synchrony during mount-
When the intracavernous pressure (ICP) is increased, an erec- ing and intromission, and sometimes during ejaculation.20,30
tion occurs, because of increased blood flow within the penis. This model has also been used to examine the neurophysio-
This model therefore measures erection but does not account logical mechanisms involved in female sexual climax and
for skeletal muscle contractions, which are required to represents changes in vaginal blood flow and pressure, and
provide a full rigid erection. vasocongestion, as well as anal sphincter and pelvic floor con-
tractions, many of which are associated with sexual arousal
and climax in women.8,31–33
The urethrogenital reflex
The UG reflex is centrally generated and is triggered by
Ejaculation is the expulsion of fluids from the urethra facili- a spinal pattern generator, which involves multiple spinal
tated by rhythmic perineal muscle contractions.24–26 Closure segments that co-ordinate somatic, sympathetic and parasym-
of the bladder neck and urethral sphincter by sympathetic and pathetic activity of the sexual organs.13,17,34,35 There are many
somatic pathways prohibits retrograde ejaculation to the similarities between the UG reflex and sexual climax: they are
prostate and seminal vesicles, and prevents urine flow during relative insensitivity to gonadal hormones, both are the prod-
ejaculation. The urogenital (UG) reflex model was developed uct of spinal generators, both require co-ordinated autonomic
by McKenna and colleagues, in an attempt to develop a model and somatic neural mechanisms, and the UG reflex and climax
of erection and ejaculation in which neurophysiological is similar in males and females.11,13,27,31,36–42
recordings could be made and examined in relationship to
genital reflexes.13,17 The model comprises pudendal sensory
nerve stimulation, which reliably evokes a co-ordinated Forebrain regions involved in male
response consisting of clonic contractions of the perineal sexual reflexes
muscles (the ischiocavernosus and bulbocavernous muscles),
increases in ICP, rhythmic firing in the cavernous nerve, and Early research studies confirmed that the forebrain was
expulsion of the urethral contents (ejaculation) (Figure 7.2). essential for male sexual behavior. In rodents, the olfactory
44 Textbook of Erectile Dysfunction

system is also important in sexual motivation. The olfactory– of the MPOA induced rhythmic firing of the pudendal motor
vomernasal system sends direct inputs to the medial amygdala, nerve, indicative of the UG reflex (Figure 7.4).52
which is important in sexual behavior in multiple species.43–45 Since the MPOA does not project directly to the spinal cord
The medial preoptic area (MPOA) receives inputs from the regions that co-ordinate the sexual output, facilitation of
amygdala, and many studies have shown that the MPOA is sexual reflexes must relay through sites within the brain for
necessary for the execution of male sexual behavior.46–48 the appropriate response to occur. Data from my laboratory
Lesions of the MPOA and adjacent anterior hypothalamus and others suggest that the periaqueductal gray (PAG) is an
caused copulation deficits in several species.3,44,49,50 Stimulation important region containing the descending pathway from
of the MPOA induced or facilitated sexual behavior and the MPOA to the spinal cord.53 Electrolytic lesions or lido-
rhythmic firing of the pudendal motor nerve and penile caine injections into the PAG blocked the MPOA-induced
erection (Figure 7.3).46,48,51–53 Electrical and chemical stimulation activation of the UG reflex, confirming that neurons in the
MPOA project through the PAG to mediate the perineal
muscle activity (Figure 7.5).53
In addition, a major neuroanatomical pathway from the
MPOA through the PAG was mapped using neuroanatomical
tracing techniques (Figure 7.6).41 The observation that acti-
vation of neurons in the MPOA initiates the UG reflex not
3V only agrees with other published work, but also supports use-
fulness of the UG reflex model in elucidating some of the
f excitatory pathways involved in sexual function. The MPOA
contains a high density of neurons that concentrate gonadal
androgens, and it is extensively interconnected to many other
brain regions, including the limbic system and lower auto-
nomic brainstem nuclei.41,54–57 Therefore, the MPOA is capa-
MPO ble of integrating sensory and hormonal signals that initiate
LPO
sexual reflexes in males. Activation of the MPOA can also
MPA facilitate female sexual responses. However, MPOA lesions do
not abolish erections evoked by masturbation and do not
SCh decrease sexual motivation, suggesting that other brain regions
OX are important for other components of sexual behavior.58,59
Growing evidence suggests that the paraventricular nucleus
of the hypothalamus (PVN) is important for penile erections.
Figure 7.3 Photomicrograph illustrating the location of a
Stimulation of the PVN evokes erections in both awake and
DL-homocysteic acid injection (arrow) into the medial preoptic
anesthetized rats, and lesions of the PVN decrease the pro-
area that was successful in eliciting the urethrogenital (UG)
reflex. The photomicrograph is superimposed onto a coronal erectile effects of various compounds. One mechanism of
section of the forebrain showing the adjacent brain structures. PVN-mediated erections is activation of oxytocin neurons
3V, third ventricle; f, fornix; LPO, lateral preoptic area; MPA, that project directly to the lumbosacral spinal cord.60 Different
medial preoptic area; MPO, medial preoptic nucleus; OX, optic brain pathways contribute to the regulation of the various
chiasm; Sch, suprachiasmatic nucleus. components of sexual behavior; for example, PVN neurons

Pudendal
motor branch

Blood
pressure

10 sec

Figure 7.4 Polygraph tracing demonstrating the effect of bilateral electrical stimulation of the medial preoptic area (MPOA) on the
urethrogenital (UG) reflex. The male rat was anesthetized and spinally intact. Electrical stimulation of the MPOA (250 uA/0.2 msec
pulses at 50 Hz, 1 sec on/off, indicated by the black bar in the timer trace). Note: blood pressure increase during the stimulation and
the UG reflex (indicated by the coordinated rhythmic firing of the pudendal motor nerve branch) was present at the termination of
the stimulus. From reference 53 with permission.
 Central nervous system control of sexual function in males and females 45

PAG

RN

ml

Figure 7.5 Photomicrograph and corresponding coronal diagram illustrating the regions of the periaqueductal gray (PAG) matter
that, when damaged, blocked the medial preoptic area (MPOA)-initiated urethrogenital reflex. On the photograph, arrows show
location of bilateral lidocaine injections that blocked the MPOA-initiated UG reflex; the diagram shows the lesion areas (black
circles) that consistently blocked the output from the MPOA. 3, trigeminal nucleus; PAG, periaqueductal gray; ml, medial lemniscus;
RN, red nucleus.

do not regulate mounting behavior, which may be primarily forebrain have been identified that demonstrate increases in
controlled by the MPOA.61 c-fos activity, which correlates to specific stages of sexual
Cortical activity was found following electrical stimulation behavior. In summary, the bed nucleus of the stria terminalis
of the dorsal nerve of the penis or clitoris.62,63 In humans, (BNST) and the medial amygdala are thought to receive
positron emission tomography and functional magnetic reso- chemosensory signals that are processed through the acces-
nance imaging have been used to examine brain regions that sory olfactory bulb, and the BNST is involved in sexual behav-
show an increased cerebral blood flow during specific activities ior related to previous sexual experiences. Consummatory
related to sexual function.64–66 These studies have primarily sexual behavior increases neural activity in the MPOA and the
used visual sexual stimuli with arousal, but a few studies have subparafascicular thalamic nucleus (SPFp). The SPFp projects
examined areas specifically activated with vaginocervical to the MPOA and posterior nucleus of the amygdala, where
stimulation and ejaculation/orgasm.65,66 Areas commonly neural activity is abundant after copulation.70,71
activated with arousal include the anterior cingulate and
insular cortex, striatum, amygdala, and hypothalamus. These
sensory pathways may also be important in psychogenic sexual Transneuronal tracing studies
arousal and nocturnal erections. Additional areas activated Pseudorabies virus (PRV) is an alpha-herpes virus that is tran-
with vaginocervical stimulation or ejaculation included the synaptically transported within the CNS.75–77 The virus crosses
cerebellum, ventral tegmental area (VTA), and thalamus. synapses and is self-amplifying (as a result of nuclear replica-
Many of these brain regions are involved in sexual responses tion) and is therefore extremely useful in mapping the CNS
seen in animal models and are present and activated in circuits that innervate a variety of peripheral organs.78 The
transneuronal tracing and c-fos studies. virus is injected into a peripheral organ and is retrogradely
transported through the ganglia and spinal cord to the brain.
We have used this technique to map the CNS circuits that
C-fos studies project to the penis, perineal muscles, vagina, and clitoris in
Immunohistochemical staining for the transcription factor rats (Figure 7.7).56,79–81
encoded by the immediate early gene, c-fos, have been used to Similar labeling patterns were seen in the brain after injec-
identify brain neurons that are activated with visceral and tions of the penis, perineal muscles, vagina and clitoris, sug-
sensory stimuli.67–71 However, these studies cannot distinguish gesting a common hierarchical control over these pelvic
between neurons that are activated in response to the initiation organs. Neurons consistently labeled in the forebrain included
of sexual function and those that are involved in the execution the MPOA, the PVN (see Figure 7.7), the lateral hypothalamus,
of the response. Studies to date have identified neurons in the and the VTA.79,80 The VMN was labeled only in females.
forebrain that are activated in response to mounts, intromis- Increasing the survival time allows labeling of second- and
sions, ejaculation, lordosis, and vaginocervical stimulation in third-order neurons, i.e. labeling of neurons that are in syn-
rodents.70–74 These studies have confirmed the importance of aptic contact to the already retrogradely labeled neurons.
the MPOA and PVN in sexual response, as well as the VTA Longer survival times labeled cells in the BNST and cortex,
and ventromedial nucleus of the hypothalamus (VMN), which suggesting neurons in these forebrain areas project to hypo-
is essential for lordosis. In addition, other areas within the thalamic neurons. In the brainstem, areas constantly labeled
46 Textbook of Erectile Dysfunction

4.5 4.8

5.2 5.8

Figure 7.6 Photomicrograph showing the pathway through the periaqueductal gray (PAG) from the medial preoptic area (MPOA).
The anterograde tracer, biotin dextran amine, was injected into the MPOA, and labeled fibers can be seen in the PAG on both sides
of the brain, but primarily ipsilateral to the injected side (left). Retrogradely labeled cells (seen on the right) were also found in the
PAG following injection of the retrograde dye, Flurogold, into the lumbar spinal cord. Scale bars = 500 µm. The numbers at bottom
right indicate distance (mm) from bregma.

included the PAG, Barrington’s nucleus (the pontine micturi- other forebrain regions, such as the amygdala, BNST, nucleus
tion center), the A5 noradrenergic cell group (see Figure 7.7), accumbens, and SPFp, appear to play a role in the execution
the nucleus paragigantocellularis (nPGi) (see Figure 7.7), and and reward aspects of sexual function. Sexual function is
the raphe pallidus and raphe magnus. These brainstem areas probably initiated by separate excitatory pathways or via
project to pelvic efferents, and the nPGi plays an important disinhibition of neurons that tonically inhibit sexual reflexes
role in controlling spinal sexual reflexes.82–84 (e.g. via the nPGi).

Summary
The forebrain regions identified to date appear to regulate the Brainstem regions controlling
initiation and execution of sexual function, and many brain sexual reflexes
regions contain neurons whose activity is modulated by pelvic
sensory input. These areas in turn regulate autonomic and The UG reflex could not be elicited by genital stimulation in
motor output that is characteristic of sexual behavior. The animals with intact spinal cords and, therefore, the UG reflex
MPOA is important for the integration of sensory and hor- must be inhibited from a supraspinal site.13,17 This made this
monal signals related to sexual function; the PVN is impor- model ideal for isolating the inhibitory brain neurons. In a
tant for penile erections; the VMN is essential for lordosis; series of physiological, anatomical, and pharmacological
 Central nervous system control of sexual function in males and females 47

(a) (b)

(c)

Figure 7.7 Photomicrographs illustrating pseudorabies virus (PRV)-labeled neurons in (a) the paraventricular nucleus of the
hypothalamus (PVN), (b) A5 noradrenergic cells, and (c) nucleus paragigantocellularis (nPGi), 4 days after injection of PRV into the
vagina and clitoris of a female rat. Modified from reference 56.

studies my group identified the source of the descending The nPGi has long been thought to be involved in the
inhibition of sexual reflexes in males.79,82,85–87 Electrolytic and regulation of cardiovascular systems and pain. However,
neurotoxic lesions of the rostral pole of the ventral medulla this area has been shown to contain excitatory and inhibi-
(specifically the nPGi) were equivalent to spinal transections tory neurons that respond to genital stimulation and mani-
in removing the descending inhibition. Use of neurotoxic pulations of the pelvic, pudendal, and dorsal nerve of the
lesions indicated that the elimination of the inhibition was penis.83,84,93,95–98 This area projects to and receives projec-
due to destruction of cell bodies in the nPGi and not axons of tions from the lumbosacral spinal cord.82,86 While changes
passage (Figure 7.8). in cardiovascular responses, respiration, and nociception
Neuroanatomical tracing studies confirmed that the nPGi accompany sexual function, the nPGi may co-ordinate the
projects to and receives inputs from pelvic efferent neurons homeostatic responses to behavioral activation of many
and interneurons in the lumbosacral spinal cord that modu- types.
late pelvic reflexes.86,88,89 Neurons in the nPGi area are also Other brainstem regions labeled from PRV tracing studies
transneuronally labeled following virus injection into the include the A5 area, the A6 area (locus coeruleus), and the
penis, perineal muscles, uterus, and clitoris.80,81,90 Lesions of sub-coeruleus. These noradrenergic groups project directly to
this area also facilitate ex copula sexual reflexes and improve the lumbosacral cord.79,80,99,100 The functional significance of
ejaculatory performance.91,92 Excitatory and inhibitory neurons these cell groups remains unknown. However, pelvic efferent
in the nPGi respond to genital stimulation in the female rat neurons receive a dense noradrenergic innervation that is
and to manipulations of the pelvic and pudendal nerves and sexually dimorphic, suggesting a role in sexual behavior.101
the dorsal nerve of the penis in the male.4,93 These studies In addition, the VTA has been shown to play a role in the
demonstrate that the nPGi tonically inhibits somatomotor sexual behavior.102 Lesions of the midbrain raphe facilitate
output and receives sensory information related to sexual male sexual behavior,103 but this region was not often labeled
function. The nPGi receives inputs from the MPOA, the PVN, in the tracing studies and therefore may modulate sexual
and the PAG.41,55,94 The PAG is important for sexual function, function via forebrain pathways. However, the caudal raphe,
and is the major relay region for forebrain inputs as they including the raphe magnus and raphe pallidus, project
descend to the spinal cord.41,53,56 directly to the spinal cord and may regulate nociception during
48 Textbook of Erectile Dysfunction

Before lesion
Spinal and peripheral innervation
BC EMG The internal reproductive organs and external genitalia are
primarily regulated by three branches of the nervous system:
parasympathetic (the pelvic nerve), sympathetic (the hypo-
gastric nerve), and somatic (the pudendal nerve). In addition,
240 the vagus nerve innervates the uterus and cervix and may
160 Urethral pressure relay viscerosensory inputs during sexual function, especially
80
after spinal cord injury. Sexual reflexes include concomitant
activation or inhibition of these nerves, and genital sensory
0 input is received via these nerves. The autonomic and somatic
mmHg Occlusion
innervation of the pelvic organs has been reviewed in detail by
several authors5,104–106 and is thus only briefly summarized in
Bilateral KA lesion this chapter.

Somatic control
The pudendal nerve provides efferent innervation of the
striated perineal muscles: the ischiocavernosus, the bulbo-
240 spongiosus (also known as the bulbocavernosus), the ischio-
160 urethralis, and the external anal and urethral sphincters.
Pudendal motor neurons – the dorsolateral (DL) nucleus and
80
dorsomedial (DM) nucleus, also called the spinal nucleus of
0 the bulbocavernosus – in the rat are located in the L5 and L6
mmHg Occlusion segments of the spinal cord. The pudendal motor neurons in
non-rodent species examined to date, are located in Onuf’s
C1 spinal transection nucleus. The afferent spinal innervation of the pudendal
sensory branch arises from the dorsal root ganglion (DRG) in
L6 and S1 segments. These primary afferents terminate in the
medial edge of the dorsal horn, on both sides of the spinal
cord, and the midline dorsal gray commissure (DGC).

240
Autonomic control
The preganglionic neurons (PGNs) of the pelvic nerve are
160
located in the intermediolateral column (IML, also called the
80 sacral parasympathetic nucleus) in the L6–S1 segments of
0 the spinal cord. Dendrites of the PGNs extend medially, into
mmHg Occlusion
the lateral funiculus, and dorsally, along the lateral edge of the
dorsal horn. The afferent (sensory) fibers of the pelvic nerve
Figure 7.8 Recordings demonstrating the urethrogenital (UG) are found in Lissauer’s tract and along the medial and the
reflex in response to elevations of intraurethral pressure lateral edge of the dorsal horn. The sympathetic PGNs of the
(occlusion) after bilateral kainic acid (KA) lesion of the nucleus hypogastric nerve are located bilaterally in the IML and DGC,
paragigantocellularis (middle panel). The reflex could not be in spinal segments T13–L2. Only a few hypogastric afferent
elicited by elevations of intraurethral pressure before the lesion fibers have been found in the superficial lateral and medial
(top panel, occlusion). The bottom panel shows that the kainic margins of the dorsal horn. The cavernous nerve is important
acid lesion was as effective in abolishing the descending in the mediation of the vasodilatory component of penile
inhibition as C1 spinal transection. The top trace in each panel erection and vasocongestion of the clitoris.
shows electromyographic activity of the bulbospongiosus
muscle (BC EMG). With permission from reference 82.
Sensory mechanisms
The pelvic and hypogastric nerves convey sensory informa-
sexual function.79,80 Barrington’s nucleus in the dorsal pons tion primarily from the internal pelvic organs, while the sen-
was also consistently labeled after injection of PRV into the sory innervation from the genitals and skeletal muscles is
penis and perineal muscles.79,80 Neurons in this area project to provided by the pudendal nerve. The hypogastric, pelvic, and
the pre-ganglionic parasympathetic neurons of the pelvic pudendal nerve afferents are sensitive to circulating gonadal
nerve. This area has for a long time been known to regulate steroid hormones. The autonomic afferents relay sensory and
micturition, and may mediate a variety of straining reflexes. noxious information from the internal genital organs, vagina,
To date a role for Barrington’s nucleus in sexual reflexes has and skin.106,107 The pudendal inputs regulate the level of sexual
not been established. receptivity received from peripheral stimulation and can
 Central nervous system control of sexual function in males and females 49

involved in genital function, and these studies have shown

that afferents synapse on multiple interneurons in the spinal
cord, which then relay through a spinal pattern generator,
DH
PGNs, and motor neurons to mediate the appropriate output.
Stimulation of genital afferents results in labeled neurons in
the medial dorsal horn, the DGC, the intermediate gray mat-
DGC ter, and the lateral gray matter (Figure 7.9), and the putative
neurotransmitters involved in relaying this activity have been
mapped. The distribution of interneurons is consistent with
IML
the distribution of pelvic sensory terminals and is similar in
males and females.40,42,111 Transneuronal tracing studies found
the majority of labeled spinal neurons in the DGC and in the
CC vicinity of the IML of the thoracic–lumbar sacral cord, similar
to that seen in the c-fos studies.80,81,90 This complex system
allows co-ordination of sexual reflexes and inhibition of
bladder function.
One group of neurons in the lumbar medial gray matter has
VH been shown to be critical for ejaculation in rats.112,113 These
neurons (termed LSt cells) project to the thalamus and con-
tain galanin and are activated specifically with ejaculatory
behavior and with the UG reflex in males but not in
females.40,42,112

Figure 7.9 Photomicrograph illustrating c-fos-labeled nuclei

in L6 of the spinal cord after activation of the urethrogenital
(UG) reflex. Note the many fos-labeled nuclei in the dorsal
Neurotransmitters
horn, dorsal gray commissure, and intermediolateral cell Pharmacological studies have shown that many neurotrans-
column. CC, central canal; DH, dorsal horn; DGC, dorsal gray
mitters act in the brain and spinal cord to modulate male and
commissure; IML, intermediolateral cell column; VH, ventral
horn.
female sexual behavior. For further information on specific
neurotransmitters, the reader should examine reviews on the
specific compound of interest.
trigger ejaculation and lordosis.13,108,109 Branches of the puden- Briefly, serotonin has both a facilitatory and inhibitory
dal nerve innervate the penis or clitoris, the perineal skin, effect on sexual function, and different receptor subtypes
the skeletal muscles, and the urethra. The distribution of regulate various components of sexual behavior. Increased
the sensory afferents allows them to transmit considerable levels of serotonin in the CNS resulting from serotonin
information relevant to mating, such as initiation and strength reuptake inhibitors mediate the high incidence of orgasmic
of sexual arousal, the location and movement of the penis, and dysfunction seen with antidepressant therapy in humans and
climax. The pelvic nerve mediates sensory information relat- delay ejaculation in rats.86,114–117
ing to sexual arousal and the luteinizing hormone–prolactin Dopamine has a facilitatory effect on sexual behavior and
surge that occurs after mating or cervical stimulation in sexual motivation associated with reward in both males
female rodents, which often accompanies pregnancy or pseudo- and females via its action on brain reward pathways (e.g. the
pregnancy.10 Vagal afferents may also be involved in pregnancy amygdala, the nucleus accumbens, the hypothalamus, the
or pseudo-pregnancy.110 VTA).119 Multiple neurotransmitters (e.g. glutamate, sero-
tonin, nitric oxide, and oxytocin) interact with the dopamine
pathways that are involved in sexual function.118 Noradrenergic
fibers are abundant in spinal regions that regulate pelvic
Spinal pathways function, and electrophysiological studies have shown that
Intrinsic spinal pathways are vital for relaying and translating adrenergic drugs alter the activity of the hypogastric, pelvic,
the peripheral sensory inputs to the appropriate efferent out- and pudendal nerves.119,120 Administration of clonidine inhibits
put (e.g. genital stimulation leads to genital arousal and the erections, penile reflexes, and vaginal blood flow; and intra-
cognitive associated mood changes). In addition, psychogenic thecal infusion of norepinephrine accelerates pelvic thrusting,
erections are initiated in sensory brain systems, which then suggesting a facilitatory effect of the exogenous drug on the
relay to the arousal and erectile centers in the spinal cord. activity of lumbosacral motoneurons.
Sexual responses comprise a co-ordinated activation of sym- Oxytocin is released during sexual behavior, and adminis-
pathetic, parasympathetic, and somatic output, and the spinal tration of oxytocin (into the MPOA or VMN) facilities female
cord circuits and pathways function as the spinal pattern sexual behavior and elicits penile erections.60,121 Melanocortin
generator for these responses. acts via the CNS to stimulate arousal behaviors and penile
A number of neuroanatomical and electrophysiological erections122–124 via melanocortin 3 and melanocortin 4 receptors
studies have examined the location of spinal interneurons in the VMN, PVN, and spinal cord.
50 Textbook of Erectile Dysfunction

Higher sensory
inputs
Summary
Cortex, amygdala,
BNST, thalamus This chapter has attempted to summarize what is presently
Hormonal known about the CNS regions that regulate sexual responses.
MPOA, PVN,
inputs Over the past 50 years there has been an increasing volume of
VMN
research on the neural control of sexual function, using a vari-
ety of approaches, which has resulted in the identification of
Reticular formation, PAG, VTA several specific brain nuclei and pathways that regulate sexual
nPGi responses in males and females. Neuroanatomical techniques
(c-fos, transneuronal tracing) have allowed visualization of the
neurons that are activated with specific components of sexual
function. Brain imaging techniques have also provided impor-
Spinal cord tant information, allowing correlation with animal studies.
Genital T13–L2 Sexual reflexes are regulated by highly integrated spinal and
Sexual reflexes
stimulation L3–L4
L5–S1
brain autonomic and somatic pathways (Figure 7.10). The
MPOA is important for the integration of sensory and hor-
monal signals related to sexual function; the cortex, amygdala,
Figure 7.10 The basic central nervous system control of sexual
reflexes. Higher sensory inputs are integrated with hormonal BNST, and thalamus play a role in the execution and reward
inputs in the medial preoptic area (MPOA), which then relays aspects of sexual function. The PVN and VMN play an
information through the brainstem to the spinal cord. The important role in penile erection and lordosis, respectively.
paraventricular nucleus of the hypothalamus (PVN) regulates Many of these brain nuclei project to and relay through the
penile erections, and the ventromedial nucleus of the hypo- PAG and medullary reticular formation, although there is a
thalamus (VMN) is essential for lordosis. The forebrain regions direct innervation to the lumbosacral cord from the PVN. The
including the cortex, amygdala, bed nucleus of the stria terminals spinal cord pathways, especially those mediating the physio-
(BNST), thalamus, and ventral tegmental area (VTA) are important logical changes associated with the UG reflex, are tonically
for sensations, reward, and motivational aspects of sexual inhibited by neurons in the nPGi. Many of these brain regions
function. The brainstem inputs onto the spinal cord circuits
also receive ascending sensory inputs from the pelvic, puden-
regulating sexual reflexes are primarily inhibitory. Neurons in
dal, and hypogastric nerves.
the nucleus paragigantocellularis (nPGi) contribute to this
inhibition. Excitatory pathways may relay through the midbrain
periaqueductal gray (PAG) to the spinal cord or via disinhibition
of nPGi neurons. Genital stimulation can initiate motor output Acknowledgments
by activating spinal cord systems directly. Sympathetic, para-
sympathetic, and somatic systems are interconnected by spinal I would like to thank Dr Kevin McKenna, Marsha List, Jennifer
interneurons which regulate the spinal motor output leading to Bradley, Karla Gravitt, Jessica Weidey, and Dr Rong Cai for
sexual reflexes. their contributions to the research.

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8 Ejaculatory physiology
Levent Gurkan, Austin DeRosa, and Wayne JG Hellstrom

Introduction sphincter, among others. There are several types of receptors

present in the glans penis, but most numerous are the free
Over 200 years ago, the renowned English surgeon John nerve endings that can sense deep pressure and pain. In a
Hunter provided the first insights into the physiology of ejacu- study conducted by Halata and Munger, it was observed that
lation and, in particular, the role of the seminal vesicles during free nerve endings are present in almost every dermal papilla
this phenomenon. He sought to explain why the consistency as well as scattered throughout the deeper dermis of the
of the ejaculate differed depending on the timing of discharge human glans penis.3 In addition, Pacinian and Ruffini corpus-
from the penis, noting that initially semen was like ‘cream’ but cles have also been identified to a lesser extent (with a 10:1 ratio
then turned ‘less viscid’ as the discharge continued. He even of free nerve endings to corpuscles), though their significance
went to the extremes of scientific endeavor by dissecting a is not well documented.3
man immediately after he was killed by a cannon ball, in order Although the penis contains a high density of sensory fibers,
to identify further the precise anatomy of the ejaculatory tactile sensitivity is relatively low compared with other parts of
mechanism and prove that the consistency of semen found in the body.3,4 For example, typical cutaneous mechanoreceptors
post mortem examinations was not due to autolysis.1 such as Meissner’s and Merkel cell corpuscles, which are well
Since the days of John Hunter, ejaculatory dysfunction is represented in the glabrous skin of the digits, are rare, if
recognized as the most prevalent male sexual disorder.2 This not completely absent, in the glans. An exception to this rule
fact, along with major advancements in technology, have led is the transitional region located between the external and
us to a greater understanding of the physiology of ejaculation internal surface of the prepuce that is continuous with the
and have consequently provided new insights into potential frenulum and removed with circumcision. This area has a
treatments for ejaculatory dysfunction. high density of fine-touch neuroreceptors, including Meissner’s
The process of ejaculation consists of two major phases: corpuscles.3,5
emission and expulsion. Emission refers to the deposition of Early research based on histological studies hypothesized
sperm into the posterior urethra, where it forms ejaculate that patients with premature ejaculation had higher penile
upon mixing with secretions from the prostate gland and sensitivities. However, this postulate has recently been contra-
seminal vesicles. Next, expulsion consists of the rhythmic dicted by a human study, which revealed no correlation
antegrade advancement of the semen through the urethra between ejaculatory latency time and penile sensitivity mea-
and out the penile meatus. These two elements are mediated sured with a vibrometer.6
by a complex interplay between various somatic, sympathetic,
and parasympathetic elements of the nervous system.3 This
chapter discusses the basic components of the ejaculatory Afferent pathway
reflex, beginning with the initial sensory stimuli and ending The majority of free nerve endings identified in the penis are
with ejaculation proper. A brief review of the putative neuro- projections from small myelinated and unmyelinated A-δ or
transmitters affecting ejaculation is included at the end of C nerve fibers.3,7 Sensory stimuli from these nerves travel
the chapter. along the dorsal nerve of the penis, a sensory branch of the
pudendal nerve. After joining the pudendal nerve, signals
travel to the lower lumbar and upper sacral segments (L6–S1)
Stimulation and receptors of the spinal cord.4 From here, sensory stimuli are conducted
through the lumbar spinothalamic cells (a population of
The exact nature of the afferent stimuli that are necessary to specialized interneurons in the spinal cord, collectively referred
trigger ejaculation are not well documented but most likely to as the ejaculatory generator) and projected on the thalamus
involve some combination of somatosensory, visceral sensory, via the spinothalamic tract. Preliminary studies suggest that
and proprioceptive inputs.4 Direct sensory input is accom- the lumbar spinothalamic cells are only activated at the onset
plished through stimulation of various receptors located of ejaculation. In addition to this major pudendal nerve input,
mostly in the glans penis, but also in surrounding structures there are a number of animal studies that implicate the pelvic
such as the penile shaft, perineum, testes, scrotum, and anal and hypogastric nerves in relaying pre-ejaculatory sensory

54
 Ejaculatory physiology 55

signals, though they appear to be more involved in the sym- The urethrogenital reflex cannot be elicited in intact rats
pathetic control of ejaculation.4 without first performing thoracic spinal transection or pro-
ducing a lesion in the nPGi. Furthermore, numerous studies
have confirmed that lesions of the nPGi facilitated ejaculation
Central control of ejaculation in copulating rats.10
On the other hand, the MPOA has well-documented excita-
It is well appreciated that higher centers of the brain receive tory effects on ejaculation. In several studies, both phases of
sensory information related to ejaculation, but the precise ejaculation were abolished with lesions inflicted upon the
neuronal pathways for processing and relaying ejaculatory MPOA.11 Moreover, electrical stimulation of the MPOA elicits
sensory information after it reaches the thalamus have yet ejaculation. This region of the hypothalamus has not been
to be identified.8 Several animal studies employing Fos expres- shown to have direct connections with the lumbosacral spinal
sion as a signal marker for areas of the brain that are active cord area, but rather projects heavily on the nPGi via the peri-
during ejaculation have revealed a sub-circuit during male aqueductal gray matter. The MPOA is hypothesized to lower
sexual activity that corresponds to ejaculation alone.4 Specifi- the ejaculatory threshold by removing tonic inhibition on the
cally, the posterior dorsal preoptic nucleus, the bed nucleus spinal ejaculatory generator by the nPGi.12
of the stria terminalis, the medial amygdala, and the posterior The full significance of the PVN is still being investigated,
thalamus are the regions that show substantial neural activa- but this pathway contains oxytocin as its neurotransmitter
tion with ejaculation (see Figure 8.1).9 and is considered to have an overall excitatory effect on ejacu-
After the processing of ejaculatory sensory stimuli in the lation. Fibers from the PVN project directly to autonomic
supraspinal sub-circuit, additional regions of the brain exert preganglionic neurons in the lumbosacral spinal cord and
descending inhibitory or excitatory control on the spinal ejacu- pudendal motor neurons located in the L5–L6 spinal segment
latory generator. These sites, identified as the medial preoptic of the rat.13 Stimulating the PVN elicits both erection and
area (MPOA), the paraventricular nucleus of the hypotha- ejaculation; however, a lesion of this nucleus does not pre-
lamus (PVN), and the nucleus paragigantocellularis (nPGi), clude erection or ejaculation.4
act in concert with each other to modulate the ejaculatory
phenomenon.
The nPGi projects to the pelvic efferents and interneurons The spinal ejaculatory generator
in the lumbosacral spinal cord and exerts powerful inhibitory
effects on the spinal ejaculatory generator, employing sero- Despite supraspinal influence, the ejaculatory phenomenon is
tonin (5-hydroxytryptamine or 5-HT) as its neurotransmitter.4 largely a spinal reflex. Perhaps the best evidence to support
this precept is the ability to induce ejaculation spontaneously
in patients that have had a complete spinal transection at T10
Cerebral cortex or above.14 In these spinal cord injury (SCI) patients, activa-
tion of this reflex arc depends largely on the intensity of the
afferent input. It has been shown that SCI patients who fail to
respond to vibratory stimulation for ejaculation using a single
vibrostimulator may indeed successfully ejaculate with the use
of additional vibrostimulators (see Figure 8.2).15
The spinal ejaculatory generator is the synchronization
Thalamus
center for ejaculation. Its fundamental role lies in the integra-
PVN tion of both central and peripheral inputs to construct a
well-co-ordinated output to the genitalia and surrounding
PAG structures, to allow for normal ejaculation.16 Given that ejacu-
MPOA
lation can occur in the absence of supraspinal input, this
discussion of the reflex arc will begin where we left off, with
(-) the arrival of the sensory stimuli at the spinal ejaculatory
generator.
nPGi As previously discussed, the spinal ejaculatory generator is
made up of highly specialized interneurons called lumbar
spinothalamic cells. A selective lesion to these cells will elimi-
nate ejaculation without affecting other aspects of sexual
behavior.4 Lumbar spinothalamic cells were previously noted
(+)
to have afferent projections to the thalamus. In addition, these
(-)
cells also have efferent projections to:
Ejaculatory centers
• the sacral parasympathetic nucleus, which contains viscera
Figure 8.1 Brain structures and putative central pathways motor neurons that travel mainly in the pelvic nerves and
involved in ejaculation. MPOA, medial preoptic area; PAG, control a variety of visceral pelvic organ functions;4
periaqueductal gray; nPGi, paragigantocellular nucleus, PVN: • the sympathetic preganglionic neurons (the dorsal central
paraventricular thalamic nucleus. nucleus and the intermediolateral cell column), located at
56 Textbook of Erectile Dysfunction

Thalamus paired hypogastric nerves proceed to join the pelvic nerve and
form the pelvic plexus.
The pelvic plexus represents the integration center for
DGC sympathetic and parasympathetic fibers. The parasympathetic
fibers arise from the sacral plexus at levels S2–S4. From here,
T12–L2
they travel via the pelvic nerve to the pelvic plexus to be inte-
IML
grated with sympathetic impulses. Branches from the pelvic
plexus innervate the bladder neck, seminal vesicles, prostate,
SMG vas deferens, epididymis, and urethra.19
Alpha-adrenergic receptors are involved in both central
L2–L4 nervous system-controlled bulbospongiosus muscle contrac-
LST tions and peripherally induced seminal vesicle contractions.
Support for the first statement derives from a study that
SHP SPG demonstrated that intraventricular injection of 8-hydoxy-2-
(di-n-propylamino) tetralin induced bulbospongiosus muscle
S2–S4 contractions that were partially inhibited by intravenous
Onuf’s administration of tamsulosin, an alpha-blocker.20 Support for
PN nucleus the second statement comes from findings that abnormal
PdN ejaculation associated with alpha-blockers is also observed in
PP SCI patients.21 Additionally, seminal vesicles express alpha-1
HN adrenoreceptors at the mRNA level, with alpha-1A, alpha-1B
and alpha-1D subtypes being present in a 75:11.7:13.3 ratio;
Figure 8.2 Schematic representation of the hypothesis this distribution explains in part the ejaculatory disturbances
regarding spinal ejaculatory generator control over ejaculation. clinically observed, with various alpha-blockers having dif-
Note that most of the evidence has been acquired from rat ferent affinities for each of the alpha-adrenergic receptor
studies. DGC, dorsal gray commissure; IML, intermediolateral subtypes.22,23
cell column; SHP, superior hypogastric plexus; SMG, superior In response to sympathetic stimuli arriving via the hypo-
mesenteric ganglion; LST, lumbar spinothalamic cells; HN, gastric nerves, postganglionic neurons that project onto the
hypogastric nerve; SPG, sacral parasympathetic nucleus; PN,
seminal tract release norepinephrine. Norepinephine activates
pelvic nerve; PP, pelvic plexus; PdN, pudendal nerve.
alpha-1-adrenergic receptors, increasing levels of calcium and
actin–myosin interaction. This causes smooth muscle contrac-
spinal levels T12–L2, where they send postganglionic fibers tions of the vas deferens, an increase in luminal pressure in the
to the pelvis via the hypogastric and to a lesser extent the cauda epididymis and proximal vas, and antegrade propulsion
pelvic nerve;7 of spermatozoa into the ampulla of the vas. The distention of
• the bulbospongiosus motor neurons (Onuf ’s nucleus), the ampullary wall of the vas deferens causes a nerve impulse
located in the anterior horn of spinal segments S2–S4. This that elicits contraction and thus movement of the seminal
nucleus harbors the pudendal motor neurons that innervate contents into the posterior urethra.19 Simultaneously, the
the striated muscles involved in ejaculation – specifically, sympathetic impulses elicit ejection of prostatic and seminal
the bulbospongiosus, ishiocavernosus, and transverse vesicle fluid into the posterior urethra, thereby completing the
perineal muscles.4,17 emission phase of ejaculation.4
The expulsion phase of ejaculation involves somatic motor
neurons whose major role is to facilitate the antegrade propul-
Efferent pathway and end-organs sion of semen out of the urethra. Although the efferent nerves
in this reflex are somatic and thus innervate striated muscle,
The emission pattern of ejaculation in humans consists of an expulsion is largely under the influence of the autonomic
interplay between parasympathetic and sympathetic outputs nervous system which acts through the spinal ejaculatory
that involve a co-ordinated closure of the bladder neck and generator’s projections upon Onuf’s nucleus.24
contraction of the seminal vesicles, vas deferens, and prostate. By careful measurements of perineal muscle activity in
In animal models, bladder neck closure is solely under sympa- human subjects, it has been revealed that during the expulsion
thetic control.4,18 However, the seminal tract is under dual phase there is synchronous activation of the ischiocavernosus,
innervation, with the parasympathetic nerves stimulating bulbospongiosus, and levator ani muscles, with contraction
glandular secretion and the sympathetic nerves inducing of the external anal and urethral sphincters.16,25,26 Typically,
smooth muscle contraction.16 an ejaculatory response will provoke between 10 and 15 con-
The sympathetic projections that control emission originate tractions. These contractions are regular and are initially
in cell bodies located in the lateral column of the thoracolum- spaced 0.6 seconds apart with subsequent intervals increasing
bar spinal cord and project to the sympathetic chains bilaterally by 0.1 seconds.25 It is of interest to note that contractions of
at the level of T12–L2. From the sympathetic chain, the nerves the striated muscles occur concurrently with the pleasurable
then travel through several plexuses or the splanchnic nerves sensation referred to as orgasm.26 Similarly, increased contrac-
(or both) to reach the superior hypogastric plexus, below the tions of the anterior abdominal wall musculature have been
bifurcation of the aorta. From the superior hypogastric plexus, electromyographically recorded during ejaculation.27
 Ejaculatory physiology 57

The concept that a high-pressure chamber develops in the anesthesia of the urethra or pharmacological inhibition of
prostatic urethra during the emission phase before the forward seminal emissions failed to prevent ejaculation in copulating
propulsion of the ejaculate has only been recently documented. rats.34 Pharmacological inhibition in volunteer human patients
In 2000, the pressure profiles throughout the different urethral using phenozybenzamine also failed to prevent ejaculation.26
segments were registered in five healthy male volunteers Perhaps most contradictory is the fact that ejaculatory motor
undergoing ejaculation. These sophisticated measurements patterns continue in patients after cystectomy, prostatectomy,
were performed using a 10F balloon catheter with pressure and vesiculectomy, suggesting that emission is not required
transducers along the catheter from the bladder neck to for the ejaculation process.35 Taken into context, these studies
the external sphincter. Pressure readings over 500 cmH2O should not completely discount the notion that distention of
have been measured in the proximal urethra while the pres- the urethra contributes to ejaculation, but rather should pro-
sure distal to verumontanum never exceeded 400 cmH2O. mote further investigation of this important topic. Giuliano
These findings support the concept that the ejaculate pro- and Clement suggest that perhaps the expulsatory reflex can
pelled through the urethra follows a pressure gradient, which occur even in the absence of sexual cues, as a mechanism to
prevents retrograde ejaculation.28 It has also been documented prevent ‘deleterious accumulation’ of fluid within the urethro-
that prostatic vascular flow in men dramatically increases genital tract.16 Nevertheless, the spinal ejaculation generator
after ejaculation and continues for at least 24 hours after each of the rat that integrates peripheral afferent and central efferent
ejaculation.29 Hence, frequent ejaculation may indeed be inputs to formulate an autonomic ejaculatory output is the
related to overall prostatic health. Another complementary most promising current model to understand triggers and
urethral pressure study conducted in mongrel dogs collected initiators of ejaculation.16
simultaneous recordings of prostatic tissue electrical activity.
Simultaneous increases in prostatic electromyographic activ-
ity and pressure were recorded with each ejaculatory spurt. Neurotransmitters and ejaculation
This study elegantly proves that the prostate contracts during
each ejaculation pushing out retained prostatic secretions.30 There are numerous neurotransmitter systems involved in the
To hark back to the days of John Hunter, further research ejaculatory phenomenon at both the spinal and supraspinal
has uncovered much information about ejaculation and, levels. The central serotonergic and dopaminergic neurons are
consequently, the reason why ‘ejaculate becomes less viscous considered by most authorities to have the most significant
further along in expulsion.’1 The sequential release of acces- role,2,36 whereas acetylcholine, epinephrine, neuropeptides, oxy-
sory gland secretions (seminal plasma) gives rise to the major- tocin, gamma-aminobutyric acid, and nitric oxide (NO) have
ity of the content of semen, while spermatozoa provides less all been shown to play a secondary role. As with most aspects
than 5% of total ejaculate volume. The purpose of the seminal of ejaculation, the neurochemical pathways are extremely
plasma is to provide a protective and nutritious medium for complex and difficult to study, making it challenging to
the sperms’ travel through the hostile acidic environment of identify the precise role of each neurotransmitter in the ejacu-
the female reproductive tract. The average volume of male latory process. Discussion of each neurotransmitter involved
human ejaculate is 2–5 ml, the volume coming primarily from in the ejaculatory mechanism is beyond the scope of this
the contributions of the seminal vesicles, prostate gland, and chapter. Therefore, focus is directed toward three recognized,
bulbourethral glands. The first fractions of the ejaculate are clinically important neurotransmitters: dopamine, serotonin,
rich in sperm and in prostatic secretions. Major portions of and NO.
the later fractions of ejaculate come from the seminal vesicles,
which provides the main energy source for the sperm in the
form of fructose. Dopamine
Dopamine is generally considered to have a primary and
facilitative role in ejaculation. In rat studies, dopamine levels
Triggers of ejaculation originating from the MPOA progressively increase during
copulation, culminating in ejaculation.36 It is important to
Many questions remain unanswered about the actual triggers note, however, that five subtypes of dopamine receptors exist,
for ejaculation, though there have been several plausible making it difficult to identify the precise dopamine subtype
theories put forth. In 1974, Marberger suggested that the involved in ejaculation. The dopamine receptors are generally
deposition of the seminal fluid in the posterior urethra, with classified into two major groups: D1-like receptors (D1 and
simultaneous closure of the bladder neck, creates distention D5) and D2-like receptors (D2, D3, and D4). To exemplify this
of the bulbous (posterior) urethra. This distention, in turn, point, it has been shown that stimulation of MPOA D2–D3
initiates a sensory–motor reflex that is projected through the receptors by the D2–D3 agonist quinelorane promotes seminal
spinal ejaculation generator to the pelvic muscles, causing emission and ejaculation in rats.37 In another investigation, a
rhythmic muscular contractions and antegrade propulsion of microinjection of a non-selective dopamine antagonist into
the urethral content.31 This theory is supported by animal the MPOA reduced the ejaculatory response.38 In another
studies that demonstrated initiation of ejaculation after study, intracerebroventricularly delivered 7-hydroxy-2-(di-n-
infusion of saline32 or seminal emission33 into the posterior propylamino) tetralin induced rhythmic bulbospongiosus
urethra. muscle contractions and ejaculation. In this study the effect
Naturally, there have been several clinical and experimental of 7-hydroxy-2-(di-n-propylamino) tetralin was inhibited by
studies that have contradicted this theory. For example, both co-injection of a non-selective D2–D3 antagonist and a D3
58 Textbook of Erectile Dysfunction

antagonist, but not by injection of a preferential D2 anta- 5-HT1a receptor becomes desensitized, thereby allowing SSRIs
gonist. The authors suggest that targeting D3 receptors alone to have their effect of delaying ejaculation. Although these
may provide a therapeutic approach for treating many ejacu- findings give us an explanation as to why SSRIs are effective
latory disorders in humans.39 This study had an ancillary with chronic treatment, it does not clarify the reason why they
observation regarding bulbospongiosus muscle contractions, are not effective in the acute phase, as high extracellular 5-HT
which have the same organized pattern of contractions for concentrations are achieved with acute administration of
different doses of 7-hydroxy-2-(di-n-propylamino) tetralin. SSRIs.
These results suggest that once the threshold for brain D3 One hypothesis implicated the involvement of oxytocin in
receptor stimulation is reached, there is a programmed SSRI-induced delayed ejaculation.44 Two oxytocinergic neuronal
response, probably handled at the spinal level.39 This finding systems in the central nervous system can be distinguished:
may have profound implications regarding the neurobio- the magnocellular and the parvocellular. Magnocellular sys-
logical basis for studying and treating premature ejaculation. tems are located in the hypothalamic supraoptic nucleus and
in the anterior and posterior paraventricular hypothalamic
nucleus. 5-HT is one of a range of neurotransmitters that
modulate oxytocin release, and all oxytocinergic cell groups
Serotonin receive some serotonergic activation, mainly originating from
Perhaps the most studied neurotransmitter with regard to the dorsal and median raphe nuclei in the brainstem. It has
ejaculation is 5-hydroxytryptamine (5-HT), also known as been documented that intracerebroventricular injection of
serotonin. There are 15 different known 5-HT receptor sub- 5-HT, systemic injection of the 5-HT releaser (fenfluramine
types, which are grouped into seven major classes (5HT1–7), or p-chloroamphetamine), and systemic injection of 8-OH-
with each one having a different location and function. With DPAT (8-hydroxy-2(di-n-propylamino)tertraline), a selective
the exception of the 5-HT3 receptor, all receptors are coupled 5-HT1a receptor agonist, causes significant increase in oxytocin
to secondary messengers by G proteins. Recognized 5-HT release through activation of several subtypes of 5-HT recep-
receptors that are important for ejaculation include the soma- tors, among which 5-HT1a receptors located on the cell body
todendritic autoreceptors (5-HT1a), the presynaptic autore- of oxytonergic neurons are the most extensively studied.
ceptors (5-HT1b, 5-HT1d), the signaling receptors (5-HT2c), Although the exact mechanism is unknown, it has been docu-
and the reuptake transporters. Each one of these receptors mented that oxytocin levels are elevated with sexual arousal
plays a specific role in the activation and cell signaling of the and ejaculation. High oxytocin levels reduce the number of
serotonin system with regard to ejaculation.2,40 Many of these intromissions required for ejaculation, shorten the ejacula-
5-HT receptor subtypes are localized in the thoracolum- tory latency time, and decrease the time to semen emission in
bosacral cord, in addition to higher centers, the vas deferens, different species. Hence, it is hypothesized that high 5-HT
and the seminal vesicles.41 levels, caused by SSRIs, also stimulate the 5-HT1a receptors
The 5-HT1a somatodendritic autoreceptors in the mesence- located on the oxytonergic neurons, which causes oxytocin
phalic and medullary raphe, when stimulated, are responsible release and has a proejaculatory effect. This phenomenon
for decreasing 5-HT release into the synapse and thereby counteracts the delaying effect of 5-HT on ejaculation, through
reducing ejaculatory latency through a negative feedback 5-HT1b and 5-HT2c receptors activation. As the 5-HT1a recep-
mechanism.41 In contrast to the somatodendritic 5-HT1a tors become desensitized from the consistently high 5-HT
receptors, presynaptic and postsynaptic 5-HT1b and postsyn- levels, oxytocin secretion diminishes and the delaying effect
aptic 5-HT2c receptors are responsible for decreasing ejacula- on ejaculation by SSRIs ensues.44
tory behavior in rats.16 Since the early 1980s, it has been well Furthermore, 5-HT1a receptors located in different loca-
known that increasing 5-HT levels inhibits the ejaculatory tions, such as the brain, raphe nuclei, spinal cord, and auto-
reflex in laboratory animals. Central injection of 5-HT and nomic ganglia, may have different effects on the ejaculatory
systemic injection of the 5-HT precursor 5-hydroxytryptophan process.16,45 In summary, given the relationship between the
causes delayed ejaculation in rats, and the increased activation serotonergic system and the excitatory or inhibitory effect on
of postsynaptic 5-HT1b or 5-HT2c receptors (or both) most ejaculation, it is likely that ejaculatory disorders are caused by
probably mediate this effect.41 altered levels of 5-HT or altered sensitivity of the ejaculatory
Under normal circumstances, 5-HT is released from axon modulating centers in the central nervous system.41 This
terminals; it binds to nearby serotonin receptors, induces a hypothesis provides the pathophysical basis for many of the
variety of effects, and is then quickly removed from the extra- ejaculatory disorders, though further investigation is indis-
cellular space by 5-HT transporters. The concept that people putably required.
with premature ejaculation might benefit from increased extra-
cellular 5-HT levels emerged from the clinical observations of
depressed patients on selective serotonin reuptake inhibitors
(SSRIs). SSRIs act by blocking 5-HT transporters, thus increas- Nitric oxide
ing the concentration of 5-HT by between two- and four-fold Recently, PDE-5 inhibitors have gained attention in the treat-
in the synapse, as measured by microdialysis experiments in ment of premature ejaculation, drawing attention to the role
rats.42 Indeed, some studies reported complete abolition of of NO in the ejaculatory mechanism. In the late 1990s, it was
ejaculation with acute administration of SSRIs; however, postulated that elevated levels of NO in the MPOA accelerated
many other studies failed to replicate these results with acute dopamine release and facilitated the male copulatory beha-
administration of SSRIs.43 With chronic use (2–6 weeks), the vior of rats. It has been documented that microinjections
 Ejaculatory physiology 59

with a NO synthase inhibitor, N-nitro–L-arginine methyl ester, • Ejaculation consists of two phases: emission (deposition
decreased the number of erections, but also increased the of ejaculate into the posterior urethra) and expulsion
number of seminal emissions in male rats.46,47 Further support (rhythmic antegrade advancement of ejaculate through the
comes from studies involving mice lacking endothelial nitric urethra).
oxide synthase (eNOS −/− mice). It has been shown that these • Ejaculation is accomplished through a spinal reflex that is
mice ejaculate with a shorter latency period and require less modulated by supraspinal pathways.
stimulation to ejaculate compared with genetically intact • The afferent stimuli from the penis and surrounding struc-
mice.48 It is presumed that in the absence of eNOS, NO anta- tures travel along the pudendal nerve to the spinal cord.
gonism of the sympathetic control of ejaculation is reduced, They are processed by lumbar spinothalamic cells with
accounting for the overactive, sympathetically mediated ejacu- supraspinal influences, with relaying to efferent stimuli
latory response in these mice.49 There is evidence that NO (via sacral parasympathetic nuclei, sympathetic pregan-
plays a major role in seminal vesicle muscle contractions, as glionic neurons, and Onuf’s nucleus).
it was recently documented that these contractions can be • Signals arising from these nuclei travel along the pelvic,
inhibited in vitro by NO donor drugs and PDE-5 inhibitors.50 hypogastric, and pudendal nerves to stimulate end-organs.
Responses to these stimuli include the closure of the bladder
neck, emission, and propulsion of semen by rhythmic
Summary muscular contractions.
• Known supraspinal sites involved in the control of ejacula-
• The ejaculatory phenomenon has been studied for over tion are the MPOA, PVN, nPGi, posterior dorsal preoptic
200 years, and it continues to be an area of active research. nucleus, bed nucleus of stria terminalis, medial amygdala,
There is a paucity of medications that provide both effi- and posterior thalamus.
cacy and lack of adverse effects for various ejaculatory • The major neurotransmitters involved in the ejaculatory
conditions. mechanism include serotonin, dopamine, and NO.

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Brain Res 1992; 596: 73–9. alpha-1 adrenoceptor antagonists is not retrograde ejaculation but
11. Arendash GW, Gorski RA. Effects of discrete lesions of the sexually a loss of seminal emission. Int J Urol 2006; 13: 1311–16.
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35. Bergman B, Nilsson S, Petersen I. The effect on erection and receptor. Brain Res 1999; 821: 414–25.
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37. Bazzett TJ, Eaton RC, Thompson JT, et al. Dose dependent D2 48. Kriegsfeld LJ, Demas GE, Huang PL, et al. Ejaculatory abnormali-
effects on genital reflexes after MPOA injections of quinelorane ties in mice lacking the gene for endothelial nitric oxide synthase
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38. Pehek EA, Warner RK, Bazzett TJ, et al. Microinjection of cis- 49. Cellek S, Moncada S. Nitrergic control of peripheral sympathetic
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area impairs sexual behavior of male rats. Brain Res 1988; 443: other species. Proc Natl Acad Sci U S A 1997; 94: 8226–31.
70–6. 50. Orhan I, Onur R, Tasdemir C, et al. Sildenafil citrate inhibits ago-
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9 Endocrinology of male sexual function
Mario Maggi, Giovanni Corona, and Gianni Forti

Introduction which are in continuous communication. Testicular activity is

in fact regulated by intra-testicular factors (including testos-
Male sexual activity consists of those physiological, anatomical, terone) and by extra-testicular trophic factors produced by
behavioral, and psychological functions that favor the union the pituitary, i.e. by the gonadotrophins luteinizing hormone
of male gamete to female gamete, thus ensuring continuation (LH) and follicle stimulating hormone (FSH), which in turn
of the species. Although it is not essential for individual survival, are tightly regulated by the hypothalamic peptide gonado-
it is pivotal for species survival, and, therefore, tightly con- tropin-releasing hormone (GnRH). Circulating testosterone
trolled by two apparently distinct and autonomous systems: (T) binds with high affinity to a carrier protein, sex hormone
the nervous system and the endocrine system, which carry – binding globulin (SHBG), which also binds other sex steroids
by neural impulses (nervous system) or by chemical media- such as estrogens, although with lower affinity. The fraction of
tors (endocrine system) – sexual information from center to T unbound to SHBG is termed free T, and is thought to repre-
periphery and back. Nowadays, it is clear that these two systems sent the bioactive fraction of total T. Measurement of free T
constitute a co-ordinated network controlling, in an interlock- represents the cornerstone of evaluating the androgen state.
ing way, the entire cycle of the male sexual response, starting However, it is not an easy task, because the commercially
from the desire phase and ending in the orgasm phase. Separa- available direct methods, based on a labeled T analog, are often
tion between sexual hormones – substances that are secreted unreliable, and separation of unbound T fraction at equili-
into the circulation and act as chemical effectors in other brium dialysis is much too technically difficult. Therefore, at
tissues – and sexual neurotransmitters – substances that are the present time the gold standard method for free T determi-
released from the nerve endings and act within the synapses – nation is the calculation of the free fraction,4 as derived from
is no more than virtual. Oxytocin and α-melanocyte stimu- measurement of its total fraction and its carrier protein SHBG,
lating hormone are the best example. These two peptides act according to a standard formula5 (available at http: //www.
as hormones that stimulate, respectively, epididymal contrac- issam.ch/freetesto.htm). In target tissues, T bioactivity can be
tility and darkening of the skin, and as neurotransmitters further increased by its reduction to dihydrotestosterone
within the hypothalamus, that co-ordinate sexual arousal and (DHT) through two distinct 5α-reductase (5αR) isoforms:
the corresponding behavior.1–3 5αR type 1, which is androgen-independent, and 5αR type 2,
This chapter describes the interaction between the ‘classic’ which is more tightly androgen-controlled. In addition, T
hormones and male sexual response, because the role of the and its precursor, ∆4-androstenedione, can be actively trans-
nervous system is extensively covered elsewhere. It essentially formed though P450 aromatase to other active metabolites:
deals with the effects of hormones (testosterone, prolactin, such as estrone and estradiol (E2). Hence, T exerts biological
and thyroid hormones) that have proven action on at least actions in part by itself, and in part through its reduction or
some aspect of sexual behavior (sexual desire, sexual arousal, aromatization to dihydrotestosterone (DHT) and estrogens,
orgasm, and ejaculation), and it is mostly focused on results respectively. However, measurement of circulating DHT is
obtained in the human male, although results from animal often considered useless, because it does not reflect target
studies will also be considered. tissue production of the hormone, while measurement of E2
in men is generally considered unreliable, because the avail-
able assays are designed for detecting the ovulatory peak in
Testosterone women.6 Figure 9.1 summarizes the major biological effect
of testosterone.
Testosterone production and activity The hypothalamus–pituitary–testis axis is maintained in a
The testis is the key organ for male reproductive and sexual constant, tight equilibrium by the negative feedback of testic-
fitness. It secretes two main products, both essential for a ular products on the secretion of the hypothalamic hormone
successful mating strategy: testosterone, the main androgen GnRH and gonadotropins from the pituitary gland. Testoster-
produced by the Leydig cells, and mature germinal cells (sperm). one and its active metabolites, DHT and estrogens, down-
Testosterone and sperm are produced in two distinct areas regulate GnRH and LH secretion, while the tubular product,
within the testis, the Leydig cells and the tubules, respectively, mainly the inhibin family, exerts a parallel negative feedback

61
62 Textbook of Erectile Dysfunction

Androgen Mood
GnRH receptor
Voice

DHT Skin

5α 7%
Sperm

R1
Pituitary

&
2
Muscle
Free Erythrocytes
LH, FSH Male external
Testosterone
& internal genitalia

Skeleton

Ar
Testosterone

om
+

at
as
0.
SHBG

2%

e
ERα and ERβ

Testosterone
Testis Estrogens

Figure 9.1 Testosterone formation and activity in the male. Green arrows represent stimulatory pathways, red arrows represent
inhibitory pathways. SHBG, sex hormone binding globulin; ER, estrogen receptor; 5αR1, 5α-reductase type 1; 5αR2, 5α-reductase
type 2.

loop on FSH. Alteration of this axis results in male hypogo- female phenotype (as in Leydig cell hypoplasia type 2, com-
nadism, defined as impaired testosterone secretion or activity plete androgen insensitivity, or absence of 17-β-hydroxysteroid
and decreased sperm production. dehydrogenase) to various defects in virilization – micropenis,
hypospadia, cryptorchidism – (as in impaired secretion or
activity of GnRH). In early-onset hypogonadism (EOH) (i.e.
Male hypogonadism starting in the peri-pubertal period), because of milder central
Male hypogonadism is usually categorized based on the site of or peripheral defects (as in Klinefelter’s syndrome), there
dysfunction, as either: might be a delay in the onset of puberty with an overall euno-
choidal phenotype, including scant body hair, high-pitched
• primary hypogonadism if the testis is dysfunctional and voice, and small testes, penis and prostate. In late-onset hypo-
fails to release its products, although super-stimulated by gonadism (LOH), symptoms are relatively mild and insidious
the pituitary; or and can be difficult to recognize and, therefore, to treat. In
• secondary hypogonadism if the testis is normal, but inade- addition, in LOH, the site of origin of the problem is often
quately stimulated by gonadotropins. unclear, because of mixed contributions of testicular and
hypothalamus–pituitary failure. EOH and, in particular,
Hence, the first type of hypogonadism is also defined as hyper- VEOH are rather uncommon problems (although not rare,
gonadotropic and the second one as hypogonadotropic. In with prevalence ranging from one in 500 for Klinefelter’s syn-
addition, a hypogonadism-like syndrome can also derive from drome to one in 100,000 for complete androgen insensitivity)
a reduced sensitivity (or insensitivity) to T and its metabolites and are more appropriately treated by dedicated specialists;
(DHT and estrogens) or because of a reduced bioavailability on the other hand, LOH is a very common disorder but it
of the hormone due to an increase in its carrier protein, SHBG. often goes unrecognized by general practitioners.7
Finally, hypogonadism can be congenital or acquired later,
during childhood or adult life. Table 9.1 summarizes the main
causes of male hypogonadism divided according to the afore- Hypogonadism and erectile dysfunction
mentioned criteria. Sexual dysfunction can be considered the hallmark of hypo-
Interestingly, signs and symptoms of hypogonadism are gonadism, being present in all the forms, irrespective to the
quite similar irrespective of the site of origin of the disease.7 site of origin and the age of onset of the disease. In fact, in
However, they differ greatly according to the age at onset of adult life, T is considered the hormonal fuel of sexual desire
the hypogonadism. In other words, the phenotype of the and also plays an important role in regulating other aspects
hypogonadal patient is more often affected by the age of onset of male sexual response, such as penile erection (both sponta-
than by the site of origin (Figure 9.2). In very early-onset neous and sexually induced) and frequency of intercourse and
hypogonadism (VEOH) (i.e. starting during fetal life), symp- masturbation. A relationship between low T and delayed
toms may be dramatic, spanning from an almost complete orgasm8 and low volume of ejaculates (T is the main trophic
 Endocrinology of male sexual function 63

Table 9.1 Etiology of male hypogonadism. The typical Idiopathic

hormonal pattern is reported in brackets. Note that Functional disorders
conditions reported in italics are only characterized by Hyperprolactinaemia (prolactinoma, hypothyroidism,
impaired sperm production and not by abnormal testos- antidopaminergic drug-induced, serotoninergic
terone synthesis and/or activity. KAL-1: anosmin or drug-induced, opiate-induced)
Kallmann protein; FGFR-1, fibroblastic growth factor Nutritional
receptor-1; PROK-2, prokineticin-2; PROKR-2, proki-
Critical illness
neticin-2 receptor, GnRH, gonadotrophin releasing
hormone; GPR-54, G-protein-coupled receptor-54; Excessive exercise (rare)
DAX-1, dosage-sensitive sex reversal congenital adrenal Diabetes mellitus
hypoplasia critical region on the X chromosome-1; Metabolic syndrome
SF-1, steroidogenic factor-1; HESX-1, HESX homeo- Cushing disease
box-1; PROP-1, prophet of Pit1, paired-like homeodo-
Drugs
main transcription factor; LHSX-3, LIM homeobox 3;
GnRHR, gonadotrophin releasing hormone receptor; Estrogens
FSH-b, follicle stimulating hormone-b subunit; LH-b, Anabolic steroids
luteinizing hormone-b subunit; STAR, steroidogenic Progestogens (including cyproterone acetate)
acute regulatory protein; 3b-HSD, 3b-hydroxysteroid
dehydrogenase; 17a-HSD, 17a-hydroxysteroid dehy- Pituitary diseases (↓ gonadotrophins, ↓ testosterone)
drogenase; 17b-HSD, 17b-hydroxysteroid dehydroge- Congenital
nase; INSL-3, insulin like3 peptide; LGR-8, leucine–rich
repeat-containing, G protein-coupled receptor-8, or Multiple hormone deficiency (including Prop-1, LHX-3,
insulin-like-3 peptide receptor; FSHR, Follicle stimu- DAX-1 mutations)
lating hormone receptor. GnRHR mutations
FSH-β and LH-β mutations
Decreased testosterone production
Pituitary aplasia or hypoplasia
Hypothalamic diseases (↓ gonadotrophins, ↓ testosterone)
Hemocromatosis
Congenital
Acquired
Kallmann syndrome (including KAL-1, FGFR-1,
PROK-2, PROKR-2 mutations) Pituitary tumors

GnRH gene deletion Functional and non-functional adenomas

Leptin and leptin receptor mutation Craniopharyngiomas

GPR-54 mutation Metastases

Prohormone convertase 1 mutation Hematologic malignancy

DAX-1 mutation Rathke’s cyst

SF-1 mutation Infiltrative

Septo–optic dysplasia (including HESX-1 mutation) Primary hypophysitis

Prader–Willi syndrome Sarcoidosis and tuberculosis, syphilis

Laurence–Moon syndrome Fungal, parasites, viral

Bardet–Biedl syndrome Head trauma

Empty sella
Acquired
Vascular
Hypothalamic tumors
Drugs
Germinomas and other germ tumors
GnRH analogs (agonists and antagonists)
Gliomas
Estrogens
Astrocytomas
Anabolic steroids
Craniopharyngiomas
Progestogens (including cyproterone acetate and
Meningioma spironolactone)
Metastases X-irradiation
Infiltrative and infective disorders
Testicular diseases (↑ gonadotrophins ± ↓ testosterone)
Langerhans’ histiocytosis
Congenital
Sarcoidosis and tuberculosis, syphilis
Encephalitis Klinefelter syndrome
Head trauma
(Continued )
64 Textbook of Erectile Dysfunction

Table 9.1 Continued Drug-induced 5α-reductase activity blockade

Finasteride (type II)
Defects of testosterone biosynthesis (STAR, 20-22
desmolase, 3β-HSD, 17α-HSD, 17-20 desmolase, Dutasteride (type I and II)
17β-HSD) Drug-induced estrogen receptor blockade
Pure gonadal dysgenesis (46 XX and 46 XY) Clomiphene, tamoxifen, raloxifene
Congenital anorchia Drug-induced aromatase activity blockade
Leydig cell hypoplasia (including type I and II for Letrozole, anastrazole, exemestane
LH–HCG receptor mutations) Increased sex hormone binding protein
Myotonic dystrophy (including type I and II) Drug induced (antiepileptic, estrogen, thyroid
Cryptorchidism (including INSL-3 and LGR-8 hormones)
mutations) Hyperthyroidism
Germinal aplasia (Del Castillo syndrome, Sertoli-cell Liver diseases
only syndrome)
Aging
Chromosome microdeletions
Autosomal translocations
FSHR mutations
Adrenoleukodystrophy factor for both prostate and seminal vesicles) has also been
Acquired
reported. Figure 9.3 depicts the association between T levels
and the aforementioned aspects of male sexuality in a large
Orchitis (including mumps and autoimmune cohort of adult subjects consulting the outpatient clinic for
disorders) sexual dysfunction at the University of Florence.
Chemotherapy Although the association between T and spontaneous or
Alkylating agents nocturnal erections is supported by several studies,9–12 the rela-
tionship between T and sex-related erections is less apparent,
Methotrexate
or not at all documented.7,12–15 One possible explanation for this
Inhibitors of testosterone synthesis phenomenon derives from experimental studies. For penile
Ketoconazole erection, the most important pathway is the nonadrenergic–
Aminoglutethimide noncholinergic pathway, which, through the release of nitric
Mitotane oxide (NO), leads to an intracellular increase of cGMP, the
main secondary messenger mediating tumescence in the
Metyrapon
penis. Interestingly, T affects both cGMP formation and
Testicular irradiation degradation. In fact, beyond the well-known role of T in regu-
Bilateral torsion lating NO formation,16–19 recent experimental evidence both
Varicocele in rodents19–22 and in humans21 showed that T also regulates
Bilateral trauma the expression of phosphodiesterase (PDE) type 5, the hydro-
lytic enzyme involved in cGMP breakdown. This antithetical
General diseases (including renal failure, liver cirrhosis,
role of T seems to be the main way through which the
diabetes mellitus)
peripheral hormonal regulation of penile erections occurs.
Decreased testosterone bioactivity (≈↑ gonadotrophins, ≈↑ Because T positively controls both the initiation of the erectile
testosterone) process (through NO synthase, NOS) and the end (through
Congenital PDE-5), its net effect on erection might result as modest.
Hence, erections are still possible in hypogonadal conditions,
Aromatase deficiency
where decreased cGMP formation, caused by impaired NO
5α-reductase type II deficiency production, may be counterbalanced by reduced PDE-5
Androgen receptor alterations activity and cGMP hydrolysis. The main physiological action
Complete androgen insensitivity syndromes of T is therefore to adjust the erectile process in a timely
Partial androgen insensitivity syndromes way as a function of sexual desire, thereby temporally aligning
erections to sex. This is, most probably, the main reason
Kennedy syndrome and other extensions of CAG
why T controls the process of erection initiation (through
repeats
NOS) and termination (through PDE-5). Accordingly, penile
Acquired erection is not a random phenomenon but a discrete, tem-
Drug-induced androgen receptor blockade porally adjusted event, consequent to sexual desire and
arousal.
Steroidal antiandrogen (cyproterone acetate,
spironolactone) A trophic effect of T on penile architecture has also been
demonstrated in various animal species.7,22 In animal models,
Non-steroidal antiandrogen (flutamide, bicalutamide,
androgen deprivation by surgical and medical castration
nilutamide)
resulted in loss of trabecular smooth muscle and increase in
 Endocrinology of male sexual function 65

Full
male
1/100
LOH

Masculinization EOH 1/1000

Incidence
1/10000
VEOH

Full 1/100000
female

–1 –3 0 3 10 30 100
Age (years)

Figure 9.2 Characteristics of male hypogonadism, reported according to the age of onset of the disease and the patient’s phenotype.
Schematic prevalence in male population is also shown. Size of ellipsis reflects on the x axis (logarithmic scale) age range of onset
and on ordinates (logarithmic scale): incidence (right axis, logarithmic scale) and phenotype (left axis, arbitrary masculinization unit).
VEOH, very early-onset hypogonadism – i.e. starting during fetal life for absence of testosterone formation or activity (e.g. Leydig cell
hypoplasia type 2, complete androgen insensitivity or absence of 17β-hydroxysteroid dehydrogenase (yellow ellipsis), or impaired
secretion or activity of GnRH (red ellipsis)): for causes see Table 9.1; EOH, early-onset hypogonadism – i.e peri-pubertal onset, as in
Klinefelter’s syndrome (blue ellipsis); LOH, late-onset hypogonadism – i.e. in adulthood or aging (also termed andropause, gray
ellipsis). Adapted from Morelli et al.7

deposition of extracellular matrix, producing diffuse fibrosis in distinct areas of the human brain, including the temporal,
and erectile dysfunction (ED).7,23–25 The androgen-dependent preoptic, hypothalamus, amygdala, midbrain, frontal, and
loss of erectile response is often restored by androgen prefrontal areas and the cingulate gyrus (Brodman area 24,
administration.7,22,24 In addition, it has also been shown that T BA24).33–38 BA24 is part of the limbic cortex deeply involved
is involved in the maturation of penile tissue composition by in balancing emotional behavior and generalized arousal
promoting the commitment of pluripotent stem cells into reaction; it has been found in two studies to be activated by
the myogenic lineage and inhibiting their differentiation in explicitly erotic films by using positron emission tomogra-
the adipogenic lineage.26–28 Accumulation of adipocytes in the phy39 or functional magnetic resonance imaging.40 Interest-
subtunical region of the corpus cavernosum might contribute ingly, T supplementation to hypogonadal men with several
to the impairment of the veno-occlusive mechanism.17 Hence, symptoms, including lack of libido, increased blood perfusion
androgens are important for maintaining the contractile (assessed by single-photon emission computed tomography)
apparatus and for the formation and degradation of the main in BA24, in the midbrain, and in the superior frontal gyrus
relaxing factor, cGMP.7 (BA8), as well as reducing hypogonadal symptoms.38 Stoleru
and colleagues previously identified another androgen-sensitive
brain area by describing a clear positive association between
circulating T plasma levels and BA37 (the middle occipital
Hypogonadism and hypoactive sexual desire gyrus) during exposure to erotic movies, whereas during neu-
Human male sexual behavior is a multifaceted phenomenon – tral exposure the relationship was still significant, but with a
indeed, it can be profoundly affected by psychological, rela- negative relationship.39 Activation of BA37 by visual sexual
tional, social, and cultural factors in addition to the effect stimulation was confirmed in a further study,41 and related to
androgens. However, it is widely recognized that T is a clear processing novel visual stimuli. Hence, several cerebral areas
determinant of sex drive and of the motivation to seek sexual closely linked to sexual drive are androgen-sensitive. How-
contact. Several controlled and uncontrolled studies in hypo- ever, it should be noted that sexual desire or motivation is
gonadal men demonstrate an unequivocal role for T substitu- different from, although closely related to, sexual arousal. The
tion in restoring sexual desire, spontaneous sexual thoughts, latter refers to the cognitive and emotional component
and attractiveness to erotic stimuli.3,29,30 It is less clear how responsible for bringing males to the threshold for initiating
and where T exerts these sex-activating effects in the human copulation (feeling sexually excited) and includes penile erec-
brain. Animal studies clearly indicate that sex steroid receptors tion.42 Most of the functional brain imaging studies in humans
are expressed in the central nervous system (CNS) and that T mentioned so far referred more to sexual arousal (and erec-
controls the activity of several neurotransmitters involved in tion) than to sexual motivation.
sex-seeking behavior, such as dopamine.31,32 However, little The interaction between androgen level and sexual behavior
information is available at present on mapping sex steroid is further complicated by the fact that they are mutually
receptors in the human CNS. Androgen receptors are present dependent and can therefore feedback iteratively. In fact, not
66 Textbook of Erectile Dysfunction

1.9 (a) (b) (c)

1.8

1.7
TT nmol/L

**
** ** * ***
1.6 **
***
1.5

1.4

1.3

No Mild Moderate Severe No Mild Moderate Severe No Mild Moderate Severe

Hypoactive sexual desire Lack of sex-related erections Lack of nocturnal erections

1.9 (d) (e) **

**
1.8 ***
**
1.7 **
TT nmol/L

1.6

1.5

1.4

1.3
0 1–2 3–7 >7 0 1–2 3–7 >7
Sexual intercourse/month Masturbation/month

Figure 9.3 Testosterone plasma levels in 2218 patients afferent to the Andrology Unit for Sexual Disorders at the University of
Florence. Parameters in abscissa are derived from SIEDY structured interview and its Appendix A.81 (a) Hypoactive sexual desire.
no, the patient’s desire is unmodified or increased; mild, desire is moderately reduced in <50% of potential occasions; moderate,:
desire is reduced in >50% of potential occasions; severe, the patient has had no desire to make love. (b) Lack of sex-related erections.
no, <25% of cases; mild, 26–50% of cases; moderate, 51–75%; severe, >75%. (c) Lack of nocturnal erections. no,: the patient reports
spontaneous nocturnal or morning erections, with the same frequency previously observed; mild, nocturnal or morning erections are
present, but their frequency is somewhat lower than that observed previously; moderate, the frequency of nocturnal or morning is
reduced by at least 50%; severe, no nocturnal or morning erections are present. (d) Number of episodes of sexual intercourse per
month. (e) ∫∫Number of episodes of masturbation per month TT, total testosterone. *p<0.01, **p<0.005; ***p<0.0001 vs the first
point. Taken from Morelli et al., 20077, Traish et al.16 and from unpublished observations.

only can T affect sexual activity, but sexual behavior also clearly under androgen regulation. This might explain why,
positively affects T production. An often-cited, single-subject even in absence of T, there are penile erections (as in children
observation published almost 40 years ago in Nature opened and eunuchs), which are, however, not often finalized to sex-
up this second scenario.43 An island resident observed an ual intercourse, because of the blunted sexual motivation.
increase in beard growth on the day preceding and also during
his occasional visits to his mainland lover.43 During the follow-
ing years only scanty reports substantiated this anecdotal Prolactin
report, demonstrating a rise in T during sexual intercourse44,45
or exposure to erotic movies.46 Conversely, other reports Prolactin (PRL) is a 23 kDa polypeptide secreted by lactotropha
addressing the question of a sexual activity-induced rise in cells of the anterior pituitary.56–58 As well as the usually pre-
T plasma levels were negative.47–51 However, Stoleru and dominant monomer, circulating forms of PRL include high-
colleagues, sampling male volunteers every 10 minutes for molecular-weight forms such as macroprolactin (>100 kDa),
12 hours, found an increased pulsatile release of LH, with a a biologically inactive complex of PRL and immunoglobulin
consequential increase in T, occurring soon after exposure to G.59,60 PRL is unique among anterior pituitary hormones in
erotic movies but not to neutral movies.52 In line with this that it is under tonic hypothalamic inhibition via dopamine
finding, in the past few years Jannini and colleagues have pro- (D2 receptors) produced by tubero-infundibular neurons.
duced compelling evidence that has robustly substantiated Hormonal factors facilitating prolactin secretion or production
the hypothesis of an LH-mediated, sex-induced drive in T include estrogens, thyrotropin-releasing hormone (TRH), which
production.53–55 also stimulates production of thyrotropin (thyroid stimulating
In conclusion, T tightly regulates penile responsiveness to hormone, TSH), serotonin, and endogenous opiates.
sexual stimuli, controlling both the initial and final steps of In contrast to the clear function of PRL in female repro-
erections and synchronizing them to sexual desire, which is duction (i.e. promoting breast feeding), the physiological
 Endocrinology of male sexual function 67

role of this hormone in the male is still obscure. Gene dele-

tion of PRL, or of its receptor (PRLR), does not alter male Table 9.2 Etiology of male hyperprolactinemia. An
reproductive fitness,56–58 although PRLR is expressed in the male increase in prolactin may derive from an abnormal
brain, testis, and accessory glands56 and even in the penis.61 detection of biologically inert high-molecular-weight
However, the physiological effect of PRL on male reproductive form of prolactin (pseudo-hyperprolactinemia) or from
fitness remains unknown, though a wealth of data demon- physiological or pathological conditions.
strated a marked inhibitory effect of hyperprolactinemia on
Physiologic
sexual desire,3,62–66 most probably because of effects on hypotha-
lamic GnRH (and therefore on T production) or on dopa- Stress (including venepuncture)
mine production and turnover (see below). Several studies Sleep
have shown that PRL increases following male orgasm,3,67–69
Orgasm
hypothesizing a negative feedback control of this PRL surge
on sexual motivation and therefore contributing to the post- Exercise
orgasmic refractory period. However, it is noteworthy that the Breast nipple or areola stimulation
post-orgasmic rise in PRL is relatively modest and is similar
Pseudo-hyperprolactinemia
in men and women, and that women are less prone to post-
orgasmic refractoriness and satiety. In addition, PRL increases Macroprolactin
during other emotional, stressful, or disturbing conditions
Pathologic
(including venipuncture) or following stimulation of the nipple
or areola.70 Besides these physiological conditions (Table 9.2), Hypothalamic–pituitary stalk damage
disruption of hypothalamic dopaminergic inhibition or pertur-
bation of the portal circulation, as occurs in sellar or parasellar Hypothalamic tumors
tumors, might also cause hyperprolactinemia (see Table 9.2). Germinomas and other germ tumors
The same condition can be associated with primary hypothy- Gliomas
roidism (because of the PRL-stimulating hormone TRH) and Astrocytomas
with the use of drugs that block dopaminergic transmission
Craniopharyngiomas
(antipsychotics and antiemetics) or that increase serotoninergic
transmission (antidepressants) (see Table 9.2). Meningioma
Although the physiological role of PRL in males is not Metastases
completely understood, it is reported that hyperprolactinemia Infiltrative and infective disorders
in men results not only in decreased libido but also in erectile, Langerhans’ histiocytosis
orgasmic, and ejaculatory dysfunction, decreasing sperm pro-
Sarcoidosis and tuberculosis, syphilis
duction and causing infertility.62–66
The prevalence of mild hyperprolactinemia (MHPRL, Encephalitis
defined as PRL >420 mU/liter or 20 ng/ml) in male subjects Head trauma
with sexual dysfunction is quite variable, ranging in preva-
Pituitary diseases
lence from more than 13%71 to less than 2%.72 In contrast,
severe hyperprolactinemia (SHPRL, defined as PRL >735 mU/ Pituitary tumors
liter or 35 ng/ml) is relatively rare (with a prevalence of less Prolactinoma
than 1%).62,66,73 In one of the largest studies published so far,
Acromegaly
involving 2146 patients with sexual dysfunction, MHPRL was
found in 69 (3.3%) and SHPRL in 32 (1.5%) cases.73 Interest- Plurihormonal adenoma
ingly, among patients with MHPRL, repeat blood sampling Macroadenoma with stalk compression
revealed normal PRL values in 47.8% of cases, most probably Infiltrative
as a result of venipuncture stress. On the other hand, the same
Primary hypophysitis
study showed that in patients with SHPRL, false-positive cases
could also derive from the presence of macroprolactin (9.4%), Sarcoidosis and tuberculosis, syphilis
which can be easily ruled out by the reproducible polyethylene Fungal, parasites, viral
glycol (PEG) test.60 It is also interesting to emphasize that Head trauma
SHPRL underlined an organic problem in the hypothalamus– Empty sella
pituitary region in two-thirds of cases and a drug-induced
X-irradiation
condition in almost one-third (Figure 9.4).73 Interestingly, in
this study, a severely reduced libido was associated with a Systemic disorders
10-fold higher chance of having SHPRL (see Figure 9.4), while Chronic renal failure
no association was observed between MHPRL and hypoactive
sexual desire. However, less than one-tenth of subjects com- Hypothyroidism
plaining of hypoactive sexual desire had SHPRL (positive pre- Epileptic seizures
dictive value, 6.4%; negative predictive value, 99.5%). In fact, Herpes zoster
other endocrine factors as well as psychological, relational,
and organic factors, including medications, can affect human (Continued )
68 Textbook of Erectile Dysfunction

Table 9.2 Continued SSRI antidepressant

Drug induced
SNRI & atypical
Antipsychotics and other dopamine receptor blockers antidepressant
(including antiemetic)
Antipsychotic
Phenothiazines (chlopromazine, mesoridazine,
thioridazine, fluphenazine, perphenazine,
trifluoperazine) Benzamides

Butyrophenones (haloperidol, pimozide, fluspirilene,

penfluridol, risperidone) Hypoactive sexual desire
Benzamides (sulpiride, amisulpride, levosulpiride,
cisapride, metoclopramide) Positive pituitary MRI
Thioxanthenes (chlorprothixene, thiothixene)
Dopamine synthesis inhibitors Hypothyroidism
α-Methyldopa
Catecholamine depletors Severe hypogonadism

Reserpine
Antidepressants 0.01 0.1 1 10 100 1000

Selective serotoninergic reuptake inhibitors (citalopram, Figure 9.4 Age-adjusted odd ratio (OR) for different parameters
paroxetine, sertraline, fluoxetine, fluvoxamine, associated with mild hyperprolactinemia (prolactin (PRL) levels
escitalopram) >420 mU/liter (20 ng/ml), closed diamonds) or severe hyperpro-
Serotoninergic–noradrenergic reuptake inhibitor and lactinemia (PRL levels >735 mU/liter (30 ng/ml), open diamonds).
atypical antidepressants (venlafaxine, trazodone, SSRI, selective serotoninergic reuptake inhibitor; SNRI/atypical,
mirtazapine, bupropion) serotoninergic–noradrenergic reuptake inhibitor atypical anti-
Tricyclics (chlorimipramine, amitriptyline) depressants; hypoactive sexual desire, moderate to severe hypo-
active sexual desire as assessed by SIEDY structured interview
Opiates score (question number 14: ‘In the past 3 months, did you
H2 antagonist have more or less desire to make love?’; rating 0, no; rating 1,
Cimetidine mild reduction; rating 2, moderate reduction; rating 3, severe
reduction). Positive pituitary magnetic resonance imagine (MRI),
Ranitidine detection of abnormality in sellar or parasellar regions on MRI.
Calcium-channel blockers Hypothyroidism (TSH >4 mU/liter). Severe hypogonadism: total
Verapamil testosterone <8 nmol/L.
Hormones
Estrogens
Antiandrogens In addition, SHPRL is a medical problem that must be recog-
Anticonvulsants nized and treated, not only because a sellar or parasellar tumor
Phenytoin might be detected by pituitary imaging (see Figure 9.4), but
also because removing the underlying disorder will restore
sexual activity.73 An overt hypogonadism is not always present
in hyperprolactinemic subjects; therefore, measuring PRL
sexual desire independently of PRL.63,66 Conversely, the major- only in those subjects with low T might result in underestima-
ity of subjects with SHPRL have hypoactive sexual desire tion of the condition. Hence, in our view, PRL should be
(positive predictive value, 70%; negative predictive value, assayed in all patients with any decrease of sexual desire, even
86.1%).73 Although SHPRL is usually associated with second- if it is perceived as mild.
ary hypogonadism, due to a PRL-dependent decrease in LH
secretion (see Figure 9.4), PRL seems to play a direct role in
the control of male sexual desire through central dopamine Thyroid hormones
metabolism.74 Accordingly, in hyperprolactinemic subjects,
testosterone treatment was not able to restore libido,75 while The thyroid gland produces, under TSH control, two major
prolactin-lowering drugs were very effective both in raising active hormones, thyroxine (T4) and tri-iodothyronine (T3),
testosterone levels and sexual desire.65,73,76 which circulate in human blood tightly bound to carrier
In conclusion, MHPRL has modest or undetectable effects proteins, including thyroxine binding globulin. Free fractions
on male sexual behavior, and is often the result of medications of thyroid hormones are the biologically active hormones
or venipuncture stress. In contrast, SHPRL, severely compro- (FT4 and FT3), which regulate protein, fat, and carbohydrate
mising sexual desire, almost always causes sexual dysfunction. metabolism. Hence, all organs and tissues are at least partially
 Endocrinology of male sexual function 69

3 systematically studied77 until recently. In a consecutive series

of 755 men presenting with sexual dysfunction, a two-fold
greater prevalence of hyperthyroidism was evident among the
2.5 men with premature ejaculation.78 This figure is confirmed in
* a larger sample (of 1854 men), showing that subclinical or
overt hyperthyroidism (TSH <0.2 mU/L, with normal or
2 elevated FT3 and FT4) was present in less than 1% of those
(% Hyperthyroidism)

not complaining of premature ejaculation, while it was pre-

sent in 2.3% of those with premature ejaculation (Figure 9.5).
1.5 Similarly, Carani and colleagues, in a small multicenter, pro-
spective study, demonstrated that 50% of hyperthyroid
patients have premature ejaculation, a prevalence that was
substantially reduced (15%) by treating the underlying disease,
1
with a consequent doubling of ejaculatory latency.79 In the
same study it was shown that medical treatment of the oppo-
site state, hypothyroidism, resulted in a two-fold decrease in
0.5
ejaculatory latency and a reduction in delayed ejaculation.79
Hence, the view that thyroid hormones regulate the ejacula-
tory reflex is emerging.80 The study by Carani and colleagues
0 also suggests that low sexual desire and ED might be due to
no PE PE
hypothyroidism and can be treated by normalizing thyroid
Figure 9.5 Prevalence of premature ejaculation (PE; %) in hyper- hormones.79 The underlying pathogenic mechanisms are not
thyroid patients (TSH <0.2 mU/liter with or without elevated free completely understood. Although it is possible that a hypo-
thyroid hormones) and euthyroid patients, attending an Andro- thyroidism-induced PRL rise could mediate these negative
logical Unit for Sexual Dysfunction at the University of Florence effects on male sexuality (see Figure 9.4),73 a direct role for
(n=1879). *p < 0.05. From Corona et al., 200478 and unpublished thyroid hormones on reproductive tissues has also been
observation. postulated.30,79 More studies are needed to clarify the role of
thyroid hormones.
affected by thyroid diseases. For instance, both hypothyroidism In conclusion, thyroid disease could underlie some form of
and hyperthyroidism result in clear alterations in the cardio- sexual dysfunction in the male. Measurement of TSH (and
vascular and mental state. However, the association between possibly FT3 and FT4) is encouraged in subjects who present
thyroid diseases and sexual dysfunction in men has not been with premature ejaculation.

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5. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of humans? Examining the clinical and preclinical evidence. J Sex
simple methods for the estimation of free testosterone in serum. Med 2006; 3: 382–404.
J Clin Endocrinol Metab 1999; 84: 3666–72. 15. Gooren LJ, Saad F. Recent insights into androgen action on the
6. Nelson RE, Grebe SK, OKane DJ, et al. Liquid chromatography- anatomical and physiological substrate of penile erection. Asian J
tandem mass spectrometry assay for simultaneous measurement of Androl 2006; 8: 3–9.
estradiol and estrone in human plasma. Clin Chem 2004; 50: 373–84. 16. Vignozzi L, Corona G, Petrone L, et al. Testosterone and sexual
7. Morelli A, Corona G, Filippi S, et al. Which patients with sexual activity. J Endocrinol Invest 2005; 3 Suppl 28: 39–44.
dysfunction are suitable for testosterone replacement therapy? J 17. Traish AM, Toselli P, Jeong SJ, et al. Adipocyte accumulation in
Endocrinol Invest 2007; 30: 880–8. penile corpus cavernosum of the orchiectomized rabbit: a poten-
8. Corona G, Mannucci E, Petrone L, et al. Psychobiological tial mechanism for veno-occlusive dysfunction in androgen defi-
correlates of delayed ejaculation in male patients with sexual ciency. J Androl 2005; 26: 242–8.
dysfunctions. J Androl 2006; 27: 453–8. 18. Morelli A, Filippi S, Zhang XH, et al. Peripheral regulatory mecha-
9. Schiavi RC, White D, Mandeli J, et al. Hormones and nocturnal nisms in erection. Int J Androl 2005; 28: 23–7.
penile tumescence in healthy aging men. Arch Sex Behav 1993; 19. Morelli A., Filippi S., Vignozzi L, et al. Physiology of erectile func-
22: 207–15. tion: an update on intracellular molecular processes. EAU-EBU
10. Granata AR, Rochira V, Lerchl A, et al. Relationship between sleep- Update Series 2006; 4: 96–108.
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22. Traish AM, Park K, Dhir V, et al. Effects of castration and androgen 1992; 52: 195–7.
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J Androl 2003; 24: 381–7. plasma testosterone. Arch Sex Behav 1973; 2: 309–15.
24. Traish AM, Kim NN. The physiological role of androgens in penile 48. Stearns EL, Winter JS, Faiman C. Effects of coitus on gonadotropin,
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25. Shen ZJ, Zhou XL, Lu YL, et al. Effect of androgen deprivation on 49. Lee PA, Jaffe RB, Midgley ARJr. Lack of alteration of serum gonad-
penile ultrastructure. Asian J Androl 2003; 5: 33–6. otropins in men and women following sexual intercourse. Am J
26. Bhasin S, Taylor WE, Singh R, et al. The mechanisms of androgen Obstet Gynecol 1974; 120: 985–7.
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target of androgen action. J Gerontol 2003; 58: M1103–10. and plasma testosterone levels in normal human males. Arch Sex
27. Singh R, Artaza JN, Taylor WE, et al. Androgens stimulate myo- Behav 1976; 5: 125–32.
genic differentiation and inhibit adipogenesis in C3H 10T1/2 pluri- 51. Brown WA, Monti PM, Corriveau DP. Serum testosterone and
potent cells through an androgen receptor-mediated pathway. sexual activity and interest in men. Arch Sex Behav 1978; 7:
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28. Singh R, Artaza JN, Taylor WE, et al. Testosterone inhibits adipo- 52. Stoleru SG, Ennaji A, Cournot A, et al. A LH pulsatile secretion and
genic differentiation in 3T3–L1 cells: nuclear translocation of testosterone blood levels are influenced by sexual arousal in
androgen receptor complex with beta-catenin and T-cell factor 4 human males. Psychoneuroendocrinology 1993; 18: 205–18.
may bypass canonical Wnt signaling to down-regulate adipogenic 53. Jannini EA, Screponi E, Carosa E, et al. Lack of sexual activity from
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29. Christiansen K. Behavioural effects of androgen in men and serum testosterone. Int J Androl 1999; 22: 385–92.
women. J Endocrinol 2001; 170: 39–48. 54. Carosa E, Benvenga S, Trimarchi F, et al. Sexual inactivity results
30. Bhasin S, Enzlin P, Coviello A, et al. Sexual dysfunction in men and in reversible reduction of LH bioavailability. Int J Impot Res 2002;
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31. Robbins A. Androgens and male sexual behaviour. From mice to 55. Carosa E, Martini P, Brandetti F, et al. Type V phosphodiesterase
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33. Rance NE, McMullen NT, Smialek JE, et al. Postmenopausal 57. Bole-Feysot C, Goffin V, Edery M, et al. Prolactin (PRL) and its
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34. Sarrieau A, Mitchell JB, Lal S, et al. Androgen binding sites 58. Sobrinho LG. Prolactin, psychological stress and environment in
in human temporal cortex. Neuroendocrinology 1990; 51: humans: adaptation and maladaptation. Pituitary 2003; 6: 35–9.
713–16. 59. Guay AT, Sabharwal P, Varma S, et al. Delayed diagnosis of
35. Puy L, MacLusky NJ, Becker L, et al. Immunocytochemical detec- psychological erectile dysfunction because of the presence of
tion of androgen receptor in human temporal cortex characteriza- macroprolactinemia. J Clin Endocrinol Metab 1996; 81: 2512–14.
tion and application of polyclonal androgen receptor antibodies in 60. Fahie-Wilson MN, John R, Ellis AR. Macroprolactin; high molecu-
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36. Donahue JE, Stopa EG, Chorsky RL, et al. Cells containing immu- 61. Ra S, Aoki H, Fujioka T, et al. In vitro contraction of the canine
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J Comp Neurol 2000; 425: 422–35. 63. Corona G, Petrone L, Mannucci E, et al. The impotent couple: low
38. Azad N, Pitale S, Barnes WE, et al. Testosterone treatment enhances desire. Int J Androl 2005; 28: 46–52.
regional brain perfusion in hypogonadal men. J Clin Endocrinol 64. Lenzi A, Lombardo F, Salacone P, et al. Stress, sexual dysfunctions,
Metab 2003; 88: 3064–8. and male infertility. J Endocrinol Invest 2003; 26: 72–6.
39. Stoleru S, Gregoire MC, Gerard D, et al. Neuroanatomical corre- 65. Ciccarelli A, Guerra E, De Rosa M, et al. PRL secreting adenomas
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41. Arnow BA, Desmond JE, Banner LL, et al. Brain activation and docrine response to orgasm during sexual arousal in men. J Endo-
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10 Pathophysiology of erectile
dysfunction: molecular basis
Biljana Musicki and Arthur L Burnett

Introduction Major scientific advances have occurred in the study of

erection physiology at the molecular level. Specific signaling
The pathophysiology of erectile function refers to derange- pathways have been described that provide a molecular bio-
ment of the normal erectile response and, as a scientific field, logic basis for penile erection. Our current understanding is
implies investigation of biological factors and underlying that penile erection is mainly mediated by the nitric oxide
molecular mechanisms associated with these derangements. (NO) pathway.3,4 NO is synthesized by neuronal nitric oxide
This area of scientific knowledge has been built on clinical synthase (nNOS), expressed in autonomic nerve endings, and
observations and experimental studies. Clinically, various by endothelial nitric oxide synthase (eNOS), expressed in
disease states and risk factors, such as diabetes, hypertension, vascular and sinusoidal endothelium of the penis. Neuronally
atherosclerosis, and cardiovascular diseases, have been asso- derived NO initiates penile erection, while endothelial NO
ciated with erectile dysfunction (ED). Experimental studies maintains erection.5 Accordingly, the common factors con-
have been carried out to elucidate specific derangements and tributing to ED include reduced activity of nNOS and eNOS
specific mechanisms associated with the disturbances that and decreased NO bioavailability (Figure 10.2). cGMP and
underlie ED. cAMP are primary intracellular mediators of corporal smooth
It may be helpful to consider the causes, conditions, and muscle relaxation.3,4 Opposing this activity, the RhoA–Rho-
molecular mechanisms of ED in the context of the normal kinase signaling pathway is the main mediator of cavernosal
erectile response. Penile erection is a complex neurovascular tissue contraction.6–8 Derangements of these mechanisms
process involving relaxation of the corpus cavernosal smooth probably explain the pathophysiology of ED associated with
muscle combined with increased arterial inflow into the penis different disease states.
and restricted venous outflow from the penis. The process In this chapter we present current knowledge of the patho-
relies on a co-ordination of the nervous system, including physiology of ED. Our intent is to describe two major catego-
the hypothalamus, the spinal cord, and peripheral nerve dis- ries of the erection paradigm, vasculogenic and neurogenic,
tributions to the penis. It is also influenced by hormonal sub- but consider these in reference to ED. Hormonal influences
stances acting within the penis. Co-ordination extends to on ED are handled elsewhere in the book. After describing
cellular components of the penile vascular response, such as these two major categories, we proceed with a description of
endothelial cells, smooth muscle cells, and locally released major disease states associated with ED, detailing molecular
biochemical factors. Defective regulation of penile erection mechanisms associated with each disease state.
can be associated with alteration in any of these components
(Figure 10.1).
Current knowledge supports particular mechanisms of Vasculogenic erectile dysfunction
vascular biology in the penis as fundamental properties of
erection physiology. The balance between vasorelaxation and Accumulating evidence indicates that ED is predominantly a
vasoconstriction determines penile flaccidity versus erection. vascular disease. Vasculogenic ED may be due to arterial or to
Relaxation of the corporal smooth muscle is the key determi- cavernosal dysfunction (veno-occlusive), resulting in reduced
nant of the erectile response. It permits engorgement of the blood inflow into the penis, or excessive blood outflow from
corpora cavernosa with blood. Compression of the dilated the penis. Vasculogenic ED refers to the derangements in the
blood vessels against the rigid tunica albuginea restricts function and structure of endothelial and smooth muscle cells
venous drainage (veno-occlusion), allowing penile rigidity. in the penis. The inability of the endothelium to produce vaso-
The achievement of normal veno-occlusion is primarily deter- relaxing messengers, increased vasoconstriction, and reduced
mined by the content of functional corporal smooth muscle endothelium-dependent vasodilatory response of smooth
and by structural integrity of the erectile tissue.1,2 Thus, fac- muscle cells are all sources for the development of endothelial
tors that impede vasorelaxation or promote vasoconstriction dysfunction in the penis and for vasculogenic ED. eNOS-
would be considered effectors of ED pathophysiology. Similarly, mediated and NO-independent vasorelaxation are downregu-
factors that disrupt veno-occlusion would also be considered lated in various diseases states. Smooth muscle signaling is
effectors of ED pathophysiology. affected by upregulation of the vasoconstricting pathways and

72
 Pathophysiology of erectile dysfunction: molecular basis 73

Parkinson’s disease Diabetes

Aging mellitus Hypercholesterolemia Hypertension
Alzheimer’s disease
Brain Stroke
Encephalitus
Diabetes mellitus
Endothelial cells Smooth muscle cells

• Decreased vasorelaxation • Increased vasoconstriction

Spinal cord injury • Cellular destruction • Fibrosis
Spinal cord Multiple sclerosis
Vertebral disc disease

Pelvic surgery ED
Peyronie’s disease
Penis Aging
Diabetes mellitus Figure 10.3 Major molecular mechanisms of vasculogenic ED.
Vascular diseases Vasculogenic ED results from derangements in the function or
structure of endothelial and smooth muscle cells in the penis.
Figure 10.1 Common medical conditions associated with ED eNOS-mediated and NO-independent vasorelaxation is down-
and their putative levels of effect based on the neuroaxis of regulated, while smooth muscle vasoconstriction is upregulated.
penile erection. The regulation of penile erection involves the Impaired growth factor and cytokine signaling leads to endothe-
co-ordination of the nervous system (i.e. brain, spinal cord, and lial destruction and tissue fibrosis.
peripheral nerves) and the vascular circulation of the penis.

and peripheral artery disease. In fact, vascular ED appears to

be one of the earliest signs of systemic microvascular and
macrovascular diseases and may be considered an early marker
nNOS for cardiovascular disease.10
NO The following section represents a sub-categorization of
L-Arginine
Smooth muscle cell major vasculogenic molecular mechanisms involved in normal
Nitrergic nerve erectile function. This framework can be applied to facilitate
sGC 5′-GMP
PDE-5 understanding of mechanisms of vasculogenic ED.
L-Arginine NO GTP cGMP cGKI

Endothelial nitric oxide synthase

eNOS
Penile erection In normal endothelial function, NO has vasodilatory pro-
Endothelial cell perties and counterbalances RhoA–Rho-kinase-mediated
vasoconstriction, thus regulating vascular tissue homeostasis.
Figure 10.2 NO-mediated penile erection. NO is synthesized Conversely, in pathologic conditions, eNOS uncoupling and
from its precursor L-arginine by nNOS and eNOS, primarily formation of peroxynitrite from the reaction of NO with
localized in autonomic nerve endings and endothelial cells of superoxide anion results in pro-oxidant effects of NO. The
the penis, respectively. In response to psychogenic and reflexo- balance between NO bioavailability, vasoconstrictor function,
genic neuronal impulses, activation of nNOS initiates penile and vascular generation of ROS is crucial for maintaining
erection. Blood-flow-related mechanisms facilitate and main-
normal erectile ability. eNOS is regulated transcriptionally
tain maximal erection by phosphorylation and activation of
eNOS. NO diffuses to adjacent smooth muscle cells where it
and post-translationally.11 The latter mechanisms involve
activates soluble guanylyl cyclase (sGC) and increases the pro- calcium–calmodulin binding, fatty acid modification, altera-
duction of 3′,5′-cyclic guanosine monophosphate (cGMP) from tions in intracellular translocation, substrate and cofactor
5′-guanosine triphosphate (GTP). Subsequent activation of cGMP- availability, dimerization of the enzyme subunits, binding to
specific protein kinase I (cGKI) reduces contractile activity other proteins, and phosphorylation. Phosphorylation of
and promotes relaxation of smooth muscle cells and erection. eNOS at Ser-1177 by shear stress and vascular endothelial
Degradation of cGMP in the penis to inactive 5′-GMP, which growth factor (VEGF) increases the enzyme’s activity, while
terminates NO signaling and returns the penis to the flaccid phosphorylation of eNOS at Thr-495 decreases the enzyme’s
state, is catalyzed primarily by PDE-5. activity. Interaction of eNOS with heat-shock protein (Hsp)
90 positively regulates the enzyme’s activity, whereas interac-
tion of eNOS with caveolin-1 negatively regulates the enzyme’s
impaired growth factor and cytokine signaling (Figure 10.3). activity.12 Derangements in any of the molecular pathways
Increases in oxidative stress, which refers to the imbalance that regulate eNOS may induce vasculogenic ED.
between the production and elimination of reactive oxygen
species (ROS),9 affect normal penile erection and are featured
in the development of vasculogenic ED. Endothelial dysfunction Nitric oxide-independent endothelium-derived
is an early stage of vascular damage, which can lead to more relaxing factors
severe changes, such as atherosclerosis in the systemic vascula- Endothelial cells release other vasodilators besides NO, inclu-
ture, and it manifests itself clinically as coronary, renal, cerebral, ding prostacyclin and endothelium-derived hyperpolarizing
74 Textbook of Erectile Dysfunction

factor (EDHF). Prostacyclin, synthesized by both the endothe- RhoA

lium and smooth muscle, is involved in cAMP-mediated
smooth muscle relaxation.13 Endothelium-dependent vasodi- Rho-Kinase
lation in smaller arteries and arterioles is mostly attributed
to non-NO, non-prostacyclin-induced hyperpolarization
mediated by EDHF. There is considerable controversy regard- MLC phosphatase-P (inactive)
ing the identity and the mechanism of action of EDHF. It is MLC MLC-P
thought that the hyperpolarization of smooth muscle cell MLC kinase
membrane by EDHF predominantly involves activation of
calcium-dependent potassium channels.14 While the exact
role and mechanism of their action remain to be fully eluci- Relaxation Contraction
dated, decreased production or action of NO-independent
vasorelaxing factors in the penis may contribute to vasculo- Figure 10.4 RhoA–Rho-kinase pathway in penile smooth
genic ED. muscle contraction. Activation of G protein-coupled receptors
activates RhoA. RhoA-activated Rho-kinase phosphorylates and
inhibits myosin light chain phosphatase (MLC phosphatase-P).
Smooth muscle mediators Inhibition of MLC phosphatase increases myosin light chain
phosphorylation (MLC-P), which promotes the actin–myosin
The degree of contraction of the corpus cavernosum smooth
cross-bridge cycling rate, resulting in smooth muscle contraction.
muscle and the functional state of the penis is determined by Dephosphorylation of MLC promotes corporal smooth muscle
the balance between pro-erectile and anti-erectile (vasocon- relaxation.
strictive) mechanisms, which operate physiologically in the
penis. Vasoconstriction is evoked by norepinephrine through
alpha-adrenergic receptors, endothelins, angiotensins, and oxidases, cyclo-oxygenases, and mitochondrial electron
thromboxane A2. Agonist-induced activation of G protein- transport.9 Superoxide anion may directly inactivate NO and
coupled receptors increases influx of extracellular calcium decrease its bioavailability. Moreover, the reaction of super-
and increases phospholipase C (PLC) activity. PLC cleaves oxide anion and NO results in the formation of reactive nitro-
membrane-bound phosphatidyl inositol into inositol tris- gen species such as the highly toxic molecule peroxynitrite.
phosphate and diacylglycerol, resulting in an elevation of Peroxynitrite may cause oxidative damage to DNA, proteins
intracellular calcium concentrations.15 During this phase, and lipids, uncouple eNOS, promote release of vasocons-
calcium–calmodulin activates myosin light chain kinase, trictors, increase apoptosis, and cause tissue injury and
leading to increased phosphorylation of myosin light chain, inflammation.9,18 Enzymes that degrade ROS, such as super-
actin–myosin assembly, and initiation of smooth muscle oxide dismutase, catalase, and glutathione peroxidase, play
contraction.16,17 Increased production of vasoconstrictors may an important role in the cellular protection against ROS.18
decrease vasodilation and result in ED. Increased oxidative stress has been implicated in the patho-
physiology of ED (Figure 10.5).

RhoA–Rho-kinase pathway
Growth factors and cytokines
While smooth muscle contraction is regulated primarily by
cytosolic calcium, once the calcium levels return to basal levels, Growth factors act as paracrine and autocrine regulators in the
the calcium-independent increase in vascular smooth muscle vasculature. Vascular endothelial growth factor (VEGF),19–21
tone, known as calcium-sensitization, takes over. This path- insulin-like growth factor (IGF) and its binding proteins,21
way involves RhoA and its downstream effector Rho-kinase. basic fibroblast growth factor (bFGF),22 and transforming
Activated Rho-kinase phosphorylates myosin light chain phos- growth factor (TGF)-beta-123 have been characterized in the
phatase and thereby inhibits its activity, resulting in enhanced penis. VEGF is an angiogenic factor that directly activates
contractile response at low calcium levels (Figure 10.4).6–8 eNOS24 and regulates apoptosis.25 IGF-1 has been implicated
Upregulated function or activity of the RhoA–Rho-kinase in the regulation of vascular smooth muscle proliferation and
pathway may increase smooth muscle contractility and result migration, and it plays a role in the control of cell growth, cell
in ED. survival, and mitogenesis.26 The cytokine TGF-beta-1 promotes
the synthesis of collagen and inhibits growth of vascular
smooth muscle cells.27 Impaired production of growth factors
Reactive oxygen species and cytokines and their impaired signaling in the penis accord-
ROS may affect eNOS activity, endothelial NO availability, ingly may impact the function and structure of endothelial
smooth muscle cell integrity, and RhoA–Rho-kinase pathway and cavernosal smooth muscle cells.
function. Superoxide anion is produced in a variety of cells,
including vascular smooth muscle cells and endothelial cells.
Many other ROS are formed secondary to reactions involving Neurogenic erectile dysfunction
superoxide. Potential sources of superoxide anion include
nicotinamide adenine dinucleotide phosphate [NAD(P)H] Neurogenic ED results from any defect in neurotransmission
oxidase, uncoupled eNOS, xanthine oxidase, peroxisomal to the smooth muscle of the penis. It can be related to trauma
 Pathophysiology of erectile dysfunction: molecular basis 75

Oxidative–nitrosative stress

Cell type Endothelial cells Smooth muscle cells Nerve cells

Mechanism • eNOS uncoupling, • RhoA–Rho-kinase • nNOS uncoupling (?),

protein interaction • Ion channels protein interaction,
subcellular localization, (Potassium channels) subcellular localization,
phosphorylation phosphorylation (?)
• NO-independent factors • Inducible NOS
• PARP

Effect
• Decreased • Increased • Altered
vasorelaxation vasoconstriction neurotransmission
• Endothelial cell loss • Fibrosis • Neurodegeneration

ED

Figure 10.5 Proposed model of oxidative–nitrosative stress in ED. Several ROS, such as superoxide anion, hydrogen peroxide,
hypochlorous acid, hydroxyl radical, reactive aldehydes, lipid peroxides, and peroxynitrite, are believed to mediate cellular
degeneration in vasculogenic and neurogenic ED states. Peroxynitrite formation resulting from the direct interaction between
superoxide ion and an excess of NO (such as inducible NOS-generated NO) is referred to as nitrosative stress. ROS may attack
proteins, lipids, and nucleic acids, and they may further generate ROS and potentiate oxidative–nitrosative stress. ROS may produce
a number of pathological effects at all cellular levels involved in penile erection. Some of the effects are unique for different cell
types, while some other effects may be common among different cell types. Numerous effectors and signaling mechanisms are targets
for ROS, such as guanylyl cyclase, phospholipases, phosphatases and protein kinases, ion channels, gene expression and production
of growth factors, stress response elements, and apoptosis pathways. All NOS isoforms are subject to ‘uncoupling’ by ROS as a result
of oxidation of the zinc thiolate cluster of the enzyme and the cofactor tetrahydrobiopterin, and the decreased availability of the NOS
substrate L-arginine, destabilizing the NOS dimer and resulting in the increased production of ROS and reduced NO production by
the enzyme. ROS may activate numerous transcriptional factors such as nuclear factor-kappa-B (NF-κB), hypoxia-inducible factor-
1-alpha (HIF-1-alpha), and activator protein-1 (AP-1). Activation of poly (ADP-ribose) polymerase (PARP) in response to ROS-
mediated DNA strand breaks depletes intracellular energy reserves and causes necrotic cell death. Similarly, changes in anti-apoptotic
markers, such as phosphorylated protein kinase B (Akt), B-cell CLL/lymphoma 2 (Bcl-2) and phosphorylated BCL2-antagonist of cell
death (Bad), and pro-apoptotic markers, such as active caspase-3 and BCL2-associated X protein (Bax), may result in apoptosis
affecting different cell types. ROS may also affect the production and action of growth factors and cytokines involved in erection. In
endothelial cells, ROS may affect eNOS-dependent and NO-independent vasorelaxing factors, resulting in decreased vasorelaxation
and endothelial cell loss. In smooth muscle cells, ROS can affect vascular reactivity via direct action on receptors, ion channels (for
potassium, calcium, sodium, and chloride) or via specific signaling pathways, such as activation of the RhoA–Rho-kinase pathway,
resulting in increased vasoconstriction and tissue fibrosis. Neuronal cell death may occur as a result of PARP activation and increased
apoptosis, resulting in altered neurotransmission and neurodegeneration. Many other, still not fully explained, mechanisms may also
be involved in oxidative–nitrosative stress-induced ED.

to nerves, such as occurs in spinal cord injury; it can occur Neuronal nitric oxide synthase
after injury of nerves as a consequence of surgeries for cancer Nitrergic neurotransmission refers to neuronal NO signaling
of the prostate, bladder and colon; and it can be an associated in penile erection. The nitrergic activation of penile erection
element of a neurological disease such as multiple sclerosis. involves discrete brain regions such as the medial preoptic
More commonly, neurogenic ED results from the degenera- area (MPOA)29,30 and the paraventricular nucleus (PVN)31–33
tion and loss of the nerves associated with non-traumatic within the hypothalamus where the erectile stimuli originate,
chronic diseases such as diabetes. Although the molecular the L6–S1 region of the spinal cord, and the peripheral nerves
mechanisms underlying neurogenic ED are not well under- of the corpora cavernosa.34 Accordingly, any disease state
stood, the principal theories include impairment in nNOS involving disturbances in nitrergic transmission represents a
function and NO bioavailability, reduced blood supply to neurologic basis of ED.
nerve tissue, deficiency of neurohormonal growth factors, and nNOS activity is regulated at the transcriptional level and
increased oxidative stress.28 by multi-site phosphorylation, protein–protein interactions,
The following section represents a sub-categorization of and subcellular localization mechanisms.35–38 Psychogenic
major neurogenic molecular mechanisms involved in normal and tactile (reflexogenic) stimuli initiate penile erection
erectile function. This framework can be applied to facilitate through the activation of nNOS. This is achieved mainly by
understanding of mechanisms of neurogenic ED.
76 Textbook of Erectile Dysfunction

depolarization-induced calcium entry and calcium binding NOS substrate, L-arginine,65,69,70 reduced activation of protein
to calmodulin by means of calcium flux through the N- kinase G-I by cGMP,71 and excessive cGMP degradation by
methyl-D-aspartate receptor (NMDAR).39 Both the NMDAR upregulated PDE-5.72 Increased phosphorylation of eNOS at
and inhibitors of nNOS activity, such as protein inhibitor of Thr-495, a negative eNOS regulatory site, prevents eNOS
NOS (PIN) and the carboxyterminal PDZ ligand of nNOS phosphorylation at Ser-1177, a positive eNOS regulatory site,
(CAPON), are expressed in pelvic ganglia and penile nerves and prevents eNOS activation in the penis by shear stress, a
(in the case of PIN, NMDAR, CAPON)40,41 and in the hypo- physiological eNOS stimulator in the vasculature.68 At the
thalamic and spinal cord regions involved in penile erection smooth muscle cell level, vasoconstriction is increased mainly
(in the case of PIN).42 Derangement of nNOS expression and through an upregulation of endothelin and RhoA–Rho-kinase
nNOS activity, including its interaction with its modulators, activation.72–74
may compromise nitrergic control of erection. Cavernosal smooth muscle cells progressively degenerate,
owing to increased apoptosis and impaired growth factor and
cytokine signaling in the penis. Enhanced apoptotic and
Other neurotransmitters decreased anti-apoptotic activities have been demonstrated in
A host of neurotransmitters besides NO are involved in penile the corpora cavernosa of aged animals.75,76 The production of
erection. At the levels of brain and spinal cord they include VEGF64 and IGF-177 is decreased, while TGF-beta-1 produc-
facilitatory neurotransmitters of penile erection (such as tion is increased78 in the penis of aged animals. The molecular
dopamine, acetylcholine, oxytocin, and adrenocorticotropic– explanation for the stimulatory effects of VEGF on penile
alpha-melanocyte-stimulating hormone), or inhibitory neuro- erection is preservation of eNOS function via phosphoryla-
transmitters (such as gamma aminobutyric acid (GABA), tion24 and preservation of corporal smooth muscle integrity
serotonin, and opioid peptides).43–47 It is possible that defective through the inhibition of apoptosis.25 Increased production of
neurotransmission involving such neurochemicals contributes the cytokine TGF-beta-1 promotes the synthesis of collagen,
to neurogenic ED. inhibits growth of vascular smooth muscle cells, and causes
tissue fibrosis.27 Apoptosis and degeneration of smooth mus-
cles, increase in connective tissue, and fibrosis in the penis all
Growth factors and neurotrophic factors lead to corporal veno-occlusive dysfunction and ED.75,79
Many paracrine and autocrine factors can modulate the erec- Molecular mechanisms underlying decreased neurogenic-
tile response by affecting neuronal development and neuron mediated corpus cavernosum relaxation associated with aging
regeneration. They include classic neurotrophins (such as involve disturbances in the central and peripheral systems
nerve growth factor (NGF)),48 brain-derived neurotrophic fac- of neurotransmission. Central neuropathy involves increased
tor (BDNF),49,50 neurotrophin-3 (NT-3), and neurotrophin-4 apoptosis in the hypothalamic PVN and MPOA.80 Neuronal
(NT-4),51 growth factors (fibroblast growth factor, VEGF, IGF-1 loss in the brain has been attributed to an increase in the
and IGF binding protein-3),52,53 immunophilin ligands,54–58 rate of apoptosis by oxidative and nitrosative stress. The hypo-
and atypical neurotrophic factors (such as growth hormones,59 thalamic PVN and MPOA of aged rats exhibit increased
the glial cell derived neurturin,60 the morphogenic sonic expression of inducible NOS,80 which may lead to excessive
hedgehog protein,61 and erythropoietin).62 Impairment in the production of NO and consequently of peroxynitrite. Peripheral
production and action of these factors may compromise mechanisms have been attributed to a reduction in nitrergic
penile erection. penile nerve fibers in the penis and decreased nNOS expres-
sion and activity,81–83 resulting in insufficient production of
NO at the penile nerve terminals in response to sexual stimu-
Reactive oxygen species lation. Inadequate nNOS activation in the penis of aged rats
As with endothelial-dependent vasorelaxation, nitrergic neuro- may be restored by inhibition of PIN, implying a role for this
transmission may be affected by oxidative stress. The brain endogenous nNOS inhibitor in the pathophysiology of age-
has relatively low levels of antioxidant defenses and a high associated neurogenic ED.84
lipid content, which is highly susceptible to ROS attack.63
Increases in oxidative stress may initiate apoptosis in nitrergic
nerves, affect nNOS dimerization, and reduce NOS cofactor Diabetes mellitus
availability.
Diabetes mellitus is one of the major risk factors for ED. It
has been estimated that 50–75% of diabetic men have ED.85
Aging Multiple mechanisms involving vasculogenic and neurogenic
factors are involved in ED associated with diabetes. Nutrition,
ED is highly associated with aging. Age-related ED is due to endocrine disorders, and anti-diabetic drugs have also been
vasculogenic and neurogenic factors. The vasculogenic com- implicated in the etiology of diabetic ED.86 Molecular mecha-
ponent of age-related ED includes disturbances at the level nisms involving oxidative stress may be common to both vascu-
of both endothelial and smooth muscle cells of the penis and lopathy and neuropathy in the diabetic penis.
its vascular supply. At the endothelial level, decreased NO- Metabolic disorders associated with diabetes include hyper-
mediated vasorelaxation has been attributed to impaired glycemia, excess free fatty acids, and insulin resistance. Hyper-
eNOS expression (decreased or increased),64–68 decreased glycemia is a fundamental metabolic insult in diabetes.
eNOS activity and phosphorylation,68 decreased content of the Hyperglycemia-induced oxidative stress may trigger several
 Pathophysiology of erectile dysfunction: molecular basis 77

pathways involved in the pathogenesis of diabetic complica- Hypercholesterolemia

tions. They include protein kinase C (PKC) activation and the
shift of glucose metabolism from the glycolytic pathway to Hypercholesterolemia resulting in atherosclerosis of the
minor forms of glucose metabolism, such as aldose reductase, penile vasculature is one of the leading causes of ED. ED has
hexosamine, and advanced glycation end-products (AGEs) been attributed to both vasculogenic and neurogenic factors,
pathways.87 Each pathway becomes perturbed as a consequence although the molecular mechanisms of the latter are largely
of hyperglycemia-mediated superoxide anion overproduction unknown.
by the mitochondrial electron transport chain.88 Activation of Decreased NO signaling and increased oxidative stress have
all these pathways has been implicated in the pathophysiology been postulated to be major molecular factors contributing to
of diabetic ED, as described below. hypercholesterolemia-induced ED. Reduced NO signaling in
Vascular impairment in the diabetic penis is due to reduced the penis occurs by several mechanisms:
vasorelaxation, increased vasoconstriction, and the loss of func-
tion and structure of smooth muscle cells. Endothelium- • reduction in eNOS expression;125,126
mediated vasorelaxation is decreased as a result of impaired • reduction in eNOS activity caused by decreased content of
127
eNOS expression,89,90 decreased eNOS activity (caused by L-arginine, decreased eNOS phosphorylation at Ser-
decreased availability of L-arginine91,92 and decreased eNOS 1177,125,126,128,129 increased caveolin-1 expression130 and its
phosphorylation at Ser-1177),93 dysregulation of cGMP- interaction with eNOS (Musicki and Burnett, unpublished
dependent protein kinase 1,94 decreased NO-independent data), which negatively regulates eNOS, and increased
relaxing factors,13,95,96 and decreased number of endothelial eNOS uncoupling (Musicki and Burnett, unpublished
cells.97 Increased flux of glucose through the hexosamine data); and
pathway generates N-acetylglucosamine (O-GlcNAc), which • deranged cGMP signal transduction pathways.131
prevents eNOS phosphorylation specifically at Ser-1177 and
its activation by shear stress and VEGF.93 Increased generation Endothelium-independent relaxation132,133 of the corpus cav-
and activity of the RhoA–Rho-kinase vasoconstrictive signaling ernosum is also decreased. Oxidative modification of low-
pathway89,98 further hampers vasorelaxation. Irreversible non- density lipoprotein (LDL), the major carrier of plasma
enzymatic reactions between high levels of glucose, proteins, cholesterol, plays a crucial role in the development of hyper-
and nucleic acids produce AGEs, which accumulate in the cholesterolemia-associated atherosclerosis. LDL can undergo
collagen of the diabetic tunica and endothelial and smooth oxidative modification by superoxide and peroxynitrite, and
muscle cells of the penis.99–101 AGEs alter extracellular matrix, it accumulates in atherosclerotic plaques. Corpus cavernosal
activate cellular receptors that stimulate ROS production, and tissue of cholesterol-fed animals exhibits increased production
alter intracellular protein function.102 Upregulated PKC in the of superoxide anion,131,134 caused by activated NAD(P)H
corpus cavernosum103 may increase NAD(P)H oxidase activity, oxidase131 and uncoupled eNOS (Musicki and Burnett, unpub-
inhibit post-translational activation of eNOS, induce eNOS lished data). eNOS uncoupling is not only associated with
uncoupling, and induce vasoconstriction, thereby reducing increased superoxide anion formation, which reacts with NO,
the bioavailability of NO.104 Increased aldose reductase activity thereby further generating peroxynitrite, but also with reduced
leads to accumulation of polyols, especially sorbitol, which NO production, because the electron flux is shifted from
18
L-arginine to molecular oxygen.
increases the consumption of NAD(P)H, a cofactor in NO
production, consequently reducing NO levels88 and resulting Vasoconstriction is increased through an upregulation of
in impaired vasorelaxation of the corpus cavernosum.105 As in cavernosal Rho-kinase activity.126 In the corpus cavernosum
age-related ED, changes in the production of growth factors the content of smooth muscle cells, endothelial cells, and
VEGF,106 IGF-1,107–109 basic fibroblast growth factor,110 and elastic fibers decreases, while collagen content increases.132,135–
137
TGF-beta111 promote apoptosis25,106,112,113 and induce a loss Reduced production of growth factors VEGF128,138 and basic
of smooth muscle cells, collagen deposition in the corpora fibroblast growth factor130,139 has been implicated in the impaired
cavernosa, and fibrosis. function and structure of endothelial and smooth muscle cells.
Diabetes-associated ED is also characterized by central and The effect of hypercholesterolemia on neurogenic neuro-
peripheral neuropathy.114 Central neuropathy involves a loss transmission remains largely unknown. Histological studies
of nNOS within the PVN of the hypothalamus.115 Diabetes is have shown damage to dorsal and cavernous nerves, with a
the most common cause of peripheral neuropathy. It has been decrease in the number and size of unmyelinated axons.136
attributed to progressive deterioration of nitrergic neurons, Future studies are needed to understand better the pathology
owing to apoptosis and decrease in nNOS content.116–121 In of neurogenic ED associated with hypercholesterolemia.
type 1 diabetic rats, decreased nNOS content in the axons of
nitrergic nerves, possibly caused by a defect in axonal trans-
port, is followed in more advanced diabetes by apoptosis Hypertension
of nitrergic nerve cell bodies. This leads to irreversible loss
of nNOS content and nitrergic function and a decrease in Approximately 30% of male hypertensive patients have ED.140
nerve fibers.122 Apoptotic cell death has been attributed to Despite many epidemiologic studies showing the link between
increased oxidative stress caused by the synergistic action of hypertension and ED, scientific studies establishing the cellu-
endogenous neuronal NO and extracellular AGEs.116,122,123 lar and molecular mechanisms for this link are sparse.
Altered sonic hedgehog signaling has also been implicated in Both endothelium-dependent141,142 and neurogenic NO-
diabetic neurogenic ED.124 and carbon monoxide-dependent relaxation of the corpus
78 Textbook of Erectile Dysfunction

cavernosum143 are decreased in hypertensive rats. Vascular dis- Summary and conclusion
turbances may result from decreased eNOS expression,144–146
increased cGMP degradation by upregulated PDE-5 and Many advances in the understanding of basic erection physio-
decreased NO bioavailability,147 and increased oxidative logy and pathophysiology have been made in the past 10 years.
stress143 in the penis. Endothelium-independent relaxation of These advances have revealed the complexity of regulation
the erectile tissue is enhanced in spontaneously hypertensive of erectile function, both under normal conditions and in
rats, possibly as a compensatory mechanism resulting from association with various disease states. Multiple molecular
defective endothelium-dependent relaxation.141,142 Increased pathways and mechanisms at the central nervous system level
peripheral vascular resistance in hypertension-associated ED and at the peripheral level regulate the normal erectile
is associated with increased RhoA expression and Rho-kinase response, and disturbances at any level will result in ED. The
activity in the penis.148,149 Angiotensin II is a potent vasocon- identification of the roles and mechanisms of action of vari-
strictor implicated in the development and maintenance of ous mediators, as well as their interactions, in normal erectile
hypertension. Within the vascular wall, angiotensin II, through function is a major scientific development in the study of ED.
the angiotensin I receptor, stimulates the production of ROS However, the precise physiologic and pathophysiologic mech-
by activation of NAD(P)H oxidase.150 While the corpus caver- anisms are still incompletely known. For example, there are
nosum of spontaneously hypertensive rats exhibits increased many unanswered questions about the role of oxidative stress
lipid peroxidation and decreased superoxide dismutase (SOD) and the sources of ROS in the penis, the role and regulation of
levels,143 the source of ROS has not been investigated. Blood the RhoA–Rho-kinase pathway, the factors involved in the
vessels manifest decreased lumen diameter and thickening of regulation of eNOS and nNOS function, and the neurogenic
the wall.151 Morphologic changes in the penis involve endothe- mechanisms involved in erection biology. In addition, while
lial and smooth muscle damage, smooth muscle proliferation, many ED presentations may share similar underlying mole-
increased collagen deposition, and thinning of the tunica cular derangements, recent studies have demonstrated that a
albuginea.142,152–154 unique molecular determinant or mechanism may predomi-
nate in a specific disease state. Further studies are needed to
elucidate specific mechanisms associated with specific disease
Metabolic syndrome states. Further understanding of the molecular basis of ED
The metabolic syndrome (also known as syndrome X and may lead to the development of new therapeutic avenues
insulin resistance syndrome) refers to a minimum of three of based on targeting a specific mechanism associated with a
the following disorders, each of which is an independent risk specific ED condition.
factor for ED: abdominal obesity, hypertension, insulin resis-
tance, high fasting blood glucose, and dyslipidemia.155 A high
incidence of metabolic syndrome has been demonstrated in
men with ED.156–159 In an animal model of metabolic syndrome, Acknowledgment
decreased erectile response has been attributed to increased
smooth muscle contraction.160 However, the exact molecular This work was supported by NIH/NIDDK grants DK067223
mechanisms by which the combination of different derange- and DKDK064679 (to ALB), and DK075782 and DK074826
ments produces ED are poorly defined to date. (to BM).

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76. Yamanaka M, Shirai M, Shiina H, et al. Loss of anti-apoptotic endothelial and smooth muscle density in the corpora caver-
genes in aging rat crura. J Urol 2002; 168: 2296–300. nosa of streptozotocin induced diabetic rat. J Urol 2000; 164:
77. Liu X, Lin CS, Spencer EM, et al. Insulin-like growth factor-I pro- 1807–11.
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78. Dahiya R, Chui R, Perinchery G, et al. Differential gene expres- lin is mediated via Rho-kinase beta. Int J Impot Res 2003; 15:
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201–6. ucts in human penis: elevation in diabetic tissue, site of deposi-
79. Ferrini MG, Kovanecz I, Sanchez S, et al. Long-term continuous tion, and possible effect through iNOS or eNOS. Urology 1997;
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Reprod 2007; 76: 915–23. aminoguanidine on erectile function in streptozotocin-diabetic
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81. Carrier S, Nagaraju P, Morgan DM, et al. Age decreases nitric 402–7.
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1997; 157: 1088–92. products: a review. Diabetologia 2001; 44: 129–46.
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103. Angulo J, Cuevas P, Fernández A, et al. Enhanced thromboxane 124. Podlasek CA, Zelner DJ, Harris JD, et al. Altered sonic hedgehog
receptor-mediated responses and impaired endothelium-dependent signaling is associated with morphological abnormalities in
relaxation in human corpus cavernosum from diabetic impotent the penis of the BB/WOR diabetic rat. Biol Reprod 2003; 69:
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2006; 319: 783–9. 125. Xie D, Kontos CD, Donatucci CF, et al. Cholesterol feeding
104. Hink U, Li H, Mollnau H, et al. Mechanisms underlying endothe- reduces vascular endothelial growth factor signaling in rabbit
lial dysfunction in diabetes mellitus. Circ Res 2001; 88: E14–22. corporal tissues. J Sex Med 2005; 2: 634–40.
105. Keegan A, Jack AM, Cotter MA, et al. Effects of aldose reductase 126. Park K, Kim SW, Rhu KS, et al. Chronic administration of an
inhibition on responses of the corpus cavernosum and mesen- oral Rho kinase inhibitor prevents the development of vasculo-
teric vascular bed of diabetic rats. J Cardiovasc Pharmacol 2000; genic erectile dysfunction in a rat model. J Sex Med 2006; 3:
35: 606–13. 996–1003.
106. Jesmin S, Sakuma I, Salah-Eldin A, et al. Diminished penile 127. Azadzoi KM, Goldstein I, Siroky MB, et al. Mechanisms of
expression of vascular endothelial growth factor and its receptors ischemia-induced cavernosal smooth muscle relaxation impair-
at the insulin-resistant stage of a type II diabetic rat model: a pos- ment in a rabbit model of vasculogenic erectile dysfunction.
sible cause for erectile dysfunction in diabetes. J Mol Endocrinol J Urol 1998; 160: 2216–22.
2003; 31: 401–18. 128. Ryu JK, Cho CH, Shin HY, et al. Combined angiopoietin-1 and
107. Pu XY, Hu LQ, Wang HP, et al. Improvement in erectile dysfunc- vascular endothelial growth factor gene transfer restores cavernous
tion after insulin-like growth factor-1 gene therapy in diabetic angiogenesis and erectile function in a rat model of hypercholes-
rats. Asian J Androl 2007; 9: 83–91. terolemia. Mol Ther 2006; 13: 705–15.
108. Shirai M, Yamanaka M, Shiina H, et al. Vascular endothelial 129. Ryu JK, Shin HY, Song SU, et al. Downregulation of angiogenic
growth factor restores erectile function through modulation of factors and their downstream target molecules affects the deterio-
the insulin-like growth factor system and sex hormone receptors ration of erectile function in a rat model of hypercholesterolemia.
in diabetic rat. Biochem Biophys Res Commun 2006; 341: Urology 2006; 67: 1329–34.
755–62. 130. Bakircioglu ME, Hsu K, El-Sakka A, et al. Effect of a Chinese
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function in diabetic rats by insulin: possible role of the insulin- erectile dysfunction. J Urol 2000; 164: 1798–801.
like growth factor system. Endocrinology 1998; 139: 3143–7. 131. Shukla N, Jones R, Persad R, et al. Effect of sildenafil citrate and
110. Suetomi T, Hisasue S, Sato Y, et al. Effect of basic fibroblast a nitric oxide donating sildenafil derivative, NCX 911, on caver-
growth factor incorporating gelatin microspheres on erectile nosal relaxation and superoxide formation in hypercholestero-
function in the diabetic rat. J Urol 2005; 173: 1423–8. laemic rabbits. Eur J Pharmacol 2005; 517: 224–31.
111. Ahn GJ, Sohn YS, Kang KK, et al. The effect of PDE5 inhibition 132. Kim JH, Klyachkin ML, Svendsen E, et al. Experimental hyper-
on the erectile function in streptozotocin-induced diabetic rats. cholesterolemia in rabbits induces cavernosal atherosclerosis
Int J Impot Res 2005; 17: 134–41. with endothelial and smooth muscle cell dysfunction. J Urol
112. Seftel AD, Maclennan GT, Chen ZJ, et al. Loss of TGFbeta, apop- 1994; 151: 198–205.
tosis, and Bcl-2 in erectile dysfunction and upregulation of 133. Behr-Roussel D, Bernabe J, Compagnie S, et al. Distinct mecha-
p53 and HIF-1alpha in diabetes-associated erectile dysfunction. nisms implicated in atherosclerosis-induced erectile dysfunction
Mol Urol 1999; 3: 103–7. in rabbits. Atherosclerosis 2002; 162: 355–62.
113. Yamanaka M, Shirai M, Shiina H, et al. Diabetes induced erectile 134. Kim SC, Kim IK, Seo KK, et al. Involvement of superoxide radical
dysfunction and apoptosis in penile crura are recovered by insu- in the impaired endothelium-dependent relaxation of cavernous
lin treatment in rats. J Urol 2003; 170: 291–7. smooth muscle in hypercholesterolemic rabbits. Urol Res 1997;
114. McVary KT, Rathnau CH, McKenna KE. Sexual dysfunction in the 25: 341–6.
diabetic BB/WOR rat: a role of central neuropathy. Am J Physiol 135. Yesilli C, Yaman O, Anafarta K. Effect of experimental hyper-
Regul Integr Comp Physiol 1997; 272: R252–67. cholesterolemia on cavernosal structures. Urology 2001; 57:
115. Zheng H, Bidasee KR, Mayhan WG, et al. Lack of central nitric 1184–8.
oxide triggers erectile dysfunction in diabetes. Am J Physiol Regul 136. Gholami SS, Rogers R, Chang J, et al. The effect of vascular
Integr Comp Physiol 2007; 292: R1158–64. endothelial growth factor and adeno-associated virus mediated
116. Cellek S, Rodrigo J, Lobos E, et al. Selective nitrergic neurode- brain derived neurotrophic factor on neurogenic and vasculo-
generation in diabetes mellitus: a nitric oxide-dependent pheno- genic erectile dysfunction induced by hyperlipidemia. J Urol
menon. Br J Pharmacol 1999; 128: 1804–12. 2003; 169: 1577–81.
117. El-Sakka AI, Lin CS, Chui RM, et al. Effects of diabetes on nitric 137. Nehra A, Azadzoi KM, Moreland RB, et al. Cavernosal expand-
oxide synthase and growth factor genes and protein expression ability is an erectile tissue mechanical property which predicts
in an animal model. Int J Impot Res 1999; 11: 123–32. trabecular histology in an animal model of vasculogenic erectile
118. Podlasek CA, Zelner DJ, Bervig TR, et al. Characterization dysfunction. J Urol 1998; 159: 2229–36.
and localization of nitric oxide synthase isoforms in the BB/WOR 138. Xie DH, Thompson MA, Pippen AM, et al. Decreases in corporal
diabetic rat. J Urol 2001; 166: 746–55. VEGF expression precede vasoreactivity changes in cholesterol
119. Vernet D, Cai L, Garban H, et al. Reduction of penile nitric oxide fed rabbits. J Urol 2005; 173: 1418–22.
synthase in diabetic BB/WORdp (type I) and BBZ/WORdp (type 139. Dai Q, Silverstein AD, Davies MG, et al. Systemic basic fibro-
II) rats with erectile dysfunction. Endocrinology 1995; 136: blast growth factor induces favorable histological changes in the
5709–17. corpus cavernosum of hypercholesterolemic rabbits. J Urol 2003;
120. Akingba AG, Burnett AL. Endothelial nitric oxide synthase 170: 664–8.
protein expression, localization, and activity in the penis of the 140. Kloner R. Erectile dysfunction and hypertension. Int J Impot Res
alloxan-induced diabetic rat. Mol Urol 2001; 5: 189–97. 2007; 19: 296–302.
121. Azadzoi KM, Saenz de Tejada I. Diabetes mellitus impairs neuro- 141. Behr-Roussel D, Chamiot-Clerc P, Bernabe J, et al. Erectile dys-
genic and endothelium-dependent relaxation of rabbit corpus function in spontaneously hypertensive rats: pathophysiological
cavernosum smooth muscle. J Urol 1992; 148: 1587–91. mechanisms. Am J Physiol Regul Integr Comp Physiol 2003; 284:
122. Cellek NA, Foxwell NA, Moncada S. Two phases of nitrergic R682–8.
neuropathy in streptozotocin-induced diabetic rats. Diabetes 142. Behr-Roussel D, Gorny D, Mevel K, et al. Erectile dysfunction: an
2003; 52: 2353–62. early marker for hypertension? A longitudinal study in spontane-
123. Cellek S, Qu W, Moncada S. Synergistic action of advanced ously hypertensive rats. Am J Physiol Regul Integr Comp Physiol
glycation end products and endogenous nitric oxide leads to 2005; 288: R276–83.
neuronal apoptosis in vitro: a new insight into selective nitrergic 143. Ushiyama M, Morita T, Kuramochi T, et al. Erectile dysfunction
neuropathy in diabetes. Diabetologia 2004; 47: 331–9. in hypertensive rats results from impairment of the relaxation
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evoked by neurogenic carbon monoxide and nitric oxide. 152. Toblli JE, et al. Morphological changes in cavernous tissue in
Hypertens Res 2004; 27: 253–61. spontaneously hypertensive rats. Am J Hypertens 2000; 13:
144. Toblli JE, Cao G, Casas G, et al. In vivo and in vitro effects of 68692.
nebivolol on penile structures in hypertensive rats. Am J Hyper- 153. Jiang R, Chen JH, Jin J, et al. Ultrastructural comparison of penile
ten 2006; 19: 1226–32. cavernous tissue between hypertensive and normotensive rats.
145. Yono M, Yamamoto Y, Yoshida M, et al. Effects of doxazosin on Int J Impot Res 2005; 17: 417–23.
blood flow and mRNA expression of nitric oxide synthase in the 154. Okabe H, Hale TM, Kumon H, et al. The penis is not protected –
spontaneously hypertensive rat genitourinary tract. Life Sci 2007; in hypertension there are vascular changes in the penis which are
81: 218–22. similar to those in other vascular beds. Int J Impot Res 1999; 11:
146. Mazza ON, Angerosa M, Becher E, et al. Differences between 133–40.
Candesartan and Hydralazine in the protection of penile struc- 155. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syn-
tures in spontaneously hypertensive rats. J Sex Med 2006; 3: drome among US adults: findings from the third National Health
604–11. and Nutrition Examination Survey. JAMA 2002; 287: 356–9.
147. Shamloul R, Wang R. Increased intracavernosal pressure response 156. Demir T. Prevalence of erectile dysfunction in patients with
in hypertensive rats after chronic hemin treatment. J Sex Med metabolic syndrome. Int J Urol 2006; 13: 385–8.
2006; 3: 619–27. 157. Müller A, Mulhall JP. Cardiovascular disease, metabolic
148. Wilkes N, White S, Stein P, et al. Phosphodiesterase-5 inhibition syndrome and erectile dysfunction. Curr Opin Urol 2006; 16:
synergizes rho-kinase antagonism and enhances erectile response 435–43.
in male hypertensive rats. Int J Impot Res 2004; 16: 187–94. 158. Esposito K, Giugliano F, Martedì E, et al. High proportions of erec-
149. Chitaley K, Webb RC, Dorrance AM, et al. Decreased penile tile dysfunction in men with the metabolic syndrome. Diabetes
erection in DOCA-salt and stroke-prone spontaneously hyperten- Care 2005; 28: 1201–3.
sive rats. Int J Impot Res 2001; 13: S16–20. 159. Kupelian V, Shabsigh R, Araujo AB, et al. Erectile dysfunction as
150. Touyz RM. Intracellular mechanisms involved in vascular remod- a predictor of the metabolic syndrome in aging men: results from
elling of resistance arteries in hypertension: role of angiotensin II. the Massachusetts Male Aging Study. J Urol 2006; 176: 222–6.
Exp Physiol 2005; 90: 449–55. 160. Wingard C, Fulton D, Husain S. Altered penile vascular reactivity
151. Mulvany MJ. Vascular remodelling of resistance vessels: can we and erection in the Zucker obese-diabetic rat. J Sex Med 2007;
define this? Cardiovasc Res 1999; 41: 9–13. 4: 348–63.
11 Neurotransmitters in the corpus
cavernosum: nitric oxide and beyond
Anthony J Bella, William O Brant, Gerald B Brock, and Tom F Lue

Introduction response of calcium transport and calcium sensitizing mecha-

nisms to relaxant and contractile factors determines smooth
Cavernous smooth muscle contraction and relaxation, and the muscle tone, and thus, erectile state.4
resultant states of penile flaccidity and erection, are primarily In this chapter, the principal and secondary neurotrans-
dependent upon cytosolic calcium levels.1 Smooth muscle mitters responsible for the contraction and relaxation of
tone is itself regulated by the complex interplay between extra- cavernous smooth muscle are reviewed, as are primary
cellular signals and intracellular events governing vasorelaxant mechanisms of action (cAMP and cGMP second messenger
and vasoconstrictive physiologic mechanisms.2 The neuro- signaling systems), and the role of RhoA–Rho kinase in calcium
transmitters of the corpus cavernosum are responsible for sensitization.
smooth muscle effects via activation of downstream second
messenger molecules, alteration of ion channel permeabilities,
and activation of cell-to-cell communication through gap Neurotransmitters of the
junctions.3 The primary molecular events for penile erection
may be summarized as follows. corpus cavernosum
1. In the flaccid state, cavernosal smooth muscle contrac- Flaccidity and detumescence
tion is maintained by vasoconstrictors such as nor- The primary local control of penile detumescence is adrenergic
epinephrine and endothelin-1 (ET-1).4 The downstream (Figure 11.1). Alpha-adrenergic nerve fibers and receptors
RhoA–Rho-kinase signaling pathway maintains constric- have been identified in the cavernosal and helicine arteries,
tion of the cavernosal arterioles and sinuses, helping to as well as in corporal smooth muscle, and norepinephrine
maintain the penis in the flaccid state.2 Intrinsic myogenic is considered the principal neurotransmitter controlling
activity also contributes to maintenance of smooth muscle penile flaccidity and detumescence.7 Adrenergic receptors
tone.5 outnumber cholinergic fibers in the penis, and receptor-
2. Following sexual stimulation, nitric oxide (NO) is released binding studies have shown the ratio of alpha-adrenoceptors
from non-adrenergic non-cholinergic nerve endings and to beta-adrenoceptors to be almost 10:1.8 Functionally, adren-
the endothelium of the penis. NO is the principal neuro- ergic stimulation results in vasoconstriction of the penile
transmitter mediating penile erection and is synthesized arteries and contraction of the trabecular smooth muscle,
by neuronal NO synthase (nNOS) and endothelial NO causing a reduction in arterial inflow and collapse of the
synthase (eNOS).6 lacunar spaces, respectively.7,9 Trabecular smooth muscle con-
3. NO activates the cGMP–protein kinase G (PKG) signaling traction causes decompression of the drainage venules from
cascade, resulting in corporal smooth muscle relaxation, the cavernous bodies, allowing flow to the lacunar spaces.4
reduced resistance of cavernosal arterioles, and increased Contemporary understanding of sympathetic contraction
blood flow to the corpora cavernosa.2–4 The end result is suggests that this process is mediated by activation of more
an erect penis. than one alpha-receptor subtype sensitive to norepinephrine, as
4. Detumescence occurs as NO release ceases and cGMP is well as secondary responses to circulating catecholamines.3,10,11
broken down by phosphodiesterases. In addition, sympa- Activation of postsynaptic alpha-1a- and alpha-1d-adrenergic
thetic discharge occurs if sexual stimulation results in receptors (the dominant penile subtypes) provokes an initial
ejaculation.1 release of intracellular calcium, followed by subsequent extra-
cellular calcium entry for the maintenance of the contractile
These processes are dependent upon calcium homeostasis, tone.1,12 Contraction is then modulated by presynaptic alpha-
which is achieved in the penile smooth muscle by voltage-gated 2-adrenergic receptors.1,9 Of note, alpha-2a-, alpha-2b-, and
channel influx of extracellular calcium membrane-bound alpha-2c-adrenoreceptors are present on cholinergic nerve
receptor activation allowing influx of calcium through receptor- terminals within the penis, inhibiting non-adrenergic, non-
operated channels, and specific signaling pathways stimulated cholinergic transmitter release by prejunctional norepineph-
by calcium release from the sarcoplasmic reticulum.3 The net rine in addition to producing postjunctional vasoconstriction;

83
84 Textbook of Erectile Dysfunction

Adrenergic Smooth-
muscle cell Endothelial
Norepinephrine cell

G protein
α1 α2
Effector
(phospholipase C)

Diacylglycerol Receptors Adenylyl

cyclase

Protein Endothelins
kinase C Increased Decreased
inositol cAMP
triphosphate

Prostaglandin F-2α

Ca2+– Myosin light-

Endoplasmic calmodulin chain kinase
reticulum
Inactive

Ca2+–calmodulin–myosin
light-chain kinase complex
Active
Myosin light-chain
phosphorylation
Increased
Ca2+ Ca2+
Cycling of myosin
cross-bridges along actin Stimulation
Inhibition

Smooth-muscle
contraction

Figure 11.1 Molecular mechanism of penile smooth muscle contraction. Norepinephrine, endothelins and prostaglandin F-2α
activate receptors on smooth muscle cells to initiate the cascade of actions leading to an elevation of intracellular calcium
concentrations and smooth muscle contraction. From N Engl J Med 2000; 342: 1802–13.

these dual mechanisms function to maintain flaccidity. From G protein-coupled receptors mediate the contractile response
a clinical standpoint, the physiologic importance of adrener- through Gq stimulation and the cascade of phospholipase C
gic signaling has been confirmed by intracavernous injection activation, generation of inositol triphosphate and subsequent
of alpha-blocking agents, such as phentolamine, and alpha- increase in intracellular calcium; functionally, penile injection
agonists, such as phenylephrine, which result in penile erection of angiotensin II reverses spontaneous erections in dogs
and detumescence, respectively.3 and, in contrast, the angiotensin I receptor antagonist losartan
Prostaglandins are derived from arachidonic acid via the increases intracavernous pressures.3,15,18 Physiologically, intra-
cyclo-oxygenase mechanism, and several constrictor prosta- cavernous blood levels of angiotensin II are higher than the
noids, including prostaglandin I-2 (PGI-2), prostaglandin levels in systemic peripheral blood, and the levels increase in
F-2α (PGF-2α), and thromboxane A2 (TXA2) are synthesized the detumescence phase of human erection.19 Animal studies
by human cavernous tissue.1,4 Production of constrictor have also recently demonstrated that administration of an
prostanoids antagonizes effects of relaxant prostaglandins, angiotensin I receptor antagonist restored erectile function
including prostaglandin E-1 (PGE-1).4,13 In vitro studies have in normotensive aged rats.20 Therefore, human and animal
confirmed that prostanoids influence the tone and sponta- studies suggest that local production of angiotensin II may
neous activity of isolated trabecular muscle, while functional increase penile smooth muscle contractility by way of angio-
characterization of human trabecular and arterial penile tensin I receptors, facilitating penile detumescence.1
smooth muscle has demonstrated that only thromboxane Endothelins (ET) are potent vasoconstrictors produced by
prostanoid receptors mediate contractile effects of prostanoids the endothelial cells, occurring as three distinct subtypes: ET-1,
in the penis.12,13 Functionally, it has also been observed in vitro ET-2 and ET-3. ET-1 has been suggested as a likely mediator
that constrictor prostanoids, when simultaneously released for detumescence, because it is synthesized by the sinusoidal
with NO, attenuate the dilator effect of the NO.1,4,14 endothelium and possibly by trabecular muscle itself, it elicits
As angiotensin II has been identified at physiologic levels strong in vitro contractions of corpus cavernosa smooth
in the cavernous bodies of the human penis, the renin– muscle, and it is more potent that its counterparts.3,21–23 ET-1
angiotensin system may also play a role in the maintenance of also potentiates the constrictor effects of catecholamines on
penile smooth muscle tone.1,3 Angiotensin II, detected in both trabecular smooth muscle.24 Two receptors for endothelin
endothelial and smooth muscle cells of the corpus cavernosa, have been identified to date. ETA primarily is localized in vas-
evokes in vitro contraction of human and rabbit corporal cular smooth muscle and mediates vasoconstriction while its
smooth muscle via angiotensin I subtype receptors.15–17 These counterpart, ETB, is predominantly found in the endothelium
 Neurotransmitters in the corpus cavernosum: nitric oxide and beyond 85

and mediates vasodilation of vascular tissues (local release The cGMP signaling pathway is principally responsible for
of NO).3 The mechanism of intracellular transduction for both penile erection. The most physiologically relevant target for
receptors is the degradation of inositol phosphate, resulting in NO is soluble guanylyl cyclase (sGC); NO, because of its small
the release of intracellular calcium and activation of protein size, diffuses into the cell and binds to sGC in the cytoplasm.34
kinase C (PKC).1,3,21 Endothelin has been suggested to regulate Activation of the NO–sGC–cGMP pathway results in smooth
smooth muscle proliferation in the penis by regulating gene muscle relaxation, as the ‘second messenger’ cGMP activates
expression.25 It is also of interest that a recently reported study cGMP-dependent protein kinases, resulting in phosphorylation
demonstrated increased mean plasma levels for both ET-1 of specific proteins and ion channels.1 The soluble isoform
and AT-2 in patients with erectile dysfunction (ED), identify- sGC plays a pivotal role in erectile function because it pro-
ing these two molecules as exciting targets requiring further vides the link between NO and cGMP, which represent the
study.26 extracellular and intracellular signaling molecules for penile
Other neurotransmitters localized to the penis that demon- erection, respectively.35
strate vasoconstrictor actions include neuropeptide Y, arginine Protein kinase G (PKG), also known as cGMP-dependent
vasopressin, and substance P. The clinical significance of these kinase (cGK), is the principal receptor and mediator for
molecules remains to be elucidated. cGMP signals.3,27 Regulation of cavernous smooth muscle
In summary, current evidence suggests that maintenance of tone occurs through PKG-I alpha and beta isoforms; follow-
the cavernous smooth muscle in a semicontracted (flaccid ing activation, PKG-1 activates potassium channels and the
penis) state is dependent upon four mechanisms: sodium–potassium–adenosine triphosphatase (Na+–K+–
ATPase) pump.6 Inhibition of calcium influx leads to decreased
• intrinsic myogenic activity; levels of intracellular calcium and cavernous smooth muscle
• adrenergic neurotransmission; relaxation.4
• endothelium-derived contracting factors, such as angio- In summary, activation of non-adrenergic, non-cholinergic
tensin II, PGF-2α, and ET-1; nerves to the corpus cavernosum as a result of sexual stimula-
• and calcium-sensitizing pathways (see the section on tion results in NO release, activation of soluble guanylyl
RhoA–Rho kinase, pages 87–88).1,5 cyclase, and cGMP production. Subsequent downstream events
On the other hand, and as described previously, detumescence lead to smooth muscle relaxation. eNOS activation in response
occurs as a result of: to shear stresses to the endothelial lining contributes to rigidity
and maintenance of penile erection. Phosphodiesterase-5
• the cessation of NO release; terminates cGMP signaling by catalyzing hydrolysis to GMP.
• sympathetic discharge at ejaculation, and Although the cGMP-signaling pathway is also activated by
• the breakdown of cGMP by phosphodiesterases. natriuretic peptides, including atrial, brain, and C-type forms,
their role (if any) in physiologic penile erection remains to be
determined.1
Penile erection
Nitric oxide and the cGMP signaling pathway
Nitric oxide (NO), which is released from non-adrenergic,
non-cholinergic neurotransmission and from the endothe- The cAMP signaling pathway and penile erection
lium, is the principal neurotransmitter mediating penile The cyclic adenosine monophosphate signaling molecules
erection (Figure 11.2).1,3,4,27 NO is a highly reactive and chemi- include adenosine, calcitonin gene-related peptides (CGRPs),
cally unstable free radical molecule known to regulate a diverse prostaglandins, and vasoactive intestinal polypeptide (VIP).4,27
range of physiologic functions, including smooth muscle These molecules bind and activate specific cytoplasmic mem-
relaxation, central and peripheral neurotransmission, platelet brane receptors, forming ligand-receptor complexes which
reactivity, and cytotoxicity of immune cells.28 NO increases interact with downstream G proteins and activate adenylyl
the production of cGMP, which in turn relaxes the cavernous cyclase (AC) (see Figure 11.2).1 AC increases intracellular
smooth muscle;29 nitric oxide synthase (NOS) uses L-arginine, an cAMP levels, which, in turn, activates the principal cAMP
amino acid, and molecular oxygen to form NO and the amino receptor, protein kinase A (PKA).1,3,27 PKA, also termed
acid L-citrulline via a reaction that also requires NAD(P)H cAMP-dependent kinase (cAK), regulates the subsequent
and tetrahydrobiopterin substrates (Figure 11.3).30 Three phosphorylation of a wide variety of cytoplasmic and nuclear
isoforms of NOS have been identified: neuronal NOS (nNOS), compartment downstream targets.36 Of the more than 100
endothelial NOS (eNOS), and inducible NOS (iNOS). nNOS is different cellular proteins identified as physiologic substrates
expressed in the cholinergic nerves of the penis, while eNOS of PKA, three substrate proteins have been identified in penile
is found in the endothelium. Contemporary data suggest tissue: phosphodiesterases (PDEs), cAMP-responsive element-
that nNOS-derived NO is responsible for the initiation of binding proteins (CREBs), and ATP-sensitive potassium
the smooth muscle relaxation, whereas inositol triphosphate (KATP) channels.1 Cytoplasmic levels of calcium are reduced by
kinase–Akt-dependent phosphorylation and activation of eNOS activated cAMP–PKA signaling, leading to cavernous smooth
leads to sustained NO production, maximal rigidity, and muscle relaxation; the role of this pathway in endogenous
maintenance of erection.31,32 Both of these isoforms require physiologic erection remains unclear but is probably limited
calcium and calmodulin for activity.27 On the other hand, to a minor role.4 Exogenous stimulation using agents such as
iNOS is calcium-independent and is upregulated following PGE-1, which lead to cAMP activation, however, is a clinically
exposure to inflammatory mediators.33 robust method of eliciting an erection. cAMP is inactivated
86 Textbook of Erectile Dysfunction

Cavernous nerve
Adrenergic
Smooth-
muscle cell
Cholinergic

Endothelial
cell Acetylcholine Forskolin

Prostaglandin E-1
Increased
inositol
triphosphate Receptors
G protein
Adenylyl
Ca2+ cyclase
L-Arginine cAMP
PDE-2,
O2 -3, -4
eNOS ATP

5’ AMP

Papaverine
cAMP-
Endoplasmic specific protein
Cavernous reticulum kinase
nerve
Ca2+
K+
Decreased Ca2+
Ca2+

Myosin
Nitric head detaches
oxide cGMP- from actin
specific protein
kinase
Non-adrenergic,
non-cholinergic
Smooth-
K+ muscle
Guanylyl relaxation
cyclase
cGMP
PDE-5
GTP

5’ GMP
Ca2+

Sildenafil Stimulation
Papaverine
Zaprinast Inhibition

Figure 11.2 Molecular mechanism of penile smooth muscle relaxation. The intracellular second messengers mediating smooth
muscle relaxation, cAMP and cGMP, activate specific protein kinases, which then phosphorylate target proteins and cause opening
of potassium channels, closing of calcium channels, and sequestration of intracellular calcium by the endoplasmic reticulum. The
resultant fall in intracellular calcium leads to smooth muscle relaxation. PDE, phosphodiesterase. From N Engl J Med 2000; 342:
1802–30.

by cleaving back to AMP by the action of cAMP-binding intracorporeal injection of VIP has not produced rigid erec-
phosphodiesterases.3 tion, but can improve success rates when combined with
VIP is a potent vasodilator, which is structurally related to papaverine and phentolamine.39,40 Although the role of VIP in
pituitary AC-activating polypeptide (PACAP).35 The human penile erection remains incompletely elucidated, VIP release
penis is richly supplied with nerves containing VIP, including has not been shown to be essential for neurogenic relaxation
a larger percentage of corporal trabecular and perivascular of human cavernous smooth muscle to date.41,42
nerve fibers.36,37 Interestingly, these fibers often demonstrate The most abundant prostanoids in the smooth muscle of
the presence of NOS, leading to the supposition that VIP may the human penis are PGE-1 and PGE-2. Of the four prosta-
act with NO as a possible co-mediator of penile erection.3 glandin receptors modulating relaxation, only EP-2 and EP-4
Unlike NO, VIP binding leads to smooth muscle relaxation subtypes are present in the arterial and trabecular smooth
through increased cAMP and PKA activation, inducing closure muscle of the penis.13 These receptors are coupled to an alphas-
of calcium channels and opening of potassium channels; VIP containing G protein, stimulating AC to increase intracellular
expression also appears to be androgen-independent.38 In men, cAMP; PGE-1 and PGE-2 activation of the cAMP pathway
 Neurotransmitters in the corpus cavernosum: nitric oxide and beyond 87

GTP

NADPH NADP+

Guanylate
L-Arg NO
cyclase
NOS + L-Citrulline
Ð

L-NAME
cGMP

Figure 11.3 Calcium influx triggers the activation of nitric oxide synthase (NOS), initiating the conversion of L-arginine (L-Arg) to
L-citrulline and nitric oxide (NO). NO diffuses to adjacent cells and activates soluble guanylate cyclase. Guanylate cyclase converts
GTP to cGMP, a second messenger that initiates smooth muscle relaxation. L-NAME, L-nitro-arginine methyl ester. From Textbook of
Erectile Dysfunction. Oxford: ISIS Medical Media, 1999 117–22.

relaxes the corpus cavernosum.13 Although prostaglandins Although acetylcholine is not the predominant neurotrans-
and prostaglandin receptors in erectile tissue have been clearly mitter, it does contribute indirectly to penile erection by
demonstrated, their roles in spontaneous physiologic erection acting via prejunctional muscarinic receptors to inhibit the
are yet to be defined. On the other hand, intracorporeal injec- release of norepinephrine from adrenergic neurons and
tion of PGE-1 has been safely used as an effective treatment stimulation of NO release from endothelial cells.1,9
for ED worldwide for more than 20 years.43 PGE-1-induced In the human corpus cavernosum, noradrenergic responses
elevation of intracellular levels of cAMP is three- to 10-fold, are under nitrergic control; high concentrations of norepi-
activating PKA and decreasing intracellular calcium levels and nephrine in the penis fail to show an effect when nitrergic
activating KCa channels; a secondary effect is the inhibition of neurotransmission is operating.4 Adrenergic neurons, as men-
norepinephrine release by binding prejunctional EP-13 tioned above, can also regulate the release of NO while acti-
receptors, which offsets corporal sympathetic tone.3,44,45 vation of the NO–cGMP-dependent protein kinase type 1
Transurethral application of PGE-1, although less robust (cGKI) pathway leads to inhibition at several sites of the
than intracorporeal injection, is an effective ED treatment noradrenergic contractile pathway in the vascular smooth
alternative for some men. muscle by impairing phospholipase C production of inositol
Calcitonin gene-related peptides (CGRP) are potent vaso- triphosphate, inositol triphosphate receptor activity, and the
dilators released from perivascular nerve fibers and have been RhoA–Rho-kinase pathway.1,4,52–54 However, interaction sites
localized to the cavernous nerves, cavernous arteries, and have not yet been identified in penile smooth muscle, but
corporal smooth muscle.1,3 CGRP acts through the calcitonin nitrergic–noradrenergic imbalance secondary to defective
receptor-like receptor (CRLR), and has demonstrated a nitrergic neurotransmission has been demonstrated in penile
dose-related increase in penile arterial inflow and erection tissue from patients with ED.4,55,56 Cholinergic activity reduces
when administered intracorporeally in ED patients.1,46,47 constrictor (adrenergic) tone and facilitates NO-mediated
Animal studies have shown that adenovirus-mediated gene smooth muscle relaxation; pharmacologic blockade of mus-
transfer of CGRP enhances the erectile response in aged carinic receptors has been shown to reduced erectile response
rats, apparently by increasing cAMP levels in the corpora to electrostimulation of the cavernous nerves.27,57
cavernosa.48 Adenosine, acting through A2 receptors that are
coupled to Gs proteins, has also been shown to stimulate AC
and subsequent vasorelaxation. Whether adenosine plays a
role in physiologic erection is unclear, since intracavernous RhoA–Rho kinase pathway and
injection in the dog has been shown to induce full erections calcium sensitization
but, in another study, treatment with the adenosine receptor
inhibitor Psp-theophylline (8-SPT) did not alter pelvic nerve Normal erectile function is dependent upon vasorelaxation
stimulation-induced tumescence, suggesting a lack of adeno- induced by neurotransmitter release overcoming vasocon-
sine involvement in this process.1,49,50 Also, intracorporeal striction of corporal smooth muscle.2 Reduced smooth muscle
injection of adenosine in humans has not resulted in penile vasorelaxation or increased vasoconstriction leads to impaired
erection to date.49 erectile function; in contrast to the understanding of NO-
induced penile smooth muscle relaxation, limited informa-
Cholinergic mechanisms and nerve–neurotransmitter tion is available on vasoconstrictive mechanisms.1,2 Several
interactions contemporary studies suggest that RhoA–Rho-kinase mediated
Acetylcholine, the primary neurotransmitter of the para- calcium sensitization plays a significant role in the regulation
sympathetic nervous system, has been shown to be released of corpora smooth muscle tone and maintains the penis in the
from human erectile tissue when electrically stimulated, and flaccid state.58–60
before the identification of NO, it was thought to be the pri- Once cytosolic calcium returns to basal levels, and the penis
mary neurotransmitter responsible for physiologic erection.3,51 attains the flaccid state, calcium-sensitizing pathways are the
88 Textbook of Erectile Dysfunction

NA ET-1 vascular tone, the function of RhoA–Rho-kinase in ED has

not been fully elucidated.2 The emerging consensus is that
tonic cavernous smooth muscle tone (the flaccid state) is
governed by calcium-sensitizing pathways, most likely via
RhoA–Rho-kinase signaling.64
RhoA–GTP

Rho-kinase
Conclusions
- Penile erection is dependent upon cavernous smooth muscle
MLC phosphatase relaxation. A large body of evidence supports NO as the key
MLC MLC-P
mediator of this process, as NO released by nNOS found in
MLC kinase
the cavernous nerve terminals initiates the erection and eNOS
mediated NO helps maintain rigidity. The NO–cGMP signaling
Smooth muscle Smooth muscle pathway activates protein kinase G, which acts upon potas-
relaxation contraction sium and calcium channels to lower cytosolic calcium levels
and facilitate smooth muscle relaxation. Phosphodiesterases
Figure 11.4 RhoA–Rho-kinase calcium sensitization pathway. hydrolyze cGMP to GMP, allowing for cavernous smooth
ET-1, endothelin receptor; GTP, guanosine triphosphate; MLC, muscle to regain tone (flaccid state) as cytosolic calcium levels
myosin light chain; MLC-P, phosphorylated myosin light chain; increase; PDE-5 inhibitors used for the treatment of ED
NE, norepinephrine. From Weir AJ, Kavoussi LR, Novick AC, inhibit the catalytic activity of phosphodiesterase on cGMP.
Pestin AW, Peters CA, eds. Campbell–Walsh Urology, 9th edn. Cytoplasmic levels of calcium are also reduced by activated
Philadelphia: Saunders Elsevier, 2000.
cAMP–PKA signaling, leading to cavernous smooth muscle
relaxation. The role of this pathway, which may be activated
key regulators of smooth muscle tone. The RhoA–Rho kinase by CGRPs, prostanoids, VIP, and adenosine, remains unclear
pathway is able to perform this function via activation of for physiologic erections, but is probably limited to a minor
excitatory receptors coupled to G proteins, which results in role. From a practical standpoint, the use of intracavernosal
contraction by increasing calcium sensitivity but without (exogenous) PGE-1 to activate cAMP signaling has proven to
concurrent changes in cytosolic calcium levels.1,59 Activated be a safe and robust treatment for ED of various underlying
Rho-kinase phosphorylates, and thereby inhibits, the regulatory etiologies.
subunit of smooth muscle myosin phosphatase.1 This pre- Maintenance of the semicontracted, flaccid state is depen-
vents dephosphorylation of myofilaments, thus maintaining dent upon several mechanisms that regulate cavernous
contractile tone (Figure 11.4).61 RhoA, a small, monomeric G smooth muscle tone. These include intrinsic myogenic activ-
protein that activates Rho-kinase, acts as the molecular switch ity, adrenergic neurotransmission, endothelium-derived con-
between the inactive GDP-bound state in the cytosol and the tracting factors such as angiotensin II, PGF-2α, and ET-1, and
active GTP-bound state found mainly in the plasma mem- calcium-sensitizing pathways. Emerging evidence suggests that
brane.2 Rho-kinase, one of the downstream targets of RhoA, the RhoA–Rho-kinase signaling pathway may be the primary
consists of alpha and beta isoforms that have been shown to determinant of tonic contraction.
be involved in erectile function.61–63 Both RhoA and Rho- Impairment of neurogenic and endothelium-dependent
kinase are expressed in penile smooth muscle; it is of interest NO release or dysregulation of cavernosal neurotransmitter
that the amount of RhoA expressed in the cavernous smooth function may result in an imbalance between smooth muscle
muscle is 17-fold higher than that in vascular smooth mus- vasorelaxation and increased vasoconstriction, leading to
cle.61 Once activated, RhoA–Rho-kinase enhances calcium impaired erectile function. Advances in the understanding of
sensitivity through phosphorylation of the myosin light chain penile neurobiology and its relationship to erectile function
(MLC) phosphatase targeting subunit (MYPT1), inhibiting (and dysfunction) have identified several candidate neuro-
MLC phosphatase activity. Smooth muscle contraction results transmitters as potential targets for ED treatments; in most
as MLC phosphorylation is increased.2,58–63 Although increased cases, however, their roles in the erectile process and as can-
RhoA–Rho-kinase activity has been shown to cause increased didate therapies remain to be determined.

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12 Receptor pharmacology related to
erectile dysfunction
Christian Gratzke, Tamer Abouschwareb, George J Christ, and
Karl-Erik Andersson

Introduction Oxytocin
Oxytocinergic spinal projections from the supraoptic and
Penile erection is initiated after central processing and integra- paraventricular nuclei of the hypothalamus are likely to influ-
tion of stimuli (e.g. tactile, visual, olfactory, and imaginative). ence the sacral autonomic outflow more than the somatic
Signals are generated to the peripheral tissues and the final outflow.17,18 The finding that immunoreactive oxytocin-
response is mediated by co-ordinated spinal activity in the containing spinal neurons associate with sacral preganglionic
autonomic pathways (to the penis) and somatic pathways (to neurons supports the idea that oxytocin has an important
the perineal striated muscles). The central regulation of penile role in the autonomic spinal circuitry that mediates penile
erection involves many transmitters and transmitter systems, erection.19,20
the details of which are still not completely known. Some of Oxytocin is a potent inducer of penile erection when
the anatomical areas of the brain that relate to sexual function injected into the lateral cerebral ventricle, the PVN, or the
have been defined, including the medial amygdala, medial hippocampus of laboratory animals; intrathecal oxytocin can
preoptic area (MPOA), paraventricular nucleus (PVN), peri- also initiate an erection. These erections can be blocked by
aqueductal gray, and ventral tegmentum.1–3 In rats, electrical the administration of oxytocin antagonists given intracere-
stimulation of the MPOA,4 the PVN,5 or the hippocampal broventricularly or intrathecally, or by electrolytic lesion of
formation6 can elicit an erectile response. the PVN. Additionally, non-contact erections can be reduced
Spinally, there seems to be a network consisting of pri- by a selective oxytocin receptor antagonist administered into
mary afferents from the genitals, the spinal interneurons, the lateral ventricles, which supports the view that oxytocin
and the sympathetic, parasympathetic, and somatic nuclei. mediates this response.21
This network appears capable of integrating information Succu et al. (2007) analyzed the effect of proerectile doses of
from the periphery and eliciting reflexive erections; and it the selective dopamine D4-agonist PD-168077 and apomor-
also seems to be the recipient of supraspinal information.7 phine, a mixed dopamine receptor agonist, injected into the
The degree of preservation of sensory function in the T11–L2 PVN, on the concentration of extracellular dopamine and its
dermatomes could be used to determine the potential for main metabolite, 3,4-dihydroxy-phenylacetic acid (DOPAC),
psychogenic erectile responses in men with spinal cord in the nucleus accumbens in male rats.22 Both drugs induced
injury.8 penile erection episodes that were reduced to various extents
Peripherally, the balance between factors that control the by D2–D3 and D4 antagonists. The proerectile effect and
degree of contraction of the smooth muscle of the corpora the concomitant increase in dopamine and DOPAC concentra-
cavernosa determines the functional state of the penis. Many tion in the nucleus accumbens dialysate were almost com-
details of neurotransmission, impulse propagation, and intra- pletely abolished by the potent oxytocin receptor antagonist
cellular transduction of signals in penile smooth muscles d(CH2)5Tyr(Me)2-Orn8-vasotocin, given into the lateral
remain to be elucidated. However, the information on both ventricles. The authors concluded that stimulation of dopamine
central and peripheral control mechanisms involved in erec- receptors (mainly of the D2 to D4 subtype) in the PVN induces
tion is rapidly expanding, and new details are continuously the release of oxytocin in brain areas that influence the activity
added.1,9–16 of the mesolimbic dopaminergic neurons that mediate the
appetitive and reinforcing effects of sexual activity.
Oxytocin increases nitric oxide (NO) production in the
Central neuromediation PVN,13,23 and nitric oxide synthase (NOS) inhibitors prevent
penile erection and yawning in rats induced by oxytocin,
The central mechanisms controlling erection include supraspi- dopamine, excitatory amino acids, m-chlorophenylpiperazine
nal as well as spinal pathways. The current knowledge about [m-CCP, a 5-hydroxy triptomine (S-HT)-2C receptor agonist],
these mechanisms is largely based on experimental data from and adrenocorticotropic hormone (ACTH)–alpha-melanocyte
animals (mainly rats). stimulating hormone (MSH). Yawning is a phylogenetically old,

91
92 Textbook of Erectile Dysfunction

stereotyped event that occurs alone or associated with and dopaminergic mechanisms regulating penile erection in
stretching or penile erection in humans and animals under conscious rats and concluded that proerectile activity medi-
various conditions.24 It has been suggested that NO acts as an ated via D2-like receptors (and possibly via D4-like receptors)
intracellular rather than an intercellular modulator inside the may be dependent on supraspinal and spinal oxytocin recep-
paraventricular oxytocinergic neurons in which NO is formed tors, and that oxytocin-mediated erection (supraspinal and
to facilitate the expression of this phylogenetically old event spinal) requires basal D2-like receptor (and possibly D4-like
by guanylate cyclase-independent mechanisms.24,25 It is likely receptor) activation.41 The same group aimed to identify D4
that this involves the parvocellular neuron population within receptor signal transduction pathways in vivo.42 They showed
the nucleus.25 that the selective dopamine D4 agonist PD168077 induced
Plasma oxytocin concentrations are known to be elevated c-Fos expression and extracellular signal regulated kinase
following sexual stimulation in humans;1 however, the rele- (ERK) phosphorylation in the PVN. The selective dopamine
vance of the oxytocinergic pathway has never been established. D4 receptor antagonist A-381393 blocked both c-Fos expres-
This makes it of interest to explore the therapeutic potential sion and ERK-1 and ERK-2 phosphorylation produced by
of this system. PD168077. In addition, PD168077-induced ERK-1 and ERK-2
phosphorylation was prevented by SL327, an inhibitor of
ERK-1 and ERK-2 phosphorylation. Interestingly, treatment
Dopamine with A-381393 alone significantly reduced the amount of Fos
Central dopaminergic neurons project to the MPOA and the immunoreactivity compared with basal expression observed
PVN.26 Furthermore, dopaminergic neurons have been iden- in vehicle-treated controls. Dopamine D4 receptor and c-Fos
tified that travel from the caudal hypothalamus to innervate co-expression in the PVN was observed using double immuno-
the autonomic and somatic nuclei in the lumbosacral spinal histochemical labeling, suggesting that PD168077-induced
cord.27,28 Thus, dopamine can be expected to participate in the signaling may result from direct dopamine D4 receptor
regulation of both the autonomic and somatic components of activation. The authors concluded that these results demon-
the penile reflexes. strate functional dopamine D4 receptor expression and natural
Both the two major families of dopamine receptors, the coupling in the PVN that is linked to signal transduction
D1-like receptors (D1, D5) and the D2-like receptors (D2, D3, pathways that include immediate early gene and MAP kinase
and D4)29 have been associated with central erectile functions; activation. Furthermore, the ability of the selective dopamine
however, the D2-like receptor subtype seems to have the D4 antagonist A-381393 alone to reduce c-Fos expression
predominating effect. The non-selective dopamine receptor below control levels was interpreted to indicate the presence
agonist, apomorphine, when administered systemically to of a tonic dopamine D4 receptor activation under basal
male rats, was found to induce penile erection,30 simultane- conditions in vivo.
ously producing yawning and seminal emission. Similarly, Brioni et al. reported that the dopamine D4 receptor plays
low-dose systemic administration of other dopamine agonists a role in the regulation of penile function using a selective
initiates erection.1 The effects of these agonists can be attenu- dopamine D4 receptor agonist, ABT-724, with no effect on
ated by centrally acting, but not by peripherally acting, dopamine D1, D2, D3, or D5 receptors.43 ABT-724 facilitated
dopamine receptor antagonists. penile erection in a dose-dependent fashion when given sub-
Injection of apomorphine into the MPOA demonstrated cutaneously to conscious rats, an effect that was blocked by
that low levels of dopaminergic stimulation, via D1 receptors haloperidol and clozapine (acting centrally and peripherally)
in particular, facilitated erections.31 In contrast, dopaminergic but not by domperidone (acting only peripherally). A proerec-
antagonists injected into the MPOA decreased the number tile effect was observed after intracerebroventricular, but not
of penile reflexes.32,33 In the PVN, similar experiments have intrathecal, administration, suggesting a supraspinal site of
established that D2-like receptors, rather than D1-like recep- action. The drug seemed to be without emetic effects in a ferret
tors, primarily facilitate erections.1 model of emesis,44 and it was suggested that ABT-724 could be
The erection following paraventricular D2-like receptor useful for the treatment of erectile dysfunction (ED).
stimulation apparently involves oxytocinergic neurotrans- The same group identified a structurally distinct D4-selective
mission. Dopaminergic neurons impinge on oxytocinergic cell agonist with superior oral bioavailability to that of ABT-724
bodies in the PVN,34,35 and apomorphine-induced penile for the potential treatment of ED. Optimization with the
erection is prevented dose-dependently by oxytocin receptor (N-oxy-2-pyridinyl) piperidine template led to the discovery
antagonists36 or by electrolytic lesions of the PVN that deplete of ABT-670, which exhibited excellent oral bioavailability in
the oxytocin content.37–39 Conversely, injection of oxytocin the rat, dog, and monkey (68%, 85%, and 91%, respectively)
into the PVN induced erections that were not attenuated by with comparable efficacy, safety, and tolerability to that of
dopamine receptor blockade, suggesting that dopaminergic ABT-724.45 Injection of apomorphine into the lumbosacral
neurons activate oxytocinergic neurons in the PVN, and that subarachnoid space was reported to impair ex copula (i.e.
released oxytocin then accounts for the erectile response. outside the context of copulation) penile reflexes, slow the
Melis et al. showed that penile erections in male rats induced rate of copulation, and decrease the number of intromissions
by selective dopamine D4 agonists were reduced by selective preceding ejaculation,46,47 suggesting an inhibitory effect on
dopamine D4 antagonists, voltage-dependent calcium channel spinal erectile mechanisms. This is in contrast to recent find-
blockers, neuronal NOS (nNOS) inhibitors, and oxytocin ings showing that intrathecal injection of apomorphine in rats
receptor antagonists given in the lateral ventricles, but not in evokes erection in both normal animals and in animals in
the PVN.40 Martino et al. investigated central oxytocinergic which the spinal cord has been transected.48,49 Most likely,
 Receptor pharmacology related to erectile dysfunction 93

stimulation of the dopaminergic system can produce erection Nitric oxide

both at supraspinal and spinal sites. Several investigators have shown that within the central
As mentioned above, systemically administered apomor- nervous system (CNS), NO can modulate sexual behavior
phine enhances seminal emission. Pehek et al. found that and penile erection.66–70 NO may act in several discrete brain
apomorphine injected into the PVN, but not into the MPOA, regions, such as the MPOA69,70 and the PVN.5,54 NO produc-
enhanced seminal emission.47 Recording of intracavernosal tion increases in the PVN of male rats during non-contact
pressure in the non-anesthetized rat after systemic adminis- penile erections and copulation, confirming that NO is a
tration of apomorphine showed that the pressure response physiological mediator of penile erection at the level of the
consisted of both smooth and striated muscle components.50 PVN.68
This implies that systemic apomorphine has effects not only As mentioned previously, injection of NOS inhibitors
on the sacral parasympathetic output, but also on somatic intracerebroventricularly or in the PVN prevents penile
pathways. erectile responses induced by dopamine agonists, oxytocin,
and NMDA in rats. NO may also mediate the actions of
ACTH–alpha-MSH and 5-HT-2C agonists, which elicit erec-
Adrenocorticotropic and related peptides tions when injected into the intracerebroventricular system,
Intracerebroventricular administration of ACTH and alpha- according to mechanisms unrelated to oxytocinergic neuro-
MSH induces penile erection – along with grooming, stretch- transmission.67 The inhibitory effect of NOS inhibitors was
ing, and yawning.1,2,51 These effects are most probably not observed when these compounds were injected concomi-
mediated via stimulation of melanocortin (MC) receptors, of tantly with L-arginine, the substrate for NO.67
which five different subtypes have been cloned and Zheng et al. examined the role of NO within the central
characterized.52,53 Alpha-MSH–ACTH seem to act in the nervous system component of the behavioral responses,
hypothalamic periventricular region, and grooming, stretch- including erection in diabetic rats.71 Four weeks after strepto-
ing, and yawning, but not penile erection, was reported to zotocin (STZ) and vehicle injections, NMDA-induced erec-
be mediated by MC4 receptors.51,54 It is unclear, however, tion, yawning, and stretch responses through the PVN were
what MC receptor subtype or subtypes can be linked to the significantly blunted in diabetic rats compared with control
erectile responses. For example, the MC3 receptor is found rats. Examination of nNOS protein by Western blot analysis
in high density in the hypothalamus and limbic systems,39 indicated a reduced amount of nNOS protein in the PVN of
regions known to be important for erectile functions. The site rats with diabetes compared with control rats. Furthermore,
and mechanism of action of alpha-MSH–ACTH seem to be restoring nNOS within the PVN by gene transfer using adeno-
different from those involving dopamine or oxytocin.15 viral transfection significantly restored the erectile and yawn-
Martin et al. concluded that current evidence indicates ing responses to NMDA in diabetic rats. The authors concluded
that the MC4 receptor subtype contributes to the proerectile that a blunted NO mechanism within the PVN may contribute
effects observed with melanocortin pan-receptor agonists.55 to NMDA-induced ED observed in diabetes mellitus.
However, the putative receptor subtypes, pathways and mech-
anisms implicated in mediating the proerectile effects of Serotonin
melanocortin remain to be fully elucidated.
Neurons containing serotonin (5-HT) can be found in the
Melanotan II, a synthetic analog of alpha-MSH,
medullary raphe nuclei and ventral medulla reticular forma-
when given subcutaneously, was shown to have proerectile
tion (including the rostral nucleus paragigantocellularis), and
effects in men with psychogenic impotence.56 Still the thera-
bulbospinal neurons containing 5-HT project to the lumbar
peutic potential of alpha-MSH analogs remains to be
spinal cord in the rat and cat.1 Some serotonergic fibers occur
established.57–59
in close apposition to sacral preganglionic neurons and motor
neurons, and synapses were demonstrated at the ultrastruc-
tural level.20 These morphological findings support the
Excitatory amino acids involvement of 5-HT in both the supraspinal and spinal
Microinjections of L-glutamate into the MPOA elicits an pharmacology of erection, with participation in both the
increase in intracavernous pressure,4 and behavioral studies sympathetic and parasympathetic outflow mechanisms.
have shown that N-methyl-D-aspartate (NMDA) increases In animals, 5-HT seems to exert a general inhibitory effect
the number of penile erections when injected into the PVN.60–62 on male sexual behavior,72 although the amine may be inhibi-
Furthermore, NMDA, amino-3-hydroxy-5-methyl-isoxazole- tory or facilitatory depending upon its action at different sites
4-propionic acid (AMPA), or trans-1-amino-1,3-cyclo- and at different 5-HT receptors within the CNS.73,74 This may
pentadicarboxylic acid (ACPD) increases intracavernosal explain conflicting reports of 5-HT agonists either enhancing
pressure when injected into the PVN.63 The effect of NMDA or depressing sexual function. Yonezawa et al. found that
was prevented by intracerebroventricular administration of p-chloroamphetamine (PCA), an indirect 5-HT agonist, elic-
an oxytocin antagonist.60 The NOS signal transduction path- ited both penile erection and ejaculation simultaneously in
way is considered to mediate the effect of NMDA. Injection of anesthetized rats.75 It was suggested that these effects were
the amino acid leads to an increased concentration of NO mainly produced by the release of 5-HT as limited to the lower
metabolites in the PVN,64 and the administration of NOS spinal cord or peripheral sites (or both). The use of selective
inhibitors, both into the PVN and intracerebroventricularly, 5-HT receptor agonists and antagonists can reveal different
blocked the NMDA effect.60,65 components of male copulatory behavior.9
94 Textbook of Erectile Dysfunction

Kimura et al. investigated the effects of the novel 5-HT2C Opioid peptides
receptor agonist YM348 on intracavernosal pressure in anes- Available information supports the hypothesis that opioid
thetized rats.76 YM348 induced penile erection and increases µ-receptor stimulation centrally prevents penile erection by
in intracavernosal pressure, and it was significantly inhibited inhibiting mechanisms that converge upon central oxyto-
by the selective 5-HT-2C receptor antagonist SB242084. cinergic neurotransmission.1 In rats, morphine injected into
YM348 decreased the latency of intracavernosal pressure but the PVN prevents non-contact penile erections (i.e. when
did not affect the quality of its duration, peak pressure, and penile erection is induced in the male by the presence of an
area under the curve, even at the highest dose. The authors inaccessible receptive female) and impairs copulation. These
concluded that activation of the 5-HT-2C receptor increased morphine effects are apparently mediated by prevention of
intracavernosal pressure and, as a result, induced penile the increased NO production that occurs in the PVN during
erection. sexual activity.87 Morphine also prevents apomorphine-,
5-HT-2C receptors seem to mediate erectile responses,77 oxytocin-, NMDA-, and non-contact-induced penile erection
and stimulation of 5-HT-2C receptors increased circulating and yawning by inhibiting NOS activity in the PVN.88–90
oxytocin.78 NOS inhibitors administered intracerebroven-
tricularly prevented 5-HT-2C-receptor-mediated erectile
responses.67 These findings suggest that both oxytocin and Prolactin
NO are involved in 5-HT-2C-receptor-mediated erections.
Long-term hyperprolactinaemia can depress sexual behavior,
reduce sexual potency in men, and depress genital reflexes in
rats.74,91 Acute and chronic central prolactin treatment in rats,
Norepinephrine however, may have, respectively, stimulatory and inhibitory
The information on noradrenergic mechanisms involved in effects on male sexual behavior.92 Correspondingly, striatal
the central neuromediation of penile erection is sparse; how- dopaminergic activity was shown to be increased and decreased
ever, the current data suggest that increased noradrenergic by acute and 5-day central prolactin treatment,92 supporting
activity stimulates, whereas decreased noradrenergic activity the view that the effects of prolactin are associated with
inhibits sexual function.7,72,79 changes in striatal dopaminergic activity. Prolactin has been
shown to inhibit the dopaminergic incertohypothalamic
pathway to the MPOA.93
In humans, it is still unclear whether the negative effects
Gamma-aminobutyric acid
of hyperprolactinemia on erectile function are mediated
Cumulative data resulting from investigations on the role of centrally by way of reduction in sexual interest and sex drive,94
gamma-aminobutyric acid (GABA) in penile erection indicate or through a direct effect of prolactin on corpus cavernosum
that this neurotransmitter may function as an inhibitory smooth muscle contractility. In dogs, a direct effect on the
modulator in the autonomic and somatic reflex pathways corpus cavernosum was suggested.95 In any case, the effect
involved in penile erection.80 Activation of GABA(A) receptors seems independent of circulating testosterone levels and
in the PVN reduced apomorphine-, NMDA-, and oxytocin- gonadal axis function.96
induced penile erection and yawning in male rats.80 Paick et al. evaluated 261 men for anthropometry, hormone
Dorfman et al. (2006) examined age-related changes of the levels, metabolic profiles, and lifestyle factors.97 Erectile func-
GABA(B) receptor in the lumbar spinal cord of Sprague– tion was evaluated using the self-administered International
Dawley rats of different ages using quantitative autoradio- Index of Erectile Function. Patients were classified into two
graphy.81 GABA(B) receptor affinity showed significant groups based on the six-item erectile-function domain, as
age-dependent and regional increases. However, the decrease those with sexual activity and those without. The authors
in GABA(B) receptors in aged rats did not seem to be related found a significant difference in mean prolactin level between
to the inhibitory function in penile erection. patients with sexual activity and those without. A higher pro-
lactin level was associated with a greater likelihood of sexual
inactivity. Thus, prolactin levels might play a role in sexual
Cannabinoids activity in men with ED.
Administration of endogenous and exogenous cannabinoids
was shown to be associated with changes in penile erection
and modulation of male sexual behavior.82,83 The cannabi- Sex hormones
noid CB-1 receptor antagonist SR141716A was shown to Androgens, particularly testosterone, are necessary (though
potentiate the penile erection responses to apomorphine in not sufficient) for sexual desire in men. They are essential in
rats.84 It was also shown that cannabinoid CB-1 receptors the maintenance of libido and have an important role in
present in the PVN may influence erectile function and sex- regulating erectile capacity.98–102 In men with normal gonadal
ual activity, possibly by modulating paraventricular oxyto- function, however, there is no correlation between circulating
cinergic neurons that mediate erectile function.85 It was testosterone levels and measures of sexual interest, activity, or
demonstrated that SR141716 induced penile erection by a erectile function.103 Following castration in the male (which
mechanism that involves excitatory amino acid neurotrans- may reduce plasma testosterone levels by 90%),104 or other
mission causing activation of nNOS in paraventricular oxyto- causes leading to a reduction in androgen levels, there is
cinergic neurons.86 generally a decline in libido, and sometimes in erectile and
 Receptor pharmacology related to erectile dysfunction 95

ejaculatory functions. Testosterone administration restores long-acting testosterone undecanoate.122 In all patients, serum
sexual interest and associated sexual activity in hypogonadal testosterone levels were restored to normal within 6–8 weeks.
or castrated adult men.105–107 The testosterone dose–response Restoring testosterone levels to normal in men with proven
relationships for sexual function and visuospatial cognition subnormal testosterone levels was found to improve libido
differ in older and young men, with higher testosterone doses in most subjects and to improve erectile function in more
being needed in the elderly for normal sexual functioning.101 than 50% of these men. It may take 12–24 weeks before the
El-Sakka et al. assessed the pattern of age-related testosterone effects of testosterone manifest themselves. Furthermore, in
depletion in patients with ED.108 They found a significant normal subjects, it has been shown that there is a relationship
decrease in testosterone level throughout the 4-year follow up between bioavailable testosterone and the frequency, dura-
in patients with ED. Patients with decreasing testosterone tion, and degree of nocturnal penile tumescence.116,123 Other
were older than patients with a steady testosterone level. studies performed in eugonadal men have shown that high
When castration has been performed in humans, the testosterone may promote sexual arousal with no significant
resultant sexual function may range from a complete loss of changes in sexual activity.124 Several studies, however, suggest
libido to continued normal sexual activity. Thus, the role of that testosterone replacement therapy in relatively modest
androgens in erectile function is complex, and androgen deficiency states may improve erections in a minority of
deprivation may not always cause erectile dysfunction, either patients.120,121,125,126
in humans109 or in rats.110 Data from the Massachusetts Male Aging Study revealed
Suzuki et al. studied the effects of castration and testosterone the association between ED and total testosterone, bioavailable
replacement on intracavernosal pressure elicited with electrical testosterone, sex hormone-binding globulin, and luteinizing
stimulation of the MPOA and cavernous nerve in castrated hormone (LH).127 The authors concluded that there was no
male rats with and without testosterone replacement.111 The association among total testosterone, bioavailable testosterone,
erectile response was expressed as the ratio of the intra- sex hormone-binding globulin, and ED. However in men with
cavernous pressure to the blood pressure. The ratios during an increased level of LH, testosterone levels were associated
cavernous nerve stimulation of the animals at 2, 4, and 8 weeks with a decreased risk of ED.
after castration were significantly lower than those of the intact Sex hormones can induce structural changes in the nervous
animals. However, the erectile responses were not eliminated. system, including alterations in cell size and number, neural
In contrast to these peripherally evoked responses, erectile connectivity, and neural sprouting.128–131 These changes, which
responses elicited by electrical stimulation of the MPOA were may result in sex differences (sexual dimorphism), are obvi-
eliminated following castration. After testosterone replace- ous in most mammalian species during the prenatal or early
ment, both erectile responses were restored. The authors postnatal periods. There is evidence, however, that brain
therefore concluded that testosterone plays important roles regions containing sex hormone-accumulating neurons in
in both the central and peripheral neural pathways for the adult animals possess a considerable plasticity in response to
maintenance and restoration of erectile capacity. sex steroids, and that androgens have the potential to stimu-
In hypogonadal men, it is known that exogenous testoster- late the growth of neuronal processes and remodel neural
one administration stimulates both sleep-related erections circuits also in the adult brain.132–134 Naturally occurring,
and erectile responses to visual erotic stimulation.112–114 Serum socially induced changes in androgen levels were not shown to
testosterone levels, however, have to fall to well below the induce morphological changes of the motor neurons of the
lower end of the normal laboratory range before nocturnal spinal nucleus of the bulbocavernosus muscle.135
penile tumescence is impaired.115 In healthy men, testosterone The MPOA of rats and the spinal nucleus of the bulbo-
enhances sexual desire and the rigidity of nocturnal penile cavernosus1 are sexually dimorphic model systems that have
tumescence, and leads to more rigid spontaneous erections been well investigated. In humans, the localization and
with longer duration.114,116 It is therefore possible that testos- morphology of neurons innervating the small, striated pelvic
terone acts on the motor neurons that supply the striated muscles correspond to that of Onuf’s nucleus X.136,137 This
muscles of the penis. Other reports suggested that the site of nucleus, similar to its rat homolog (the spinal nucleus of the
androgen action within the penile tissue might be on the pro- bulbocavernosus), contains fewer motor neurons in the female
erectile postganglionic parasympathetic neurons.117 Castra- than in the male.138
tion studies in rats revealed that testosterone deprivation
might alter the dorsal nerve ultrastructure, since the diameter
of both myelinated and unmyelinated axons appeared smaller Peripheral neuromediation
as assessed by transmission electron microscopy.118 Spontane- The different structures of the penis receive sympathetic,
ous nocturnal erections are androgen-dependent102,119 they parasympathetic, somatic, and sensory innervation.1,139 The
are impaired in states of androgen deficiency and restored nerves contain different transmitters, and the nerve popula-
with androgen replacement. Erections in response to visual tions have been categorized as adrenergic or cholinergic or non-
erotic stimuli, on the other hand, are partly independent of adrenergic, non-cholinergic (NANC). It should be stressed
androgens119,120 They persist in hypogonadal men and are not that these nerves often contain more than one transmitter or
altered by androgen replacement.112,121 Thus, there may be one transmitter–modulator generating enzymes, such as NOS and
androgen-dependent system in the brain subserving sexual heme oxygenases (HO). One important population of nerves in
arousability and sexual desire, and one androgen-independent the corpora cavernosa contains not only acetylcholine, but also
involving response to moving visual stimuli.102 Yassin et al. NOS, vasoactive intestinal polypeptide (VIP), and neuropep-
treated hypogonadal men with ED with intramuscular tide Y.140,141 If co-released, the different transmitters–modulators
96 Textbook of Erectile Dysfunction

may interact, implying that the end result may be more com- regulation of tone in corpus cavernosum smooth muscle is
plex than would be suggested from an experimental situation, still unclear. Prejunctional alpha-2-ARs have been shown to
where often the effect of a single agent is investigated. inhibit stimulus-evoked release of norepinephrine from nerves
It is not only the nerves, but also the endothelium of the in the human corpus cavernosum. Stimulation of prejunc-
vasculature of the penis that produces and releases transmitters tional alpha-2-ARs in horse penile resistance arteries was also
and modulators that can influence the contractile state of the shown to inhibit NANC-transmitter release.151 This might be
corpus cavernosum smooth muscle. In addition they may also one of the mechanisms by which norepinephrine maintains
have other important functions. detumescence. Morton et al. assessed the response of dorsal
and cavernous penile arteries on alpha-AR-selective agonists
and antagonists in the rabbit.152 They found a predominant,
Norepinephrine and alpha-adrenoceptors functional alpha-1A-AR population with little evidence of
It is generally accepted that the penis is kept in the flaccid state other alpha-1A-AR subtypes in cavernous arteries; there
mainly via a tonic activity in adrenergic nerves releasing nor- seems to be evidence for the presence of alpha-2-AR in dorsal
epinephrine.142 Norepinephrine stimulates alpha-adrenoceptors arteries. The authors concluded that alpha-antagonists with
(ARs) in the penile vasculature and in the corpus cavernosum, affinity for alpha-1A- or alpha-2-ARs would potentially have
producing contraction. Both alpha-1-ARs and alpha-2-ARs proerectile properties.
have been demonstrated in human corpus cavernosum tissue,
but available information supports the view of a functional
predominance of alpha-1-ARs. This may be the case also in Endothelins and endothelin receptors
the penile vasculature, although a contribution of alpha-2- Endothelins (ETs) have been demonstrated in penile erectile
ARs to the contraction induced by norepinephrine and elec- tissues and may contribute to the maintenance of corporal
trical stimulation of nerves cannot be excluded.1 smooth muscle tone.1 Cultured endothelial cells from the
The mRNAs of all the subtypes of alpha-1-AR with a high human corpus cavernosum, but not non-endothelial cells,
affinity for prazosin (alpha-1A-, alpha-1B-, and alpha-1D- express ET-1 mRNA. In the endothelium of human cavern-
ARs) have been demonstrated in human corporal tissue. ous tissue, intense ET-like immunoreactivity has been
However, Goepel et al. have shown that alpha-1A, alpha-1B, observed; immunoreactivity has also been observed in the
and alpha-2A receptor protein were predominantly expressed, cavernous smooth muscle. Binding sites for ET-1 have been
and that the alpha-1D-AR is present only at the mRNA demonstrated by autoradiography in the vasculature and
level.143 The functional alpha-1-AR proteins in human corpus cavernous tissue. As both ETA and ETB receptors have
cavernosum tissue were characterized by Traish et al. using been found in human corporal smooth muscle membranes,
receptor-binding and isometric tension experiments.144 Their it cannot be excluded that both receptor subtypes are
results demonstrated the presence of alpha-1A-, alpha-1B-, functional.
and alpha-1D-ARs, and they suggested that the norepinephrine- ET-1 potently induces slowly developing, long-lasting con-
induced contraction in this tissue is mediated by two or pos- tractions in different smooth muscles of the penis: muscles in
sibly three receptor subtypes. the corpus cavernosum, cavernous artery, deep dorsal vein,
An additional alpha-1-AR subtype with low affinity for and penile circumflex veins.1 Contractions can also be evoked
prazosin (alpha-1L), probably representing a conformational in human corpus cavernosum tissue by ET-2 and ET-3,
state of the alpha-1A-AR, has been suggested to be of impor- although these peptides have a lower potency than ET-1.153
tance in human penile erectile tissues.145 In rats, alpha-1B- and The contractions induced by ET-1 are dependent on both
alpha-1L-AR subtypes seem functionally relevant for erectile transmembrane calcium flux (through voltage-dependent or
function, and alpha-1B- or alpha-1L-AR subtype selective receptor-operated calcium channels, or both) and on the
antagonists (or both) were suggested to represent advantages mobilization of inositol trisphosphate-sensitive intracellular
in the treatment of ED.146 The distribution of alpha-1-AR calcium stores.1
subtypes in the penis and systemic vasculature, however, may Mumtaz et al. assessed the effect of ET-1 and its possible
not be the same in rats and humans, and the method of study role in the alpha-1-AR pathway during the erectile process by
may influence the results. For example, Hussain and Marshall using organ bath studies of cavernosal smooth muscle con-
found that the alpha-1D-AR predominated in several systemic traction in the rat.154 ETA receptors were found to play a greater
rat vessels in vitro,147 which may not be the case in humans.148 role than ETB receptors in ET-1-induced rabbit cavernosal
Similarly, Tong and Cheng found alpha-1A-ARs to be respon- smooth-muscle contraction and the detumescence process.
sible for the contractile response of rat corpus cavernosum,149 The alpha-1-AR-dependent pathway did not involve the ETA
which does not seem to be in agreement with the in vivo or ETB receptors.
data. Even if much available in vitro information suggests that
Expression of mRNA for alpha-2A-, alpha-2B-, and alpha- ETs may be of importance for erectile physiology and
2C-ARs in whole human corpus cavernosum tissue has been pathophysiology, the role of the peptides in vivo is unclear.
demonstrated. Radioligand binding revealed specific alpha- Blockade of the ETA receptor or the ETB receptor has no effect
2-AR binding sites, and functional experiments showed on the erectile response induced by maximal ganglionic stim-
that the selective alpha-2-AR agonist, UK 14,304, induced ulation in rats.155 This may seem to reflect a minimal role of
concentration-dependent contractions of isolated strips of ET-1 in the erectile response in the rat; however, the results do
human corpus cavernosum smooth muscle.150 Whether or not rule out that ETs may play a role in keeping the penis in a
not these alpha-2-ARs are of importance for the contractile flaccid state, or that ETs may be associated with ED.
 Receptor pharmacology related to erectile dysfunction 97

In a rat model of chronic cocaine administration, Kendirci contribution of the different forms of NOS to erection has not
et al. found significantly increased plasma big-ET-1 levels in the been definitely established. However, more than one isoform
cocaine treatment group compared with control animals.156 of nNOS may be involved.160
In the penis, cocaine administration significantly increased Mice lacking both eNOS and nNOS have erections, show
ETA receptor expression compared with saline controls, while normal mating behavior, and respond with erection to elec-
ETB receptor expression was not altered. Cocaine-treated rats trical stimulation of the cavernous nerves.163,165,166 Surprisingly,
showed also significantly decreased endothelial NOS (eNOS) isolated corporal tissue from both wild-type and NOS-deleted
expression and NO production. The authors concluded that animals has demonstrated similar responses to electrical stim-
cocaine administration significantly reduces erectile function ulation. However, Hurt et al. showed that alternatively spliced
in rats. The pathophysiologic mechanisms that are probably forms of nNOS are major mediators of penile erection.163
involved include increased plasma big-ET-1 levels, increased cGMP signals via different receptors in eukaryotic cells,
penile ETA receptor expression, and reduced penile eNOS including ion channels, phosphodiesterases, and protein
expression. kinases. At present, the molecular targets that are activated
ETs may function not only as a long-term regulator of by cGMP in order to execute the relaxation of penile smooth
corporal smooth muscle tone, but also as a modulator of the muscle are not known. Two different cGMP-dependent
contractile effect of other agents, such as norepinephrine,157–159 protein kinases (cGK-I and cGK-II) have been identified in
or as a modulator of cellular proliferation and phenotypic mammals. Inactivation of cGK-I in mice abolishes both NO–
expression. cGMP-dependent relaxation of vascular and intestinal smooth
muscle and the inhibition of platelet aggregation, causing hyper-
tension, intestinal dysmotility, and abnormal hemostasis.167
Acetylcholine and cholinergic receptors Hyun et al. suggested that lithium, by interfering with the NO
The importance of parasympathetic nerves for producing pathway in both the endothelium and the nitrergic nerves, can
penile erection is well established.1 Penile tissues from humans result in impairment of both the endothelium- and NANC-
and several animal species are rich in cholinergic nerves,112,123,124 mediated relaxation of rat corpus cavernosum.168 Male cGK-I-
from which acetylcholine can be released by transmural deficient mice seem to have very low reproductive capability,
electrical field stimulation. In isolated corpus cavernosum probably owing to the markedly reduced ability of their
cells, carbachol consistently produces contraction. This means corpus cavernosum tissues to relax in response to NO, whether
that relaxation induced by acetylcholine can be obtained by it is neuronally or endothelially released or exogenously
inhibition of the release of a contractant factor, such as norepi- administered.169 Analysis of the NO–cGMP-induced relaxation
nephrine, or else it is produced by the release of a relaxation- clearly shows that cGK-I is the major mediator of the cGMP
producing factor, such as NO. signaling cascade in murine corpus cavernosum tissue. Its
Bozkurt et al. analyzed the presence of neuronal nicotinic absence cannot be compensated for by the cAMP signaling
acetylcholine receptors in rabbit corpus cavernosum tissue cascade.169 Taken together, these findings suggest that activa-
and the possible mechanisms underlying the potentiation of tion of cGK-I is a key step in the signal cascade leading to
electrical field stimulation-induced relaxation by nicotine.160 penile erection.
The authors showed that nicotine acts on the nicotinic acetyl- Bivalacqua et al. investigated the expression of cGMP-
choline receptors located on the nitrergic nerves, thereby dependent protein kinase (PKG)-1-alpha and PKG-1-beta in
evoking the release of NO from these nerve terminals and the corpus cavernosum and evaluated the effect of adenoviral
so inducing relaxation response in rabbit corpus cavernosum gene transfer of PKG-1-alpha to the erectile compartment on
tissue. erectile function in a rat model of diabetes.170 They found
It is important to stress that parasympathetic nerve activity PKG-1-alpha and PKG-1-beta activities to be reduced in the
is not equivalent to the actions of acetylcholine; other trans- erectile tissue of the diabetic rat. Gene transfer of PKG-1-
mitters may be released from cholinergic nerves.140,141 Para- alpha to the penis restored PKG activity and erectile function
sympathetic activity may produce penile tumescence and in vivo in diabetic rats. They concluded that gene therapy
erection by inhibiting the release of norepinephrine through procedures targeting PKG-1-alpha might be an interesting
stimulation of muscarinic receptors on adrenergic nerve future therapeutic approach to overcoming diabetic ED resis-
terminals or by releasing NO and vasodilating peptides from tant to oral pharmacotherapy.
nerves and endothelium (or both). Angulo et al. evaluated the influence of protein kinase C
(PKC) activity on penile smooth muscle tone in tissues from
diabetic and non-diabetic men with ED.171 They found that
Nitric oxide and the guanylate cyclase–cGMP pathway overactivity of PKC in diabetes is responsible for enhanced
It is widely accepted that NO plays an important role in the contraction and reduced endothelium-dependent relaxation
relaxation of the corpus cavernosum smooth muscle and of human corpus cavernosum smooth muscle. Thus, the
vasculature.1,161 In vitro, several investigators have shown that authors concluded that such alterations can result in ED.
both acetylcholine-mediated and neuronally mediated relax-
ation in animal and human corpus cavernosum involves the
release of NO, or a NO-like substance.1 Both the nerves (nNOS) Vasoactive intestinal polypeptide and vasoactive
and the endothelium (eNOS) of the corpus cavernosum may intestinal polypeptide receptors
be the source of the NO, the former initiating erection, and the Mammalian penises are richly supplied with nerves contain-
latter providing sustained maximal erection.160–164 The relative ing vasoactive intestinal polypeptide (VIP).139 The majority of
98 Textbook of Erectile Dysfunction

these nerves also contain immunoreactivity to NOS, and co- dopamine D1 and D2 receptor proteins. Immunohistochemi-
localization of NOS and VIP within nerves innervating the cally, peripheral dopamine D1 and D2 receptor proteins were
penis of both animals and humans has been demonstrated by detected in dorsal nerves, dorsal vessels, and corpus cavernosal
many investigators. It seems that most of these NO- and VIP- smooth muscle. d’Emmanuele di Villa Bianca demonstrated
containing neurons are cholinergic, since they also contain that both D1 and D2 receptors were expressed in the human
vesicular acetylcholine transporter (VAChT),140,141 which is a corpus cavernosum, D1 receptors being two-fold more abun-
specific marker for cholinergic neurons. VIP receptors (types dant than D2 receptors, and that both receptors were mainly
1 and 2), linked via a stimulatory G protein to adenylyl cyclase, localized on the smooth muscle cell component.177 They
are considered to mediate the actions of the peptide.153 The concluded that apomorphine had a peripheral relaxant direct
importance of the different subtypes of VIP in penile tissues effect, as well as an anti-adrenergic activity, and that human
has not been clarified. VIP-related peptides (such as pituitary corpus cavernosum possessed more D1-like receptors (D1
adenylyl cyclase-activating peptide (PACAP), which has been and D5) than D2-like receptors (D2, D3 and D4). Both D1-
found to be co-localized with VIP in penile nerves), seem to and D2-like receptors were mainly localized on smooth mus-
act through one of the VIP receptors. The stimulatory effect of cle cells, and the relaxant activity was most probably mediated
VIP on adenylyl cyclase leads to an increase in cAMP, which by D1-like receptors, partially through NO release from
in turn activates cAMP-dependent protein kinase. endothelium.
Undeniably, VIP has both an inhibitory and relaxing effect Apomorphine may thus not only amplify sexual and copu-
on strips of human corpus cavernosum tissue and cavernosal latory behavior but also, by a complementary role, amplify
vessels in vitro, but it has been difficult to show convincingly neurogenically mediated erections by acting in the periphery.178
that VIP released from nerves is responsible for relaxation of On the other hand, Matsumoto et al. investigated the role
penile smooth muscle in vitro or in vivo.1,172 Thus, the role of of peripheral dopamine receptors for regulation of penile
VIP as a neurotransmitter or modulator of neurotransmission erection.179 They found that in isolated corpus cavernosum
in the penis has not been established. Even if its physiological from rats, pre- and postjunctional effects of apomorphine
role in penile erection and in ED remains to be settled, VIP appeared to involve dopamine D1- and D2-like receptors, as
receptors in the penis are an interesting therapeutic target. well as alpha-adrenoceptors. At relevant systemic doses of
apomorphine, however, peripheral effects of the compound
were unlikely to contribute to its proerectile effects in rats.
Prostanoids and prostanoid receptors
Human corpus cavernosum tissue has the ability to synthesize
various prostanoids, and it has the additional ability to meta- Serotonin and serotonin receptors
bolize them locally.1,173,174 The production of prostanoids can Peripheral serotonin (5-HT) receptors have been suggested as
be modulated by oxygen tension, and it is suppressed by participating in the control of penile flaccidity and detume-
hypoxia. Corresponding to the five primary active prostanoid scence,180 but their importance has not been definitely
metabolites [prostaglandin (PG) D-2, PGE-2, PGF-2, PGI-2, established. Studies in animals (rats and rabbits) sug-
and thromboxane A2 (TXA2)], there are five major groups of gested involvement of 5-HT-1A, 5-HT-1B, and 5-HT-2A
receptors that mediate their effects (the DP, EP, FP, IP, and receptors.181,182 In the human corpus cavernosum the presence
TP receptors). cDNAs encoding representatives of each of of 5-HT-4 receptors was reported by Hayes et al.,183 and
these groups of receptors have been cloned, including several Uckert et al. demonstrated 5-HT-1A-mediated contractions
subtypes of EP receptors. in this tissue.180 Further studies by Lau et al. confirmed these
Penile tissues may contain most of these groups of recep- findings, and it was suggested that 5-HT may play a role in the
tors; however, their role in penile physiology is still far from human detumescence process, via 5-HT-1A, 5-HT-2A, and
established.173,174 Prostanoids may be involved in contraction 5-HT-4 receptors.184
of erectile tissues via PGF-2α and TXA2, stimulating throm-
boxane (TX) and FP receptors and initiating phosphoinosit-
ide turnover, as well as in relaxation via PGE-1 and PGE-2, Endocannabinoids
stimulating EP receptors (EP2–EP4) and initiating an increase Little information exists concerning the peripheral effect of
in the intracellular concentration of cAMP. Prostanoids may cannabinoids on corpus cavernosum tissue. Ghasemi et al.
also be involved in the inhibition of platelet aggregation and investigated the effect of the endogenous cannabinoid, anan-
white cell adhesion, and recent data suggest that prostanoids damide, on the NANC relaxant responses to electrical field
and transforming growth factor (TGF)-beta-1 may have a role stimulation in isolated rat corpus cavernosum.185 They showed
in the modulation of collagen synthesis and in the regulation that anandamide has a potentiating effect on NANC-mediated
of fibrosis of the corpus cavernosum.175 relaxation of rat corpus cavernosum through both cannabi-
noid receptor type 1 (CB1) and vanilloid receptors. Further-
more, they demonstrated that the NO-mediated component
Dopamine and dopamine receptors of the NANC relaxant responses to electrical stimulation is
Hyun et al. found dopamine D1 and D2 receptor gene expres- involved in this enhancement. The same group studied the
sion in rat corpora cavernosa.176 In situ hybridization signals effect of biliary cirrhosis on NANC-mediated relaxation of rat
for dopamine D1 and D2 receptor mRNAs were localized corpus cavernosum and the possible roles of endocannabinoid
to corpus cavernosal tissues and dorsal vessels in the rat and NO systems in this model.186 NANC-mediated relaxation
penis, and Western blot analyses confirmed the presence of was enhanced in corporal strips from cirrhotic animals.
 Receptor pharmacology related to erectile dysfunction 99

Anandamide potentiated the relaxations in both groups. AM251 Since RhoA–Rho-kinase-mediated calcium sensitization is
(a CB1 receptor antagonist) and capsazepine (a vanilloid important for regulation of smooth muscle contraction,
TRPV1 receptor antagonist), but not AM630 (a CB2 receptor increased RhoA–Rho-kinase activity may lead to abnormal
antagonist), prevented the enhanced relaxations of cirrhotic contractility of the corpora cavernosa. Evidence has been
strips. The non-selective NOS inhibitor L-NAME and the presented that elevated RhoA–Rho-kinase activity contributes
selective neuronal NOS inhibitor L-NPA inhibited relaxations to the pathogenesis of diseases such as diabetes and hyperten-
in both groups, but cirrhotic groups were more resistant to sion, and possibly to other conditions associated with ED,
the inhibitory effects of these agents. Relaxations to sodium such as hypogonadism and aging.190 Several studies have sug-
nitroprusside (NO donor) were similar in tissues from the gested that NO inhibits RhoA–Rho-kinase activity,192–194 but
two groups. The authors concluded that cirrhosis potentiates the detailed mechanisms by which this regulation occurs are
the neurogenic relaxation of rat corpus cavernosum, probably yet to be determined.
via the NO pathway and involving cannabinoid CB1 and Vignozzi et al investigated the effect of testosterone on the
vanilloid receptors. RhoA–ROCK (Rho-kinase) signaling in diabetes.195 The
Western blot experiments revealed the presence of both authors found that over-expression of RhoA–ROCK signaling
CB1 and CB2 receptors at specific bands.187 CB1- and CB2- contributes to diabetes-related ED. Moreover, treating hypo-
immunoreactivity (-IR) was found in nerve fibers within and gonadism in the course of diabetes may maintain erectile func-
between strands of corporal smooth muscle. CB1- and CB2-IR tion also by normalizing RhoA–ROCK pathway upregulation.
nerves also expressed immunoreactivity for NOS and TRPV1. Theoretically, suppression of an increased RhoA–Rho-
In contrast, neither CB1 nor CB2 nerves were co-localized kinase activity is an attractive therapeutic principle in ED.
with calcitonin gene related peptide (CGRP)– or tyrosine However, the ubiquitous occurrence of the Rho–Rho-kinase
hydroxylase (TH)–containing nerves. pathway limits the use of Rho-kinase inhibitors. If regulators
Anandamide (10−9 to 10−4 M) had no direct contractile effects of RhoA–Rho-kinase uniquely expressed in penile tissue can
on corporal smooth muscle, no relaxant effects on precon- be demonstrated, they may be targets for drugs. This will
tracted preparations, and no significant effect on phenyleph- potentially lead to the development of new therapeutic agents
rine-induced contractions. However, anandamide inhibited for the treatment of ED.
electrically evoked smooth muscle relaxations at 10 µM and Demir et al. investigated the relationship of adrenergic
100 µM (p = 0.01). Further studies are needed to establish the responses in corpus cavernosum tissues in the presence of
role of the endocannabinoid system in erectile tissue. bladder outlet obstruction using the alpha-1-AR receptor
antagonist doxazosin and the Rho-kinase inhibitor Y-27632.196
The contractility of human corpus cavernosum was increased
in the presence of bladder outlet obstruction; doxazosin and
The RhoA–Rho-kinase pathway Y-27632 generated effective corpus cavernosum smooth
A major mechanism of the calcium sensitization of smooth muscle relaxation in the presence of obstruction. Doxazosin
muscle contraction is through the inhibition of the smooth and Y-27632 may therefore be the alternatives for the treat-
muscle myosin phosphatase (MLCP). The resulting myosin ment of ED associated with benign prostatic hyperplasia.
phosphorylation and subsequent smooth muscle contraction
therefore occurs without a change in sarcoplasmic calcium
concentration. Several studies have revealed important roles Sex hormones
for the small GTPase, RhoA, and its effector, Rho-associated The peripheral effects of sex hormones on penile smooth
kinase (or Rho-kinase) in calcium-independent regulation of muscle have not been established.98,99 Penile erectile tissue
smooth muscle contraction. The RhoA–Rho-kinase pathway from patients undergoing sex reassignment operations after
modulates the level of phosphorylation of the myosin light estrogen treatment has been used in several studies, including
chain of myosin II, mainly through inhibition of myosin those focusing on receptor-mediated responses in human cor-
phosphatase.188,189 This calcium-sensitizing RhoA–Rho-kinase pus cavernosum tissue. It has been claimed that hormonal
pathway may also play a synergistic role in cavernosal vaso- treatment does not qualitatively change responses to drugs
constriction to maintain penile flaccidity.190 Rho-kinase is and electrical field stimulation.197,198 However, this is still open
known to inhibit myosin light chain phosphatase and to to discussion, since systematic comparisons between tissues
directly phosphorylate myosin light chains, resulting in a net from these patient groups and normal subjects have not been
increase in activated myosin and the promotion of cellular performed.
contraction. Although Rho-kinase protein and mRNA have In vivo studies of castrated dogs suggest that androgen
been detected in cavernosal tissue, the role of Rho-kinase in deficiency has direct effects on the function of the erectile
the regulation of cavernosal tone is not established. Using the tissues, resulting in a higher tone of the detumescence factors
Rho-kinase antagonist Y-27632, Chitaley et al. examined the than could be explained by an incomplete relaxation of the
role of Rho-kinase in cavernosal tone, based on the hypothesis trabecular smooth muscle.199 In isolated human corpus
that antagonism of Rho-kinase results in increased corpus cavernosum pre-treated with testosterone for 30 minutes,
cavernosum pressure, initiating the erectile response indepen- testosterone appeared to have no effect on contraction or
dently of NO. They found that Rho-kinase antagonism stimu- relaxation.200 On the other hand, castration enhanced NANC
lated rat penile erection independently of NO, and suggested nerve-mediated relaxation in corpus cavernosum tissue from
that this principle could be a potential alternative avenue for rabbits.201,202 Since the response to the NO donor morpholino-
the treatment of ED.191 sydnonimine was the same in corpus cavernosum tissue from
100 Textbook of Erectile Dysfunction

controls and castrated animals, it may be assumed that the analysis. There was a significant difference in the maximal
responsiveness of the penile erectile tissue to NO was not intracavernosal pressure response between groups. Total axon
changed. In castrated animals, however, there was a reduction counts did not differ between treatment groups. Castrated
in the release of norepinephrine from adrenergic nerves animals had lower nNOS axon counts than intact animals.
caused by electrical stimulation.202 The hormonal changes The authors concluded that castration resulted in a decreased
caused by castration, which include a change in the balance erectile response to electrostimulation following nerve graft-
between androgens and estrogens, may additionally stimulate ing. This may be due to decreased graft nNOS-positive
the synthesis or release of NO. The influence of androgens on axonal regeneration, and it may have important implications
erectile function may be mediated by the NO–cGMP pathway in patients in whom cavernous nerve grafting could be
to a significant extent, even though non-NO-dependent path- considered.
ways may have been demonstrated.98,99 Androgens may regulate the alpha-AR responsiveness of
The effects of castration and testosterone replacement cavernous smooth muscle. Compared with normal rats,
on peripheral autonomic control of penile erection have been castrated animals showed an enhanced reactivity to alpha-1-AR
studied in dogs203 and rats.117 The findings in the dog study stimulation.205 Androgens may also have important functions
suggest that castration and the resulting low plasma testoster- in the intrapenile mechanisms of erection. In the penis, andro-
one levels did not directly affect penile erectile ability through gen deprivation leads to smooth muscle cell apoptosis, a rela-
actions on peripheral nerves or corpora cavernosa. In the rat tive increase in connective tissue content, and a consequently
study, it was shown that castration reduced the erectile reduced relaxation of the erectile tissue.98,206–209
response, and that testosterone could restore it. It was
concluded from these experiments, which included pregangli-
onic axotomy of the pelvic nerves, that testosterone enhances
the erectile response to cavernous nerve stimulation acting Conclusion
peripherally to the spinal cord, with proerectile postganglionic
parasympathetic neurons as the hormonal target.117 The central regulation of the erectile process is still only partly
A rat study evaluated whether testosterone deprivation known. Central transmitter systems, which seem to be depen-
effects axonal regeneration in cavernous nerve grafts or the dent on androgens as well as NO, may be the targets of future
erectile response to cavernous nerve graft stimulation.204 drugs aimed at the treatment of ED. In penile erectile tissues,
Sprague–Dawley rats underwent bilateral cavernous nerve the different steps involved in neurotransmission, impulse
neurotomy, followed by unilateral nerve graft using the gen- propagation, and intracellular transduction of neural signals
itofemoral nerve. Rats were then randomized to three groups: require further investigation. Increased knowledge of the
castrated, intact, and testosterone-treated. At 3 months grafts central and peripheral changes associated with ED may lead to
were explored and electrostimulation was performed, with an increased understanding of these pathogenetic mechanisms
responses in terms of intracavernosal pressure recorded. and therefore to new treatments and possibly even to preven-
Grafted nerves were then harvested for immunohistochemical tion of the disorder.

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outlet obstruction. J Urol 2006; 175: 2345–9. 204. Syme DB, Corcoran NM, Bouchier-Hayes DM, Morrison WA,
197. Adaikan PG, Karim SM. Adrenoreceptors in the human penis. Costello AJ. The effect of androgen status on the structural and
J Auton Pharmacol 1981; 1: 199–203. functional success of cavernous nerve grafting in an experimental
198. Hedlund H, Andersson KE. Comparison of the responses to drugs rat model. J Urol 2007; 177: 390–4.
acting on adrenoreceptors and muscarinic receptors in human 205. Reilly CM, Stopper VS, Mills TM. Androgens modulate the
isolated corpus cavernosum and cavernous artery. J Auton alpha-adrenergic responsiveness of vascular smooth muscle in
Pharmacol 1985; 5: 81–8. the corpus cavernosum. J Androl 1997; 18: 26–31.
199. Muller SC, Hsieh JT, Lue TF, Tanagho EA. Castration and 206. Baskin LS, Sutherland RS, DiSandro MJ, et al. The effect of testos-
erection. An animal study. Eur Urol 1988; 15: 118–24. terone on androgen receptors and human penile growth. J Urol
200. Kimura K, Hashine K, Tamura M, Kawanishi Y, Imagawa A. Effect 1997; 158: 1113–18.
of testosterone on contraction and relaxation of isolated human 207. Shabsigh R. The effects of testosterone on the cavernous tissue
corpus cavernosum tissue. Int J Imp Res 1990; 2 Suppl 1: 53. and erectile function. World J Urol 1997; 15: 21–6.
201. Andersson KE, Holmquist F, Bodker A. Castration enhances 208. Shabsigh R, Raymond JF, Olsson CA, O’Toole K, Buttyan R.
NANC nerve-mediated relaxation in rabbit isolated corpus Androgen induction of DNA synthesis in the rat penis. Urology
cavernosum. Acta Physiol Scand 1992; 146: 405–6. 1998; 52: 723–8.
202. Holmquist F, Persson K, Bodker A, Anderson KE. Some pre- 209. Traish AM, Park K, Dhir V, et al. Effects of castration and andro-
and postjunctional effects of castration in rabbit isolated corpus gen replacement on erectile function in a rabbit model. Endocri-
cavernosum and urethra. J Urol 1994; 152: 1011–16. nology 1999; 140: 1861–8.
13 Environmental erectile dysfunction
Arthur L Burnett

Introduction smoking and alcohol consumption on erectile function (see

recent reports of the United States Surgeon General and the
In the course of recent medical advances brought to the clinical Board of Science and Education and Tobacco Control
management of erectile dysfunction (ED) in recent years, such Resource Centre of the British Medical Association).11,12 The
as highly publicized effective oral pharmacotherapy for the idea that environmental exposures may represent a risk factor
condition, additional emphasis has now been given to its for ED borrows from concepts that were developed in the field
public health significance. Epidemiologic studies have esta- of male reproductive function that suggested that certain
blished reasonably well the high frequency of ED presently pesticides, solvents, and related chemical agents may affect
worldwide, despite variations in diagnostic definitions of the fertility.13–16 Additionally, early citations in the medical litera-
disorder. Overall prevalence rates of ED range between 10% ture have documented men reporting ED whose occupations
and 20%, with the majority of studies reporting an overall rate included agricultural and industrial work.13,14,17,18
closer to 20%.1 Although incidence data for the disorder are The intent of this chapter is both to evaluate the currently
scant, estimates approach 26 cases per 1,000 men annually, available observational and experimental data linking envi-
according to the longitudinal analysis of the often-quoted ronmental and occupational exposures with the development
Massachusetts Male Aging Study (MMAS) representing men of ED and to determine pathophysiologic concepts in support
40–69 years of age.2 Further, a longitudinal study of placebo- of this link. This exercise also explores whether environmental
treated men in the Prostate Cancer Prevention Trial who were exposures should be assigned merely an association with ED
55 years or older found an incident ED rate of 57% at 5 years or whether these possibly represent a cause for this disorder.
and 65% at 7 years.3 Accordingly, the evaluation aptly applies rigorous causality cri-
Such studies have also served to enumerate primary risk teria as promoted by the First US Surgeon General’s Advisory
factors for ED, which have an impact on frequency rates.4–6 Committee on Smoking and Health in 1964.19 Several criteria
Aging, diabetes, cardiovascular disorders, hypertension, dys- to be considered with respect to a causal association include
lipidemia, obesity, cigarette smoking, and prostate disorders consistency, specificity, strength, temporality, and coherence.20
all show positive relationships with the occurrence of the Consistency is met by repeated studies that examine different
disorder. Frequency estimates are further impacted by the clinical settings, subjects, eligibility criteria, and exposure
severity and duration of associated risk factors. Ongoing opportunities. Specificity refers to a dose–response effect with
scientific investigations are useful to define the biological basis an assessment that establishes independence of a potential
and the extent to which highly prevalent medical conditions risk variable. Strength identifies the relative risk estimation.
and other risk factors adversely affect the physiology and Temporality implies that the effect occurs with the onset of the
molecular mechanisms of penile erection. The public health exposure and, supposedly, the effect is diminished with cessa-
emphasis associated with ED also affords societal prevention tion of the exposure. Coherence means that a biological mech-
opportunities to develop and implement programs to lessen anism has been explored and found to be tenable. Satisfaction
its occurrence. Indeed, observational and interventional stud- of these criteria would strongly support the proposal that
ies have begun to explore the extent to which ED risk factors environmental exposures qualify as a causal basis for ED.
are modifiable, with subsequent improvement in health out-
comes and quality of sexual life.7–10
A growing interest in the field along the lines of identifying Biologic basis for exposure risks
at-risk populations and specific risk factors for ED pertains to
environmental exposures to toxicants or other unhealthful A major consideration in advancing the current proposal
substances. Precisely, it may be hypothesized that deleterious is the extent to which a biological basis can be offered to
exposure to chemical and physical agents generated and explain the possible harm of environmental exposures on
released into a person’s surroundings constitutes a risk factor erectile function. In this regard, it would be important to
for developing ED. The proposal is far from implausible, and determine whether plausible biological mechanisms can be
the notion of environmental exposure risks mimics wide- formulated in support of this premise, in accordance with
spread concerns of possibly adverse health effects of cigarette how chemical and physical agents feasibly disturb erection

106
 Environmental erectile dysfunction 107

regulatory determinants or physiologic processes of the These circumstances introduce the possibility of information
erectile response. bias, possibly toward underestimating the effects of the
Current lines of thought suggest that environmental toxi- environmental exposure. Some studies have applied external
cants exert a principal effect by deranging endogenous indicators (e.g. known location and duration of exposure) in
hormones involved in reproductive and sexual function. an effort to state the exposure risk, although the exact expo-
The majority of environmental toxicology studies have sure conditions (i.e. the intensity and frequency of exposure)
centered on the threat of various compounds on male repro- are generally elusive. With respect to erectile function assess-
ductive health, homeostasis, and physical development.15,16 ment, a single-item assessment (e.g. ‘Do you experience diffi-
These compounds have been collectively termed ‘endocrine culty getting or maintaining an erection that is rigid enough
disrupters’ as defined by the United States Environmental for satisfactory sexual intercourse?’) has gained prominence,
Protection Agency.21 They include pesticides (e.g. 2,4-dichloro- particularly for population-based epidemiologic studies.31
phenoxyacetic acid (2,4-D), dichlorodiphenyl trichloroethane This brief manner of data collection may also introduce the
(DDT), dieldrin), plasticizers (e.g. styrene, phenols, and possibility of information bias, probably toward under-
phthalates), and industrial chemicals [e.g. polychlorinated reporting. In addition, it frequently does not reveal the severity
biphenyls (PCBs) and dioxins].22–24 In light of the documented of the erectile impairment. However, the findings usually
anti-androgenic or estrogenic properties of many of these provide insight into the probable significance of the problem
environmental chemicals, it is conceivable that they have a within the general population.
negative impact on erectile function. This contention is
consistent with accumulating evidence that erectile function
is a hormone-dependent process. Various lines of evidence Case series
indicate that androgens are involved in maintaining the Several descriptions of a link between environmental expo-
responsiveness of penile vascular smooth muscle to sexual sure and ED qualify as observational case series. As such, they
stimuli, priming erection regulatory factors such as signaling are limited by not having true comparison groups. With
by the erection mediator nitric oxide (NO), and optimizing expectations that increasingly formal studies will emerge that
function of central neuronal nuclei responsible for penile may provide more robust data, these reports are nonetheless
erection.25–27 informative.
Alternative proposals have centered on possible effects of With a report published in 1970, Espir et al. may be
environmental chemicals as neurotoxins and the plausibility credited with first bringing attention to the matter of environ-
that these could impair the neurogenic basis of penile erec- mental chemicals potentially affecting erectile function.17
tion. Studies from the 1950s and 1960s have shown that various These investigators observed that four farm workers in the UK
compounds (e.g. di-isopropyl fluorophosphates, organophos- who had been using herbicides and pesticides in intensive
phorus insecticides) produce toxic effects by inhibiting cholin- agriculture over a 1-year interval lost erectile ability. Organo-
esterase and acetylcholinesterase activity, thereby causing an phosphorus chemicals were implicated as the environmental
accumulation of acetylcholine and eventually persistent depo- exposure, and disruption of testosterone metabolism was
larization at cholinergic nerve endings.28,29 Contributions of inferred.32 Upon discontinuing working with the chemicals,
the cholinergic system at either central or peripheral levels to all men recovered erectile function.
the regulation of penile erection would conceivably then be Oliva et al. studied the ED risk associated with chemical
potentially compromised by environmental toxicant expo- and physical environmental agents in men located in a highly
sure. It would be presumptuous at this time to imply that such agricultural and industrial region of Argentina who sought
exposure directly affects the neuronally based NO signal trans- medical attention for their erectile impairment.33 The investi-
duction pathway, which operates as the predominant neuro- gators determined that 28% of the 199 men were exposed
regulatory control system for penile erection.30 to pesticides or to solvents, with median exposure times of
12 years or 14 years, respectively. Confounding lifestyle and
medical risk factors for ED were noted in this population,
Epidemiologic evidence including cigarette smoking (in 31%), alcohol abuse (in 33%),
diabetes (in 11%), hypertension (in 34%), cardiovascular dis-
Observational data
eases (in 16%), and therapeutic drugs (in 22%).
In exploring the association between environmental exposure In a single case report, Park et al. associated chronic expo-
and the occurrence of ED, as for many epidemiologic studies sure to methyl bromide with ED.34 The patient, who had been
attempting to link a health risk factor and impaired sexual working in the fumigation department at a public food quar-
function, some consideration should be given to ascertaining antine station for 12 years, was confirmed to manifest a
observational data. For this analysis, self-reporting and appli- peripheral sensorimotor polyneuropathy, consistent with
cation of other subjective instruments (e.g. logs, question- the known neurotoxicity associated with this fumigant. Upon
naires, and sexual function inventories), rather then objective, discontinuing his job, his recovery of spontaneous erectile
quantitative measurements, were commonly used to deter- function was minimal.
mine substance exposure and erectile performance. A special
concern associated with documenting environmental expo-
sure subjectively is the difficulty in recording exposure level (i.e. Population-based studies
the dosage effect), which is generally derived retrospectively More valid appraisals of the effects of environmental toxi-
and may also not be accurately identified by the person at risk. cants on erectile function have been obtained through
108 Textbook of Erectile Dysfunction

cross-sectional, random surveys of a sample population. adjusted odds ratio 6.7; 95% CI 1.2–35.9, respectively) com-
Several levels of investigation into the widely ranging occupa- pared with unexposed workers.
tional hazards of chemical compounds on reproductive and Sexual dysfunction observed in male viscose rayon factory
sexual functions have been undertaken. One early study workers in Belgium were speculated to be the result of their
focused on the effects on reproductive ability of long-term potentially toxic exposure to carbon disulfide, which is stan-
occupational exposure to lead. Lancranjan et al. carried dardly used in this industry, and it prompted an epidemio-
out a comprehensive clinical and toxicological assessment logic investigation. In their questionnaire-based study,
of 100 workmen who had a mean occupational exposure of Vanhoorne et al. found that the complaint of ED was regis-
8.5 years (range: 1–23 years) working at a storage battery plant tered at a frequency rate of 15.7% (18 of 116 men) among
in Bucharest as well as 50 technicians and office workers of exposed workers, representing a significantly greater occur-
this plant who worked in annex workrooms in a lead-polluted rence than the rate of 3.8% (3 of 79 men) found in non-
environment for a mean of 6 years (range: 1–27 years).13 In exposed workers.37
the course of evaluating the fertility of these men, the investi- Additional studies support the direct association between
gators assessed that, by sexual history, there was a high rate of pesticide exposure and ED. Amr et al. conducted an epide-
‘pathologic erections’ in the lead-exposed workmen (33%) miologic investigation in Egypt to determine whether pesti-
compared with that of their coworkers (14%), who were cides frequently used in the agricultural region (e.g. carbamates,
verified to have a physiologic, non-toxic absorption of lead. pyrethroids, and organophosphates) exert adverse effects
This approach to the evaluation of environmental occupa- on erectile function.38 The study population consisted of
tion risk on reproductive ability was similarly undertaken in randomly selected workers – 208 pesticide formulators and
the USA by the National Institute for Occupational Safety and 172 pesticide applicators – whose responses to standardized
Health (NIOSH). Under such auspices,5 Landrigan et al. health questionnaires were compared with that of 223 unex-
described the risk of ED among 39 randomly selected male posed control subjects (72 from an urban textile factory, who
chemical workers employed at a large manufacturing plant in were matched with the pesticide formulators, and 151 from a
Alabama in 1981 who were exposed to the stilbene derivative rural area, who were matched with the pesticide applicators),
4,4′-diaminostilbene-2,2′-disulfonic acid (DAS), a chemical who were otherwise matched for age and socioeconomic and
used in the production of optical brightening agents.14 By educational levels. The formulators were directly exposed to
interview, 14 (36%) of these workers were identified as expe- pesticides for at least 40 hours per week for at least 9 months
riencing ED, and 8 (29%) of 28 exposed workers who under- of the year for at least 2 consecutive years, and the applicators
went hormonal evaluation were found to have reduced serum were exposed for at least 2 consecutive years during standard
testosterone measurements (less than 300 mg/ml). The latter farm work. ED was significantly more frequent in the exposed
finding suggested to the investigators that the adverse health group (the pesticide formulators) than in the unexposed con-
effects may have been associated with the estrogenic activity of trol group, 26.9% vs 4.2% (p < 0.001). Both the pesticide for-
the chemical. mulators and the applicators demonstrated a significantly
The official report released by NIOSH in the USA in 1990, greater frequency of psychiatric disorders than the control
known as The Health Hazard Evaluation, comprised a formal group.
questionnaire survey conducted during 1981–1983 among
men working in the area of the aforementioned chemical
plant that manufactured DAS.35 Among 44 men aged 20–57 Disease correlates
years comprising the study population, 11 (25%) reported It is surmised that several relationships between environmental
current or previous ED that developed after beginning work exposure and ED risk can be characterized, which may con-
(and over an average length of employment of 4.7 years). Low tribute toward affirming the risk association. Type of exposure,
levels of serum testosterone (less than 350 ng/dl) were found dose–response effect, the effect of risk factor covariates, and
in 16 (37%) of the men. The second report of the NIOSH the effects of discontinuation of exposure represent such
Health Hazard Evaluation, which was a questionnaire-based disease correlates. From the aforementioned section, it would
survey conducted in 1991, compared self-reported sexual appear that various types of environmental exposure correlate
function in 30 male workers who were currently manufactur- with ED. Passive exposure to cigarette smoke, which contains
ing DAS, 20 former DAS workers, and 35 workers who manu- numerous pollutants, represents a further example of a type of
factured plastics additives in a different manufacturing area environmental exposure that has been shown to be a risk
(unexposed workers).36 Adjusting for age, currently exposed factor for ED. According to a prospective analysis of the
workers were more likely than unexposed workers to score Massachusetts Male Aging Study, the odds of incident ED
in the lowest quartile for ‘physiologic competence’ (a measure were more than doubled in people exposed to passive cigarette
of erection ability) (adjusted odds ratio 1.9; 95% CI 0.6–6.4) smoke, if present both at home and at work, compared with
and ‘activity–performance factor II’ (a measure of ejaculatory the odds in unexposed people (adjusted odds ratio 2.07; 95%
function) (adjusted odds ratio 5.8; 95% CI 1.3–27.3). Currently CI 1.04–4.13, p = 0.04).4 In contrast, passive exposure at home
exposed workers were also more likely than unexposed workers or at work alone did not increase the odds of incident ED in
to score in the lowest quartile for ‘sexual interest’ (adjusted non-smokers, but each increment of exposure did increase the
odds ratio 1.9; 95% CI 0.5–7.2). Former DAS workers reported estimated likelihood of ED in smokers.4 A similar analysis
problems associated with ‘activity–performance factors I and resulted from the Boston Area Community Health survey,
II’ (measures of quality of erection and ejaculatory function, which determined that men passively exposed to cigarette
respectively) (adjusted odds ratio 2.2; 95% CI 0.5–10.1 and smoke had a moderate, statistically non-significant increase in
 Environmental erectile dysfunction 109

ED (adjusted odds ratio 1.33; 95% CI 0.69–2.55) compared sleep and are diminished in men with presumably organic
with those who had never smoked and had not been exposed ED.40 Applying NPT in a study of Argentinean agricultural
to passive smoking.39 and industrial workers, Oliva et al. determined that the risk of
The relationship between the amount of exposure to an having a flat erectile pattern was significantly increased in
environmental toxicant and the extent of ED would describe those with pesticide exposure (odds ratio 7.1; 95% CI 1.5–33.0)
a dose–response effect. Support for this concept is provided in and solvent exposure (odds ratio 12.2; 95% CI 1.2–124.8), with
the literature. Among 150 men with lead exposure categorized a slightly elevated risk to a non-significant degree from expo-
as being ‘poisoned’ or having ‘moderate’ absorption, ‘slight’ sure to heat (odds ratio 1.7; 95% CI 0.3–9.4).33
absorption, and ‘physiologic’ absorption, rates of ‘pathologic
erections’ were 48%, 33%, 22%, and 14%, respectively.13 Among
viscose rayon workers, those who were chemically exposed Clinical toxicologic assessment
to carbon disulfide with a high cumulative exposure index The quantitative measurement of environmental chemicals in
score (amount and duration of exposure >300 mg/m3 years) the tissues of people suspected to be exposed to such agents
manifested a significantly higher ED rate (20%) than that who report ED offers an elegant approach to study their pos-
(9.1%) for men with a low cumulative index score (>300 mg/ sible role in the etiology of ED. Such an evaluation equates to
m3 years).37 In a similar way, a direct correlation between assaying for biomarkers of environmental chemical exposure.
duration of exposure and frequency of ED was found among In a clinic-based case control study conducted in Kingston,
Egyptian pesticide formulators.38 For exposure durations of Ontario, Polsky et al. explored whether organochlorines,
≤5 years, ≤10 years, ≥15 years, and ≥20 years, ED rates were which are related to such pollutants as polychlorinated biphe-
12.2%, 17.8%, 35%, and 35.8%, respectively, with statistically nyls and chlorinated pesticides and which are measurable in
significant differences shown for the two longer durations blood, are associated with ED risk.41 The investigators found
compared with the shorter durations. In another study, which that plasma levels of an assortment of these compounds were
applied a logistic regression analysis and a reference group of no different among 101 men presenting with ED and 234
men with normal erectile function to calculate strength of asso- comparable control subjects, after adjusting for age, total lip-
ciation, objectively confirmed ED was found to be greater in ids, and health condition confounders. Results from this study
men who were frequently exposed to pesticides (odds ratio 8.4) would imply that environmental chemicals are uninvolved in
than in men who were so exposed only occasionally (odds ED risk. However, the investigators conceded that, since the
ratio 4.4).33 magnitude of the risk in the general population may be low, a
The premise that environmental exposure adversely affects study with a larger sample size may be required to detect the
erectile function would seemingly be strengthened by epi- actual risk. The study also does not exclude the possibility that
demiologic evidence that discontinuation of exposure permits in an affected person a sufficiently toxic exposure to environ-
recovery of erectile function. In support of this concept, it was mental chemicals may yet comprise a significant ED risk.
shown that farm workers who developed ED after exposure to Lancranjan et al. studying the effect of lead on reproductive
toxic chemicals recovered erectile function after discontinuing ability among workers in a storage battery plant in Bucharest,
their occupations.17 On the other hand, a fumigator intoxi- also evaluated the levels of toxic absorption of lead and lead
cated by occupational methyl bromide did not recover erec- metabolites in blood and urine and a basic hematologic screen
tions after discontinuing his occupation.34 An explanation for along with urinary 17-ketosteroid (17-KS) levels as a measure
the discrepancy follows the differences in amount of exposure of Leydig cell function.13 The investigators showed toxicologic
in these two examples, the former consisting of 1 year of abnormalities to a greater extent in pathologic lead-exposed
exposure and the latter consisting of 12 years of exposure; groups with higher rates of erection difficulties in contrast
discontinuation of exposure after a significant life-time inter- with control subjects, affirming that such parameters may
val may fail to modify the frequency of ED. Under conditions serve as indicators of erectile impairment in lead-exposed
of long-term exposure, irreversible erectile impairment may people. They did not find a relationship between the level
conceivably have developed. of lead absorption and 17-KS elimination, which together
with observed abnormal fertility parameters in lead-exposed
workers led them to suggest that the likely toxic effects of
Clinical data the heavy metal on the body, including the testis, is exerted
It would be meaningful to evaluate a link between environ- by mechanisms other than disrupted function of the hypotha-
mental exposure and ED based on objective criteria. The lamic–pituitary–gonadal axis.
supposition is that quantitative measurements can be used to In another clinic-based case control study performed in
offer indices of the integrity of erectile function among people Cairo, Egypt, Anis et al. studied the potential for chronic lead
exposed to environmental toxicants. exposure to have caused ED in 34 men presenting with the
condition who were scheduled to undergo penile prosthesis
surgery.42 The investigators found that 16 of the 34 patients
Penile tumescence studies (47%) and none of clinically matched control subjects had
Nocturnal penile tumescence (NPT) monitoring provides elevated serum levels of lead (>25 g/dl). They further found
a non-invasive diagnostic technique to quantify erection that the serum lead level significantly correlated with
physiology objectively during the naturally occurring cycle of cavernous tissue lead levels in the patient group and also
sleep-related penile erections. These spontaneous episodes of observed lead granule deposition histologically in cavernous
tumescence normally accompany rapid eye movement (REM) tissue removed from patients at the time of their surgeries.
110 Textbook of Erectile Dysfunction

Additionally, they confirmed higher serum levels of reactive dearth of these studies hampers the ability to reach a definitive
oxygen species and lower levels of antioxidants, indicating the conclusion.
presence of oxidative stress, in people with a high serum lead The strength of the association also rests on limited avail-
level compared with those with a low serum lead level. The able information at this time, although description of dose–
findings suggest that lead toxicity may serve as a risk factor for response relationships for several exposure circumstances
ED and probably exerts effects pathogenically by oxidative contributes to this line of support. Other correlates, such as
stress mechanisms. temporality of the association, lend support as well, with a few
observational and experimental studies demonstrating that
ED follows environmental exposures and that erectile func-
Experimental data tion is recoverable after the offending exposure is removed.
Experimental studies in which controlled exposures to envi- However, observational findings do indicate the likelihood
ronmental chemicals are applied provide an additional that erection recovery after exposure removal occurs appre-
approach to ascertain the consequences of the exposure on ciably only after a limited extent of life-time exposure.
erectile function. Such studies commonly apply rigorous Coherence of the association largely derives from experi-
scientific methodology (e.g. random allocation of subjects to mental studies, which have tested for plausible mechanisms
experimental and control groups, the use of different control for the deleterious effects of environmental chemicals on
groups, and the application of blinding procedures to reduce erectile function. Leading possibilities in this regard include
bias), and as such offer the most robust data from which to hormonal derangements and neurotoxicity. However, the
draw conclusions regarding risk associations. As one would exact mechanisms for erectile impairment remain unclear,
suspect, such ideal studies in which environmental exposures and much more biomedical research will be required to
are controllably delivered to humans are nearly impossible to advance concepts in this area.
conduct. An informative perspective is provided, however, It is acknowledged that confounding issues could hinder
when examining the results from several experiments testing assessments of causation in this field of study. One concern
the effects of cigarette smoking on erectile function in humans. pertaining to population-based studies is whether a poten-
These experiments, which mainly consisted of either acute tially toxic exposure is so pervasive in a certain community of
exposure or exposure discontinuation study designs, showed interest that it produces a magnitude of risk that is artifactu-
direct temporal and dosing level effects of cigarette smoking ally increased. This difficulty describes prevalence bias. The
on various erectile parameters.43–47 assignment of risk for a certain chemical exposure at a public
Animal models offer another useful approach for investigat- health level would require the study of a sufficiently large
ing the association between environmental chemical exposure population base with appropriate control groups. As a related
and ED. Brien et al. studied the effects of p, p-dichlorodiphenyl concern, associated with such epidemiologic studies, a par-
dichloroethylene (p,p-DDE), a prominent and persistent ticular exposure may introduce consequences that secondarily
metabolite of the insecticide DDT, on erectile function in a rat affect penile erection. Such an example of misattribution
model of apomorphine-induced erections.48 The investigators would be that of chemically exposed workers who experience
found that animals given a single intraperitoneal dose of psychological and general health ill-effects that subsequently
the chemical agent had decreased erectile function for at least interfere with sexual interest and activity. Use of validated
2 weeks compared with responses of control rats. However, questionnaires specific for erection ability may serve optimally
they were able to reverse the ED in p,p-DDE-treated rats using to evaluate environmental exposures as a primary risk factor.
high doses of testosterone. The investigators concluded that
p,p-DDE exerts a deleterious effect on penile erection, pre-
sumably by interference with androgen-mediated mecha- Conclusion
nisms. The conclusion is consistent with the known action of
this chemical agent as an androgen receptor antagonist and This analysis of clinical epidemiologic and biomedical scien-
supports altered steroid hormone function resulting from tific studies examining the association between environmental
certain chemical exposures as a proximate basis for environ- exposures and ED offers several conclusions. There is enough
mental ED. intriguing information to raise the possibility of environmental
exposures as a risk factor for ED. However, it is acknowledged
that limited information has been produced thus far in this
Synthesis of the evidence field of study. At this time, it seems reasonable to suggest that
environmental chemical exposures may have a negative impact
Available evidence indicates that environmental chemical on erectile function. However, the scope of evidence is pres-
exposure constitutes a plausible risk factor for ED. However, ently insufficient to prove direct causal associations in many
the causal basis for this association must be carefully evaluated. instances, and further scientific investigation is needed. It will
Several criteria require consideration prior to establishing be necessary to conduct additional observational studies with
causation per se. With regard to consistency of the association, rigorous outcome assessments, along with corroborative basic
both case series and population-based studies establishing scientific studies delineating biological mechanisms for the
rates of ED among people exposed to various environmental risk association. In the mean time, current information appro-
chemicals provide meaningful support. Population-based priately raises awareness of the potential risk and supports
studies afford a more accurate observational basis for this prudent recommendations to limit exposures to reduce
assessment than uncontrolled case series, although the relative possible morbidity.
 Environmental erectile dysfunction 111

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9. Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes dysfunction: a study in a consulting population. J Androl 2002; 23:
on erectile dysfunction in obese men: a randomized controlled 546–50.
trial. JAMA 2004; 291: 2978–84. 34. Park HJ, Lee KM, Nam JK, et al. A case of erectile dysfunction
10. Esposito K, Ciotola M, Giugliano F, et al. Mediterranean diet associated with chronic methyl bromide intoxication. Int J Impot
improves erectile function in subjects with the metabolic syn- Res 2005; 17: 207–8.
drome. Int J Impot Res 2006; 18: 405–10. 35. Quinn MM, Wegman DH, Greaves IA, et al. Investigation of reports
11. Burnett AL. Erectile dysfunction. In: Samet JM, Norman LA, of sexual dysfunction among male chemical workers manufactur-
Wilbanks C, eds. The Health Consequences of Smoking: A ing stilbene derivatives. Am J Ind Med 1990; 18: 55–68.
Report of the Surgeon General. Atlanta: US Department of 36. Whelan EA, Grajewski B, Wild DK, et al. Evaluation of reproduc-
Health and Human Services, Centers for Disease Control and tive function among men occupationally exposed to a stilbene
Prevention, National Center of Chronic Disease Prevention derivative: II. Perceived libido and potency. Am J Ind Med 1996;
and Health Promotion, Office on Smoking and Health, 2004: 29: 59–65.
767–76. 37. Vanhoorne M, Comhaire F, De Bacquer D. Epidemiological study
12. Editorial Board of Science and Education, British Medical Associa- of the effects of carbon disulfide on male sexuality and reproduc-
tion. Smoking and Reproductive Life: The Impact of Smoking on tion. Arch Environ Health 1994; 49: 273–8.
Sexual, Reproductive and Child Health. London: BMA, 2004: 5–7. 38. Amr MM, Halim ZS, Moussa SS. Psychiatric disorders among
13. Lancranjan I, Popescu HI, Gavanescu O, et al. Reproductive ability Egyptian pesticide applicators and formulators. Environ Res 1997;
of workmen occupationally exposed to lead. Arch Environ Health 73: 193–9.
1975; 30: 396–401. 39. Kupelian V, Link CL, McKinlay JB. Association between smoking,
14. Landrigan PJ, Melius JM, Rosenberg MJ, et al. Reproductive haz- passive smoking, and erectile dysfunction: results from the Boston
ards in the workplace. Development of epidemiologic research. Area Community Health (BACH) Survey. Eur Urol 2007; 52:
Scand J Work Environ Health 1983; 9: 83–8. 416–22.
15. Toppari J, Larsen JC, Christiansen P, et al. Male reproductive health 40. Levine LA, Lenting EL. Use of nocturnal penile tumescence and
and environmental xenoestrogens. Environ Health Perspect 1996; rigidity in the evaluation of male erectile dysfunction. Urol Clin
104: 741–803. North Am 1995; 22: 775–88.
16. Cheek AO, McLachlan JA. Environmental hormones and the male 41. Polsky JY, Aronson KJ, Heaton JP, et al. Pesticides and polychlori-
reproductive system. J Androl 1998; 19: 5–10. nated biphenyls as potential risk factors for erectile dysfunction. J
17. Espir ML, Hall JW, Shirreffs JG, et al. Impotence in farm workers Androl 2007; 28: 28–37.
using toxic chemicals. BMJ 1970; 1: 423–5. 42. Anis TH, El Karasky A, Mostafa T, et al. Chronic lead exposure
18. Sabroe S, Olsen J. Health complaints and work conditions among may be associated with erectile dysfunction. J Sex Med 2007; 4:
lacquerers in the Danish furniture industry. Scand J Soc Med 1979; 1428–34.
7: 97–104. 43. Gilbert DG, Hagen RL, D’Agostino JA. The effects of cigarette smok-
19. US Department of Health, Education, and Welfare. Smoking and ing on human sexual potency. Addict Behav 1986; 11: 431–4.
Health. Report of the Advisory Committee to the Surgeon General 44. Glina S, Reichelt AC, Leão PP, et al. Impact of cigarette smoking
of the Public Health Service. Washington, DC: US Department of on papaverine-induced erection. J Urol 1988; 140: 523–4.
Health, Education, and Welfare, Public Health Service, 1964. PHS 45. Abber JC, Lue TF, Orvis BR, et al. Diagnostic tests for impotence:
Publication, No. 1103. a comparison of papaverine injection with the penile-brachial
20. Hill AB. The environment and disease: association or causation? index and nocturnal penile tumescence monitoring. J Urol 1986;
Proc R Soc Med 1965; 58: 295–300. 135: 923–5.
21. Ginsburg J. Tackling environmental endocrine disrupters. Lancet 46. Levine LA, Gerber GS. Acute vasospasm of penile arteries in
1996; 347: 1501–2. response to cigarette smoking. Urology 1990; 36: 99–100.
22. Korach KS. Surprising places of estrogenic activity. Endocrinology 47. Guay AT, Perez JB, Heatley GJ. Cessation of smoking rapidly
1993; 132: 2277–8. decreases erectile dysfunction. Endocr Pract 1998; 4: 23–6.
23. Colborn T, vom Saal FS, Soto AM. Developmental effects of 48. Brien SE, Heaton JP, Racz WJ, et al. Effects of an environmental
endocrine-disrupting chemicals in wildlife and humans. Environ anti-androgen on erectile function in an animal penile erection
Health Perspect 1993; 101: 378–87. model. J Urol 2000; 163: 1315–21.
14 Erectile dysfunction and treatment of
carcinoma of the prostate
Culley C Carson III

Introduction preservation may be associated with ED. The most important

apparent treatment risk is damage to the cavernosal nerves,
Prostate cancer is the most common non-skin cancer in avoided by surgical procedures employing the ‘nerve-sparing
American men and is the second leading cause of cancer approach’. Nerve-sparing radical prostatectomy was first
deaths. As many as 230,000 American men were diagnosed reported by Walsh et al. in 1982, and over the past 20 years
with prostate cancer in 2007 and almost 30,000 die of the it has been adopted by urologic surgeons throughout the
disease annually. Treatments for this universally feared malig- world.2
nancy include radical surgery, radiation therapy, and medical Preserving the neurovascular bundles posterolateral to the
therapy. All these therapeutic alternatives can result in dis- prostatic capsule saves the innervation of the corpus caver-
orders of continence and in erectile dysfunction (ED) – nosum smooth muscle. Described anatomically by Walsh and
decreasing the ability to obtain and maintain an erection Donker in 1982, this anatomic radical prostatectomy demon-
satisfactory for vaginal penetration – which have a profound strated significant improvements in erectile function following
impact on men’s quality of life. Because men diagnosed careful nerve-sparing surgery.2 Quinlan et al. reported the first
with prostate cancer are often over age 50, prostate cancer and results of a nerve-sparing approach, with more than 90%
its treatment are compounded by other risk factors for ED. preserved erectile function in men under the age of 50 and
Men from 50 to 70 years of age have progressive increases in 25% in men over 70.3
prostate cancer incidence and prevalence with each decade, The etiology of ED following prostate cancer therapy,
associated with a doubling in incidence of ED from aging and whether surgical or non-surgical, includes organic and psy-
other independent risk factors.1 chogenic causes. The impact of prostate cancer on the patient
Treatment of carcinoma of the prostate affects both vas- and his partner are significant. The diagnosis of a frequently
cular and neurologic supply to the penis, which, with the fatal disease produces significant anxiety and depression
addition of increased vascular and psychological risk factors, amongst both the patient and his family.4,5 Organic causes of
increases the risk of ED. With the improvement in surgical ED include not only neurologic injury, but also arterial insuf-
techniques and the advent of refined nerve-sparing prostatec- ficiency, veno-occlusive dysfunction, and anatomic structural
tomy in open, laparoscopic, and robotic-assisted prostatectomy, changes of the penis. Patients treated with androgen depriva-
significant preservation of erectile function can be accom- tion therapy during radiation therapy or independently will
plished in comparison with the older, non-nerve-sparing also have significant hormonal etiology for their ED.
techniques. Despite these refinements, however, there is a Basic science research has demonstrated significant changes
significant prevalence of ED following even the best bilateral in the corpus cavernosum after denervation of the prostate.
nerve-sparing radical prostatectomy. Other treatment modali- User et al. have documented significant changes in corpus
ties, including external beam radiation therapy, brachytherapy, cavernosum wet weight as well as mRNA content of corpus
cryotherapy, high-intensity focused ultrasound (HIFU), and cavernosum smooth muscle tissue as early as 7 days after
androgen deprivation therapy, are also associated with ED. denervation.6 Progression of these changes continued through-
out the 60 days of their study, and were significantly different
from the situation in control animals. Thus denervation may
produce immediate, long-lasting, and even permanent changes
Etiology of erectile dysfunction in the ability of the corpus cavernosum. Electron microscopy
following treatment of prostate cancer in these same animals demonstrated substantial apoptosis of
perivascular and cavernosal smooth muscle and destruction
Because radical prostatectomy continues to be the gold stan- of intracavernosal endothelial cells. These changes, similar to
dard for the treatment of organ-confined prostatic carcinoma, those seen with high cholesterol diets and other vascular risk
the majority of investigations, reports, and outcomes have factors to the corpus cavernosum, demonstrate acceleration of
been reported with surgery for the treatment of prostate cancer. destruction of the vascular and endothelial cell component of
Because the prevalence of pre-existing ED in men over the the corpus cavernosum.7 In a corpus cavernosal biopsy study
age of 50 is as high as 50%, even the best nerve and vascular of men 6 months after radical prostatectomy, Schwartz et al.

112
 Erectile dysfunction and treatment of carcinoma of the prostate 113

have demonstrated an increase in fibrotic tissue in the corpus unilateral nerve-sparing prostatectomy.17 In men in their 50s,
cavernosum and a relative decrease in smooth muscle content.8 return of potency was 82% and 33%, respectively; in men
In their small study, prophylactic treatment with high-dose in their 60s, 61% and 51%, respectively in men in their, 70s,
sildenafil was able to reverse the trend of increasing cavernosal 48% and 40%, respectively. Scardino et al. reported similar
smooth muscle fibrosis. data with further restoration of erectile function between
Despite the overwhelming evidence that nerve injury pro- 24 and 36 months.18 In patients less than 60 years of age who
duces ED following radical prostatectomy, there are other underwent bilateral nerve-sparing prostatectomy, full erec-
causes of ED from the surgical procedure. Nehra et al. in tion was reported in 70% at 24 months vs 76% at 36 months.
1997 reported significant numbers of accessory pudendal This difference between the groups was also demonstrated at
arteries surrounding the prostate in 35% of men undergoing all age groups. While also seen in patients with unilateral
nerve-sparing radical prostatectomy. In this study, 50% of nerve-sparing prostatectomy, the improvement was less
the men with accessory pudendal arteries had left-sided, 25% robust in patients less than 60 years of age, improving from
had right-sided, and 25% had bilateral accessory pudendal only 26% to 30% between 24 and 36 months. Saranchuck
arteries. In many of the patients studied, these accessory et al. showed that improvement in erectile function after
pudendal arteries were the principal if not sole blood supply radical prostatectomy plateaus at 24–30 months after surgery
to the corpora cavernosa.9 Mulhall and Graydon in 1996 and that beyond that time little additional ED improvement
reported vasculogenic causes of ED in a group of men under- is seen.19
going bilateral nerve-sparing radical prostatectomy. They were While these reports from centers of excellence are encour-
studied with penile Doppler studies and dynamic infusion aging, other studies examining the results of radical prostatec-
cavernosography and cavernosometry (DICC).10 Of these 10 tomy in a community-based population do not support this
men, all had some degree of arterial insufficiency on Doppler high return of erectile function. Stanford et al., using a medi-
blood flow studies, and 6 had bilateral arterial insufficiency. care database in patients undergoing radical prostatectomy of
In addition, 4 of the 10 men also exhibited veno-occlusive mixed variety and followed for more than 18 months, found
abnormalities. Rogers et al. have likewise documented that that 60% of patients reported ED.20 Similarly, Rabbani et al.
preservation of accessory pudendal arteries during radical followed 200 men who were potent preoperatively for 2–51
prostatectomy may enhance recovery of sexual function in months and found progressive improvement in erectile func-
both its interval and completeness.11 Preserving accessory tion from 12 to 48 months.21 Of the men studied, 145 were
pudendal arteries, which may be the principal blood supply fully potent preoperatively as measured by International Index
to the corpora cavernosa, will result in earlier return of of Erectile Function (IIEF) scores >26. At 12 months post-
erections and improved postoperative rigidity. operatively, 22% were normally functional, with only 8%
In those patients undergoing radiation therapy, relative reporting a normal IIEF score. At 24 months, 54% were nor-
radiation dose to the penile bulb appears to be associated mally functional, with 28% reporting a normal IIEF score. At
with ED.12 This radiation dose to the penile bulb has also been 48 months, 83% were normally functional, with 51% reporting
suggested to be an etiologic explanation for ED in patients a normal IIEF score. While these data are helpful, 49% of the
undergoing brachytherapy.13,14 Radiation injury to the peripro- patients at 48 months were using sildenafil.
static tissues can also result in nerve injury. Because radiation In a comparison of men undergoing radical prostatectomy
effects are of slow onset and long progression, ED may not or external beam radiation therapy for organ-confined carci-
appear until 1–3 years after completion of treatment.15,16 noma of the prostate, data from the CapSure Study suggest
comparable rates of sexual function during the first 12 months
following treatment.22 During the second year, however,
Prevalence of erectile dysfunction patients treated with external beam radiation therapy showed
following prostate cancer treatment a significant decline in sexual function compared with a
continued improvement in those patients undergoing radical
The prevalence of ED in men over 50 is greater than 50%, with prostatectomy, supporting the concept of delayed effect on
more than 10% of such men having complete ED, and this nerve function, penile bulb, and ultimately ED in those
prevalence rises with age such that more than 30% of men patients undergoing even the best-designed conformal radia-
over the age of 60 have complete ED.1 These data must be tion therapy.22 Mantz et al., in a study of 114 men with local-
clearly considered when evaluating the return of erectile func- ized prostate cancer undergoing conformal external beam
tion following treatment of prostate cancer. Initial results radiation therapy with a mean follow-up of 18.5 months,
from nerve-sparing prostatectomy prior to the advent of also demonstrated a declining erectile function rate with
clinically standardized questionnaires suggested significant time. They reported ED in 2% of pre-radiation potent men
improvements in erectile function in men following radical at 1 month, 8% at 12 months, 25% at 24 months, and 33% at
prostatectomy in the younger age group. Indeed men under 36 months.23
age 50 had a >90% recovery of erections compared with <25% While the studies investigating erectile function following
in those men over 70 years of age.3 Subsequent studies have brachytherapy are few, data suggest that brachytherapy is
confirmed the importance of bilateral nerve-sparing prostat- also associated with delayed-onset ED. Burnett et al. reported
ectomy and age. Catalona et al., using standardized question- a meta-analysis of risk for ED of between 36% and 63%
naires, showed that 91% of men under 50 with bilateral for external beam radiation therapy.24 Sanchez-Ortiz et al.
nerve-sparing prostatectomy experienced return of potency reported 171 men undergoing brachytherapy for organ-
by 24 months postoperatively compared with only 50% with confined carcinoma of the prostate with a mean age of
114 Textbook of Erectile Dysfunction

69 years and followed for 25 months.25 At 2 years following three times weekly and those receiving observation only. In
brachytherapy, 51% reported complete or partial ED. The the patients receiving injection therapy, 67% reported return
meta-analysis noted previously reports an ED rate of between of spontaneous erections sufficient for satisfactory coitus
14% and 61% with brachytherapy. compared with only 20% in the observation group.33
Cryotherapy also has few studies with small number of In a similar study, Brock et al. evaluated return of spontaneous
patients followed for evaluation of erectile function. Chaikin erections in a group of men using intracavernous alprostadil
et al. reported 36 men assessed using the Global Assessment injection for restoration of erectile function and for coitus.34
Question by a telephone questionnaire at 12 months after These investigators showed an improvement in penile hemo-
cryotherapy.26 Of the 28 respondents, 90% reported severe or dynamics and a return or improvement in spontaneous erec-
complete ED.26 Shelley et al. reported 38 patients followed for tions in men with arteriogenic ED.
36 months following cryotherapy for localized carcinoma of The introduction of phosphodiesterase (PDE) inhibitors
the prostate; 13% of these patients had recovered satisfactory for the effective oral treatment of ED has stimulated interest
potency while an additional 34% were able to achieve satisfac- in the use of these agents for the prophylaxis of ED following
tory erections using sildenafil, injection therapy, intraurethral nerve-sparing radical prostatectomy. These agents have been
therapy, or a vacuum erection device.27 Long et al. reported demonstrated to stimulate nocturnal erections in men with
an 84% rate of ED at 1 and 2 years of follow-up,28 while Bahn both normal and deficient erectile function, suggesting that
et al. reported that 47% of patients followed for 3 years have regular use of a PDE-5 inhibitor may improve vascular flow
restoration of erectile function.29 Ismael et al. reported a rate and oxygenation of the corpus cavernosum smooth muscle
of complete ED of 86% for salvage cryotherapy after radiation tissue while the neuropraxia associated with radical prostate-
therapy.30 ctomy resolves. Montorsi et al. demonstrated that sildenafil
Thus, it is clear that all methods of treatment of localized 100 mg taken at bedtime would lead to a significant increase
carcinoma of the prostate are associated with ED. The accu- in nocturnal erections compared with placebo.35 While studies
mulating data, both in basic science laboratories and in men to support the use of PDE-5 inhibitors for prophylaxis are
followed postoperatively, suggest that nerve damage or long- few, Padma-Nathan et al. reported a multicenter placebo
lasting neuropathy may result in significant corpus caverno- controlled prospective study using sildenafil 50 mg or 100 mg
sum apoptosis of smooth muscle cells, especially in the at bedtime beginning 4 weeks following nerve-sparing radical
subtunical area associated with endothelial cell dysfunction, prostatectomy. Patients were treated prophylactically for
and ultimately in destruction: this apoptosis of smooth mus- 36 weeks and assessed 8 weeks after discontinuation of treat-
cle in the corpus cavernosum leads ultimately to significant ment. Rigorous outcome measures of erectile function were
veno-occlusive incompetence and ultimately to ED. With the used, including the IIEF score. At the time of assessment,
significant prevalence of accessory pudendal arterial supply with patients in both groups taking no sildenafil, 27% of
to the corpora cavernosa, injury to this arterial supply to the patients who had previously received sildenafil demonstrated
penis may also increase apoptosis and decrease oxygen supply return of normal spontaneous erections as measured by an
and transport to the corpus cavernosum, resulting in veno- IIEF score of >8 for questions asking whether erections were
occlusive incompetence. This process, purportedly mediated rigid enough for penetration and satisfactory for completion
through an increased production of transforming growth of sexual intercourse. This compared with 4% in the placebo
factor (TGF)-beta ultimately results in tissue damage, corpus group (p = 0.0156). A subset of these patients underwent
smooth muscle fibrosis, and in some patients decreased penile nocturnal penile tumescence (NPT) RigiScan studies, the
length.31,32 findings of which supported the questionnaire-based results.
Althogh the return of erectile function in 27% of patients is
less than would be expected in populations of patients under-
going adequate nerve-sparing prostatectomy, the difference
Postoperative penile rehabilitation between treated and placebo patients strongly suggests that
maintaining oxygenation with prophylactic treatment during
Maintaining erectile function following the treatment of resolution of neuropathy is an important concept in treat-
carcinoma of the prostate is theoretically best carried out by ment of patients following radical prostatectomy.36 A recent
preserving arterial inflow and nerve supply to the corpus study from our institution reviewed 27 patients undergoing
cavernosum. Despite this concept of maintaining smooth free-hand bilateral nerve-sparing radical laparoscopic pros-
muscle health during resolution of postoperative neuropathy, tatectomy. Patients were begun on postoperative day 1 with
improving oxygenation of the corpus cavernosum smooth tadalafil 20 mg, dosed every 3 days. Outcome measurements
muscle while healing is taking place is likely to improve ulti- included presence of erections, success of intercourse, and
mate outcomes and return of erectile function. While the IIEF questionnaires. At 6 weeks, 16 of 18 patients reported
concept of prophylactic or preventative rehabilitation of ED erections, with 9 of 18 having successful intercourse. At
following treatment of carcinoma of the prostate is enticing, 6 months, 9 of 9 patients in this preliminary report had erec-
there are few data to clearly support this concept. The first tions, with 7 of 9 having successful intercourse. IIEF scores for
clinical study to suggest that prophylaxis is effective was both erectile function and intercourse satisfaction improved
reported by Montorsi et al. using intracorporeal injection from 6 weeks to 6 months, the erectile function domain
therapy with alprostadil beginning 4 weeks following nerve- measuring 15.8 at 6 weeks and 17 at 6 months (out of a maxi-
sparing radical prostatectomy. The authors divided their post- mum of 30) and intercourse satisfaction measuring 7.5 at
operative patients into those receiving alprostadil injections 6 weeks and 8.0 at 6 months (out of a maximum of 15).37
 Erectile dysfunction and treatment of carcinoma of the prostate 115

Treatment of erectile dysfunction to placebo compared with 62% to tadalafil on the GAQ. If the
patients who had some residual function following surgery
following prostate cancer treatment were separated, 24% responded to placebo compared with
71% to tadalafil 20 mg (p < 0.001). When using the more rig-
In men with ED following treatment of carcinoma of the pros-
orous end-point of the SEP question 3 (‘Did your erection last
tate, a number of treatment alternatives are currently avail-
long enough to have successful intercourse?’) 19% of the total
able. Expectant therapy is reasonable since erectile function
group responded to placebo compared with 41% to tadalafil.
improves with time following nerve-sparing radical prostat-
In those with some residual function, 26% responded posi-
ectomy. Rehabilitation with treatment for ED, however, as has
tively to placebo compared with 52% to tadalafil. This dem-
been discussed may improve ultimate outcomes and permit
onstrates that tadalafil is successful after radical prostatectomy
sexual function during the healing process. Initial treatment
but that patients who had some residual function were more
should be carried out with the most conservative and effective
likely to be successful than those patients without residual
treatment available. This usually represents the use of oral
function following surgery. This method of evaluating data
medications, most commonly the PDE-5 inhibitors. Currently
may standardize patients for better surgical procedures and
there are three PDE-5 inhibitors available throughout most of
more effective nerve sparing.42
the world: sildenafil, tadalafil, and vardenafil. Each of these
Vardenafil has likewise undergone a double-blind, placebo-
agents has undergone testing in patients following radical
controlled, multicenter study to evaluate its effectiveness in
prostatectomy. Sildenafil, the first of these agents to be mar-
patients following bilateral nerve-sparing radical prostatecto-
keted for use in men with ED, has been used in more than
my.43 In a global study of 427 men aged 44–77 years, patients
25 million men worldwide with excellent efficacy in restoring
were treated in a double-blind placebo-controlled cross-over
erectile function and safety. Contraindications for all PDE-5
12-week study employing vardenafil 10 mg and 20 mg and
inhibitors in patients using nitrate medications for cardiovas-
placebo. In this bilateral and unilateral nerve-sparing pros-
cular disease are important to note; however, the cardiovascular
tatectomy group, GAQ was positive in 13% of patients taking
profile of all three PDE-5 inhibitors confirms the safety of these
placebo compared with 59% of men taking vardenafil 10 mg
agents in most aging men with a variety of etiologies for ED.
and 65% of men taking vardenafil 20 mg (p < 0.0001). When
Sildenafil, the first PDE-5 agent to be used in post radical
using the SEP question 3, 10% responded affirmatively to
prostatectomy patients, demonstrated initial results of 43%
placebo compared with 37% to vardenafil 10 mg and 34% to
improvement in erections compared with 15% for placebo.
vardenafil 20 mg.
Because this population was mixed, including men who had
In summary, PDE-5 inhibitors appear to be the most con-
undergone nerve-sparing prostatectomy and men who had
venient and effective method for treatment of ED following
undergone non-nerve-sparing prostatectomy, further stratifi-
radical prostatectomy. The use of PDE-5 prophylaxis, although
cation of patients was used to demonstrate a 72% improvement
still controversial, appears to be a safe and effective way of
in erection in those patients undergoing bilateral nerve-sparing
improving the physiology of the corpus cavernosum and of
prostatectomy.38 Subsequent reports by Zippe et al. strongly
maintaining oxygenation and smooth muscle health while the
supported the improvement in response to sildenafil in those
neuropraxia following radical prostatectomy resolves. In those
patients undergoing bilateral nerve-sparing prostatectomy.39
patients with ED following radical prostatectomy, however,
While those patients undergoing unilateral nerve sparing were
the use of PDE-5 inhibitors appears to be effective for the
in an intermediate category, those patients without nerve
treatment of ED following nerve-sparing prostatectomy.
sparing had absent erectile response. A partner study per-
Successful results are best with excellent nerve-sparing opera-
formed by the same group reflected similar outcomes in
tions and increasing time following radical prostatectomy
partners of the patients reported in this study. Hong et al.
to permit resolution of neuropraxia. Because head-to-head
also demonstrated improvement in erectile function with
studies are not available for patients following radical pros-
sildenafil treatment and increasing time from radical prostate-
tatectomy, the relative effectiveness of the various PDE-5
ctomy.40 Ability to penetrate, reported by Zippe et al. with
inhibitors in this setting cannot be adequately assessed.
sildenafil, was 71.7% with bilateral nerve-sparing surgery,
50% with unilateral nerve-sparing surgery, and 15.4%
with non-nerve-sparing surgery (p = 0.001).39 Spousal
satisfaction for these same patients was 66%, 41.6%, and
15.4%, respectively (p = 0.001). Feng et al. studied 316 patients
1–4 years following radical prostatectomy and demonstrated Failure of phosphodiesterase type 5
response to sildenafil of 26% at less than 6 months, 36% inhibitor therapy
at 6–12 months, 50% at 12–18 months, and 60% at 18–
24 months, again reflecting the improvement in erectile In patients in whom PDE-5 inhibitor therapy fails, a number
function with time.41 of options are available. These include combination therapy,
In a trial of 303 patients at North American and European vacuum erection devices, intracavernosal injection therapy,
centers, patients were treated for 3 months in a double-blind intraurethral therapy, and penile prosthesis implantation.
placebo-controlled trial of tadalafil 20 mg versus placebo.42 Each of these methods for treatment was available before the
Intercourse success rates were measured with the Sexual Event introduction of PDE-5 inhibitors and continues to be useful,
Profile (SEP) as well as the Global Assessment Question effective, and safe for patients with ED following treatment of
(GAQ). In all patients evaluated, 23% of patients responded prostate cancer.
116 Textbook of Erectile Dysfunction

Combination therapy has been used in a variety of forms respond to a switch to PDE-5 inhibitors. Indeed, Raina et al.
following radical prostatectomy. The use of combination of evaluated 49 men following radical prostatectomy who had
intraurethral alprostadil with oral sildenafil has been success- responded to intracavernosal injection therapy but who
fully used in several studies. Nehra et al. reported 28 men fail- desired less invasive therapy. Patients were treated with
ing intraurethral alprostadil or sildenafil.44 Of these 28 men, sildenafil 50 mg or 100 mg and only 19% of patients found
17 had undergone radical prostatectomy, 15 of which were sildenafil to be suboptimal. In a group of patients with lower
bilateral nerve-sparing procedures. All 17 were demonstrated SHIM scores on injection therapy, patients continued to use
to have veno-occlusive incompetence. Patients were crossed sildenafil occasionally, enhancing their erections in combina-
over to the other alternative of therapy and failed this cross- tion with intracavernosal injection therapy.49 Adverse events
over. Once after failure, patients were treated with a combina- associated with intracavernosal injection therapy are well
tion of intraurethral alprostadil 500 µg and placebo. All 28 known, and include painful erections, ecchymosis and hema-
patients had successful erectile function and intercourse, and toma of the injection site, and prolonged erections.
continued to use the medication an average of 3.6 times Vacuum erection devices (VEDs) have also been widely
monthly for 30 months. Mydlo et al. likewise combined intra- used for patients following radical prostatectomy. While the
cavernosal alprostadil with sildenafil.45 In a group of men who VED has been available for many years and was developed by
failed each of these therapies, more than 90% were success- a patient who had a non-nerve-sparing radical prostatectomy,
fully treated with a combination of intraurethral alprostadil its effectiveness is limited to patients with poor response
and sildenafil. This included 19 patients following radical to pharmacologic therapy. Opsomer et al. treated 110 men
prostatectomy. Intraurethral alprostadil has been used alone with ED with VED. These patients were effectively treated
and, as noted above, with sildenafil for the treatment of ED for ED with no significant complications.50 Baniel et al.
following radical prostatectomy. Costabile et al. reported on treated 85 men with postradical prostatectomy ED. Seventy-
384 patients following radical prostatectomy and ED treated eight (92%) responded to VED with erections satisfactory for
with medicated urethral suppository for erection (MUSE). vaginal penetration. Only 11 (14%), however, agreed to con-
Responses showed that 70.3% had sufficient erections when tinue VED treatment at home. At 1 year, 7 (9%) continued to
MUSE was first administered in the office and that 57.1% had use VED and another 4 patients (5%) used a combination of
erections satisfactory for normal function at home.46 Raina VED and intracorporeal injection.51 Adverse events associated
et al., more recently, reported a series of 54 men treated with with VED include corporeal fibrosis, pain, and inhibition of
intraurethral alprostadil and followed with the Sexual Health ejaculation.52
Inventory for Men (SHIM). A total of 55% of men achieved In patients in whom less invasive therapeutic alternatives
and maintained sufficient erectile function for coitus and 48% fail, implantation of inflatable penile prosthesis is an excellent
continued long-term therapy, averaging more than 2 years.47 method for rehabilitation following radical prostatectomy.
Compliance with intraurethral alprostadil in this series was Penile prostheses have long been used for the treatment of ED
63%. Adverse events of transurethral alprostadil in both series of various etiologies with excellent results in patients who are
included urethral and penile pain and burning, as well as not candidates for, or who respond poorly to, less invasive
inadequate erections. therapy. With newer penile prostheses, mechanical reliability
Intracavernosal injection therapy has been used for more after 5 years approaches 90%, and at 5–10 years, 91% of
than two decades. The use of intraurethral alprostadil injection patients have erections suitable for coitus. Indeed, patients
for prophylaxis was previously discussed.33 Use of intracaver- feel strongly that they would undergo the procedure again
nosal alprostadil injection for the treatment of ED in men and are quite satisfied with treatment.53 In patients with
following radical prostatectomy has been demonstrated to be non-nerve-sparing prostatectomies or in those with high
effective for many years. Linet and Ogrinc reported satisfac- risk for ED, penile prostheses can be placed at the time of
tory sexual activity in responders to intracavernosal alprostadil prostatectomy. Good results have also been reported with
in 94% of injections.47 Principal adverse events included penile placement of the prosthesis reservoir at the time of surgery.54
pain, and rarely, prolonged erections. Claro et al. also demon- Indeed, patients who have had previous inflatable penile
strated significant success rates using a trimix of papaverine, prostheses can easily, safely, and effectively undergo radical
phentolamine, and prostaglandin-E1, with 94.6% of patients retropubic prostatectomy for carcinoma of the prostate with
having erections satisfactory for vaginal penetration.48 Mydlo expected continued device function and low morbidity.55
et al., in a retrospective study, treated 34 men who had under- Simultaneous placement is also possible at the time of radical
gone nerve-sparing radical prostatectomy with subsequent prostatectomy.56
ED with a combination of sildenafil or vardenafil plus intra- Similar excellent results have been demonstrated with
cavernosal injection. Of patients who failed oral therapy, 68% penile prostheses following external beam radiation therapy
responded to intracavernosal injection therapy.45 Unfortu- for prostate cancer. Dubocq et al. followed 34 patients who
nately, patient compliance with intracavernosal injection had received external beam radiation therapy for organ-
therapy and maintenance of this method of treatment has confined prostate cancer.57 The average age was 67 years
been demonstrated to be limited. Because of the invasiveness and patients were followed up for a mean 40 months. No
of therapy, progressive decreases in response, and difficulty patients sustained infection or erosion and 71% of patients
with therapy, many patients will discontinue intracavernosal used their prosthesis once per week or more for sexual inter-
injection with time. Many patients, however, on long-term course, 17% used it twice monthly, and 12% were not sexually
intracavernous therapy if they are satisfactory responders may active although their implant continued to function normally.
 Erectile dysfunction and treatment of carcinoma of the prostate 117

No increase in complications or morbidity was identified in specificity (54%). The authors – high-volume radical pros-
these patients. Carson et al., in a multicenter study, compared tatectomy surgeons – felt that the role for intraoperative
patients without radical prostatectomy with those who had neurostimulation was limited.60 While the use of the caverMAP
undergone radical prostatectomy.53 No difference was found and nerve stimulation at the time of radical prostatectomy is
between the groups in device infection or mechanical malfunc- interesting and potentially useful, the current device and its
tion rates, or in inflation. Indeed, when asked about erections results suggest the need for a more effective neurostimulation
suitable for coitus, 90% of patients with radical prostatectomy device for the technique to be clinically useful for most
responded affirmatively, compared with 90.6% of those urologic surgeons.
patients without radical prostatectomy. In answer to the satis-
faction question, ‘Would you undergo the procedure again?’
90.4% of radical prostatectomy patients responded affirma- Cavernous nerve
tively compared with 86.5% of patients without radical interposition grafting
prostatectomy.53
Evaluation of nerve function during radical prostatectomy Nerve grafting has been used widely by the neurosurgery com-
for preservation and nerve replacement has long been pur- munity for peripheral nerve resection and regeneration using
sued. Because identification of the cavernous nerves is diffi- both autologous nerve interposition grafts and nerve conduits.
cult and because there is a plexus rather than a defined nerve The results of these nerve regeneration procedures vary with
structure, localization can be challenging. Nerve localization, surgeon, nerve location, and patient response. Because most
therefore, has been purported to be helpful in nerve preserva- of these nerves are specific nerve bundles and not nerve plex-
tion, especially in patients with malignancy close to or through uses, the use of cavernous nerve interposition grafts is more
the prostatic capsule. Lue et al. reported the use of an intra- challenging. Clearly, however, nerve grafts in patients who
operative nerve-stimulation device associated with monitor- are not candidates for bilateral nerve-sparing radical prostat-
ing of penile tumescence.58 This electrode array device is ectomy may improve postoperative rehabilitation and erectile
placed where cavernous nerves are suspected to be and a function. Kim et al., in 1999, reported a technique for the use
biphasic current is applied to the nerve bundles. Beginning at of sural nerve interposition grafting in patients who under-
low intensities of 8 mA and increasing to 20 mA, the cavernous went non-nerve-sparing prostatectomy for locally extensive
nerves are stimulated, which results in penile tumescence, or high-grade carcinoma of the prostate.61 The patients who
which is monitored by a mercury penile strain gauge. Changes had non-nerve-sparing prostatectomy would be expected to
in cavernosal tumescence as small as 0.5% can be measured. have little or no erectile function both early and in late fol-
Because of the multineuronal character of the neurovascular low-up. A total of 23 of 28 initially grafted men were followed
bundle, however, responses are variable and sometimes at least 12 months.62 Of the patients followed, 26% had spon-
include detumescence as well as tumescence: if stimulation is taneous erections without PDE-5 inhibitors, 26% had partial
predominantly sympathetic and less parasympathetic, detu- erections, and 48% had no response. With the use of sildena-
mescence may be expected. Clinical studies by Klotz and Her- fil, however, the ability to achieve satisfactory vaginal penetra-
schorn in 21 men with erections preoperatively and tion was increased to 43%. Using historical controls, only 1 of
identification of neurovascular bundles using the caverMAP 70 non-nerve-sparing prostatectomy patients would be
device, only 2 of 19 patients with good intraoperative responses expected to respond. Similarly, the data from Zippe et al. with
and surgery designed to preserve the areas identified had non-nerve-sparing prostatectomy suggest that only 15% of
inadequate erections postoperatively, a response of 94%.59 In patients will respond to sildenafil.39 While this study was not
a subsequent multicenter study, 35 patients were evaluated 12 placebo-controlled, neither was it randomized nor blinded, it
months following intraoperative pudendal nerve stimulation appears to demonstrate some effectiveness of sural nerve
(caverMAP)-assisted nerve-sparing radical prostatectomy. grafting in the restoration of normal erectile function. In an
While 31% of patients had a bilateral caverMAP response and additional study reported by Chang et al. of 30 patients fol-
27 patients had a unilateral caverMAP response (with 3 patients lowed for 23 months, 18 (60%) had erectile function with
having no response), there was no significant difference among 43% capable of vaginal penetration.63 This includes 7 patients
the three groups in erectile function. A multi-institutional (23%) without sildenafil and 6 patients (20%) using sildenafil.
study performed in the USA evaluated 50 patients for caver- In a review of 44 patients undergoing nerve grafting, Secin
MAP stimulation during radical prostatectomy. All patients reported a 34% rate of erectile function but a consistent rate
had organ-confined carcinoma of the prostate and satisfactory of penetration of only 11%. No correlation for success was
response to preoperative IIEF questions. Patients were less found when assessing for patient age, nerve used, hormone
than 60 years old and were followed for 3, 6, and 12 months therapy, salvage radiation therapy, or ED medications.
following surgery. A total of 90% of these patients had suc- While these data are indeed interesting, the number of
cessful bilateral nerve-sparing radical prostatectomy, with current patients undergoing non-nerve-sparing radical pros-
10% undergoing unilateral nerve-sparing prostatectomy. A tatectomy is limited. It is clear that the nerve-grafting procedure
positive response from stimulation was observed in 87.8%, has a significant learning curve and should be confined to cen-
but responses included tumescence and detumescence, ters with significant experience in harvesting and placing the
detumescence alone, and tumescence. Tumescence alone was sural nerve graft. Even with expert surgical procedures, how-
found in only 6.4% of patients. Review of the data demon- ever, available studies are not conclusive in reporting the effec-
strated a high sensitivity (88%), but a disappointedly low tiveness of nerve grafting and improving erectile outcomes.64
118 Textbook of Erectile Dysfunction

Compliance In the 21st century, however, effective treatment alternatives

are available for patients with prostate cancer who want to
Quality of life studies have consistently reported that erectile continue to have functional erections. Prophylactic therapy
and sexual function are important to patients and their may, in the future, provide an excellent method for maintain-
partners after prostate cancer treatment, and the age of ing functional penile physiology during the resolution of
patients treated for prostate cancer continues to decline. How- neuropraxia. Prophylaxis using PDE-5 inhibitors may preserve
ever, several studies have reported poor patient compliance smooth muscle and endothelial function for future satisfac-
and interest in being treated for erectile and sexual concerns.65 tory erectile function. In those patients needing ED therapy
This disconnection between patient concerns, quality of life, following treatment for prostate cancer, PDE-5 inhibitors
and compliance with treatment is indeed concerning and may continue to be the first-line therapy. In those patients in whom
represent a need for physicians and healthcare providers to PDE-5 inhibitors fail, combination therapy, intraurethral
encourage patients and partners, to be available for counsel- alprostadil, intracavernosal injection therapy, and VED therapy
ing, and to continue to follow sexual dysfunction as closely as are all non-surgical alternatives. In those patients in whom
the cancer status of these men. less invasive therapy fails or who prefer a more definitive treat-
ment alternative, penile prosthesis implantation will restore
erectile function effectively and with excellent postoperative
Conclusion results and satisfaction rates. The development of further
techniques for identifying periprostatic nerve bundles and
Because prostate cancer occurs in men in the middle and older replacing damaged nerves may be helpful. The use of nerve
age groups, risk factors for ED are significant. All prostate growth factors and neuroregenerative strategies, as well as
cancer treatments increase the risk of ED. While the treat- gene therapy to replace or supplement poorly functioning
ments are associated with organic causes of ED, diagnosis of corpus cavernosum smooth muscle tissue, may provide addi-
prostate cancer may be associated with psychogenic causes of tional alternatives for the prophylaxis and treatment of these
ED and sexual dysfunction for both the patient and his partner. patients in the years to come.

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15 Vascular risk factors and erectile
dysfunction
Graham Jackson and Alethea Cooper

Introduction markers reflecting low-grade systemic inflammation has

provided further insight into the mechanistic aspects, offering
With the introduction of the phosphodiesterase (PDE) type 5 a potential diagnostic role and therapeutic target.8 This review
inhibitors came a better understanding of the causes of erectile focuses mainly on modifiable risk factors.
dysfunction (ED). Previously believed to be predominantly a
psychological problem, ED is now recognized to be mainly Lifestyle
organic in origin.1,2 However men with an organic cause may
One of the most important developments has been the role of
also have psychological problems as a consequence, and men
intensive lifestyle modification in improving erectile function
with principally a psychological etiology may also have organic
and decreasing cardiovascular inflammatory markers of risk.9
issues. Therefore it is important not to be too rigid when
Atheromatous plaques are complex and dynamic and it is
attributing cause and effect and to address all aspects of each
plaque composition rather than volume that influences the
patient’s presentation. Whatever the risk factors we need to
risk of a clinical cardiac event.10 A reduction in lipid content
remember individual patients need help not statistics, though
of the plaque and the accumulation of macrophages and
statistics guide management.
lymphocytes, whilst increasing vascular smooth muscle cells
Penile erection is a vascular event under neural control and
(VSMC) and the thickness of the fibrous cap, will improve
is determined by the balance between arterial inflow and
endothelial function, whereas VSMC apoptosis will reduce
venous outflow. Vascular arterial abnormalities will therefore
cap thickness, increase the necrotic content and plaque inflam-
affect erectile function and it is vasculogenic ED that has been
mation, leading to plaque instability and vulnerability.11 Most
the subject of detailed evaluation.3,4 Endothelial dysfunction is
atheroma is sub-clinical and in its early phases more easily
now recognized to be the fundamental fault leading to ED. As
influenced in a beneficial way, emphasizing the important
the endothelium is the same in the penile arteries as the coro-
link between ED and early phase silent CAD with regard to
nary arteries, ED and coronary artery disease (CAD) share the
using ED as a marker for aggressive risk reduction.12 Indeed,
same vascular risk factors (Table 15.1). The greater weight of
ED may offer the chance to alter the natural history of athero-
endothelium relative to the smaller penile arteries might
sclerosis throughout the vascular tree and, importantly, the
explain why ED can preceed a cardiac event or predict sub-
coronary circulation.
clinical CAD and in turn why ED is common in the presence
The presence of unavoidable risk factors for vascular dis-
of known CAD.5
ease requires the patient to be even more careful regarding
The identification of vascular risk factors has been important
reducing modifiable risk factors. We cannot pick our parents
not just to our understanding of mechanisms of disease – in
or avoid getting older and most men would not wish to change
this case ED – but has allowed therapeutic targeting of the
sex, so we should try to make life’s journey as healthy (and
endothelium with resulting clinical benefit.
enjoyable) as possible. The enjoyable component is funda-
mental to quality of life – death is a sharp end-point for risk
reduction but if length of life is not altered but quality is then
Vascular risk factors risk reduction is just as important.
Risk factors are associated with but not necessarily causative
of vascular disease. They can be considered unavoidable (age, Obesity and physical activity
sex, family history) or modifiable (lifestyle, obesity, physical It is difficult to separate obesity from physical inactivity and
inactivity, cigarette smoking, diabetes, hypertension, and both increase the incidence of ED and CAD.13 The Rancho
hyperlipidemia).6 In addition, the metabolic syndrome, which Bernado study followed 570 men over 25 years and observed
is a cluster of vascular risk factors, including central obesity, age, overweight [body mass index (BMI) >28 kg/m2], and
hyperlipidemia, hypertension, and insulin resistance is associ- hyperlipidemia were major risk factors for the development of
ated with both ED and hypogonadism.7 ED and that men with three or more risk factors had a 2.2-fold
Whilst endothelial dysfunction remains the common deno- increased risk of ED compared with men with no baseline risk
minator linking ED to vascular disease, the role of inflammatory factors.14

120
 Vascular risk factors and erectile dysfunction 121

24
Table 15.1 Shared risk factors between coronary
artery disease and erectile dysfunction
20
Coronary artery disease Erectile dysfunction

Age Age
16

IIEF score
Dyslipidemia Dyslipidemia
Hypertension Hypertension
Diabetes Diabetes 12
Smoking Smoking
Sedentary lifestyle Sedentary lifestyle
8
Obesity Obesity
Depression Depression
4
Male sex Coronary artery disease, Baseline 2 Years Baseline 2 Years
peripheral vascular disease Intervention group Control group
(n = 55) (n = 55)

Figure 15.1 Individual changes in erectile function score of

In the National Health and Nutrition Examination Survey obese men. Data markers with error bars indicate mean (SD).
(NHANES) analysis of data from 2001–2002 involving 3500 IIEF, International Index of Erectile Function. From JAMA 2004;
men aged over 20 years of age there was an independent asso- 291: 2978–84.20
ciation between the risk factors of obesity, smoking, diabetes,
and hypertension and the probability of self-reported ED.15 advice about food types they also had personal activity
Obesity conferred a 60% increased ED risk. Longitudinal data training, including advice on walking, games like soccer, and
from the Massachusetts Male Aging Study (MMAS) showed swimming. After 1 year of monthly meetings with their nutri-
that a baseline BMI >28 significantly predicted the onset of ED tionalists and exercise trainers they met twice monthly for a
over an 8-year follow-up.16 In a study from the Netherlands, further year.
men aged 50–70 years with a BMI of 25–30 kg/m2 increased When assessed at 2 years, the BMI had decreased from
their odds ratio for ED to 1.5 and those with a BMI >30 kg/m2 36.9 kg/m2 to 31.2 kg/m2 in the intervention group and 36.4 kg/
to 3.0 compared with a normal BMI <25 kg/m2.17 m2 to 35.7 kg/m2 in the control group (p < 0.001). Of interest,
Therefore obesity has been confirmed as a risk factor for the inflammatory markers interleukin 6 (IL-6) also decreased
ED in large-scale cross-sectional and longitudinal studies. In (p = 0.03), as did C-reactive protein (CRP) (p = 0.02). Physical
the Health Professionals Follow-Up Study (HPFS), the impact activity increased more in the intervention group, from
of obesity, physical activity, alcohol use, and smoking on ED 48 minutes/week to 195 minutes/week compared with an
was assessed in 22,086 men aged 40–75 years over 14 years.9 increase of 51 minutes/week to 84 minutes/week in the con-
Of men who were healthy without overt evidence of cardio- trols (p < 0.001). ED improved significantly more in the inter-
vascular disease or diabetes and no ED in 1986, 17.7% devel- vention group, with their International Index of Erectile
oped ED during follow-up. Obesity nearly doubled the risk of Function (IIEF) score increasing from a mean of 13.9 to 17
ED (multivariate relative risk 1.9 compared with men of ideal (p < 0.001), and in 17 men the score was over 22 (Figure 15.1).
weight in 1986). Obesity was found to be a significant inde- The mean score in the control group was stable (13.5 to 13.6)
pendent risk factor for ED in the Men in Australia Telephone though 3 men achieved a score over 22. The authors showed,
Survey (MATeS) study.18 using multivariate analysis, that improvements in BMI and
Obesity is an independent risk factor for CAD and is asso- physical activity as well as in CRP, were independently and
ciated with elevated levels of inflammatory markers, which significantly associated with an improved IIEF score. They
are in turn associated with endothelial dysfunction.13,19 This concluded that one-third of obese men with ED can improve
low-grade inflammation may be an important pathophysio- their erectile function as a result of intensive lifestyle changes.
logical link between obesity, ED, and CAD and the metabolic They also identified a reduction in inflammatory markers,
syndrome.7 which may well have had a significant impact on endothelial
A study of 110 obese men aged 35–55 years with a BMI function, emphasizing again the link between obesity, ED,
≥30 kg/m2 (normal ≤ 25 kg/m2; pre-obese 25–30 kg/m2) assessed and CAD.
the degree to which weight loss combined with increased The potential clinical cardiovascular benefit is worth
physical activity affected erectile function.20 None of the men emphasizing. ED often precedes a cardiac event by 2–3 years,
were diabetic, hypertensive, or hyperlipidemic. In a single- and cardiac events are associated with increased levels of
blind fashion, half were randomized to active intervention circulating inflammatory and endothelial-prothrombotic
and half given general information about healthy eating and markers.3 By reducing the risk factors for ED we may, within
exercise. The intervention group were given detailed advice the 2–3 year time window, reduce or prevent a subsequent
about how to lose 10% or more weight, attended monthly cardiovascular event.
group sessions, were set targets, were taught how to reduce A sedentary, inactive life has been linked to ED (Figure 15.2).
calories, and were allocated food diaries. As well as detailed In the HPFS, ED was associated with the level of physical
122 Textbook of Erectile Dysfunction

35
31.8
30

25

20 17.5*
Men with ED (%)
15 13.9†

10

Less than average 5

Average
0
More than average
Physical activity
*Odds ratio(OR)=0.46(CI, 0.27-0.76).
†
OR=0.35(CI, 0.22-0.54).

Figure 15.2 Physical activity and the prevalence of erectile dysfunction (ED). *Odds ratio (OR) = 0.46 (CI 0.27–0.76); †OR = 0.35
(CI 0.22–0.54). From Int J Impot Res 2003; 15: 253–7.21

activity as well as BMI.9 When the men were categorized With obesity increasing the incidence of ED by 30%, and
according to their level of physical fitness, the less active (those weight loss combined with physical activity decreasing ED
with higher levels of sedentary behavior) were independently by 30%, the Princeton Consensus emphasized the impor-
linked to ED. All types of exercise reduced the incidence of tance of lifestyle intervention, particularly in men with ED
ED. Running at least 2.5 hours a week was associated with a and CAD, because of the benefit throughout the vascular
30% relative risk reduction for ED compared with no regular tree.5
activity, and 1.5 hours running or 3 hours of rigorous outdoor
work reduced the relative risk by 20%.
In the Global Study of Sexual Attitudes and Behaviour
(GSSAB), 31.8% of men who had less than average levels of Smoking
physical activity had ED compared with 13.9% of men who In HPFS, smoking increased the risk of developing ED by
exercised more than average.22 Lack of exercise therefore 50%.9 In MMAS, men who smoked at baseline increased their
increased the ED risk 2.5 times. risk of developing moderate or total ED to 24% compared to
In the MMAS, 593 men without ED at baseline and with no non-smokers, at 14% (p = 0.01).16 In hypertensive men the
evidence of heart disease, diabetes, or prostate cancer were probability of complete ED was doubled. Smoking has been
followed for 8 years. Men who were initially sedentary but shown to interfere significantly and adversely with the cavern-
took up exercise had a lower risk of ED compared with those ous veno-occlusive mechanism and to reduce erectile response
who remained inactive throughout.23 to intracavernous injections.26,27
The cardiovascular benefit of regular exercise is well Cigarette smoking is arguably the leading preventable cause
known, as is the increased risk from both obesity and inactiv- of CAD. The risk compared with that of non-smokers is
ity. Regular physical activity (20–30 minutes or more each increased by 60%. Peripheral vascular disease occurs in only
day) to the point of slight breathlessness (‘can walk and talk’) 6% of middle-aged adults who do not smoke, in 12% of ex-
is beneficial with regard to reducing the likelihood of a car- smokers, and in 18% of current smokers.28 Following smoking
diac event or recurrence after an event. At 12 years in the cessation the CAD risk falls within months and reaches the
HPFS of 44,452 men aged 40–75 years brisk walking for 30 level of non-smokers in 3–5 years.
minutes a day reduced the incidence of CAD by 18%.24 In the The benefit of smoking cessation on ED is not proven,
British Regional Heart Study (BRHS), which examined perhaps owing to an irreversible effect from prolonged tobacco
changes in physical activity over 14 years in 5934 men aged use.23 Chronic smoking leads to a considerable decrease in
40–59 years at baseline, men who took up even light activity penile and neuronal nitric oxide synthase (NOS) activity.
experienced a 34% mortality reduction over the subsequent 4 Neuronal NOS may be subject to increased degradation, or
years even though the exercise was taken up in later life.25 damage to nerve terminals (i.e. a tobacco-related neuropathy)
Similar exercise-related benefits have been recorded for may be responsible for the lack of a perceived benefit from
stroke. Because ED and CAD increase in incidence with age smoking cessation, since penile endothelial NOS appears to
and because weight loss and increased physical activity reduce react to electrical field stimulation.2
the development of both, the recommendation ‘physically When considering overall vascular health, advice and
fit = sexually fit’ unites the mechanistic with the clinical end- support to enable patients to stop smoking is an essential
point reality.5 lifestyle intervention.
 Vascular risk factors and erectile dysfunction 123

The metabolic syndrome of binge drinking. In addition men with a very high alcohol
The metabolic syndrome consists of a cluster of risk factors that intake are unlikely to participate in studies of risk association
increase the risk of cardiovascular disease and type 2 diabetes.29 and reduction so data are at present inconclusive.5
It is characterized by abdominal obesity, hyperlipidemia,
glucose intolerance, hypertension, and insulin resistance. It is
Specific cardiovascular risk factors
associated with pro-inflammatory markers and endothelial
dysfunction and an increased incidence of moderate to severe Hypertension, hyperlipidemia, and diabetes increase the risk
ED in men over 50 years of age.30 Furthermore, ED may of ED and CAD. ED in the absence of cardiac symptoms
predict the metabolic syndrome in men with a BMI <25 kg/m2 predicts a subsequent cardiac event in a significant number
who otherwise would be considered to be at low cardiovas- of men.5 The lifestyle changes already discussed will have a
cular risk.31 beneficial impact on these risk factors.
As the components of the metabolic syndrome increase Hyperlipidemia inhibits NOS. A high level of LDL choles-
so does the presence of organic ED. In addition there has terol and a low level of HDL cholesterol increase the risk of
been reported a three-fold increase in the prevalence of developing ED, probably because of impaired endothelium-
hypogonadism, and as the number of criteria for the meta- dependent relaxation. Many clinical trials evaluating lipid-
bolic syndrome increases so does the incidence of hypo- lowering therapy, mainly with statins, have demonstrated
gonadism.7 The strong association between the metabolic increased plaque stability and reduced cardiac and cerebral
syndrome and hypogonadism has led to the speculation that events to be more effective than dietary advice.35 Unfortunately,
testosterone replacement might be a therapeutic option.32 lipid-lowering therapy with statins and fibrates can cause
To date, however, the evidence primarily supports a lifestyle reversible ED.36 Statins are more likely to induce ED in men with
approach. multiple cardiovascular risk factors.37 A small study reported
The Mediterranean-style diet (rich in whole grain, fruits, improved ED in men treated with atorvastatin and sildenafil
vegetables, legumes, and walnut and olive oil) was evaluated compared with sildenafil alone, which fits with the observation
in 35 men with 30 acting as controls.33 All had the metabolic that the effectiveness of sildenafil is increased in the presence
syndrome and ED. The intervention group were given detailed of good metabolic cardiovascular risk factor control.38,39
dietary advice, targets were set, and monthly small-group ses- Hypertension is a major risk factor for both ED and CAD.
sions offered for support. Men in the control group were given Cavernous artery insufficiency was reported in 85% of 117
general oral and written information about healthy foods but hypertensive patients.40 ED is present in up to 17% of men at
no individualized support. After 2 years markers of endothelial the initial hypertensive diagnosis. The incidence rate of ED in
function and inflammation significantly improved in the treated hypertensives is 68% (7.6% mild, 15.4% moderate,
intervention group but not the control group. In the interven- and 45.2% severe according to the IIEF).41 It is believed that
tion group, 13 men achieved an IIEF of 22 or higher compared underlying vascular disease (i.e. the impact of hypertension
with only 2 in the control group. The intervention group had on the endothelium) is the main cause of hypertensive ED,
a significant decrease in glucose, insulin, low-density lipopro- though drug therapies may exacerbate the problem.1,5 Treat-
tein (LDL) cholesterol, triglycerides, and blood pressure ing hypertension is associated with ED, especially if thiazide
with a significant increase in high-density lipoprotein (HDL) drugs are used. Valsartan, an angiotensin II receptor antago-
cholesterol. Fourteen men in the intervention group had glu- nist, has been shown to not induce ED compared with the
cose intolerance and 6 had diabetes at baseline, but by 2 years combined beta- and alpha-blocker carvedilol.42 This may be as
the number had reduced to 8 and 3, respectively. a result of angiotensin II upregulating PDE-5 and its antago-
The metabolic syndrome was evaluated in the West of nism neutralizing this effect. The importance of asking about
Scotland Coronary Prevention Study (WOSCOPS), which ED before initiating therapy and mentioning the potential
studied 6000 men over 5 years. The metabolic syndrome was adverse effect of therapy is an essential part of treatment, facil-
associated with a 3.7-fold increased risk for CAD and a 24.5- itating patient adherence to therapy. If ED is a problem when
fold increased risk for the development of diabetes.34 managing hypertension, using valsartan and the alpha-blocker
Several studies have shown that lifestyle modification is the doxazosin minimizes the risk of ED developing as an adverse
first-line treatment for the metabolic syndrome, with focused effect.43
pharmacological treatment controlling hyperlipidemia, hyper- Diabetes is recognized to be a ‘cardiovascular equivalent’ so
tension, and hyperglycemia conferring additional benefit that a man with diabetes and no cardiac history is considered
where indicated. to have the same cardiac risk as a non-diabetic who has already
What we see here is the evidence of multiple risk factor sustained a myocardial infarct.44 ED is a common complica-
reduction benefiting a multiple risk factor state in terms of tion of diabetes affecting over 50% of diabetic men. The cause
both ED and CAD risk. There is also emerging a potentially is a combination of autonomic neuropathy, peripheral vascular
important link between inflammatory markers and their disease, CAD, drug therapy, and at times psychological factors.
modification in the ED/CAD context and its therapy. In the MMAS, complete ED occurred three times more fre-
quently in diabetics than non-diabetics.16 ED is more common
than diabetic retinopathy or nephropathy and may be the first
sign of diabetes in 12% of patients. In a study of 133 men with
Alcohol type 2 diabetes and angiographically confirmed silent CAD
Excess alcohol intake per se increases cardiovascular risk but compared with 127 men with diabetes and no evidence
there is little evidence of an ED risk other than the acute effect of myocardial ischemia (non-invasively evaluated), the
124 Textbook of Erectile Dysfunction

prevalence of ED in those with silent CAD was 34% and those of ≥16 on the five-item version of the Mental Health Index) at
without 4.7% (p = 0.0001).45 ED was an independent predictor baseline in a 5-year follow-up study.49 In men free of ED at
of silent CAD above hyperlipidemia, smoking, and microal- baseline (determined by two self-report items, adapted from
buminuria. Therefore a diabetic with ED and no cardiac the questionnaire used in the MMAS), the incidence of ED at
history is at significantly higher risk of CAD than a diabetic 5 years was 59 per 1000 person-years (95% CI 39–90) in men
without ED. with depressive mood and 37 per 1000 person-years (95%
CI 32–43) in men without depressive symptoms. After control-
ling for possible confounding variables (age, education, marital
Depression status, BMI, smoking, diabetes, hypertension, heart disease,
Depressive disorders range from mild symptoms to major cerebrovascular disease, and medication use), the incidence of
depression with core symptoms of sadness or loss of interest ED was 4.5 times higher in men with treated depressive symp-
or pleasure in usual activities for a period of at least 2 weeks toms at follow-up, but just 1.2 times higher in those with
accompanied by at least five of the following: sleep difficulties, untreated depressive symptoms at follow-up, compared with
fatigue, low self-esteem, guilt, psychomotor agitation or those free of depressive symptoms and not taking medication
retardation, and loss of appetite. Not surprisingly depressive for psychological disorders at baseline. In men free of depres-
symptoms may cause loss of libido and reduced sexual func- sive symptoms but who used antipsychotic medication, the
tion but, conversely, ED may also lead to depression. Cross- risk of ED was doubled. The adjusted incidence density ratio
sectional studies have demonstrated a relationship between of depressive mood was 1.9 (95% CI 1.1–3.3) in men with ED
ED and depression but it remains unclear whether depression compared with those without it at baseline. The authors
causes ED and, if so, what the underlying mechanism may be. describe a bi-directional relationship between depression and
The evidence that depression promotes CAD events in clini- ED, stating that ED may independently cause or increase
cally healthy people as well as in patients with known coro- depression, and that moderate or severe depressive mood or
nary heart disease is more established.46 By analogy, it is antidepressant medication may cause ED. A suggested mecha-
conceivable that depression may cause vascular disease in the nism is decreased blood flow to the penis and inhibition of
penile arteries, therefore providing another link to ED. Analy- penile smooth muscle relaxation resulting from depression
sis of cross-sectional results from the MMAS a decade ago inhibiting the activity of parasympathetic nerves. The authors
established a relationship between ED and depression suggest low power in the MMAS as an explanation for the
independent of aging, level of education, heart disease, diabe- discrepancy between the MMAS results and their study.
tes, physical activity, and other potential confounders.47 The results of the Finnish study highlight the potential
Symptoms of depression (measured using the Centre for for antidepressant medication to cause ED. Drugs such as
Epidemiologic Depression Scale (CES-D) and defined as a tricyclic antidepressants and selective serotonin reuptake
score ≥16) were present in 12% of men with both ED and inhibitors, which are commonly used to treat depression, may
depression across all ages. The estimated odds ratio for ED be associated with male sexual dysfunction, including new-
was 1.82 in men who had depressive symptoms compared onset ED, and they should be taken into consideration when
with those who did not. treating depression.50
In the MMAS, men were followed up for an average of Further evidence is needed to support a bi-directional
8.8 years, enabling a prospective analysis of a possible caus- relationship, but given the well-supported association
ative relationship between depression and ED.48 Excluding between ED and depression, it is appropriate that patients
men with ED, diabetes, or heart disease at baseline (as well as presenting with ED should be screened for depression and
those who had undergone radical prostatectomy), 778 men vice versa.
were studied. Symptoms of depression were present in 9% at
baseline. At follow-up 168 of the men were classified as having
moderate or complete ED (by self-administered questionnaire Conclusion
with specific items as well as by a single-item global self-
assessment). However, the presence of depressive symptoms ED and CAD frequently co-exist, and ED may occur 2–3 years
at baseline was not a significant predictor of incident ED before a cardiac event. ED and CAD share the same vascular
(p = 0.12), with a greater percentage of men without depres- risk factors and a man with ED with or without CAD history
sive symptoms developing ED than those with depressive should have his risk factors aggressively treated. Low-grade
symptoms at baseline (21.3% vs 13.2%). inflammation links ED and CAD and is increased with increas-
This result is at odds with the conclusion of a study of ing lifestyle risk factors and decreased with intervention. ED is
1683 men aged 50, 60, or 70 years from a Finnish cohort, predominantly a vascular disease and, like diabetes, it should
11.4% of whom demonstrated depressive symptoms (a score be considered a ‘cardiovascular equivalent’.

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16 Mediterranean diet and
erectile dysfunction
Dario Giugliano, Myriam Ciotola, Francesco Giugliano,
Massimo D’Armiento, and Katherine Esposito

Introduction Although the relationship between obesity and ED may not

be readily apparent, a growing body of evidence implicates
Erectile dysfunction (ED) is one of the most common chronic central adiposity as key regulator of inflammation.9 Among the
disorders, affecting more than 100 million men worldwide; various adipokines released by the visceral adipocytes, both
30 million men in the United States may have ED.1 Sexual tumor necrosis factor-alpha and interleukin (IL)-6 seem to
problems appear to be widespread in society, influenced by play a major role since they can depress endothelial function.10
both health-related and psychosocial factors, and they are asso- As endothelial dysfunction is increasingly acknowledged as
ciated with impaired quality of life. Although many treatment an early sign of generalized atherosclerosis and associates with
options are available, none of them offers a complete response ED,11 one possible mechanism linking obesity to ED may be
in all patients. Thus, as with many other medical diseases, pre- through the increased release of adipokines.12
vention may be the most effective approach to alleviating the We evaluated associations between erectile function, endo-
consequences of sexual dysfunctions. thelial function and markers of systemic vascular inflamma-
tion in 80 obese men, aged 35–55 years, divided into two equal
groups according to the presence or absence of erectile dys-
Lifestyle and erectile dysfunction function.13 Compared with non-obese age-matched men,
obese men had impaired indices of endothelial function and
Epidemiological studies suggest that modifiable health beha- higher circulating concentrations of the proinflammatory
viors are associated with a reduced risk of ED. In the Health cytokines IL-6, IL-8, and IL-18, as well as C-reactive protein
Professionals Follow-up Study,2 several modifiable lifestyle (CRP). Endothelial function showed a greater impairment in
factors, including physical activity and leanness, were associ- impotent obese men as compared with potent obese men,
ated with maintenance of good erectile function. For instance, while circulating CRP levels were significantly higher in obese
men with a body mass index (BMI, calculated as weight in men with erectile dysfunction (Table 16.1). The association
kilograms divided by the square of height in meters) higher between International Index of Erectile Function (IIEF) score
than 28.7 are likely to carry a 30% higher risk of erectile and indices of endothelial dysfunction supports the presence
dysfunction than those with a normal BMI (25 or lower). of a possible common vascular pathway underlying both con-
Similarly, men in the highest quintile of physical activity carry ditions in obese men. Defective nitric oxide (NO) activity,
a 30% lower risk of ED than those in the referent quintile linked to reduced NO availability, could provide a unifying
(sedentary men). The link between physical activity and ED explanation for this association (Figure 16.1). In particular, in
seems to be operative also in diabetic men.3 Information on isolated corpus cavernosum strips from patients with erectile
erectile function was obtained in 1040 diabetic patients dysfunction, both neurogenic and endothelium-dependent
selected from male patients (age >18 years) treated in 26 dia- relaxation are impaired.14
betes clinics in Israel: leisure time and work-related physical Strong epidemiological evidence links the subsequent risk
activity and consumption of small amounts of alcohol were of erectile dysfunction to the presence of well-recognized risk
found to be protective: 0.51 (odds ratio 0.36–0.72) and 0.70 factors for coronary heart disease, such as smoking, diabetes,
(0.51–0.97), respectively. Data from other surveys also indi- hypertension, and dyslipidemia.6,7,15 Interestingly enough, all
cate a higher prevalence of impotence in obese, sedentary these factors are linked to lifestyle. As four of the five compo-
men.4,5 Prospective studies, such as the 9-year follow-up study nents of the metabolic syndrome are risk factors for erectile
from the Massachusetts Male Aging Study (MMAS)6 and dysfunction and are also characterized by abnormal endothe-
the 25-year follow-up Rancho Bernardo Study,7 reported lial function, we postulated an association between erectile
that body weight was an independent risk factor for ED, with dysfunction and the metabolic syndrome, and tested the
a risk exceeding 90% of controls (odds ratios 1.93 and 1.96, hypothesis that erectile dysfunction was more prevalent in
respectively). In general, subjects with ED tend to be heavier men with the metabolic syndrome.16 Compared with 50 age-
with a greater waist maeasurement than subjects without and weight-matched control subjects, 100 patients with the
ED, and they are also more likely to be hypertensive and metabolic syndrome had an increased prevalence of erectile
hypercholesterolemic.8 dysfunction (26.7% vs 13%, p = 0.03); moreover, there was an

126
 Mediterranean diet and erectile dysfunction 127

Endothelial function score CRP (mg/L)

Table 16.1 Correlations between International Index N=62 N=25 N=13
6
of Erectile Function (IIEF) score and metabolic param-
eters, cytokine levels, and indices of endothelial func- 4
tion in 80 obese men with erectile dysfunction. 2
0
IIEF score p Value
9
Weight −0.40 <0.01
6
BMI −0.37 <0.01
3
WHR −0.35 <0.01
0
Glucose −0.08 =0.15
45
Insulin −0.04 =0.24

ED (%)
30
Cholesterol −0.15 =0.08
15
HDL-Cholesterol 0.08 =0.09
0
Triglycerides −0.09 =0.12 Number of componentsof the metabolic syndrome
IL-6∗ −0.10 =0.06
Figure 16.2 In 100 patients with the metabolic syndrome, the
IL-8∗ −0.18 <0.05 prevalence of erectile dysfunction (ED) (bottom) increases with
IL-18∗ −0.14 =0.08 the number of components of the syndrome, in association with
CRP∗ −0.25 <0.02 an increase in C-reactive protein (CRP) levels and a reduction in
endothelial function score (middle). Adapted from Diabetes
∗Log-transformed data. Care 2005; 28: 1201–3.16
BMI, body mass index; WHR, waist–hip ratio; HDL, high-density
lipoprotein; IL, interleukin; CRP, C-reactive protein.
Adapted from J Endocrinol Invest 2004; 27: 665–9.13 disease and free of traditional cardiovascular risk factors
present widespread abnormality of endothelial function,19 as
has been seen in patients with cardiovascular risk factors.
Obesity Unhealthy diets Sedentary According to a rising popular view, subjects with ED seem
Metabolic syndrome behavior to have a vascular mechanism similar to that seen in athero-
Oxidative sclerosis11 and therefore a diagnosis of ED may be seen as a
High-fat stress Psychological sentinel event that should prompt investigation for CHD in
meals stress
asymptomatic men.20
As ED and atherosclerosis may share some pathways,21 it
seems reasonable to assume that dietary factors, which are so
Impaired NO important in reducing the burden of CHD disease,22 may also
bioavailability play a role in reducing the occurrence of ED. For example, there
are several observational studies associating the Mediterranean
diet with a lower risk of CHD morbidity and mortality.23–26
Figure 16.1 Lifestyle choices may cause early injury in
endothelial cells through oxidative stress, with resultant Moreover, some randomized clinical trials have shown a
decreased availability of nitric oxide (NO). beneficial effect of this dietary pattern on secondary preven-
tion of CHD.27,28 The effect of the Mediterranean diet on CHD
can be mediated through multiple biological pathways other
than serum lipids, including reduction of oxidative stress and
increase in erectile dysfunction prevalence (IIEF <21) as the
subclinical inflammation, amelioration of endothelial dys-
number of components of the metabolic syndrome increased,
function and insulin sensitivity, and mitigation of blood
associated with a linear increase in CRP levels and a linear
pressure and thrombotic tendency.29,30
impairment of endothelial function score, suggesting that the
We have found that the intake of some foods was less rep-
cumulative burden of cardiovascular risk may be central to
resented in subjects with ED;8 in particular, the calculated
the pathogenesis of ED (Figure 16.2).
intakes of vegetables, fruits, and nuts, and the ratio of mono-
unsaturated to saturated lipids were significantly lower in men
with ED (Figures 16.3 and 16.4). Interestingly, each of these
Dietary factors and nutrients has been associated with a decreased risk of CHD,
erectile dysfunction through an effect of improving endothelial dysfunction31 and
decreasing inflammation.32 In general, the intake of foods that
A high prevalence of ED in patients with cardiovascular risk are more likely to be associated with an increased CHD risk
factors has been reported.6,7,17 Moreover, patients with ED have was higher in men with ED, whereas the intake of foods that
an increased prevalence of coronary heart disease (CHD) and are associated with a decreased CHD risk was reduced.
peripheral vascular diseases.18 Kaiser et al. have shown that sub- The concept of dietary patterns has recently attracted con-
jects with ED but without evidence of clinical cardiovascular siderable interest in the field of nutritional epidemiology.33
128 Textbook of Erectile Dysfunction

Subjects with ED Subjects without ED

g/day
600

525
500 491

400
354
321
300
241 255
200
160 150
120 110
100

Vegetables Fruits and nuts Dairy products Cereals Meat

Figure 16.3 The intake of several food groups was significantly different between subjects with or without erectile dysfunction
(ED). Adapted from Int J Impot Res 2006; 18: 370–4.8

Subjects with ED Subjects without ED

g/day

40
34
32
30
25
23
20

10.2
10

9.2
2
1.6
1.45
1

M/S Legumes Fish Olive oil

Figure 16.4 The intake of several food groups and of monosaturated and saturated fatty acids was significantly different between
subjects with or without erectile dysfunction (ED). M/S, ratio of monounsaturated to saturated fatty acids. Adapted from Int J Impot
Res 2006; 18: 370–4.8

In a sub-cohort of healthy men from the Health Professionals association of increasing adherence to Mediterranean diet and
Follow-up Study, Fung et al. discerned two major dietary pat- reduced prevalence of ED.
terns: the prudent pattern, characterized by higher intake of In our study,8 we found that a dietary pattern that was high
fruit, vegetables, whole grains, and poultry; and the Western in fruit, vegetables, nuts, whole grains, and fish but low in
pattern, characterized by a higher intake of red meat, high-fat red and processed meat and refined grains was more repre-
dairy products, and refined grains.34 A positive correlation has sented in men without ED than in men with ED. This dietary
been found between the Western dietary pattern and plasma pattern is quite similar to the traditional Mediterranean diet,
biomarkers of obesity and cardiovascular disease risk, such as which is characterized by a high intake of vegetables, legumes,
plasma concentrations of markers of inflammatory dysfunc- fruits and nuts, and cereals, and a high intake of olive oil associ-
tion (CRP) and endothelial dysfunction [intercellular adhe- ated with a low intake of saturated fats, a moderate intake of
sion molecule (ICAM)-1, vascular cell adhesion molecule fish, a low-to-moderate intake of dairy products, a low intake of
(VCAM)-1, and P-selectin].35 Moreover, a dietary pattern that meat and poultry, and a regular but moderate intake of ethanol,
was high in sugar-sweetened soft drinks, refined grains, diet primarily in the form of wine and generally during meals.38
soft drinks, and processed meat but low in wine, coffee, cruci-
ferous vegetables, and yellow vegetables was associated with
an increased risk of diabetes and inflammatory markers in the The Mediterranean diet
Nurses’ Healthy Study.36 As inflammation may play a caus-
ative role in ED,37 a reduced low-grade inflammation brought Mortality statistics from the World Health Organization
about by healthy dietary patterns may be implicated in the database covering the period 1960 to 1990 have provided
 Mediterranean diet and erectile dysfunction 129

intriguing evidence that something unusual has been affect-

Table 16.2 Dietary pattern characteristic of the tradi-
ing, in a beneficial way, the health of the Mediterranean
tional Mediterranean diet
populations, and in particular, with respect to CHD. Even
though health care for many of these populations was inferior • High consumption of fruits (3–4 servings/day)
to that available in northern Europe and North America and • High consumption of vegetables (2–3 servings/day)
the prevalence of smoking was unusually high, death rates in • High monounsaturated-to-saturated fat ratio (≥2)
the Mediterranean region were generally lower and adult life • Daily consumption of cereals (whole grains) and
expectancy generally higher in comparison with the economi- legumes
cally more developed countries, particularly among men.39 • Moderate consumption of fish and nuts (4–5 servings/
In a recent large prospective survey involving about 22,000 week)
adults from Greece (the Greek cohort of the EPIC study), • Moderate consumption of wine (1–2 glasses/day)
there has been shown to be an inverse correlation between a • Low consumption of meat and meat products
greater adherence to the Mediterranean diet and death.23 In (4–5 servings/month)
particular, approximately a two-point increment (out of nine) • Daily consumption of low-fat dairy products
in the Mediterranean diet score was associated with a 25%
reduction in total mortality and a 33% reduction in CHD
mortality. These associations were independent of sex, smok-
ing status, level of education, BMI, and level of physical to be consumed most frequently and the top to those to be
activity. Moreover, the relation was significant among partici- consumed rarely, with the remaining foods occupying inter-
pants 55 years of age or older, but not among younger partici- mediate positions.
pants, indicating an increasing cumulative exposure to a The first clinical trial evidence in support of the health
healthier diet may be beneficial. In other studies, adherence to benefits of the Mediterranean diet came from the Lyon Diet
similar healthful lifestyle practices has been found to be asso- Heart Study,27 in which 605 patients who had had a myocardial
ciated with an 83% reduction in the rate of CHD, a 91% infarction were randomly assigned to a Mediterranean-style
reduction in diabetes in women, and a 71% reduction in diet or a control diet resembling the American Heart Asso-
colon cancer in men.40 More recently, Knoops et al. from ciation Step I diet. The Lyon Heart Study was aimed to test
the Netherlands, France, Spain, and Italy, showed that in whether a Mediterranean type of diet may be superior to the
European men and women aged 70–90 years, adherence to a classic dietary counseling given by cardiologists in secondary
Mediterranean diet pattern, moderate alcohol consumption, prevention of coronary disease. The Mediterranean diet model
non-smoking status, and physical activity were each associ- supplied 30% of energy from fats and less than 10% of energy
ated with a lower rate of all-cause mortality.25 Taken together, from saturated fatty acids. Regarding essential fatty acids, the
the combination was associated with a mortality rate of about intake of 18:2(n-6) linoleic acid was restricted to 4% of energy
one-third that of those with none or only one of these protec- and the intake of 18:3(n-3) alpha-linolenic acid provided
tive factors. These healthy behaviors were not extreme: for more than 0.6% of energy. In practical terms, the dietary
example, the physical activity criterion could be met by half an instructions could be summarized as follows: more grains
hour of walking daily. and bread; more cereals, legumes and beans; more fresh veg-
etables and fruits; more fish, less meat (beef, lamb, pork), sau-
sages and luncheon meats (to be replaced by poultry); and no
Interventional studies butter and cream (to be replaced by canola oil-based marga-
The traditional Mediterranean diet, based on food patterns rine with a trans-fatty acid content of less than 5%). Finally,
typical of many regions in Greece and southern Italy in the the oils recommended for salad and cooking were exclusively
early 1960s, may be thought as having the components olive and canola (erucid acid-free rapeseed oil) oils. In the
indicated in Table 16.2. The main characteristics of the study, the most frequent non-fatal events were new acute
Mediterranean diet include an abundance of plant food (fruits, myocardial infarction and episodes of unstable angina, which
vegetables, whole-grain cereals, nuts, and legumes), olive oil are commonly due to the rupture of an atherosclerotic plaque.
as the principal source of fat, fish and poultry consumed in The risk of these two end-points was reduced by about 70%
low-to-moderate amounts, a relatively low consumption by the Mediterranean diet, indicating that the biological changes
of red meat, and moderate consumption of wine (normally associated with it resulted in a significant local anti-inflamma-
with meals). So, the dietary patterns that prevail in the tory effect. The number of new episodes of heart failure was
Mediterranean region have many common characteristics: also reduced in the Mediterranean group. Total cholesterol,
total lipid intake may be high, as in Greece (around or in systolic blood pressure, leukocyte count, female sex, and aspi-
excess of 40% of total energy intake), or moderate, as in Italy rin were each significantly and independently associated with
(around 30% of total energy intake); the Italian variant of the recurrence, indicating that the Mediterranean diet does not
Mediterranean diet is characterized by a higher consumption alter the usual relationships between risk factors of coronary
of pasta, whereas in Spain, fish consumption is particularly disease and recurrence, at least quantitatively.
high. In all instances, however, the ratio of monounsaturated Singh et al. tested an ‘Indo-Mediterranean’ diet in 1000
to saturated fats is much higher than in other places of the patients in India with existing coronary disease or at high risk
world, including northern Europe and North America. It has of coronary disease.28 Compared with the control diet, the inter-
become customary to represent the Mediterranean diet in the vention diet – characterized by increased intake of mustard or
form of a pyramid, the base of which refers to foods that are soybean oil, nuts, vegetables, fruits, and whole grains – reduced
130 Textbook of Erectile Dysfunction

Number of subjects with the metabolic syndrome

24
Baseline 2 years

Intervention diet Control diet

80
20

60

16

IIEF Score
40

20 12

0
3 4 5 3 4 5 8
Number of components of the syndrome

Figure 16.5 In patients with the metabolic syndrome, a 2-year

intervention study mainly based on a Mediterranean-style diet
(intervention diet) decreased the prevalence of the syndrome by 4
up to 50%. Adapted from JAMA 2004; 292: 1440–6.29 Baseline 2 years Baseline 2 years
Intervention group Control group
(N=55) (N=55)
the rate of fatal myocardial infarction by one-third and the
rate of sudden death from cardiac causes by two-thirds. Figure 16.6 In obese subjects with erectile dysfunction (ED) at
Esposito et al. explored possible mechanisms underlying a baseline, a 2-year intervention program of lifestyle changes
dietary intervention. The authors randomized 180 patients targeted at increasing physical activity and reducing body
(99 men, 81 women) with metabolic syndrome to a Mediter- weight was associated with normalization of erectile function in
ranean-style diet (instructions about increasing daily con- about one-third of the subjects. IIEF, International Index of
Erectile Function. Adapted from JAMA 2004; 291: 2978–84.41
sumption of whole grains, vegetables, fruits, nuts, and olive
oil; n = 90) vs a cardiac-prudent diet with fat intake less than
30% (n = 90).29 Physical activity increased equally in both non-consecutive days, which had to be done the week before
groups. After 2 years, body weight decreased more in the the meeting with the nutritionist. Men in the control group
intervention group than in the control group, but even after were given general oral and written information about healthy
controlling for weight loss, inflammatory markers and insulin food choices and exercise at baseline and at subsequent
resistance declined more in the intervention group than in the bimonthly visits, but no specific individualized programs
control group, whereas endothelial function improved more were offered to them. After 2 years, men randomized to the
in the intervention group. Only 40 patients in the intervention intervention had lost significantly more weight, had increased
group still had metabolic syndrome after 2 years compared their physical activity, had experienced favorable changes
with 78 patients on the control diet (Figure 16.5). These results in physiologic measures of endothelial dysfunction, and
suggest a plausible mechanism for the beneficial effects of the had significant improvement in their ED score compared
Mediterranean diet. with men in the control group (Figure 16.6).
This study provided evidence that sustained lifestyle changes
can partially ameliorate ED in obese men. In the Massachusetts
Mediterranean diet and erectile dysfunction Male Aging Study, Derby et al. found that men who were
ED and endothelial dysfunction may have some shared overweight at baseline were at an increased risk of developing
pathways,21 through a defect in NO activity that may be inhib- erectile dysfunction regardless of whether they lost weight
ited through age-, disease-, and behavior-related pathways. during the follow-up records.42 About one-third of obese men
Intervention on modifiable health behaviors, especially with ED regained their sexual activity after 2 years of adopting
reducing body weight and increasing physical activity, may in healthy behaviors, mainly regular exercise, a Mediterranean-
theory be a safe strategy to reduce the risk of both ED and style diet, and weight reduction. This may be in line with epi-
endothelial dysfunction. We hypothesized that lifestyle demiological evidence that physical activity was associated
changes aimed at reducing body weight and increasing physi- with a 30% lower risk of ED, while obesity was associated with
cal activity would induce amelioration of erectile and endothe- a 30% higher risk of ED. Additionally, men in the intervention
lial functions in obese men. We conducted a randomized program showed improvement in the number of surrogate
controlled trial involving 110 obese men with ED.41 Men traditional and novel cardiovascular risk factors, which were
assigned to the intervention group were entered in an intensive better than those seen in control men.
weight-loss program, involving personalized dietary counsel- We analyzed the effect of Mediterranean diet on ED in sub-
ing, exercise advice, and regular meetings with a nutritionist jects with the metabolic syndrome.43 Sixty-five men with
and personal trainer. The dietary advice was tailored to each the metabolic syndrome and ED were enrolled in the study; 35
man on the basis of food records collected on three out of them were assigned to the intervention diet and 30 to
 Mediterranean diet and erectile dysfunction 131

Basal 2 years
IIEF score
24
22
20
18
16
14
12
10
8
6
4
2

Mediterranean diet Control diet

Figure 16.7 Effect of a Mediterranean-style diet on the International Index of Erectile Function (IIEF) score in patients with metabolic
syndrome and erectile dysfunction at baseline. In the intervention group (Mediterranean diet), patients experienced a significant
improvement in IIEF score. Adapted from Int J Impot Res 2006; 18: 405–10.43

the control diet (Figure 16.7). The recommended composition strongly suggested to halt the progression of the epidemic and
of the dietary regimen was carbohydrates 50–60%, proteins may also be a safe strategy for dealing with the ongoing
15–20%, total fat <30%, saturated fat <10%, and <300 mg of increase in sexual problems in the population.
cholesterol consumed per day. Moreover, subjects were Despite increased public awareness of the importance of
advised to consume at least 250–300 g of fruits, 125–150 g of diet in decreasing the risk of chronic disease, large gaps remain
vegetables, and 25–50 g of nuts per day; in addition, they were in food-based recommendations and actual dietary practice of
also encouraged to consume 400 g of whole grains (legumes, the population. A substantial body of knowledge demon-
rice, maize, and wheat) daily and to increase the consumption strates that the abundant consumption of food of plant origin,
of olive oil. including vegetables, fruit, and whole grains, convey a markedly
After 2 years, men on the Mediterranean diet consumed a lower risk of coronary disease. From a public health perspec-
greater percentage of calories from polyunsaturated and mono- tive it is not essential to wait for elucidation of every mecha-
unsaturated fat, and they had a greater intake of omega-3 fatty nism underlying health promotion activities and interventions;
acids and a lower untake of saturated fat than controls. Total given the simplicity of the diet quality score, increasing the
fruit, vegetable, nuts, and whole grain intakes and olive oil intake of recommended foods represents a practical recom-
consumption were also significantly higher in the interven- mendation for improving health. A recent statement from the
tion group. There were 13 men in the intervention group and American Heart Association declares that the most prudent
2 in the control group (p = 0.015) that reported an IIEF score of and scientifically supportable recommendation for the general
22 or higher. In the intervention group, changes in IIEF score population is to consume a balanced diet with an emphasis on
were related to increased intake of fruits, vegetables, nuts, and antioxidant-rich fruits and vegetables and on whole grains.44
legumes (p < 0.01) and to the ratio of polyunsaturated to sat- When diet provides a sufficient supply of antioxidants, there
urated lipids (p < 0.02). Nutrient intake (34% of the variance, is no need for supplements.
p = 0.01), endothelial function score (14% of the variance, Higher levels of consumption of olive oil are considered to
p = 0.045), and CRP (16% of the variance, p = 0.03) were be the hallmark of the traditional Mediterranean diet. Other
independent predictors of IIEF score and explained almost important plant-based sources of monounsaturated fatty
64% of the variability in its changes. acids include nuts and canola (rapeseed) oil. Monounsatu-
rated fat, whether from olive oil or other sources, may have
the same beneficial effects on blood lipids and oxidative stress,
Conclusion but this possibility has not been fully studied. Both the Lyon
Diet Heart Study and the recent Indian study have emphasized
Men with ED show, compared with age-matched men with- canola (rapeseed) oil as a source of alpha-linolenic acid. Thus,
out ED, a difference in lifestyle attitudes that may play a role a Mediterranean-type diet, with high intake of fruits, vegeta-
in the development and progression of ED. In particular, the bles, nuts, legumes, and minimally processed grains, despite
prevalence of unhealthy dietary patterns and physical inactiv- differences resulting from its ‘translation’ into other cultures,
ity were significantly higher in men with ED. At a time in can use food options beyond olive oil for increasing the intake
which obesity and the metabolic syndrome have become a of monounsaturated fats and polyunsaturated fats at the
public health crisis, modification of behavioral risk factors is expense of saturated and trans-fats and refined carbohydrates.
132 Textbook of Erectile Dysfunction

Endothelial dysfunction
NO
ET-1
ATII
oxLDL

Hyperglycemia Hyperlipidemia

‘Oxidative’ stress ‘Toxic’ remnants

Labile glycation Lipolysis products – ↑FFA ED
Activation of coagulation
Endothelial dysfunction

Figure 16.8 In the postprandial state, acute variations in plasma glucose and lipid levels following ingestion of unhealthy foods
may cause endothelial dysfunction, which is considered one important factor in the development of erectile dysfunction (ED). FFA,
free fatty acids; NO, nitric oxide; ET-1, endothelin-1; AT, Angiotensin II; oxLDL, oxidized LDL lipoprotein.

Dietary patterns in Greece and other Mediterranean countries Dietary factors may be important in the development of
are changing rapidly, with increased consumption of satu- ED, and for claims for the widespread application of current
rated fat and refined carbohydrates. The healthy Mediterra- nutritional guidelines, which insist upon increasing consump-
nean diet in Italy is being abandoned by the population. From tion of vegetables, fruit, nuts and healthy fats, the intake of
a historic perspective45 the association of the Mediterranean which is less represented in ED patients. There is enough
diet with some of the greatest ancient civilizations – Greek, scientific evidence47 to indicate that consumption of unhealthy
Etruscan, and Roman – may have been coincidental, although diets may be a causative factor in progression of atherogenesis
the pioneering British nutritionist John Waterloo has argued: (Figure 16.8). Promotion of healthful lifestyles (including
‘It is difficult to conceive how the Greeks and Romans could Mediterranean-style diets and exercise) for primary preven-
have achieved such remarkable feats, which involved far more tion, among people of all ages, may yield great benefits and
than a small elite, if they had not in general had an adequate reduce the burden of chronic diseases, including the burden
and nourishing diet’.46 of sexual dysfunction.

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29. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean- 45. Giugliano D. The Mediterranean Diet: Origins and Myths.
style diet on endothelial dysfunction and markers of vascular Reddick, FL: Idelson-Gnocchi Publishers, 2000.
inflammation in the metabolic syndrome: a randomized trial. 46. Trichopoulou A. The Mediterranean Diet: Origins and Myths by
JAMA 2004; 292: 1440–6. Giugliano D, Sedge M, Sepe J. N Engl J Med 2001; 344: 940. Book
30. Carluccio MA, Siculella L, Ancora MA, et al. Olive oil and red review.
wine antioxidant polyphenols inhibit endothelial activation: anti- 47. Esposito K, Ceriello A, Giugliano K. The effects of diet on inflam-
atherogenic properties of Mediterranean diet phytochemicals. mation. Emphasis on the metabolic syndrome. J Am Coll Cardiol
Arterioscler Thromb Vasc Biol 2003: 23: 622–9. 2006; 48: 677–85.
17 Pharmacological risk factors for
altered male sexual function
Michael G Wyllie

Introduction Drug-induced effects on

Until recently, iatrogenic sexual dysfunction was rarely listed the behavioral component
with drug precautions; such effects were considered to be on sexual response
unfortunate, but predictable. Although these effects were
viewed as relatively unimportant compared with the primary The behavioral component of sexual response encompasses
therapeutic benefits, actual or anticipated male sexual dys- the integration of sensory inputs with the cognitive, emotional,
function caused patient non-compliance with drug therapies and desire components for the initiation and maintenance of
and reluctance to undergo surgical procedures. These events sexual drive.6–8 These agents are often separated into psycho-
produced significant changes in pharmaceutical marketing, pharmacological drugs and neuropharmacological drugs;
research, and clinical practice. First, the limited profitability however, the distinction between psychopharmacological and
of drug therapies that produced sexual disorders led to an neuropharmacological is ambiguous, because specific neural
appreciation of quality-of-life issues. This, in turn, led to pathways of human male sexual function have not been com-
the development of new drug therapies with fewer side- pletely identified and psychotropic effects could influence any
effects. The identification of sexual side-effects of drugs in aspect of the neural integration. The most obvious effects
humans, coupled with concomitant characterization in ani- noted by the patient and the clinician are those on general
mals, provided a foundation for pharmacological strategies to behavior or specific sexual behavior. Drugs with general
treat sexual disorders. Judicious exploitation of side-effects is sedative effects that can alter sexual behavior include anti-
being employed to treat different types of sexual complaints, hypertensives, anticonvulsants, hypnotics, anorexics, antide-
such as premature ejaculation. This overview provides exam- pressants, antipsychotics, and anxiolytics.5,7
ples of iatrogenic sexual dysfunction associated with drug Direct effects on sexual behavior occur through effects on
treatments. the brain areas responsible for regulating sexual drive. These
Erectile dysfunction due to prescription medications is areas include the medial pre-optic area (MPOA) of the ventral
under-reported but paradoxically a wide range of drugs have diencephalon, the mesencephalic central gray nucleus, the
been implicated with altered sexual function (Table 17.1).1–9 amygdala, and the hippocampus.6,11 These areas, particularly
There are several classification schemes for grouping the MPOA, are thought to be responsible for sexual drive and
drugs with sexual side-effects. The most common has been emotional control of peripheral sexual reflexes. Pharmaco-
categorization by therapeutic indication, for example anti- logical and histochemical studies have identified a variety of
hypertensives, antidepressants and antiandrogens.1–4 However, receptor subtypes in the MPOA, including peptidergic, choli-
therapeutic indications do not necessarily describe the mecha- nergic, dopaminergic, adrenergic and serotonergic receptors,
nism or site of action of the iatrogenic effects, with the excep- and receptors for reproductive hormones.6,9,11,12,13 The mono-
tion of androgen blockers. An alternative scheme is to segregate aminergic and hormonal receptors have been the most exten-
drugs by their mechanisms of action on the sexual response sively studied.
cascade: interest, performance, satisfaction.5 Since this classi- Sexual dimorphism of the central nervous system (CNS) is
fication is the same as that used for designing new drugs to regulated by fetal and neonatal levels of circulating androgens
alleviate sexual disorders, it provides a link between preclinical and estrogens: sexual behavior can be altered by changes in
studies that explore the origins of male sexual function and the MPOA induced by supplementation or denial of sex
clinical studies that exploit novel or existing pharmacological steroids. Yet, in adults, there is a poor correlation between
preparations for the treatment of sexual interest, performance circulating testosterone levels and measures of sexual interest,
and satisfaction. The subdivisions of this classification scheme sexual activity, or erectile function. Among geriatric patients,
include: a central behavioral component, a central–spinal reflex the complaint of impotence and the incidence of hypogo-
component, and an end-organ component. Drugs are also nadism are statistically independent.14,15 Not surprisingly,
segregated by effect, as being psychopharmacological, neuro- endocrinopathy as the cause of impotence is variable, with
pharmacological, and smooth muscle or vascular drugs.10 an incidence from 1 to 35%.16 Despite routine endocrine

134
 Pharmacological risk factors for altered male sexual function 135

Table 17.1 Reported sexual side-effects of drugs

Drug type Libido or desire Erectile function Ejaculatory function

Sympatholytics

Bethanidine Suppression Suppression Suppression

Debrisoquine Suppression Suppression Suppression
Guanethidine Suppression Suppression Suppression
Guanadrel Suppression Suppression Suppression
Alpha-methyldopa Suppression Suppression Suppression
Reserpine Suppression Suppression Suppression
Adrenergic

Alpha-1 agonists Enhancement

Ephedrine Enhancement
Phenylpropanolamine Enhancement
Pseudoephedrine Enhancement
Alpha-2 agonist
Clonidine Suppression Suppression
Alpha-1 antagonists
Phenoxybenzamine Mixed Suppression
Phentolamine Mixed Suppression
Prazosin Mixed Suppression
Doxazosin Enhancement Suppression
Tamsulosin None Marked suppression
Alpha-2 antagonists
Yohimbine Enhancement Enhancement
Delequamine Enhancement Enhancement
Beta-adrenergic antagonists
Atenolol Suppression
Labetalol Suppression Suppression
Metoprenol Suppression Suppression
Oxyprenolol Suppression Suppression
Pindolol Suppression
Propranolol Suppression Suppression Suppression
Timolo Suppression Suppression
Diuretics

Acetazolamide Suppression
Amiloride Suppression Suppression
Bendroflumethiazide Suppression
Chlorthalidone Suppression Suppression
Dichlorphenamide Suppression Suppression
Methazolamide Suppression Suppression
Spironolacotone Suppression Suppression
Anti-Parkinson’s drugs

Apomorphine Enhancement Enhancement

Bromocriptine Enhancement Enhancement
Deprenyl Enhancement
(Continued )
136 Textbook of Erectile Dysfunction

Table 17.1 Continued

Drug type Libido or desire Erectile function Ejaculatory function

L-Dopa Enhancement Enhancement Enhancement

Lisuride Enhancement Enhancement
Pergolide Enhancement Enhancement Enhancement
Anticholinergics

Anisotropine Suppression
Clidinium Suppression
Dicylclomine Suppression
Glycopyrrolate Suppression
Hexocyclium Suppression
Homatropine Suppression
Mepenzolate Suppression
Methantheline Suppression
Oxybutynin Suppression
Propantheline Suppression
Tridihexehtyl Suppression
Antipsychotics

Benperidol Suppression Suppression

Butaperazine Suppression Suppression Suppression
Chlorpromazine Suppression Suppression Suppression
Chlorprothixene Suppression Suppression Suppression
Fluphenazine Suppression Suppression Suppression
Haloperidol Suppression Suppression
Mesoridazine Suppression Suppression
Molidone Priapism
Perphenazine Suppression Suppression Suppression
Pimozide Suppression Suppression Suppression
Sulpiride Suppression Suppression
Thiothixene Suppression Suppression
Thioridiazine Suppression Suppression Suppression
Trifluoperazine Suppression Suppression Suppression
Anxiolytics

Benzodiazepines
Alprazolam
Chlordiazdepoxide Suppression
Diazepam Suppression
Flurazepam Enhancement
Lorazepam Suppression
Azapirone
Buspirone Enhancement Enhancement Enhancement
Antidepressants

Tricyclic antidepressants
Amitriptyline Suppression Suppression Suppression
Amoxapine Suppression Suppression Suppression

(Continued )
 Pharmacological risk factors for altered male sexual function 137

Table 17.1 Continued

Drug type Libido or desire Erectile function Ejaculatory function

Clomipramine Suppression Suppression Suppression

Desipramine
Imipramine Suppression Suppression Suppression
Maprotiline Suppression Suppression Suppression
Nortriptyline Suppression Suppression Suppression
Protripryline Suppression Suppression Suppression
Monoamine oxidase inhibitors
Iproniazid Suppression Suppression
Isocarboxazid Suppression
Mebanazine Suppression
Pargyline Suppression Suppression
Phenelzine Enhancement Suppression Suppression
Transcypromine Enhancement
Trazodone Enhancement Enhancement Enhancement
Specific serotonin reuptake
inhibitors
Fluoxetine Suppression Suppression Suppression
Paroxetine Suppression Suppression Suppression
Sertraline Suppression Suppression Suppression
Norepinephrine uptake inhibitors
Viloxazine Enhancement
Dopamine uptake inhibitors
Bupropion Enhancement
Nomifensine Enhancement
Lithium Suppression Suppression
Opioid agonist
Methadone Suppression Suppression Suppression
Opioid antagonists
Naloxone Enhancement
Naltrexone Enhancement

Endocrine therapies

Estrogen
Ethinyl estradiol Suppression
Androgens
Methandrostenenolone Suppression
Norethandrolone Suppression
Progestin
Hydroxyprogesterone Suppression Suppression
Medrogesterone Suppression
Medroxyprogesterone Suppression
Progesterone Suppression Suppression
Antiandrogen
Cyproterone acetate Suppression

(Continued )
138 Textbook of Erectile Dysfunction

Table 17.1 Continued

Drug type Libido or desire Erectile function Ejaculatory function

Miscellaneous

Amphetamine Suppression Suppression

Baclofen Suppression Suppression
Barbiturates Suppression/? Suppression
Cimetidine Suppression Suppression
Clofibrate Suppression Suppression
Digoxin Suppression Suppression
Disopyramide Suppression
Disulfiram Suppression
Ethosuximide Suppression
Fenfluramine Suppression Suppression
Heparin Priapism (an infrequent
observation of sustained
erection)
Hydralazine Suppression(?)
Metoclopramide Suppression Suppression
Naproxen Suppression
Nifedipine Mixed
Phenytoin Suppression Suppression
Primadone Suppression Suppression
Verapamil Mixed

screening in the evaluation of male sexual dysfunction, the involvement of dopaminergic or adrenergic receptors (or
exact role of androgen levels in erectile dysfunction (ED) both) in the central regulation of sexual drive.
remains to be elucidated. With castration, sexual function The theory of dopaminergic receptor involvement is
may range from a complete loss of libido to continued normal further supported by the observations of increased libido in
sexual activity. Spontaneous nocturnal erections are androgen- patients treated with dopamine agonists (apomorphine and
dependent. Erections in response to visual erotic stimuli, on pergolide) and dopamine reuptake inhibitors (nomifensine
the other hand, appear to be independent of androgens. and bupropion).18,19 In animal studies, activation of central
Another consequence of pharmacological or surgical dopaminergic receptors by systemic administration of the
castration is hot flushes, which occur in the majority of agonists apomorphine or quinelorane increases sexual beha-
patients (77% and 58%, respectively). The physiology is poorly vior in rats at doses that do not affect prolactin secretion or
understood, but is believed to be related to changes in the elicit other responses.20 In contrast to dopaminergic agonists,
hypothalamus which is in proximity to the thermoregulatory dopaminergic antagonists (antipsychotics) suppress sexual
system. drive in both patients and animals.4,7 In addition to the effects
on central and peripheral neuronal function, dopaminergic
antagonists can also suppress sexual responses through the
Dopaminergic mechanisms induction of hyperprolactinemia and secondary hypogona-
One of the milestone observations on the psychopharmaco- dism. Currently, bromocriptine is the only dopaminergic
logical control of sexual response was the finding of increased agonist approved for treating erectile disorders, but only for
libido in parkinsonian, psychiatric, and impotent patients hyperprolactinemia-induced dysfunction.
receiving the catecholamine precursor L-dopa.17 In laboratory
animals and patient populations, similar effects were also
observed with deprenyl (a monoamine oxidase B inhibitor), Adrenergic mechanisms
cocaine (a catecholamine reuptake inhibitor), and amphet- Adrenergic receptors have important roles in the central con-
amine (a catecholamine-releasing agent).4,7,8,13 In contrast to trol of sexual response. Amplification of noradrenergic trans-
these stimulatory effects, suppression of sexual behavior in mission with a selective norepinephrine reuptake inhibitor,
animals and of libido in patients has been reported with reser- viloxazine, markedly increased libido in depressed patients.7,21
pine and alpha-methyldopa, which deplete functional pools These effects did not correlate with the antidepressant activ-
of catecholamines in neurons.8,11 These results suggest the ity of this compound. There have been a few clinical reports
 Pharmacological risk factors for altered male sexual function 139

of decreased libido with alpha-1-adrenergic antagonists These drug-induced disorders of the erectile reflex include
(prazosin and phenoxybenzamine), alpha-2-adrenergic agonists failure to initiate erection, failure to maintain erection, spon-
(clonidine), and beta-adrenergic antagonists (propranolol). taneous erections unaccompanied by interest, and priapism.
The reports match animal investigations in males, with either
prazosin or clonidine suppressing mating behavior and
yohimbine, an alpha-2-adrenergic antagonist, increasing Dopaminergic mechanisms
sexual behavior.22 The psychopharmacological effects of Dopaminergic agents also affect erectile responses in men and
yohimbine may, in part, be responsible for its reported efficacy laboratory animals without changing sexual behavior, pre-
in the treatment of subgroups of patients with erectile dys- sumably by altering reflex pathways. Spontaneous erections
function.23 The stimulatory effect of yohimbine has recently were first noted as side-effects in patients treated with L-dopa
been used to counteract the sexual disorders induced by or dopaminergic agonists. Recently, subcutaneously adminis-
serotonin reuptake inhibitors (SSRIs, see below). tered apomorphine has been shown to induce penile erections
in normal volunteers and patients. Apomorphine induces
yawning, stereotypical sexual behavior, and erections in
Serotonergic mechanisms rodents. Erections have been induced in 67% of psychogeni-
With the recent success of SSRIs and other newly developed cally impotent patients in one series; dosage-related nausea
serotonergic drugs, knowledge both of the sexual side-effects and vomiting have been a problem with both subcutaneous
and of new uses of these agents has rapidly expanded. In pre- and oral formulations. Presumably, patients must have an
clinical studies, suppression of sexual behavior and subse- intact end-organ (i.e., non-vasculogenic erectile dysfunction)
quently suppression of erectile and ejaculatory response has to respond to apomorphine.19,30 The response to dopaminer-
been demonstrated, with direct or indirect augmentation of gic receptor stimulation with apomorphine is not accompa-
central serotonin activity with 5-HT (5-hydroxytryptamine, nied by increases in libido.30 Although erections have been
serotonin) loading, specific serotonin reuptake inhibitors noted as side-effects of oral dopaminergic agonist therapy,
(SSRIs), releasing agents or postsynaptic agonists.13,24 These the incidence of this response appears to be far greater with
effects correlated with reports of suppressed libido and subcutaneous administration. In parallel to these clinical
anorgasmia in patients treated with the 5-HT-releasing agent studies, dopaminergic agonist-induced erections have also
fenfluramine and various other SSRIs. The effects of SSRIs in been observed in rats and rhesus monkeys.26 In contrast to
prolonging the latency of the ejaculatory reflex in animals and agonists, erectile dysfunction is a reported side-effect of drugs
men has been sufficiently reproduced to be proposed as a with dopaminergic antagonist activity.4,8
therapy for premature ejaculation.
Serotonin may have both facilitating and inhibiting effects Serotonergic mechanisms
on sexual behavior, depending on the receptor subtype, loca-
tion of receptors and species examined. 5-HT-1A agonists can Unlike dopamine, serotonin appears to have different effects
inhibit erection and promote ejaculation; 5-HT-1C agonists on the central and peripheral components of the sexual
promote erection; 5-HT-2 agonists both inhibit and facilitate response. Amplification of serotonergic activity through the
various aspects of sexual behavior. 5-HT-1A autoreceptor administration of serotonin-releasing agents or agonists also
agonists, such as buspirone, increase sexual behavior in male induces spontaneous erections in rats and rhesus monkeys.31,32
rats and rhesus monkeys.25,26 These studies correlate with the In contrast, in humans SSRIs result in sexual effects that are
clinical findings on buspirone. In one human trial, buspirone primarily suppressive, although case reports of improvements
increased libido and other sexual responses in male and female in erectile function have been published.33,34 The erectogenic
patients with generalized anxiety disorders.27 Several more effects of serotonin have been proposed to be mediated by the
selective and more potent 5-HT-1A agonists have been 5-HT-C receptor subtype.6,31 These effects may contribute
reported to have robust effects on sexual performance and to the induction of priapism in patients treated with the anti-
may become clinical candidates.26 In addition to 5-HT-1A depressant trazodone and to the increase in erectile activity
autoreceptor agonists, postsynaptic 5-HT-2 receptor antago- during rapid eye movement (REM) sleep. The primary trazo-
nists augment sexual behavior and indirectly enhance peri- done metabolite meta-chlorophenyl piperazine (mCPP) is a
pheral sexual reflexes.12,24,28 These laboratory studies suggest serotonergic agonist that induces erections in rats and rhesus
that 5-HT-2 receptor antagonism can contribute to the monkeys and selectively increases the firing rate of the penile
enhanced libido and erectile response noted in clinical studies nerve and cavernosal blood pressure in rats.31,32 These studies
with trazodone.29 indicate that a serotonergic agonist could be useful for erectile
dysfunction, particularly if drugs with appropriate receptor
specificity can be developed. Again, it must be emphasized
that serotonin has both facilitating and inhibiting effects on
Drug-induced effects sexual behavior, depending on the receptor subtype, the loca-
on erectile reflexes tion of receptors, and the species being tested.
Major roles for opioid receptors have been proposed, based
In addition to their effects on the diencephalic areas involved on a variety of laboratory and clinical studies.9,35 The loss of
in sexual regulation, drugs can also suppress or induce the the ability to achieve or maintain erection has been a noted
erectile reflex through actions on sites in the brainstem and side-effect in heroin- and methadone-addicted patients.4,8,9
spinal cord that regulate the autonomic control of erection. Decreased sexual desire was also noted in many of these
140 Textbook of Erectile Dysfunction

patients, suggesting a CNS-depressant effect. Spontaneous muscle levels of cAMP (e.g. prostaglandin E1), cGMP (e.g.,
erections are reported side-effects during treatment with the NO releasers), or cAMP and cGMP (papaverine and other
opiate antagonists naloxone and naltrexone in heroin- or phosphodiesterase inhibitors). The underlying pathophysio-
methadone-addicted patients. In a single-blind study with logy and the drugs developed on this basis are described in
impotent patients, naltrexone produced significant increases other chapters within this textbook.
compared with placebo in both sexual performance and the
number of morning and spontaneous erections; improved
sexual performance was reported in 11 of 15 patients with
psychogenic impotence.36 In an uncontrolled study, 6 of 7 Drug-induced effects on ejaculatory
idiopathic impotent patients were restored to full erectile reflex control
function with naltrexone therapy.37 Naloxone has also been
reported to induce full erections lasting an hour in normal The ejaculatory-phase events include the induction of seminal
volunteers when combined with yohimbine, presumably emission, ejaculation, and perceptual changes associated with
through the additive effects of these agents on sexual orgasm. Agents that alter the ejaculatory phase may do so
response. directly by affecting performance, or indirectly by affecting
Until recently, iatrogenic erectile dysfunction associated sexual satisfaction. The predominant drug-induced disorders
with anticholinergic drugs was thought to be mediated exclu- of this phase include delayed or absent ejaculation, retrograde
sively through a vascular pharmacological mechanism by ejaculation, and suppressed seminal emission.35 These side-
which anticholinergic drugs block the effects of parasympa- effects are associated with agents that alter the central or
thetic-induced release of endothelial cell-derived relaxation peripheral components of the seminal emission–ejaculation
factors (e.g. nitric oxide, NO) that relax the cavernosal smooth reflex. As in the case of the behavioral and erectile phases,
muscle. Regardless of the mechanism, blockade of muscarinic drugs that affect dopaminergic or serotonergic receptor
receptors appears to be responsible for the reported erectile activity are thought to modulate the central component of
failures associated with drugs such as imipramine and other the ejaculatory reflex.8
tricyclic antidepressants.3,4,8 The best evidence for this was the In laboratory animals, pharmacological agents that increase
discovery that bethanechol could reverse erectile failure caused dopaminergic receptor activity shorten ejaculatory latency
by these drugs.38 and induce seminal emission in normal animals and restore
Drug therapies that alter sympathetic neural activity also ejaculatory capacity to dysfunctional animals. Examples of
are associated with erectile disorders. The maintenance of the such agents include L-dopa, deprenyl, and dopaminergic
penis in a flaccid condition is dependent upon a continuous agonists.1,13 Conversely, agents that decrease dopaminergic
stimulation of alpha-1-adrenergic receptors on the smooth activity (dopamine antagonists) increase ejaculatory latency
muscle of the corpora cavernosa through the tonic release of and reduce ejaculatory capacity.13 The clinical correlates
norepinephrine from sympathetic terminals. It has been pro- include premature seminal emission or ejaculation in parkin-
posed that the sinusoidal endothelium also contributes to the sonian patients treated with L-dopa or pergolide, and delayed
maintenance of tone (flaccidity) by synthesis and release of or absent ejaculation in patients treated with antipsychotics.8,17
endothelins. Drug regimens that increase peripheral adrener- A practical application of this last-named side-effect has
gic tone have been reported to cause erectile failure, whereas been the use of low-dose therapies of thioridazine or metoclo-
those that decrease postsynaptic alpha-1-adrenergic receptor pramide to treat premature ejaculation.8
activity are associated with reports of priapism.3 Chronic The effects of serotonergic agents on ejaculatory reflexes in
treatments with amphetamine and cocaine, which indirectly laboratory animals have been more controversial. In experi-
increase alpha-1-adrenergic receptor activity, have been asso- ments with mating animals, pharmacological agents that
ciated with the side-effect of erectile failure. In contrast, a increase release or inhibit synaptic uptake of 5-HT or directly
variety of drugs with alpha-1-adrenergic antagonist activity, stimulate postsynaptic 5-HT receptors have been shown to
as is the case with some antihypertensives and antipsychotics, delay or suppress ejaculatory responses.6 Agents that decrease
have been reported to cause priapism. The priapism associ- serotonergic activity, such as serotonergic neurotoxins or
ated with trazodone has also been theorized to be mediated antagonists, have the opposite effect. However, serotonergic
through its alpha-1-adrenergic antagonist activity.39 This agonists and releasing agents can also induce spontaneous
mechanism may explain the sporadic observation of priapism ejaculation in animals. In clinical studies with SSRIs, pro-
with drugs possessing alpha-1-adrenergic antagonist activity.6 tracted ejaculatory latencies in patients were so reproducible
These effects also justify the current evaluations of oral alpha- that these agents were employed as treatments for premature
1-adrenergic antagonists for erectile disorders. ejaculation (see Chapter 62). Other antidepressants that
Pharmacological studies in vitro on corporal smooth muscle inhibit 5-HT uptake (e.g. tricyclic antidepressants) also pro-
have provided evidence that many new vascular therapies duce these side-effects.8,43 These clinical effects appear to
have erectogenic effects.40–42 Since the inadvertent discovery correlate to the effects observed in animals during mating
that hypogastric arterial infusion of papaverine induces erec- conditions. Furthermore, anorgasmia induced by tricyclic
tion, these agents have been clinically exploited in pharmaco- antidepressants and monoamine oxidase inhibitors (which
logical erection programs. The erectile reflex has been suppress metabolism of 5-HT) can be reversed by the admin-
modulated at the level of the end-organ by intracavernous istration of a serotonergic antagonist, cyproheptadine.8
injection, and by topical or urethral agents. The most effica- As seminal emission and antegrade ejaculation are pro-
cious corporal relaxants act by increasing corporal smooth cesses that are primarily controlled by sympathetic activity,
 Pharmacological risk factors for altered male sexual function 141

pharmacological agents that deplete functional pools of alpha-1-adrenergic antagonist activity: these include the anti-
catecholamines or have alpha-1-adrenergic antagonist activ- hypertensives phenoxybenzamine, phentolamine, prazosin and
ity are known to suppress ejaculatory capacity and induce tamsulosin; and the antipsychotics thioridazine, chlorprom-
retrograde ejaculation.3,7,35 The agents that diminish presyn- azine, triflupromazine and mesoridazine. In contrast to the
aptic norepinephrine release include reserpine, alpha-methyl- effects of alpha-1-adrenergic antagonists, sympathomimetic
dopa, guanethidine, guanadrel, bethanidine, and derisoquine. agents, such as pseudoephedrine, ephedrine, and phenylpro-
Other drugs associated with this side-effect have significant panolamine, have been used to treat retrograde ejaculation.35

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17. Barbeau, A. l-Dopa therapy in Parkinson’s disease: a critical review evidence for naltrexone stimulation of erectile activity in patient
of nine years’ experience. Can Med Assoc J 1969; 101: 59–69. therapy. Psychoneuroendocrinology 1989; 14: 103–11.
18. Crenshaw T, Goldberg J, Stern W. Pharmacologic modification of 37. Goldstein JA. Erectile function and naltrexone. Ann Intern Med
psychosexual dysfunction. J Sex Marital Ther 1987; 13: 239–50. 1986; 105: 799.
19. Del Bene E, Fanciullacci M, Poggioni M, et al. Apomorphine and 38. Gross MD. Reversal by bethanechol of sexual dysfunction caused
other dopamine modifiers of human sexual and nocioceptive by anticholinergic antidepressants. Am J Psychiatry 1982; 139:
tonus. In: Segal M, ed. Psychopharmacology of Sexual Disorders. 1193–4.
London: Libbey 1985: 145–153. 39. Saenz de Tejada I, Ware CJ, Blanco R. Pathophysiology of pro-
20. Foreman MM, Gehlert DR, Schaus JM. Quinelorane, a potent longed penile erection associated with trazadone use. J Uro1 1991;
and selective dopamine agonist for the D2-like receptor family. 145: 60–4.
Neurotransmissions 1995; 11: 1–5. 40. Andersson K-E. Pharmacology of lower urinary tract smooth
21. DeLeo D, Magni G. Does viloxazine really improve sex drive? A muscle and penile erection. Pharmacol Rev 1993; 45: 253–308.
double blind controlled study. Br J Psychiatry 1986; 148: 597–9. 41. Andersson KE, Wagner G. Physiology of penile erection. Physiol
22. Clark JT, Smith ER, Davidson J. Evidence for modulation of sexual Rev 1995; 75: 191–236.
behavior by alpha adrenoceptors in male rats. Neuroendocrinol- 42. Rayner HC, May S, Walls J. Penile erection due to nifedipine.
ogy 1985; 41: 36–43. Sr Med J 1988; 296: 137.
23. Riley AI, Goodman R, Kellett JM, Orr R. Double blind trial of 43. Girgis S, El-Haggar S, EI-Hermouzy S. A double-blind trial of
yohimbine hydrochloride in the treatment of erection inadequacy. chlomipramine in premature ejaculation. Andrologia 1982; 14:
Sex Marital Ther 1989; 4: 17–26. 364–8.
18 Male sexual dysfunction and
the prostate
Michael G Wyllie

Introduction although there is a close association. In instances where a

relationship has been suggested, the relevance of such reports
There is a variety of ways in which the topic of male sexual should be considered in relation to the weight of formal
dysfunction and the prostate could be tackled. However, the evidence.2,3 Warranting particular scrutiny is the strength of
content of this chapter is largely restricted to analyzing the the association (as measured by increases in the relative risk of
impact of drugs used for the treatment of lower urinary tract ED with LUTS), the presence of a quantifiable dose–response
symptoms (LUTS) associated with benign prostatic hyperpla- effect (i.e. does more severe LUTS equate with more severe
sia (BPH) on sexual function, and the potential utility of ED?), and a temporal relationship between the development
phosphodiesterase (PDE) 5 inhibitors in the treatment of of these disorders (i.e. disease progression). Most importantly,
LUTS. Covered elsewhere in this textbook is the impact of the the observed epidemiological data should be underpinned
urological surgeon. What is not covered is the role of the pros- by having some potential underlying pathophysiological or
tate in normal sexual function. What follows are some key biological explanation. It is worth pointing out that in this
messages rather than a comprehensive review of the literature. context there is emerging evidence that ED and LUTS have
The focus is on the information that is most relevant to the some physiological, pathological, and molecular components
management of BPH patients with and without comorbid in common.4 In particular, the possibility that they may both
sexual dysfunction (SD). result in compromised intra-organ vascular perfusion deserves
further investigation.
Several epidemiological studies, either by original design or
retrospective subset analysis (caveat emptor) have attempted
The link between benign prostatic to examine the relationship between sex and the prostate. One
hyperplasia, lower urinary tract of the more important studies is the MSAM-7,1 which sug-
symptoms, and sexual function gested a strong association between the frequency of sexual
intercourse and the patient’s International Prostate Symptom
LUTS and sexual dysfunction are highly prevalent in aging Score (IPSS). The IIEF score was also significantly associated
men, and both conditions have a significant negative impact with LUTS severity. Authors have noted that the association
on overall quality of life. It would appear that neither BPH nor between LUTS and sexual dysfunction persisted after control-
LUTS per se, when corrected for age, adversely affects sexual ling for age and other co-morbidities such as hypertension
function. However, a particularly relevant question is whether and diabetes, which are known to have an impact on sexual
or not men with LUTS and BPH are at increased risk of sexual function. Measures of ejaculatory disorders, including reduced
problems. To address this, we must firstly determine what we ejaculate and ejaculation pain, were also strongly associated
mean by sexual function. It is more than just erectile function; with LUTS. The results of the MSAM-7 suggest that the
indeed sexual function should be regarded as encompassing majority of older men have active sex lives and that the sever-
several different aspects or ‘domains.’ Some of these aspects ity of LUTS is an independent risk factor for sexual disorders.
are characterized or captured in the International Index of Obviously, any therapy that has a negative impact on sexual
Erectile Function (IIEF). By way of generalization, male sexual function would be of considerable concern to the majority
dysfunction may manifest as decreased libido, ejaculatory of men, but especially to those already experiencing sexual
dysfunction, erectile dysfunction (ED), or a combination of dysfunction or in a high-risk category for the development of
all three of these conditions. As is described below, many of sexual dysfunction.
the currently available therapies for LUTS and BPH have the New data are, however, increasingly emerging to indicate
potential to affect sexual function, both negatively and posi- potential links at epidemiological, physiological, pathophy-
tively, and either acutely or after long-term administration. siological, and treatment levels between sexual dysfunction
Despite evidence based on a large and increasing number of and LUTS.5 If there is some degree of intimate association
epidemiological studies, such as the Multinational Survey of between BPH and LUTS and sexual dysfunction that is more
the Aging Male (MSAM-7)1 (see below), a causal association than coincidental, this may have implications for the clinical
between LUTS and ED has not yet been firmly established, management of these disorders, as well as for the development

142
 Male sexual dysfunction and the prostate 143

of treatment algorithms. For example, treatment of one con- Table 18.1 AUA meta-analysis of outcomes of
dition might have an impact, either positive or negative, on medical therapies: estimates of occurrence of sexual
the other. In addition, there are specific drug interaction issues, adverse events.
e.g. the potential vasoactive synergy of alpha-blockers and
PDE-5 inhibitors that may have to be carefully considered in Median % (95% Cl) problems with
the treatment algorithm not only for BPH patients but also for
Therapy Ejaculation Erection Libido
patients with ED and comorbid BPH.
However, even assuming there is some degree of comor- alpha-blockers
bidity or shared pathophysiology, the question remains as
to why urologists or primary care physicians should worry Alfuzosin – 3 (1–6) 1 (0–4)
about sexual dysfunction in men with LUTS. The relation- Doxazosin 0 (0–2) 4 (1–8) 3 (2–6)
ship between the two dysfunctions is important for several Tamsulosin 10 (6–15) 4 (1–8) –
reasons: Terazosin 1 (1–2) 5 (3–8) 3 (1–5)

• Additional information on risk factors for either condi- Hormonal

tion could be important for diagnosis of likely comorbid Finasteride 4 (3–5) 8 (6–11) 5 (4–7)
conditions.
• There is an increasing number of affected men, given the Combined
‘graying’ of the population. Alfuzosin/finasteride 1 (0–2) 8 (5–11) 2 (1–4)
• Many BPH patients have comorbid ED or ejaculatory
Doxazosin/finasteride 3 (2–6) 10 (7–14) 3 (1–5)
disorders and do not want an exacerbation or precipitation
of their sexual dysfunction. Terazosin/finasteride 7 (5–10) 9 (1–13) 5 (3–8)
• Many currently available LUTS treatments (medical Placebo 1 (1–1) 4 (3–5) 3 (3–4)
and surgical) affect sexual function. The impact of drugs
Adapted from reference 6.
used in the treatment of BPH is summarized immedi-
ately below; that of the surgeons is covered elsewhere
(see Chapter 64).
regression of the hyperplasia. Evidence showing reduction in
prostatic mass or volume has accrued from many long-term
Drugs for benign prostatic studies involving both of the 5-alpha-reductase inhibitors. The
onset of clinical benefit (occurring after 6 months’ treatment)
hyperplasia and their relationship is much slower than the almost immediate reduction in intra-
with sexual dysfunction prostatic DHT levels, consistent with symptom improvement
being secondary to reduction in tissue proliferation or even
Symptomatic BPH (i.e. LUTS) is almost invariably treated increased apoptosis. The first 5-alpha-reductase inhibitor, fina-
with one of two classes of agents – either alpha-adrenoceptor steride, inhibits only one isozyme (5-alpha-reductase-2), and
antagonists (alpha-blockers) or members of the ‘prostate- dutasteride, an inhibitor of both isozymes, was subsequently
shrinking’ 5-alpha-reductase inhibitor class. In general, developed to overcome perceived efficacy limitations. The
despite reasonably convincing data and dozens of abstracts on assumption behind the development of dutasteride was that a
the clinical advantages of combination therapy, each drug dual isozyme inhibitor would lead to a greater and more rapid
class is generally used as monotherapy; the clinical benefit reduction in intra-prostatic DHT levels, with corresponding
perceived by many key academic opinion leaders is perhaps improved efficacy. Evidence has emerged that the reduction
outweighed by cost concerns on the part of patients or their in DHT can be more rapid with dutasteride but there is little
healthcare providers, who are not easily influenced by statistics. convincing evidence of efficacy beyond that attained with
The impact of these drugs on sexual function is summarized finasteride.
in qualitative terms in Table 18.1, adapted from a meta-analysis From the experience – albeit in prostate cancer patients – of
carried out by the AUA and published in 2003.6 more effective androgen ablators (e.g. gonadotropin releasing
hormone (GnRH) agonists, which reduce both testosterone
and DHT to near castration levels), and from our knowledge
Impact of 5-alpha-reductase inhibitors on of the role of androgens in the control of sexual function, it
sexual function was predicted by many that the 5-alpha-reductase inhibitors
The first drug class to be widely approved, exemplified would produce some degree of sexual dysfunction. Although
by finasteride and dutasteride, was the 5-alpha-reductase this is the case, at least with respect to reduction in libido and
inhibitors, commonly referred to as ‘prostate shrinkers’. These desire, the incidence emerging over almost two decades of
drugs act by inhibiting the conversion of testosterone to its 5-alpha-reductase inhibitor therapy, was relatively low (<5%)
primary metabolite, dihydrotestosterone (DHT), which is and ironically may be lower for dutasteride, the inhibitor of
considered to have the major androgenic influence on the both isozymes, than for finasteride,7 although direct side-to-
prostatic nuclear androgen receptor. As prostatic prolifera- side evaluations have not been undertaken. When observed,
tion is highly androgen-dependent, the reduction in overall sexual dysfunction is apparent at time points in clinical trials
androgenic load thereby reduces prostatic growth and causes well before treatment efficacy is observed, consistent with the
144 Textbook of Erectile Dysfunction

sexual dysfunction being dependent on alteration in androgen Sympathetic

load, but temporally related to DHT reduction. nervous
system
The precise relationship between androgens and any or all
aspects of sexual function remains to be established. Testos- Alpha-2
receptor NA
terone replacement or supplementation has been shown to
augment sexual function and restore potency in hypogonadal

Phen
and ‘normal’ men. Likewise, in support of a link, androgen -
NA
ablation in prostate cancer patients, as described above, can
reduce sexual function. However, there are several anomalies.
First, GnRH analogs, such as cetrorelix, although rapidly pro- NA
ducing near-castration androgen levels in BPH patients, NA
appear to be largely without effect on sexual function at doses Phen Dox
Alpha-1 NA
that appear, at least in clinical trials, to improve LUTS dra- receptor
matically. At least two clinical trials in BPH have shown that
cetrorelix is clinically effective within weeks (an anomalously Contraction
Cavernosal
quick onset of action if the effect is secondary to androgen smooth muscle cell
reduction), whereas there is little or no short- or long-term
impact on sexual function.8 Secondly, the degree of sexual Figure 18.1. Noradrenergic synaptic dynamics within the
function observed with chronic administration of 5-alpha- sympathetic innervation of the corpus cavernosum. Noradrena-
line (NA; norepinephrine) release from the nerve terminals acts on
reductase inhibitors is surprisingly low, although DHT levels
postjunctinal alpha-1-adrenoceptors to produce smooth muscle
can be reduced by over 95%.
relaxation and detumescence. The selective alpha-1-adrenocep-
tor antagonist, doxazosin (Dox), and the mixed alpha-1/2 adre-
noceptor phentolamine (Phen), block this effect. The amount of
Impact of alpha-blockers on sexual function
noradrenaline entering the synaptic cleft and thereby the mag-
There are even more anomalies in the sexual clinical profile of nitude of the postjunctional response is controlled by prejunc-
the alpha-blockers. Alpha-blockers have provided the main- tional alpha-2-autoreceptors for NA. As NA builds up it switches
stay of front-line treatment of LUTS for over 25 years, and off further release. The process is unaffected by Dox. However,
their clinical profile from billions of patient days is well docu- as a consequence of blocking these alpha-2-adrenoceptors,
mented. As a class they were originally assumed to improve Phen enables the build-up of NA to occur in the synapse. The
symptoms by acting initially on the sympathetic nervous law of mass action would predict that NA would competitively
counteract the postjunctional alpha-1-adrenoceptor blocking
system outflow to periurethral intra-prostatic stromal tissue
action of Phen resulting in a diminution of the erectogenic
to reduce urethral resistance and thereby increase uroflow.
response.
Secondary to this reduction in obstruction after a few months,
an improvement in bladder-based irritative symptoms would that Georg Bartsch’s group in Innsbruck has consistently
be expected. Certainly, the immediate improvement in uro- suggested that all effects of alpha-blockers within the urogen-
flow (after the first dose) and the time to full effect (12 weeks ital sinus are in fact secondary to changes in local blood flow
or so) is consistent with this hypothesis. More recently, within target organs – specifically in the case of alpha-blockers
evidence has emerged that all symptom improvements can in LUTS, changes within the bladder rather than the prostate.9
be related to changes in local vascular perfusion within the Consistent with this basic hypothesis, there appears to be a
bladder.9 The alpha-1-adrenoceptor is subdivided into three particularly good correlation between alpha-blocker-induced
subtypes, alpha-1A receptors, alpha-1B receptors and alpha-ID changes in detrusor blood flow and oxygenation and improve-
receptors. Blockade of the A and D subtypes is generally ment in IPSS.
considered important for the relief of LUTS. If the LUTS improvement is secondary to local organ
On the basis of our knowledge of the autonomic control vascular perfusion changes, it would be expected that dihy-
of penile erection, alpha-blockers, by reducing the flaccidity- dropyridine calcium-channel blockers would be effective,
inducing sympathetic nervous system, would be expected to particularly in the many BPH patients with comorbid hyper-
be pro-erectile (Figure 18.1). One has to look closely in the tension. Should this be the case, the incidence of BPH should
literature to find unequivocal evidence to support this hypo- be less in the many antianginal and antihypertensive clinical
thesis. Indeed, alpha-blockers injected intracorporally at trials conducted with calcium-channel blockers than in the
extremely low doses are certainly erectogenic.10 In addition, equivalent placebo groups and the equivalent age-matched
in reasonably controlled clinical studies, oral doxazosin has population at large. One for the epidemiologists?
been shown to reduce the incidence of ED, and in long-term Does the erectogenic action of doxazosin represent a class
studies to reduce the appearance of ED11 and to sensitize the effect? As with the overall clinical profile of doxazosin, there is
corporal tissue to other erectogenic agents.12 The assumption some evidence in several studies that alfuzosin improves erec-
is that this effect represents an extension of the generalized tile function whereas neither of the other quinazoline alpha-
action of the drug on resistance vessels within the penile blockers, prazosin and terazosin, appears to have any positive
vasculature rather than any particular specificity of the drug or negative effect (though this may be because this issue has
for penile tissue. not been examined in the clinic with any degree of rigor).
It is pertinent to note, and relevant to later discussion on the Tamsulosin, the structurally dissimilar sulphonamide and the
impact of PDE-5 inhibitors on LUTS symptoms (see below), most recently introduced member of the alpha-blocker class,
 Male sexual dysfunction and the prostate 145

has a somewhat unique profile. Several large clinical studies the impact of PDE-5 inhibitors on bladder, prostatic
show that tamsulosin can produce ‘abnormal’ ejaculation in and urethral function. Of particular interest are the studies
up to 30% of patients, depending on dose.13 As there is little relating to LUTS. The potential therapeutic applications for
evidence of changes in ejaculatory function to this extent with BPH and urinary urge incontinence were first recognized by
alfuzosin, doxazosin, prazosin, or terazosin, it is unlikely that Pfizer in the form of a patent as far back as 1999;16 part of the
this is a class effect for all alpha-blockers. Although several experimental evidence offered, in addition to PDE-5 isozyme
studies have attempted to determine the underlying mecha- location, was the finding of inhibition of spontaneous myo-
nism of action, results have been equivocal and are often con- genic activity in strips prepared from unstable human detrusor
tradictory. What is clear is that the abnormal ejaculation muscle. This was followed relatively quickly by clinical support
cannot be accounted for by the receptor-binding profile of in the form of a (now largely ignored) study conducted in
tamsulosin across the three alpha-1-adrenoceptor subtypes; 2000 in the UK in BPH patients and published in 200217 and
its profile on the three subtypes is not different from that of followed by several additional studies in both BPH and ED
the quinazoline alpha-blockers to an extent that could account patients. Although the original study was not using end-points
for such a major clinical difference, either with respect to effi- now considered de rigueur, the findings were essentially similar
cacy or the ejaculatory dysfunction. The favored view to the much more comprehensive studies conducted several
is that tamsulosin has an additional action, over the same years later.18
concentration range (in the test tube and animals), or dose In general within the urogenital sinus the sympathetic
range (in the clinic), at dopamine and serotonin receptors.14 nervous system and the NO-dependent non-adrenergic non-
The laboratory and animal data linking both systems to ejacu- cholinergic (NANC) systems act in apposition (Figure 18.2).
latory function is to a certain extent supported by clinical On that basis one would have anticipated that PDE-5 inhibi-
data, in particular, from large phase 3 studies in over 1200 tors would have the profiles of functional alpha-blockers (i.e.
subjects, in which the modified selective serotonin reuptake activation of NANC would be equivalent to blocking the
inhibitor (SSRI) dapoxetine, increases ejaculation latency sympathetic nervous system). In one key study, sildenafil has
albeit in patients with premature ejaculation.15 Although not been shown to increase vascular perfusion in the prostate,
formally evaluated to the same extent as dapoxetine several
SSRIs are widely used ‘off-label’ as front-line therapy for
premature ejaculation (see Chapter 62). An action on cen- Sympathetic Non-adrenergic
tral serotoninergic pathways could well translate into a nervous non-cholinergic
system (NANC) system
change in ejaculatory function. Likewise, some anecdotal
clinical data suggesting that the dopamine partial agonist
apomorphine increases the force of ejaculation would be
consistent with an interaction between tamsulosin and dopa-
mine receptors, accounting for the observed abnormal ejacu- NA NOS
lation. In radioligand-binding studies and in the rat in vivo,
tamsulosin has been shown to interact with both dopamine Alpha-1
and serotonin receptors. Ironically, determination of the pre- NA NA receptor NO NO
cise pharmacological basis for tamsulosin’s action on the
ejaculatory reflex could lead to the development of novel PGE1 Contraction Relaxation
therapy for the treatment of either premature ejaculation or Cavernosal
smooth muscle cell
retarded ejaculation. Detumescence
Erection

Endothelium NOS
The potential of phosphodiesterase ACh

type 5 inhibitors in treating lower

PGE1
urinary tract symptoms
Figure 18.2 Cavernosal smooth muscle tone is the prime
The history and clinical efficacy of PDE-5 inhibitors in determinant of the degree of erection; smooth muscle relaxation
the treatment of ED has been well documented since the produces tumescence and rigidity, whereas detumescence
arrival of sildenafil onto the marketplace a decade ago (see occurs subsequent to smooth muscle relaxation. The predominant
Chapters 30–32). Not surprisingly, being the prototype of a neurotransmitter pathways are the sympathetic noradrenergic
new mechanistic class, sildenafil and its more recent clones, and non-adrenergic (NANC) pathways. Nitric oxide (NO)
tadalafil and vardenafil, have been subsequently more widely released from the latter activates the intracellular enzyme
cascade culminating in relaxation of the corporal smooth
evaluated for other potential clinical utilities; indeed PDE-5
muscle. Acting in apposition to this is the sympathetic nervous
inhibitors are now also approved in several countries for the system; noradrenaline (NA; norepinephrine) released from
treatment of pulmonary hypertension. nerve terminals acts on postjunctional alpha-1-adrenoceptors
The PDE-5 isozyme is fairly widely and yet discretely distri- to produce detumescence. Other transmitter substances
buted within the urogenital sinus. This is covered in much more or neuromodulators, particularly acetylcholine (Ach) and
detail in Chapter 28. Perhaps not surprisingly, therefore, sev- prostaglandin E1 (PGE1), can directly or indirectly alter smooth
eral preclinical and clinical studies have been undertaken on muscle tone. NOS = NO synthase.
146 Textbook of Erectile Dysfunction

which is consistent with its general vasoactivity in vascular In the future, there may be certain situations, particularly
resistance vessels. In physiological terms, such a profile would in patients with comorbid BPH and ED, in which PDE-5
be indistinguishable from that of an alpha-blocker. Given this inhibitor monotherapy could have a role to play in a holistic
potential functional equivalence, PDE-5 inhibitors would be approach to managing the BPH patient. However, it should
expected to have a similar clinical profile to alpha-blockers be remembered that no PDE-5 inhibitor is approved by
such as alfuzosin and doxazosin and, based on the human the regulators for treating BPH and also that there could
in vitro work (see above), perhaps to have a greater effect on be considerable cost implications of daily PDE-5 inhibitor
irritative symptomatology. In several well-designed clinical administration.
trials, it has become apparent that although there is a clinically Cost considerations would also seem to rule out widespread
significant effect on IPSS there is either little or no accompa- use of combination therapy with alpha-blockers and PDE-5
nying urodynamic change and, where there is such a change, inhibitors, as would the potential for augmentation of vascu-
it is not correlated with changes in symptoms. Overall the lar side-effects. For these reasons, the clinical utility of PDE-5
degree of improvement in IPSS was equivalent to that of inhibitors, to a large extent predictable from the basic molec-
alpha-blockers but, importantly from the point of view of ular and pharmacological activities, may not progress beyond
clinical benefit, reached the level (>3) considered to be likely being of academic interest.
to be perceived by patients as an advantage. The limitations of
the IPSS, designed to capture the overall LUTS symptom
complex rather than individual components, preclude the Summary
drawing of any meaningful conclusion about a preferential
effect on irritative versus obstructive symptoms. Although the Many BPH patients have comorbid LUTS and ED, which
overall clinical profile was not quite as expected, the degree of should be taken into consideration in the selection of appro-
symptomatic improvement was encouraging and would priate therapy. Several of the drugs used in the treatment of
appear to warrant further clinical evaluation. LUTS can have an adverse event on sexual function (e.g. finas-
The precise relationship between LUTS and ED is receiving teride, dutasteride, and tamsulosin). Most of the other
increasing attention because both are common, are often approved alpha-blockers have little effect on sexual function
co-associated, and have considerable impact on quality of life. (prazosin and terazosin) or may have slightly beneficial effects
As summarized elsewhere, there is evidence of potential (alfuzosin and doxazosin).
pathophysiology linking both dysfunctions. The most intri- As might have been anticipated from isozyme distribution
guing concepts based on the vascular activity of drugs effec- studies and their action as functional sympatholytics, the
tive in both LUTS and ED, is that the clinical manifestations PDE-5 inhibitor class does have a beneficial effect on LUTS.
could be secondary to local ischemia within the target organs. Paradoxically, the improvement in LUTS is achieved in the
Paradoxically, it seems that alpha-blockers, which appear to absence of any obvious urodynamic changes. Although it is
improve vascular perfusion within the bladder, also improve tempting to conclude that PDE-5 inhibitors may become
uroflow in BPH patients whereas PDE-5 inhibitors, which the therapy of choice for the many men with comorbid
affect prostatic vascular perfusion, do not. LUTS and ED, cost considerations may preclude this. The
Overall, however, it remains unlikely that the observed cost of regulatory approval may prove an additional deterrent
clinical benefit of PDE-5 inhibitors in LUTS is secondary to pharmaceutical companies. As such, a branded PDE-5
to the psychological impact of improving erectile function. inhibitor may never reach the market place as approved
Further evidence for a direct action on the organs associated therapy for the treatment of BPH. We may have to wait until
with LUTS is that there is no absolute correlation between the first generic PDE-5 inhibitor arrives to circumvent cost
improvement in IIEF and improvement in IPSS. concerns.

REFERENCES

1. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms 6. AUA guideline on management of benign prostatic hyperplasia
and male sexual dysfunction: the Multinational Survey of the Aging (2003). Chapter 1: Diagnosis and treatment recommendations.
Male (MSAM-7). Eur Urol 2003; 44: 637–49. J Urol 2003; 170: 530–47.
2. Reggio E, de Bessa J, Jr., Junqueira RG, et al. Correlation between 7. Carbone DJ Jr., Hodges S. Medical therapy for benign prostatic
lower urinary tract symptoms and erectile dysfunction in men hyperplasia: sexual dysfunction and impact on quality of life. Int J
presenting for prostate cancer screening. Int J Impot Res 2007; 19: Impot Res 2003; 15: 299–306.
492–5. 8. Lepor H. The role of gonadotropin-releasing hormone antagonists
3. Ponholzer A, Temml C, Obermayr R, Madersbacher S. Association for the treatment of benign prostatic hyperplasia. Rev Urol 2006;
between lower urinary tract symptoms and erectile dysfunction. 8: 183–9.
Urology 2004; 64: 772–6. 9. Pinggera GM, Mitterberger M, Pallwein L, et al. alpha-
4. Berger AP, Deibl M, Leonhartsberger N, et al. Vascular damage Blockers improve chronic ischaemia of the lower urinary tract in
as a risk factor for benign prostatic hyperplasia and erectile dys- patients with lower urinary tract symptoms. BJU Int 2008; 101:
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5. Ponholzer A, Madersbacher S. Lower urinary tract symptoms and 10. Giraldi A, Wyllie M, Wagner G. Abanoquil, a new alpha-1 adre-
erectile dysfunction; links for diagnosis, management and treat- noceptor antagonist. In vitro and in vivo effect on erectile tissue.
ment. Int J Impot Res 2007; 19: 544–50. Int J Impot Res 2000; 12 Suppl 1: S37–40.
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11. Grimm RH, Jr., Grandits GA, Prineas RJ, et al. Long-term effects on 15. Andersson KE, Mulhall JP, Wyllie MG. Pharmacokinetic and pharma-
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19 Basic assessment of the patient with
erectile dysfunction
Roger S Kirby and Michael G Kirby

Introduction quantify the extent of ED. The two with the greatest facility
are those developed by O’Leary et al.1 and by Rosen et al.2
Erectile dysfunction (ED) has traditionally been one of those (Tables 19.1 and 19.2).
hidden conditions that has been ignored by patients and Although such questionnaires are undoubtedly valuable,
doctors alike. With the progressive increase in life expectancy, they do focus exclusively on the functional element of ED.
and with the increasing quality of health and life in older A more complex question is the extent to which sexual dys-
people, the number of men who suffer from ED is ever increas- function affects the quality of life; recently, Wagner et al.
ing. The advent of effective oral therapy and the publicity that addressed this important issue.3 Their questionnaire, developed
surrounded it brought ED into the public domain in a way following interviews with patients presenting with ED both in
that it had never been before, and as a result there are increas- the UK and the USA, is set out in Table 19.3.
ing numbers of men seeking treatment. The sexual experience questionnaire4 (Table 19.4) is a new
Traditionally therapy for ED was the domain of hospital instrument to assess patient-reported outcomes recording
specialists but it is increasingly clear that many men are best function, health-related quality of life, and satisfaction. Not-
managed in the community either by primary care physicians withstanding the value of these questionnaires, it is often help-
or by nurse specialists. Although therapy in the community ful to start a face-to-face interview with a brief explanation
is clearly desirable, there are a number of issues that have of the distinction between loss of libido, ED, and ejaculatory
thus far impeded such approaches. One of these issues is disturbance. By far the most common presenting complaint
education. is that of reduced rigidity of erections; less commonly, the
Over the past two decades, knowledge of the pathogenesis patient complains of a total absence of erectile activity. Inade-
of ED has expanded considerably and, with this, there has quate erection hardness will result in penile buckling or curving
been a parallel increase in the variety and complexity of inves- of the erection column about its neutral axis and thus failure
tigations employed to establish the cause of the disorder in the of penetration and the inability to achieve successful inter-
individual patient. However, despite the highly technological course. Quantitative assessment of erection hardness in the
diagnostic modalities now available, the basic principle taught clinical setting offers physicians a brief and easy means of
to every medical student – and one that is especially impor- monitoring response to ED therapy.5
tant in the evaluation of the man suffering from ED – must Enquiry should concentrate initially on this element of the
not be forgotten: that accurate diagnosis depends on a careful symptoms and their duration, as well as on the rapidity and
history and physical examination, the results of which are particular circumstances of onset. A key question is obviously
supplemented by tailored special investigations. Subsequent whether the impairment of erections is consistent, rather than
chapters dwell in some depth on the still evolving and increa- ‘situational’ with preservation of nocturnal and early-morning
singly sophisticated modalities of diagnosis used in ED, but in erections. Although the majority of physicians are now
this chapter the question of how the patient and his partner acquainted with the loose association between preservation of
should be initially assessed is addressed. the nocturnal and early-morning erections and psychogenic
impotence, most patients do not make this connection. A use-
ful guide to the severity of the problem is to enquire when
History penetrative intercourse was last possible – not uncommonly
the surprising reply is received, that this was accomplished
Because of the sensitive nature of the complaint of ED, it is only a few days ago!
of paramount importance to establish a relationship of trust Discreet enquiry should also be made as to whether the
between patient and clinician at an early stage. Building this problem is confined to sexual encounters with one partner or
rapport requires more time and patience than is usually whether it is also present with other partners. The partner’s
required in, for example, the assessment of a patient with attitude to the potency problem should also be established.
benign prostatic enlargement, and appointment schedules Questions about deviant sexual behavior or taboo practices
need to be adjusted accordingly. Recently, several formal symp- at this early stage, although relevant, risk compromising the
tom scores have been developed and validated, which aim to developing relationship between interviewer and patient.

148
 Basic assessment of the patient with erectile dysfunction 149

Table 19.1 A brief sexual function inventory. (From ref. 1, with permission)

SEXUAL DRIVE—Let’s define sexual drive as a feeling that may include wanting to have a sexual experience (masturbation or
intercourse), thinking about having sex or feeling frustrated due to lack of sex.

1. During the past 30 days, on how many days have No days Only a Some days Most days Almost
you felt sexual drive? few days every day
0 1 2 3 4
2. During the past 30 days, how would you rate your None at all Low Medium Medium High High
level of sexual drive?
0 1 2 3 4
ERECTIONS

3. Over the past 30 days, how often have you Not at all A few times Fairly often Usually Always
had partial or full sexual erections when you were
sexually stimulated in any way?
0 1 2 3 4
4. Over the past 30 days, how often have you had
erections; how often were they firm enough to have
sexual intercourse? 0 1 2 3 4
5. How much difficulty did you have getting an Did not get A lot of Some Little difficulty No
erection during the last 30 days? erections at all difficulty difficulty difficulty
0 1 2 3 4
EJACULATION

6. Over the past 30 days, how much difficulty have Have had A lot of Some Little difficulty No
you had in ejaculating when you have been no sexual difficulty difficulty difficulty
sexually stimulated? stimulation in
past month
0 1 2 3 4
7. In the past 30 days, how much did you consider Did not climax Big Medium Small problem No
the amount of semen you ejaculate? problem problem problem
0 1 2 3 4
PROBLEM ASSESSMENT
8. In the past 30 days, to what extent have you Big problem Medium Small Very small No
considered a lack of sex drive to be a problem? problem problem problem problem
0 1 2 3 4
9. In the past 30 days, to what extent have you
considered your ability to get and keep an erection
a problem? 0 1 2 3 4
10. In the past 30 days, to what extent have you
considered your ejaculation to be a problem? 0 1 2 3 4
OVERALL SATISFACTION
11. Overall, during the past 30 days, how satisfied Very Mostly Neutral or Mostly Very
have you been with your sex life? dissatisfied dissatisfied mixed satisfied satisfied
0 1 2 3 4

Although libido is usually preserved in men presenting with The previous medical history should include a brief survey
ED, inevitably increasing the psychological frustrations of of sexual history, which may provide a clue to a congenital
the patient, a decline of sexual drive may suggest an endo- problem, due perhaps to a veno-occlusive disorder or congeni-
crinological cause of the problem and this should be carefully tal chordee. Previous surgery, especially pelvic surgery for
documented. Ejaculation is much less commonly affected bowel, bladder, or prostatic malignancy, reconstructive vas-
than erection itself, but enquiry should be made as to whether cular surgery, or renal transplantation, may obviously be
ejaculation is premature, delayed, dry (as commonly occurs relevant. Multi-system disorders may result in impotence and
following transurethral resection of the prostate), or absent can sometimes present with this symptom. Hypertension
altogether. and diabetes mellitus are by far the most common of these
150 Textbook of Erectile Dysfunction

Table 19.2 Individual items of International Index of Erectile Function (IIEF) Questionnaire and response options
(US version). (From ref. 2, with permission).

Question* Response options

Q1: How often were you able to get an erection during sexual 0 = No sexual activity
activity? 1 = Almost never/never
Q2: When you had erections with sexual stimulation, how 2 = A few times (much less than half the time)
often were your erections hard enough for penetration? 3 = Sometimes (about half the time)
4 = Most times (much more than half the time)
5 = Almost always/always
Q3: When you attempted sexual intercourse, how often were 0 = Did not attempt intercourse
you able to penetrate (enter) your partner? 1 = Almost never/never
Q4: During sexual intercourse, how often were you able to 2 = A few times (much less than half the time)
maintain your erection after you had penetrated (entered) 3 = Sometimes (about half the time)
your partner? 4 = Most times (much more than half the time)
5 = Almost always/always
Q5: During sexual intercourse, how difficult was it to maintain 0 = Did not attempt intercourse
your erection to completion of intercourse? 1 = Extremely difficult
2 = Very difficult
3 = Difficult
4 = Slightly difficult
5 = Not difficult
Q6: How many times have you attempted sexual intercourse? 0 = No attempts
1 = One to two attempts
2 = Three to four attempts
3 = Five to six attempts
4 = Seven to ten attempts
5 = Eleven + attempts
Q7: When you attempted sexual intercourse, how often was it 0 = Did not attempt intercourse
satisfactory for you? 1 = Almost never/never
2 = A few times (much less than half the time)
3 = Sometimes (about half the time)
4 = Most times (much more than half the time)
5 = Almost always/always
Q8: How much have you enjoyed sexual intercourse? 0 = No intercourse
1 = No enjoyment
2 = Not very enjoyable
3 = Fairly enjoyable
4 = Highly enjoyable
5 = Very highly enjoyable
Q9: When you had sexual stimulation or intercourse, how 0 = No sexual stimulation/intercourse
often did you ejaculate? 1 = Almost never/never
Q10: When you had sexual stimulation or intercourse, how 2 = A few times (much less than half the time)
often did you have the feeling of orgasm or climax? 3 = Sometimes (about half the time)
4 = Most times (much more than half the time)
5 = Almost always/always
Q11: How often have you felt sexual desire? 1 = Almost never/never
2 = A few times (much less than half the time)
3 = Sometimes (about half the time)
4 = Most times (much more than half the time)
5 = Almost always/always
Q12: How would you rate your level of sexual desire? 1 = Very low/none at all
2 = Low
3 = Moderate
4 = High
5 = Very high

∗All question are preceded by the phrase “Over the past 4 weeks”.

(Continued )
 Basic assessment of the patient with erectile dysfunction 151

Table 19.2 Continued

Question* Response options

Q13: How satisfied have you been with your overall sex life? 1 = Very dissatisfied
Q14: How satisfied have you been with your sexual 2 = Moderately dissatisfied
relationship with your partner? 3 = About equally satisfied and dissatisfied
4 = Moderately satisfied
5 = Very satisfied

Q15: How do you rate your confidence that you could get 1 = Very low
and keep an erection? 2 = Low
3 = Moderate
4 = High
5 = Very high

∗All question are preceded by the phrase “Over the past 4 weeks”.

(and the family history may provide a clue), but alcoholism,

Table 19.3 QOL-MED questionnaire: item list
thyroid dysfunction, hemochromatosis, and other systemic
1. I feel frustrated because of my erection problem disorders should be borne in mind (Table 19.6).
2. My erection problem makes me feel depressed Of the neurological disorders that may cause ED, multiple
3. I feel like less of a man because of my erection sclerosis is the most frequently encountered, but ED is seldom
problem a presenting feature of the disease. Another diffuse disease
4. I have lost confidence in my sexual ability affecting the central nervous system, however, may produce
5. I worry that I won’t be able to get or keep an ED as its earliest presenting manifestation: this disease, origi-
erection nally known as the Shy–Drager syndrome but now more com-
6. My erection problem is always on my mind monly termed multiple system atrophy (MSA), is characterized
7. I feel that I have lost control over my erections by selective degeneration of autonomic neurons in the central
8. I blame myself for my erection problem
nervous system (CNS). In this disorder there is progressive
9. I feel angry because of my erection problem
10. I worry about the future of my sex life
selective cell loss from the pons, medulla, and cerebellum, as
11. I have lost pleasure in sex because of my erection well as degeneration of the neurons of the intermediolateral
problem cell column of the thoracolumbar sympathetic outflow and
12. I am embarrassed about my problem sacral parasympathetic outflow (Figure 19.1). The condition
13. I worry about being humiliated because of my affects patients in their middle age, with a male–female ratio
problem of 2:1. In the male, ED is accompanied by frequency and
14. I try to avoid having sex urgency of micturition, which may be confused with bladder
15. I feel different from other men because of my erection outflow obstruction resulting from benign prostatic enlarge-
problem ment. An important sign that may provide a clue to this some-
16. I get less enjoyment out of life because of my erection times elusive diagnosis is postural (orthostatic) hypotension,
problem
caused by impaired sympathetic vasoconstrictor tone, and
17. I feel guilty about my erection problem
18. I am afraid to ‘make the first move’ towards sex
this can usually be demonstrated on measuring blood pres-
19. I worry that my partner blames herself for my erection sure in the standing and lying positions.6
problem The vascular endothelium provides the source of the critical
20. I worry about letting her down because of my erection association between ED and cardiovascular events, because
problem it plays a vital role in regulation of the circulation. Hyper-
21. I worry that I’m not satisfying her because of my tension, ischemic heart disease, and hypercholesterolemia
erection problem can all lead to abnormalities of the vascular smooth muscle
22. I worry that we are growing apart because of my cells and the extracellular matrix. This endothelial cell dysfunc-
erection problem tion can precede the formation of atherosclerotic plaques and
23. I worry that she is looking for someone else because of is common in cardiovascular disease (CVD) and diabetes.7
my problem
Patients with diabetes have endothelial dysfunction and
24. I feel that she blames me for my erection problem
25. I worry that she thinks I don’t want her because of my
an increased risk of developing cardiovascular complications.
erection problem Impaired endothelium-dependent vasodilatation via nitric
26. I have trouble talking to her about my problem oxide (NO) is also well documented in coronary artery dis-
27. My erection problem interferes with my daily ease and in conditions such as diabetes, hypertension, and
activities dyslipidemia.8
ED can also provide an important measure of CVD pro-
(Reproduced from ref. 3 with permission.)
gression and severity. For example, patients with single-vessel
152 Textbook of Erectile Dysfunction

Table 19.4 Sexual experience questionnaire (Sex-Q)4

Instructions

For each of the following questions, place an ‘X’ in the one box that best describes your answer.

Over the past 4 weeks

1. How often were you able to maintain an erection for as long as you wanted to?
Never or almost never Rarely Sometimes Usually Always or almost
always
□ □ □ □ □
2. During sexual intercourse, how often were you able to penetrate your partner?
Never or almost never Rarely Sometimes Usually Always or almost
always
□ □ □ □ □
3. How much have you worried about whether you could get an erection?
Not at all worried A little worried Somewhat worried Very worried Extremely worried
□ □ □ □ □
4. How confident were you that you could get an erection when you wanted to?
Not at all confident A little confident Somewhat confident Confident Very confident
□ □ □ □ □
5. How satisfied were you with the hardness of your erections?
Very dissatisfied Dissatisfied Equally satisfied and Satisfied Very satisfied
dissatisfied
□ □ □ □ □
6. How satisfied were you with the duration of your erections?
Very dissatisfied Dissatisfied Equally satisfied and Satisfied Very satisfied
dissatisfied
□ □ □ □ □
7. How satisfied were you with your level of sexual desire?
Very dissatisfied Dissatisfied Equally satisfied and Satisfied Very satisfied
dissatisfied
□ □ □ □ □
8. How satisfied were you with your overall sexual activity?
Very dissatisfied Dissatisfied Equally satisfied and Satisfied Very satisfied
dissatisfied
□ □ □ □ □
9. How much pleasure did you get from sexual activity?
No pleasure Little pleasure Some pleasure Much pleasure Great pleasure
□ □ □ □ □
10. How confident were you that you could satisfy your partner during sexual activity?
Not at all confident A little confident Somewhat confident Confident Very confident
□ □ □ □ □
11. How often did you achieve mutual satisfaction with your partner?
Never or almost never Rarely Sometimes Usually Always or almost
always
□ □ □ □ □
12. How satisfied were you with your ability to control the timing of your ejaculations?
Very dissatisfied Dissatisfied Equally satisfied and Satisfied Very satisfied
dissatisfied
□ □ □ □ □
 Basic assessment of the patient with erectile dysfunction 153

Table 19.5 Erection hardness score Table 19.6 Continued

0 Penis does not enlarge Abnormalities of hypothalamopituitary function
Congenital
1 Penis is larger but not hard
LH-FSH deficiency (Kallmann’s syndrome)
2 Penis is hard but not hard enough for penetration Congenital hypogonadotrophic hypogonadism
3 Penis is hard enough for penetration but not Panhypopituitarism
completely hard Acquired
Trauma, infiltrative disease, tumors of pituitary, etc.
4 Penis is completely hard and fully rigid Exogenous hormones
How would you rate the hardness of your erection? Hyperprolactinemia
Primary gonadal abnormalities
Chromosomal abnormalities (e.g. Klinefelter’s syndrome)
Table 19.6 Organic causes of erectile dysfunction Bilateral anorchia
Gonadal toxins
Congenital deformities Drug-induced gonadal damage (chemotherapeutic agents)
Epispadias Gonadal injury (trauma/mumps/torsion)
Hypospadias
Congenital chordee
Microphallus
Mechanical
Morbid obesity
Peyronie’s disease
Bilateral hydrocele
Phimosis
Tethered frenulum
Carcinoma of penis
Postsurgical
Cystectomy, urethrectomy
Radical prostatectomy
Abdominoperineal resection of rectum
Low anterior resection of rectum
Rectal pull-through procedures
Transurethral resection of prostate
External sphincterotomy
Vascular insufficiency
Aorto-iliac disease (Leriche syndrome)
Internal iliac atheroma
Atheroma of pudendal vessels
Distal vessel disease
Post-priapism
Smoking
Anemia
Veno-occlusive dysfunction
Post-pelvic fracture
Metabolic disorders
Diabetes mellitus
Hemochromatosis
Alcoholism Figure 19.1 A section through the spinal cord of a man who
Sickle-cell disease suffered from multiple system atrophy. There is selective loss of
Hepatic/renal failure cell bodies from Onuf’s nucleus.
Scleroderma
Thyroid disease
Adrenal disease ischemic heart disease have firmer erections and less difficulty
Neurogenic disorders in obtaining an erection than those patients with two- or
Multiple system atrophy three-vessel disease,9 the penis thereby acting as a barometer
Spinal cord lesions of cardiovascular status.
Multiple sclerosis
Tabes dorsalis
Peripheral neuropathies Early identification of coronary heart disease risk
Spina bifida A study of a group of healthy men complaining of ED found
Amyotrophic lateral sclerosis
that 60% had abnormal cholesterol levels, and >90% showed
(Continued ) evidence of penile arterial disease during Doppler ultrasound
154 Textbook of Erectile Dysfunction

imaging.10 In another study it was discovered that 80% of

asymptomatic males with ED displayed at least one risk factor Table 19.7 Pharmacological agents associated with
for CVD. Patients who subsequently underwent coronary erectile dysfunction
angiography were found to have significant coronary artery
Major tranquillizers
disease, with over half diagnosed with multi-vessel disease.11
Phenothiazines, e.g. fluphenazine, chlorpromazine,
Therefore, routine investigations into the ED patient’s cardio- promazine, mesoridazine
vascular status can aid the identification of previously undiag- Butyrophenones, e.g. haloperidol
nosed CVD. Thiorxanthines, e.g. thiothixene, chorprothixene

Antidepressants
Tricyclics, e.g. nortriptyline, amitriptyline, desipramine,
Drug history doxepin
MAO inhibitors, e.g. isocarboxazide, phenelzine,
A detailed history of all concomitant medications is impor-
tranylcypromine, pargylene, procarbazine
tant in the evaluation of patients with ED, since many pharma- Lithium
cological agents may be associated with problems of potency
(Table 19.7). Often, it is difficult to decide whether it is the Anxiolytics
drug itself or the condition for which it is being administered Benzodiazepines, e.g. chlordiazepoxide, diazepam,
(e.g. hypertension) that has caused the symptom. chlorazepate
Antihypertensive agents have often been cited as the most Anticholinergics
common medication-related cause of ED.12 Clonidine, methyl- Atropine
dopa, and reserpine, all of which share a centrally acting sym- Propantheline
patholytic effect, are associated with an incidence of ED in Benztropine
about one-quarter to one-third of patients treated, but these Dimenhydrinate
agents are now seldom used therapeutically. The precise Diphenhydramine
mechanism by which they impair potency is unclear, but they
Cardiac
probably directly reduce libido by a central effect, and they
Digoxin
may also elevate serum prolactin levels. Peripherally acting Lipid-lowering agents
alpha-adrenoceptor blockers, such as phenoxybenzamine
(which produces mixed alpha-1 and alpha-2 blockade) and Antihypertensives
the newer alpha-1-selective adrenoceptor blockers, prazosin, Diuretics, e.g. thiazides, spironolactone
doxazosin, and terazosin, are less commonly associated with ED. Vasodilators, e.g. hydralazine
In fact, from their vasodilator action on cavernosal vessels, Central sympatholytics, e.g. methylodopa, clonidine,
one might expect their effect to be mildly beneficial. How- reserpine
Ganglion blockers, e.g. guanethidine,
ever, by blocking the sympathetically mediated closure of the
bethanidine
bladder neck at the time of ejaculation, they may occasionally Beta-blockers, e.g. propranolol, metoprolol,
produce retrograde ejaculation. Indeed, the alpha-1A-selective- atenolol
adrenoceptor blocker tamsulosin seems to be particularly Calcium-channel blockers
potent in this respect.13 In the Treatment of Mild Hyperten- ACE inhibitors
sion Study (TOMHS), most classes of antihypertensive agent
(diuretic, beta-blocker, angiotensin-converting enzyme inhibi- Recreational drugs
tor, and calcium-channel blocker) were associated with a Alcohol
Marijuana
higher incidence of sexual dysfunction than placebo.14 By con-
Amphetamines
trast, the alpha-1-adrenoceptor blocker doxazosin appeared Barbiturates
less likely than placebo to produce this effect, suggesting Nicotine
a beneficial action of reduced alpha-1-adrenoceptor tone Opiates
(Figure 19.2). The angiotensin receptor blocking drugs may
have significant advantages. Fogari et al. have demonstrated Anti-androgenic
that valsartan may have a beneficial effect on ED.15 Cyproterone acetate
In other studies, beta-adrenoceptor blockers have often Flutamide
Casodex
been reported to cause ED (especially at higher doses), directly
LHRH analogs
by a peripheral action on the corporal tissue and also perhaps Estrogens
by a central effect on libido.16 Their ability to penetrate 5-alpha-reductase inhibitors
the CNS and induce a sympatholytic effect depends on their
lipid solubility. Newer beta-blockers, such as atenolol, are less Miscellaneous
lipid-soluble and seem to cause less impairment of sexual Cimetidine
function. Clofibrate
Diuretics have also been linked with ED: in particular, Metoclopramide
Baclofen
spironolactone has been reported to induce gynecomastia,
Indometacin
ED, and reduced libido in some patients,17 and vasodilators (+ many others)
such as hydralazine also seem to produce ED.18
 Basic assessment of the patient with erectile dysfunction 155

100 100
25 25
20 20
Percent

15.7

Percent
15.7
15 15
10 7.9 6.7 10 7.9
6.5 4.9 6.7 6.5 4.9
5 2.8 5 2.8
0 0
Acebutolol Amlodipine Chlorthali- Doxazosin Enalapril Placebo Acebutolol Amlodipine Chlorthali- Doxazosin Enalapril Placebo
(n=72) (n=59) done* (n=70) (n=71) (n=61) (n=118) (n=72) (n=59) done* (n=70) (n=71) (n=61) (n=118)
Treatment group Treatment group
*p = 0.01 vs placebo; p across drug groups 0.05 *p = 0.01 vs placebo; p across drug groups 0.05

(a) (b)

Figure 19.2 Impact of various classes of antihypertensive therapy on erectile function as reported in the TOMHS study.14 Incidence
of men reporting (a) an inability to obtain erection, (b) an inability to maintain erection, by treatment group (24 months).

Clinical experience confirms that certain antihypertensive ED by several mechanisms: these include peripheral neuro-
drugs affect not only the blood pressure, but also compliance pathy, testicular dysfunction, and an effect on the hypo-
of the erectile tissue, resulting in a functional venous leak. thalamopituitary axis, as well as impaired hepatic function
This may impair erectile function as much as arteriosclerotic resulting in increased serum estrogen levels.26 Even moderate
changes of the vascular system secondary to hypertension.19 doses of alcohol may impair erectile function (although, frus-
It must be remembered that, in some patients with partial tratingly, they also increase libido). As a consequence, patients
vasculogenic ED, high systolic arterial pressures may be with potency problems should usually be advised to reduce
required to achieve sufficient cavernosal artery flow for erec- their alcohol consumption, as well as to refrain from cigarette,
tion. Lowering blood pressure into the normal range in itself cigar, and pipe smoking.
may, therefore, compromise penile blood flow to some extent
and induce or exacerbate ED.20
Many major and minor tranquilizers and hypnotics have Physical examination
been reported to cause both diminished libido and ED.21 Anti-
depressants such as monoamine oxidase inhibitors and tricy- A thorough physical examination is an important part of the
clic compounds may cause ED, probably by decreasing libido. basic assessment of the man with ED; care should be taken to
The minor tranquillizers or anxiolytic agents, particularly the look for clinical signs of thyroid underactivity or overactivity,
benzodiazepines, exert a depressive effect on the brainstem, as well as stigmata of liver failure or anemia. Hypertension
limbic system and septal region; libido can also be reduced and other serious cardiovascular pathology must also be
and ED may follow. Meprobamate, barbiturates, and other excluded. All peripheral pulses should be palpated and any
sedative hypnotics all exert a central effect similar to that cardiac murmurs or arrhythmias identified. A focused neuro-
of the benzodiazepines, with consequent effects on erectile logical examination is valuable, with special attention being
function and libido. paid to the sacral spinal outflow. Saddle anesthesia, with loss
Drugs with anti-androgenic activity, such as ketoconazole, of bulbocavernosus reflex in combination with a lax anal
cyproterone acetate, and the histamine receptor blocker sphincter, may suggest the presence of an occult cauda equina
cimetidine,22 are known to cause diminished potency; how- lesion. This disorder may occasionally present with ED as a
ever, interestingly, bicalutamide and flutamide, which are result of a central prolapse of an intervertebral disc or a slow-
pure anti-androgens, seem to spare, in relative terms, both growing lumbar or sacral intraspinal tumor.
potency and libido, while still effectively blocking androgen Examination of the external genitalia should be performed
receptors. This effect has been suggested to be the result of with a view to excluding congenital or acquired abnormalities
elevated serum testosterone levels. The luteinizing hormone of the penis itself. Peyronie’s plaques should be sought along
releasing hormone analogs, such as goserelin and leuprolide, the palpable length of the corpora, and the patient should be
induce medical castration and are almost always associated questioned about the presence of pain on intercourse or
with ED, as well as with profound suppression of libido. By erectile deformity. Preputial abnormalities, such as tethering
contrast, 5-alpha-reductase inhibitors produce ED and loss of the frenulum or phimosis, may occasionally present with
of libido in only 3–5% of patients.23 This suggests that testos- ED, as may a spectrum of other genital abnormalities, includ-
terone, rather than its 5-alpha-reduced form dihydrotestos- ing microphallus, epispadias, and squamous cell carcinoma of
terone, is mainly responsible for the maintenance of erectile the penis. The presence of small testes and reduced or absent
function and libido. secondary sexual characteristics may suggest hypogonadism,
Recreational drugs such as marijuana and, especially, and it is worth enquiring about the frequency of necessity for
cocaine and heroin24 may also cause impotence and reduce facial shaving, as this may decline with androgen insufficiency.
libido, and are associated with a reduction of testosterone The anterior chest wall should be examined to exclude gyne-
levels. Cigarette smoking, probably by virtue of its vasocon- comastia, and enquiry should be made about galactorrhea.
stricting effect or by the induction of atheroma, has also been Causes of primary hypogonadism and testicular failure are
reported to cause impaired potency.25 Alcoholism may induce listed in Table 19.6; when any of these are present they
156 Textbook of Erectile Dysfunction

are usually an indication for referral for specialist endocrine

opinion.
Digital rectal examination should be performed in men
with ED to assess prostatic size and consistency. If the pres-
ence of benign prostatic enlargement is detected, a urinary
flow rate should be determined and the patient warned that
androgen therapy may risk exacerbation of bladder outflow
obstruction. The presence of prostatic nodules should raise
the possibility of early prostatic cancer and a prostate-specific
antigen (PSA) value should usually be measured, at least in
men over the age of 45. If the level of this marker is raised, a
prostatic biopsy under transrectal ultrasound control may be
necessary; in these circumstances, androgen replacement
therapy is contraindicated, at least until adenocarcinoma of
the prostate is excluded.

Special investigations
Figure 19.3 A CT scan demonstrating a craniopharyngioma in
Investigation of the male patient with ED must, obviously, be a man presenting with hyperprolactinemia resulting in ED. The
tailored specifically to the individual concerned and any leads patient also complained of headaches and visual disturbances.
given by the history or examination. Baseline hematological
and biochemical screens are necessary, which should exclude
diabetes mellitus. Also included are liver function tests to
exclude hepatic impairment, which may be associated with
increased serum estrogen levels and reduced plasma testos-
terone. The baseline values are also useful if papaverine or
hormone-replacement therapy is subsequently employed,
because of the occasional hepatotoxicity associated with these
treatments.
Estimation of serum hormone levels is expensive, and some
investigators suggest that a single measurement of serum
testosterone is all that is required.27 In occasional cases of
hyperprolactinemia, however, serum testosterone may be just
within normal limits, and a space-occupying lesion of the
pituitary fossa (Figure 19.3) is obviously something that must
not remain undetected.28,29 Many clinicians dealing with ED
routinely measure testosterone, prolactin, and sex hormone-
binding globulin. Patients with significant abnormalities of
serum testosterone or prolactin levels often respond well to
treatment.30 As discussed previously, a PSA value should be
obtained to assess the probability of the patient harboring an
incidental prostate carcinoma.
While sophisticated neurological testing is not possible in
the office setting and there are currently no accurate methods
for testing the autonomic nerve supply to the genitalia, bio-
thesiometry is an accurate measure of peripheral sensation and
Figure 19.4 The biothesiometer consists of a hand-held
can be applied to the penis (Figure 19.4). The biothesiometer
vibratory wand, a rheostat for control, and a measurement
tests vibratory sensation and can be compared with a normal gauge. From www.biothesiometer.com.
age-adjusted nomogram for standardization (Figure 19.5).
The sensation is first tested on the index fingers by applying
the vibrating wand lightly and increasing vibration frequency clinicians withhold this diagnostic test until the second visit, it
with the rheostat until first sensation. The procedure is is often convenient to employ a small test dose (1.25–2.5 µg)
repeated on the inner thighs, penile shaft, and finally the glans on the first attendance. Prior to administration of this com-
penis. Patients with peripheral neuropathy, penile nerve pound, the patient must be warned about the possibilities of
damage, and Peyronie’s disease will exhibit reduced sensation bruising (which is of little significance) and of a prolonged
for age. response (>6 hours), which must be treated by corporal
Often, the most valuable information obtained in an out- aspiration or intracorporal phenylephrine or other alpha-
patient or office setting is the assessment of response to inter- adrenergic injection within 6–8 hours. A signed consent form
cavernosal prostaglandin E-1 (PGE-1).31 Although some is useful, as well as a detailed description of whom to contact
 Basic assessment of the patient with erectile dysfunction 157

The second Princeton consensus on sexual dysfunction and

18 cardiac risk stated that the recognition of ED as a warning sign
16 of silent vascular disease has led to the concept that a man
Biothesiometry (Ave.)

14 with ED and no cardiac symptoms is a cardiac (or vascular)

12 patient until proved otherwise. Men with ED and other
10
cardiovascular risk factors should be counseled in lifestyle
8
modification.32
6
4
2
0
20 30 40 50 60 70
Conclusion
Age (years) The initial basic assessment of ED is of some importance,
because it is the main opportunity for the clinician to establish
Figure 19.5 A standard nomogram for vibratory sensation a rapport with the patient. This first meeting, if effectively and
and age was compiled by measurement of biothesiometry on sympathetically handled, can set this relationship on the
350 normal patients. (Courtesy of C Carson, MD.) course towards a successful outcome for the patient, the doctor,
and the partner.
and what to do should the erection fail to disappear sponta- With the advent of new, effective, non-invasive therapies,
neously. An absent or impaired response may be an indication such as intra-urethral PGE-1 and the phosphodiesterase type
for color Doppler scanning of the cavernosal and dorsal penile 5 inhibitors (sildenafil, vardenafil, and tadalafil) the history
arteries, with higher dosage of PGE-1 to exclude arterial insuf- and examination have assumed an even more important role
ficiency or venous leakage. This investigation is indicated in in ED, since many patients will wish to start therapy without
patients in whom reconstruction would be considered, and it proceeding with invasive investigations. However, the impor-
can be arranged before the second consultation. Further tance of excluding other important pathologies, such as
details of this and other special investigations for elucidating diabetes mellitus, hypertension, or pituitary tumor, should
the cause of impaired erectile potency are discussed in greater not be underestimated.
detail in subsequent chapters. In particular, Chapter 33 is Many of the issues raised in this chapter are addressed more
relevant, since there is increasing evidence that ED may act as extensively in subsequent chapters; however, as in most other
a harbinger of a cardiovascular event caused by more wide- areas of life, the need for special care and attention to detail at
spread atherosclerosis. More intensive testing to establish the outset of the process of diagnosis and treatment remains
cardiovascular risk may therefore be indicated. paramount.

REFERENCES

1. O’Leary MP, Fowler FJ, Lenderking WR, et al. A brief male 10. Billups K, Friedrich S. Assessment of fasting lipid panels and
sexual function inventory for urology. Urology 1993; 46: Doppler ultrasound testing in men presenting with erectile
697–706. dysfunction and no other medical problems. J Urol 2000;
2. Rosen RC, Riley A, Wagner G, et al. An International Index of 163: 147.
Erectile Function (IIEF): a multidimensional scale for assessment of 11. Pritzker MR. The penile stress test: a window to the heart of man?
erectile dysfunction. Urology 1997; 49: 822–30. Circulation 1999; 100: 3571.
3. Wagner TH, Patrick DL, McKenna SP, Froese PS. Crosscultural 12. Forsberg L, Gustavii B, Hojerback T, Olsson AM. Impotence,
development of a quality of life measure for men with erection smoking and orgasmic-ejaculatory response in human males. Fertil
difficulties. Qual Life Res 1996; 5: 443–9. Steril 1979; 31: 589.
4. Mulhall JP, King R, Kirby M, et al. Evaluating the sexual experience 13. Abrams P, Schulman CC, Vaage S. Tamsulosin, a selective alpha
in men: validation of the sexual experience questionnaire. J Sex 1c adrenoceptor antagonist: a randomized controlled trial in
Med 2008; 5: 365–76. patients with benign prostatic obstruction. Br J Urol 1995; 76:
5. Mulhall JP, Goldstein I, Bushmakin AG, Cappelleri JC, Hvidsten K. 325–36.
Validation of the Erection Hardness Score. J Sex Med 2007; 4: 14. Grimm RH, Gregory A, Prineas RJ, et al. Long-term effects on sex-
1626–34. ual function of five antihypertensive drugs and nutritional hygienic
6. Bannister R. Clinical features of progressive autonomic failure. In: treatment in hypertensive men and women. Hypertension 1997;
Bannister R, ed. Autonomic Failure. A Textbook of Clinical Dis- 29: 8–14.
orders of the Autonomic Nervous System, 2nd edn. Oxford: Oxford 15. Fogari, et al. Sexual activity in hypertensive men treated with
University Press, 1988: 267–88. valsartan or carvedilol: A crossover study. Am J Hypertensive
7. Kirby M, Jackson G, Betteridge J, Friedli K. Is erectile dysfunction 2001; 14: 27–31.
a marker for cardiovascular disease? Int J Clin Practice 2001; 55: 16. Horowitz JD, Gobel AJ. Drugs and impaired male sexual function.
614–18. Drugs 1979; 18: 206.
8. Quyyumi AA, Dakak N, Mulcahy D, et al. Nitric oxide activity in 17. Greenblatt DJ, Kochweser J. Gynaecomastia and impotence: com-
the artherosclerotic human coronary circulation. J Am Coll Cardiol plication of spironolactone. JAMA 1983; 223: 83–7.
1997; 29: 308–17. 18. Papadopoulos C. Cardiovascular drugs and sexuality. Arch Intern
9. Greenstein A, Chen J, Miller H, et al. Does severity of ischaemic Med 1980; 140: 1341.
coronary disease correlate with erectile function? Int J Impot Res 19. Müller SC, El-Damanhoury H, Rüth J, et al. Hypertension and
1997; 9: 123–6. impotence. Eur Urol 1991; 19: 29–34.
158 Textbook of Erectile Dysfunction

20. Wein AJ, Van Arsdalen K. Drug-induced male sexual dysfunction. 27. Pryor JL, Johnson AR, Jarrow JP. Editorial comment. Is routine endo-
Urol Clin North Am 1988; 15: 23–31. crine testing of impotent men necessary? J Urol 1992; 147:
21. Mitchell JE, Popkin MK. Antidepressant drug therapy and sexual dys- 1542–4.
function in men: a review. J Clin Psychopharmacol 1983; 3: 76–84. 28. McClure RD. Endocrine investigation and therapy. Urol Clin North
22. Pedan NR, Cargill JM, Browning MCK, et al. Male sexual dysfunc- Am 1987; 14: 471–88.
tion during treatment with cimetidine. Br Med J 1979; i: 659. 29. Leonard MP, Nickel CJ, Morales A. Hyperprolactinaemia and
23. Gormley G, Stoner E, Bruskewitz RC, et al. The effect of finasteride impotence: why, when and how to investigate. J Urol 1989; 142:
in men with benign prostatic hyperplasia. N Engl J Med 1992; 327: 992–4.
1185–91. 30. Carini C, Zini D, Balini A, et al. Effects of androgen treatment in
24. Mirin SM, Meyer RE, Mendelsohn JH, Ellinghoe J. Opiate use and impotent men with normal and low levels of free testosterone.
sexual function. Am J Psychiatry 1980; 137: 909. Arch Sex Behav 1990; 19: 223–34.
25. Shabsigh R, Fishman I, Schum C, Dunn JK. Cigarette smoking and 31. Stackl W, Hasun R, Marberger M. Intracavernous injection of pros-
other vascular risk factors in vasculogenic impotence. Urology taglandin E1 in impotent men. J Urol 1988; 140: 66–71.
1991; 38: 227–32. 32. Jackson G, Rosen RC, Kloner RA, et al. The second Princeton con-
26. Whalley LJ. Sexual adjustment of male alcoholics. Acta Psychiatr sensus on sexual dysfunction and cardiac risk: new guidelines for
Scand 1978; 56: 281–7. sexual medicine. J Sex Med 2006; 3: 28–36.
20 The contemporary role of penile
duplex scanning in sexual dysfunction
Gerald Brock and Anthony Bella

Introduction and background resulted, and the golden age of duplex scanning passed. Addi-
tionally, the reproducibility of duplex results was questioned.22,23
Advances in our understanding of which men develop sexual Cost, the reality that PDE-5 inhibitors would be effective
problems is a fairly recent phenomenon, aided by several large regardless of the etiology of ED, and the development of goal-
population-based studies, such as the Massachusetts Male oriented treatment algorithms that eliminated a diagnosis as
Aging Study and the Global Study for Attitudes and an essential part of the management approach all limited the
Behaviors.1–4 It can, however, be argued that the modern age role of ultrasound in ED.24
of erectile dysfunction (ED) management began with the Over the past decade a refined approach has developed
refined knowledge of the physiology of erection, based on the towards imaging in sexual medicine. Duplex Doppler ultra-
landmark studies from Krane, Goldstein, Lue and others in sound has proven its utility in predicting success for Peyronie’s
the 1980s using animal models and human volunteers.5–8 reconstructive surgery and in defining the potential for rever-
These studies investigated the cellular basis of erectile func- sibility of vascular insufficiency prior to proceeding to penile
tion and allowed for a greater appreciation of the fundamental implantation.25–28 Use of ultrasound scanning in cases of pria-
role played by relaxation of the cavernous smooth muscle in pism to define high flow or low flow is without question.29,30
initiating and maintaining erection. Early work in dog and Although the surgical management of venous leak remains
monkey models demonstrated the essential vascular nature of dubious, demonstration of high-end diastolic flow remains a
erection and the control mechanisms that fail in dysfunction. reliable indicator of veno-occlusive dysfunction and frequently
Subsequently proven in humans, the findings of these studies serves as the initial screening modality prior to the more inva-
served as the trigger that led to the development of multiple sive and costly testing with dynamic infusion cavernosometry
agents delivered through an intracavernous approach able to and cavernosography.31–33 Penile fracture, subtle forms of
restore erectile function to men with neurogenic and vascular Peyronie’s disease (including newly described variants) are
causes of their ED.9 often appreciated only with duplex scanning.34–36 Finally,
Among the most dramatic advances in ED management at among the population of men who wish to have a more com-
that time was the ability to visualize the vascular deficiency in plete understanding of the etiology of their condition, investi-
‘real time’ with equipment that was present in most large gations like duplex Doppler remain essential. This indication
hospitals and peripheral clinics. The ability to visualize peak has recently become more relevant as several reports have
cavernosal arterial pulse waves and determine the extent of linked ED of vascular origin as a potential harbinger of future
vascular insufficiency by means of duplex scanning was an eye cardiovascular events. The ability to define the extent of
opener to clinicians (Figure 20.1). The duplex scanner was a arterial insufficiency particularly in young men, may provide
quantum leap forward and proved to be an approach that clinicians with sufficient lead time (thought to be roughly
rapidly gained worldwide acceptance. Within a decade of its 3 years) to modify risks and thus avoid strokes and myocardial
first description,10,11 duplex Doppler penile ultrasound scan- infarcts.37–40
ning became an essential minimally invasive component of This chapter provides a critical contemporary review of
many ED assessment approaches. Technological improve- current indications and utility for duplex scanning in sexual
ments in equipment, the advent of color Doppler, and power dysfunction.
Doppler further added to the utility of these imaging machines.
Researchers worldwide using duplex scanners reported on
age-specific flow rates, novel diagnostic protocols, and clinical Peyronie’s disease and variants
scenarios in which ultrasound scanning was clinically
essential.12–20 Although initially described more than 250 years ago, Peyronie’s
The discovery and subsequent approval of phospho- disease remains an important clinical entity for physicians
diesterase type 5 (PDE-5) inhibitors for ED in the late 1990s who treat it and for the 2–7% of men who are affected by this
made vascular testing less relevant.21 Most clinicians recognized localized fibrosing condition. The classical description is one
rapidly that, although imaging provided information to the of a triphasic disease state, where initial pain transitions into
patient and clinician, in most cases no change in management penile deformity and subsequently stabilizes.41 Although the

159
160 Textbook of Erectile Dysfunction

(a) (b)

Figure 20.1 (a) Normal vascular response is seen in this longitudinal view of the corpora: peak flow >35 cm/seconds, rapid rise
time, and no end-diastolic flow is shown. (b) Impaired flow, with reduced peak flow and slower rise time.

true pathogenesis remains to be fully elucidated, many reports Priapism

describe early trauma and a delaminating series of events
generally related to sexual activity that lead to scarring of the Defined as persistent tumescence without sexual stimulation,
tunica albuginea.42 The penile shape change relies on the priapism is generally classified into low-flow (veno-occlusive)
normally compliant and elastic tunica albuginea becoming and high-flow (arterial) forms. This distinction is an impor-
rigid, inducing a curve towards the scar with erection. The tant one, since low-flow priapism is an ischemic process and
majority of men report a dorsal curve with a discrete palpable a medical emergency whereas high-flow arterial priapism
plaque. While only the most severely affected people generally is not. Management algorithms rely on clinical history, mea-
proceed to surgical therapy, use of minimally invasive intra- surement of intra-penile blood gases, and presenting com-
lesional approaches with verapamil and interferon has plaints to determine the pathogenesis; however, use of duplex
increased the need for localization of the plaque and physio- imaging is an integral component of evaluation in most
logic assessments of the penile anatomy. Novel approaches to cases.45
diagnosis and management of Peyronie’s disease have evolved While it is beyond the scope of this chapter to list the causes
over the past few years, with proteomics – the measurement and conditions associated with veno-occlusive ischemic pria-
of altered protein patterns within the tunica layers with various pism, urgent diagnosis and treatment with alpha-agonists or
stages of injury – being one.43 Peyronie’s disease may manifest shunting (or both) is essential to prevent long-term fibrosis
itself in a large number of variations, impacting on the tunica and ED. Figure 20.3 demonstrates the extent of localized
at the periphery or within the septum (Figure 20.2). fibrosis that often results from extended periods of low-flow
Several decision points in managing men with Peyronie’s priapism.
disease exist. Among those with disease requiring treatment, The less common subtype of priapism, high-flow arterial
localization of the plaque is generally possible with palpation priapism, is not a urologic emergency, and a complete evalua-
alone; however, subtle and evolving pathology may be realized tion using duplex scanning is often essential for optimal
only through imaging. Additionally, providing physiologic management. Recently, reports have demonstrated that this
data on cavernosal arterial flow and end-diastolic flow as an form of priapism is not as benign a condition as was initially
indicator of veno-occlusive dysfunction compliments the his- thought, with the long-term incidence of ED being significant.
tory of erectile capacity. Among men with Peyronie’s disease The etiology is usually a small tear in the cavernosal artery
who have poor erections, consideration of reconstruction is as a consequence of penile straddle injury, in which the
not recommended and a primary penile implant is our usual blunt trauma induces a flap and a high arterial fistula
approach.29,33 develops, with blood entering the cavernosal body without
Recently, there have been a number of reports describing limitation by the resistance vessels. This induces a non-
variants of Peyronie’s disease in which duplex scanning has ischemic process in which tumescence without full rigidity
been instrumental in their elucidation. Initially reported and exists.46,47
published by our group and subsequently supported by publi- The utility of the duplex scanner in this condition is
cations from Tom Lue and his colleagues, intraseptal scars and without question. It provides for a diagnosis, localizes the
discrete intra-penile injury may be detected in selected patients side and exact extent of the injury, and facilitates emboliza-
complaining of acute onset of pain. The ability to localize the tion via angiography. Additionally, in cases in which smaller
pathology and provide objective evidence of the source of injuries can be identified, conservative management may be
pain and deformity is often valued by the patients.34,44 warranted.
 The contemporary role of penile duplex scanning in sexual dysfunction 161

(a) (b)

(c) (d)

Figure 20.2 (a) A dorsal scar in Peyronie’s disease in a cross-sectional view. (b) A peri-spongiosal scar located at the ventral aspect.
(c) This septal scar was not palpable on digital exam in a young male patient complaining of penile pain but little deformity.
(d) Punctate calcifications. These are often only detectable on imaging.

Penile fracture
This uncommon penile injury is most often reported as a
consequence of direct axial pressure on an erect penis during
intercourse, resulting in a tear of the fibroelastic tunica.48 Pain
and a cracking sound are usually reported, with rapid hema-
toma formation at the site of injury. The tunica is thinnest at
the lateral aspects and this is the most frequent anatomical
location of the injury. Use of duplex scanning in cases of
penile fracture has been reported. The ability to define the
extent and location of the tunica albuginea tear and the state
of the cavernosal artery are key aspects determining the
management.49 Duplex scanning enables the disrupted tunica
to be easily localized and visualization of other injuries, such
as the spongiosum can also be assessed (Figure 20.4). Injury to
the spongiosum, although not common, has been reported
Figure 20.3 Corporal fibrosis following priapism. The ability with penile fracture, and it generally involves more extensive
to establish the extent of the penile scarring pre-operatively pelvic injuries, as defined recently by Wessells et al., whose
when a salvage implant is planned, can be essential in work has facilitated the prediction of spongiosal trauma
management. following pelvic trauma.50
162 Textbook of Erectile Dysfunction

Table 20.1 Duplex protocol

• Allow the patient to position himself in a quiet room

• Explain the steps to allow adequate relaxation and
reduce the potential for sympathetic tone to affect the
reliability and reproducibility of the test
• Scan to assess the cavernosal anatomy
• Describe the location of the cavernosal arteries and the
presence of any pathology, calcification, foreign material
(such as sutures) and tunical integrity
• If an oral PDE-5 inhibitor is used, this should be given to
reach a peak concentration at the time of the study. Use
of intracavernous injection followed by 5–30 minutes
of measurements with and without self-stimulation is
performed to allow for maximum cavernous smooth
muscle relaxation
• Measure arterial lumen diameter, flow, and resistance
Figure 20.4 Scan of a young patient who experienced penile values
pain during intercourse and was found to have a disruption of
• Prior to completion of the study, provide results and
his tunica. Primary repair was carried out.
assess to prevent priapism in cases in which intracaver-
nous injection was used
Diagnosis of penile conditions
with duplex scanning
been recently demonstrated through the ability to record
Duplex scanning provides elegant pictures and clinically changes in flow rate with improved health status.54 In situa-
relevant information on the responsiveness of both the arte- tions in which vascular surgery (either arterial or venous) is
rial and venous systems to vasoactive stimuli. Use of in-office being considered, a formal angiogram is appropriate. In most
vasoactive injection testing without imaging provides similar situations, however, the duplex scan provides adequate vascu-
information without the ability to comment on whether mild- lar testing.
to-moderate vascular disease exists. This is an important A wide variety of protocols exists for duplex scanning in
evolving area of sexual medicine, since recent reports have health and disease, although common themes across the many
linked early diagnosis of ED to future risks of cardiovascular reports exist. Initial assessment for anatomical integrity is
events. The presence of arterial vascular pathology of the followed by evaluation of cavernous smooth muscle relax-
cavernosal system in younger men (aged 30–50 years) has ation and determination of penile rigidity and deformity, if
been identified as an important independent risk factor for present (Table 20.1). Most protocols require between 10 and
cardiovascular disease.37,38 60 minutes and may necessitate a second intra-penile injection
In an attempt to minimize the degree of invasiveness of or redosing of the PDE-5 inhibitor to ensure that maximum
Doppler investigations, researchers have described a wide flow is measured, in an environment in which sympathetic
range of protocols using oral PDE-5 inhibitors as the arterial tone does not adversely effect results.
activator coupled to direct visual sexual stimulation and self-
stimulation. The classical approach of using intracavernous
vasoactive agents provides for an assessment of the arterial Conclusions
and venous systems isolated from their neural axis. The ability
to utilize oral agents is a breakthrough since it reduces the risk Duplex scanning equipment appropriate for penile indica-
of priapism, pain, and tissue injury as a consequence of the tions has advanced significantly over the past two decades
intra-penile injection.31,51 Timing of the PDE-5 inhibitor since the original reports of its utility in diagnosing male ED
should be optimized to allow scanning to be performed at the were published. Currently, there exists a wide range of sexual
peak concentration of the agent, coupled to direct self-stimu- concerns for which penile duplex scanning has value. Although
lation or visual sexual stimulation. At present the degree of initially described for use in determining cavernosal arterial
standardization (normal values) and reproducibility with oral flow as a means of arriving at a diagnosis, duplex scanning for
agents is not established to the same extent as it is with intra- this indication is less common today. The development of non-
cavernous injections.13,14,52 invasive therapies for sexual dysfunction has made the use of
Normative age-related cavernous artery flow rates have invasive diagnostic approaches less attractive as a component
been described for men following intracavernous vasoactive of the standard ED work-up.
injections.12 In general, peak arterial flows >30 cm/second Our enhanced understanding of the physiology of erection
with resistive indices >0.8 are considered normal. The ability coupled to evolving therapeutic approaches for sexual dys-
to predict success for subsequent therapy has recently been function has altered the positioning of duplex imaging in ED
reported and may further support the value of duplex scan- management over the past decade. While goal-directed
ning as part of the initial patient assessment in selected situa- approaches for ED management remain the cornerstone of care
tions.53 The sensitivity of a well-conducted examination has described in most ED guidelines worldwide, with investigations
 The contemporary role of penile duplex scanning in sexual dysfunction 163

of etiology generally listed as optional, imaging remains an • when penile prosthesis surgery for ED is planned, to
important tool for the specialist in selected situations. Duplex assess arterial function and so rule out a reversible
scanning remains clinically useful in: condition; and
• when greater understanding of the etiology is requested by
• suspected high-flow priapism, to determine the site of injury the patient and his partner.
and the side involved prior to angiographic embolization;
• in cases of penile trauma, to define the extent of penile The future of duplex imaging in specialty erectile clinics in
fracture and to establish cavernosal artery integrity; the management of the myriad of penile conditions outlined
• in Peyronie’s disease and its several variants, to arrive at above remains bright. It is cost-efficient and often irreplace-
a diagnosis, to provide prognostic information, to define able, directly altering treatment approaches. For these reasons
the extent of the disease, and to predict the likelihood it is likely to remain a vital tool for the busy specialist in sexual
of success; medicine in the years to come.

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and controls. Eur Urol 1992; 21: 22–6. 77: 189–90.
164 Textbook of Erectile Dysfunction

34. Bella AJ, Sener A, Foell K, Brock GB. Nonpalpable scarring of the 45. Berger R, Billups K, Brock G, et al. Report of the American Founda-
penile septum as a cause of erectile dysfunction: an atypical form tion for Urologic Disease (AFUD) Thought Leader Panel for evalu-
of Peyronie’s disease. J Sex Med 2007; 4: 226–30. ation and treatment of priapism. AFUD Thought Leader Panel
35. Cerone JS, Agarawal P, McAchran S, Seftel A. Penile fracture on Evaluation and Treatment of Priapism. Int J Impot Res 2001;
with isolated corpus spongiosum injury. Int J Impot Res 2006; 33: 13 Suppl 5: S39–43.
218–20. 46. Caumartin Y, Lacoursière L, Naud A. High-flow priapism: An over-
36. Bhatt S, Kocakoc E, Rubens DJ, Seftel AD, Dogra VS. Sonographic view of diagnostic and therapeutic concepts. Can J Urol 2006; 13:
evaluation of penile trauma. J Ultrasound Med 2005; 24: 3283–90.
993–1000. 47. Bivalacqua TJ, Burnett AL. Priapism: new concepts in the
37. Thompson IM, Tangen CM, Goodman PJ, et al. Erectile dysfunc- pathophysiology and new treatment strategies. Curr Urol Rep
tion and subsequent cardiovascular disease. JAMA 2005; 294: 2006; 7: 497–502.
2996–3002. 48. Kervancioglu S, Ozkur A, Bayram MM. Colour Doppler sono-
38. Grover SA, Lowensteyn I, Kaouache M, et al. The prevalence of graphic findings in penile fracture. J Clin Ultrasound 2004; 33:
erectile dysfunction in the primary care setting: importance of risk 38–42.
factors for diabetes and vascular disease. Arch Intern Med 2006; 49. Pandyan GV, Zaharani AB, Al Rashid M. Fracture penis: an analy-
166: 213–19. sis of 26 cases. Scientific World Journal 2006; 29: 2327–33.
39. Watts GF, Chew KK, Stuckey BG. The erectile-endothelial dysfunc- 50. Basta AM, Blackmore CC, Wessells H. Predicting urethral injury
tion nexus: new opportunities for cardiovascular risk prevention. from pelvic fracture patterns in male patients with blunt trauma.
Nat Clin Pract Cardiovasc Med 2007; 4: 263–73. J Urol 2007; 177: 571–5.
40. Heruti RJ, Uri I, Arbel Y, et al. Erectile dysfunction severity might 51. Baçar MM, Batislam E, Altinok D, Yilmaz E, Baçar H. Sildenafil
be associated with poor cardiovascular prognosis in diabetic men. citrate for penile hemodynamic determination: an alternative to
J Sex Med 2007; 4: 465–71. intracavernosal agents in Doppler ultrasound evaluation of erectile
41. Kovac JR, Brock GB. Surgical outcomes and patient satisfaction dysfunction. Urology 2001; 57: 623–6.
after dermal, pericardial, and small intestinal submucosal grafting 52. Shamloul R. Peak systolic velocities may be falsely low in
for Peyronie’s disease. J Sex Med 2007; 4: 1500–8. young patients with erectile dysfunction. J Sex Med 2006; 3:
42. Kadioglu A, Sanli O, Akman T, et al. Graft materials in Peyronie’s 138–43.
disease surgery: a comprehensive review. J Sex Med 2007; 4: 53. Huang ST, Hsieh ML. Different hemodynamic responses by
581–95. color Doppler ultrasonography studies between sildenafil non-
43. Domes T, De Young L, O’Gorman DB, et al. Is there a role for responders and responders. Asian J Androl 2007; 9: 129–33.
proteomics in Peyronie’s disease? J Sex Med 2007; 4: 867–77. 54. Sighinolfi MC, Mofferdin A, De Stefani S, et al. Immediate improve-
44. Brant WO, Bella AJ, Garcia MM, et al. Isolated septal fibrosis or ment in penile hemodynamics after cessation of smoking: previous
hematoma–atypical Peyronie’s disease? J Urol 2007; 177: 179–82. results. Urology 2007; 69: 163–5.
21 Imaging in erectile dysfunction
David Rickards

Introduction In cavernosometry, it is whether or not the plug goes in that

is being looked for and, in order to visualize potential leaks,
Vasculogenic causes account for up to 50% of erectile dys- contrast media is injected. First, however, the taps have to be
function (ED) patients. A number of techniques are available turned on with an injection of a vasoactive drug into the side
to investigate both the arterial and venous components of of the penis.
erection. Some have already fallen into disuse (e.g. the penile It is important to get the patient to relax as much as pos-
brachial index) and some have perhaps not achieved the sible, since anxiety compromises erectile response. Such a
popularity they deserve (e.g. radionuclide imaging). Color situation is not easily obtained considering the invasiveness of
Doppler ultrasound imaging is widely used to investigate arte- the procedure. The distal two thirds of the penis are swabbed
rial inflow, cavernosometry is used to investigate venous with antiseptic. Into one of the corpora cavernosa, an 18F
drainage, and, more recently, magnetic resonance imaging butterfly needle is inserted at a point between the proximal
(MRI) is being used to investigate underlying pathological two-thirds and the distal third of the penis. This is important
conditions associated with ED. This chapter deals with caver- because in the proximal penis there is a septum between
nosometry and MRI. the corpora, which is absent distally. This allows for bilateral
In my unit, patient selection for these studies is made by the perfusion of vasoactive drugs and contrast medium. Into the
referring urologist or andrologist. The vast majority of patients other corpus at the same level, a 21F needle is inserted. That
have already been investigated by non-radiological studies the needles are correctly sited is evidenced by blood refluxing
and the implications of those are that a vasculogenic cause is from them. If no blood is seen, a small amount of contrast
likely. can be injected under fluoroscopic control. If the needles are
correctly sited, the contrast will be seen to flow easily from the
tip of the needle. If not correctly sited, contrast will pool at
the end of the needle and the patient will experience a sharp
Cavernosometry localized pain.
The 21F needle is connected to a pressure transducer and
Little has changed in this procedure since it was first described the larger 18F needle is attached to a 250 ml bottle of contrast
in the 1980s. It is invasive and painful and it utilizes ionizing medium (urographin 150) via a pump (Figure 21.1).
radiation, contrast media, and vasoactive drugs. It is not a Through one of the needles, a vasoactive drug is injected,
procedure to subject a patient to lightly, and only those who usually, prostaglandin E-1 20 µg, but other can be used, such
might benefit and would agree to undergo venous surgery as papaverine 30–60 mg or trimix, a combination of papaver-
should be considered. Modern urodynamic equipment usually ine, phentolamine, and prostaglandin. Trimix should be used
comes with a dedicated cavernosometry program, which ren- only if the other two agents produce no effect. The smaller 21F
ders the procedure much safer because of pressure-sensitive needle is flushed with saline and that it is recording pressures
pumps that prevent unduly high pressures being generated is confirmed by gently squeezing the penis. Immediately after
within the cavernosa. Cavernosometry is only performed the vasoactive drug has been injected, the pressure transducer
once a penile Doppler has proved that there is no arterial is set to zero and the pressure is monitored and recorded.
insufficiency. Once the vasoactive drug starts to take effect, the pressure
within the corpora will start to rise. In pathological states,
the pressure won’t rise very much because of the patient’s
Technique impotence. Once it has risen and stabilized, the pump is
The patient is placed supine on a fluoroscopy table once the activated.
procedure has been explained and written consent has been Modern cavernosal packages will increase the rate at which
given. To explain the procedure, the analogy of filling a the pump instills contrast until a cavernosal pressure of
bath is useful. To fill a bath, the taps are turned on and the 100 mmHg or 120 cm water is achieved. The pump will then
plug inserted so the bath fills. The taps are the arteries, the automatically reduce its rate of infusion until a rate is found
plug the veins, and the bath the erectile tissues of the penis. at which the cavernosal pressure is maintained at 100 mmHg.

165
166 Textbook of Erectile Dysfunction

Figure 21.1 Schematic representation of cavernosometry. An

18F needle in one corpus is connected to a bottle of contrast
(Con) via a multi-speed pump (P). The other needle is connected
to a pressure recording device via a pressure transducer (T).

Figure 21.3 Venous leak seen on cavernosometry. A large

draining vein is identified (arrow), arising from the dorsal vein.

Figure 21.2 Contrast is seen within the corpora and no draining

veins can be identified in this cavernosometric image.

When contrast is being injected, the patient is turned into a

semi-oblique position and exposures are made of the base of
the corpora and the leaking veins identified.

Interpretation of results Figure 21.4 A number of veins (arrowed) can be seen in this
Where there is no leak, rates of less than 50 ml/min and a cavernosometric image, arising from the dorsal vein and the
maintenance flow rate of less than 5 ml/min are required to superficial crural veins.
induce a pressure of 100 mmHg. Films taken at the height of
erection will show a small amount of contrast within the cor-
pora and no draining veins can be identified (Figure 21.2). Complications
Venous leaks manifest themselves in two ways. Firstly, an Penile bruising is minimized by tight bandaging after the
infusion rate up to a maximum of 100 ml/minute eventually needles are removed. Contrast reactions are rare. Priapism
induces a cavernosal pressure of 100 mmHg, and a mainte- can be expected in 10% of patients.
nance flow rate of more than 25 ml/min is needed. Fluoro-
scopic images will show draining veins (Figures 21.3, 21.4).
Once all the relevant information has been gathered, tumes- Magnetic resonance imaging
cence induced is allowed to subside by allowing the needles to
freely drain. Once detumescence has occurred, the needles can MRI has been used to diagnose several penile disorders,
be removed. including damaged erectile tissue caused by fracture or other
 Imaging in erectile dysfunction 167

Figure 21.7 Low-signal lesion in the distal corpora cavernosa

as a result of a penile fracture.

Figure 21.5 MRI showing clear disruption of the tunica

albuginea in the mid-penile shaft.

Anatomy and technique

The corpora and spongiosum are of intermediate to high
signal intensity on T1-weighted sequences and high intensity
on T2-weighted sequences. The spongiosum has similar signal
intensity to that of the glans penis. High-resolution, small-
field-of-view, thin-slice T2-weighted sequences with fat sup-
pression in orthogonal planes using a surface coil are ideal.
The penis should be taped to the anterior abdominal wall.
Contrast enhanced scans are obtained using three-dimensional
fat-saturated gradient echo volumes with 30 second acquisi-
tions. All scans are performed following administration of intra-
cavernosal vasoactive drugs unless contraindicated (e.g. in sickle
call disease).

Penile trauma
Penile trauma is rare; when it does occur it is most commonly
experienced during intercourse or masturbation or by falling
on the erect penis. Unilateral rupture of the tunica albuginea
is usually the result of trauma and if not surgically repaired,
Figure 21.6 MRI showing clear disruption of the corpora
deformity and erectile dysfunction may occur. The diagnosis
cavernosa secondary to penile fracture.
of rupture of the tunica is made when there is disruption seen
in the tunica albuginea (Figure 21.5).
trauma and Peyronie’s disease. MRI is also useful in the Localization of the penile fracture (Figures 21.6, 21.7) is
investigation of the anatomy of the penile shaft and crurae useful to the surgeon, allowing smaller localized incisions to
and the internal pudendal and penile vessels. repair the fracture, rather than extensive degloving.
22 Neurophysiologic testing in
erectile dysfunction
Yoram Vardi and Ilan Gruenwald

Introduction spasticity is typical of pyramidal lesion (e.g. after a stroke

or in multiple sclerosis), and rigidity occurs in extra-
Erectile dysfunction (ED) in patients with neurological dis- pyramidal disorders (e.g. Parkinson’s disease).
orders that affect the central nervous system (CNS) or peri-
pheral nervous system (PNS) is often suspected to be neurogenic.
Whilst medical history and clinical examination provide the Sensory examination
basis for diagnosis of neurogenicity of ED, a large variety of The sacral-innervated area includes the buttocks, the peri-
tests are available to the clinician for further evaluation. Tests neum, the penis, the scrotum, the posterior parts of the thighs,
can be classified into those detecting somatic motor pathways, and the plantar and lateral dorsal parts of the foot. Sensory
sensory pathways, reflexes, and autonomic responses. How- examination should identify the presence of sensory loss.
ever, despite the variety of tests, diagnosis of neurogenic Further, sensory examination can distinguish disorders of
etiology for sexual dysfunction in clinical practice is not a large nerve fibers from disorders of small nerve fibers. Large
simple task. fibers affect the sensations of touch, vibration, and joint posi-
A major difficulty in the use of neuropsychological tests tion. Touch can be examined using cotton or a finger, and
to diagnose the neurogenic etiology of ED is the lack of a vibration can be tested by using a 128 Hz vibrating fork. A dis-
‘gold standard’ test by which neurogenic ED is defined and order of the small fibers affects the sensations of temperature
to which all tests can be compared. As the search for such and pain. Thermal sensation is examined by using water tubes
a test continues, one has to accept the impreciseness of this containing warm and cold water (the patient being asked to
diagnosis and the difficulties in assessing the usefulness of identify the sensation evoked by the tube). For pain, a pin is
the various neuropsychological tests discussed later in this the easiest method (the patient being asked to verify the sharp-
chapter. ness and painfulness of the sensation evoked).

Reflexes
The neurological examination
The major sacral reflex is at the Achilles tendon. The most
Discussion of the full neurological examination is beyond important surface reflex is the Babinski response. A positive
the scope of this chapter, and therefore a brief description Babinski response is a strong indication of a central lesion to
is given for a short assessment of the neural function of the motor tract, at some level along the upper motor neuron.
the sacral region, consisting of motor, sensory, and reflex Another superficial reflex of possible relevance is the cremas-
examinations. teric reflex, an L1 level reflex elicited by tactile stimulation
along the inner thigh. These reflexes disappear both in lesions
of the CNS and in lesions of the PNS.
Motor examination The bulbocavernosus reflex can be elicited at the bedside by
The motor examination should consist of the following performing a rectal examination with one hand and squeezing
assessments and considerations. the glans penis with the other. A contraction of the anal
sphincter should be felt by the examiner.
• Plantar flexion of the foot and abduction of the thighs are
L5–S1 innervated functions.
• Hyperextension of the thigh is done by the gluteus maxi- Clinical relevance
mus, via roots S1 and S2. Data gathered from the neurological examination should help
• Power of the anal sphincter, an S2–S4-innervated muscle, in establishing neurological abnormality, and in distinguish-
is tested by rectal examination. ing between lesions of the CNS and the PNS. Detailed features
• Muscle tone is assessed by asking the patient to relax his are summarized in Table 22.1. Having completed the clinical
lower limbs and then to flex and extend them several times. examination, one gets a more precise idea of the type of neural
Increased tone is an expression of a central motor lesion, injury the patient is suspected to have, and the appropriate

168
 Neurophysiologic testing in erectile dysfunction 169

Clinical role Diseases that affect the continuity of the

Table 22.1 Features that characterize central and
pudendal nerves can be diagnosed with this technique. Lumbar
peripheral lesions according to physical examination
disc disorders, pelvic anatomical lesions, and pelvic surgery
Central nervous system Peripheral nervous system can damage both somatic pudendal and autonomic hypogas-
lesions lesions tric and pelvic nerves (or their roots) and be diagnosed by
pelvic floor EMG.
Hyperactive tendon reflexes Hyporeflexia or areflexia
High muscle tone of the Flaccid muscle tone
spastic or rigid type Magnetic stimulation
Positive Babinski’s sign Clear atrophy Application of a magnetic field over the scalp above the motor
Lack of significant muscle Muscle fasciculation cortex induces an electrical field and activation of the corti-
atrophy cospinal (pyramidal) tract. Activation can also be achieved by
Sensory loss in a hemi-body Sensory loss in the magnetic stimulation over the relevant spinal roots. It should
distribution or in the lower distribution of a dermatome be noted that the pyramidal fibers and their subsequent
limbs or a peripheral nerve alpha-motor neurons are large and fast myelinated fibers.
Response can be recorded from activated striated muscle by
surface or needle electrodes.
tests can be selected to supplement and establish further the
correct diagnosis. Procedure A magnetic coil is positioned above the scalp or
spine, and discharged. The procedure is painless. The recorded
response can be facilitated if the subject is asked to partially
contract the recorded muscle during stimulation. Central
Neurophysiological tests conduction time is calculated by subtracting the latency
between the nerve root and the muscle from the latency
Tests of the motor system
between the cortex and the same muscle.
Electromyography
A comprehensive description of electromyography (EMG) is
beyond the scope of this chapter. Briefly, the electrodiagnostic Normal findings A study by Opsomer et al. recorded a
test has two subtests—nerve conduction study (NCS) and cortex–bulbocavernosus muscle latency of 28.8 ms during rest
needle electromyography (EMG) both reflect activity in large and 22.5 ms during contraction in 18 healthy male volunteer
myelinated somatic fibers. subjects. Central conduction times for the bulbocavernosus
muscle were 22.4 ms at rest and 15.1 ms with facilitation.1 In a
study by Dressler et al. a central motor conduction time of
Procedure Needle electromyography is performed by insert- 15.7 ms was reported in six normal males.2
ing a special needle into the skeletal muscle, and recording
activity in several situations. First, a recording is made in
resting muscle, which should be electrically silent. In the case Clinical role In a small number of patients with neurogenic
of an axonal lesion to the innervation of the recorded muscle, ED, abnormalities of conduction have been reported.1
abnormal spontaneous activity starts 1–2 weeks after injury
and usually abates 3–4 months later.
Then, a recording is made under conditions of mild activa- Tests of sensory system
tion of the muscle, in which case individual motor units can Penile biothesiometry
be seen. The shape of the motor units changes after injury to Biothesiometry is a cost-effective sensory screening test that
the innervation of the recorded muscle – units grow larger measures the vibration perception threshold of the skin. This
and longer and have many polyphasic potentials. This occurs procedure is performed using a portable hand-held electro-
roughly 1 month after denervation, and remains present for magnetic vibration placed through a flat round probe. Vibra-
many years. tion amplitude is controlled by the examiner, and is said to
Finally, a recording is made under conditions of full power be linearly related to the applied voltage, which can range
recruitment – the subject is requested to contract the muscle from 0 V to 50 V.
fully while the recording is being taken. A reduced recruit-
ment pattern is seen in denervation.
In the context of ED, the skeletal muscles of relevance are Procedure This test is performed by application of the
the bulbocavernosus muscle and the anal sphincter. vibrating head perpendicular to the skin. Stimulus intensity is
gradually increased from zero until vibration is felt by the sub-
ject; the amplitude at this level is measured and recorded as
Normal findings In the normal pelvic floor, no activity is the vibration perception threshold. Usually three or more
seen at rest, units are of less than 10 ms duration, and recruit- readings are taken, and the mean is regarded as the resulting
ment is full. threshold. In addition to the appearance threshold, one could
170 Textbook of Erectile Dysfunction

Table 22.2 Normative values of penile biothesiometric study according to age groups

Finger Shaft Glans

Age (years)
Study I Study II Study I Study II Study I Study II

17–29 5 7 5 7 6 9
30–39 5 7 6 9 7 11
40–49 5 8 6 9 7 11
50–59 6 9 8 12 9 15
60–69 6 10 9 15 10 16
70–75 7 13 14 18 16 21
3 4
Study I: Urol Clin North Am 1988; 15: 77–80; Study II: Eur Urol 1991; 20: 67–69.
Units are in volts/micrometer (a measure of vibration perception).
In study I the oldest older age group was 70–75, while in study II it was 71–80.

also measure the disappearance threshold. The stimulation given, whereas the response is subjective. The thermal sensa-
site can be anywhere on the body surface. Routinely, tests are tions and pain are somatic, but they are conveyed by small
performed either on distal extremities or, in the urological nerve fibers and therefore abnormal findings might be an
context, on the penis, either at the shaft or the glans. indirect reflection of an autonomic neuropathy.

Normal findings Two studies are available that provide Procedure Thresholds for these sensations are obtained by
normative data for penile biothesiometry. One by Padma- attaching to the skin a thermode that is capable of changing its
Nathan (Study I in Table 22.2) looked at 118 potent males, temperature in a controlled manner. The subject is requested
yielding an age stratified nomogram.3 A second by Breda et al. to comment on the perceived sensations in response to series
(Study II in Table 22.2) studied 350 men across all age groups.4 of thermal stimuli.
Age dependency is noted, which can be explained by skin
atrophy or by progressive loss of peripheral neurons with
increasing age. Normals findings Normative data for penile thermal sensa-
tions were given by Yarnitsky et al.6 In a group of 25 normal
volunteers, 95% upper limit values obtained through the
Clinical value Two studies have attempted to evaluate method of limits were 27.1°C for cold sensation and 35.6°C for
the role of biothesiometry in the evaluation of ED. Padma- warm sensation, using an adapted temperature of 32°C and a
Nathan tested biothesiometry against penile evoked potentials.3 rate of temperature change of 1°C per second (Table 22.3).
In a group of 137 men with ED, 38 had normal vibratory
thresholds, 80% of which had normal evoked potentials. This
figure increased to 93% in patients less than 60 years old. Of Clinical role Bleustein et al. found that, in a group of
the 99 patients with an abnormal threshold, only 47% had
107 patients, warm thermal threshold measurements (taken at
abnormal evoked potentials. The author concluded that penile
the glans penis) can be used to assess the neurological status
biothesiometry is far more sensitive than evoked potentials,
of the penis, thus offering a quick, non-invasive, accurate
making it an excellent screening tool for sensory deficit in
method of evaluating penile neuropathy in an office setting.7
ED. Bemelmans et al. studied 31 men with ED, testing
biothesiometry against penile and foot evoked potentials
and bulbocavernosus reflexes.5 They looked for a correlation
between results, but found none. The authors concluded Dorsal nerve conduction
that biothesiometric investigation of penile glans innervation
Dorsal nerve conduction measures the conduction velocity
is unsuited for the evaluation of penile innervation and can-
along the dorsal penile sensory nerve (a pudendal branch) by
not replace neurophysiological investigation. These studies
applying electrical stimulation at one end and recording the
obviously cannot provide a clear conclusion regarding the
evoked potential (EPH) at the other. Conduction studies as a
role of biothesiometry in ED evaluation, but this simple cost-
rule, sample the fastest, myelinated fibers.
effective screening tool can be useful in selecting patients for
more sophisticated neurophysiological evaluation.
Procedure Indirect measurement of conduction velocity
was described by Gerstenberg and Bradley, who performed
Thermal testing bulbocavernosus reflex latency measurement using stimula-
Thermal testing is a psychophysical test, in which an objective tion at two sites – the distal end and the proximal end of the
stimulus – a controlled quantitated temperature surge – is penis. Latency difference was used to calculate dorsal nerve
 Neurophysiologic testing in erectile dysfunction 171

Table 22.3 Normal values for penile thermal testing

Normal values
Method, modality
Patients (n) Mean temperature ± SD (°C) 95% normal upper limit∗

Limits, cold sensation 32 29.9 ± 1.4 27.1

Limits, warm sensation 35 34.0 ± 0.8 35.6
Levels, cold sensation 35 31.2 ± 0.6 30.0
Levels, warm sensation 35 32.0 ± 0.4 33.7

∗Although the 95% confidence limit is calculated based on two-tailed values, only the upper limits (beyond which subjects are considered
abnormally hyposensitive) are shown. Data from J Urol 1996; 156: 391–3.7

conduction velocity.8 In 1984, Bradley et al. directly measured and the recording of the scalp response time. As scalp responses
the conduction velocity of the dorsal nerve using the following have low amplitude, averaging is usually required. Most SEP
technique.9 The penis is gently stretched and two stimulating studies utilize large nerve fibers in the PNS, and dorsal
electrodes 0.5 cm in diameter are pasted on the dorsum of the columns in the CNS en route to the primary somatosensory
glans 1–2 cm apart. Two disk recording electrodes are placed cortex. In the context of ED, several strategies have been
on the dorsum of the penile shaft near the symphysis pubis. utilized for SEP studies: stimuli have been applied to the dorsal
A square wave stimulus with a duration of 0.1 ms and a penile nerve, the vesicourethral junction, and the lower limb
frequency of 1.7 Hz is delivered, and the action potential is nerves.
recorded. Distance is divided by latency to calculate conduc-
tion velocity. Several technical modifications of this test have
been suggested.10,11
Procedure Electrical stimuli of non-painful intensity are
repeatedly given to the stimulation site. Usually several hun-
dreds are required in order to record a clear response. Electro-
Normal findings Bradley et al. found a mean normal velo-
encephalogram electrodes are mounted on scalp sites
city of 27.4±3.4 m/s and a mean amplitude of 12±6.1 µV.
appropriate for somatosensory recordings. Recording can also
When a 1-pound (454 g) weight was added (thus stretching
be obtained from the spinal cord. Specific machinery is
the penile shaft), the velocity increased to 33±3.8 m/s.9
required for amplification, filtration, and averaging of the
When Clawson et al. used an alternative stretching device they
recorded signals.
noted a mean velocity of 36.2+3.2 m/s and an amplitude of
2.29+1/08 µV in 20 normal subjects.11

Normal findings Opsomer et al. described normal values in

Clinical role Gerstenberg and Bradley tested 14 diabetic 18 subjects, finding response over the scalp at a maximal
patients with ED, using bulbocavernosus reflex latency calcu- latency of 44.2 ms.1 Mean central conduction time was 27 ms
lations.8 Velocity for normal controls was 23.5 m/s with a (range 23.5–30.4 ms). Ertekin et al. found a mean peak of the
range of 21.4 m/s to 29.1 m/s, compared with diabetics whose scalp wave at 43 ms in 14 normal subjects.14
mean conduction velocity was 10.9 m/s. Lin and Bradley
measured slower velocity in the dorsal nerve in 20 insulin-
dependent diabetic patients with ED than in normal controls.12
In both studies, no comparison was made with diabetic potent Clinical role Ertekin et al. found prolonged SEP latency in
patients. Kaneko and Bradley found that the average conduc- ED patients with CNS disorders – in 55% of multiple sclerosis
tion velocity in diabetic patients with ED was 37 m/s compared patients with ED, in 33% of patients with spinal cord lesions
with 45 m/s13 in non-diabetic patients. and in 17% of patients with Parkinson’s disease; and normal
Nerve conduction of the dorsal nerve of the penis can be latency for patients with psychogenic ED and diabetic patients
valuable in the evaluation of peripheral sensory nerve func- with ED.14 Pickard et al. found prolongation of the SEP
tion, especially in patients with diabetes. However, the sensi- latency in neurogenic ED, but noted that the results could
tivity and specificity of this test have not been evaluated, and be predicted by history and physical examination, leaving
technical questions are still unanswered. Consequently, the little clinical value for the test.15 Spudis et al. evaluated the
role of this test in the evaluation of ED is limited. amplitude of the negative wave of the SEP.16 They studied
128 unclassified ED patients, searching for a detector of
neurogenic etiology; 16.4% of the patients had abnormal
findings, and the authors suggested that SEP could be used
Somatosensory evoked potential studies as a screening tool for neurogenic ED. Tackmann et al.
Somatosensory evoked potential (SEP) studies are based on studied 246 patients, in 63 of whom a pathological response
the application of an external stimulus to sensory receptors was found.17
172 Textbook of Erectile Dysfunction

Testing of the reflexes other hand, found 19 pathological results in a group of 90 ED

Bulbocavernosus reflex patients. However, 8 of these had normal nocturnal penile
tumescence, so calling into question the specificity of this test
Measurement of the bulbocavernosus reflex has been com-
in the evaluation of ED.24
monly used in the evaluation of underlying neurological
disorders in erectile and lower urinary tract dysfunctions. This Specifically in diabetic patients, Parys et al. found patho-
test was first described by Rushworth18 and introduced into logical results in 21% of patients with ED.25 Desai et al. raised
clinical routine by Ertekin and Reel.19 The bulbocavernosus the question of the role of sacral response studies in diabetic
reflex attempts to determine the integrity of the neural reflex ED, suggesting a low yield of the tests.26 Similarly, Vardi et al.
arch of the sacral cord, S2–S4. The afferent arm of the reflex found pathological bulbocavernosus reflex responses in only
consists of the pudendal nerve and its distal sensory branch, 4.5% of 45 diabetic ED patients.27
the dorsal penile nerve. Efferently, it is the pudendal nerve The authors of this chapter suggest a problem-oriented
that serves the reflex. A prolonged bulbocavernosus reflex approach in the use of the bulbocavernosus reflex. The test is
latency or the absence of a reflex is considered a sign of most relevant for patients with lesions in the lower spinal cord
neurological dysfunction. (cauda and pelvis). Pathology to the roots or pudendal nerves
is likely to result in a prolonged or absent response. The use of
the bulbocavernosus reflex in patients with polyneuropathy
Procedure Stimulating surface electrodes are placed on (including those with diabetes) and in patients with no suspi-
the penis and a concentric needle electrode is inserted in cion of a neurogenic cause for their ED is discouraged.
the bulbocavernosus muscle either on one side or on the
midline. Localization of the needle is verified by observing the
electrical response to a manually elicited reflex, as well as Testing of the autonomic nervous system
through asking the patient to contract and relax his pelvic
Sympathetic skin response
floor muscles. Stimulation is administered through elec-
trodes placed on the penile shaft using rectangular stimuli of A systemic sympathetic activity can be evoked by various
0.1–0.5 ms at random intervals. Bulbocavernosus reflex maneuvers such as a painful stimulus, a deep breath, or mental
response and latency time are monitored and recorded by an effort. The response is believed to reflect sudomotor activity,
EMG amplifier. A major technical point is relaxation of which is mediated by cholinergic sympathetic fibers. This is an
the muscle by the patient. Barron et al. suggested surface objective neurophysiological measure of autonomic activity,
recording of the reflex, by placing the electrode over the and hence it is attractive for detection of autonomic dysfunc-
perineal musculature.20 tion as a cause of ED and ejaculatory problems.
Aside from this technique, several similar techniques have
been described with different stimulation and recording sites: Procedure A skin response can be picked by mounting
stimulus can be applied at the vesicourethral junction,21,22 two electrodes on the penis as well as on the hand or the foot.
perineum, or at the anal sphincter.23 Usually an electrical stimulus is used, owing to convenience
of recording. One of the major limb nerves is stimulated
Normal findings Tackmann et al. studied 39 potent males, electrically, and a recording window of at least 2 seconds’
finding a mean bulbocavernosus reflex latency of 34.6 ms duration is opened.
(95th percentile 43.9 ms, 99th percentile 44.9 ms).17 Sarica
and Karacan found a latency of 33.3 ± 3.7 ms in 14 normal
controls.21 Bemelmans et al. found a range of 20–40 ms in Normal findings Derouet et al. studied 20 normal volun-
50 healthy volunteers.22 Ertekin and Reel found a range of teers.30 The median nerve at the wrist was stimulated, with
27.5–42.5 ms in 14 normals subjects.19 recordings from both the penis and the leg. Penile response
was recorded in 80% of subjects, and the mean latency was
1.4 seconds, while mean latency to leg was 1.3 seconds.
Clinical role In the pioneering paper by Ertekin and Reel, a Ertekin et al. studied the amplitude in 14 normal subjects
substantial prolongation of reflex latency was found in cases of the sympathetic skin response, finding an amplitude of
of ED caused by cauda equina lesions, and, to a lesser degree, 1.1 ± 0.9mV in the flaccid state and 0.55 ± 0.6mV during
in polyneuropathies.19 A normal response was found for papaverine-induced erection.28
patients with spinal cord disease and functional ED. Later
studies can be found that advocate routine use of this test
because of the high rate of abnormality, as well as studies Clinical role Derouet et al. found prolonged latency of the
criticizing its indiscriminate use because of the low rate of sympathetic skin response in 12 out of 46 patients, some of
abnormality, at least in some etiological groups. Tackmann et which could have neurogenic ED (e.g. resulting from diabetes
al. found pathological results in 125 of 252 patients with ED or vincristine).29 Zgur et al. found a 53% diminution of the
of various etiologies: 5 out of 7 with multiple sclerosis, 26 out amplitude of the sympathetic skin response measured on the
of 46 with polyneuropathies, 16 out of 23 with trauma, and 78 limbs of 30 diabetic patients.30 Dettmers et al., also measuring
out of 176 patients with ED but no neurological disorder.17 on the limb, found the sympathetic skin response to be
Bemelmans et al. studied 126 patients with ED of various the least sensitive test in diagnosing neurogenic ED when
etiologies, finding pathology in 21%.22 Lavoisier et al., on the compared with the bulbocavernosus reflex and pudendal
 Neurophysiologic testing in erectile dysfunction 173

somatosensory evoked potentials.31 Data are very limited subjects nearly full synchrony is expected. Yarnitsky et al.
regarding the clinical use of this test. At the present time no found that some of the activity in the corpora is simultaneous
firm conclusion can be drawn. with limb activity in response to sympathetic activating
maneuvers (see above) and therefore some of the corporal
activity is part of a generalized sympathetic response, and
Corpus cavernosum electromyography only the rest is specific penile activity.38
In the absence of any definitive test for the diagnosis of
neurogenic ED, efforts have been made over the past decade
Clinical role Abnormal potentials, with loss of synchrony
to record electrical activity from the smooth muscle in the
between the two corpora, is seen in many ED patients (51.6%
corpora cavernosa. If successful, this method is expected to of 214 patients in Stief’s study).34 Wagner et al. found desyn-
give a direct definitive diagnosis of neurogenic ED.
chronization between the two corpora in 6 out of 10 diabetic
patients with ED and in 18 out of 23 patients after radical
cystectomy.35 These results are controversial in the experience
Procedure Recording can be made either by a surface elec-
trode over the penile shaft or by a needle electrode inserted of the present authors39 and of others.40 Recently, Jiang et al.
made an effort to standardize the recording methodology
into the corporal tissue. Long recording sessions (typically
(using multichannel monopolar recording), to control the
at least 30 minutes) are required, and the equipment should
measurement conditions, and to define exactly the parameters
be able to work at a very low band pass, since the routine
filter setting is 0.1–30 Hz.32 Jiang et al. have suggested using that are used to characterize corpus cavernosum potentials.36
Meulaman et al., using the same methodology, have been
corpus cavernosum EMG during morning naps and have been
able to discriminate between ED patients with conditions
able to show that this methodology is feasible and valid.34
that are associated with cavernous smooth muscle degenera-
They demonstrated that corpus cavernosum potentials con-
sistently disappeared during tumescence and erection, while tion or autonomic neuropathy, and men with normal erectile
function.37
continuous oscillations in the potential reappeared during
detumescence.33 Despite the fact that corpus cavernosum EMG may be able
to give a direct measure for neurogenic ED, it has never
reached clinical application owing to a lack of standard equip-
Normal findings Stief et al. described normal potentials ment and standard recording techniques, a lack of consensus
(surface-recorded), with 8–18 second duration and an amp- on the measurable parameters, and a lack of objective criteria
litude between 250 µV and 750 µV, with between eight and to characterize the recorded signals. Until clearer basic work,
22 phases.34 These authors and others35–37 give importance to normative data, and solid clinical data are available, this
the synchrony of activity between the two corpora; in normal method cannot be recommended for clinical use.

Brain Spinal cord Root Nerve Penis

Motor
EMG

Mag

Sensory

SEP

BIO (large)

TT (small)

Reflex
BCR

Autonomic
CC/EMG
SSR
hand stimulation

Figure 22.1 Characteristics of each neurophysiological test and the relative anatomical neural pathways that they investigate.
Arrows indicate tests when a stimulus–response relationship is studied, loops represent reflexes, and blank lines represent tests that
sample ongoing activity. Large and small relate to fiber size in the peripheral nervous system. EMG, electromyography; MAG,
magnetic stimulation; DNV, dorsal nerve velocity; SEP, somatosensory evoked potentials; BIO, biothesiometry; TT, thermal testing;
BCR, bulbocavernosus reflex; CC/EMG, corpus cavernosum EMG; SSR, sympathetic skin response.
174 Textbook of Erectile Dysfunction

Conclusion • Patients with a history compatible with polyneuropathy,

such as in diabetes or renal failure, after chemotherapy,
The neurophysiological evaluation of the patient with ED and with hereditary neuropathies. In such cases the focus
should be specifically tailored for the individual patient – no of evaluation is in the peripheral system – nerve conduc-
‘automatic’ routine work-up can be prescribed. We suggest tion studies, EMG, and thermal testing in the lower limbs
its use in several groups of patients, divided mostly by are the most relevant tests.
history (Figure 22.1). • Patients with a history suggestive of a low spine or
pelvic disorder interfering with penile innervation, such
• Patients suspected of having CNS lesions, such as multiple as herniated lumbar disc, pelvic fracture, and radical
sclerosis and Parkinson’s disease. For these patients, as prostatectomy. EMG of the sphincter muscles, bulbo-
can be seen in Figure 22.1, magnetic stimulation and SEP cavernosus reflex testing, dorsal nerve conduction
studies are the most relevant tests, evaluating motor and studies, and magnetic stimulation of the genitalia are
sensory function, respectively. recommended.

REFERENCES

1. Opsomer RJ, Caramia MD, Zarola F, et al. Neurophysiological 17. Tackmannn W, Porst H, Van Ahlen H. Bulbocavernous reflex
evaluation of central–peripheral sensory and motor pudendal latencies and somatosensory evoked potentials after pudendal
fibres. Electroencephalogr Clin Neurophysiol 1989; 74: 260–70. nerve stimulation in the diagnosis of ED. J Neurol 1988; 235:
2. Dressler D, Schonle PW, Neubauer H. Central motor conduction 219–25.
time to bulbocavernosus muscle: evaluation by magnetic brain 18. Rushworth G. Diagnostic value of the electromyographic study of
stimulation and testing of bulbocavernosus reflex. J Neurol 1990; reflex activity in man. Electroencephalogr Clin Neurophysiol 1967;
237: 239–41. 25: 65–73.
3. Padma-Nathan H. Neurologic evaluation of erectile dysfunction. 19. Ertekin C, Reel F. Bulbocavernosus reflex in normal men and in
Urol Clin North Am 1988; 15: 77–80. patients with neurogenic bladder and/or ED. J Neurol Sci 1976; 28:
4. Breda G, Xausa D, Giunta A, et al. Nomogram for penile biothesi- 1–15.
ometry. Eur Urol 1991; 20: 67–9. 20. Barron AS, Mazliah J, Hoch Z, et al. A non-invasive electro-
5. Bemelmans BLH, Hendrikx LBPM, Koldewijn EL, et al. Compari- physiological indicator of organic ED in diabetic men. Electro-
son of biothesiometry and neuro-urophysiological investigations myography. Clin Neurophysiol 1988; 28: 39–43.
for the clinical evaluation of patients with erectile dysfunction. 21. Sarica Y, Karacan I. Bulbocavernous reflex to somatic and visceral
J Urol 1995; 153: 1483–6. nerve stimulation in normal subjects and in diabetics with ED.
6. Yarnitsky D, Sprecher E, Vardi Y. Penile thermal sensation. J Urol J Urol 1987; 138: 55–8.
1995; 156: 391–3. 22. Bemelmans BLH, Meuleman EJH, Anten BWM, et al. Penile
7. Bleustein CB, Eckholdt H, Arezzo JC, Melman A. Quantitative sensory disorders in erectile dysfunction: Results of a comprehen-
somatosensory testing of the penis: optimizing the clinical neuro- sive neuro-urophysiological diagnostic evaluation in 123 patients.
logical examination. J Urol 1995; 169: 2266–9. J Urol 1991; 146: 777–82.
8. Gerstenberg TC, Bradley WE. Nerve conduction velocity measure- 23. Pedersen E, Klemar B, Schroder HD, et al. Anal sphincter responses
ment of dorsal nerve of penis in normal and ED males. Urology after perianal electrical stimulation. J Neurol Neurosurg Psychiatry
1983; 21: 90–2. 1982; 45: 770–3.
9. Bradley WE, Lin JT, Johnson B. Measurement of the conduction 24. Lavoisier P, Proulx J, Courtois F, et al. Bulbocavernosus reflex: its
velocity of the dorsal nerve of the penis. J Urol 1984; 131: validity as a diagnostic test of neurogenic ED. J Urol 1989; 141:
1127–9. 311–14.
10. Fanciullacci F, Colpi GM, Beretta G, et al. Nerve conduction 25. Parys BT, Evans CM, Parsons KF. Bulbocavernosus reflex latency in
velocity of dorsal nerve of penis: a modified technique. Urology the investigation of diabetic ED. Br J Urol 1988; 61: 59–62.
1991; 38: 540–4. 26. Desai KM, Dembny K, Morgan H, et al. Neurophysiological
11. Clawson DR, Cardenas DD, et al. Dorsal nerve of the penis nerve investigation of diabetic ED. Are sacral response studies of value?
conduction velocity: A new technique. Muscle Nerve 1991; 14: Br J Urol 1988; 61: 68–73.
845–9. 27. Vardi Y, Yarnitsky D, Smiri W, et al. Bulbocavernous reflex
12. Lin JTY, Bradley WE. Penile neuropathy in insulin-dependent latency in evaluation of diabetic ED. Int J Impot Res 1992; 4:
diabetes mellitus. J Urol 1985; 133: 213–15. 175–8.
13. Kaneko S, Bradley WE. Penile electrodiagnosis. Value of bulbo- 28. Ertekin C, Colakoglu Z, Altay B. Hand and genital sympathetic skin
cavernosus reflex latency versus nerve conduction velocity of the potentials in flaccid and erectile penile states in normal potent
dorsal nerve of the penis in diagnosis of diabetic ED. J Urol 1987; men and patients with premature ejaculation. J Urol 1995; 153:
137: 933–5. 76–9.
14. Ertekin C, Akyurekli O, Gurses AN, et al. The value of somatosensory- 29. Derouet H, Jost WH, Osterhage J, et al. Penile sympathetic
evoked potentials and bulbocavernosus reflex in patients with ED. skin response in erectile dysfunction. Eur Urol 1995; 28:
Acta Neurol Scand 1985; 71: 48–53. 314–19.
15. Pickard RS, Powell PH, Schofield IS. The clinical application of 30. Zgur T, Vodusek DB, Krzan M, et al. Autonomic system dysfunction
dorsal penile nerve cerebral-evoked response recording in the in moderate diabetic polyneuropathy assessed by sympathetic skin
investigation of ED. Br J Urol 1994; 74: 231–5. response and valsalva index. Electroencephalogr Clin Neurophysiol
16. Spudis EV, Stubbs AJ, Skowronski T. Cerebral-evoked response 1993; 33: 433–9.
from stimulation of dorsal nerve in ED men. Urology 1989; 34: 31. Dettmers C, Van Ahlen H, Faust H, et al. Evaluation of erectile
370–5. dysfunction with sympathetic skin response in comparison to
 Neurophysiologic testing in erectile dysfunction 175

bulbocavernous reflex and somatosensory evoked potentials of the 36. Jiang X, Holsheimer J, Wagner G, et al. A reproducibility study of
pudendal nerve. Electroencephalogr Clin Neurophysiol 1994; 34: corpus cavernosum electromyography in young healthy volunteers
437–44. under controlled conditions. J Sex Med 2007; 4: 183–90.
32. Vardi Y, Bernabe J, Dashkovsky A, et al. Electrical activity from rat 37. Meuleman E, Jiang X, Holsheimer J, Wagner, et al. Corpus
corpora is affected by pharmacological but not mechanical intra- cavernosum electromyography with revised methodology: an
corporal manipulation. Pflugers Arch 1995; 436: 882–6. explorative study in patients with erectile dysfunction and
33. Jiang X, Meuleman EJ, Wijkstra , et al. Corpus cavernosum electro- men with reported normal erectile function. J Sex Med 2007; 4:
myography during morning naps in healthy volunteers: further 191–8.
evidence that corpus cavernosum potentials reflect sympatheti- 38. Yarnitsky D, Sprecher E, Barilan Y, et al. Corpus cavernosum elec-
cally mediated activity. J Urol 2005; 174: 1917–20. tromyogram: spontaneous and evoked electrical activities. J Urol
34. Stief CG, Djamilian M, Anton P, et al. Single potential analysis of 1995; 153: 653–4.
cavernous electrical activity in ED patients: a possible diagnostic 39. Vardi Y, Gruenwald I, Sprecher E. The role of corpus cavernosum
method for autonomic cavernous dysfunction and cavernous electromyography. Curr Opin Urol 1995; 10: 635–8.
smooth muscle degeneration. J Urol 1991; 146: 771–6. 40. Bemelmans BLH, Meuleman EJH, Koldewijn EL, Notermans, et al.
35. Wagner G, Gerstenberg T, Levin RJ. Electrical activity of corpus Critical appraisal of penile electromyography. Neurophysiological
cavernosum during placidity and erection of the human penis: investigations of the electrical activity of cavernous smooth
A new diagnostic method. J Urol 1989; 142: 723–5. muscles. International. Int J Impot Res 1992; 4(Suppl 2): A25.
23 Biopsy of the corpus cavernosum
Eric Wespes

Introduction arteries. Cavernometry readings were similar after the biopsy

to what they were before.
The cavernous sinusoids, consisting of bundles of smooth
muscle, elastic fibers, and collagen, represent the key to the
problem of erectile dysfunction (ED); demonstration of
alterations in them could eventually spare patients from Discussion
reconstructive surgical treatment. Electron microscopic stud-
ies have demonstrated modification of the smooth muscle The Biopty gun procedure is cost effective and can be
cells in patients with vascular impotence.1,2 However, the performed in the office under local anesthesia. The total pro-
tissues examined were obtained during surgery, when the cedure usually lasts less than 10 minutes. The place of this
therapeutic procedure was already being performed. method in the assessment of patients with ED and a definition
Vasculogenic impotence represents the most important of the histological criteria by light or electron microscopic
etiology in organic ED. Several different techniques have studies must be determined to include or exclude patients for
been developed to diagnose arterial or venous insufficiency.3 penile surgery.
Duplex sonography in conjunction with intracavernous When this new simple technique for obtaining cavernous
injection of vasoactive drugs is the gold standard method for tissue was first described, it was considered to be very aggres-
providing information about arterial blood flow into the sive.6 It is clear that it is an invasive technique that does not yet
penis.4 Pharmacocavernometry and cavernography appear have a place in the investigation or the treatment of patients
to be able to determine the venous hemodynamic status of with ED.7 However, it has been used by other well-known
the corporal bodies.5 Use of the Biopty gun to perform penile teams to study the pathophysiology of impotence8 or other
biopsy under local anesthesia appears to be a simple and penile pathologies, such as Peyronie’s disease.9
reliable method to obtain sufficient tissue for histologic Advances in impotence research and increased knowledge
analysis. of the pathophysiology of ED have demonstrated that the
erectile response decreases with age. Elderly men take longer
to obtain an erection and find it more difficult to sustain
one. The prevalence of ED ranges from 52% in men aged
Description of the biopsy method 40–70 years to > 95% in men older than 70.10 Relaxation of the
intracavernous smooth muscles is the key factor in the mech-
First approximately 1 ml lidocaine is infiltrated into the skin anism of penile erection. We have demonstrated that the
of the penis. The puncture is performed in the balanopre- percentage of penile muscular cells decreases with aging: it is
putial groove on the dorsolateral side. The biopsy needle is 46% in men younger than 40 years, 40% in men between
introduced longitudinally through the tunica albuginea into 41 and 60 years, and 35% for men older than 60 years.11 This
the corpus cavernosum. With one hand, the penis is kept decrease in smooth muscle content may be responsible for
slightly stretched and, with the other hand, the needle is the decline in erection in older men.
fired from an anterior to a posterior trajectory. The needle is This reduction occurred throughout both cavernous bodies.
then removed and the tissue fragments are placed in Bouin’s Vascular impotence is a diffuse penile disease; therefore, a
solution. cavernous body biopsy can be used to study the penile structure
In all the patients, adequate tissue was obtained for histo- in the assessment of vascular impotence.12
logical analysis. Corpus cavernosum tissue can be easily iden- In patients with organic ED, a decrease in smooth muscle
tified with the intracavernous smooth muscle fibers and cells was observed and the decrease is more important in
collagen. None of the outpatients experienced significant pain patients with arterial disease.13 Objectively, the percentages
at biopsy or required any postoperative analgesia. No lesions of elastic fibers in corpus cavernosum tissues in potent and
were observed with the Doppler analysis of the cavernous impotent men have been measured. The mean percentage

176
 Biopsy of the corpus cavernosum 177

of elastic fibers was 9% in normal patients. In patients biopsies both during surgery and 6 months after surgery
with venous leakage, a significant decrease in the amount of under local anesthesia have demonstrated preservation of
elastic fibers of 5.1% was observed. In patients with arterial the percentage of smooth muscle cells in patients treated with
disease, the decrease was 4.3%. No correlation was observed daily use of sildenafil 50 mg or 100 mg.22
between the reduction of the elastic fiber quantification and In aged rats, fibrosis of the cavernous tissue is observed.
age. Change in elastic fiber content may alter the relaxation Exploring the pathogenesis of this phenomenon in rats,
properties of cavernosal tissue and play a role in the develop- the first important finding is that tumor growth factor (TGF)
ment of ED.14 beta-1 is higher in penile tissue of old rats than in the penile
The role of the different components of the corpus caver- tissue of young rats.23 Under normal conditions, TGF-beta-1
nosum is very important in the physiopathology of ED. The maintains cell numbers by directly inhibiting cell prolifera-
precise function of collagen fibers in erectile physiology is tion and by controlling the potent mitogenic actions of
controversial. My team measured the different types of col- platelet-derived growth factor (PDGF), a companion cytokine.
lagen (I, III, IV) in the corpus cavernosum of impotent and TGF-beta-1 also regulates the amount of extracellular matrix
potent men using cell image analysis and immunohisto- (ECM) by balancing new synthesis and deposition of ECM by
chemistry. We found differences in the distribution of colla- degradation and removal with proteases. Under ischemic
gen I, III, and IV in each pathological group (arterial ED, conditions, TGF-beta-1 induces its own mRNA, leading to a
cavernovenous ED, and psychogenic ED). The augmentation further increase in TGF-beta-1 synthesis, which reinforces the
of collagen I and the light diminution in collagen III make development of severe fibrosis. TGF-beta-1 gene expression
the corpus cavernosum less compliant, which is traduced is significantly increased in the penile tissue of older rats com-
clinically by an alteration in the filling of the vascular spaces pared with young rats. Hypoxia has been demonstrated to
and by dysfunction of the veno-occlusive mechanism. The induce the expression of TGF-beta-1 in several tissues;
diminution in collagen IV shows an alteration in the function therefore, penile ischemia may cause increased TGF-beta-1
of endothelial cells. That we found a diminution in collagen expression, leading to ECM deposition and, eventually, penile
IV content in the psychogenic group makes us infer that fibrosis.
psychogenic impotence could be the first stage of organic A correlation between oxygen tension in the human penis
impotence.15 has been demonstrated with the percentage of smooth muscle
Objective quantification showed no difference in the num- fibers.24 Therefore, the number of muscular fibers depends
bers of cavernous endothelial cells between potent and impo- on good oxygenation of the penis; otherwise, ischemia
tent men, which is surprising considering that the other penile induces fibrosis by stimulating TGF-beta-1. It seems that the
structures (smooth muscle cells, collagen fibers, and elastic histological alterations start distally, in the very small penile
fibers) demonstrate modification in impotent patients. How- arteries.25
ever, the function of the endothelial cells could be perturbed Apoptosis is another phenomenon that occurs after neural
and be the origin of ED.16 lesions, mainly in patients operated on for radical prostatec-
Study of the intracavernous structures allows us to tomy. Bilateral cavernous neurotomy induced significant
appreciate the therapeutic effects of oral drugs, intracavernous apoptosis of smooth muscle cells on postoperative day 2 in
injections, or surgery. To better select responders and non- rats, particularly in the subtuncal area, causing veno-occlusive
responders to sildenafil, a hemodynamic and morphometric dysfunction; however, the endothelial cells did not demonstrate
study in non-responders was conducted. Severe vascular any apoptotic mechanism.26 The difference between smooth
lesions and atrophy of the smooth muscle cells are observed muscle fibers, in which degeneration occurred, and the endo-
mainly in non-responders. Age, diabetes, and hypogonadism thelial cells, in which there were no alterations, could explain
seem not to be related to the failures. Poor responses to why the benefit induced by a reliability phosphodiesterase
intracavernous injections could be used as a predicting test type 5 inhibitor approach compared with on demand or every
for sildenafil users. Apomorphine should not be given to the day or every other day does not make any difference.27 The
non-responders.17 endothelial cells and their production of neurotransmitters
In patients treated with intracavernous prostaglandin are not perturbed.
E-1 injections, this drug does not seem to influence growth
factor in vivo as it has been demonstrated in vitro,18 and
therefore it does not decrease the percentage of collagen
tissue that could be used for remodeling penile smooth Conclusion
musculature.19 In patients operated on for venous ligation,
the best results are obtained in those with sufficient smooth Penile biopsy is certainly a method that can allow the study of
muscle content.20 the intracavernous structures. What its place will be in the
Penile biopsies performed 2 and 12 months after radical assessment of patients with erectile dysfunction remains to be
prostatectomy have shown a progressive increase in penile determined. At the present time, it is certainly not recom-
organized collagen content and a decrease in smooth muscle mended by any guidelines. However, in the future, with new
cells and elastic fibers.21 therapeutic approaches such as gene therapy, it could be
Early use of high doses of sildenafil after radical prostatec- integrated into the therapeutic arsenal for the treatment of
tomy could preserve smooth muscle content. Percutaneous patients with ED.
178 Textbook of Erectile Dysfunction

REFERENCES

1. Persson C, Diederichs W, Lue TF, et al. Correlation of altered 16. Sattar AA, Schulman CC, Wespes E. Objective quantification of
penile ultrastructure with clinical arterial evaluation. J Urol 1989; cavernous endothelium in potent and impotent men. J Urol 1995;
142: 1462–8. 153: 1136–8.
2. Jevtich MJ, Khawand NY, Vidic B. Clinical significance of ultra- 17. Wespes E, Rammal A, Garbar C. Viagra non-responders: haemody-
structural findings in the corpora cavernosa of normal and impo- namic and morphometric studies. J Urol 2003; 169: 244 (abstract).
tent men. J Urol 1990; 143: 289–93. 18. Moreland RB, Traish A, McMillin MA, et al. PGE1 suppresses the
3. Krane RJ, Goldstein I, Saenz de Tejada I. Impotence. New Engl J induction of collagen synthesis by transforming growth factor-β1 in
Med 1989; 321: 1648–59. human corpus cavernosum smooth muscle. J Urol 1995; 153:
4. Lue TF, Hricak H, Marich KW, et al. Vasculogenic impotence 826–34.
evaluated by high resolution ultrasonography and pulsed Doppler 19. Wespes E, Sattar AA, Noël JC, Schulman CC. Does prostaglandin
spectrum analysis. Radiology 1985; 155: 777–81. E1 therapy modify the intracavernous musculature? J Urol 2000;
5. Wespes E, Delcour C, Struyven J, et al. Pharmacocavernometry– 163: 464–6.
cavernography in impotence. Br J Urol 1986; 58: 429–33. 20. Wespes E, Moreira de Goes P, Sattar AA, et al. Objective criteria
6. Wespes E, Depierreux M, Schulman CC. Use of Biopty gun for in the long-term evaluation of penile venous surgery. J Urol 1994;
corpus cavernosum biopsies. Eur Urol 1990; 18: 81–3. 152: 888–90.
7. Wespes E, Amar E, Hatzichristou D, et al. Guidelines on erectile 21. Iacono F, Giannella R, Somma P, et al. Histological alterations in
dysfunction. Eur Urol 2002; 41: 1–5. cavernous tissue after radical prostatectomy. J Urol 2005; 173:
8. Hussain S, Nehra A, Goldstein I, Krane RJ. Percutaneous core 1673–6.
biopsy of the penis. Int J Impot Res 1998; 10: 57–9. 22. Schwartz EJ, Wong P, Graydon J. Sildenafil preserves intracorpo-
9. Mirone V, Imbimbo C, Palmieri A, et al. A new biopsy technique to real smooth muscle after radical retropubic prostatectomy. J Urol
investigate Peyronie’s disease associated histologic alterations: results 2004; 171: 771–4.
with two different forms of therapy. Eur Urol 2002; 42: 239–44. 23. Dahiya R, Chui R, Perinchery G, et al. Differential gene expres-
10. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its sion of growth factors in young and old rat penile tissues is
medical and psychological correlates: results of the Massachusetts associated with erectile dysfunction. Int J Impot Res 1999; 11:
Male Aging Study. J Urol 1994; 151: 54–61. 201–6.
11. Wespes E, Moreira de Goes P, Schulman CC. Age-related changes 24. Sattar AA, Salpigides G, Vanderhaeghen JJ, et al. Cavernous
in the quantification of the intracavernous smooth muscles in oxygen tension and smooth muscle fibers: relation and function.
potent men (abstract). J Urol 1998; 159: 379. J Urol 1995; 154: 1736–9.
12. Wespes E, de Goes PM, Schulman CC. Vascular impotence: focal 25. Wespes E, Raviv G, Vanegas JP, et al. Corporeal veno-occlusive
or diffuse penile disease. J Urol 1992; 148: 1435–6. dysfunction: a distal arterial pathology? J Urol 1998; 160:
13. Wespes E, de Goes PM, Schiffmann S, et al. Computerized analysis 2054–7.
of smooth muscle fibers in potent and impotent patients. J Urol 26. User HM, Hairston JH, Zelner DJ, et al. Penile weight and cell
1991; 146: 1015–17. subtype specific changes in a post-radical prostatectomy model of
14. Sattar AA, Wespes E, Schulman CC. Computerized measurement of erectile dysfunction. J Urol 2003; 169: 1175–9.
penile elastic fibres in potent and impotent men. Eur Urol 1994; 27. Montorsi F, Salonia A, Gallina A, et al. There is no significant
25: 142–4. difference between on-demand PDE5-I vs PDE5-I as rehabilitative
15. Raviv G, Wespes E, Vanegas JP, et al. Difference in glycohis- treatment in patients treated by bilateral nerve-sparing radical ret-
tochemical lectin staining of collagen fibers in the corpora caver- ropublic prostatectomy. Presented at the Meeting of the American
nosa of normal and impotent men. J Androl 1996; 17: 187–93. Urological Association, 20–25 May, 2006, in Atlanta, GA.
24 Endocrine evaluation of male
sexual function
Sanjay N Mediwala and Glenn R Cunningham

Introduction whilst a history of reduced libido and spontaneous erections

are suggestive of hypogonadism in the patient who has com-
The endocrine evaluation of male sexual function centers pleted development normally. The quality of morning erections
primarily on the history and the physical and laboratory correlates with nocturnal penile tumescence.16 Breast discom-
evaluation of three endocrine conditions: hypogonadism, fort may be an early symptom of gynecomastia. Hair pattern –
hyperthyroidism, and diabetes (with associated neuropathy specifically, loss of body, axillary and pubic hair and a
and vasculopathy). Diagnosis of hypogonadism leads to its noticeable reduction in shaving – can be suggestive of hypo-
own differential diagnosis: testicular failure versus central gonadism, as can reduced muscle mass and strength.1 Hot
hypogonadism. flushes are suggestive of primary hypogonadism, but can be
caused by central hypogonadism.
Psychiatric symptoms, including lack of energy, irritability,
Hypogonadism sad moods, decreased enjoyment of life and decreased sense
of well-being, have been mentioned in reviews of hypogonadal
Hypogonadism is defined as a clinical syndrome that results men. These symptoms may be present in a subset of the
from failure of the testes to produce physiological levels of hypogonadal population, though pervasive symptoms linked
testosterone (androgen deficiency) and the normal number solely to hypogonadism are unlikely.
of spermatozoa (due to disruption of one or more levels of In a short-term study of induced hypogonadism in young,
the hypothalamic–pituitary–gonadal axis).1 Low testosterone otherwise healthy men without prior psychiatric history,
levels are observed in 2–21% of men presenting to a physician 1 month of testosterone suppression led to symptoms of
with erectile dysfunction (ED).2,3 Most of the variation prob- depression in 3 of 31 men. The feeling of being emotionally
ably is due to differences in patient populations. Diagnosis of charged decreased with induced hypogonadism. The subjects’
hypogonadism is important because it may provide clues to daily rating of sadness, anxiety, irritability, mood lability, and
underlying illnesses such as hypothalamic, pituitary or testic- anhedonia did not change during the time of hypogonadism,
ular disease, hemochromatosis, or obstructive sleep apnea.4 nor did measurements of mood stability, social avoidance,
Further, hypogonadism itself has been associated with reduced work productivity, aggression, or impulsivity.17 Studies of
life expectancy,5 increased risk of having or of developing elderly hypogonadal men have been conflicting and their
the metabolic syndrome,6,7 development of type 2 diabetes,6,8,9 interpretation limited by lack of controls.18 Most indicate that
increased visceral fat,10 and increased risk of coronary heart some patients exhibit depressed mood, but severe depression
disease.11,12 The management of hypogonadism with these con- is rarely, if ever, caused by testosterone deficiency.
ditions in older men is more controversial.13 Once diagnosed, Several questionnaires have been used to screen for
however, hormonal therapy is an option that has been demon- hypogonadism. Unfortunately, each lacks specificity and
strated to improve many domains of sexual function.14 some lack sensitivity. Most experts think that they are not
helpful.

Clinical history
Research continues to clarify the role of androgens in male Physical examination
sexuality. Sexual desire, the production of seminal fluid, and The physical examination for endocrine causes of hypo-
penile tumescence are responsive to androgen.15 The clinical gonadism focuses on the physical signs of completed puberty
history, however, may only provide general clues as to the and evidence for acquired post-pubertal androgen deficiency.
diagnosis of hypogonadism, and can be quite variable. The Body hair pattern should be examined. The appearance of
clinical presentation varies on the basis of the severity a female escutcheon (triangular escutcheon) and lack of
and length of androgen deficiency, age, associated illnesses, androgen-dependent hair on the chin, cheeks, upper lip, inner
and androgen sensitivity. thighs, and lower back are suggestive of longstanding hypo-
A history of non-completion of puberty provides immediate gonadism. Gynecomastia (concentric breast tissue that is
concern for the possibility of longstanding hypogonadism, palpable as a discrete subareolar plaque) results from the

179
180 Textbook of Erectile Dysfunction

relative increased ratio of estradiol to testosterone (from

Table 24.1 Conditions associated with altered SHBG
peripheral conversion of testosterone to estradiol).19
When there is concern that the individual may have Decreased SHBG Increased SHGB
longstanding hypogonadism (extending from puberty), body
proportions should be measured. In normal development Moderate obesity Aging
from childhood to adulthood, there is a progressive decrease Nephrotic syndrome Hepatic cirrhosis
in upper to lower body ratio from 1.7 at birth to 1.0 at normal Hypothyroidism Hyperthyroidism
cessation of growth. Delayed puberty results in delayed
Use of glucocorticoids, progestins, Use of anticonvulsants
skeletal maturation and epiphyseal closure, and thus to an
and androgenic steroids Use of estrogens
upper to lower body ratio of <1.0 and an arm span >6 cm HIV infection
more than height.20 The upper body length should be mea-
SHBG, sex hormone binding globulin. From J Clin Endocrinol Metab
sured from the top of the pubic symphysis to the crown of the
2006; 91: 1995–2010.
head. The lower body length is the distance from the top of
the pubic symphysis to the sole of the foot. Long slender hands
(arachnodactyly) with long thin nail plates, similar to the
findings in Marfan’s syndrome, may be present. Profound
acquired hypogonadism is associated with accelerated bone free or bioavailable testosterone measurement or a low total
turnover, and hypogonadism in the elderly may affect bone and a normal free or bioavailable testosterone level.
density by reducing both testosterone and estradiol levels.21 The typical reference range for a total testosterone measure-
Osteopenia and vertebral compression may result in loss of ment is 280–1000 ng/dl. If conditions that alter SHBG are
height, though this may be unrecognized by the patient. present, studies for free or bioavailable testosterone should
Examinations of the scrotal contents and the prostate be performed, but these studies should be done in reference
are critical. A testicular volume <4 ml or length less than laboratories, since local laboratories often measure free tes-
2.5–3 cm in the longest dimension, is pre-pubertal in size.22 tosterone by analog displacement immunoassay, an inaccu-
Males who have completed Tanner 5 development will typi- rate technique.24 Alternatively, using the concentrations of
cally have a testicular volume of >20 ml and a length >4.5 cm total testosterone, serum albumin, and SHGB to calculate bio-
in the longest axis.23 Testes <4.0 cm are generally considered available testosterone has been shown to be reliable,25 and
to be abnormal in adult men. Testosterone deficiency in calculators are readily available.26 A testosterone value mildly
younger men can cause regression of prostate size. However, below the reference range for the laboratory should be con-
the older man with benign prostatic hyperplasia may have firmed with a second measurement, since 30% of these patients
an enlarged prostate that does not regress very much with may have normal values on repeat measurement.1
androgen deficiency. It is important to exclude a prostate
nodule or induration prior to treatment with testosterone,
since clinical prostate cancers are usually androgen-responsive Luteinizing hormone and follicle stimulating hormone
at the time of diagnosis. Once a low testosterone value has been established, measure-
Specific findings can assist in the diagnosis. Anosmia or ment of serum gonadotropins will help to localize the cause
midline defects can be associated with hypogonadotropic of hypogonadism. Low testosterone results in decreased nega-
hypogonadism, including Kallman’s syndrome. tive feedback to the hypothalamus and pituitary, leading to
increased secretion of luteinizing hormone (LH) and follicular
stimulating hormone (FSH). An (inappropriately) normal or
Laboratory evaluation frankly low serum LH and FSH in the setting of low testoster-
one is indicative of central hypogonadism. Elevated LH and
Testosterone FSH are appropriate pituitary responses, thus indicating
The diagnosis of hypogonadism rests on the symptoms and testicular failure as the cause of low testosterone. Causes of
signs discussed above and on documentation of reproducibly testicular and central hypogonadism are listed in Table 24.2.
low morning testosterone levels. The serum testosterone It should be noted that longitudinal studies have shown
should be measured between 7.00 am and 10.00 am because an age-related decline in serum levels of total, free, and bio-
diurnal variation occurs in younger and middle-aged men. available testosterone in healthy older men, an increase in
The choice of testosterone assay depends on the clinical SHBG with the decline in free and bioavailable testosterone
scenario. Testosterone circulates in three fractions: free, tightly occurring earlier. Usually this decline is associated with only
bound to sex hormone binding globulin (SHBG), and loosely small increases in FSH and LH until after the age of 70, and
bound to albumin. Only between 0.5% and 3% of testosterone thus it has been attributed mostly to secondary (central)
is free. The free and albumin-bound fractions are considered hypogonadism.1
bioavailable. The total testosterone and bioavailable testoster- In cases of central hypogonadism, imaging of the pituitary
one fraction are proportional provided there are no altera- should be considered – see below.
tions in SHBG. However, numerous conditions can result in
elevated or decreased SHBG fractions (Table 24.1) and will
alter the total testosterone measurement. These conditions Blood count
may or may not affect the free or bioavailable levels. Thus, a Androgens stimulate erythropoiesis by increasing both renal
patient can have a normal total testosterone level and a low production of erythropoietin and proliferation of erythroid
 Endocrine evaluation of male sexual function 181

Table 24.2 Causes of hypogonadism Table 24.3 Medications that cause hyperprolactinemia

Central hypogonadism Testicular failure Antipsychotic agents

Secondary Aging Tricyclic antidepressants

Blunt head trauma Cryptorchidism (bilateral) Opiates

Congenital (Kallman’s syndrome, Drugs (ketoconazole, Cocaine

septo-optic dysplasia, Prader– cancer chemotherapy) Verapamil
Willi syndrome, GnRH receptor Irradiation Alpha-methyldopa
mutations, and others)
Orchitis (mumps, AIDS, Metoclopramide
Drugs (estrogen, progestins, leprosy, and others)
GnRH agonists, GnRH Chlorpromazine
Trauma, torsion
antagonists); past history of From Mayo Clin Proc 2005; 80: 1050–7.31
anabolic steroid use Genetic: Klinefelter’s
syndrome; androgen
Tumors, including prolactinoma biosynthesis defects;
and other pituitary tumors, and myotonic dystrophy
craniopharyngioma thyroidism, hypothalamic lesions, renal insufficiency, cirrhosis,
Idiopathic and chest wall lesions, further evaluation is usually indicated
Panhypopituitarism –
acquired
if the prolactin level is >35 ng/mL.

Tertiary
Aging Imaging
Chronic liver disease For those patients with central (hypogonadotropic) hypo-
Chronic renal disease gonadism and for those with unexplained hyperprolactinemia
(>35 ng/ml), imaging of the pituitary, typically with magnetic
Congenital isolated FSH and
resonance imaging (MRI), can be used to identify structural
LH deficiency
abnormalities. The prevalence of imaging abnormalities has
Hemochromatosis been shown to be inversely proportional to serum testoster-
Malnutrition one when levels are subnormal. In one study, the hypogona-
Sarcoidosis dotropic ED patients in the lowest quintile of testosterone
values had a 21.2% prevalence of hypothalamic or pituitary
GnRH, gonadotropin releasing hormone; FSH, follicle stimulating
hormone; LH, luteinizing hormone.
imaging abnormalities. The overall rate of imaging abnor-
malities was 6.7%.2
Generally accepted guidelines state that imaging of
precursors.27 In the androgen-deficient male, the red blood the pituitary is indicated in cases of more severe central
cell concentration drops to the normal reference range for hypogonadism (testosterone <150 ng/dl) or when there is
females, approximately a 10% drop.28 The anemia is normo- suspicion of pituitary disease (such as in cases of panhypopi-
cytic, and may be reversed by testosterone replacement. tuitarism, persistent hyperprolactinemia, or symptoms of
tumor mass effect).2,32 MRI scans may be obtained for younger
men who have testosterone levels <200 ng/dl.
Prolactin
The patient with low testosterone and low or inappropriately
normal LH should be screened for hyperprolactinemia. The Hyperthyroidism
prevalence of hyperprolactinemia in men with erectile dys-
function (ED) is estimated at 2.4–4%, and treatment may Hyperthyroidism, a condition of excessive thyroid hormone
result in return of erectile function. Somewhat more contro- release, can have significant effects on erectile function. It has
versial is the screening of patients with ED but normal testos- been proposed that hyperthyroidism increases aromatization
terone values for hyperprolactinemia. Buvat showed that half of testosterone into estrogen. The increase in estrogen raises
of the 12 ED patients in his study with moderate hyperpro- levels of SHBG. Although free testosterone levels are usually
lactinemia (i.e. prolactin levels >35 ng/dl) had normal testos- normal, the ratio of estrogen to free testosterone is altered,
terone values.29 The ED of most men with mild increases which may contribute to ED.33 It has also been posited that the
in serum prolactin is not improved by treatment aimed at increase in adrenergic tone caused by hyperthyroidism may
lowering serum prolactin. cause ED, either through effects on smooth muscle or via
Hyperprolactinemia can cause hypogonadism by suppres- behavioral or psychiatric effects.34
sion of gonadotropin-releasing hormone from the hypothal- The most common symptoms of hyperthyroidism are
amus. In addition, prolactin may interfere with the conversion hyperactivity, irritability, heat intolerance, palpitations,
of testosterone to dihydrotestosterone. Loss of libido is a pro- fatigue, and weight loss. Physical signs include tachycardia,
minent feature often reported in cases of hyperprolactinemia.30 tremor, goiter, warm skin, proximal muscle weakness, and
Since hyperprolactinemia can be caused by a variety of eyelid retraction.35 Biochemical diagnosis is made through
medications (Table 24.3),31 prolactin-secreting tumors, hypo- the identification of high levels of thyroid hormone (total or
182 Textbook of Erectile Dysfunction

free T4 or T3) with a low serum thyroid stimulating hormone should be focused on the identification of pubertal status, risk
level. factors for hypogonadism, libido, and the presence of noc-
turnal or early morning erections. The physical examination
should identify patterns of body hair, testicular size, gyne-
Diabetes mellitus comastia, and muscle strength.
Additional work-up includes routine chemistries and blood
Erectile dysfunction is more prevalent in diabetic men than in counts, early morning testosterone, lipid profile, fasting
non-diabetic men, with an estimated prevalence of between glucose, hemoglobin A1c, thyroid hormone assays, and
20% and 71%. Neuropathy and vasculopathy are typically electrocardiography.
implicated as the cause.36 In addition, however, low testoster- The free or bioavailable testosterone should be measured
one and low SHBG appears to serve as a risk factor for the when conditions exist that alter SHBG, and there should be at
future development of diabetes,8 and the prevalence of low least two consistent values below the reference range with
bioavailable and free testosterone is greater in type 2 diabetic associated symptoms to make the diagnosis of hypogonadism.
men.37 Testosterone treatment may be beneficial in some of Once the diagnosis of hypogonadism is made, further evalua-
these men. Low testosterone levels may be a cause of failure to tion with FSH and LH can localize the site of the endocrine
respond to a phosphodiesterase type 5 inhibitor (PDE5I). The dysfunction, whether it is central or testicular. In the presence
topic of diabetes and ED is addressed in Chapter 59. of central hypogonadism, prolactin should be checked. Imaging
is restricted to those cases with total testosterone <150 ng/dl,
persistent hyperprolactinemia, or other findings suggestive of
Conclusion hypothalamic or pituitary lesions.
Once a diagnosis of hypogonadism is made, consideration
The endocrine evaluation of ED should begin with identifica- should be given to assessment of the bone mineral density for
tion of the symptoms and signs of hypogonadism. The history osteoporosis.

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Society clinical practice guideline. J Clin Endocrinol Metab 2006; 14. Isidori AM, Giannetta E, Gianfrilli D, et al. Effects of testosterone
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2. Citron JT, Ettinger B, Rubinoff H, et al. Prevalence of hypothalamic– crinol (Oxf) 2005; 63: 381–94.
pituitary imaging abnormalities in impotent men with secondary 15. Carani C, Bancroft J, Granata A, Del Rio G, Marrama P. Testoster-
hypogonadism. J Urol 1996; 155: 529–33. one and erectile function, nocturnal penile tumescence and
3. Soran H, Wu FCW. Endocrine causes of erectile dysfunction. Int J rigidity, and erectile response to visual erotic stimuli in hypo-
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Endocrinol Metab 2002; 87: 3394–8. erectile dysfunction. J Clin Endocrinol Metab 1995; 80: 1985–8.
5. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testoster- 17. Schmidt PJ, Berlin KL, Danaceau MA, et al. The effects of pharma-
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6. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex 18. Sternbach H. Age-associated testosterone decline in men: clinical
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diabetes in middle-aged men. Diabetes Care 2004; 27: 1036–41. 19. Carlson HE. Gynecomastia. N Engl J Med 1980; 303: 795–9.
7. Kupelian V, Page ST, Araujo AB, et al. Low sex hormone-binding 20. Lifshitz F, Botero D. Worrisome Growth. In: Lifshitz F, ed. Pediatric
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nonobese men. J Clin Endocrinol Metab 2006; 91: 843–50. elderly men and its clinical and therapeutic implications. Endocr
8. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Tes- Rev 2005; 26: 833–76.
tosterone, sex hormone-binding globulin, and the development of 22. Waaler PE, Thorsen T, Stoa KF, Aarskog D. Studies in normal male
type 2 diabetes in middle-aged men: prospective results from the puberty. Acta Paediatr Scand 1974; 249(Suppl): 1–36.
Massachusetts Male Aging Study. Diabetes Care 2000; 23: 490–4. 23. Anglade RE, Oates RD. Male reproductive dysfunction. In:
9. Selvin E, Feinleib M, Zhang L, et al. Androgens and diabetes in men: Siroky MB, Oates RD, Babayan RK, editors. Handbook of Urology:
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27. Ferrucci L, Maggio M, Bandinelli S, et al. Low testosterone levels 33. Morales A, Buvat J, Gooren LJ, et al. Endocrine aspects of sexual
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29. Buvat J. Hyperprolactinemia and sexual function in men: a short 35. Jameson JL, Weetman AP. Disorders of the thyroid gland. In:
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31. Molitch ME. Medication-induced hyperprolactinemia. Mayo Clin 36. Brown JS, Wessells H, Chancellor MB, et al. Urologic complica-
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32. AACE Hypogonadism Task Force. American Association of 37. Kapoor D, Aldred H, Clark S, et al. Clinical and biochemical assess-
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25 The biopsychosocial evaluation
of erectile dysfunction
Stanley E Althof and Rachel Needle

Introduction In addition to the biopsychosocial model, another organi-

zing principle of evaluation is the division of etiological
Erectile dysfunction (ED) is a complex amalgam of inter- variables into predisposing, precipitating, maintaining, and
related biological, psychological, and contextual variables that contextual factors.10,11 Predisposing factors may make a man
combine to produce a distressing symptom for the man and susceptible to ED. These may include diabetes, hypertension,
his partner. Historically, ED was conceptualized in binary substance abuse, restrictive upbringing, disturbed family rela-
terms – it was either psychogenic or organic. In the 1980s, tionships, inadequate sexual information, and traumatic early
when fewer treatment options were available, this paradigm sexual experiences. Precipitating factors are ones that trigger
simplified treatment planning. Psychogenic patients were the onset of ED and include a new medication, surgery, psy-
referred for psychotherapy, patients deficient in testosterone chological impact of an illness or its treatment, depression,
received hormone replacement, and patients with other anxiety, infidelity, and relationship distress. Maintaining
‘organic’ conditions were referred for penile prostheses. factors, which reinforce the persistence of the symptom,
Over time a third category, mixed erectile disorder, evolved include performance anxiety, guilt, psychiatric disorder, rela-
to account for those patients with both psychological and tionship discord, loss of attraction between partners, fear of
organic factors. Yet, the notion of ‘mixed’ conveys a static intimacy, impaired self-image, restricted foreplay, sexual
rather than interactive and changeable concept. Disease myths, and poor communication. Finally, contextual factors
conditions often change, as do psychological issues. include the current stresses in the man’s or couple’s life (e.g.
These shortcomings led to the development of the present unemployment, problems with the children).12
biopsychosocial model that captures the ever-changing influ- Using the biopsychosocial model, this chapter presents an
ences of biology and psychological life.1–7 It is a dynamic and organized, step-by-step guide to the comprehensive assess-
additive model. Regardless of the precipitating causes, over ment of ED. It follows a logical progression, examining all
time, changes in both biological and psychosocial domains relevant biomedical and psychological aspects that may
occur. This biopsychosocial model encompasses both the account for the symptom of ED and other related sexual pro-
psychological life of the man; the impact that the dysfunction blems such as hypoactive sexual desire disorder (HSDD) and
has upon the man and couple’s sexual life; and the fluctuating ejaculatory dysfunctions. Such an evaluation is a collaborative
influence of medication, lifestyle, and disease. By incorporating enterprise between the clinician and patient that offers the
these issues into a global assessment of sexual problems, one patient a fresh perspective on the problem. The clinical syn-
arrives at a more accurate and comprehensive understanding thesis derived from this process serves as a pragmatic road
of what precipitates and maintains the ED. map for treating all the biopsychosocial variables identified
Additionally, the biopsychosocial model enables stepwise that precipitate or maintain the symptom of ED.
treatment recommendations in both the psychological and Finally, there are diagnostic scales that clinicians may
biological domains. The model also explains the failure of utilize to supplement the sexual history. This chapter also
treatments for biological problems that ignore relevant psy- briefly reviews these scales, specifically addressing how they
chological contributions, and psychological treatments that may best be utilized in assessing ED.
disregard the biomedical factors.
Biomedically, ED may be a symptom and latent signal Approach to the assessment
for cardiovascular disease,8 a complication of diabetes or
hypertension, an unfortunate consequence of a radical pros- It is important that the patient and clinician are mutually
tatectomy, or an adverse side effect of medications, like beta- involved in the assessment process. Taking a collaborative
blockers.9 Psychologically, interpersonally, and contextually, approach, the clinician collects the sexual, medical, and psycho-
ED may stem from excessive performance anxiety or distracti- logical information, which he or she synthesizes into a cohe-
bility, depression, a deteriorating interpersonal relationship, sive treatment plan. When questions are asked in a logical and
substance abuse, or stress from life events that threaten to empathetic manner, the patient often gains a fresh perspective
overwhelm the psychological resiliency of the man.10 on the multiple issues related to his sexual problem.

184
 The biopsychosocial evaluation of erectile dysfunction 185

When a patient (and potentially his partner) begins assess- • Was the onset of the ED gradual or dramatic? If dramatic
ment, they often characterize the ED in phrases such as, ‘My look for temporal precipitants (e.g. patient started a new
penis doesn’t get hard any more’. The patient usually has an medication, patient was laid off from his job).
unsophisticated view of his ED and the impact on his life. • Course of the ED: has it become better or worse over time?
Often he is unaware of the relationship between his symptom Delineate what led to any improvement or any worsening,
and multiple disease processes, and similarly he fails to appre- and delineate specific times when the problem was better
ciate whether the sexual dysfunction is a result of, or is causing, or worse.
disruptions in his relationship or problems in his psychological
health.13
Although the majority of partners do not participate in the Current experience
initial assessment meeting, when present, their perspective is Ask the patient to describe a recent sexual experience.
frequently illuminating. Often, the partner has important
insights regarding the relationship dynamics and is an impor- • Ask the patient to describe in detail his last sexual
tant ally in the success of any treatment intervention.14 experience and what he was thinking and feeling at each
The assessment begins by focusing on the presenting point.
complaint (the ED), and branches out to assessing other areas
of sexual function. The medical history is then obtained, Probing what the man was thinking and feeling at each point,
followed by a history of social relationships and mental health and the partner’s response, illuminates the process. For exam-
factors. The flow of the questions should be qualitative and ple, did he wish to avoid lovemaking, have little confidence he
naturalistic. The assessment outline that follows is meant could achieve an erection, was he angry at his partner, or
to guide the clinician from the first-person standpoint. Each afraid of her contempt, and so on. This will help to identify
clinician has his/her own personal style and our suggestions the degree of performance anxiety, lack of confidence, distract-
are not meant to supplant their technique. ibility, attraction to the partner, the partner’s response, and
when during the course of lovemaking the patient might have
lost his erection.
Introduction
We begin by asking the patient ‘What brought you in to see
Treatment avoidance
us?’ Or, if we know his visit concerns a sexual problem, we ask
him to clarify the nature of his sexual problem. If you find that ED was present for more than 6 months prior
to the current evaluation, inquire as to why the patient did not
• What brings the patient in for their appointment? come in sooner. This is important because it may predict the
• What is the nature of the sexual problem? issues that could lead to early discontinuation of treatment.
It is equally important to ascertain what motivated him
to present at this time. These motivations may be utilized to
Clarification of the sexual problem help him to continue with treatment. Some men are moti-
Even though the patient has self-diagnosed his ED, ensure vated to seek treatment because of spousal pressure or con-
that the problem presented is not HSDD, premature ejacula- cern. Alternatively, avoiding treatment may have served a
tion, or delayed ejaculation. Sometimes, patients may use the positive function at some point in the marriage when the
term ED to describe other sexual problems or multiple sexual spouse was depressed, or it may have preserved the quality
issues. If the patient acknowledges multiple sexual problems, of the relationship when a spouse was unwilling to be
take a separate history for each dysfunction (see below). Ask sexual.13,15
about other sexual dysfunctions including:
• Determine the patient’s current motivation for treatment.
• HSDD or lack of sexual desire; • If the symptom has been present for more than 6 months,
• premature ejaculation; and determine what prevented him from coming in sooner.
• delayed ejaculation. • Assess the degree of denial, embarrassment, and resistance
to treatment.
• Assess if others in the patient’s life may have suggested that
Ascertaining the onset and course he receive treatment.
of the erectile dysfunction • Find out about the partner’s response to his seeking help.
These questions will clarify whether the ED is lifelong or
acquired, and what factors precipitate and maintain the
dysfunction. Previous treatment for ED
Ascertain if the patient has been previously treated for ED,
• When did the patient first notice the ED symptoms? what type of treatment he had, and why he might have stopped.
Although the patient offers a date, ask if the problem For example, the previous treatment may have focused solely
ever occurred before the given date. Often patients fail on a psychological approach, ignoring relevant biomedical
to report previous episodes of ED unless specifically features. Additionally, reviewing the patient’s previous treat-
asked. ment experience may reveal barriers that could render the
186 Textbook of Erectile Dysfunction

current treatment effort unsuccessful (e.g. unrealistic treat- Patient’s sexual desire
ment expectations, partner’s genital pain).13,16 Ask the following questions and consider the following
protocols if the patient acknowledges other sexual problems
• Determine if the patient has previously received treatment at the beginning of the assessment, or if the potential for other
for ED. sexual problems is exposed through questions about tumes-
• If so, what was the outcome? cence, intercourse, and so on.
• If patient discontinued treatment, determine the reason or
reasons for discontinuation. • Ensure that the patient has normal sexual interest by asking
• Evaluate whether the patient properly used the treatment. about how often he experiences sexual desire. We ask
For example, if using a phosphodiesterase (PDE) type 5 patients, ‘If you had an orgasm today, when would you
inhibitor, did he expect an erection without sexual stimula- expect that you would want to have another orgasm?’
tion, or did he know about the food interactions of certain • If the patient experiences desire less than once monthly,
PDE-5 inhibitors? take a careful history of his desire (e.g. what was it like
when he was 20, 40, and 60 years old? What medical or life
events, if any, were associated with its decline?)
Evaluating rigidity and tumescence
• Consider blood tests for testosterone levels.
Utilizing a 0–10 scale – where 0 equals absolutely no erec- • Review medications for agents that may decrease libido.
tion, 5 a midpoint where there is half tumescence and half
rigidity, and 10 a stand-up, rock-hard erection – ask the
patient to rate his erection under each of the following Ejaculatory problems
conditions: Ask the following questions if the patient acknowledges other
sexual problems at the beginning of the assessment, or if
• upon awakening;
the potential for other sexual problems is exposed through
• with fantasy alone, no physical stimulation;
questions about tumescence, intercourse, and so on.
• when trying to create an erection (masturbation);
• during foreplay with the primary partner; • How long after penetration does the patient ejaculate?
• with attempts at intercourse with the primary partner; and • How much voluntary control can he exert over when he
• with attempts at lovemaking with another partner. ejaculates?
• Are there times that he has difficulty reaching orgasm?
If the patient has been previously treated, determine the
• Ascertain if certain medical conditions (e.g. lower urinary
effectiveness of the treatment by asking the same sequence of
tract symptoms) have contributed to the ejaculatory
questions when he was using the intervention (e.g. to rate the
problem.18
quality of erections on a 0–10 scale during foreplay when
• Review medications for agents that may delay ejaculation
using sildenafil).
(e.g. selective serotonin reuptake inhibitors).
Such answers illuminate the severity of the patient’s ED and
its etiology. For example, patients who achieve 50% erections If premature or delayed ejaculation is acknowledged, take a
under all circumstances are likely to have a primarily organic detailed history of these problems and how they relate to the
form of ED. Variability in the ratings (e.g. patient reports ED. Consider treating the ejaculatory disorder.19
strong erections in the morning and with masturbation but
poor erections with foreplay and intercourse) is highly sugges-
tive of primarily psychogenic ED.12 The latter may point to a Patient’s sexual satisfaction
need for couples or sex therapy, medical treatments coupled
Enquire about the patient’s current level of sexual satisfaction.
with psychotherapy, or other options.12,13,17
Obviously the ED will diminish his sexual satisfaction,
although there may be other factors that can also contribute
Intercourse (e.g. an unenthusiastic sexual partner, patient not receiving
sufficient sexual stimulation). Think about how these might
Intercourse capability, frequency, and quality expose issues
affect treatment compliance.
that precipitate and maintain ED. These include expectations
of sexual relationship (both the partner’s and the patient’s
own) or sex-role demands.13,14 Ask about: Partner response
• frequency of intercourse; It is important to determine the partner’s response to the
• ejaculatory difficulty in intercourse; and ED. Ask whether the partner misses sexual intimacy, is
• satisfaction with intercourse. she angry or frustrated that the patient has delayed seeking
treatment, or is she pleased that sexual life is behind them?
If the patient reports no intercourse activity or has not been Will she be a willing and supportive partner in the patient’s
able to have intercourse for a sustained period: treatment?

• Ask about the frequency of non-coital sexual contact. • Does the partner know the patient is here for evaluation?
• Determine when he was last able to engage in successful • What is the partner’s response to the ED?
sexual intercourse. • Is she interested in resuming lovemaking?
 The biopsychosocial evaluation of erectile dysfunction 187

Does she have any sexual problems, such as low desire or Non-sexual relationships with a partner
genital pain? Women in the perimenopausal or menopausal Given that, on average, men wait 3–6 years after the onset of
years who are not taking hormone replacement therapy (HRT) ED to present for treatment, it seems obvious that the sexual
are more prone to genital pain with intercourse. It may be symptom can have a negative impact on the relationship.
necessary to talk with the patient and perhaps the partner After the onset of ED, the frequency of sexual activity drops
about the use of lubricants as an adjunct to intercourse or to dramatically as do expressions of intimacy, like hand-holding,
discuss non-coital sexual behaviors or, possibly, HRT.15 touching, and so on. Men wish to avoid embarrassment and
tend to withdraw emotionally. The partner assumes that he is
• Does the patient’s partner have any medical problems that no longer attracted to her or, in some cases, she may think
would interfere with resuming lovemaking? that he is involved with someone else. Additionally, she stops
• Does the partner have any sexual problems? initiating lovemaking, sensing his discomfort or disinterest.
The relationship becomes more like a brother–sister relation-
Medical history ship than that of two lovers. Thus restoring sexual intimacy
must overcome the relationship obstacles that have arisen
Chronic illnesses, medications, and surgeries may be causes
during the years of asexuality. Additionally, issues with trust,
of ED. It is necessary to ask about all medical conditions,
infidelity, sex-role demands, and power struggles are frequently
medications, and surgeries, as well as the psychological impact
identified as interpersonal problems in partner relationships
of the illness or its treatment, on the patient. The temporal
by those with ED.12,13,16,20,21 It is vital to ascertain the dynamics
relationship between the diagnosis or beginning a medication
and solidarity of the partner relationship of the patient, and
and the onset of ED may be very important. Ask about:
the partner herself. Ask about the following (whether or not
• chronic illnesses; the partner is attending the assessment):
• medications;
• satisfaction with current partner relationships;
• surgeries;
• previous relationships and sexual functioning within those
• the temporal relationship between diagnosis of an illness
relationships;
and ED;
• the impact of ED on the current relationship;
• the temporal relationship between beginning a medication
• struggles over power, control, intimacy, or finances with
and ED; and
the partner;
• the relationship between a surgery and ED.
• any medical conditions that the partner has that interfere
It is important to ask the patient about current or past with the sexual relationship;
diagnosis of Sexually Transmitted Infections (STIs). Ask • the partner’s level of sexual desire and overall sexual
the patient if he has ever been diagnosed with an STI. If he functioning;
answers yes, the clinician should ask about treatment and the • the partner’s mental health; and
psychosocial impact diagnosis has had, and should counsel • current stresses on the relationship (e.g. money, in-laws,
the patient accordingly. children).

• Have you ever been diagnosed with a sexually transmitted

infection (STI)? Vocational life and patient occupation
• Have you been treated for an STI? If so, what did treatment Work-related stress or concerns about financial well-being
consist of? may contribute to or maintain ED. Evaluate the following:
• What was the psychosocial impact of being diagnosed with
an STI? • work satisfaction;
• stresses at work; and
• threat of job loss or unemployment.
Lifestyle factors
Lifestyle factors such as cigarette smoking, excessive con- Men tend to be psychologically naïve concerning how stress in
sumption of alcohol, and substance abuse have all been their lives produces physical symptoms. They are able to
associated with diminished erectile function. ED has been acknowledge that work stress may result in headaches or
shown to be more prevalent in some illicit substance abusing stomach problems but seem less in tune with the impact of
groups than in the general population.9,16,20 Additionally, work stress on their sexual function.
partners can be turned off by the man’s obesity, smoking,
or alcohol consumption. Without some behavior change,
Major stress and stress management
ED treatment is not likely to succeed. Assessment of risk
behaviors should include: Life stressors, such as bankruptcy, children with addiction,
ill parents or siblings, or the diagnosis of a serious health
• smoking; problem in the patient or partner, and how the patient under-
• alcohol consumption (if high, take a history of alcohol stands and manages these stressful issues can contribute to
abuse); ED. Combined exposure to acute and chronic stress, as well as
• drug use (take a history of substance abuse); and internal attributions for the source of stress, contributes to
• the partner’s response to these lifestyle factors. erectile difficulties.20
188 Textbook of Erectile Dysfunction

• Ask the patient about major stresses in his life, and • The patient has acquired ED that started 6 years prior
ascertain how he deals with them. to evaluation and that has become progressively worse.
He has both diabetes and hypertension, and he takes
medication that might cause ED. He has no symptoms
Mental health history of depression or other affective disorders, but he is expe-
Mental health disorders like clinical depression have been riencing relationship struggles with his wife.
related to ED as a precipitating and maintaining factor, and as
an inhibitor of successful psychological treatment.10,13,14,16 The clinician can outline the following treatments:
Additionally, performance anxiety, distractibility, and negative
• PDE-5 inhibitors, intracavernosal injection therapy, and
expectations of success exacerbate the ED. Ascertain potential
marital counseling.
mental health diagnoses by asking about symptomatology
related to ED-contributing disorders: The clinician must decide whether to offer all the treatments
concomitantly or whether they should be staged. Should the
• performance anxiety and distractibility;
marital therapy precede the ED treatment or vice versa?
• depression – mood, sleep, appetite, decreased energy
When offering treatment recommendations the clinicians
levels, outlook on the future, suicidal ideation or wishes,
should:
libido, prior history of depression or a family history of
depression; and • discuss with the patient the necessity for any further diag-
• generalized anxiety disorder – shortness of breath, racing nostic testing (e.g. nocturnal penile tumescence);
heart, decreased concentration, nervousness or agitation, • discuss all treatment options with the patient in terms of
sleep disturbance, excessive or unrealistic fears, worry. the potential benefits and side-effects;
• instill hope that the sexual problem can be improved and
note that there are multiple options available to help the
Scales to assess ED
patient;
Self-administered questionnaires are powerful tools in the • ascertain if the patient’s expectations regarding treat-
evaluation of ED.22 Two excellent measures are the Sexual ment are realistic and, if not, help patient to set realistic
Health Inventory for Men (SHIM)23 and the International expectations;
Index of Erectile Function (IIEF).24 The SHIM is an abbre- • review the potential barriers to successful resumption of
viated and slightly modified form of the IIEF. lovemaking and the use of medical or psychological treat-
The SHIM is a five-item Likert-type scale that diagnoses the ments, ascertaining if any of following interfere with the
presence and severity of ED. A 5-year review on the SHIM patient’s treatment – length of abstinence, decreased sexual
revealed that it is a useful, quick, and inexpensive tool that can interest, partner disinterest, a partner who is unaware that
be used to complement clinical judgment for the diagnosis, the patient is coming for treatment, non-sexual relation-
treatment, and management of ED. ship problems, depression in the patient or his partner,
The IIEF contains 15 items that are divided into five unique medical problems in either partner;
domains: erectile function, intercourse satisfaction, orgasmic • answer the patient’s questions; and
function, sexual desire, and overall satisfaction. It is most • set up a follow-up appointment.
useful for assessing erectile function, intercourse satisfaction,
and overall satisfaction.
Questionnaires to assess depression may also be a helpful
adjunct to the clinician. Two well-validated measures for
Conclusion
depression include the Beck Depression Inventory25 and the A biopsychosocial evaluation results in the identification of
Center for Epidemiological Studies Depression Scale.26 all the relevant biological, psychological, interpersonal, and
contextual variables that blend together to precipitate and
maintain the distressing symptom of ED. Such a carefully
Clinician synthesis of all biological, psychosocial, and crafted evaluation results in patients having realistic treatment
sexual variables that appear to be related to the expectations, a fresh perspective on their difficulties, optimism
erectile dysfunction that they can be helped, and a positive attitude toward treat-
Once all of the information has been collected, the clinician ment. These factors will probably result in improved treatment
can now combine his or her clinical judgment and biopsycho- compliance. Validated questionnaires can serve as a useful
social correlates of the patient’s ED to formulate recommen- adjunct to the evaluation but are no substitute for the clinician
dations. An example follows. taking a careful and comprehensive history.
 The biopsychosocial evaluation of erectile dysfunction 189

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26 Erectile dysfunction: the
couple context
William A Fisher, Alexandra McIntyre-Smith, and Michael Sand

Introduction sample of 2810 subjects, Wagner et al. found that female

partners of men with ED were considerably more likely to
Erectile dysfunction (ED) is a prevalent1–3 and distressing4,5 have a sexual dysfunction of their own, compared with
condition experienced by millions of men1–3 and their female partners of men who did not have ED.19 Women
partners6,7 worldwide. ED has predictable negative effects on who indicated that their partner had ED (compared with
sexual and relationship functioning of both members of the women whose partners did not) reported substantially higher
couple.8–15 It may be viewed as a shared sexual dysfunction rates of inhibited sexual interest (60% vs 29%), lubrication
that has reverberating negative effects not only on sexual and problems (44% vs 11%), and orgasmic difficulties (52% vs
relationship satisfaction, but also quality of life. In the era of 20%). Parallel findings are reported by Chevret et al.20 In a
effective phosphodiesterase (PDE) type 5 inhibitor therapy, study of 721 French couples, these investigators reported
ED is often reduced to medical management focusing mainly that female partners of men with ED had lower overall sexual
on the functionality of the penis, to the exclusion of the patient satisfaction, lower sex drive, and lower overall life satisfaction
and his partner’s sexual and relationship issues.11,12,16 There is than female partners of sexually functional men. In related
consistent evidence to suggest that Master and Johnson’s research, Chevret et al. found that women’s sexual satisfac-
assertion that ‘…there is no such thing as an uninvolved tion, sex drive, and general life satisfaction declined as a
partner…’ in couples in which there is a sexual dysfunction17 direct function of the decline in the male partner’s ability
is as clinically relevant today as when first proposed four to penetrate and to maintain penetration in penile–vaginal
decades ago. intercourse.21 Convergent results are reported by Çayan
In accord with the perspective that ED may be viewed et al., who found that Turkish women whose partners had ED
as a shared sexual dysfunction affecting both men and their (38 subjects) had lower female sexual function inventory
partners, the current chapter examines ED in the context of (FSFI)22 scores on every dimension, including sexual arousal,
the couple. It reviews research on the effects of ED on the lubrication, orgasm, satisfaction, and pain, compared with
female partner’s sexual satisfaction, on the female’s partner women whose partners did not have ED (49 subjects).23 Inter-
influence on the male partner’s inclination to seek treatment dependence of couple sexual function was yet again docu-
for ED, on couple communication and non-communication mented in a study of 1768 patients registered in general
about ED, and on the effects of treatment of ED on the female practices in England.8 Among men and women who indicated
partner. that they had a sexual problem, 23% reported that their
The chapter concludes with suggested strategies for inte- partner had a sexual problem as well; only 14% of men and
grating the female partner into the ED treatment paradigm. women who did not have a sexual problem reported that their
We note that this discussion situates ED in the context of partner had such a difficulty.
male–female couples and does not address ED in male–male Fisher et al. provide an illustration of the impact that male
relationships, owing to the fact that existing research focuses partner ED has on female partner sexual function in a multi-
on heterosexual relationships. Based upon preliminary national study of 293 heterosexual couples in which the male
evidence,18 and pending evidence to the contrary, we believe partner had ED.9 These investigators report that male and
that many of the issues discussed here may generalize to male– female partners showed substantial agreement in their per-
male couples.17 ceptions of the male’s ED as mild, moderate, or severe, and
substantial agreement in their views of the man’s ED as a tem-
porary or permanent condition. Critically, males with ED and
their female partners both retrospectively reported substantial
Erectile dysfunction: a shared decline in the frequency of couple sexual activity after the
sexual dysfunction development of the male partner’s ED. Convergent results
were observed by Blumel et al. in a sample of 534 otherwise
Considerable evidence confirms the comorbidity of ED healthy middle-aged women who had ceased partnered sexual
in the male with impaired sexual function in the female activity;24 male partner ED was the most frequently cited rea-
partner. For example, in a nationally representative Swedish son for cessation of partnered sexual activity among women

190
 Erectile dysfunction: the couple context 191

100 100

Women responding ‘almost always’

Women responding ‘almost always’

Pre-ED Partner using PDE-5 inhibitor

Currently 85 Partner not using PDE-5 inhibitor
80 74 75 80

or ‘most times’ (%)

or ‘most times’ (%)

64 *
60 60 * 56
54
* * **
47 46 43 46
* 40
* 39 40
40 33 30

20 20
*
7
4 4 2
0 0
Sexual Sexual Orgasm Pain Satisfaction Sexual Sexual Orgasm Pain
desire arousal during sex desire arousal

Figure 26.1 Women partners of men with erectile dysfunction Figure 26.3 Association of partners’ use or non-use of phos-
(ED) – retrospective reports of declines in sexual desire, sexual phodiesterase (PED) type 5 inhibitors on the sexual experience
arousal, orgasm, and sexual satisfaction (after J Sex Med 2005; of women partners of men with erectile dysfunction (after J Sex
2: 675–84).9 ∗p < 0.05. Med 2005; 2: 675–84).9 ∗p < 0.05.

100 dysfunction may lead to development of ED in the male.

Women responding ‘almost always’

Mild
Moderate In this regard, Speckens et al. compared the sexual and relation-
* Severe *
80 74 74 74 * 74 ship functioning of female partners of 71 men with organic ED
or ‘most times’ (%)

65 63 65 63 67 (n = 71) and 34 men with non-organic ED.14 Female partners

60 * of men with non-organic ED reported higher levels of sexual
* 50
45 dysfunction, including vaginismus and dyspareunia, predat-
40 *
32
ing onset of the male partner’s non-organic ED, as well as
higher levels of current relationship tension, suggesting that
20 female sexual dysfunction may contribute to the development
4 2 4 of ED in the male partner, at least in the presumably non-
0 organic case. Similarly, McCabe et al. reported that Australian
Sexual Sexual Orgasm Pain Satisfaction
desire arousal during sex men with ED (compared with men who did not have ED)
reported greater perceived or directly experienced pressure to
Figure 26.2 Association of male partners’ self-reported severity perform sexually, suggesting a female partner role in the
of ED and female partners’ sexual experience (after J Sex Med development or maintenance of ED.25
2005; 2: 675–84).9 ∗p < 0.05. In addition to comorbidity of male partner ED and female
partner sexual dysfunction, some evidence exists to link ED
under 45 years of age. Moreover, of central relevance to the with couple relationship concerns. For example, McCabe
consideration of impairment in female partner sexual func- reports that in a sample of sexually functional and sexually
tion as a result of ED, Fisher et al. found that women whose dysfunctional men, lower levels of multiple aspects of couple
partners had ED retrospectively reported that significant and intimacy (emotional, social, sexual, recreational, and intellec-
substantial declines in their own sexual desire, sexual arousal, tual aspects) were reported by men with ED, as were lower
orgasm, and satisfaction had followed the male partner’s levels of several quality of life measures.26 Similar findings for
development of ED (Figure 26.1).9 These investigators also reduced quality of life are reported by Tan et al. in a study of
noted an association between the severity of the male part- a large sample of men with and without ED drawn from five
ner’s ED and the extent of decline in the female partner’s regions in Asia.15 Also in this vein, in an internet-based study
orgasm and sexual satisfaction (Figure 26.2). In addition, of 700 US men aged 40–70, 111 men with ED reported lower
female partners of men with ED who had utilized PDE-5 levels of relationship function compared with 589 men who
inhibitor therapy reported better sexual functioning (i.e. lesser did not have ED.27 In a related study of a small sample of
declines in sexual desire, arousal, and orgasm) than female 30 men with ED and their partners, findings indicated that
partners of men who had not used PDE-5 inhibitor therapy men with ED attributed blame and responsibility for their
(Figure 26.3). sexual dysfunction to themselves more frequently than to
The possibility that the male partner’s ED contributes to other causes, that female partners of men with ED attributed
the development of the female partner’s sexual dysfunction9 is blame and responsibility to the male partner more frequently
strengthened by evidence reported by Riley,12 who reported than to other causes, and that blaming the partner for ED was
that 62% of female partners of men with ED have sexual dif- associated with poorer martial adjustment.13
ficulties of their own and ‘…in only 8% of cases did the female Further evidence of the interdependence of couple mem-
sexual dysfunction precede the onset of the ED’. Moreover, in bers affected by ED is provided by research concerning men’s
addition to the likelihood that the male partner’s ED may inclination or disinclination to seek treatment for ED.28 In a
contribute to the onset of female partner sexual dysfunction, large multinational cohort of 2912 men with ED, the odds that
we note that the reverse may also be true: female sexual men with ED had utilized PDE-5 inhibitor treatment more
192 Textbook of Erectile Dysfunction

than once were significantly increased among men with ED Couple communication about
who had spoken to their partner about their sexual dysfunc-
tion, among men with ED who perceived their partner to erectile dysfunction
be keen to find a solution to their problem, and among men
In view of the fact that ED is associated with impairment of
with ED who were fearful of losing their partner because of
sexual function in both partners, as well as suggestive evidence
their sexual dysfunction. Conversely, significantly decreased
that ED may be related to lessened couple intimacy and part-
odds of utilizing PDE-5 inhibitors were observed among men
ner blame, it would seem important to understand more
who perceived their partners to be uninterested in sex and
about the occurrence and impact of couple communication
among men who found it impossible to speak with others
about this sexual dysfunction.
about ED.
Findings concerning the extent of couple communication
Additional evidence of female partner influence on ED
about ED are sparse. It has been pointed out that, at least in
treatment is provided in a recent study of 293 men with ED
principle, men with ED may wish to communicate with their
and their female partners.29 Men with ED who had female
partners about their sexual dysfunction or they may not wish
partners who stated that ‘I would give almost anything to cure
to do so.32 Correspondingly, partners of men with ED may
his ED’ and that ‘Taking a drug to treat ED would be a good
wish to communicate about the sexual dysfunction or they
thing to do’ were significantly more likely to seek treatment
may be uninterested in doing so. Potential positive or negative
for their sexual dysfunction. Conversely, men with ED whose
results of a match between the communication wishes of men
female partners believed that ED had not seriously affected
with ED and their partners (i.e. both want to communicate
their sex life and who endorsed the view that ‘Taking a drug
about this subject or neither wishes to do so) or of communi-
to treat ED is very dangerous’ were significantly less likely to
cation mismatches (i.e. one partner wants to communicate
seek treatment. Similarly, in a large multinational sample of
and the other does not) may be significant but remain to be
2912 of men with ED, those who were influenced by their
investigated. Clinically, co-presentation of male and female
spouse or partner to see a physician about their sexual dys-
couple members for consultation about ED is a rare occur-
function were substantially more likely to have used PDE-5
rence in most treatment settings. Similarly, Mirone et al.
inhibitor therapy repeatedly compared with men who had not
report that in a sample of 12,761 at least somewhat commu-
been subject to partner influence.30
nicative male callers to an Italian ED hotline, only 59% of men
Further evidence of partner influence is provided in the
with ED reported that they had talked with their partner about
study by Tan et al. of 10,934 men from five regions of Asia.15
their sexual dysfunction.33 Moreover, a study by Klotz et al.
Among men with ED in this sample, the spouse or partner was
revealed that fewer than 40% of a German ED patient sample
reported to be the most common influence on ED treatment-
successfully treated with PDE-5 inhibitors shared the fact that
seeking behavior in four out of five regions, and there was a
they were using this treatment with their sexual partners,
strong correlation between a man’s concern about satisfying
including 21% of men with mild ED, 47% of men with mode-
his partner’s sexual needs and his likelihood of seeking ED
rate ED, and 93% of men with severe ED.34 Much remains to
treatment.
be learned about the frequency with which men and their
Additional evidence of the female partner’s influence on
partners communicate about ED, about the characteristics of
ED treatment is drawn from a study of a small sample of men
couples who do and who do not communicate about this sub-
with psychogenic ED who had a 6-week trial of PDE-5 inhi-
ject, and about the consequences of couple communication or
bitor therapy followed by a 6-week unmedicated follow-up
lack of communication about ED.
period.31 Higher odds for unmedicated recovery of erectile
Research undertaken by Fisher, Meryn, and colleagues
function in the follow-up period were found among men who
sought to address some of the gaps in knowledge about cou-
perceived that their partner supported continued PDE-5
ple communication concerning ED.6,7 These investigators
inhibitor treatment at baseline.
assembled a multinational sample of 449 men with ED and
In summary, observational evidence consistently demon-
429 partners of men with ED (not, however, partners of
strates the comorbidity of ED in the male with impaired
one another). Some of these men and women had commu-
sexual function in the female. Limited evidence suggests
nicated with their partner about ED and others reported
that the emergence of ED in the male partner may predate
minimal or no communication about this topic. As can be
development of sexual function concerns in the female, and
seen in Figure 26.4, men who reported absent or minimal
suggests that female sexual dysfunction may contribute to
communication about ED with their partner found this
emergence or maintenance of ED in the male partner in some
situation to be an emotionally costly one, with nearly three-
situations. While causal direction is not definitive, the inter-
quarters of these men reporting negative affective responses to
dependence of male partner and female partner sexual func-
the lack of communication with their partner concerning
tion appears to be the rule in couples affected by ED. Some
their sexual dysfunction. Men with ED reported an array
evidence also indicates that ED may be associated with male
of reasons for not speaking with their partners about ED
partners’ reports of reduced couple intimacy and reduced
(Figure 26.5), including couple-relevant reports that ED is
relationship functioning, and that partner blame for ED is
too embarrassing to talk about and fear that their partner’s
frequent and is associated with relationship distress. On the
reaction would make them feel worse than they already did.
basis of these findings, it seems reasonable to conceptualize
Strikingly similar reactions were found among 271 female
ED as an often-shared sexual dysfunction that may have rever-
partners of men with ED who had not communicated with
berating negative effects on couple sexual and relationship
their partners about ED; they experienced nearly identical
satisfaction.
 Erectile dysfunction: the couple context 193

80
74
70

60

% Responding 50

40
30
30 26 26 25
21 23
19
18
20

10

0
e

lty

ed

ed

us

ss

se
siv

te

se
ui

le
xio

he
m

at
tr a

es
en

lp
ha

ol

t
An
us

He
pr

Is

of
eh

As

De
Fr

y
pr

An
Ap

Figure 26.4 Emotional responses of 265 men with erectile dysfunction to lack of communication about this condition with their
female partner (after J Mens Health Gend 2005; 2: 64–78).6

I don’t have erection difficulties all the time 63

I think I need to see a physician first 71

I don´t know where or how to begin 66

It is too embarrassing to talk about it 58

I feel that my partner´s reaction may make

55
me feel worse

0 10 20 30 40 50 60 70 80
% Responding

Figure 26.5 Reasons provided by 265 men with erectile dysfunction for not talking with their female partners about their erection
difficulties (after J Mens Health Gend 2005; 2: 64–78).6

negative emotional reactions as a result of their lack of com- and understanding, mixed with feelings of embarrassment,
munication (Figure 26.6) and strikingly similar reasons for relief, and hope (Figure 26.9).
not talking with their partners about the sexual dysfunction In summary, evidence concerning the extent and impact of
(Figure 26.7), including entirely parallel feelings of embar- couple communication is limited and observational, but a
rassment and fear of making the male partner feel worse than number of patterns emerge from existing literature. First,
he already did. Firmly establishing common – but never communication between men with ED and their partners
shared – barriers to communication about ED, men with ED about ED seems to be remarkably infrequent in relation to a
and partners of men with ED reported again strikingly similar sexual dysfunction that is generally apparent to both couple
thoughts about what might motivate them to talk with one members and often has negative effects on both partners.
another about ED, including the mutual but unspoken beliefs Second, men with ED and female partners of men with ED
that they would talk with their partner about it if they thought appear to find failure to communicate about this topic to be
their partner wanted to talk about it, if they thought there was consistently emotionally costly and appear to avoid commu-
an effective treatment for the condition, and if they thought nication for identical reasons, those reasons having to do with
the condition would last a long time (Figure 26.8). We note as embarrassment, fear of hurting one another’s feelings, and
well the finding that among both 184 men with ED and 158 lack of trust that an effective remedy for ED may exist. Those
female partners of men with ED who had spontaneously com- couple members who have communicated about ED report
municated about ED, predominant feelings reported during a that initial conversations about this topic were more often
first conversation about this subject were feelings of support characterized by feelings of support, understanding, relief,
194 Textbook of Erectile Dysfunction

79
80

70

60

% Responding
50
39
40
31 31 29
30 26 25
19 22
20 15 17

10

0
e

lty

ed

ed

ss

ive

e
u
siv

te

se

es
ui

le
xio
m

at

ct

ct
tra

es

th
en

lp

je
ha

ol

tra
An
us

He
pr

Re
Is

of
eh

As

at
De
Fr

y
pr

Un

An
Ap

Figure 26.6 Emotional responses of 271 female partners of men with erectile dysfunction to lack of communication about this
condition with their male partner (after J Mens Health Gend 2005; 2: 64–78).6

I don’t want to make him feel worse than

71
he probably does

It is too embarrassing for him to talk about it 75

I think he needs to talk to a physician first 65

He does not have erectile difficulties all the time 65

I don’t know where or how to begin 64

0 10 20 30 40 50 60 70 80 90
% Responding

Figure 26.7 Reasons provided by 271 female partners of men with erectile dysfunction for not talking with their male partners about
their erection difficulties (after J Mens Health Gend 2005; 2: 64–78).6

Women and hope than by nervousness or embarrassment, and they

If I thought 48 Men
she/he wanted to presumably avoid the emotional costs reportedly occasioned
41
talk about it by couples who do not communicate about ED.
If there was an
effective 45
treatment 44
available
If I knew the 31
Shared benefits of treatment for
cause of my/his
condition
43 erectile dysfunction
If I thought my/his 27
PDE-5 inhibitor therapy has reliable and substantial benefit for
condition is going 34 ED symptom improvement or remission in men.35,36 More-
to last over, published reports indicate that PDE-5 inhibitor therapy
0 20 40 60 may result in improvement in men’s general mental health,37
% Responding relationship satisfaction,38,39 and depressive symptoms.40 The
Figure 26.8 Factors reported by 265 men with erectile impact of PDE-5 inhibitor or other treatment of male ED on
dysfunction (ED) and 271 female partners of men with ED that his female partner, however, is a separate and critically impor-
might have encouraged couple communication about ED (after tant one, given the shared nature of sexual dysfunction and
J Mens Health Gend 2005; 2: 64–78).6 the potentially shared impact of treatment of ED.
 Erectile dysfunction: the couple context 195

Supported 47 Men
Women
Understood 34

Embarrassed 33

Relieved 29

Hopeful 21

Supportive 42
Understanding 35

Nervous 29

Relieved 21

Hopeful 16

0 10 20 30 40 50
% Responding

Figure 26.9 Emotions experienced by 184 men with erectile dysfunction (ED) and 158 female partners of men with ED during initial
couple conversation about ED (after J Mens Health Gend 2005; 2: 64–78).6

Initial evidence, collected early in the era of direct physical function, intercourse satisfaction, and overall satisfaction.48
treatment of ED, indicated that the use of external vacuum Critically, female partners of men treated with sildenafil
devices resulted in increased frequency of orgasm and sexual reported increases in Female Sexual Function Inventory (FSFI)
satisfaction for both men and their female partners, as well as domains of satisfaction, arousal, and orgasm, and lessened
decreased psychiatric symptoms in men (but not their coital pain.
partners).41 Parallel findings were reported for patient and In yet another double-blind placebo controlled trial,
partner; with increases in intercourse frequency, arousal, Edwards et al. reported positive effects of treatment with vard-
orgasm, and sexual satisfaction following self-injection of par- enafil on 260 men and their partners, including improvements
paravine hydrocholoride and phentolamine mesylate.42,43 in both couple members’ confidence, ease of erection, plea-
At least eight recent studies have examined the impact of sure, satisfaction with erectile function, and satisfaction with
PDE-5 inhibitor treatment on men with ED and their female orgasm.49
partners. Ichikawa et al. reported on a small, self-selected In a related double-blind study of 611 men with ED and
Japanese sample of female partners of men with ED treated their partners, Ralph et al. report that vardenafil (versus
clinically with sildenafil.44 In this sample, 67% of female part- placebo) treatment resulted in a significant increase in patient
ners indicated some level of satisfaction with treatment and partner sexual satisfaction and that degree of improve-
and 67% wanted their partners to continue with treatment. ment in erectile function was strongly correlated with increases
Among the 20% of female partners who were dissatisfied in female partners’ satisfaction with treatment.50
with treatment, both partners indicated that therapy was not Two additional reports examined the impact of vardenafil
effective, that adverse side effects were experienced by the treatment on 229 men with ED and their female partners in a
male partner, or that the female partner had a concurrent double-blind placebo controlled trial.51,52 Results51 showed
sexual dysfunction. that vardenafil was efficacious in restoring erectile function in
Rosen et al. have reported open-label pilot research with a men with ED and that satisfaction with multiple domains
relatively small sample of men with ED and their female part- of sexual quality of life53 of patient and partner were restored
ners.45 Findings indicated that sildenafil treatment of the male to pre-ED levels in the majority of vardenafil-treated men
partner resulted in significant improvements in each domain with ED and their female partners (Figures 26.10 and 26.11).
of male sexual function, including desire, erection, orgasm, In addition, a pooled analysis of three double-blind,
and overall satisfaction. Notable significant improvements placebo-controlled studies involving the vardenafil treatment
were seen in female partners’ ratings of their arousal, pleasure, of 788 men with ED and their female partners demonstrated
and orgasm. that men with ED treated with vardenafil (versus placebo),
In a much larger, double-blind, placebo-controlled study of and their female partners, reported increases in multiple
the impact of tadalafil treatment on men with ED and their measures of sexual function including male and female part-
female partners, Althof et al. reported that treatment with ner reports of increased pleasure from sexual activity, satisfac-
tadalafil (versus placebo) was efficacious in improving erectile tion with orgasm, and satisfaction with medication.54
function.46 Furthermore, treated patients and their partners In summary, at least 10 separate studies – six of them
reported increased overall satisfaction with their sexual double-blind, placebo controlled studies involving all three
experience, with female partners reporting even more post- widely available PDE-5 inhibitor drugs and two non-blinded
treatment satisfaction than the male patients. studies involving vacuum constriction devices and intracaver-
In a double-blind, placebo-controlled study of 180 men nosal injections – consistently showed efficacy of treatment in
with ED and their partners, Heiman et al. reported that restoring erectile function for men with ED and substantial
sildenafil treatment effectively improved men’s International parallel improvements in multiple domains of the untreated
Index of Erectile Function (IIEF)47 domain scores for erectile female partner’s sexual function and sexual satisfaction, in
196 Textbook of Erectile Dysfunction

100 Summary
Three issues emerge from research concerning effects of
80 71* 69* treatment of male partner ED with PDE-5 inhibitors on the
female partner.
60
1. It seems clear that given even a low threshold of female
Placebo Vardenafil
40 partner support or agreement for treatment of the male
partner, both partners’ sexual function benefits substan-
20 16 15 tially from PDE-5 inhibitor treatment of the male’s ED.
2. It seems equally clear that treatment of the male partner
0 without addressing the sexual function of the female
n= 87 98 104 partner, particularly her experience of any discomfort
Week 12 LOCF with penetrative sexual activity, and her level of sexual
desire and interest or lack of interest in treatment of the
Figure 26.10 Proportion of couples in which males with
male partner, can prove problematic.
erectile dysfunction (ED) treated with vardenafil versus placebo,
and their female partners, both report return to pre-ED levels of
3. If either the male partner’s or the female partner’s
sexual quality of life. (After J Sex Med 2005; 2: 699–708).51 wishes concerning treatment are ignored, treatment and
∗p < 0.05. LOCF, last observation carried forward. patient ethics may be compromised, and counseling
the couple with a view towards achieving a mutually
acceptable compromise is indicated. Providing that even
reliable demonstrations that treating ‘him’ appears to benefit minimal attention is paid to addressing the wishes of
‘her’ as well. both the male and the female partner in management of
ED, it may often be possible to manage such situations
with brief discussion, and referral for more intensive
Selection of female partners in the studies counseling may not be necessary.
We note that selection of female partners in studies of the
impact of PDE-5 inhibitors on female partners of men with
ED could potentially be a crucial factor limiting the generali-
zability of these results. None of these studies, however, selec- Integrating the female partner into
tively enrolled only highly motivated or supportive female treatment for erectile dysfunction
partners. Rosen et al. recruited men with female partners who
were ‘willing to participate in the study’,45 Althof et al. recruited In light of the comorbidity of male partner ED with female
men with female partners who ‘provided written informed partner sexual function concerns, a considerable number of
consent’,46 Heiman et al. excluded only men with female part- influential clinicians have advocated approaches to the
ners with ‘significant dyspareunia or lifelong significant sexual management of erectile dysfunction that are couple inclusive –
dysfunction’,48 Edwards et al. recruited patients who had part- that is, approaches that attempt to address the sexual status
ners ‘willing to participate in the study’,49 and in still another and preferences of both couple members.11,57–61 Suggestions
study, female partners had to be ‘willing to participate in the for couple-inclusive approaches to the management of ED that
study, who had sexual functioning not consistent with a sex- integrate PDE-5 inhibitor treatment have been articulated for
ual dysfunction, and were not unmotivated to support treat- both the primary-care58 and sex-therapy setting.16,17,57,59–62 A
ment of their male partner’.51,52 While these procedures were recently published consensus document, based on the recom-
to a modest degree selective, they do not appear to have been mendations of general practitioners, family physicians, sexual
unduly so, and it is to be hoped that competent clinical medicine specialists, urologists, psychologists, and researchers
practice would generally screen out or clinically address men highly experienced in this area, and vetted by a wider group of
whose female partners are opposed to treatment or who report experts from around the word, established a number of sug-
dyspareunia or significant sexual dysfunction. Published gestions for a couple-inclusive approach to ED management
qualitative findings in fact indicate that female partners of including the following.58
men with ED who are treated with PDE-5 inhibitors have ‘…
mentioned various direct and indirect “pressures” which they • It is recognized that there may be patient or partner barri-
experienced once a partner commenced using […a PDE-5 ers, including patients’ beliefs, preferences, and cultural
inhibitor]. Some felt pressured to engage in sexual relations and religious influences, that may limit the clinician’s abil-
once a man had taken […a PDE-5 inhibitor]… A few women ity to include both partners directly in the treatment set-
commented that they had been satisfied with their sex lives ting. At the same time, patients may provide useful
prior to the advent of […the PDE-5 inhibitor] and the changes information about partners that can assist in appropriate
brought about by a partner’s use of the drug were not management of the male partner’s ED while taking into
welcomed.’55 At the same time, case reports have been pub- account the female partner’s situation and the couple con-
lished concerning female distress when the male refused treat- text as much as possible.
ment for ED, including ‘…couples whose marital situation • It is recognized that there may be clinician barriers,
worsened after the husband refused to take sildenafil for including available clinician time, training, and comfort
erectile failure’,56 in once case leading to divorce. level constraints, that may require management via
 Erectile dysfunction: the couple context 197

Female partners
100
Placebo Placebo (baseline)

Vardenafil Vardenafil (baseline)

80 Better
*
72 *
* * 69
* * 68 68 *
* * 64 * 65
64 63 63 64
LS mean score

60
Same as
prior to ED
40 37 39
34
31 31 31 32
29 29 29
33
31 31 30
29 29 30 29 29 29
26 27 25 26 27
24
20 23 Worse
19 20
18

0
Frequency Duration Ease of Ease of Ease of Pleasure of Carefree Pleasure Pleasure Partner
of sex of sex insertion achieving initiating anticipation feelings of orgasm overall pleasure
(a) orgasm sex

Male patients
100

80 Better

* * * * *
* 65 * 66 67 * 66 67
64 63 65
*
60 *
LS mean score

60 59

Same as
prior to ED
40
35 33
31 32
29 29
26 27
25 24 31 30 31
29 29 28 29
26 27
25 24 25 23 24
20 Worse
19 20 19 20
17
14

0
Frequency Duration Ease of Ease of Ease of Pleasure of Carefree Pleasure Pleasure Partner
of sex of sex insertion achieving initiating anticipation feelings of orgasm overall pleasure
(b) orgasm sex

Figure 26.11 Reported change in specific domains of sexual quality of life of males with erectile dysfunction (ED) and their female
partners, as a function of vardenafil versus placebo treatment of the male with ED. (After J Sex Med 2005; 2: 699–708).51 ∗p < 0.05.

strategies as diverse as investing time early in treatment of extent and nature of his communication with his partner
ED to avert repeat visits with treatment failures later on, to about ED and his view of his partner’s sexual concerns and
establishing a referral network for patients and partners level of support for treatment. A number of questions that
presenting with difficulties beyond the clinician’s level of clinicians may ask patients with ED in relation to their
expertise or comfort. partner’s sexual interest, concerns, and support for ED
• While it is preferable to bring both patient and partner treatment appear in Table 26.1.
into the treatment setting, this is often not practically • It may prove useful to provide specific information not
possible. Accordingly, the clinician may communicate to only to the patient with ED but to the female partner as
the patient the desirability of including the partner in the well, by way of providing the male patient with printed
treatment process at a later stage and in all possible ways, or internet-based information concerning topics that may
and the clinician can attempt to assess, via the patient, the assist with treatment efficacy and adherence and with
198 Textbook of Erectile Dysfunction

the female’s vaginal health, on dyspareunia, on self-image,

Table 26.1 Questions to help assess the patient’s level
and the like may be helpful as well.
of communication with his partner about his erectile
• Couple-based follow-up to monitor and adjust treatment
dysfunction, and levels of partner support.
in relation to patient and partner satisfaction or dissatis-
Have you spoken with your partner about your erection faction is crucial.63,64
problem?
Is your partner supportive of you getting treatment to
improve your erection? Summary
Does your partner have any concerns about the treatment?
Research into the management of ED with a couple-inclusive
Does your partner want to come and talk to me or to approach suggests that men may accept a couple approach in
another doctor about improving your sex life together?
the treatment of their ED in preference to alternative physical
Does your partner have any sexual health or other health treatments.65 We note as well that despite widespread clinical
issues that you know of? and research support for a couple-inclusive approach to ED
Is there anything else I should know to help me understand treatment that addresses the needs of both men and their
this problem? partners, no comparative tests of PDE-5 inhibitor therapy
After Can J Human Sex 1998; 7: 213–29.57
alone versus PDE-5 inhibitor therapy plus couple-inclusive
management could be identified in the research literature.
Such research would obviously represent a sought-after evi-
partner understanding and support. This may include dence base for couple-inclusive treatment. Until such research
information on the nature of ED, on treatment options for becomes available, the weight of evidence indicating the
this condition, on the recognition that ED may be a shared comorbidity of ED with female partner sexual concerns and
sexual problem that affects both the male and the female the generally quite positive impact of treatment of male ED on
partner, and on the likelihood that treatment may affect the female partner, provides a strong circumstantial basis for
both partners and that both partners may need to com- a couple-inclusive approach to ED therapy. At a minimum
municate about and accommodate themselves to treat- this will assess female partner sexual status and support for
ment. Information on natural effects of aging on sexual therapy, and follow-up of the effects of therapy in an effort to
desire and response, on specific effects of menopause on restore sexual satisfaction in couples affected by ED.

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tile dysfunction. Psychosom Med 2003; 65: 709–18. 130–6.
32. Dorey G. Partners’ perspective of erectile dysfunction: literature 51. Fisher WA, Rosen RC, Mollen M, et al. Improving the sexual
review. Br J Nursing 2004; 10: 187–95. quality of life of couples affected by erectile dysfunction: a double-
33. Mirone V, Gentile V, Zizzo G, et al. Did men with erectile dysfunc- blind, randomized, placebo-controlled trial of vardenafil. J Sex
tion discuss their condition with partner and physicians? A survey Med 2005; 2: 699–708.
of men attending a free call information service. Int J Impot Res 52. Goldstein I, Fisher WA, Sand M, et al. Women’s sexual function
2002; 14: 256–8. improves when partners are administered vardenafil for erectile
34. Klotz T, Mathers M, Klotz R, et al. Patients responding to phospho- dysfunction: a prospective, randomized, double-blind, placebo-
diesterase type 5 inhibitor therapy: what do their sexual partners controlled trial. J Sex Med 2005; 2: 819–32.
know? J Sex Med 2007; 4: 162–5. 53. Woodward JM, Hass SL, Woodward PJ. Reliability and validity of
35. Rosen RC, McKenna KE. PDE-5 inhibition and sexual response: the Sexual Life Quality Questionnaire (SLQQ). Qual Life Res 2002;
pharmacological mechanisms and clinical outcomes. Annu Rev 11: 365–77.
Sex Res 2002; 13: 36–88. 54. Rosen RC, Fisher WA, Beneke M, et al. The COUPLES-project: a
36. Hellstrom WJ, Gittelman M, Karlin G, et al. Padma-Nathan H. pooled analysis of patient and partner treatment satisfaction scale
Vardenafil for treatment of men with erectile dysfunction: efficacy (TSS) outcomes following vardenafil treatment. BJU Int 2007; 99:
and safety in a randomized, double-blind, placebo-controlled trial. 849–59.
J Androl 2002; 236: 763–71. 55. Potts A, Grace V, Gavey N, et al. ‘Viagra stories’: Challenging
37. Giuliano F, Peña B, Mishra A, et al. Efficacy results and quality- ‘erectile dysfunction’. Soc Sci Med 2004; 59: 489–99.
of-life measures in men receiving sildenafil citrate for the treatment 56. Wise TN. Psychosocial side effects of sildenafil therapy for erectile
of erectile dysfunction. Qual Life Res 2001; 10: 359–69. dysfunction. J Sex Marital Ther 1999; 25: 145–50.
38. Althof SE, O’Leary MP, Cappelleri JC, et al. Self-esteem, confi- 57. Basson R. Integrating new biomedical treatments into the assess-
dence, and relationships in men treated with sildenafil citrate for ment and management of erectile dysfunction. Can J Hum Sex
erectile dysfunction. J Gen Intern Med 2006; 21: 1069–74. 1998; 7: 213–29.
200 Textbook of Erectile Dysfunction

58. Dean J, Rubio-Aurioles E, McCabe M, et al. Integrating 62. Weeks GR, Gambescia N. Erectile Dysfunction: Inegrating
couples in ED treatment: improving the sexual experience of the Couple Therapy, Sex Therapy, and Medical Treatment. New York:
couple. Manuscript submitted for publication. Int J Clin Prac WW Norton, 2000.
2007. 63. Lue TF, Giuliano F, Montorsi F, et al. Summary of the recommenda-
59. Hawton K. Integration of treatments for male erectile dysfunction. tions on sexual dysfunctions in men. J Sex Med 2004; 1: 6–23.
The Lancet 1998; 351: 7–8. 64. Albaugh J, Amargo I, Capelson R, et al. Health care clinicians in
60. Leiblum SR, Rosen RC. Couples therapy for erectile disorders: sexual health medicine: focus on erectile dysfunction. Urol Nurs
conceptual and clinical considerations. J Sex Marital Ther 1991; 2002; 22: 217–32.
17: 147–59. 65. Wylie KR. Male erectile disorder: characteristics and treatment
61. McCarthy BW. Relapse prevention strategies and techniques with choice of a longitudinal cohort study of men. Int J Impot Res 1997;
erectile dysfunction. J Sex Marital Ther 2001; 27: 1–8. 9: 217–22.
27 Primary care evaluation
and treatment of erectile
dysfunction: American perspective
Richard Sadovsky and Martin Miner

Defining primary care patients visiting primary care clinicians has increased and
patients have become more ethnically and racially diverse.2
Primary care clinicians are the first point of contact with the The duration of visits to the doctor is decreasing, with a recent
healthcare system for many people in the USA. Although this study of the length of ambulatory visits to primary care clini-
care may be episodic or involve only a single visit initiated to cians showing a mean of 16.3 minutes;3 this is possibly asso-
meet a specific need, primary care clinicians usually provide ciated with the availability of non-physician support personnel
continuous and comprehensive care for patients using a and with the issues around health maintenance organizations
biopsychosocial model. This involves learning more about as payers. These and other changes, such as an increase in
a patient than just his or her chief complaints and most single-specialty and multi-specialty group practice, computer-
superficial needs. ization of the office, more complex reimbursement methods,
Primary care for adults is provided by a variety of clinicians, and an increasingly educated patient population, have occu-
including nurse practitioners, physicians’ assistants, and family pied some of the energy that would better be turned toward
physicians. The values and roles of individual clinicians are patient care and prevention of disease.
complex because they may depend on the person’s value system Health care clinicians have been ambivalent about sexuality
and practice model.1 Most primary care clinicians will rou- for a long time. Most early research was done by non-physician
tinely address problems with high morbidity and mortality, social scientists.4 Medical school instruction related to sex is
disabling conditions, conditions for which there are clear limited to some anatomy and physiology, information about
standards of care, and perhaps those with well-established AIDS and sexually transmitted diseases, and lectures on ‘alter-
management guidelines. The demands of their patient and the native’ lifestyles such as homosexuality. There is a conspicuous
personal interest of the clinician will also affect the choice of absence of courses on sex in general. Clinicians avoid discuss-
issues that the clinician addresses. ing sexual concerns even when a problem is suspected, citing
Issues that involve quality of life commonly fall into a lower lack of knowledge and skills as a common reason.5 Clinicians
priority category. Patients may not feel that they are important are often concerned that a sexual dysfunction like ED will
or clinicians do not recognize ‘improving quality of life’ as become a complex, time-consuming condition that cannot be
being a high priority. This is especially true when the quality- managed properly under pressures of current reimbursement
of-life issue involves very personal issues and more difficult methods.6 However, pioneering primary care clinicians, includ-
language. Addressing quality-of-life issues around sexual dys- ing both physician and non-physician clinicians, reviewed the
function are even more difficult, partly because there are impact of sexual problems on health and psychosocial issues
complex psychosocial issues involved and because treatments and reviewed possible management strategies.7,8
are not well standardized – except for erectile dysfunction The motivation for primary care clinicians to help patients
(ED). Social taboos about discussing sex or considering sex a with sexual dysfunction should be high (Table 27.1).9 Unfor-
legitimate personal need also hinder communication about tunately, while general sexual dissatisfaction is very high
sexual dysfunction. among men, reported at a rate of 75% noting at least one
problem with dissatisfaction, avoidance, infrequency, or non-
communication,10 70% of men with ED go untreated.11 Specific
Trends in primary care involvement sexual dysfunction is prevalent, reported in approximately
in sexual health one-third of men over the age of 18, with premature ejacula-
tion as the most common sexual dysfunction reported by
Many factors have recently changed the work of primary care men, followed by ED.10,12 Yet men continue not to seek treat-
clinicians. Trends in population demographics, the aging of ment, mistakenly believing that ED is a normal part of aging,
patients, managed care, and medical technology have altered or being embarrassed to discuss the condition with their
demand and actual primary care activity. The mean age of clinicians.

201
202 Textbook of Erectile Dysfunction

smoking and smoking-related illness, lower urinary tract

Table 27.1 The potential value of ED enquiry
symptoms (LUTS) associated with benign prostatic hyperplasia
and management
(BPH), depression, acute or chronic anxiety and stress, and
1. Resolve a prevalent disorder obesity all represent risk factors for the presence of ED.15–18
2. Successful treatment can improve negative self-image Organic ED is likely to be a reliable signal of systemic vascular
and diminished quality of life resulting from sexual disease and endothelial function and may even be the first
dysfunction for both patient and partner recognized evidence of the presence of yet-undiscovered
3. Improve depression vascular risk factors such as hypertension, hyperlipidemia,
4. Identify occult medical and psychosocial conditions: or diabetes.19 In a study of men seeking medical advice for
• Diabetes ED, many were newly diagnosed with a comorbid condition
• Hyperlipidemia after they had sought attention for the ED complaint. These
• Coronary artery disease and peripheral vascular included a new diagnosis of hypertension (18%), diabetes
disease (16%), BPH (15%), ischemic heart disease (5%), prostate
• Neurologic disease cancer (4%), and depression (1%).20 Up to 15% of previously
• Depression healthy men presenting with ED have abnormal blood glucose
• Relationship issues levels.21 Abnormal cholesterol profiles were discovered in 60%
• Environmental issues (e.g. socioeconomic problems) of men complaining of ED without a prior history of cardiac
• Other psychosocial concerns disease.22 In a study of 200 men with ED who underwent lipid
profiling (that had not been previously performed), 75% of
5. Minimize iatrogenic ED
these men with ED had dyslipidemia.23
6. Promote better overall health in men
7. Have a positive impact on intimate relationships, which
In a study involving patients receiving care in Canadian
contribute to psychosocial well-being and physical primary care clinicians’ offices, a significant relationship was
health noted between ED and hyperglycemia, diabetes, and the
8. Improve clinician–patient relationship metabolic syndrome.24 Another large self-reporting survey
9. Increase physician work satisfaction study noted that traditional modifiable risk factors for cardio-
vascular disease were independently associated with ED,
ED, erectile dysfunction. Adapted from Int J Clin Pract 2003; 57:
601–8.29
including diabetes (odds ratio 2.69), obesity (odds ratio 1.60),
current smoking (odds ratio 1.74), and hypertension (odds
ratio 1.56). These authors implied that mitigation of these risk
factors might not only ameliorate ED but also improve health
Experiencing a sexual dysfunction is highly associated with
outcomes.25
a number of unsatisfying personal experiences and relation-
Recent studies support the relationship between ED and
ships. Men with ED experience a diminished quality of life
actual cardiovascular disease. The first study using stress
when measured as low physical satisfaction, low emotional
myocardial perfusion computed tomography found that men
satisfaction, and low general happiness.13 Reports of low self-
with ED exhibited more severe coronary heart disease and left
esteem and relationship difficulties indicate the effect of ED
ventricular dysfunction than those without ED.26 A prospec-
on function and satisfaction with daily life activities. There
tive analysis of men randomly assigned to the placebo arm of
are also some preliminary reports that sexual dysfunction
the Prostate Cancer Prevention Trial (PCPT) revealed that
can contribute to initiating clinical anxiety and depression
men with ED are at significantly greater risk (p < 0.001) of
syndromes. If ‘morbidity’ is defined as the consequences of an
having a cardiovascular event – angina, myocardial infarction,
abnormally functioning, diseased organ or body system, then
or stroke – than those without ED. Furthermore, the findings
ED clearly has a recognizable morbidity.
indicate that the relationship between incident ED (the first
report of ED of any grade) and cardiovascular disease is
comparable to that associated with current smoking, family
Inquiry and management of erectile history of myocardial infarction or hyperlipidemia.27 A subse-
dysfunction as a primary care priority quent study of almost 300 men with symptoms of coronary
artery disease reported that these men experienced ED symp-
Several factors make primary care the ideal place for discus- toms first, on average 3 years beforehand.28
sions about sexual issues.14 First, longitudinal and personal Once it is recognized that ED is more than simply a quality-
relationships with patients are an asset in discussing and of-life issue, it is a simple step to acknowledge that ED is a
resolving sexual problems; second, the multifactorial issues very common and important problem among patients seen
around ED are appropriately evaluated by the patient’s clini- in a primary care office.29 If ED is truly a signal of endothe-
cian; and third, the long-term follow-up that is needed to be lial dysfunction and both of cardiovascular disease risk as
certain that a sexual dysfunction is resolved is well suited to well as of actual disease, then identifying ED, especially vascu-
primary care. logenic ED, becomes a priority.30 ‘A flagging penis should
Recently, ED has been found to be more relevant than raise the red flag of warning, to evaluate the patient for arterial
simply being a quality-of-life issue with psychosocial mor- disease elsewhere’.31 ‘By monitoring a patient’s sexual well-
bidity. The comorbidities most often presenting with ED are being, added insight into the progression of his cardiovas-
those frequently seen in primary care practices. Diabetes, cular disease can be obtained and his treatment adjusted
dyslipidemias, hypertension, coronary artery disease, cigarette accordingly.’32
 Primary care evaluation and treatment of erectile dysfunction: American perspective 203

Clinicians are accustomed to asking patients about exercise

Table 27.2 Discussing sexual matters
‘tolerance’ or ‘capacity’ in order to evaluate cardiovascular
function and reserve. With the recognition of the relation Your approach sets the tone:
between ED and cardiovascular disease, it would not be diffi-
• Take the initiative
cult for clinicians to add a brief question about erectile ‘toler- • Use language that is simple and direct
ance’ or ‘capacity’ with the understanding of potentially • Maintain a sense of privacy and confidentiality
identifying cardiovascular disease risk factors or actual disease • Keep your attitude non-judgmental, caring, and respectful
among men who report ED. Some epidemiologic experts have • Provide explanations and allow for questions
noted that the higher death rate and likely lower health status • Acknowledge and explore the patient’s responses
among middle-aged men in the USA compared with England • Promote on optimistic attitude
is probably caused by the increased prevalence of hyperten- Taking a sexual history:
sion, diabetes, and cardiovascular disease.33 Although the
death rate evens out as the men get beyond middle age, the • Routinely ask all patients about their sexual history
• Add sexual health questions on patient history forms
increased rate of vascular risk factors in the USA puts even
• Use a screening test to uncover erectile dysfunction
more obligation on American clinicians to inquire about erec-
when performing a comprehensive evaluation
tile function among middle-aged men. If clinicians more
thoroughly screened ED patients for cardiovascular disease, Give patients the opportunity to discuss sexual problems
risk reduction might offset its development or progression.34 they now have or may develop in the future:
We are also learning that being part of a good relationship • Discuss sexually transmitted disease prevention
is not just a quality-of-life issue, but can also promote good
Ask questions to clarify the problem more precisely:
health. A popular idea in the lay press – that loving, supportive
relationships can make you healthier – has support in clinical • How severe is the problem?
studies. The breakdown of a significant personal relationship • What caused the problem?
• How long has the problem existed?
is one of the most stressful life events and has an impact on
general health and quality of life.35 Although sex is not essential
for supportive, healthy relationships, the amount of sexual
intimacy in loving relationships has been correlated with ease with one of these more active approaches and incorporate
relationship satisfaction.36 ED negatively affects relationships, it into discussions with patients. Questions about sexual mat-
with one survey of ED sufferers noting that 80% of respon- ters are appropriate either during the initial formal history,
dents indicate some form of relationship difficulty because of during the review of systems, during a follow-up visit, or during
their ED and 12% say that the condition prevented them from appropriate stages of the physical examination. These questions
forming relationships.14 need to be sensitive to cultural, religious, and educational dif-
ferences. Using terminology that is clear, simple, and respectful
of the patient’s feelings can facilitate communication, as can
Talking to patients and partners the use of synonyms that will increase the likelihood that lan-
guage common to the patient will be used. The sex difference
Patients may either present with symptoms of ED or have risk between a female clinician and a male patient may initially
factors that prompt screening. Since the yield of screening is cause some discomfort, but many men report feeling more
related to the frequency of ED in the population, men who comfortable discussing sexual issues with female clinicians.37
should be screened include: those over 40 years of age; those Being polite and respectful, yet displaying an appropriate level
with a predisposing comorbidity such as cardiovascular disease, of interest in the patient’s personal life, is the best overall
diabetes, or depression; and anyone else who the clinician approach to encouraging conversation about sexual activity.
feels may be having difficulty with physical intimacy. Initially using ‘open-ended’ questions, such as ‘Tell me a
Patients with sexual concerns report feeling most comfort- little about your sexual activities?’, ‘Have you been sexually
able discussing these issues with their family clinician and active with a partner in the past 6 months?’, or simply ‘How’s
expect to receive advice and treatment.12 Introduction of your sex life?’, encourages the patient to speak more openly.
sexual activity as a legitimate topic for conversation with In men with chronic illnesses or risk factors for ED, ask ‘How
patients can be done passively or actively. Examples of passive has your illness affected your sex life?’ This question may
approaches to engaging the patient would be to leave pam- be preceded with a brief statement about the importance of
phlets about sex-related topics or self-evaluation material sexual activity to an individual’s health: ‘In order to protect
such as the Sexual Health Inventory for Men (SHIM) in the your health, I need to ask you some questions about your
waiting room or to hang educational posters in patient care sexual life. Are you romantically or sexually involved with
areas. Inclusion of one or more questions about sexual activity anyone?’ Occasionally a question about ‘concerns’ is useful
in a printed history form completed by the patient requires because it is both open-ended and problem oriented:18 ‘Do
more active patient participation. you or your partner have any sexual concerns?’ Offering
Clinicians initiate more of the verbal interaction than do some specific examples might also be useful: ‘Do you or your
patients, and clinicians control the content, pace and length of partner have any sexual difficulties or concerns such as with
the interview. A truly active approach to initiating discussions your interest level, erections, ejaculation?’ Questions should
about sexual activity is probably the most efficient discussion- be used that cannot be answered by a simple ‘yes’ or ‘no’ since
initiating technique (Table 27.2). Clinicians should develop yes–no questions will close off discussion.18
204 Textbook of Erectile Dysfunction

Another technique is to use a permission-giving question time, recognition should be made of the patient’s problem
that tells the patient that you will not be surprised if he reports or concern and another time should be scheduled to discuss
a problem and that demonstrates respect and sensitivity to the it further. Just spending time clarifying the nature of the
patient. An example of this would be to say to a patient with problem can lead to more effective treatment and may, in
diabetes, ‘Many of my male patients with diabetes report some itself, be therapeutic.41 Alternatively, the patient can be given
difficulty having an erection. Have you noticed any problems?’ a referral to another clinician if the primary care clinician
This allows the patient to answer openly without anticipating is uncomfortable, but even a proper referral requires some
that the physician would be surprised or shocked by their further exploration.
answer. Using synonyms such as ‘getting hard’ or ‘coming’ Knowing about a patient’s sexuality is important to the
may help the patient to understand the question better. clinician who is truly interested in the patient’s health and
Encouraging a patient’s response with ‘facilitating’ gestures happiness. ‘Do you have sex with men, women, or both?’ is
such as good eye contact, nodding affirmatively, summing up a common way of demonstrating an acceptance of varying
what the patient has told you, and expressing optimism that sexual orientations. Using the term ‘partner’ rather than
the problem can be resolved improves communication. ‘spouse’ or ‘wife’ conveys the fact that the clinician is not
If the primary care clinician plans to manage sexual dis- making any assumptions regarding sexual orientation. Homo-
orders further, it is helpful to obtain more information about sexual men are more likely to confide important information
the characteristics of the specific problem. The first charac- and to follow a provider’s advice if they feel accepted and
teristic is to determine whether the problem is psychogenic or understood. Patients must be able to involve lovers or other
organic. To distinguish most psychogenic ED disorders from support people in examinations and treatment decisions.
potentially organically induced disorders, ask a combination
of three questions:
1. ‘Do you ever wake up with an erection before having to
The next step after erectile
urinate?’ dysfunction has been identified
2. ‘If you experiment and touch yourself when your partner
is not around, can you get an erection?’ The primary care clinician who identifies the patient with ED
3. ‘Can you get an erection at any time of night or day, has accomplished a lot. This information can be used to:
during any form of sexual activity, with any partner?’
• initiate evaluation for psychologic and organic comorbid
A positive response to these questions indicates stress or conditions, including risk factors for neurovascular disease;
anxiety as the trigger of the ED, rather than a physical cause or • refer the patient to an appropriate clinician;
a medication adverse effect. • open up further discussion to confirm whether ED is
The second characteristic to determine is whether the the primary sexual problem or whether it is secondary to a
problem is lifelong or acquired. Dysfunctions that are more difficulty with some other phase of the male sexual cycle,
recently acquired are more amenable to briefer treatments such as libido or ejaculation; and
while those that are lifelong often require further psycho- • work with the patient on a management plan.
therapy or clinical investigation.
The third characteristic to determine is whether the problem This flexibility of response by the primary care clinician to
is generalized or situational. Situational problems hint at dif- the patient’s ED is illustrated by the algorithm ALLOW
ficulties with specific partners or in specific situations and (Table 27.3).42 This management plan acknowledges the need
imply a psychogenic etiology. for all primary care clinicians to enquire about sexual activity
Asking sexual partners about each other’s sexual function is while recognizing the limitations and varied interest of many
often very useful. Women ranked ‘partner sexual difficulties’ clinicians in actually managing problems. After ‘legitimizing’
as a common sexual concern.38 If both members of a couple the patient’s problems and acknowledging that sexual dys-
are in the office, it becomes easy to introduce the topic by function is an important issue, the clinician evaluates his or
asking, ‘How are you two doing together? . . . How are you her own interest and ability to work with patients who report
doing with sex?’ If only one member of a couple is available, a sexual problem. Based on this self-evaluation by the clini-
questions can still be asked both about the present patient, as cian, the next step is taken and the clinician has done it ‘ALL’
well as the partner. When a sexual dysfunction is identified, for the patient. The next step can be a referral to an appropri-
talking to the partner can reveal a different picture that may ate subspecialist to investigate further and to treat the patient’s
substantially affect management, and can also have a thera- sexual issues, or the primary care clinician can open up the
peutic effect.39,40 Relationships have a profound effect on sexual issues for further discussion and diagnostic evaluation with
health and often need to be explored to amplify the likelihood the intent of identifying an appropriate goal and a mutually
of successful resolution of the problem. acceptable treatment plan.
Often, if the patient or partner is not asked about sexual
issues, they will bring up problems at the end of the visit.
Although this may seem like an afterthought, for many it may Basic sex counseling in the primary
be one of the major (if not the major) reasons for the visit. care office
An initial impression that their problem is being dismissed
can considerably delay or prevent them from seeking further Basic sex therapy can be offered by the primary care clinician.42
help.41 If inadequate time exists to discuss the issue at that Sex therapy involves teaching improvements in sexual technique
 Primary care evaluation and treatment of erectile dysfunction: American perspective 205

Table 27.3 ‘ALLOW’ your patient to discuss sexual Table 27.5 Strategies for overcoming the barriers in
dysfunction: a management plan men’s health

Step 1: A – Ask Getting men to come in:

↓
• Promotion to men
Step 2: L – Legitimize
• Accessibility of services
↓
• Encourage consciousness about health
Step 3: L – Limitations → Refer
↓ Getting men to open up and talk:
Step 4: O – Open up for further discussion
• Questionnaire that will promote discussion
↓
• Establish rapport with whole person
Step 5: W – Work together to develop a treatment plan
• Open-ended verbal questions that initiate discussion
Adapted from Rev Urol 2002; 4 (Suppl 3): S54–63.42
Getting men to come back:
• Encourage future, possibly longer, visits
• Take home reminders
• Make appointment when patient is leaving
Table 27.4 Basic sex therapy
Helping men to make changes to improve their health:
Content • Relate need for change to presenting problem
• Find common ground on how to reduce risk and
• Reduce performance anxiety
promote health
• Improve communication between partners
• Assess barriers in partnership with patient
• Education about sex and dysfunction (verbal or
• Get commitment to change
bibliotherapy
• Note risk status and management plan in medical record
Techniques • Introduce men to relevant community support and
• Cognitive therapy to change negative thoughts to network groups
positive thoughts When they come back:
• Asking specific questions
• Be proactive in praise, and follow up prior issues
• Creating a sexual environment
• Monitor and support positive behavioral changes and
• Develop sexual skills by sensate focus exercises,
risk reduction
including increasing awareness of sexual feelings,
learning to lose and regain an erection, and transitioning Adaped from Aust Fam Phys 2003; 32: 401–794 and Pathson A. The
to intercourse ‘M’ Factor: Men and Their Health. Sydney: Simon and Schuster,
• Integrating medical and psychological treatments 1998.95

Adapted from Weeks GR, Gamebescia N. Erectile Dysfunction:

Integrating Couples Therapy, Sex Therapy, and Medical Treatment.
New York: WW Norton, 2000: 43–418 and Urol Clin North Am 2001;
28: 269–78.93
Management of erectile dysfunction
promotes good health in men
and helping the patient to concentrate on pleasure rather than Men tend to underuse health services for medical problems
simply the achievement of an erection. This may be achieved or for health promotion and disease prevention. Identified
by providing the man (or ideally, both partners in a relation- factors that have an impact upon a man’s decision to present
ship) with factual information about sexual concerns, sexual to a physician include support, help-seeking, and barriers.43
practices, and sexual response that is individualized to the Barriers in the way of men presenting to the physician
specific patient or couple, and by attempting to reduce perfor- include a sense of immortality and invulnerability, difficulty
mance anxiety (Table 27.4). Encourage partners to discuss in giving up control, a belief that seeking help is unaccept-
what they enjoy about sex. More specific suggestions can be able, and a lower concern about disease prevention. Other
offered as the next level of sex therapy, encouraging couples to barriers include time and access, and having to state a reason
renew intimacy and sensuality in the relationship and to to anyone who inquires, such as a friend, family member,
extend foreplay for each other. The use of topical lubricants or or even a clinician, for the visit.43 Men receive fewer services,
estrogen replacement therapy for the woman may be essential, less health information, and are less likely to receive advice
especially if increased sexual activity is anticipated. The clini- about how changes in behavior can improve health.44 Emphasis
cian needs to have some specific knowledge about sexual per- is on common cardiovascular risk diseases including hyper-
formance and response to provide this level of counseling. tension, heart disease, and diabetes, while conditions that
The most detailed level of therapy often requires the assistance determine the patient’s quality of life are ignored.45 When
of a sex therapist and should be considered when the patient men’s health issues are considered, it usually is limited to
has been unable to understand or implement any of the more detection of prostate cancer. Specific approaches may work
basic hints or when the counseling interventions have not better in encouraging men to follow up on medical issues
worked. (Table 27.5).
206 Textbook of Erectile Dysfunction

Sexuality is an important part of one’s health.46 Sexual

Table 27.6 Initial evaluation of erectile dysfunction
activity and good health appear to be related. Laumann noted
that among men and women in his study who had no sexual History
partners in the past 12 months, 6% perceived that they were
• Libido
in ‘poor health’ compared with 2% of the entire study popu- • Ejaculatory issues (to confirm diagnosis)
lation.47 Sexual activity and happiness were also correlated in • Understanding of sexual function
this group. The impact of ED on comorbid conditions is • Hypertension
beginning to be studied. Patients with diabetes who also have • Diabetes
ED showed higher levels of frustration and discouragement • Hyperlipidemia
and a lower acceptance of diabetes. These observations were • Smoking
related to worse metabolic control and higher levels of depres- • Alcohol, substance abuse
sive symptoms.48 • Drugs (most commonly diuretics, beta-blockers, digoxin,
The epidemiology of ED demonstrates several modifiable spironolactone, antidepressants)
risk factors associated with an increased incidence of ED. • Depression, anxiety
• Hypogonadism
Identification of ED helps the physician to encourage health-
• Thyroid dysfunction
ier lifestyle activities in patients that may have an impact on • Uremia
cardiovascular risk. Men are often slow to adopt healthy • Pelvic surgery or trauma
lifestyles even when a full explanation is offered about cardio- • Partner issues
vascular risk. Associating healthier lifestyles with preservation • Nocturnal or other spontaneous erections
of or a possible improvement in impaired erectile function Physical examination
may motivate men to work harder to make healthier lifestyle
decisions. The impact of general lifestyle changes to limit pro- • Blood pressure
• Heart, peripheral pulses, thyroid, testes, prostate
gression of ED has been reviewed, noting varied results.49
• Penile anatomic abnormalities
Regular moderate physical activity seemed to reduce the risk
• Gynecomastia
of ED50 and possibly even improved symptoms of ED in some
populations.49,51 This is not surprising since the positive Laboratory tests
impacts of exercise on claudication, a common lower extrem- • Fasting glucose and lipid profile
ity symptom in patients with peripheral vascular disease, have • Blood chemistries
been well documented.52 Exercise-induced improvement in • Hemogram
claudicating symptoms may be explained by mechanisms • Serum testosterone as appropriate∗
that may also have an impact on penile artery flow, including • Cardiac evaluation with electrocardiography or exercise
testing as appropriate
measurable improvements in endothelial vasodilator func-
tion, muscle metabolism, blood viscosity, and inflammatory ∗Although most urologic and endocrine guidelines for the evaluation
response.52 of erectile dysfunction include testosterone measurement, the useful-
The risk of ED may be a smoking deterrent in younger men ness of this test among an unselected group of men initially present-
ing with erectile dysfunction remains unclear.
because of its immediacy when compared with heart disease
Adapted from Cleve Clin J Med 2005; 72: 293–311.96
and cancer.18,53 Older men may also be motivated to quit
smoking because of the link between smoking and ED.54
several phrases that describe the same phenomenon in dif-
ferent ways can make the communication clearer:
Evaluating the man with • To review a desire phase disorder, ask, ‘Do you still feel
erectile dysfunction in the mood, feel desire, have sexual thoughts or fantasies?’
ED preceded by loss of desire can signal hormonal pro-
A targeted evaluation will often find likely etiologic factors blems, relationship difficulties, medication adverse effects,
for ED.55 The evaluation of ED follows the same pattern as and depression.
the evaluation of any medical disorder. This includes a perti- • To review arousal or erection difficulties, ask, ‘Do you
nent history, physical examination, and laboratory tests have trouble getting or keeping an erection, getting or
(Table 27.6). The medical history, however, must include a keeping hard? Or both?’
sexual history. It is best not to accept the patient’s label for a • Orgasm and ejaculatory phase problems can be reviewed
disorder without first questioning and getting a clear picture by asking, ‘Do you feel you ejaculate (“come”) too quickly
of the complaint. Often less educated patients misuse medical (or too slowly, or not at all)?’ ED is common in men who,
or technical terminology. Because, for example, some men for any reason, became increasingly anxious about quick
confuse ED with premature ejaculation, asking if the erection ejaculation, delayed ejaculation, or perceived absence of
is lost before or after ejaculation can clarify the problem. ejaculation (as can occur with retrograde emission).
Learning about the patient’s past sexual history and relation- • To reveal Peyronie’s disease or pain disorders ask about ‘a
ship history can also be very revealing.56 bend to the penis’ or pain during or after sexual activity.
Questions generally review the phases of male sexual
response and focus on problems of desire, arousal and erection, The medical history should include a review of risk factors,
orgasm and ejaculation, and sexual pain. Offering the patient and screening for psychological difficulties. A medication
 Primary care evaluation and treatment of erectile dysfunction: American perspective 207

review, including over-the-counter preparations, may reveal Evaluating men with erectile function
the source of the problem because medications have been
implicated in up to 25% of cases of ED.57 Medications have for future cardiovascular risk
adverse effects on all phases of sexual functioning, making
ED can serve as a valuable signal of the need for cardiovas-
clarification of the patient’s complaint a priority before
cular assessment, especially in men with more established
ascribing symptoms to specific medication side-effects.58 Brief
coronary risk factors.65 Early recommendations are suggesting
screening for depression such as by asking ‘Do you sometimes
that men with ED should be screened for both heart disease
feel blue, down in the dumps?’ may elicit more honest
risk and depression.66–68 Depression is a known risk factor for
responses than asking ‘Are you depressed?’ Other psychiatric
cardiovascular disease.69–71 This process could lead to early
conditions such as anxiety may also be responsible for ED.
diagnosis and management. The US Preventive Services Task
The social history looking for stress surrounding a relation-
Force has found insufficient evidence to screen low-risk
ship or substance abuse including alcohol and cigarettes is
patients or patients at increased risk for the presence of
critical. Finally, a review of daily activity and a review of
cardiovascular disease using resting electrocardiography,
cardiovascular status is important to determine the potential
exercise treadmill testing, or electron beam computerized
risk of enhancing ED in patients who may have a sedentary
tomography.76 However, clinicians should investigate men
lifestyle and who may be at risk (usually minimal) for an
with ED for comorbid cardiovascular conditions that might
adverse cardiac event when sexual activity potential is
then be treated at an earlier date, and these patients should be
increased.59
assessed for coronary heart disease risk according to recom-
The physical examination should be targeted, with emphasis
mended guidelines and algorithms.72
on several areas.60,61 Immature secondary sex characteristics,
Many strategies have been suggested that include office-
including hair distribution and poor penile and testicular
friendly measurements of endothelial dysfunction along
development, may represent testosterone deficiency. Keep in
with more traditional risk assessment to clarify which men
mind that it is good practice to offer the presence of a chaper-
with ED are at increased risk of cardiovascular disease.19
one to patients having a genital examination. Many will say
A reasonable approach would be to use the Framingham
that it is not necessary, but the offer will allow the more anx-
equation, although this equation does not yet include ED as
ious patient to have the comfort of an appropriate additional
a potential predictor of coronary artery disease.73 The assess-
person in the examination room. Some men prefer to be
ment of cardiac risk after a complaint of erectile problems can
examined by a clinician of their own sex. Also consider any
potentially reduce subsequent morbidity and mortality. We
cultural differences and explore them when necessary prior to
need to determine if measures of vascular endothelial func-
initiating the genital examination.
tion can compete with other risk factors such as age, systolic
Laboratory tests useful in evaluating ED look for the risk
blood pressure, serum lipid fraction levels, blood glucose
entities already discussed.62 Prostate-specific antigen should
levels, and insulin resistance. Some experts have suggested
be considered for men over age 50 years, and at 40 years for
that men with ED are probably candidates for aggressive treat-
high-risk patients, to evaluate prostate size and tumor pres-
ment to improve endothelial function with treatments such
ence, especially if testosterone treatment is a possibility. If
as statins and angiotensin converting enzyme inhibitors or
there is any evidence of hypogonadism or if the dysfunction
angiotensin receptor blockers.74
is particularly consistent at a young age, then further hormone
evaluation becomes a higher priority.
The advanced diagnostic evaluation for ED includes tests
like nocturnal penile tumescence studies, vascular evaluation Treatment of erectile dysfunction
with sonography, biothesiometry, and other tests that can be
performed by the urologic subspecialist. These tests are some- Treatment plans need to be goal-oriented, ideally aimed
what subjective and rarely provide useful information except at satisfying the needs of both the man and his partner
in cases of trauma or other major vascular injury. and maximizing the chance of achieving patient satisfaction
If treatment is being considered for a man who has been (Table 27.7). Based on the desired outcome, treatment can be
sexually inactive for a prolonged period, a cardiac evaluation simply pharmacologic or it may include further comprehen-
determining cardiac risk needs to be done to determine the sive psychosocial and relationship counseling. In many
safety of the patient’s resuming an active sex life. Although cases, the partner can be brought in to participate in the
sexual activity requires only a slight increase in energy expen- discussion about the goal of treatment, improving the chance
diture for most men in most circumstances, there is a small of success.
absolute increase in risk of an adverse cardiac event occurring
during sex or within 2 hours of sexual activity.63 The Princeton
Guidelines help to evaluate a man’s risk for an adverse cardiac Educational and psychosocial interventions
event during or shortly after sexual activity.64 These guidelines In most cases, regardless of etiology, the treatment options
tell us that some men with active cardiac risk factors or disease of the physiologic impairment of ED are the same (see
fall into a high- or intermediate-risk category for adverse Table 27.4). Education is the first step in treatment and is
cardiovascular events and require further cardiac evaluation. personalized to the needs of the specific patient. The normal
The vast majority of men, however, fall into the low-risk cate- changes of aging are often misunderstood by patients and lead
gory for adverse cardiovascular events with increased sexual to problems. Myths and misunderstandings about sexual
activity and can safely be treated for ED.64 activity can directly cause sexual difficulties as well as generate
208 Textbook of Erectile Dysfunction

activity was associated with improved sexual function in about

Table 27.7 Comprehensive proactive approach to ED
one-third. These positive changes were associated with signifi-
management with PDE-5 inhibitors
cant improvements in erectile function, which were highly
Before treatment intervention correlated with both amount of weight loss and increased
activity levels.51 Exercise training improves endothelial func-
• Confirm diagnosis tion in the coronary79 and peripheral80 circulation in patients
• Educate about sexual myths
with cardiovascular disease. Programs designed to increase
• Discuss treatment goal(s)
• Review risk factors for ED (lifestyle, medication,
physical endurance clearly have a positive effect on vascula-
co-morbid conditions) ture, probably by improving endothelial function related to
an increase in nitric oxide (NO) production and decreased
Concurrent with initial prescription of PDE-5 inhibitors
oxidative stress, which leads to an increase in NO availability.81
• Emphasize proper use of medication These recommendations will help men be healthier and, it is
• Review partner issues (with patient and partner when hoped, happier, although their effect on erectile function may
possible) not be instantly apparent.
• Brief sexual counseling
Changing medication regimens to remove causative
• Discuss lifestyle and metabolic improvement
agents can be tried when clinically possible. Examples of
Follow-up visit(s) this might be discontinuing a thiazide diuretic and substitut-
• Review medication effectiveness during initial period of ing an alpha-adrenergic blocker, or weaning the patient from
use (patient satisfaction) digoxin if the medication is not necessary. Treatment of anti-
• Re-educate, titrate dose upward when appropriate depressant-induced sexual dysfunction can sometimes be
• Discuss any adverse effects managed by reducing drug dosages, altering the timing of
• Ask about psychosocial and/or partner issues drug dosages, taking drug holidays, adding an adjunctive
ED, erectile dysfunction; PDE, phosphodiesterase. drug, and switching to an alternative antidepressant.82 These
substitutions and eliminations may meet with some success,
but they need to be individualized depending on clinical
anxiety, guilt, and worry that have a negative impact on sexual circumstances.
response and erectile ability (see Table 27.4).18,75 Helping men
to have realistic expectations and to better understand healthy
function and honest, constructive communication with part- Direct pharmacologic and surgical treatment
ners can encourage more satisfactory sexual interaction and a Specific treatment regimens for ED include oral medications,
healthier sense of sexual nature. Research has demonstrated transurethral suppositories, intracavernosal injection, vacuum
that the amount of sexual intimacy correlates with relation- devices, and surgery. First-line therapies include oral medi-
ship satisfaction.76,77 cations and vacuum constriction devices. Oral treatments
The easily obtained erection begins to disappear in older approved in the USA by the Food and Drugs Administration
men, especially those with chronic illness, such as diabetes, include sildenafil, tadalafil, and vardenafil.83 The mechanism
hypertension, or renal disease. Direct tactile stimulation of of action, efficacy, and adverse effects of these three phospho-
the penis may be needed to obtain and maintain an erection. diesterase (PDE) type 5 inhibitors are described in other
The man becomes increasingly anxious, thereby causing chapters in this volume. Primary care clinicians are writing
further erectile difficulties. Information from the physician about 80–85% of all the prescriptions for PDE-5 inhibitors in
about these changes of aging can be extremely reassuring. the USA and are usually responding positively to patients’
Partner issues vary widely. Issues around partner choice, requests for a specific name brand.84
partner participation in sexual activity, and partner physio- Other pharmacologic treatments being used much less often
logy may influence erectile function. When vaginal dryness or by primary care clinicians include yohimbine and intraure-
vaginal atrophy leads to loss of lubrication and pain, women thral or intracavernosal injections of vasodilating medications
often lose interest in continued sexual activity. Apomorphine, a dopamine agonist that causes central initia-
tion of an erection through specific action in the brain, is
available in Europe but not in the USA. Vacuum devices are
Lifestyle and medication changes a reasonable choice for many men and their partners who
Making healthy lifestyle changes may reduce the symptoms of are in a stable relationship and are willing to accept the
ED and improve general physical health.78 Patients need to inconvenience.85
understand that what is bad for the heart is bad for the penis. Testosterone augmentation, available as skin patches, gels,
Elimination of smoking tobacco is probably helpful in reduc- buccal patches, or injections, is best reserved for patients with
ing incident ED.78 Dietary changes, including intake of reduced documented hypogonadism based on the morning serum free
cholesterol and trans-fats, elimination of hyperglycemia when testosterone level. Generally, testosterone augmentation is
present, and decreased salt intake when salt-sensitive hyper- associated with enhanced libido. This may improve erectile
tension is noted, all help to diminish progression of vascular status by restoring interest and perhaps through other neuro-
insufficiency. Exercise will increase cardiac output and hormonal mechanisms, but relying solely on testosterone
improve peripheral circulation. A recent study of obese men to restore erectile function is inappropriate.86 Testosterone
with ED without diabetes, hypertension, or dyslipidemia, augmentation requires thorough evaluation and monitoring
found that reducing caloric intake and increasing physical for prostate cancer.
 Primary care evaluation and treatment of erectile dysfunction: American perspective 209

The most common surgical treatment for ED is penile

Table 27.8 Treatment failure
implant surgery. This is a successful therapy, but it should be
reserved for patients who have considered or tried several Re-educate about appropriate goals, medication use, dose
other treatments. The surgery is irreversible and the normal titration
function of the corpus cavernosa is obliterated.
Consider more detailed psychosocial problems or
Some clinicians have advised that ED can be managed interventions
naturally, although no controlled trials exist. A dietary pro-
Consider adjunctive pharmacotherapy
gram rich in whole foods including vegetables, fruits, whole
grains, and legumes has been suggested, with key nutrients Consider alternative pharmacotherapy
including zinc, essential fatty acids, vitamin A, vitamin B6, Refer to a specialist
L-arginine, and vitamin E. Herbal supplements such as gin-
seng, gota kola, and saw palmetto have also been discussed.
Herbs, spices, and other foods reported to increase sexual
Table 27.9 Men’s misconceptions about ED
desire include nutmeg, saffron, parsley, vanilla, avocado, carrot
oil, and celery. Matters relating to sexual dysfunction are taboo
Loss of erection is not a common problem, and their
problem is unique
Optimizing treatment with ED is a normal part of aging
phosphodiesterase type 5 inhibitors ED is primarily a psychological problem and not a
physical one
PDE-5 inhibitors have been available for the treatment of ED
since 1998. The success rates achieved for significant improve- Treatment options are generally lacking or are too invasive
ment of ED (efficacy) in rigorous scientific studies range from and risky to be pursued
60% to 80% in most populations tested, and early expecta- Erections are indicators of sexual desire
tions of similar success among the general population were An erection should stay hard until ejaculation
similarly high. Unfortunately, in real life many men with ED An erection is necessary to have sexual relations
do not seem to be achieving their desired or expected goal
with these agents. The discontinuation rate for PDE-5 inhibi- ED, erectile dysfunction. Adaped from Geriatrics 1998; 53: 34–5,
39–40, 46–897 and Weeks R, Gambescia N. Erectile Dysfunction:
tor use among men diagnosed as having ED by their physi-
Integrating Couples Therapy, Sex Therapy, and Medical Treatment.
cians appears to be high, even among those who initially New York: WW Norton, 2000.18
responded to the medication, reaching up to 57% in 3-year
follow-up.87,88
Discussions about appropriate expectations are the key
outcome. Many other issues can influence the likelihood of
to optimizing outcomes from PDE-5 inhibitor therapy
achieving the desired outcomes including:
(Table 27.8). Myths and misunderstandings about sexual
activity can directly cause sexual difficulties as well as generate • the man’s psychosocial milieu;
anxiety, guilt, and worry that have a negative impact on sexual • the presence of other sexual issues or risk factors for
response and erectile ability (Table 27.9).18,75 Men need to be physical sexual dysfunction;
told that although the medication is likely to have a positive • the availability and receptivity of a partner; and
and significant effect on erectile function in men with ED, the • partner interaction.
degree of effect can vary on the basis of a variety of physiologic
and psychosocial factors. The biochemical effect of PDE-5 A trusting physician–patient partnership enhances the like-
inhibitors does not promise 100% success in all men, and it lihood of a successful therapeutic outcome. Optimism is an
appears to be decreased in men with diabetes or who have had essential management tool for clinicians to use in responding
a radical prostatectomy.89,90 to sexual issues.
An algorithm meant to deal with treatment failures includes
re-evaluation and adjustment of therapy, with treatment
for hypogonadism if present, dose titration, and patient
instruction on optimal use of medication. If the man is still
Follow-up of treatment for
not satisfied, this algorithm suggests considering alternative erectile dysfunction
oral or local therapy with additional education and counseling
followed by referral to a specialist if needed.91 Follow-up is an essential part of management of ED. Patients
Our goal as physicians for men with ED is to:92 should be seen 1 month after initiation of treatment to evalu-
ate progress. Comparison to baseline can be done by verbal
• help to improve the man’s sexual function and self-esteem; exchange or by using the standardized questionnaire measur-
• improve the man’s sense of well-being; and ing erectile function (SHIM). Reviewing the success or lack of
• improve the man’s relationships. success of treatment and any adverse effects, and considering
dose or treatment alterations, is more likely to achieve the
We know that improving physiologic erectile function in men patient’s goal. Further education or basic sex counseling can
with ED is an important part, but only one part, of the desired be provided to the patient with or without his partner.
210 Textbook of Erectile Dysfunction

Consultation with subspecialists Urologists can be helpful in difficult or complex ED situations

or when the patient presents with an anatomical problem
Consultation with subspecialists may be appropriate at varying such as Peyronie’s disease. An endocrinologist may be
intervals when managing a man with ED. The major factor is consulted to assist in managing men with difficult-to-
the primary care clinician’s comfort in discussing and manag- control diabetes, hypogonadism, or evidence of pituitary
ing treatment options. The obligation of the primary care dysfunction.
clinician is to recognize ED and to make the patient feel com- Sex therapists are practitioners in the medical or mental
fortable about seeking help. Initial work-up and treatment health field who, in addition to their basic clinical education,
can be planned by the primary care clinician who has good have had additional training in sex therapy, including
communication skills about sexual activity and who is knowl- evaluation and treatment options. Sex therapists have more
edgeable about first-line treatments. Common indications for time to talk with the patient, to work with couples and sug-
referral to an appropriate specialist include: gest enhancement techniques, and to educate couples that
there are many ways of having pleasurable sexual relations
• significant penile anatomic disease; without a firm erection. Such therapists could be physicians,
• a younger patient with a history of pelvic or perineal ministers of religion, or mental health professionals. In
trauma; the USA, the American Association of Sex Therapists and
• cases requiring vascular or neurosurgical intervention; Counselors (http://www.aasect.org) can provide a directory
• complicated endocrinopathies; for your state of trained, certified sex therapists. Most major
• complicated psychiatric or psychosocial problems; and teaching hospitals have such a trained therapist on their
• patient or physician desire for further evaluation. staff.

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CNS Spectr 2003; 8: 217–24. 85. Bosshardt R, Farwerk R, Sikora R, et al. Objective measurement of
57. Slag MF, Morley JE, Elson MK, et al. Impotence in medical clinic the effectiveness, therapeutic success, and dynamic mechanisms
outpatients. JAMA 1983; 249: 1736–40. of the vacuum device. Br J Urol 1995 Dec Suppl: 75: 786–91.
58. Finfer WW, Lung M, Stagle MA. Medications that may contribute 86. Greiner KA, Weigel JW. Erectile dysfunction. Am Fam Phys 1996;
to sexual disorders. J Fam Pract 1997; 44: 33–43. 54: 1675–82.
212 Textbook of Erectile Dysfunction

87. Helstrom WJG. Management recommendations for family physi- 92. Nusbaum MR. Therapeutic options for patients returning to sexual
cians. J Fam Pract 2005 Suppl : 32–40. activity. J Am Osteopath Assoc 2004; 104: S2–5.
88. Jiann BP, Yu CC, Su CC, Tsai JY. Complaince of sildenafil treat- 93. Rosen RC. Psychogenic erectile dysfunction. Classification and
ment for erectile dysfunction and factors affecting it. Int J Impot Res management. Urol Clin North Am 2001; 28: 269–78.
2006; 18: 146–9. 94. Hall RH. Promoting mens health. Aust Fam Phys 2003; 32:
89. Vickers MA, Satyanarayana R. Phosphosdiesterase type 5 inhi- 401–7.
bitors for the treatment of erectile dysfunction in patients with 95. Pattison A. The ‘M’ Factor: Men and their Health. Sydney: Simon
diabetes mellitus. Int J Impot Res 2002; 14: 466–71. and Schuster, 1998.
90. Montorsi F, Burnett AL. Erectile dysfunction after radical prosta- 96. Mikhail N. Management of erectile dysfunction by the primary
tectomy. BJU Int 2004; 93: 404–10. care physician. Cleve Clin J Med 2005; 12: 293–311.
91. Carson CC, Lue TF. Phosphodiesterase type 5 inhibitors for erectile 97. Burnett AL. Erectile dysfunction: a practical approach for primary
dysfunction. BJU 2005; 95: 257–80. care. Geriatrics 1998; 53: 34–5, 39–40, 46–8.
28 Phosphodiesterase type 5
inhibitors: molecular basis for
pharmacological effects
Sharron H Francis and Jackie D Corbin

Introduction promotes lowering of intracellular calcium through increased

calcium extrusion and increased calcium sequestration in
The connection between cGMP elevation and relaxation of intracellular stores, as well as desensitizing the cell to calcium
smooth muscle gained increased attention in the 1980s, owing signals. PDE-5, which specifically breaks down cGMP, is
largely to the work of Murad, Ignarro, and Furchgott, who commonly found in high abundance in cells containing PKG
demonstrated that an ‘endothelial-derived factor’ (EDRF),1–3 and is implicated as an important down-regulator of cGMP
which was later identified as nitric oxide (NO), increased signaling.
cellular cGMP and relaxed smooth muscle (Figure 28.1).
Results of in vitro studies employing cyclic nucleotide analogs
with known affinities for activation of cGMP-dependent
protein kinase (PKG) or cAMP-dependent protein kinase Selective phosphodiesterase
(PKA) supported a prominent role for cGMP and PKG, but type 5 inhibitors
not PKA, in smooth muscle relaxation.4
Identification of potent and highly selective PDE-5 inhibitors
that proved to be effective as oral medications for treatment
of ED was a medical milestone (Figure 28.3).8–10 Sildenafil,
Role of cGMP in smooth developed by Pfizer, was the first of these; it set a high
muscle relaxation standard for safety and efficacy in treating ED in a diverse
spectrum of patients. Vardenafil, a product of Bayer, and
In the early 1990s, cGMP signaling was implicated in mediat- tadalafil, a product of ICOS–Lilly, soon joined the market and
ing penile erection. At that time, pharmacological treatments provided additional therapeutic options for effective and safe
of erectile dysfunction (ED) focused largely on injections that treatment of ED.11–13 Among these three medications, vard-
elevated cAMP, including prostacyclins and papaverine, a enafil is the most potent in vitro with a PDE-5 50% inhibitory
relatively non-specific phosphodiesterase (PDE) inhibitor. concentration (IC50) of 0.1–0.4 nM compared to IC50 values
The work of numerous laboratories established that activation of 3.5 nM and 2 nM for sildenafil and tadalafil, respectively
of guanylyl cyclase by NO released from penile nerves and (Figures 28.3, 28.4).14 Udenafil, a product of Dong Pharma-
endothelium increased synthesis of intracellular cGMP.5,6 The ceuticals, was recently introduced and has an IC50 of 6 nM (see
increase in cGMP decreased the tone of smooth muscles Figure 28.3).15 In 2006, sildenafil was approved under a
encircling tonically constricted helicine arteries and lacunae separate formulation in the United States for use in treatment
of the penile corpus cavernosum; this permitted blood vessel of pulmonary hypertension; the potential for use of these
diameters to expand and accommodate increased blood flow inhibitors in treatment of other maladies related to vascular
as well as increased filling of the sinuses within the penis diseases is being increasingly appreciated.16
(Figure 28.2). Vascular smooth muscle relaxation is primarily Vardenafil, sildenafil, and tadalafil are commonly referred
mediated by cGMP binding to PKG and activating the enzyme, to as PDE-5-specific inhibitors, but PDE-5-selective inhibi-
which transfers the gamma-phosphate of ATP to serines or tors is a more accurate term.15 Owing to structural similarities
threonines (i.e. phosphorylation) in many cellular proteins. among the catalytic sites of PDEs, absolute specificity of an
In smooth muscle these proteins include phospholamban, inhibitor for one family is perhaps non-existent. Indeed,
myosin-targeting subunit of myosin light chain phosphatase, cross-reaction of vardenafil, sildenafil, and tadalafil with mem-
inositol 1,4,5-triphosphate receptor-associated PKG substrate, bers of certain other PDE families has been demonstrated.17
calcium-activated potassium channels, Rho-A, PDE-5, and Although the possibility of non-PDE target proteins for
PKG itself via autophosphorylation.7 Phosphorylation of these these medications has not been entirely excluded, evidence
proteins frequently alters their functions, many of which suggests that almost all of their known effects are mediated by
are involved in cellular calcium homeostasis. PKG action their inhibition of PDE-5 activity. This includes increased

213
214 Textbook of Erectile Dysfunction

relaxation of vascular smooth muscle, which improves erectile

Nitric Oxide Synthase
in Penile Neurons function and causes modest hypotension in some patients.
and Endothelial Cells Many of the most commonly reported adverse effects (head-
ache, facial flushing, dyspepsia, muscle aches, and stuffy
or runny nose) associated with use of these medications are
NO
Guanylyl
transitory and mostly due to vasodilatory effects in local
cyclase tissues brought on by PDE-5 inhibition.17 Diarrhea, although
a relatively uncommon adverse effect of these drugs, is also
cGMP PKG
likely to be due to inhibition of the abundant PDE-5 catalytic
n PDE-5
Inhibitio activity in gastrointestinal epithelial cells and smooth muscle.
PDE-5 5′-GMP Protein
n Visual effects (blurred vision, perturbation of color vision, or
inhibitor tio phosphorylation
ibi increased light sensitivity) may be due to sildenafil or vard-
Inh ation
Activ enafil inhibition of the PDE-6 family (retinal PDEs), which is
cGMP Relaxation of penile highly similar to PDE-5. Sildenafil inhibits members of the
analogs vascular smooth muscle PDE-6 family with an approximately 10-fold lower potency
than for PDE-5, and vardenafil inhibits the PDE-6 family with
Figure 28.1 Nitric oxide and cGMP signaling in vascular four- to 25-fold lower potency than for PDE-5. At the highest
smooth muscle cells. Nitric oxide (NO) produced by penile therapeutic doses of sildenafil, the maximum free plasma con-
neuronal and endothelial cells diffuses across the cell membrane centration approaches 40 nM, a concentration that could
into the cytosol. There, it binds to and activates the NO-sensitive inhibit a portion of the PDE-6 activity, but it is unlikely to
guanylyl cyclase, which converts GTP into cGMP. cGMP binds block other PDEs. For example, potency of sildenafil inhibi-
to and activates cGMP-dependent protein kinase (PKG) which tion of the PDE-1 family is approximately 80-fold weaker
transfers a phosphate group from ATP to a serine–threonine in a than for PDE-5 and, at the maximum free plasma concentra-
variety of proteins. Phosphodiesterase type 5 (PDE-5)-selective tion achieved in most patients, it would be predicted to have
inhibitors such as vardenafil, sildenafil, tadalafil, or udenafil
little effect.17
diffuse into the cytosol and compete with cGMP
for access to the PDE-5 catalytic site, thereby slowing cGMP
A few studies have reported that PDE-5-selective inhibitors
breakdown. In the presence of an agonist drive such as NO, possess neural effects. Hallen et al. reported that vardenafil,
cGMP accumulates, PKG becomes more activated, and tone sildenafil, and tadalafil blunted release of NO from neurons in
in the smooth muscle of the penile vasculature decreases, rabbit isolated corpus cavernosal tissue.18 It was suggested that
thereby facilitating penile erection. cGMP analogs can be this could be protective against excessive smooth muscle
both PKG activators and PDE inhibitors; after diffusing into relaxation leading to priapism; whether this effect is mediated
the cell, cGMP analogs can bind to and activate PKG as well via inhibition of neuronal PDE-5 and cGMP elevation is
as competing with cGMP for access to the PDE-5 catalytic unclear. Reports of PDE-5-selective inhibitor effects on the
site. Because of these dual actions, cGMP analogs have the central nervous system were initially met with skepticism
potential to be an even more potent medication than because the inhibitors were not believed to cross the blood–
compounds such as vardenafil, sildenafil, tadalafil, or udenafil
brain barrier, and it was conjectured that improved blood
to promote penile erection, and they would not require the
presence of an agonist drive.
flow to certain brain regions could account for the results.
However, reports of such effects on central nerves continue to
accumulate in studies using both animal models and humans.
Zhang et al. demonstrated that sildenafil or tadalafil adminis-
tration in rats improves recovery from stroke, an effect that
could be due to improved blood flow; however, sildenafil also
improves survival of neuronal cells in culture.19 Improved
Contracted Tunica albuginea object recognition memory and memory consolidation fol-
Relaxed
smooth smooth lowing administration of PDE-selective inhibitors were
muscle muscle reported.20 Results of studies in hamsters indicated that
sildenafil is effective in rapid adjustment of the circadian
Sinusoidal
clock.21 The mechanism or mechanisms mediating these
Inflow spaces processes is not known.
Tadalafil has low affinity for most PDEs other than PDE-5,
but it cross-reacts appreciably with the PDE-11 family, which
Venule
Helicine Dilated is also highly similar to PDE-5 in amino acid sequence.22
artery helicine Tadalafil potency among PDE-11 isoenzymes (PDE-11-A1,
artery
-A2, -A3, and -A4) differs by approximately 5-fold, so that
Flaccid Rigid selectivity of tadalafil for PDE-5 versus PDE-11 varies 8- to
40-fold.23 No effects that are clearly attributable to cross-
reaction between tadalafil and PDE-11 have been described, but
Figure 28.2 Schematic depiction of the hemodynamic events the physiological role of PDE-11 is unknown. The apparent
associated with penile erection. (Reproduced with permission absence of a clinical effect of tadalafil on PDE-11 may be due
from J Biol Chem 1999; 274: 13729–32).23 to the apparently restricted expression and low mammalian
 Phosphodiesterase type 5 inhibitors: molecular basis for pharmacological effects 215

HN N

H2N N N
O
OH
O O
P PDE-5
O OH
OH–
cGMP

CH3 O CH3 O CH3 O

CH3 CH3 O CH3

O HN O HN N CH3 O HN N
N N N N
N N
N N N
N
O
O S O CH3 O S O CH3 O S O
CH3
N N O HN
O
CH3
N N N

CH3 CH3

Vardenafil Sildenafil Tadalafil Udenafil

(Levitra®) (Viagra®) (Cialis®) (Zydena®)

IC50 = 0.1–0.4 nM IC50 = 3.5 nM IC50 = 2 nM IC50 = 6 nM

Figure 28.3 Comparison of the structures of cGMP and potent phosphodiesterase (PDE) type 5-selective inhibitors. In the upper part
of the figure, the insertion of an activated OH− that is generated by PDE-5 from the solvent water is depicted. Insertion of the OH− at
the phosphorous site in the ring breaks the cyclic ring to create 5′-GMP. Values for the 50% inhibitory concentrations (IC50) for
sildenafil, vardenafil, and tadalafil were determined in a head-to-head fashion as described in Blount et al;14 the value for udenafil
was taken from Beavo et al.16

100
Sildenafil
Molecular characteristics of
phosphodiesterase type 5
Phosphodiesterase activity

80

PDE-5 tissue distribution is relatively restricted; this, along

(% Control)

60 Tadalafil
with the high potency of the inhibitors in clinical use, may
40
contribute to the low incidence of side-effects.11 PDE-5 is
most abundant in smooth muscle, platelets, gastrointestinal
20 epithelial cells, and Purkinje cells. It is present in certain
Vardenafil endothelial cells and at low levels in cardiomyocytes. Since
0 PDE-5 is particularly abundant in vascular smooth muscle, all
PDE-5-selective inhibitors are likely to reduce vascular tone.
100 101 102 103 104 105 106 The three PDE-5 isoenzymes (PDE-5-A1, -A2, and -A3) are
Inhibitors (pM) alternative mRNA spliced products of a single gene; they dif-
fer in amino acid sequence only near the amino terminus, and
Figure 28.4 Potency of vardenafil, sildenafil, or tadalafil significant enzymatic differences among them have not been
inhibition of recombinant wild-type phosphodiesterase (PDE) detected.24
type 5. Inhibition curves were conducted in a head-to-head In most tissues, PDE-5 is largely cytosolic. It is composed
manner using purified recombinant human PDE-5.
of two tightly associated proteins of approximately 98 kDa
(Figure 28.5), each of which contains an amino-terminal
regulatory (R) domain and a carboxyl-terminal catalytic (C)
tissue abundance of this enzyme, especially the ‘short’ iso- domain. PDE-5 contains two types of sites that interact with
enzymes (PDE-11-A1, -A2, -A3), which exhibit higher cGMP with high specificity:24,25
tadalafil sensitivity. Sildenafil and vardenafil are weak inhi-
bitors of PDE-11. Therefore, the term ‘specific’ should be • a catalytic site where cGMP is hydrolyzed to inactive
avoided when describing PDE inhibitors, and physicians 5′-GMP; and
should be cognizant of potential for cross-reaction with • allosteric sites that are provided by one of the GAF
other PDEs. sub-domains in the R domain.
216 Textbook of Erectile Dysfunction

Catalytic domain as PKG and the PDE-5 catalytic site for binding cGMP.31
5′-GMP While bound to the allosteric sites, cGMP cannot be hydro-
Inhibitor
lyzed; this would sequester and preserve cGMP, thereby
PKG
rapidly lowering the cellular free (‘active’) cGMP level; as
ATP cytosolic cGMP declines, it could provide a reservoir for slow
cGMP P
S
release of cGMP.32

Regulatory
domain Mechanism by which inhibitors
S
block phosphodiesterase type 5
P catalytic activity
PDE-5 inhibitors that are currently in use for treatment of
ED are small molecules that contain bicyclic ring structures
that mimic the guanine ring of cGMP (see Figure 28.3). Each
competes directly with cGMP for access to the PDE-5 catalytic
Figure 28.5 A working model of phosphodiesterase type 5. site, thus inhibiting the enzyme (see Figure 28.5). These inhi-
The C domain is located in the C terminal portion of the protein bitors do not interact with the allosteric cGMP-binding sites
and contains the catalytic site; cGMP (shown as a black ball) in the R domain; nor do they bind to other known cGMP-
interacts with the catalytic site and is hydrolyzed to 5′-GMP, binding proteins. This is due to the fact that the cGMP-binding
whereas inhibitors such as vardenafil, sildenafil, tadalafil, and sites in the PDE-5 R domain, the PDE-5 C domain, and the
udenafil (shown as black diamond) interact with the catalytic catabolite-gene activator (CAP)-related sites in PKG or the
site to block cGMP hydrolysis. The R domain is located in the
cGMP-gated ion channels are evolutionarily and biochemi-
amino-terminal portion of the protein and contains the phos-
cally distinct.31 The rigorous specificity of the PDE-5 allosteric
phorylation site at Ser-102 and two GAFs (A and B), indicated
by the cross-hatched boxes. Cyclic GMP binds to the more cGMP-binding sites may aid in the development of new
amino-terminal GAF-A with high affinity and high specificity. medications that regulate PDE-5 through these sites.
The more carboxyl-terminal GAF-B contributes to dimerization PDE-5 inhibitors, whether potent or weak, and cGMP are
as well as regulatory features of the enzyme, but whether cGMP believed to utilize some of the same amino-acid contacts in
is bound to GAF-B is still not certain. the catalytic site of PDE-5; however, some of the contacts with
potent inhibitors could be stronger than those made by cGMP,
and potent inhibitors are thought to make many more con-
The cyclic phosphate ring of cGMP is hydrolyzed in the tacts than does cGMP. This is likely to account for the 1000-
catalytic site, which lies in a deep pocket near the middle of to 40,000-fold higher affinity of these molecules for the PDE-5
the C domain; zinc and another metal, perhaps magnesium, catalytic site. The contacts between the PDE-5 catalytic site
are juxtaposed in this site and in conjunction with a number and cGMP are unknown because the co-crystal structure of
of hydrophilic amino acids comprise the catalytic machinery cGMP with PDE-5 has not yet been determined.
that generates a nucleophilic hydroxyl from a solvent water The X-ray crystal structures of the PDE-5 C domain in
molecule.26,27 Insertion of the activated hydroxyl ion at the complex with vardenafil, sildenafil, or tadalafil reveal that
phosphorous site breaks the cyclic phosphate ring of cGMP each makes several kinds of amino-acid contacts with PDE-5
(see Figure 28.3).28 The affinity of the catalytic site (Km) for (Figure 28.6).33,34 These include hydrogen bonds, hydropho-
cGMP as substrate is approximately 2.5 µM but this can be bic interactions, salt bridges, and van der Waals forces. As
improved by regulatory processes. In most cells, cGMP, either expected, in the PDE-5 catalytic site each inhibitor contacts
in the basal or the stimulated state, is estimated to be <1 µM amino acids that are conserved in other PDEs and contribute
so that the catalytic site of PDE-5 would be predicted to importantly to inhibitor potency. Insights derived from the
be rarely saturated. The unique topography of the PDE-5 crystal structures were used as a guide for site-directed muta-
catalytic site provides for high cGMP affinity compared with genesis of PDE-5 to quantify the importance of these contacts
a roughly 100-fold lower affinity for cAMP (Km of approxi- for potency and selectivity of the inhibitors. These include an
mately 300 µM). invariant glutamine (Gln-817) involved in hydrogen bonding,
The PDE-5 R domain contains multiple sub-domains and a hydrophobic pocket that includes a conserved phenyla-
that contribute to regulation of cGMP signaling and modu- lanine (Phe-820), an invariant tyrosine (Tyr-612), and a clus-
lation of function in the C domain; these include a phospho- ter of other hydrophobic residues (Ala-767, Val-782, Ala-783,
rylation site at Ser-102 in human PDE-5, two GAFs (A and B), Phe-786, and Leu-804). Vardenafil and sildenafil form a
at least one of which (GAF-A) binds cGMP with high affinity, water-bridge with zinc (see Figure 28.6), one of the metals
and regulatory components within GAF-B (see Figure 28.4).29,30 that participates in hydrolysis of the cyclic phosphate ring;
(GAF is an acronym for cGMP-binding PDE, Anabaena tadalafil, which has potency similar to that of sildenafil, does
adenyl cyclases, Escherichia coli FhlA.) Allosteric binding site not make this contact. In addition to forming contacts that are
affinity for cGMP is high (KD is ∼0.2 µM), highly specific, and conserved in the PDE superfamily, each inhibitor also makes
regulated by phosphorylation at Ser-102. The allosteric cGMP- novel contacts with amino acids that are closely apposed to,
binding sites compete with other cellular proteins such but are not within, the catalytic site. These involve amino
 Phosphodiesterase type 5 inhibitors: molecular basis for pharmacological effects 217

Hydrophobic clamp

Ala767
Val782
Leu765 Gln817

Tyr612

N-2
H
H
O
H Ala783
O H
++ Phe786
Zn Phe820
H
Leu804

Ile813

Ile665
Asn662 Tyr664
Ser663

Figure 28.6 Contacts between phosphodiesterase type 5 catalytic site amino acids and sildenafil. The three most important amino
acids in providing for affinity for sildenafil, vardenafil, and tadalafil are shown in pink. Heavy bars indicate particularly strong
interactions. The ‘hydrophobic clamp’ refers to the fact that the five-member ring of sildenafil (or vardenafil, not shown) is sandwiched
between two hydrophobic amino acids (i.e. Phe-820 and Val-782). Dotted lines indicate hydrogen bonds. Nitrogen in the five-
member ring designated as N-2 has weaker electronegativity than the nitrogen (N-3) in the same position in vardenafil. Reproduced
with permission from Francis SH, Zoraghi R, Kotera J, et al. Phosphodiesterase-5: molecular characteristics relating to structure,
function, and regulation. In: Beavo JA, Housley MD, Francis SH, eds. Cyclic Nucleotide Phosphodiesterases in Health and Disease.
Boca Raton, FL: CRC Press, 2006: 131–64.24

acids that are absent in most other PDEs, thereby improving of the three inhibitors are essentially the same in its absence
selectivity for PDE-5. The effect of each contact is cumulative (Table 28.1).36 This diminished affinity for vardenafil could
and contributes to the total energy with which an inhibitor is involve loss of direct contacts between the R domain and
bound; a greater number of contacts between PDE-5 and the vardenafil, or it could be due to a conformational influence
inhibitor translate into higher binding energy and higher of the R domain on the catalytic site; no evidence has yet been
potency. The particular chemical and structural features of found for direct contacts between the R domain and varde-
each inhibitor impose constraints that foster interaction with nafil. The results emphasize that caution should be used in
the topography of the PDE-5 catalytic pocket and prevent extrapolating characteristics established with one compound
these inhibitors from binding well to the catalytic pocket of (e.g. sildenafil) to another group of compounds such as vard-
most other PDEs.27,35 enafil-based molecules.

Influence of regions outside Regulation of substrate affinity and

the phosphodiesterase type 5 catalytic activity by allosteric cGMP
catalytic site on inhibitor potencies binding or phosphorylation
and selectivities An agonist-induced increase in cGMP in smooth muscle
cells such as those in the penile corpus cavernosum activates
Although the inhibitors form most of their contacts within or a negative feedback mechanism that increases cGMP hydro-
very near the PDE-5 catalytic site, the R domain can influence lysis, and cGMP is quickly lowered to basal or near-basal
potency and selectivity of the various inhibitors. The isolated levels. This feedback is a classical mechanism for maintaining
PDE-5 C domain and full-length PDE-5 have similar affinities the concentration of a signaling ligand in a range that is opti-
for cGMP as substrate, and the catalytic rates (kcat) are similar mal for cellular responsiveness to the signal – that is, it protects
indicating that the salient features of enzyme function are not the cell from excessive accumulation of cGMP following a
altered by removal of the R domain. The potency (IC50) of signal from an agonist such as NO.
sildenafil for these two enzyme forms is similar, and this PDE-5 mediates negative feedback in the cGMP pathway24,25
also applies to the potency of tadalafil. However, the higher as follows. Upon elevation of cellular cGMP, the rate of cGMP
potency and selectivity of vardenafil over sildenafil or tadalafil breakdown by PDE-5 increases significantly since the catalytic
for PDE-5 inhibition requires the R domain, i.e. the potencies site of the enzyme is not fully occupied by cGMP; this increase
218 Textbook of Erectile Dysfunction

Table 28.1 Comparison of potency of PDE-5 inhibitors on catalytic activity of full-length PDE-5 and PDE-5
N-terminal truncation constructs

IC50

µM nM

Sildenafil-based Vardenafil-based

IBMX Tadalafil Sildenafil UK-122764 Vardenafil Demethyl BAY 511871

vardenafil

PDE-5 A B C Domain 4.6 2.9 2.3 5.4 0.3 0.3 0.4

PDE-5∆1-321 B C Domain 4.5 3.6 2.5 5.5 0.2 0.6 0.5
PDE-5∆1-419 B C Domain 4.4 3.8 2.6 5.1 0.4 0.4 0.4
PDE-5∆1-465 C Domain 4.8 3.6 3.0 5.5 2.7 5.6 3.1
C domain C Domain 4.3 3.6 2.8 5.1 2.9 3.2 2.9
(∆1-534)

Either full-length PDE-5, PDE-5∆1-321, PDE-5∆1-419, PDE-5∆1-465, or isolated C domain (∆1-534) was added to the PDE assay mixture containing
0.4 µM (final concentration) [3H]cGMP as substrate and increasing concentrations of inhibitors. [Reproduced with permission from Blount et al.,
(2006) Mol. Pharmacol. 1822–31] PDE, phosphodiesterase; IC50, 50% inhibitory concentration; C domain, catalytic domain; IBMX, 3-isobutyl-1-
methylxanthine.

in catalytic rate is strictly a process of mass action due to

Table 28.2 Involvement of phosphodiesterase type 5
substrate elevation. Cyclic GMP association with allosteric
in negative feedback control of the cGMP pathway
sites in the R domain also occurs, and increases both the affin-
ity and the hydrolytic rate of the catalytic site for cGMP. 1. ↑Substrate (cGMP) availability at the catalytic site
Increased occupation of the catalytic and allosteric sites with 2. Direct induction of a more active catalytic conformation
cGMP elicits a conformational change in the PDE-5 R domain by cGMP
that exposes Ser-102 in human PDE-5 for phosphorylation 3. ↑cGMP binding at allosteric site stimulates the catalytic
by cyclic nucleotide-dependent protein kinases. Ser-102 is site
preferentially phosphorylated by PKG, which would also be 4. ↑cGMP binding at allosteric site by cGMP binding at
activated when intracellular cGMP increases.24,25 Phospho- the catalytic site, which stimulates the catalytic site
PDE-5 exhibits increased affinity for cGMP at the allosteric 5. ↑Phosphorylation stimulated by cGMP binding at the
sites as well as the catalytic site and fosters increased catalytic site, which stimulates the catalytic site
6. ↑cGMP binding at the catalytic site increases cGMP
cGMP breakdown. These mechanisms act in concert to lower
binding to the allosteric site, which increases
cGMP levels quickly (Table 28.2).24,25 Negative feedback on
phosphorylation, which stimulates the catalytic site
the cGMP pathway is also subserved by increased sequestra- 7. ↑Phosphorylation stimulates further cGMP binding at
tion of cGMP in the PDE-5 allosteric sites, which blocks the allosteric site, which stimulates further
activation of PKG by cGMP.24,37 phosphorylation, which stimulates the catalytic site
8. ↑Sequestration of cGMP by allosteric site(s)

Regulation of phosphodiesterase type

5 affinity for inhibitors by allosteric PDE-5 R domain also increases affinity of the catalytic site for
tadalafil and perhaps for vardenafil and sildenafil as well.39
cGMP binding or phosphorylation It is likely that allosteric cGMP binding and phosphorylation of
Ser-102 occur simultaneously and work in concert to promote
Natural mechanisms that provide for negative feedback regu-
greater potency of the inhibitors. The effects of phosphoryla-
lation of cellular cGMP also regulate PDE-5 affinity for inhib-
tion on PDE-5 affinity for inhibitors should be reversed by
itors. cGMP binding to allosteric sites in the R domain
the action of phosphoprotein phosphatases such as phospho-
produces a conformational change in PDE-5 that increases
protein phosphatase-1, which has been shown to dephosphory-
affinity of the catalytic site for vardenafil, sildenafil, or tadala-
late PDE-5 efficiently in vitro as well as in intact cells.39,40
fil by approximately three-fold;14,38 thus, as cellular cGMP
increases as a result of inhibitor effects to block cGMP hydro-
lysis, more cGMP is available to occupy the allosteric sites,
which enhances catalytic site affinity for the inhibitors. This Phosphodiesterase type 5 inhibitors
type of effect is referred to as ‘feed-forward regulation’. In this promote their own potencies
case mechanisms that physiologically provide for negative
feedback regulation enhance the pharmacological efficacy of PDE-5 exhibits two components of affinity (high affinity and
the medications. Phosphorylation of Ser-102 in the human low affinity) for vardenafil, sildenafil, and tadalafil.14 The basis
 Phosphodiesterase type 5 inhibitors: molecular basis for pharmacological effects 219

for these kinetic states is not certain, but their combined influ- example. The free level of sildenafil in plasma (i.e. sildenafil
ence is reflected in inhibitor potency (IC50). Recent studies not bound to serum albumin) following ingestion of the
demonstrated that after 12 hours of exposure of PDE-5 to a medication is about 40 nM and the level of PDE-5 holoen-
medically relevant level of tadalafil or vardenafil, the low- zyme in the corpus cavernosum is about 95 nM.37 Assuming
affinity state was converted into the high-affinity state for that free inhibitor in the plasma fully equilibrates with the
the respective inhibitors (Blount M, unpublished data). This cytosol, only half of the PDE-5 would be inhibited and per-
would be predicted to increase the potency of these inhibitors. haps this degree of inhibition is sufficient for the pharmaco-
The increased affinity of PDE-5 for inhibitors is associated logical effects. However, given the high affinity of PDE-5 for
with an apparent elongation of the protein, which is presumed the inhibitors, it is predicted that inhibitor entering the cell
to be the more optimal conformer for enzymatic function. would be immediately bound so that the level of the inhibitor
that is free in the cytosol would be very low (<4 nM), but
eventually almost all of the PDE-5 catalytic sites would be
Mechanisms of phosphodiesterase filled. At that time, it is predicted that the concentration of
free inhibitor in the cytosol and the plasma would equalize,
type 5 that may contribute to but the total amount of inhibitor in the cell (at concentrations
long-lasting effects of inhibitors of 95 nM bound to PDE-5 plus 40 nM free in the cytosol,
making a total of 135 nM) would be greater than that of free
Several studies documented that relief of ED following use of inhibitor (40 nM) in an equal volume of plasma. As plasma
PDE-5-selective inhibitors persists well beyond the half-life inhibitor declines, unbound inhibitor in the cytosol would be
for plasma clearance.41,42 The molecular mechanism that predicted to decline in parallel. However, the decline in the
provides for this effect is not known. The conversion of PDE-5 inhibitor bound to PDE-5 is likely to be substantially slower,
to a conformation with higher affinity described above may owing to both the high affinity of PDE-5 for the inhibitor and
contribute to these long-lasting effects;14,38 increased affinity to the rapid and repeated rebinding of inhibitor that dissoci-
induced by a conformational change in PDE-5 would be pre- ates from the enzyme. In this scenario, the high concentration
dicted to lower the concentration required to block enzyme of cellular PDE-5 would provide more opportunities for
activity and to foster rebinding of the inhibitor to PDE-5 upon rebinding of inhibitor to PDE-5 prior to its exit from the
its dissociation. Repeated rebinding of inhibitor to PDE-5 cell.
would slow its exit from the cell and sustain the pharmaco-
logical effects for a longer period than predicted from the
plasma clearance profile. Likewise, allosteric cGMP binding Conclusion
and/or phosphorylation of PDE-5 following elevation of
cGMP (or both) would improve PDE-5 affinity for inhibitors PDE-5-selective inhibitors such as vardenafil, sildenafil, and
and translate into slowed decline of the inhibitor and its effects tadalafil have proven to be highly effective in treatment of ED.
in the cell. Lastly, the exact mechanism whereby elevation of The basic features of PDE-5 structure provide for regulation
cGMP and activation of PKG relaxes penile vascular smooth of the catalytic site of this enzyme, including modulation of
muscle is poorly understood; these effects may persist well catalysis as well as affinity for these inhibitors.
after clearance of the inhibitors from the cell.
The level of PDE-5 in smooth muscle cells of the corpus
cavernosum in combination with its high affinity for the Acknowledgments
inhibitors may also have an impact on the persistence of the
effect of these medications. One can consider sildenafil as an Supported by NIH DK40299 and DK58277.

REFERENCES

1. Murad F, Rapoport RM, Fiscus R. Role of cyclic-GMP in relax- 7. Hofmann F, Feil R, Kleppisch T, Schlossmann J. Function of cGMP-
ations of vascular smooth muscle. J Cardiovasc Pharmacol 1985; dependent protein kinases as revealed by gene deletion. Physiol
7 Suppl 3: S111–18. Rev 2006; 86: 1–23.
2. Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and 8. Rotella DP. Phosphodiesterase 5 inhibitors: current status and
contracting factors. FASEB J 1989; 3: 2007–18. potential applications. Nat Rev Drug Discov 2002; 1: 674–82.
3. Ignarro LJ, Burke TM, Wood KS, Wolin MS, Kadowitz PJ. 9. Boolell M, Allen MJ, Ballard SA, et al. Sildenafil: an orally active type
Association between cyclic GMP accumulation and acetylcholine- 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment
elicited relaxation of bovine intrapulmonary artery. J Pharmacol of penile erectile dysfunction. Int J Impot Res 1996; 8: 47–52.
Exp Ther 1984; 228: 682–90. 10. Padma-Nathan H, Steers WD, Wicker PA. Efficacy and safety of
4. Francis SH, Noblett BD, Todd BW, Wells JN, Corbin JD. oral sildenafil in the treatment of erectile dysfunction: a double-
Relaxation of vascular and tracheal smooth muscle by cyclic blind, placebo-controlled study of 329 patients. Sildenafil Study
nucleotide analogs that preferentially activate purified cGMP- Group. Int J Clin Pract 1998; 52: 375–9.
dependent protein kinase. Molecular Pharmacol 1988; 34: 11. Francis SH, Corbin JD. Phosphodiesterase-5 inhibition: the molec-
506–17. ular biology of erectile function and dysfunction. Urol Clin North
5. Bush PA, Aronson WJ, Buga GM, Rajfer J, Ignarro LJ. Nitric oxide Am 2005; 32: 419–29.
is a potent relaxant of human and rabbit corpus cavernosum. Urol 12. Goldstein I, Kim E, Steers WD, et al. Efficacy and safety of tadalafil
1992; 147: 1650–5. in men with erectile dysfunction with a high prevalence of comor-
6. Burnett AL, Lowenstein CJ, Bradt DS, Chang TSK, Snyder SH. Nitric bid conditions: results from MOMENTUS: multiple observations in
oxide in the penis: physiology and pathology. Science 1992; 257: men with erectile dysfunction in national tadalafil study in the US.
401–3. J Sex Med 2007; 4: 166–75.
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13. Giuliano F, Donatucci C, Montorsi F, et al. Vardenafil is effective 28. Francis SH, Turko IV, Corbin JD. Cyclic nucleotide phospho-
and well-tolerated for treating erectile dysfunction in a broad diesterases: relating structure and function. Prog Nucleic Acid Res
population of men, irrespective of age. BJU Int 2005; 95: 110–16. Mol Biol 2001; 65: 1–52.
14. Blount MA, Beasley A, Zoraghi R, et al. Binding of tritiated sildena- 29. Rybalkin SD, Rybalkina IG, Shimizu-Albergine M, Tang XB, Beavo
fil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site J. PDE-5 is converted to an activated state upon cGMP binding to
displays potency, specificity, heterogeneity, and cGMP stimula- the GAF A domain. EMBO J 2003; 22: 469–78.
tion. Mol Pharmacol 2004; 66: 144–52. 30. Zoraghi R, Bessay EP, Corbin JD, Francis SH. Structural and func-
15. Beavo JA, Houslay MD, Francis SH. Cyclic nucleotide phospho- tional features in human PDE-5A1 regulatory domain that provide
diesterase superfamily. In: Beavo JA, Houslay MD, Francis SH, ed. for allosteric cGMP binding, dimerization, and regulation. J Biol
Cyclic Nucleotide Phosphodiesterases in Health and Disease. Chem 2005; 280: 12051–63.
Boca Raton, FL: CRC Press, 2006: 3–17. 31. Francis SH, Blount MA, Zoraghi R, Corbin JD. Molecular proper-
16. Barnett CF, Machado RF. Sildenafil in the treatment of pulmonary ties of mammalian proteins that interact with cGMP: protein
hypertension. Vasc Health Risk Manag 2006; 2: 411–22. kinases, cation channels, phosphodiesterases, and multi-drug
17. Corbin JD, Francis SH. Pharmacology of phosphodiesterase-5 anion transporters. Front Biosci 2005; 10: 2097–117.
inhibitors. Int J Clin Pract 2002; 56: 453–9. 32. Kotera J, Francis SH, Grimes KA, et al. Allosteric sites of phospho-
18. Hallen K, Wiklund NP, Gustafsson LE. Inhibitors of phospho- diesterase-5 sequester cyclic GMP. Front Biosci 2004; 9: 378–86.
diesterase 5 (PDE 5) inhibit the nerve-induced release of nitric 33. Sung BJ, Hwang KY, Jeon YH, et al. Structure of the catalytic
oxide from the rabbit corpus cavernosum. Br J Pharmacol 2007; domain of human phosphodiesterase 5 with bound drug mole-
150: 353–60. cules. Nature 2003; 425: 98–102.
19. Zhang L, Zhang Z, Zhang RL, et al. Tadalafil, a long-acting type 5 34. Wang H, Liu Y, Huai Q, et al. Multiple conformations of phospho-
phosphodiesterase isoenzyme inhibitor, improves neurological diesterase-5: implications for enzyme function and drug develop-
functional recovery in a rat model of embolic stroke. Brain Res ment. J Biol Chem 2006; 281: 21469–79.
2006; 1118: 192–8. 35. Conti M, Beavo J. Biochemistry and physiology of cyclic nucle-
20. Rutten K, Vente JD, Sik A, et al. The selective PDE-5 inhibitor, otide phosphodiesterases: essential components in cyclic nucle-
sildenafil, improves object memory in Swiss mice and increases otide signaling. Annu Rev Biochem 2007; 76: 481–511.
cGMP levels in hippocampal slices. Behav Brain Res 2005; 164: 36. Blount MA, Zoraghi R, Ke H, et al. A 46-amino acid segment
11–16. in phosphodiesterase-5 GAF-B domain provides for high vard-
21. Agostino PV, Plano SA, Golombek SA. Sildenafil accelerates reen- enafil potency over sildenafil and tadalafil and is involved in
trainment of circadian rhythms after advancing light schedules. phosphodiesterase-5 dimerization. Mol Pharmacol 2006; 70:
Proc Natl Acad Sci USA 2007; 104: 9834–9. 1822–31.
22. Kotera J, Omori K. PDE11. In: Beavo JA, Houslay MD, Francis SH, 37. Gopal VK, Francis SH, Corbin JD. Allosteric sites of phospho-
eds. Cyclic Nucleotide Phosphodiesterases in Health and Disease. diesterase-5 (PDE-5). A potential role in negative feedback regula-
Boca Raton: CRC Press, 2006: 255–76. tion of cGMP signaling in corpus cavernosum. Eur J Biochem
23. Weeks JL 2d, Zoraghi R, Francis SH, et al. N-terminal domain 2001; 268: 3304–12.
of phosphodiesterase-11A4 (PDE11A4) decrease affinity of the 38. Corbin J, Blount MA, Weeks JL, et al. [3H]sildenafil binding
catalytic site for substrates and tadalafil, and is involved in to phosphodiesterase-5 is specific, kinetically heterogenous,
oligomerization. Biochemistry 2007; 46: 10353–64. and stimulated by cGMP. Mol Pharmacol 2003; 63: 1364–72.
24. Francis SH, Zoraghi R, Kotera J, et al. Phosphodiesterase-5: molec- 39. Bessay EP, Zoraghi R, Blount MA, et al. Phosphorylation of
ular characteristics relating to structure, function, and regulation. phosphodiesterase-5 is promoted by a conformational change
In: Beavo JA, Houslay MD, Francis SH, eds. Cyclic Nucleotide induced by sildenafil, vardenafil, or tadalafil. Front Biosci 2007;
Phosphodiesterases in Health and Disease. Boca Raton, FL: CRC 12: 1899–910.
Press, 2006: 131–64. 40. Rybalkin SD, Rybalkina IG, Feil R, Hofmann F, Beavo JA.
25. Corbin JD, Francis SH. Cyclic GMP phosphodiesterase 5: target for Regulation of cGMP-specific phosphodiesterase (PDE-5) phosphory-
sildenafil. J Biol Chem 1999; 274: 13729–32. lation in smooth muscle cells. J Biol Chem 2002; 277: 3310–17.
26. Ke H, Wang H. Structure, catalytic mechanism, and inhibitor 41. Moncada I, Jara J, Subira D, Castano I, Hernandez C. Efficacy
selectivity of cyclic nucleotide phosphodiesterases. In: Beavo JA, of sildenafil citrate at 12 hours after dosing: re-exploring the
Houslay MD, Francis SH, eds. Cyclic Nucleotide Phospho- therapeutic window. Eur Urol 2004; 46: 357–60; discussion
diesterases in Health and Disease. Boca Raton, FL: CRC Press, 60–1.
2006: 607–26. 42. Porst H, Padma-Nathan H, Giuliano F, et al. Efficacy of tadalafil
27. Ke H, Wang H. Crystal structures of phosphodiesterases and impli- for the treatment of erectile dysfunction at 24 and 36 hours after
cations on substrate specificity and inhibitor selectivity. Curr Top dosing: a randomized controlled trial. Urology 2003; 62: 121–5;
Med Chem 2007; 7: 391–403. discussion 5–6.
29 Phosphodiesterase type 5
inhibitors: non-erectile dysfunction
cardiovascular effects
Charalambos Vlachopoulos, Nikolaos Ioakeimidis, Konstantinos Rokkas, and
Christodoulos Stefanadis

Introduction pathways triggered by pressure load (Figure 29.1).2 These

findings support a possible role of the drug in modifying
Apart from corpus cavernosum, phosphodiesterase (PDE) stimulated cardiac function and reducing myocardial hyper-
type-5 isoform is expressed in various other tissues, including trophy. A significant upregulation of PDE-5 isoenzyme and
the arterial and venous vasculature, the skeletal visceral and an inotropic effect due to acute PDE-5 inhibition has been
tracheobronchial muscles, the brain, the retina, and platelets.1 reported recently in hypertrophied human and animal right
The differential distribution of PDE-5 isoenzyme in various ventricular models.4
tissues, as well as the different selectivity of the pharmacologic
agents, forms the basis for potential tissue-specific effects of
PDE-5 inhibitors. Accumulation of data in this context has Coronary vasculature
delineated the overall profile of actions of PDE-5 inhibitors, Patients with coronary artery disease exhibit reduced basal
has expanded indications of use to include idiopathic pulmo- activity of nitric oxide (NO) in the atherosclerotic epicardial
nary hypertension (specifically for sildenafil), and even shows and microvascular coronary circulation. Since PDE-5 iso-
potential for further therapeutic applications. It should be enzyme is expressed in coronary arteries, its inhibition has
stressed, however, that although the three currently available been hypothesized to augment coronary blood flow.5 Studies
agents show many similar modes of actions, an effect proven with sildenafil in dogs and humans confirmed modest flow
for one agent does not necessarily apply to the others. Further- increases in normal and diseased coronary arteries.6–8 Tadalafil
more, extrapolations of experimental evidence to the clinical improved myocardial blood flow during periods of increased
setting should be made with caution. workload in both normal and poorly perfused regions of myo-
cardium.9 Sildenafil administration may augment coronary
blood flow by improving aortic stiffness and by reducing
Effects on cardiac function and amplitude and delaying arrival of wave reflections from peri-
pheral sites.10
coronary circulation
The cardiovascular effects of PDE-5 inhibitors are summa-
rized in Table 29.1. Cardioprotective effects
Ischemic preconditioning is a powerful cardioprotective pheno-
menon according to which recurrent episodes of ischemia
Myocardium protect against future myocardial infarction and stunning.
Direct analysis of effects on cardiac function has been obtained A significant number of experimental studies have shown
in vitro, but these results remain limited and conflicting. that PDE-5 inhibitors have a preconditioning-like cardio
PDE-5 gene expression is present in human heart, although protective effect against ischemia and reperfusion injury (see
protein expression and enzyme activity have been questioned.1,2 Figure 29.1).11,12 While the increase in cGMP levels (with acti-
Recent evidence has shown that although gene and protein vation of protein kinase G and subsequent opening of the mito-
expression is indeed low, PDE-5 is compartmentalized within chondrial KATP channels) by PDE-5 inhibitors is suspected to
the myocyte and its inhibition can alter cardiac function.3 be the most likely mechanism of protection, an additional
This is not observed under resting conditions, but only when signaling cascade that may be triggered concurrently includes
the heart is stimulated (e.g. by adrenergic agonists or pressure increased expression of endothelial NO synthase (eNOS) and
overload). Indeed, there is evidence that PDE-5 inhibition by inducible NO synthase (iNOS); activation of extracellular
sildenafil can blunt the systolic responses to beta-adrenergic signal-regulated kinase and protein kinase C (PKC); and open-
stimulation and deactivate multiple hypertrophy signaling ing of the mitochondrial KATP channels.11,12

221
222 Textbook of Erectile Dysfunction

Table 29.1 Cardiovascular effects of phosphodiesterase type 5 inhibitors

Variable Pathophysiological mechanisms Clinical implications

Myocardium Suppression of beta-adrenergic or pressure Benefit in disorders in which neurohormonal

overload stimulated systolic function stimulation is enhanced such as hypertension,
left ventricular hypertrophy, and heart failure
Coronary vasculature Epicardial coronary vasodilation, increase Favorable effects in patients with vasospastic
coronary blood flow angina or diffuse coronary microvessel disease
Preconditioning-like Opening of the mitochondrial KATP channels due Preconditioning-like cardio protective effect
cardioprotection to increased cGMP levels with activation of against ischemia/reperfusion injury, potential use
protein kinase G, increased expression of eNOS in coronary artery bypass surgery
and iNOS, activation of ERK and protein kinase C
Cardiac repolarization None of the three agents are dangerously Precautions for use in patients with congenital
associated with QTc prolongation. Mild QT prolongation and with class Ia and class III
prolongation with vardenafil antiarrhythmics (vardenafil)
Blood pressure and Mild lowering of blood pressure and clinically To be further evaluated as potential
heart rate insignificant heart rate changes antihypertensive agents in essential hypertension
Pulmonary vasculature Targeting of the NO/cGMP pathway Sildenafil has been approved for the treatment of
Reduction of plasma levels of endothelin-1 idiopathic pulmonary arterial hypertension.
Inhibition of the hypoxia induced cytokine Beneficial effects in pulmonary arterial
expression (TNF-alpha, IL-1-beta) hypertension, either idiopathic or associated with
congestive heart failure, connective tissue
disease or with repaired congenital systemic–
pulmonary shunts or sickle cell disease
Peripheral vascular Reversal of endothelial dysfunction Favorable effects in patients with heart failure,
structure and function Decrease of aortic stiffness and wave reflections coronary artery disease, or hypertension, and in
patients with increased cardiovascular risk.
Symptomatic relief of patients with Raynaud’s
phenomenon
Systemic effects Potent inhibition of superoxide formation Beneficial effects in patients with risk factors and
(anti-oxidative Reduction of inflammatory markers and increased oxidative stress and subclinical
stress – inflammation) mediators inflammatory state
Platelets Increased threshold for activation of the platelet Potential adjunctive use as anti-platelets agents
glycoprotein IIb–IIIa receptor in patients with coronary artery disease.
Potential benefit in Raynaud’s phenomenon and
sickle cell disease
Neurological recovery Regulation of angiogenesis and neurogenesis, as Possible neurological functional recovery after
well as synaptic plasticity, after stroke embolic stroke (experimental studies)
ERK, extracellular signal-regulated kinase; QTc, corrected QT interval; NO, nitric oxide; TNF, tumor necrosis factor; IL, interleukin

Cardiac repolarization dose–response relationship. In healthy subjects, changes are

Cardiac electrophysiology effects of PDE-5 inhibitors, espe- of the following magnitude: sildenafil 100 mg decreases blood
cially as manifested by changes in the QT interval, have been pressure by 3.7/3.6 mmHg for systolic and diastolic pressure,
studied. None of the three agents is dangerously associated respectively; vardenafil 20 mg decreases blood pressure by
with prolongation of the corrected QT interval, although 7.5/8 mmHg; and tadalafil 20 mg decreases blood pressure by
vardenafil has a warning of use for patients with congenital 1.6/0.8 mmHg. Greater declines in blood pressure may be
QT prolongation and for patients using class Ia and III antiar- observed in treated and untreated hypertensive patients.15 In
rhythmics.13 Patients with heart failure, however, constitute a patients with severe coronary artery disease, sildenafil showed
group that warrants further investigation.14 small (<10%) but significant decreases in systemic arterial
pressures.8 Similar effects on central and peripheral hemo-
dynamic parameters in patients with coronary artery disease
Effects on blood pressure have also been reported for tadalafil and vardenafil.15
and heart rate Blood pressure effects are consistent with arteriodilatory
effects of PDE-5 inhibitors on the peripheral vasculature as a
All PDE-5 inhibitors produce rather small changes in systolic result of an increase in cGMP in vascular smooth muscle.16
and diastolic blood pressure in both the supine and standing Dilatation of the brachial artery extends even to patients
condition after a single-dose administration. There is no clear with refractory hypertension.17 Of interest is the finding that
 Phosphodiesterase type 5 inhibitors: non-erectile dysfunction cardiovascular effects 223

Left Ventricle Remodeling Preconditioning-like Cardioprotection

Sildenafil Vardenafil
Con 3 wk TAC

– Sil

+ Sil
Saline control Vardenafil
(a) (b)

Figure 29.1 Experimental studies showing cardiac effects of phosphodiesterase (PDE) type 5 inhibition. (a) Inhibition of PDE-5 with
sildenafil prevents load-induced cardiac hypertrophy; example of heart sections. (b) Representative sections of the heart demonstrating
reduction of post-ischemic infarct size 30 minutes following treatment with vardenafil. The light gray areas represent the viable areas
while the infracted ones are lighter gray or white. Note the significant viable area in the sections of the heart treated with vardenafil
as compared to saline control. Con, sham mice; TAC, transverse aortic constriction; Sil, sildenafil. Adapted with permission from
Nat Med 2005; 11: 214–222 and J Mol Cell Cardiol 2007; 42: 453–80.11

sildenafil exerts a stimulatory effect on renin secretion. Thus, the be linked at the level of the endothelium with a defective NO–
resultant increase in the activation of the renin–angiotensin cGMP system being a common abnormality.23
system could counteract the vasodilation and this could partly There are data suggesting that PDE-5 inhibitors might be
account for the rather small net effects on blood pressure by of use in reversing generalized endothelial dysfunction
PDE-5 inhibitors.18 (Figure 29.3). Acute or mid-term sildenafil treatment showed
Heart rate changes compensatory to blood pressure favorable effects on brachial artery flow-mediated dilatation
reduction have either not been shown or are clinically up to 24 hours after dosing in men with and without ED24–26
insignificant.8,16 and in patients with coronary artery disease7 and chronic heart
failure.27,28 Moreover, mid-term therapy with tadalafil led to a
significant sustained improvement of endothelial function in
Effects on pulmonary vasculature patients with increased cardiovascular risk regardless of their
degree of ED.29 Vardenafil restored impaired endothelial func-
PDE-5 isoenzyme is widely expressed in pulmonary vascular tion of cavernous and brachial arteries.30
smooth muscle and in newly muscularized distal pulmonary ED patients with or without cardiovascular risk factors
arterioles, and it is thought to limit the vasodilator and anti- exhibit reduced endothelial progenitor cells. Tadalafil (chroni-
proliferative cGMP-mediated effects of vasoactive factors such cally, in ED patients) and vardenafil (acutely, in healthy
as NO and the natriuretic peptides.19 Enhanced PDE-5 activity subjects and ED patients) increased the number of circulating
in response to chronic hypoxia has been implicated in the endothelial progenitor cells, suggesting an intriguing role of
pathophysiology of pulmonary hypertension. Thus, PDE-5 these drugs in the mobilization or production of endothelial
isoenzyme is an attractive target for the pharmacologic manip- progenitor cells that promote endothelial rehabilitation.31
ulation of pulmonary vascular function and structure. Indeed,
PDE-5 inhibitors cause relaxation of pulmonary vascular
smooth muscles by activating large-conductance, calcium- Arterial stiffness and wave reflections
activated potassium channels.20 Reduction of plasma levels of Large artery stiffness and arterial wave reflections are impor-
endothelin-1 may also account for pulmonary vasorelaxation tant determinants of left ventricular function, coronary blood
effects.21 Recent experimental studies showed that tadalafil, flow, and the mechanical integrity of arteries. They are
but not sildenafil or vardenafil, inhibited hypoxic pulmonary involved in the pathogenesis of systolic hypertension and they
vasoconstriction through attenuation of hypoxia-induced have been identified as independent markers and prognostica-
pulmonary artery cytokine expression.22 tors of cardiovascular risk. Carotid–femoral pulse wave velocity
The effects of PDE-5 inhibitors in pulmonary hypertension and wave reflections indices decreased after acute sildenafil
are shown in Figure 29.2. administration (Figure 29.4).10,32,33 Studies regarding mid-term
administration have showed favorable (Vlachopoulos C et al.,
unpublished data) and neutral effects.33
Effects on the peripheral vasculature
Endothelial function Systemic effects
Endothelial dysfunction is the key event in the pathophysi-
ology of erectile dysfunction (ED), and men with penile vas- Oxidative stress
cular dysfunction have endothelial dysfunction in other Oxidative stress is implicated in endothelial damage and
vascular beds as well. ED and generalized vascular disease may increased destruction of NO. In vitro studies showed that
224 Textbook of Erectile Dysfunction

Endothelium

Cytokines L-arginine

–
PDE-5
inhibitors Nitric oxide
–

Endothelin-1 + cGMP

Vasoconstriction KCa channels

and
proliferation

Vasodilatation Inhibition of
proliferation

Figure 29.2 Effects of phosphodiesterase (PDE) type 5 inhibitors in pulmonary hypertension. PDE-5 inhibitors increase cGMP levels
by inhibiting its degradation; they also reduce cytokine levels and decrease endothelin-1 levels.

increased production of reactive oxygen species is associated inhibitors on the latter10,24–30,32,33 could be partly attributed to
with impaired erectile response, owing primarily to reduction an anti-inflammatory action of the drug, and, indeed, this is
of NO concentrations. The inhibitory action of the NO–cGMP further supported by preliminary data from our laboratory
axis on NAD(P)H oxidase expression mediated by PDE-5 (Vlachopoulos C et al., unpublished data).
inhibition may contribute to a potent inhibition of superoxide
formation.34
Platelets
Sildenafil increases the threshold for activation of the platelet
Subclinical inflammation glycoprotein IIb–IIIa receptor without an effect on platelet
ED adds an incremental inflammatory and endothelial– degranulation.7 This is consistent with potentiation of the
prothrombotic activation on top of coronary artery disease and, anti-aggregatory action of NO donors by sildenafil.7 It has also
interestingly, equivalence between ED and coronary artery dis- been suggested that sildenafil may have a biphasic effect on
ease in terms of endothelial or inflammatory activation has platelets, consisting of an initial transient stimulatory response
been shown.35,36 There is evidence that PDE-5 inhibitors have that promotes platelet aggregation and a subsequent inhibi-
a beneficial effect on inflammatory activation. A 12-week tory response that limits thrombus size.5 Whether the observed
antioxidant treatment (propionyl L-carnitine) plus sildenafil anti-platelet effect results in a clinically relevant benefit
reduced monocyte activation and markers of endothelial requires further investigation.
damage [intracellular adhesion molecule (ICAM)-1, P-selectin]
and penile vascular damage (end-diastolic velocity) in patients
with diabetic ED.37 Furthermore, a 4-week administration Neurological recovery
of sildenafil26 and tadalafil38 showed a favorable effect on Cyclic nucleotides (cGMP and cAMP) may play a critical role
endothelium-dependent vasodilatation of cavernous arteries in modulating brain function under physiological and patho-
in men with ED that was accompanied by a favorable effect on logical conditions by affecting angiogenesis, neurogenesis,
markers of endothelial function and inflammation, including and synaptic plasticity. Sildenafil and tadalafil improved neuro-
adhesion molecules (VCAM and ICAM), endothelin-1, and logical functional recovery and selectively increased cerebral
highly sensitive C-reactive protein (hsCRP), and IL-6, as blood flow level in the ischemic boundary when administered
well as on insulin. Given the unfavorable effect of inflamma- in rat models after embolic stroke. Improved functional recov-
tion on arterial function,39 the beneficial effect of PDE-5 ery was associated with upregulation of brain cGMP levels.40
 Phosphodiesterase type 5 inhibitors: non-erectile dysfunction cardiovascular effects 225

Smoking Arteriogenic ED
FMD 6
6.0
% p = 0.035
Sildenafil

Increase in brachial
Placebo
5.0

artery FMD
4
To

4.0
p < 0.05

2
3.0

2.0
0 30 45 Sm0 Sm15 Sm30 0
(a) Time (b) Control Arteriogenic ED

18% Diabetes

16%
p = 0.008
14%
Increased cardiovascular risk patients
Brachial artery FMD

12 12%
% change from basal

(% increaee)

10 p = 0.4
10%
8
6 p < 0.01 p < 0.01 8%
14%
4 6%
2 9%
4% 8%
0
Baseline 4 weeks 2 weeks after 2%
discontinuation
0%
(c) Tadalafil Placebo (d) Pretreatment Placebo Sildenafil

Figure 29.3 Effects of phosphodiesterase (PDE) type 5 inhibitors on endothelial function as assessed by flow-mediated dilatation
(FMD) of the brachial artery: (a) Smokers (sildenafil, acute effect), (b) Patients with arteriogenic erectile dysfunction (vardenafil, acute
effect), (c) Men with erectile dysfunction (ED) and increased cardiovascular (CV) risk (tadalafil, mid-term effect), (d) Diabetic patients
(sildenafil, mid-term effect). Adapted with permission from Am J Hypertens 2004; 17: 1040–4,25 Int J Impot Res 2006; 18: 464–9,30
Eur Urol 2005; 47: 214–22,29 and Diabetes Care 2002; 25: 1336–90.24

Phosphodiesterase type 5 inhibitors Favorable modes of action of PDE-5 inhibitors include

improvement of vascular function and an ischemic precondi-
and disease states tioning-like effect. Based on these properties, they could be
potentially used as cardiovascular drugs in patients with
Coronary artery disease vasospastic angina or diffuse coronary microvessel disease5
PDE-5 inhibitors are widely used as a primary pharmaco- and in patients undergoing coronary artery bypass grafting.43
logical treatment of ED in men with and without (known) Furthermore, although their potency is modest compared
underlying cardiovascular disease. Although initial reports of with other agents that specifically target platelet adhesion and
adverse cardiac events were reported soon after approval of aggregation, their adjunctive use as anti-platelet agent could
sildenafil, a compelling body of data suggests that PDE-5 be also considered.7,43
inhibitors do not significantly increase the risk of non-fatal Despite their safe profile, PDE-5 inhibitors should not be
myocardial infarction, stroke, or cardiovascular deaths.41,42 used in patients at high risk, including those with unstable
Sildenafil, especially, has been extensively studied. A review of angina, recent myocardial infarction (<2 weeks), on life-
numerous clinical trials indicates this drug generally has a good threatening ventricular arrhythmias.41 NO donors in combina-
safety profile in men with ED and concomitant cardiovascular tion with PDE-5 inhibitors cause a profound and unpredictable
disease and its administration is not associated with ischemic decline in blood pressure and are contraindicated. Despite
events, either at the time of introduction of treatment or during some studies showing the dissipation of the interaction effect
longer-term use.5,8 Even in patients with severe coronary artery before 24 hours, to date, the 24-hour period between nitrate
disease, sildenafil does not affect coronary artery diameter and use and short-acting PDE-5 inhibitor administration (up to
basal flow, while it increases coronary flow reserve.8 48 hours for the long-acting tadalafil) appears prudent until
226 Textbook of Erectile Dysfunction

Acute effect Acute effect Mid-term effect

CAD HF arteriogenic ED

11.4 PWV 0.5 Aortic PWV response Sildenafil

PWV
11.2 Placebo (sildenafil-placebo) 8.4 Placebo
0 p<0.05
11.0 8.2
10.8 -0.5

m/sec
8
m/s

10.6 p=0.005 -1 p<0.001

m/sec
10.4 7.8
10.2 -1.5
10.0 7.6
-2
9.8 Sildenafil 7.4
9.6 -2.5
0 30 60 90 120 150 180 0 30 60 90 120 150 180 7.2
Time (min) Time (min) Day 0 Day 14

30 PWV 2 Alx response (%) Sildenafil

Placebo (sildenafil-placebo) Alx
30 Placebo
0 p <0.05
28
-2 25

p <0.001 p <0.001 20
%

-4
%

26

%
-6 15
24 10
-8
Sildenafil
5
22 -10
0 30 60 90 120 150 180 0 30 60 90 120 150 180 0
(a) Time (min) (b) Time (min) (c) Day 0 Day 14

Figure 29.4 Effects of phosphodiesterase type 5 inhibitors on aortic stiffness (PWV, pulse wave velocity) and wave reflections (AIx,
augmentation index). (a) Patients with coronary artery disease (CAD). (b) Patients with heart failure (HF). (c) Patients with arteriogenic
erectile dysfunction (ED) and increased cardiovascular risk. Adapted with permission from Vasc Med 2003; 8: 243–8,10 and Am J
Cardiol 2005; 96: 1436–40,32 and from Vlachopoulos C (unpublished data).

additional data, including information on outliers and patients Systemic hypertension

with coronary artery disease, are available.41 Data from multiple trials support safety of use of PDE-5
inhibitors in hypertensive men with ED being treated with
monotherapy or a multidrug antihypertensive regimen.15
Heart failure PDE-5 inhibitors did not increase the incidence of adverse
Patients with heart failure have an increased prevalence of ED, events or hypotensive episodes. Although PDE-5 inhibitors
and sildenafil has been shown to be safe and effective for the are no longer contraindicated with alpha-blockers, all three
treatment of ED in patients with symptomatic heart failure PDE-5 inhibitors carry precautions regarding the use of
(New York Heart Association classes II and III).19,44 The effi- alpha-blockers, owing to the possible development of ortho-
cacy of sildenafil in the treatment of pulmonary arterial static hypotension with concomitant use. Thus, administration
hypertension has prompted investigation of a potential utility and dosing should be according to the most recent package
of PDE-5 inhibition in the treatment of heart failure patients insert.41
with secondary pulmonary hypertension (see below). Silde- Although the acute blood pressure-lowering effect in treated
nafil improves cardiac performance and exercise capacity in hypertensive patients is modest, the potential of PDE-5 inhi-
heart failure patients; mechanisms include improvement of bitors as antihypertensive agents has also been explored.
endothelial function and reduction of large artery stiffness Active mid-term treatment with sildenafil reduces ambulatory
and wave reflections.27,28,32,45,46 This agent protects the alveolar– and clinic blood pressure by an extent similar to that observed
capillary membrane in chronic heart failure patients both with the other classes of antihypertensive drugs.33 In an acute
at rest and during sub-maximal exercise. It improves tissue study, an incremental antihypertensive effect of a single dose
oxygenation during exercise and gas diffusion at the lung of tadalafil has been demonstrated in uncontrolled hyperten-
level, and it protects the alveoli from exercise-induced edema sive subjects on multiple agents.49 However, at this stage, the
formation.47 Interesting experimental data suggest direct use of PDE-5 inhibitors as antihypertensive agents cannot be
myocardial effects of PDE-5 inhibition that may counteract advocated.
beta-adrenergic, hypertrophic, and pro-apoptotic signaling,
three critical pathways in the development of left ventricle
dysfunction.2 Prophylactic treatment with sildenafil prevented
apoptosis and left ventricular dysfunction in a chronic model Pulmonary hypertension
of doxorubicin-induced cardiomyopathy.48 Sildenafil has been shown to be beneficial in patients with
Experimental and clinical myocardial effects of sildenafil pulmonary arterial hypertension (Figure 29.6), either idio-
are shown in Figure 29.5. pathic or associated with heart failure, connective tissue
 Phosphodiesterase type 5 inhibitors: non-erectile dysfunction cardiovascular effects 227

3.5 Cardiac index

– Sildenafil
p =not significant p<0.0001 p <0.0001
+ Sildenafil
200

Left ventricular mass (mg)

3
Placebo
160 Sildenafil

I/min/m2
2.5
120
2
80
p < 0.001 1.5
40

0 1
1 2 3 0 60 180
(a) Week (b) Minutes

Figure 29.5 Experimental and clinical myocardial effects of sildenafil. (a) Prevention and reversal of myocardial hypertrophy and
failure induced by pressure load. (b) Increase in cardiac index due to afterload reduction in systolic heart failure. Adapted with
permission from Nat Med 2005; 11: 214–22,2 and Am J Cardiol 2005; 96: 1436–40.32

Change in 6-minute walking distance (m)

Pre-sildenafil Post-sildenafil
70
Placebo
60 Sildenafil 20 mg
Sildenafil 40 mg
50 Sildenafil 80 mg
40
LV LV
30
20
RV
RV 10
0
–10
–20
0 4 8 12
Week
(a) (b)

Figure 29.6 Improvement of hemodynamics and functional capacity by sildenafil in pulmonary hypertension. (a) Magnetic
resonance imaging angiography shows reversal of the pathological septal shift after sildenafil treatment. (b) Change from baseline to
12 weeks in the distance walked in 6 minutes. This distance increased from baseline in all sildenafil groups; the mean placebo-
corrected treatment effects were 45 m (+13.0%), 46 m (+13.3%), and 50 m (+14.7%) sildenafil for 20 mg, 40 mg, and 80 mg, respectively
(p < 0.001 for all comparisons). Adapted with permission from Circulation 2003; 108: 2066–9,20 and N Engl J Med 2005; 353:
2148–57.50

disease, or repaired congenital systemic–pulmonary shunts. Congenital heart disease

It significantly improves exercise capacity by improving Increased pulmonary vascular resistance complicating con-
pulmonary hemodynamics and reducing right ventricular genital heart disease may be caused by a dysfunction in endo-
afterload.20,50 It also reduces right ventricular mass, as deter- genous pulmonary endothelial NO production. In patients
mined by magnetic resonance imaging.20 It is well tolerated with Eisenmenger’s syndrome, sildenafil improves not only
and, on the basis of recent clinical studies, it has been hemodynamic parameters but symptomatic status and exercise
approved at a dose of 20 mg three times daily for improving capacity as well.5 Improvement of pulmonary blood flow is of
exercise tolerance in patients with idiopathic pulmonary the same magnitude as in patients with idiopathic pulmonary
hypertension.50 It should be stressed, however, that despite hypertension. Preliminary evaluation of tadalafil has shown
their common classification as PDE-5 inhibitors, all three beneficial effects of this agent on hemodynamics, tolerability,
agents are not equally efficacious in the treatment of pulmo- and efficacy over a 12-week period.52 In patients with large atrial
nary hypertension (Table 29.2).51 While a reduction in mean septal defects, sildenafil improves pulmonary arterial hemody-
pulmonary artery pressure, in pulmonary–systemic vascular namics and right ventricular function and relieves symptoms
resistance ratio, and in right ventricle afterload, as well as an associated with severe pulmonary arterial hypertension.53
increase in cardiac index, has been reported with all three
PDE-5 inhibitors, only sildenafil caused a significant improve-
ment in arterial oxygenation. The cause of these differences
Connective tissue diseases
between the agents is not known, but one possibility is the
different selectivities of the three PDE-5 inhibitors with respect Secondary pulmonary hypertension
to other PDE isoforms. These agents may also differ in their Pulmonary arterial hypertension is a frequent complication of
binding capacity to PDE-5 during hypoxia.51 connective tissue diseases. Recent studies suggest that sildenafil
228 Textbook of Erectile Dysfunction

Table 29.2 PDE-5 inhibition in patients with pulmonary hypertension: pulmonary hemodynamic effects and
functional changes

Variable Sildenafil Tadalafil Vardenafil Comments

mPAP + + + No difference in the magnitude of response among the drugs

PVR/SVR + + − Vardenafil lacks pulmonary selectivity
Cardiac index + + + No difference in the magnitude of response among the drugs
Alveolar gas exchange + − − Sildenafil exerts a favorable effect on ventilation–perfusion
matching
RV hypertrophy + ? ? During chronic hypoxia, sildenafil normalizes RVSP and
reduces right ventricle hypertrophy; the other agents not tested
Exercise capacity + ? ? Improvement in pulmonary hemodynamics and reduction in
right ventricular afterload; trials with the other agents under way
PDE, phosphodiesterase; mPAP, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance index; RV, right ventricle; RVSP, right
ventricle systolic pressure; SVR, systemic vascular resistance index

can be used as a pulmonary vasodilator in systemic sclerosis In patients with sickle cell disease and mild–moderate pulmo-
patients with secondary pulmonary hypertension. Sildenafil nary hypertension, chronic therapy with sildenafil reduced
also reduces pulmonary artery pressure and increases quality pulmonary arterial systolic pressure and improved exercise
of life in patients with systemic lupus erythematosus.54 capacity.56 Administration of sildenafil also potentiates reduc-
tion of platelet activation through NO-dependent signaling.5
Raynaud’s phenomenon These findings support a role of PDE-5 inhibitors for counter-
acting vascular dysfunction and impaired thrombotic state in
Impaired endothelial-dependent vasodilatation is implicated
such patients.
in Raynaud’s phenomenon, in which digital ischemia results
from vasoconstriction of the digital arteries, pre-capillary
arterioles, and cutaneous arteriovenous shunts. Available
evidence suggests that sildenafil and vardenafil, through their Conclusion
vasoactive and platelet-inhibitory effects, may lead to improved
A substantial body of studies shows that PDE-5 inhibitors
microcirculation, symptomatic relief and ulcer healing in
patients with vasodilator-resistant Raynaud’s phenomenon.55 have a wide multitude of actions on the cardiovascular sys-
tem. These actions carry significance in two directions. First,
Limited data suggest similar effects with tadalafil.
and most important, they support the safety of this class of
agents. Second, they show potential for indications beyond
Sickle cell disease the primary approval of these drugs. At present, sildenafil is
Increased endothelial cell activation is involved in the the only agent that has such an additional indication, namely
pathophysiology of sickle cell disease. In addition, pulmonary idiopathic pulmonary hypertension. Further data are needed
hypertension is increasingly recognized as a complication to assess the additional clinical benefit of this very promising
of sickle cell disease, with a prevalence of approximately 30%. class of agents.

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22. Tsai BM, Turrentine MW, Sheridan BC, et al. Differential effects of 43. Fung E, Fiscus RR, Yim AP, et al. The potential use of type-5
phosphodiesterase-5 inhibitors on hypoxic pulmonary vasocon- phosphodiesterase inhibitors in coronary artery bypass graft
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Surg 2006; 81: 272–8. 44. Lewis GD, Semigran MJ. The emerging role for type 5 phospho-
23. Kirby M, Jackson G, Simonsen U. Endothelial dysfunction links diesterase inhibition in heart failure. Curr Heart Fail Rep 2006; 3:
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24. Desouza C, Parulkar A, Lumpkin D, et al. Acute and prolonged exercise, neurohormonal activation, and erectile dysfunction in
effects of sildenafil on brachial artery flow-mediated dilatation in congestive heart failure: a double-blind, placebo-controlled, ran-
type 2 diabetes. Diabetes Care 2002; 25: 1336–9. domized study followed by a prospective treatment for erectile
25. Vlachopoulos C, Tsekoura D, Alexopoulos N, et al. Type 5 dysfunction. Circulation 2002; 106: 1097–103.
phosphodiesterase inhibition by sildenafil abrogates acute smoking- 46. Lewis GD, Shah R, Shahzad K, et al. Sildenafil improves exercise
induced endothelial dysfunction. Am J Hypertens 2004; 17: capacity and quality of life in patients with systolic heart failure
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26. Aversa A, Vitale C, Volterrani M, et al. Chronic administration of 1555–62.
sildenafil improves markers of endothelial function in men with 47. Bussotti M, Montorsi P, Amato M, et al. Sildenafil improves the
type 2 diabetes. Diabet Med 2008; 25: 37–44. alveolar-capillary function in heart failure patients. Int J Cardiol
27. Katz SD, Balidemaj K, Homma S, et al. Acute type 5 phospho- 2008; 126: 68–72.
diesterase inhibition with sildenafil enhances low-mediated vaso- 48. Fisher PW, Salloum F, Das A, et al. Phosphodiesterase-5 inhibition
dilation in patients with chronic heart failure. J Am Coll Cardiol with sildenafil attenuates cardiomyocyte apoptosis and left
2000; 36: 845–51. ventricular dysfunction in a chronic model of doxorubicin cardio-
28. Guazzi M, Samaja M, Arena R, et al. Long-term use of sildenafil in toxicity. Circulation 2005; 111: 1601–10.
the therapeutic management of heart failure. J Am Coll Cardiol 49. Patterson D, McInnes GT, Webster J, et al. Influence of a single
2007; 50: 2136–44. dose of 20 mg tadalafil, a phosphodiesterase 5 inhibitor, on ambu-
29. Rosano G. MC, Aversa A, Vitale C, et al. Chronic treatment latory blood pressure in subjects with hypertension. Br J Clin
with tadalafil improves endothelial function in men with increased Pharmacol 2006; 62: 280–7.
cardiovascular risk. Eur Urol 2005; 47: 214–22. 50. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil use in pulmo-
30. Mazo E, Gamidov S, Iremashvili V. The effect of vardenafil on nary arterial hypertension (SUPER) study group. Sildenafil citrate
endothelial function of brachial and cavernous arteries. Int J Impot therapy for pulmonary arterial hypertension. N Engl J Med 2005;
Res 2006; 18: 464–9. 353: 2148–57.
31. Foresta C, Caretta N, Lana A, et al. Relationship between vascular 51. Ghofrani HA, Voswinckel R, Reichenberger F, et al. Differences
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phosphodiesterase-5 inhibitors in patients with pulmonary arterial 54. Galie N, Manes A, Farahani KV, et al. Pulmonary arterial hyperten-
hypertension: a randomized prospective study. J Am Coll Cardiol sion associated to connective tissue diseases. Lupus 2005; 14:
2004; 44: 1488–96. 713–17.
52. Mukhopadhyay S, Sharma M, Ramakrishnan S, et al. Phospho- 55. Caglayan E, Huntgeburth M, Karasch T, et al. Phosphodiesterase
diesterase-5 inhibitor in Eisenmenger syndrome: a preliminary type 5 inhibition is a novel therapeutic option in Raynaud disease.
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53. Lim ZS, Salmon AP, Vettukattil JJ, Veldtman GR. Sildenafil therapy 56. Machado RF, Martyr S, Kato GJ, et al. Sildenafil therapy in patients
for pulmonary arterial hypertension associated with atrial septal with sickle cell disease and pulmonary hypertension. Br J Haematol
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30 Sildenafil: first in the therapeutic class
of phosphodiesterase type 5 inhibitors
Culley C Carson III

Introduction Pharmacokinetics
The introduction of oral agents for the treatment of erectile Specificity
dysfunction (ED) has revolutionized the treatment of men One classification of differences amongst the three PDE-5
with erection problems of all severities and etiologies. Silde- inhibitors is that of specificity for phosphodiesterase inhi-
nafil, available on the world market since 1998, was joined in bition. Because the PDE enzyme is a participant in erectile
2003 by tadalafil and vardenafil as effective safe and reliable function, inhibition is a method of facilitating erectile func-
oral agents for the treatment of ED. While these agents have tion. cGMP facilities the relaxation of smooth muscle cells in
the same mechanism of action, there are differences among the corpus cavernosum through the nitric oxide (NO) path-
the three agents. Sildenafil has the longest patient experience way. Because PDE-5 in the corpus cavernosum smooth
and the most robust data confirming its activity, safety, and muscle cells breaks down cGMP, inhibition or blockade of
tolerability. It has recently been released for use in pulmonary this enzyme will prolong the duration and increase the con-
hypertension as well as ED. centration of cGMP in the smooth muscle cell, facilitating
Among the earliest recognized phosphodiesterase (PDE) erectile function. Currently 11 families of PDEs have been
inhibitors were caffeine and theophylline.1 The first PDE identified in the human. Selectivity of the three currently
inhibitor used clinically for the treatment of ED was papa- available PDE-5 agents is predominantly for PDE-5; however,
verine, a non-selective inhibitor of PDE-5. Papaverine is there is some additional inhibition of other PDE enzymes by
administered via injection into the corpora cavernosa of the the various agents (Table 30.1). Sildenafil has excellent selec-
penis, either alone or in combination with other vasoactive tivity for PDE-5 over all the other PDEs except for PDE-6,
agents. Sildenafil, the first oral PDE-5 inhibitor, was approved which has some degree of inhibition from both sildenafil and
for use in men with ED in 1998.1 The addition of vardenafil vardenafil, most significantly sildenafil. This selectivity for
and tadalafil to the market has increased the number of PDE-6 produces a dose-related impairment of blue–green
approved PDE-5 inhibitors to three agents used throughout color discrimination and leads to the blue vision that some
the world. Each of these agents has a similar mechanism of patients report.1 This PDE-6 inhibition is not related to the
action, but there are pharmacological and clinical differences. blindness caused by non-arteritic ischemic optic neuropathy
The molecular structures of sildenafil, vardenafil, tadalafil, reported with some PDE-5 agents.
and cGMP are shown in Figure 30.1.
All three approved agents in this class have similar pharma-
cokinetic and pharmacodynamic profiles and each is effective
for all ages of patients with ED of all severities and etiologies. Absorption and metabolism
While there are clear pharmacokinetic and pharmacodynamic Because of differences in gastrointestinal absorption with fatty
differences amongst these agents, clinical differences are some- meals and time of absorption, the three drugs have differences
what more difficult to identify. Indeed the data of preference in ultimate peak plasma concentrations based on food intake.2
trials, head-to-head clinical trials, and selection trials are few. Sildenafil, when taken with a high-fat meal, has a reduction in
The differences in pharmacokinetics, while having distinct maximum concentration (Cmax) of approximately 29%, with
advantages in marketing each drug, may be difficult for delays in time to peak plasma concentration (Tmax) that can be
clinicians and patients to identify. With the lack of data as long as 1 hour.3 This interaction may result in delayed
and good-quality clinical trials, it is difficult for the clinician onset or reduced efficacy because of a decrease in peak serum
to differentiate among the three agents and to select a PDE-5 concentration. This reduction may result in treatment failure
inhibitor for a specific ED patient or a specific agent to in some patients. Thus, patients taking sildenafil should be
switch to if an initial PDE-5 agent is unsuccessful or poorly instructed to do so either 1–2 hours after eating or with a
tolerated. reduced fat meal.4

231
232 Textbook of Erectile Dysfunction

PDE5 Inhibitors

Core ring Core ring Core ring

O O O O
H
N CH3
HN O HN N O HN
N N
N N
H2N N N N N
N H H
O
O
OH
O S O O S O
O
O N N O
O
P Piperazine ring
OH Piperazine ring
O
N
N
cGMP

Sildenafil Vardenafil Tadalafil

Figure 30.1 Molecular structure of three marketed phosphodiesterase type 5 inhibitors and their molecular similarity to cGMP.

Table 30.1 PDE-5 inhibitors: selectivity for PDE-5 4 hours, but it may be clinically active for as long as 8 hours
versus other PDE isoenzymes* because of prolonged adherence to receptor sites beyond
the usual serum half-life. The clinician must be aware that
PDE Isoenzyme Sildenafil Tadalafil Vardenafil emergency treatment with nitrate medications following
ingestion of sildenafil should be delayed for 24 hours.6
PED-1 80 >4000 690
PDE-2 >19,000 >4000 62,000
PDE-3 4628 >4000 40,000 Onset of action
PED-4 2057 >4000 47,000 Multiple studies have been performed to evaluate the onset of
PDE-6 (rod) 11 188 35 activity of the three PDE-5 inhibitors. Because of the artificial
(cone) 10 153 6
nature of these studies, clinical relevance continues to be
controversial. Onset of action studies are designed to use
PDE-7 6100 >14,000 >300,000
stopwatch evaluations by patients or partners following inges-
PED-8 8500 >14,000 >300,000 tion of the PDE-5 agent. Significance in onset of action is
PDE-9 750 >14,000 5800 measured as first measurement of statistically significant dif-
PDE-10 2800 >14,000 30,000 ference in erectile function compared with placebo. While
† this statistically significant difference may occur as early as
PDE-11 780 6 1620
11 minutes with sildenafil, success at this early time occurs
*Selectivity ratio for phosphodiesterase (PDE) type 5=1 for all inhibi- for fewer than 40% of patients treated.7–9 In patients with sig-
tors; higher ratios indicate lower selectivity. nificant risk factors and comorbidities for ED, counseling to
†
Physiological role and clinical relevance are not yet known.
begin sexual activity at 15 minutes or earlier leads to treat-
From Curr Urol Rep 2003; 4: 457–65.41
ment failure and may, in the final analysis, create performance
anxiety, and patients may inappropriately lose confidence in
The cytochrome P (CYP) 450 system is the chief metabolic the treatment.
pathway for sildenafil, which is a CYP3A4 substrates. Similarly,
sildenafil has a desmethyl metabolite that accounts for approx-
imately 20% of its overall pharmacologic activity. Sildenafil
has a terminal half-life of approximately 4–5 hours.5 Excretion Drug interactions
is principally as fecal metabolites, with 80% of oral doses
Use of any PDE-5 inhibitor agent is absolutely contraindicated
excreted in the feces.5
in patients taking any form of nitric acid (NO) donor, espe-
In men ages 65 years or older, the area under the curve
cially organic nitrates. Sildenafil can potentiate the vasodilator
(AUC, i.e. the systemic exposure) of sildenafil increases by
and hypotensive effects of these agents.5,10–12 Reductions in
40%.5 Therefore, lower starting doses are recommended for
blood pressure with nitrates have been observed within
the elderly, beginning at 25 mg with dose escalation as required
24 hours after taking sildenafil; therefore, nitrates should
by patient response and side-effects.
not be used to manage acute myocardial ischemia in a patient
who has taken sildenafil within the prior 24 hours.13
Duration of action Acute postural hypotensive symptoms have also been
The three available PDE-5 inhibitors have some significant observed when sildenafil is administered together with the
differences in serum half-life. Sildenafil has a half-life of alpha-adrenergic blocker doxazosin, which is indicated for
 Sildenafil: first in the therapeutic class of phosphodiesterase type 5 inhibitors 233

the treatment of benign prostatic hyperplasia as well as hyper-

Table 30.2 Adverse events with phosphodiesterase
tension. Sildenafil at doses exceeding 25 mg should not
type 5 inhibitors
be administered within 4 hours of a patient taking an
alpha-blocker.14 Reported by >2% of patients (%)
Concomitant administration of sildenafil with other anti-
hypertensive agents (e.g. calcium-channel blockers) does not Adverse event Sildenafil Tadalafil Vardenafil
result in significant declines in blood pressure or in increased (flexible dose) (20 mg) (flexible dose)
occurrence of hypotension, syncope, or other adverse cardio- Headache 16 15 15
vascular events compared with placebo.12,15 Flushing 10 3 11
Alcohol is a mild vasodilator with effects on NO synthase
Nasopharyngitis, 4 3 9
activity and NO output by endothelial cells.16 In a placebo-
rhinitis, or nasal
controlled crossover trial involving eight healthy non-smoking
congestion
men, there were no untoward hemodynamic interactions
between sildenafil 100 mg and red wine (750 ml, 13.5% v/v) Dyspepsia 7 8 4
consumed 60 minutes after sildenafil dosing (i.e. time of peak Abnormal vision 3
plasma concentration for sildenafil).17 Red wine intake signifi- Sinusitis 3
cantly elevated cardiac index and heart rate, and sildenafil Flu syndrome 3
alone significantly lowered mean arterial pressure by up to 7%
Diarrhea 3
and peripheral vascular resistance by up to 8%. However, the
combination had no effect on any of these parameters Myalgia 3
compared with red wine alone.
Potent CYP3A4 inhibitors, including HIV protease inhi-
bitors (e.g. indinavir, ritonavir), azole antifungals, and mac-
rolide antibiotics (e.g. erythromycin, azithromycin) can increase
systemic exposure (the AUC) of sildenafil by two- to 16-fold. Safety
Conversely, CYP3A4 inducers such as rifampin can reduce
circulating PDE-5 inhibitor levels.1 Extensive treatment of patients with vascular risk factors using
Grapefruit juice inhibits first-pass CYP metabolism in sildenafil has demonstrated safety in cardiac patients. Indeed,
the gastrointestinal tract and may thus increase oral bioavail- sildenafil was originally designed as a cardioprotective agent,
ability of the PDE-5 inhibitors. A randomized crossover trial and clinical and laboratory studies have confirmed this
evaluated the effects of taking a single sildenafil 50 mg dose safety.1,5 The Princeton Consensus Guideline Conference II
1 hour before, or at the same time as, 250 ml of grapefruit carefully reviewed the risks, AEs, and safety of PDE-5 inhibi-
juice in 24 healthy male volunteers.18 Compared with water tors in men with cardiac disease.6 This expert conference, with
(reference period), grapefruit juice consumption increased meta-analysis of available phase III studies, demonstrated no
the AUC values for sildenafil and N-desmethylsildenafil by increased risk of cardiac events in patients taking PDE-5 inhi-
about 23–24% and slightly prolonged the time to peak plasma bitors compared with placebo-treated patients or patients in
concentration (by about 15 minutes). Grapefruit juice also the general, age-adjusted population with similar age and risk
rendered sildenafil pharmacokinetics more variable, and the factor profiles. Indeed, in several of the studies reviewed,
authors concluded that the combination should be avoided, patients taking regular PDE-5 inhibitors were demonstrated
especially in patients who might be prone to more marked to have fewer cardiac events than those not taking PDE-5
hemodynamic effects.18 inhibitors.13
While clinical trials of sildenafil have included large numbers
of patients with cardiovascular disease and diabetes mellitus,
they have excluded patients with unstable cardiovascular
Adverse events disease.5 Accordingly, PDE-5 inhibitors are either not recom-
Most adverse events (AEs) associated with sildenafil therapy mended or are to be used with caution in men with unstable
are caused by inhibition of PDE-5 in tissues other than the angina, recent myocardial infarction, cardiac failure, a life-
corpus cavernosum (see Table 30.2). Sildenafil-associated AEs threatening or uncontrolled arrhythmia, poorly controlled
occur in ≥3% of patients and include: blood pressure (resting blood pressure less than 90/50 mmHg
or more than 170/100–110 mmHg), or heart failure.5 In addi-
• headache in 16% of patients taking sildenafil compared tion, patients with left ventricular outflow obstruction sec-
with 4% of men receiving placebo; ondary to aortic stenosis or idiopathic hypertrophic subaortic
• flushing (10% vs 1%); stenosis, as well as men with severe autonomic insufficiency,
• dyspepsia (7% vs 2%); and may be especially sensitive to the vasodilator effects of PDE-5
• nasal congestion (4% vs 2%). inhibitors. Consensus guidelines have been issued for risk-
stratifying and counseling patients with concomitant sexual
Discontinuations because of AEs were infrequent, occurring dysfunction and cardiovascular disease.20 Men with ED and
in 2.5% of patients receiving sildenafil compared with 2.3% of associated significant cardiovascular conditions must be coun-
patients receiving placebo.5 AEs appear to decline over time in seled that there is a transient increase in the relative risk
published studies of sildenafil.19 of cardiovascular events during and within about 2 hours
234 Textbook of Erectile Dysfunction

after sexual intercourse with or without PDE-5 inhibitor of successful intercourse attempts compared with 20% in
treatment.6 a placebo group.27 In reviewing these studies, however, it is
Exercise echocardiographic studies have demonstrated that clear that 25–35% of patients in these clinical study protocols
treatment with sildenafil 50–100 mg did not adversely affect had inadequate responses to PDE-5 inhibitors.1 Sildenafil
hemodynamic variables, exercise capacity (treadmill time), or phase 3 trials were reported in the New England Journal of
time to cardiac ischemia (or first awareness of angina) in Medicine in 1998. In a dose-escalation (50–100 mg) study
patients with stable coronary artery disease.21,22 involving 329 men (mean age, 59 years) with ED for about
In clinical trials of sildenafil, the incidence rate of myocardial 5 years (organic ED in 55% or more of cases), the mean score
infarction ranged from 1.0 per 100 patient-years for patients for the erectile function domain of the International Index
taking sildenafil in open-label studies to 1.7 per 100 patient- of Erectile Function (IIEF) at the end of 12 weeks of treat-
years for those receiving sildenafil in randomized controlled ment was 22.1 (mild) in the sildenafil group compared with
trials, as against 1.4 per 100 patient-years for those random- 12.2 (moderate) in the placebo group (p < 0.001). Scores on
ized to placebo in such trials.13,23 The slight disparities between the orgasmic function, intercourse satisfaction, and overall
incidence rates of myocardial infarction across sildenafil trials satisfaction domains (but not the sexual desire domain) also
may reflect differences in age or other patient characteristics significantly improved.28
at baseline.
Even at supratherapeutic doses consistent with concomitant
treatment with CYP inhibitors or renal impairment, sildenafil Long-term efficacy
does not increase the corrected QT interval in a clinically With the increasing experience of PDE-5 inhibitor treatment
significant manner.24 Sildenafil 50–400 mg does not increase for ED, efficacy over time is becoming better documented.
the absolute QT interval, and elicited only mild rises in the Long-term studies including 5- and 6-year data from silde-
Fridericia-corrected QT interval duration 1 hour after dosing nafil have demonstrated no clinical evidence for tachyphylaxis.
in healthy adult males ages 45–60 years (mean, 53) who also Indeed, the long-standing efficacy of sildenafil, the agent
received the active control moxifloxacin.24 These findings, longest on the market, strongly suggests that this class of
together with the absence of reports of torsades de pointes agents continues to be effective with long-term use. Since
in sildenafil post-marketing surveillance databases, suggest these agents are used only on an as-needed basis, few patients
that none of the PDE-5 inhibitors causes clinically significant have taken daily doses for long periods of time. The few long-
prolongation of the QT interval.24,25 term daily dosing studies, however, have not demonstrated
Case reports have implicated PDE-5 inhibitors in non- conclusively any evidence for tolerability or tachyphylaxis.29
arteritic ischemic optic neuropathy (NAION), a rare form of Similarly, daily dosing studies, while still limited in duration,
acute blindness usually found in elderly patients with signifi- show improved, not compromised, responses in comparison
cant vascular risk factors. While fewer than 50 cases have been with on-demand dosing.30
reported in the world literature, multiple clinical, epidemio-
logic, and basic science studies have been completed to
examine the link between PDE-5 inhibitors and blindness.26 Difficult-to-treat patients
This association is not related to the blue-tinted vision All three PDE-5 inhibitors have been demonstrated to be
reported by some sildenafil patients. This latter finding is effective in patients with severe erectile dysfunction. Indeed,
transient and related to the inhibition of PDE-6 in the cones patients with prostate cancer who have had radiation therapy
of the eye. Animal studies of the optic nerve after sildenafil or radical surgery and patients with severe vascular disease,
demonstrate increased optic nerve blood flow, opposite to the diabetes, or depression are all treated satisfactorily with these
expected finding with non-arteritic ischemic optic neuro- agents. While the efficacy declines in these patients with severe
pathy. Similarly, an estimate of the frequency of cases in a erectile dysfunction, these agents are safe and effective, but
non-treated population shows similar numbers of cases to consideration in these patients should be given to increasing
that reported in association with PDE-5 use, with no signal to dosage levels to maximum acceptable dose.
increased prevalence.26 Men with diabetes mellitus are at elevated ED risk and are
The systemic exposures of sildenafil may be increased difficult to treat. Sildenafil has been demonstrated as effective
in patients with renal insufficiency or hepatic impairment. therapy for men with diabetic ED. The Sildenafil Diabetes
Starting or other doses may need to be limited to sildenafil Study Group reported that 56% of men with diabetic ED
25 mg in patients with these conditions.1,5 who received sildenafil (25–100 mg) treatment for 12 weeks
reported improved erections, in contrast to 10% of patients
receiving placebo (p < 0.001).31 In this study, 61% of men
Clinical effectiveness data randomized to sildenafil reported at least one successful
attempt at sexual intercourse compared with 22% of controls
The US Food and Drug Administration approved sildenafil in (p < 0.001).
March 1998 after extensive clinical trials. Because sildenafil Because intact innervation to the penis is necessary for
has an almost 10-year history of safety and efficacy, it has physiologic erectile responses, substantial proportions of
more extensive clinical and laboratory data to demonstrate its patients with prostate cancer experience ED following either
use in varied etiologies, populations, and severities of ED. nerve-sparing radical retropubic prostatectomy or radiation
Early data for sildenafil include a 12-week randomized, placebo- therapy. Prostate cancer patients treated with sildenafil have
controlled study of sildenafil 50 mg that demonstrated 65% shown significant improvements in erectile function. In an
 Sildenafil: first in the therapeutic class of phosphodiesterase type 5 inhibitors 235

open-label sildenafil study involving 84 men (mean age, with sildenafil 2.1 points with testosterone and placebo, a
62 years) with ED 2.1 years post-prostatectomy, 53% of statistically significant difference. Additionally, those patients
patients receiving treatment at doses of 50–100 mg reported treated with the combination therapy had an improvement in
improved erections, and 40% reported an enhanced ability to ejaculatory function.35 Doses of sildenafil above the recom-
achieve and maintain erections. Erectile function was directly mended 100 mg may be effective in some men in whom stan-
related to the degree of nerve sparing, with patients having dard doses fail. McMahon showed a 24% success rate using
had a bilateral nerve-sparing procedure tending to respond 200 mg after previous sildenafil failures. Drop-outs were 31%
better than those having had a unilateral or non-nerve-sparing and side-effects increased in all categories.36
procedure.32 Lower pathological stage and older patient age
were also predictive of improved outcomes.
Using a single question form the Erectile Dysfunction Future directions
Inventory of Treatment Satisfaction rather than the entire
instrument, Hong et al. documented a sildenafil treatment PDE-5 inhibitors were introduced in an effort to improve
satisfaction rate of only 26% between 0 and 6 months after erectile function. Their efficacy and safety have been well
nerve-sparing radical retropubic prostatectomy, which rose to recorded in millions of patients worldwide. These agents,
a maximum of 60% between the 18th and 24th postoperative however, should not be confined to the treatment of ED. Early
month.33 data support the improvement of endothelial cell-mediated
flow in peripheral arteries via the NO pathways, suggesting a
possible use for these agents as treatment for conditions
Failure of phosphodiesterase type 5 inhibitor therapy known to limit endothelial function. Sildenafil is approved in
Because as many as 30–40% of patients will not respond to the USA and in Europe for the treatment of pulmonary hyper-
PDE-5 inhibitors alone, strategies must be considered to tension. Trials have confirmed the improved pulmonary
enhance responses. Most importantly, patients must be dynamics with sildenafil, which appears to be more effective
counseled in the proper administration of PDE-5 inhibitors.34 than standard treatment, with improvements in lifestyle and
For sildenafil, patients should be counseled to avoid high-fat functional status.37–39
meals, and patients with significant comorbidities should be In addition, data have demonstrated the efficacy of chronic
advised to delay sexual stimulation for 1 hour following dosing of PDE-5 inhibitors in patients following radical pro-
administration.34 Similarly, patients should be counseled that statectomy. Rehabilitation using sildenafil was demonstrated
sexual stimulation is necessary. Dose escalation is also critical to improve post-radical prostatectomy erectile function by
in achieving therapeutic success. The majority of men in seven-fold in a study performed by Padma-Nathan et al.40
marketing studies have optimal doses of 100 mg. Studies with
sildenafil have demonstrated an improvement in response
after patients have taken sildenafil six or more times. Because Conclusion
many patients have had prolonged ED, they should be coun-
seled that multiple doses may be necessary before optimum Sildenafil is an effective and safe PDE-5 inhibitor, and the
response is achieved.4 Patients who continue to be poorly clinician now has multiple choices in treatment of patients
responsive to PDE-5 inhibitors should be further evaluated with erectile dysfunction of all severities and etiologies. Since
for hypogonadism. Indeed, sildenafil has been demonstrated no well-controlled, head-to-head selection or patient prefer-
to function poorly in the presence of low testosterone levels. ence studies are available, each clinician must choose an agent
Normalizing testosterone with testosterone gel therapy and based on the profile of the patient, his tolerance, risk factors,
maximizing the sildenafil dose to 100 mg will increase responses and side-effects. Patients in whom activity is limited because
substantially. Indeed Shabsigh et al. showed improvement in of cardiac disease should be evaluated before PDE-5 inhibitors
erectile function domain scores of the IIEF of 4.4 points in are prescribed, and no PDE-5 inhibitor should be prescribed
patients treated with testosterone and sildenafil, compared in patients taking nitrate medications.

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1. Carson CC, Lue TF. Phosphodiesterase type 5 inhibitors for erectile 7. Brock GB, McMahon CG, Chen KK, et al. Efficacy and safety
dysfunction. BJU Int 2005; 96: 257–80. of tadalafil for the treatment of erectile dysfunction: results of
2. Corbin JD, Francis SH. Pharmacology of phosphodiesterase-5 integrated analyses. J Urol 2002; 168: 1332–6.
inhibitors. Int J Clin Pract 2002; 56: 453–9. 8. Porst H, Padma-Nathan H, Giuliano F, et al. Efficacy of tadalafil
3. Padma-Nathan H, Giuliano F. Oral drug therapy for erectile dys- for the treatment of erectile dysfunction at 24 and 36 hours after
function. Urol Clin North Am 2001; 28: 321–34. dosing: a randomized controlled trial. Urology 2003; 62: 121–5;
4. McCullough AR. An update on the PDE-5 inhibitors (PDE-5i). discussion 125–6.
J Androl 2003; 24: S52–8. 9. Sussman DO. Pharmacokinetics, pharmacodynamics, and efficacy
5. Pfizer. Sildenafil citrate (Viagra) US Prescribing Information, of phosphodiesterase type 5 inhibitors. J Am Osteopath Assoc
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cardiac risk (the Second Princeton Consensus Conference). Am J cular disease. American College of Cardiology/American Heart
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11. Ishikura F, Beppu S, Hamada T, et al. Effects of sildenafil citrate 26. Gorkin L, Hvidsten K, Sobel R, Siegel R. Sildenafil citrate use and
(Viagra) combined with nitrate on the heart. Circulation 2000; 102: the incidence of nonarteritic anterior ischemic optic neuropathy.
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12. Webb DJ, Muirhead GJ, Wulff M, et al. Sildenafil citrate potenti- 27. Padma-Nathan H, Steers WD, Wicker PA. Efficacy and safety of
ates the hypotensive effects of nitric oxide donor drugs in male oral sildenafil in the treatment of erectile dysfunction: a double-
patients with stable angina. J Am Coll Cardiol 2000; 36: 25–31. blind, placebo-controlled study of 329 patients. Sildenafil Study
13. Carson CC, 3rd. Cardiac safety in clinical trials of phospho- Group. Int J Clin Pract 1998; 52: 375–9.
diesterase 5 inhibitors. Am J Cardiol 2005; 96: 37M–41M. 28. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the
14. Carson CC. Combination of phosphodiesterase-5 inhibitors and treatment of erectile dysfunction. Sildenafil Study Group. N Engl J
alpha-blockers in patients with benign prostatic hyperplasia: treat- Med 1998; 338: 1397–404.
ments of lower urinary tract symptoms, erectile dysfunction, or 29. Carson CC. Long-term use of sildenafil. Expert Opin Pharmacother
both? BJU Int 2006; 97 Suppl 2: 39–43. 2003; 4: 397–405.
15. Kloner RA, Hutter AM, Emmick JT, et al. Time course of the inter- 30. McMahon CG. Treatment of erectile dysfunction with chronic
action between tadalafil and nitrates. J Am Coll Cardiol 2003; 42: dosing of tadalafil. Eur Urol 2006; 50: 215–17.
1855–60. 31. Rendell MS, Rajfer J, Wicker PA, Smith MD. Sildenafil for treat-
16. Venkov C, Myers P, Tanner M, Su M, Vaughan D. Ethanol increases ment of erectile dysfunction in men with diabetes: a randomized
endothelial nitric oxide production through modulation of nitric controlled trial. Sildenafil Diabetes Study Group. JAMA 1999; 281:
oxide synthase expression. Thromb Haemost 1999; 81: 638–42. 421–6.
17. Leslie SJ, Atkins G, Oliver JJ, Webb DJ. No adverse hemodynamic 32. Lowentritt BH, Scardino PT, Miles BJ, et al. Sildenafil citrate after
interaction between sildenafil and red wine. Clin Pharmacol Ther radical retropubic prostatectomy. J Urol 1999; 162: 1614–17.
2004; 76: 365–70. 33. Hong EK, Lepor H, McCullough AR. Time dependent patient
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of grapefruit juice on the pharmacokinetics of sildenafil. Clin sparing radical retropubic prostatectomy (RRP). Int J Impot Res
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dysfunction in patients with cardiovascular disease: recommen- ized study of testosterone gel as adjunctive therapy to sildenafil in
dations of The Princeton Consensus Panel. Am J Cardiol 2000; 86: hypogonadal men with erectile dysfunction who do not respond to
175–81. sildenafil alone. J Urol 2004; 172: 658–63.
21. Thadani U, Smith W, Nash S, et al. The effect of vardenafil, a 36. McMahon CG. High dose sildenafil citrate as a salvage therapy for
potent and highly selective phosphodiesterase-5 inhibitor for the severe erectile dysfunction. Int J Impot Res 2002; 14: 533–8.
treatment of erectile dysfunction, on the cardiovascular response 37. Oudiz R, Roveran G, Hansen J, Sun X, Wasserman K. Effect of
to exercise in patients with coronary artery disease. J Am Coll sildenafil on ventilatory efficiency and exercise tolerance in
Cardiol 2002; 40: 2006–12. pulmonary hypertension. Eur J Heart Fail 2007; 9: 917–21.
22. Arruda-Olson A, Mahoney D, Nehra A, Leckel M, Pellikka P. 38. Guazzi M, Samaja M. The role of PDE-5 inhibitors in cardiopulmo-
Cardiovascular effects of sildenafil during exercise in men with nary disorders: from basic evidence to clinical development. Curr
known or probable coronary artery disease: a randomized cross- Med Chem 2007; 14: 2181–91.
over trial. JAMA 2002; 25: 719–25. 39. Kirsch M, Kemp-Harper B, Weissmann N, Grimminger F, Schmidt
23. Morales A, Gingell C, Collins M, Wicker P, Osterloh I. Clinical H. Sildenafil in hypoxic pulmonary hypertension potentiates a
safety of oral sildenafil citrate (Viagra) in the treatment of erectile compensatory up-regulation of NO-cGMP signaling. FASEB J
dysfunction. Int J Impot Res 1998; 10: 69–73. 2008; 22: 30–40.
24. Morganroth J, Ilson B, Shaddinger B, et al. Evaluation of vardenafil 40. Padma-Nathan H, McCullough A, Forest C. Erectile dysfunction
and sildenafil on cardiac repolarization. Am J Cardiol 2004; 93: secondary to nerve-sparing radical retropubic prostatectomy:
1378–83. Comparative phosphodiesterase-5 inhibitor efficacy for therapy
25. Ilson B, Shaddinger B, Dabiri G, et al. A definitive study of the and novel prevention strategies. Curr Urol Rep 2007; 5: 467–71.
effects of PDE-5 inhibitors on cardiac repolarization in middle- 41. Francis SH, Corbin JD. Molecular mechanisms and pharmacoki-
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75: P47. 457–65.
31 Tadalafil: Long-acting
phosphodiesterase type 5 inhibitor
Anthony J Bella and Gerald B Brock

Introduction Recent clinical reports have quantified the time to onset of

clinical effectiveness for tadalafil. The time to penile rigidity
Oral phosphodiesterase (PDE) type 5 inhibitors are the first- firm enough for sexual activity after a 20 mg dose has been
line treatment of erectile dysfunction (ED) for most patients. reported at 16 minutes in one-third of men, with more than
Owing to its efficacy, safety, ease of use, and unique pharma- 50% of men achieving increased penile rigidity sufficient
cological properties, tadalafil is preferred by many men suffer- for penetrative sexual activity at 30 minutes.15 Plasma concen-
ing from ED of varying etiologies and severity. In this chapter, trations of tadalafil reach 77% of maximum concentration by
pharmacokinetic and updated clinical data from integrated 1 hour after dosing. The time interval until most patients
analyses and postmarketing surveillance are reviewed, includ- are able to complete intercourse successfully is reported as
ing efficacy results for specific subpopulations, an evidence- 20 minutes for sildenafil 100 mg,16 approximately 25 minutes
based review of on-demand, daily and chronic-dosing regimens, for vardenafil 20 mg,17 and 30 minutes for tadalafil 20 mg;15
and compiled safety data. cohorts for these at-home studies (n=223–732) included men
with mild to severe ED and, with the exception of vardenafil,
lower doses were associated with longer onset times.6,15–18 For
Pharmacological profile example, statistically significant differences for tadalafil 10 mg
were observed at 45 minutes.19
Although sildenafil, vardenafil, and tadalafil share a common The serum half-life for tadalafil is 17.5 hours,8,20,21 compared
mechanism of action through inhibition of PDE-5 in the with approximately 3.8 hours for sildenafil6,22,23 and 4.2 hours
corpora cavernosa and the resulting decrease in breakdown of for vardenafil.6,13,24 The difference in half-life is the most
cGMP, their chemical structures and pharmacological pro- significant pharmacologic characteristic differentiating these
perties are distinct.1–5 These differences directly influence three agents. Plasma concentrations of tadalafil reach 77%
onset and duration of efficacy, resulting in unique profiles for of maximum concentration by 1 hour after dosing, and effi-
each agent. Clinically evident differences are dependent upon cacy has been established for up to 36 hours, when plasma
pharmacokinetic parameters including maximum drug con- concentrations drop to more than three-fold less than the
centration, time to peak concentration, minimal effective maximum.20,25
concentration, and duration of efficacy (the time at which
active drug concentration is greater than the minimum
effective concentration).6 Metabolism and excretion
Tadalafil is metabolized primarily via the cytochrome P450
3A4 (CYP3A4) pathway in the liver, and at therapeutic doses
Pharmacologic parameters tadalafil does not induce or inhibit CYP3A4 activity. The
The pharmacokinetic characteristics for tadalafil have been major metabolite of tadalafil is methylcatechol glucoronide,
determined both in healthy men and in those with erectile which is more than 10,000-fold less potent as a PDE-5 inhibitor
dysfunction. Key studies include an integrated analysis per- and does not contribute significantly to PDE-5 inhibitor
formed on 13 clinical pharmacology studies in healthy subjects activity.8,20,25
designed to elucidate the distribution characteristics for tada-
lafil 20 mg, a recent consolidated review of all peer-reviewed
reports, and published abstracts and regulatory filings related Effects of extrinsic and intrinsic factors
to the pharmacology of tadalafil (Table 31.1).6–8 on pharmacokinetics
Tadalafil is rapidly absorbed following oral administration, Extrinsic factors such as food and alcohol were not shown to
with a median time to maximum serum concentration of alter the rate and extent of absorption of tadalafil in healthy
2 hours,6,9 compared with sildenafil (1 hour and 1.2 hours subjects.21 This important characteristic also distinguishes
for 50 mg and 100 mg doses, respectively)6,10–12 and vardenafil tadalafil from sildenafil and vardenafil. High-fat meals (with
(0.7 hours and 0.9 hours for 20 mg and 10 mg doses, 57% of calories from fat) delay the time to maximum concen-
respectively).13,14 tration of sildenafil by 60 minutes and reduce the maximum

237
238 Textbook of Erectile Dysfunction

Table 31.1 Pharmacokinetic parameters of phosphodiesterase 5 inhibitors

Characteristic Placebo (n=74) Tadalafil treatment group

10 mg (n=74) 20 mg (n=75)
Age (years) mean±SD 58.8±10.8 57.6±10.9 59.1±12.0
Weight (kg) mean±SD 91.2±17.1 93.6±16.7 92.1±17.7
Ethnicity, N (%)
African descent 5 (6.8) 4 (5.4) 7 (9.3)
Western Asian 0 0 1 (9.3)
Caucasian 64 (86.5) 68 (91.9) 63 (84.0)
East or South-east Asian 3 (4.1) 0 0
Hispanic 2 (2.7) 2 (2.7) 4 (5.3)
Erectile dysfunction history, N (%)
≥3 months and <6 months 1 (1.4) 3 (4.1) 0
≥6 months and <1 year 4 (5.4) 5 (6.8) 8 (10.7)
≥1 year 69 (93.2) 66 (89.2) 67 (89.3)
IIEF erectile function domain score, N (%)
Mild (22–25) 9 (12.2) 10 (13.5) 11 (14.7)
Moderate (11–21) 39 (52.7) 39 (52.7) 39 (52.0)
Severe (6–10) 26 (35.1) 25 (33.8) 25 (33.3)
Comortid conditions
Hypertension 35 (47.3) 24 (32.4) 25 (33.3)
Diabetes mellitus 17 (23.0) 20 (27.0) 23 (30.7)
Depression 5 (6.8) 5 (6.8) 11 (14.7)
Hyperlipidemia 7 (9.5) 3 (4.1) 4 (5.3)
Prior use of sildenafil citrate 7 (9.5) 7 (9.5) 5 (6.7)
SD, standard deviation; IIEF, International Index of Erectile Function. From Urology 2007; 68: 689–96.6

concentration by 29% compared with fasting, while median brain, liver, skeletal muscle, and blood vessels; PDE-5 is the
time to maximum concentration for vardenafil is prolonged dominant isoform in the corpora cavernosum smooth muscle
by 1 hour.23,24,26 Moderate-fat meals (with 30% of calories from but it is also found in the lung, kidney, vascular and visceral
fat) do not reduce either of these parameters for vardenafil.26 smooth muscle, and platelets.28
Similarly, patient factors such as diabetes and renal impair- Comparisons of PDE-5 inhibition with other PDE families
ment did not cause clinically significant changes in tadalafil demonstrate in vitro specificity for PDE-5 versus PDE-6
pharmacokinetics. In a review of 227 patients with mild-to- (responsible for color vision disturbance, including a tran-
severe ED, systemic exposure to tadalafil was not influenced sient blue–green aura and discrimination difficulties) as fol-
by age, weight, smoking status, alcohol consumption, liver lows: tadalafil is 780 times more selective for PDE-5, in
enzyme status, ED severity, cardiovascular condition, or dia- comparison to 2.9 for vardenafil and 6.8 for sildenafil. Slight
betes mellitus.7 Time of administration (morning versus eve- variability in these ratios has been reported in the literature,
ning) has also not been shown to effect systemic distribution.27 owing to the timing of studies or the type of assays utilized by
These characteristics may translate into enhanced convenience different laboratories. Although in vitro selectivity ratios are
and increased patient- and partner-reported satisfaction with limited by the fact that direct extrapolation to clinical findings
tadalafil, since there is a reduced need to plan sexual activity is not possible, visual disturbances have been shown to occur
around dosing, meals, or alcohol consumption. in 11% of sildenafil patients,4,29 a small minority of those using
vardenafil,14 and approximately 0.1% of tadalafil users.30
On the other hand, the selectivity profiles for vardenafil and
Selectivity for phosphodiesterases sildenafil in relation to PDE-11, a recently described PDE
Tadalafil, sildenafil, and vardenafil are all highly selective family identified in vivo from the prostate, testes, heart, and
PDE-5 inhibitors. Each has a unique and distinct profile of pituitary and muscle tissue, are favored in comparison with
selectivity relative to the other 10 PDEs; this aspect of phar- that of tadalafil.31 The clinical implications of this potential
macology is clinically important because selectivity and pre- inhibition remain unknown, although there is evidence to
dicted side-effect profiles are related. To date, at least 11 PDE suggest a role for PDE-11 in male reproduction.31,32 Two ran-
families have been identified in tissues, including the heart, domized double-blind, placebo-controlled, parallel-group
 Tadalafil: Long-acting phosphodiesterase type 5 inhibitor 239

studies involving 421 men examined the effects on sper- 100

matogenesis of placebo versus tadalafil at 10 mg or 20 mg 90

Successful intercourse
80 75%
administered daily for 6 months (two complete human
spermatogenesis cycles); on the basis of semen profiles, no 70 61%

attempts (%)
adverse effects were noted. In the same study, serum levels of 60
testosterone, luteinizing hormone, and follicle stimulating 50 42%
40 36%
hormone were examined, with no significant changes to serum 32%
30
endocrine profiles in the 393 men completing this portion of
20
the study.33
10
0
Placebo 2.5 mg 5 mg 10 mg 20 mg
Tadalafil treatment groups
On-demand use
Figure 31.1 Effects of tadalafil on successful intercourse
Tadalafil has been approved for the treatment of ED in more attempts (SEP question 3). †SEP question 3: Did your erection
than 100 countries, with more than 10 million patients treated last long enough to have successful intercourse? = yes, *p < 0.05,
worldwide since its initial European Union approval in 2002. **p < 0.001. Adapted from J Urol 2002; 168: 1332–6.3
Tadalafil has been studied in over 100 clinical trials involving
over 12,000 men, with more than 10,000 additional patients
100
involved in ongoing studies.
Patients with normal erectile 90
function at end-point (%) 80
70
Efficacy: integrated analyses 59%
60
Efficacy and safety data for tadalafil were pooled from five 50
phase 3 multicenter, fixed-dose, parallel-group trials enrolling 40%
40
a total of 1112 patients in 74 centers.3 Integrated analysis of 30 23%
21%
these results was facilitated by common elements of study 20
11%
design, including inclusion and exclusion criteria; at baseline, 10
the study population resembled that of the Massachusetts 0
Male Aging Study (MMAS) with a mean patient age of 59,34 Placebo 2.5 mg 5 mg 10 mg 20 mg
and nearly 60% of the men were identified as having moderate- Tadalafil treatment groups
to-severe ED of varying etiologies. Common comorbidities
included hypertension (30%), diabetes (21%), and coronary Figure 31.2 Percentage of patients with normal erectile
artery disease (8%).3 After a 4-week treatment-free lead-in function at end-point. *p < 0.05, **p < 0.001. Adapted from J
period, during which at least four attempts at sexual inter- Urol 2002; 168: 1332–6.3
course occurred, patients were randomized to placebo or
tadalafil doses of 2.5–20 mg at a maximum of one dose per 100
day. All studies were conducted on an intent-to-treat basis 90 80% 80% 79%
and were analyzed over a 12-week period using outcome 80 73%
Successful intercourse

measures that included the International Index of Erectile 70

Function (IIEF), the Sexual Encounter Profile (SEP) diary, 59%
attempts (%)

60
and a global assessment question (GAQ). Co-primary efficacy
50
variables were defined as the change from baseline in the IIEF
erectile function domain questions and SEP questions 2 and 3.3 40

No restrictions were placed on food and alcohol intake or 30

timing of sexual activity. 20
At all doses, a statistically significant improvement from 10
baseline erectile function was observed for tadalafil compared 0
with placebo regardless of baseline ED etiology, severity, or ≤30 minutes >30 minutes >4 hours >12 hours >24 hours
≤4 hours ≤12 hours ≤24 hours ≤36 hours
patient age (Figures 31.1, 31.2, 31.3, 31.4). Almost 75% of
intercourse attempts were successfully completed with 20 mg Figure 31.3 Effects of tadalafil on successful intercourse
tadalafil versus 32% with placebo (p < 0.001); treatment completion (SEP question 3) with time after dosing. Adapted
effects were dose-dependent, with 35%, 50%, 67%, and 81% from J Urol 2002; 168: 1332–6.3
of patients (placebo, tadalafil 5 mg, 10 mg, and 20 mg,
respectively) reporting improved erections (GAQ, p < 0.001).
Clinically, erectile function was normalized (as defined by men and those with multiple comorbities.30,35–38 Carson et al.
an IIEF score >26) in 59% of men at a 20 mg dose compared reported that an analysis of integrated data from 11 trials
with 11% for placebo.3 comprising 2102 men and limiting tadalafil doses to either
Several updates on the efficacy and safety of on-demand 10 mg or 20 mg demonstrated mean IIEF erectile function
tadalafil have been reported, including cohorts comprising older domain score increases of 6.5 and 8.6 points, respectively,
240 Textbook of Erectile Dysfunction

15
Placebo function improved irrespective of diabetic type, the presence
Tadalafil 2.5 mg 12.2 of microvascular complications, or the type of diabetic treat-
Tadalafil 5 mg 10.4 **
Mean change from baseline

Tadalafil 10 mg 8.9 **
ment. Specifically, the proportion of men reporting the ability
8.7
10 to attain an erection (SEP question 2) was 22.2% and 22.6%
Tadalafil 20 mg ** **
for tadalafil 10 mg and 20 mg, respectively, versus a 4.1%
to endpoint

5.4 4.9
4.7
5 3.5
2.9 3.3 **
*
3.7 * decline for the non-treated group over the study period.44 In
** 2.6 response to the GAQ question, 56% and 64% of men taking
* ** 2.3 1.9
-1.6
tadalafil 10 mg or 20 mg, respectively, versus 25% in the
0 placebo arm felt treatment improved their erections (p<0.001),
Mild Moderate Severe while clinically meaningful increases in IIEF scores (>5) were
-5 observed in 56%, 44%, and 13% of groups using tadalafil
20 mg, tadalafil 10 mg, or placebo, respectively (p<0.001).44
Figure 31.4 Changes from baseline in erectile function domain Tadalafil was well tolerated, with 88% of men completing
scores of the International Index of Erectile Function at the end-
the trial.
point by baseline severity. †Baseline severity was delined by IIEF
Erectile Function domain scores: severe (1–10), moderate
Fonseca et al. have reported pooled data from 12 placebo-
(11–16), mild (17–30). *p < 0.05 **p < 0.001. Adapted from controlled trials, identifying 637 evaluable men with diabetes.45
J Urol 2002; 168: 1332–6.3 Baseline parameters included mean patient age of 57 years
and IIEF score of 12.6; compared with 1681 men without dia-
betes, tadalafil 20 mg improved all primary efficacy outcomes
compared with less than 1 point with placebo.28,30 Tadalafil versus placebo, including an average improvement of
20 mg improved erections in 84% of men versus 33% for 7.4 points for the IIEF score and a 53% rate of successful
placebo, 50% reported improved satisfaction with erectile intercourse attempts versus placebo results of 0.9 and 22%,
hardness as measured by SEP question 4 (placebo 11%), and respectively (p < 0.001).45 Treatment effects were independent
the mean success rate for intercourse attempts (SEP question 3) of type of diabetes, levels and methods of glycemic control,
was 68% for tadalafil, compared with 33% for the placebo and presence or absence of microvascular complications.
group (p < 0.001 for all outcomes).30 Parallel improvements in
patient and partner satisfaction for tadalafil compared with
placebo as measured by the Erectile Dysfunction Inventory of Efficacy following treatment for prostate cancer
Treatment Satisfaction (EDITS) were also demonstrated.35 Clinically meaningful improvements across all primary and
Cumulatively, large-scale, randomized, multicenter, double- secondary end-points (IIEF, SEP questions 2 and 3, EDITS,
blind placebo-controlled trials and post-marketing surveil- and GAQ) for on-demand tadalafil 20 mg compared with
lance have demonstrated that tadalafil is efficacious in placebo (p<0.001) for patients who had a bilateral nerve-
improving erectile function across ED etiologies and severity. sparing radical retropubic prostatectomy were demonstrated
At a dose of 20 mg, rates of successful intercourse approach in a 33-site, randomized, double-blind, placebo-controlled
70–75%, with return to normal erectile function in more than trial of 303 men with normal preoperative erectile function.46
half of patients. Successful penetration (SEP question 2) and intercourse
attempts (SEP question 3) were reported by 54% and 41% of
patients who received tadalafil or a placebo, respectively, while
Efficacy in diabetes subgroup analysis of 201 men reporting varying degrees of
Diabetes mellitus increases the risk of ED three-fold through spontaneous postoperative tumescence during baseline inter-
vascular disease, autonomic neuropathy, and endothelial course attempts yielded values of 69% and 52% for the same
dysfunction, with as many as 75% of diabetic men affected by metrics, respectively.46 Tadalafil-treated patients described
ED during their lifetime.39–41 More that 50% of men develop increased treatment satisfaction as measured by the EDITS
ED within 10 years of diabetes onset, and an earlier age of questionnaire, and 94.5% completed the study.46 Common
onset of ED in this population is frequently observed.42,43 side-effects included headache in 21%, dyspepsia in 13%, and
Significant improvements for diabetic men treated with myalgia in 7%. Tadalafil has also been shown to be an effective
tadalafil for ED were observed for all outcome measures on treatment for ED after external beam radiotherapy or
the integrated analyses previously discussed.3,30 Additionally, brachytherapy for prostate cancer.47,48
diabetes-specific trials support these findings. Saenz de Tejada Despite advances in the understanding of the underlying
et al. reported upon the efficacy and safety of tadalafil in a mechanisms responsible for post-prostatectomy ED and the
randomized, multicenter, double-blind, placebo-controlled well-described rationale for post-prostatectomy penile reha-
trial of 191 diabetic men (average duration of diabetes, bilitation, there is no consensus regarding the role of PDE-5
11.7 years) with ED, with patients randomly assigned to once- inhibitors (alone or in combination with intracavernous injec-
daily treatment with placebo or tadalafil 10 mg or 20 mg and tion) for this purpose.49,50 Although several animal studies
no restrictions for administration with respect to alcohol and support the use of PDE-5 inhibitors for the preservation of
food.44 Mean age and baseline ED severity were similar across erectile function and the prevention of corporal fibrosis, veno-
groups; 90.7% of men were type 2 diabetics, and satisfactory occlusive disease, apoptosis, and smooth muscle loss, currently
glycemic control (defined as a glycosylated hemoglobin of available clinical data are less clear.51–55 Non-randomized,
<7%) was identified in only 18.5% of patients.44 Erectile non-controlled studies for on-demand tadalafil, vardenafil,
 Tadalafil: Long-acting phosphodiesterase type 5 inhibitor 241

and sildenafil have demonstrated an improvement for post- significantly greater following tadalafil dosing (57 and 60%,
prostatectomy potency rates.5,46,56 There is no direct evidence respectively) than placebo (31 and 30%, respectively). Patient
that these compounds improve tissue oxygenation within the satisfaction and secondary outcomes for these trials are
corpora; however, these drugs appear to improve the preser- consistent with the analysis of integrated data, as are studies
vation of smooth muscle integrity following cavernosal nerve for duration of clinical effectiveness performed in specific
damage.54 populations such as men with spinal cord injuries.3,30,63
Despite the lack of standardized penile rehabilitation pro- Product labeling reflects this characteristic, indicating
grams, and the need for prospective, placebo-controlled that tadalafil may improve erectile function up to 36 hours
randomized clinical trials and further basic science studies, following ingestion.25
PDE-5 inhibitors should probably be offered (alone or as part
of combination therapy with intracavernous injections) to the
informed patient shortly after radical prostatectomy because
of potential benefits, ease of use, and patient tolerability.48,55,56 Daily administration of tadalafil
for erectile function
Tadalafil and antidepressants A wealth of clinical experience supports on-demand PDE-5
A number of studies have demonstrated the association of inhibitors as safe and efficacious agents of choice for first-line
depression with ED, including the MMAS, which identified treatment of ED in most men; efficacy rates are usually
this condition as the second most common risk factor for ED; reported in the 60–75% range; however, therapeutic success is
the prevalence of antidepressant-associated ED remains often lower in subpopulations identified as more difficult to
underestimated by physicians, since commonly prescribed treat, including diabetics and men with ED following radical
agents such as selective serotonin reuptake inhibitors (SSRIs) prostatectomy.37,64–67 Patient and partner satisfaction may also
contribute to sexual dysfunction.34,57,58 Recent evidence-based be limited by real or perceived lack of treatment flexibility or
reviews of contemporary management strategies for these spontaneity, adverse effects, or improper administration or
groups indicated that PDE-5 inhibitors appear to be an effec- use of these drugs.67,68 Criteria for therapeutic success, includ-
tive treatment option for depression- and antidepressant- ing cure of ED, pleasure, partner satisfaction, reliability, and
associated sexual dysfunction.59,60 A retrospective, pooled naturalness, may not be adequately fulfilled by on-demand
analysis of 19 double-blind, placebo-controlled trials identi- administration, especially for PDE-5 inhibitors with a shorter
fied 205 men with ED (mean age, 55) receiving antidepres- therapeutic window of opportunity.68,69 The concept of daily
sants and tadalafil 10 mg (n = 38), tadalafil 20 mg (n = 113), dosing or chronic administration was introduced as treatment
or placebo (n = 54).58 Common agents included amitryptyline, alternative for non-responders to on-demand PDE-5 inhibi-
SSRIs, and venlafaxine. Compared with placebo, improve- tor therapy and to more closely approximate ‘normal’ erectile
ments were noted in the quality of erections (76 vs 33%), suc- function; formalized study of once-daily and chronic dosing
cessful intercourse attempts (54 and 59% for tadalafil 10 mg schedules suggests that this approach is preferred by a signifi-
and 20 mg, respectively, vs 25% for placebo) and return to a cant proportion of patients, in addition to being an effective
normal erectile function as defined by an IIEF erectile func- salvage strategy for previous non-responders.68,70–78
tion score of 26 or more (51.4 and 49.1% vs 11.8%, all p values Mirone et al. reported the first comparative trial of alterna-
<0.001).58 Further prospective studies of tadalafil in this cohort tive dosing schedules for tadalafil, investigating treatment
are warranted following these initial, encouraging results since efficacy and patient preference for tadalafil 20 mg taken on-
diagnosis and treatment of ED improves quality of life in this demand versus three times per week in the dosing European
group and may influence treatment compliance or depressive Schedule Use versus on-demand Regimen Evaluation (SURE)
relapses. study.73 Scheduled dosing was preferred by 42.2% of 3861
men. McMahon reported upon the efficacy, safety, and tolera-
bility of on-demand tadalafil 20 mg versus daily dosed tadala-
Period of effectiveness fil 10 mg in 145 men; patients receiving on-demand and daily
The period of efficacy is the most significant distinguishing tadalafil experienced mean improvements of 8.3 and 11.9 for
clinical characteristic of tadalafil in comparison with sildenafil the IIEF, respectively (p < 0.001), with changes in the daily-dose
and vardenafil.61 The extended half-life of tadalafil allows for group being significantly higher than those in the on-demand
an expanded window of therapeutic responsiveness, offering group (p < 0.05).66 Positive to SEP question 3 responses were
the patient more flexibility in the timing of sexual inter- noted by 69% and 84% of men in the on-demand and daily
course.19 The time during which a PDE-5 inhibitor is effective tadalafil cohorts, respectively, compared with 30% at baseline
is important for patients, since some prefer to engage in sexual (p < 0.001), and successful completion of sexual intercourse
activity shortly after taking ED medications, while others was statistically higher for daily tadalafil than for the on-
prefer to dissociate sexual activity from dosing.6 demand regimen (p < 0.05). Both treatments were well toler-
Tadalafil was examined in two at-home, randomized, ated, with headache, facial flushing, and dyspepsia being the
placebo-controlled, parallel studies in 348 men with varying most frequently observed adverse effects.66,71 McMahon also
etiologies and severity of ED to determine the period of has reported results for efficacy and safety of daily tadalafil in
efficacy.19,62 The proportion of successful intercourse attempts 112 men with ED previously unresponsive to on-demand
(positive response to SEP question 3) at 24 and 36 hours was tadalafil; moderate-to-severe ED was treated with daily
242 Textbook of Erectile Dysfunction

tadalafil at doses of 10 mg and 20 mg for 12 weeks.70 Tadalafil with the final decision based on which of the three agents best
10 mg taken daily resulted in a mean improvement of 12.8 and fulfills the patient’s goals.83–86 Although it is tempting
8.2 from respective baseline and on-demand IIEF scores to compare efficacy and preference data from different drug
(p < 0.001), and 58% of intercourse attempts (SEP question 3) trials, this approach is potentially fraught with error owing
were successfully completed (p < 0.001).70 Improved erections to differences in research design, clinical end-points, popula-
were noted by 69% and 42% of men in the daily and on- tions, and PDE-5 dosing, delivery, and side-effect profiles.87,88
demand groups, respectively. Almost half of this study popu- Meaningful comparative data between tadalafil, vardenafil,
lation had diabetes mellitus or concurrent vascular risk factors. and sildenafil can only come from properly designed head-to-
Daily tadalafil use resulted in improvements for all efficacy head trials; however, there are no trials without methodo-
variables and demonstrated a safety profile similar to on- logical concerns available at this time.88
demand treatment, except for the incidence of headache, To date, several comparative studies have been performed
which was reported more commonly with on-demand use in an attempt to gain insight into which erectogenic agent is
(p < 0.05).70,71 preferred; although tadalafil fared favorably and was the pre-
Porst et al. reported a randomized, double-blind, placebo- ferred agent in some of these trials, methodological concerns
controlled, parallel-group, 12-week daily-dose study of 268 men, limit the applicability of these results to the general ED
with men assigned 1:2:2 to placebo, tadalafil 5 mg, and tada- population.83–86,89–91 The Treatment of ED (TED) trial exam-
lafil 10 mg taken once daily.68 The three groups reported, ined patient and partner preference and satisfaction, as well
respectively, changes of 0.9, 9.7, and 9.4 for the IIEF score, as physician-rated patient preference, in a real-world, non-
successful penetration for 11.2%, 36.5%, and 39.4% of inter- interventional multicenter study of 2425 patients who planned
course attempts, completion rates of 13.2%, 45.5%, and to change treatment from tadalafil or sildenafil to the other
50.1%, and reported rates of improved erections of 28.3%, drug.85,86 Despite similar perceptions of treatment effect, pre-
84.5%, and 84.6% for placebo, tadalafil 5 mg, and tadalafil ference was primarily based on duration of action and better
10 mg.67,68 Normalization of erectile function (defined as IIEF erections for men choosing tadalafil (1722 out of 2425, 71%)
scores of 26–30) occurred in 8.3, 51.5, and 50.5% of men (all and on better erections and drug tolerance for those choosing
comparisons significant, p <0.001).67 Only 8 treated patients sildenafil (Figures 31.5, 31.6).85 Patients (and partners) who
discontinued use because of adverse events, of which dys- changed from sildenafil to tadalafil or vice versa had greater
pepsia, headache, back pain, upper abdominal pain, and myal- treatment satisfaction as measured by the Erectile Dysfunction
gia were the most common.67,68 Buvat et al. recently presented Inventory of Treatment Satisfaction (EDITS).86 Further ran-
data from a 12-week, randomized, double-blind, placebo- domized, multicenter comparative studies and the develop-
controlled study of 268 men from the UK, Argentina, Brazil, ment of a new preference-based disease-specific health-related
France, and Germany, similarly assigned 1:2:2 to once-a-day quality of life instrument for erectile function may better
placebo, tadalafil 5 mg, or tadalafil 10 mg.74 Once-daily tadala- determine ED patients’ drug of choice.92
fil treatment resulted in increased rates of successful inter-
course, as well as in significantly more patient satisfaction
with erectile rigidity (SEP question 4) and the overall sexual Safety profile
experience (SEP question 5) compared with men reporting
successful intercourse and treated with placebo.74 Safety and adverse event profiles for the three clinically
Continuous dosing of tadalafil has been shown to improve approved PDE-5 inhibitors, including tadalafil, are reviewed
significantly all commonly utilized treatment outcome in detail in Chapter 34, as are the Princeton Consensus Guide-
measures.66,68,72–76 To date, the understanding of systemic lines for sexual dysfunctions and cardiac risk (Chapter 33).
effects secondary to prolonged continuous administration It should be emphasized that cardiac safety for PDE-5 inhibi-
for the three PDE-5 inhibitors is limited primarily to clinical tors has been clearly established. While all three agents are
trials of sildenafil for idiopathic pulmonary hypertension;67,79 contraindicated in men using or requiring nitrates for cardio-
chronic therapy probably modulates endothelial function, vascular disease, the concern about on-demand or daily PDE-5
local penile age or pathology-induced changes, and cardiovas- inhibitor use often raises concern about ‘co-administration
cular disease, resulting in improved erectile function as a effects’ in cases of cardiac emergency.93 Based on clinical
result of effects at both local and systemic levels.66,67,78,80–82 experience among thousands of men with ED and cardiovas-
In June 2007, the European Commission granted market- cular risk factors, a cardiac event should be managed at
ing authorization for tadalafil 2.5 mg and 5 mg dosed once all times in an appropriate environment with little concern
daily to treat ED; a starting dose of 5 mg is appropriate for related to long- or short-acting agents. All men considering
most men. tadalafil therapy should be aware of common side effects,
including flushing, headache, congestion, dyspepsia, and
myalgia (back ache) (Table 31.2).3,30 Although a direct rela-
Patient and partner satisfaction and tionship between PDE-5 inhibitors and non-arteric ischemic
effect on drug preference optic neuropathy has not been establish, up-to-date informa-
tion should be reviewed, as should recommendations if
Ultimately, patient preference determines the ED agent of an adverse event does occur.94 Finally, no evidence for
choice. Efficacy, safety, ease of use, cost, and as-yet unidentified tachyphylaxis has been demonstrated for PDE-5 inhibitors,
factors affect treatment response and treatment satisfaction, including tadalafil.95
 Tadalafil: Long-acting phosphodiesterase type 5 inhibitor 243

Patients preferring tadalafil

Patients changing from Patients changing from
tadalafil to sildenafil (n = 427) sildenafil to tadalafil (n = 1240)

157 Better erections 420

5 Morning erections 13
38 Better tolerated 100
24 Easier to use 82
192 Duration of action 594
3 Partner preference 6
1 Newer medication 4
0 Older medication 0
1 Financial reasons 0
6 Other reasons 21
50 40 30 20 10 0 0 10 20 30 40 50
Patients (%) Patients (%)

Patients preferring sildenafil

Patients changing from Patients changing from
tadalafil to sildenafil (n = 204) sildenafil to tadalafil (n = 347)

130 Better erections 225

0 Morning erections 1
34 Better tolerated 57
12 Easier to use 7
8 Duration of action 21
2 Partner preference 0
0 Newer medication 0
5 Older medication 7
3 Financial reasons 13
9 Other reasons 16
70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70
Patients (%) Patients (%)

Figure 31.5 Primary reasons for physician-rated patient treatment preferences. Adapted from BJU Int 2006; 98: 623–9.86

Preferred tadalafit
100 Preferred sildenafil
Preferred other than sild or tad
80 76*
No preference for either
Percent of partners

65*
Preference to stop ED medications
60

40

18
20
11 9 10
4 4
1 1
0
Tadalafil to sildenafil Sildenafil to tadalafil
(n = 86) (n = 174)

Figure 31.6 Partner-rated treatment preference. Adapted from BJU Int 2006; 98: 623–9.86
244 Textbook of Erectile Dysfunction

Table 31.2 Summary demographics, baseline characteristics, and most common treatment-emergent
adverse events

Variable Placebo Tadalafil 10 mg Tadalafil 20 mg Total

n 638 321 1143 2102
Mean (range) or n (%)
Age (years) 57 (22–81) 58 (26–81) 56 (22–88) 56 (22–88)
Age >65 years 140 (22) 96 (30) 248 (22) 484 (23)
Body mass index (kg/m2) 27.3 (18.1–53.7) 27.9 (18.2–46) 27.3 (12.7–52) 27.4 (12.7–53.7)
Duration of ED of ≥12 months 572 (90) 280 (87) 1006 (88) 1858 (88)
Cause of ED, n (%)
Organic 369 (58) 215 (67) 627 (55) 1211 (58)
Psychogenic 82 (13) 20 (6) 147 (13) 249 (12)
Mixed 187 (29) 86 (27) 369 (32) 642 (31)
IEFF EF severity, n (%)
Normal (26–30) 33 (5) 16 (5) 39 (3) 88 (4)
Mild (17–25) 212 (33) 113 (35) 425 (37) 750 (36)
Moderate (11–16) 171 (27) 84 (26) 303 (27) 558 (27)
Severe (1–10) 220 (34) 107 (33) 376 (33) 703 (33)
Medical history, n (%)
Coronary artery disease 33 (5) 17 (5) 62 (5) 112 (5)
Depression 23 (4) 15 (5) 53 (5) 91 (4)
Diabetes mellitus 130 (20) 68 (21) 223 (20) 421 (20)
Hyperlipidemia 110 (17) 51 (16) 166 (15) 327 (16)
Hypertension 189 (30) 90 (28) 337 (29) 616 (29)
Reason for discontinuance, n (%)
Completed 554 (86.8) 284 (88.5) 1025 (89.7)
Adverse event 8 (1.3) 5 (1.6) 36 (3.2)
Lack of efficacy 32 (5) 4 (1.3) 18 (1.6)
Lost to follow–up 16 (2.5) 4 (1.3) 14 (1.2)
Patient decision 16 (2.5) 12 (3.7) 26 (2.3)
Protocol violation 9 (1.4) 4 (1.3) 10 (1)
Other 3 (0.5) 8 (2.8) 10 (1)
Overall safety, n (%)
Subjects within one or more treatment- 247 (39) 185 (58) 577 (51)
emergent adverse event
Discontinuation for adverse event 8 (1.3) 5 (1.6) 36 (3.2)
Most common treatment-emergent adverse events, n (%)
Headache 30 (5) 38 (12) 175 (15)
Dyspepsia 7 (1) 23 (7) 9 (8)
Back pain 15 (2) 20 (6) 60 (5)
Nasopharyngitis 24 (4) 26 (8) 23 (2)
Myalgia 6 (1) 16 (5) 33 (3)
Flushing 8 (1) 10 (3) 39 (3)
Nasal congestion 4 (1) 11 (3) 28 (2)
Pain in limb 5 (1) 10 (3) 31 (3)
Patients were included based on a history of erectile dysfunction (ED). Subsequent assessment of ED by the International Index of Erectile Function
(IIEF) at baseline showed that a small proportion of men (4%) had an IIEF domain score of ≥26 (ED). The cause of ED was determined by the
investigators based on patient history, physical examination findings and any previous diagnostic testing. Adverse events were coded using the
MedRA dictionary (version 5.0). EF: Erectile function; with permission from reference 87, adapted from BJU Int.
 Tadalafil: Long-acting phosphodiesterase type 5 inhibitor 245

Conclusion offering added clinical benefit to patients by allowing freedom

to choose when intercourse will take place and reducing per-
Tadalafil significantly improves erectile function in men with formance anxiety associated with time constraints. Patients
ED of varying severity and etiology when taken on-demand and partners report satisfaction with penile rigidity, time to
prior to sexual activity, 5 mg daily, or on a chronic (20 mg onset, and reliability of treatment effect. Given the emerging
three times per week) basis. Clinical trials have demonstrated data for improvement in endothelial function, general vascu-
that tadalafil is well tolerated, safe and an important therapeu- lar health, and its potential to salvage erectile function in men
tic option for physicians treating men with ED. Administra- demonstrating an unsatisfactory initial response to on-demand
tion is simplified by an extended period of effectiveness and PDE-5 inhibitors, once-daily dosing offers an important
the absence of interaction with food or alcohol consumption, primary and salvage treatment strategy.

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1. Lue TF. Physiology of penile erection and pathophysiology of erec- 18. Eardley I, Ellis P, Boolell M, et al. Onset and duration of action
tile dysfunction. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, of sildenafil for the treatment of erectile dysfunction. Br J Clin
Peters CA, eds. Campbell–Walsh Urology, 9th edn. Philadelphia: Pharmacol 2002; 53: 61S–65S.
Saunders Elsevier, 2007; 718–49. 19. Padma-Nathan H, Rosen SC, Shabsigh R, et al. Tadalafil (IC 351)
2. Carson CC, Lue TF. Phosphodiesterase type 5 inhibitors for erectile provides prompt response and extended period of response
dysfunction. BJU Int 2005; 96: 257–80. for men with erectile dysfunction (ED). Int J Impot Res 2001;
3. Brock GB, McMahon CG, Chen KK, et al. Efficacy and safety of 13: S64.
tadalafil for the treatment of erectile dysfunction: results of inte- 20. Summary of product specifications [package insert] for Cialis.
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4. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in 21. Forgue ST, Patterson B, Bedding AW, et al. Tadalafil pharma-
the treatment of erectile dysfunction. N Engl J Med 1998; 338: cokinetics in healthy subjects. Br J Clin Pharm 2006; 61: 280–8.
1397–404. 22. Milligan PA, Marshall SF, Karlsson MO. A population pharma-
5. Brock G, Nehra A, Lipshultz LI, et al. Safety and efficacy of cokinetic analysis of sildenafil citrate in patients with erectile
vardenafil for the treatment of men with erectile dysfunction after dysfunction. Br J Clin Pharmacol 2002; 53: 45S–52S.
radical retropubic prostatectomy. J Urol 2003; 170: 1278–83. 23. Summary of product specifications for Viagra, sildenafil citrate.
6. Shabsigh R, Seftel AD, Rosen RC, et al. Review of time of onset and New York, Pfizer Ltd., 2003.
duration of clinical efficacy of phosphodiesterase type 5 inhibitors 24. Summary of product specifications for Levitra, vardenafil hydro-
in treatment of erectile dysfunction. Urology 2006; 68: 689–96. chloride. Bayer Healthcare, 2003.
7. Troconiz IF, Tillman C, Staab A, Rapado J, Forgue ST. Tadalafil 25. Package insert for Cialis. Indianapolis, Lilly ICOS LLC, 2003.
population pharmacokinetics in patients with erectile dysfunction. 26. Rajagopalan P, Mazzu A, Xia C, et al. Effect of high-fat breakfast
Eur J Clin Pharmacol 2007; 63: 583–90. and moderate-fat evening meal on the pharmacokinetics of vard-
8. Patterson B, Bedding A, Jewell H, Payne C, Mitchell M. enafil, an oral phosphodiesterase-5 inhibitor for the treatment of
Dose-normalized pharmacokinetics of single-dose tadalafil (IC351) erectile dysfunction. J Clin Pharmacol 2003; 43: 260–7.
in healthy volunteers [abstract 14]. Int J Impot Res 2001; 27. Patterson B, Bedding A, Jewell H, Payne C, Mitchell MI. The effect
13 Suppl 5: S63. of intrinsic and extrinsic factors on the pharmacokinetic properties
9. Eardley I, Cartledge J. Tadalafil (Cialis) for men with erectile dys- of tadalafil (ICI351). Int J Impot Res 2001; 13 Suppl 5: S62.
function. Int J Clin Pract 2002; 56: 300–4. 28. Bella AJ, Brock GB. Tadalafil: a comprehensive update. J Drug
10. Krane R, Brock G, Earley I, et al. Oral non-endocrine treatment. In: Evaluation 2004; 2: 225–46.
Jardin A, Wagner G, Khoury S, et al. eds. Erectile dysfunction. 29. Montorsi F, McDermott TED, Morgan R, et al. Efficacy and safety
Plymouth, UK: Health Publication Ltd, 2000; 241–78. of fixed-dose oral sildenafil in treatment of erectile dysfunction of
11. Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of silde- various etiologies. Urology 1999; 55: 1011–18.
nafil after single oral doses in healthy male subjects: absolute 30. Carson CC, Rajfer J, Eardley I, et al. The efficacy and safety of
bioavailability, food effects and dose proportionality. Br J Clin tadalafil: an update. BJU Int 2004; 93: 1276–81.
Pharmacol 2002; 53: 5S–12S. 31. Francis SH. Phosphodiesterase 11 (PDE 11): is it a player in human
12. Walker DK, Ackland MJ, James GC, et al. Pharmacokinetics and testicular function. Int J Impot Res 2005; 17: 467–8.
metabolism of sildenafil in mouse, rat, rabbit, dog, and man. 32. Makhlouf A, Kshirsagar A, Niederberger C. Phosphodiesterase 11:
Xenobiotica 1999; 29: 297–310. a brief review of structure, expression and function. Int J Impot Res
13. Klotz T, Sachse R, Heidrich A, et al. Vardenafil increases penile 2006; 18: 501–9.
rigidity and tumescence in erectile dysfunction patients: a RigiScan 33. Hellstrom WJG, Overstreet JW, Yu A, et al. Tadalafil has no
and pharmacokinetic study. World J Urol 2001; 19: 32–9. detrimental effect on human spermatogenesis or reproductive
14. Pryor J. Vardenafil: update on clinical experience. Int J Impot Res hormones. J Urol 2003; 170: 887–91.
2002; 14 Suppl 1: S65–9. 34. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ,
15. Rosen RC, Padma-Nathan H, Shabsigh R, et al. Determining the McKinley JB. Impotence and its medical and psychological
earliest time within 30 minutes to erectogenic effect after tadalafil correlates: results of the Massachusetts Male Aging Study. J Urol
10 and 20 mg: a multicenter, randomized, double-blind, placebo- 1994; 151: 54–61.
controlled, at-home study. J Sex Med 2004; 1: 193–200. 35. Carson CC, Shabsigh R, Segal S, et al. Efficacy, safety, and treat-
16. Padma-Nathan H, Stecher VJ, Sweeney M, et al. Minimal time to ment satisfaction of tadalafil versus placebo in patients evaluated
successful intercourse after sildenafil citrate: results of a random- in a tertiary-care academic centers. Urology 2005; 65: 353–9.
ized, double-blind, placebo-controlled trial. Urology 2003; 62: 36. Eardley I, Gentile V, Austoni E, et al. Efficacy and safety of tadalafil
400–3. in a Western European population of men with erectile dysfunc-
17. Montorsi F, Padma-Nathan H, Buvat J, et al. Earliest time of tion. BJU Int 2004; 94: 871–7.
onset of action leading to successful intercourse with vardenafil 37. Goldstein I, Kim E, Steers WD, et al. Efficacy and safety of tadalafil
determined in an at-home setting: a randomized double-blind, in men with erectile dysfunction with a high prevalence of
placebo-controlled, trial. J Sex Med 2004; 1: 168–78. comorbid conditions: results from the MOMENTUS: multiple
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observations in men with erectile dysfunction in National Tadalafil 59. Rudkin L, Taylor MJ, Hawton K. Strategies for managing sexual
Study in the U.S. J Sex Med 2007; 4: 166–75. dysfunction induced by antidepressant medication. Cochrane
38. Morgentaler A, Barada J, Niederberger C, et al. Efficacy and safety Database Sys Rev 2004; 8: CD3382.
of tadalafil across ethnic groups and various risk factors in men 60. Nurnberg HG, Hensley PL, Gelenberg AJ, et al. Treatment of
with erectile dysfunction: use of a novel noninferiority design. anti-depressant associated erectile dysfunction with depressive
J Sex Med 2006; 3: 492–503. symptoms: results of a placebo-controlled trial with sildenafil
39. Burke JP, Jacobson DJ, McGree ME, et al. Diabetes and citrate. Am J Psychiatry 2001; 158: 1623–30.
sexual dysfunction: results from the Olmsted County study of 61. Brock GB. Tadalafil: a new agent for erectile dysfunction. Can J
urinary symptoms and health status among men. J Urol 2007; 177: Urol 2003; 10 Suppl 1: 17–22.
1438–42. 62. Porst H, Padma-Nathan H, Giuliano F, et al. Efficacy of tadalafil for
40. Jackson G. Sexual dysfunction and diabetes. Int J Clin Pract 2004; the treatment of erectile dysfunction at 24 and 36 hours after dos-
58: 358–62. ing: a randomized controlled trial. Urology 2003; 62: 121–6.
41. Romeo JH, Seftel AD, Madhun ZT, Aron DC. Sexual function in 63. Wespes E, Amar E, Hatzichristou D, et al. EAU guidelines on
men with diabetes type 2: association with glycemic control. J Urol erectile dysfunction: an update. Eur Urol 2006; 49: 806–15.
2000; 163: 788–91. 64. Montague DK, Jarow JP, Brodercik GA, et al. Chapter 1: The man-
42. Francis ME, Kusek JW, Nyber LM, Eggers PW. The contribution of agement of erectile dysfunction: an AUA update. J Urol 2005; 174:
common medical conditions and drug exposures to erectile dys- 230–9.
function in adult males. J Urol 2007; 178: 591–6. 65. Lue TF, Giuliano F, Montorsi F, et al. Summary of the recommen-
43. Lehman TP, Jacobs JA. Etiology of diabetic impotence. J Urol 1983; dations on sexual dysfunction in men. J Sex Med 2004; 1: 6–23.
129: 291–4. 66. McMahon CG. Treatment of erectile dysfunction with chronic
44. Saenz de Tejada I, Anglin GT, Knight JR, Emmick JT. Effects of dosing of tadalafil. Eur Urol 2006; 50: 215–17.
tadalafil on erectile dysfunction in men with diabetes. Diabetes 67. Bella AJ, DeYoung LX, al-Numi M, Brock GB. Daily administration
Care 2002; 25: 2159–64. of phosphodiesterase type 5 inhibitors for urological and non-
45. Fonseca V, Seftel A, Denne J, Fredlund P. Impact of diabetes urological indications. Eur Urol 2007; 52: 990–1005.
mellitus on the severity of erectile dysfunction and response to 68. Porst H, Giuliano F, Glina S, et al. Evaluation of the efficacy
treatment: analysis of data from tadalafil clinical trials. Diabeto- and safety of once-a-day dosing of tadalafil 5 mg and 10 mg in
logia 2004; 47: 1914–23. the treatment of erectile dysfunction: results of a multicenter,
46. Montorsi F, Padma-Nathan H, McCullough A, et al. Tadalafil randomized, double-blind, placebo controlled trial. Eur Urol 2006;
in the treatment of erectile dysfunction following bilateral 50: 351–9.
nerve-sparing radical retropubic prostatectomy: a randomized, 69. Hanson-Divers C, Jackson SE, Lue TF, Crawford SY, Rosen RC.
double-blind, placebo-controlled trial. J Urol 2004; 172: Health outcomes important to patients in the treatment of erectile
1036–41. dysfunction. J Urol 1998; 159: 1541–7.
47. Incrocci L, Slagter C, Slob AK, Hop WC. A randomized, double- 70. McMahon CG. Efficacy and safety of daily tadalafil in men with
blind, placebo-controlled, cross-over study to assess the efficacy erectile dysfunction previously unresponsive to on-demand tadala-
of tadalafil (Cialis) in the treatment of erectile dysfunction follow- fil. J Sex Med 2004; 1: 292–300.
ing three-dimensional conformal external-beam radiotherapy 71. McMahon CG. Comparison, efficacy, and tolerability of on-
for prostatic carcinoma. Int J Radiat Oncol Biol Phys 2006; 66: demand tadalafil and daily dosed tadalafil for the treatment of
439–44. erectile dysfunction. J Sex Med 2005; 2: 415–25.
48. Schiff JD, Bar-Chama N, Ceseretti J, Stock R. Early use of a phos- 72. McMahon CG. Treatment of erectile dysfunction with chronic
phodiesterase inhibitor after brachytherapy restores and preserves dosing of tadalafil. Eur Urol 2006; 50: 215–17.
erectile function. BJU Int 2006; 98: 1255–8. 73. Mirone V, Costa P, Damber JE, et al. An evaluation of an alternative
49. Wang R. Penile rehabilitation after radical prostatectomy: dosing regimen with tadalafil, 3 times/week, for men with erectile
where do we stand and where are we going? J Sex Med 2007; 4: dysfunction: SURE study in 14 European countries. Eur Urol 2005;
1085–97. 47: 846–54.
50. Mulhall JP, Morgentaler A. Penile rehabilitation should become 74. Buvat J, Faria G, Wetterauer U, et al. Tadalafil 5 mg and 10 mg taken
the norm for radical prostatectomy patients. J Sex Med 2007; 4: once a day for the treatment of erectile dysfunction improves patient
538–43. sexual satisfaction. J Sex Med 2007; 4 (Suppl 1): 91 [abstract 84].
51. Vignozzi L, Filippi S, Morelli A, et al. Effect of chronic tadalafil 75. Costa P, Buvat J, Holmes S, et al. Predictors of tadalafil efficacy
administration on penile hypoxia induced by cavernous neuro- in men with erectile dysfunction: the SURE study comparing two
tomy in the rat. J Sex Med 2006; 3: 419–31. dosing regimens. J Sex Med 2006; 3: 1050–8.
52. Ferrini MG, Davila HH, Kovanecz I, et al. Vardenafil prevents 76. Wespes E, Moncada I, Schmitt H, et al. The influence of age on
fibrosis and loss of corporal smooth muscle that occurs after treatment outcomes in men with erectile dysfunction treated with
bilateral cavernosal nerve resection in the rat. Urology 2006; 68: two regimens of tadalafil: results of the SURE study. BJU Int 2007;
429–35. 99: 121–6.
53. Kovanecz I, Rambhatla A, Ferrini MG, et al. Tadalafil prevents the 77. Hatzimouratidis K, Moysidis K, Bekos A, et al. Treatment strategy
corporal veno-occlusive dysfunction (CVOD) that occurs follow- for “non-responders” to tadalafil and vardenafil: a real-life study.
ing bilateral cavernosal nerve resection in the rat. J Sex Med 2007; Eur Urol 2006; 50: 126–32.
4 Suppl 1: 70 (Abstract 22). 78. Hatzimouratidis K, Hatzichristou D. Phosphodiesterase type 5
54. Rambhatla A, Kovanecz I, Ferrini M, Gonzalez-Cadavid NF, inhibitors: the day after. Eur Urol 2007; 51: 75–81.
Rajfer J. Rationale for phosphodiesterase 5 inhibitor use post- 79. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy
radical prostatectomy: experimental and clinical review. Int J Impot for pulmonary arterial hypertension. N Engl J Med 2005; 353:
Res 2008; 20: 202–12. 2148–57.
55. Raina R, Pahlajani G, Agarwal A, Zippe CD. Early penile rehabili- 80. Rosano GM, Aversa A, Vitale C, et al. Chronic treatment with
tation following radical prostatectomy: Cleveland Clinic experi- tadalafil improves endothelial function in men with increased
ence. Int J Impot Res 2008; 20: 121–6. cardiovascular risk. Eur Urol 2005; 47: 214–20.
56. Lowentritt BH, Scardino PT, Miles BJ, et al. Sildenafil citrate after 81. Aversa A, Greco E, Bruzziches R, et al. Relationship between
radical retropubic prostatectomy. J Urol 1999; 162: 1614–17. chronic tadalafil administration and improvement of endothelial
57. Clayton AH, et al. Prevalence of sexual dysfunction among newer function in men with erectile dysfunction: a pilot study. Int J Impot
antidepressants. J Clin Psychiatry 2002; 63: 357–66. Res 2007; 19: 200–7.
58. Seagraves RT, Lee J, Stevenson R, et al. Tadalafil for treatment of 82. La Vignera S, Calogero AE, Cannizzaro MA, et al. Tadalafil and
erectile dysfunction in men on antidepressants. J Clin Pharmacol modifications in peak systolic velocity (Doppler spectrum dynamic
2007; 27: 62–6. analysis) in the cavernosal arteries of patients with type 2 diabetes
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after continuous tadalafil treatment. Minerva Endocrinol 2006; 31: after 6 months of treatment with tadalafil, sildenafil, and vardenafil:
251–61. results from the erectile dysfunction observational study (EDOS).
83. Eardley I, Montorsi F, Jackson G, et al. Factors associated Eur Urol 2007; 51: 541–50.
with preference for sildenafil citrate and tadalafil for treating 90. Tolra JR, Campana JM, Ciutat LF, Miranda EF. Prospective,
erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor randomized, open-label, fixed-dose, crossover study to establish
therapy: post hoc analysis of data from a multicenter, randomized, preference of patients with erectile dysfunction after taking the
open-label, crossover study. BJU Int 2007; 100: 122–9. three PDE-5 inhibitors. J Sex Med 2006; 3: 901–9.
84. Kell PD, Hvidsten K, Morant SV, Harnett JP, Bridge S. Factors that 91. von Keitz A, Rajfer J, Segal S, et al. A multicenter, randomized,
predict changing the type of phosphodiesterase type 5 inhibitor double-blind, crossover study to evaluate patient preference
medication among men in the UK. BJU Int 2007; 99: 860–3. between tadalafil and sildenafil. European Urology 2004; 45:
85. Brock G, Chan J, Carrier S, et al. The treatment of erectile dysfunc- 499–509.
tion study: focus on treatment satisfaction of patients and partners. 92. Torrance GW, Keresteci MA, Casey RW, et al. Development and
BJU Int 2007; 99: 376–82. initial validation of a new preference-based disease-specific health-
86. Lee J, Pommerville P, Brock G, et al. Physician-rated patient related quality of life instrument for erectile function. Qual Life Res
preference and patient- and partner-rated preference for tadalafil 2004; 13: 349–59.
or sildenafil citrate: results from the Canadian ‘Treatment of Erec- 93. Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunction and
tile Dysfunction’ observational study. BJU Int 2006; 98: 623–9. cardiac risk (the Second Princeton Consensus Conference). Am J
87. Bella AJ, Brock GB. Tadalafil: a clinical update. Aging Health Cardiol 2005; 96: 313–21.
2005; 1: 203–13. 94. Bella AJ, Brant WO, Lue TF, Brock GB. Non-arteritic anterior
88. Mulhall JP. Deciphering erectile dysfunction drug trials. J Urol ischemic optic neuropathy (NAION) and phosphodiesterase type-5
2003; 170: 355–8. inhibitors. Can J Urol 2006; 13: 3233–8.
89. Martin-Morales A, Haro JM, Beardsworth A, Bertsch J, Kontodimas 95. Steers WD. Tachyphylaxis and phosphodiesterase type 5 inhibitors.
S, EDOS group. Therapeutic effectiveness and patient satisfaction J Urol 2002; 168: 207.
32 Vardenafil: a biochemically potent
phosphodiesterase type 5 inhibitor
Sharron H Francis and Jackie D Corbin

Introduction vardenafil is due to its inhibition of PDE-5 hydrolysis of cGMP,

thereby fostering improved penile tumescence.5
In 2003, vardenafil hydrochloride was introduced to the
world market as a new oral therapy for treatment of erectile
dysfunction (ED). It was marketed as vardenafil hydrochlo- Vardenafil inhibition of PDE-5
ride trihydrate under the brand name Levitra® by Bayer Phar-
maceuticals Corporation and is presently used under licence Vardenafil mimics the PDE-5 substrate, cGMP, and spatial
by GlaxoSmithKline and Schering Corporation. It rapidly components of the vardenafil molecule compete directly
gained approval in countries around the world as a safe with cGMP for access to the catalytic pocket of this enzyme
and effective treatment for ED. The chemical name for (Figure 32.3). The overall structure of vardenafil bears some
vardenafil is piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7- resemblance to that of cGMP, as can be seen in Figures 32.3a
propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl] and 32.3b; Figure 32.3b displays space-filling models to depict
sulfonyl]-4-ethyl-, monohydrochloride trihydrate (Figure 32.1), more accurately the molecular features of cGMP and varde-
the empirical formula is C23H32N6O4S.HCl.3H2O, and the mole- nafil; in cGMP, the guanine and the cyclic phosphate ring that
cular weight is 579.1g/mol.1 Vardenafil, the active agent, is a is appended to the ribose provide critical determinants for
potent inhibitor of phosphodiesterase (PDE) type 5, which interaction with the PDE-5 catalytic site. The ribose does not
breaks down cGMP in cells. make particularly important contacts with the enzyme. Cyclic
GMP is shown in the anti conformation, which evidence
suggests is the orientation of the ribose and phosphate moi-
cGMP and vardenafil in eties when the substrate is bound to the PDE-5 catalytic site.
penile erection Vardenafil lacks the cyclic phosphate ring that is acted on by
the catalytic machinery of the enzyme, but the bicyclic ring in
Penile erection is mediated by elevation of cGMP in smooth vardenafil mimics the guanine in cGMP (see Figure 32.3), and
muscle cells of the penile vasculature in response to erogenous evidence suggests that it exploits many of the contacts that the
stimuli that induce the release of nitric oxide (NO) from nitrer- guanine makes with the PDE-5 catalytic site. The orientation
gic neurons or endothelial cells that line the blood vessels of the piperazine ring in vardenafil shown here is based on
(Figure 32.2).2,3 Cyclic GMP interacts with cGMP-dependent that reported earlier for sildenafil. The potency (affinity) of
protein kinase (PKG), which phosphorylates a number of vardenafil to inhibit PDE-5 catalytic activity (half maximum
proteins leading to lowering of intracellular calcium through inhibitory concentration, IC50 = 0.09nM) was determined to
increased calcium extrusion from the cell and increased seques- be about 25,000-fold greater than the affinity of the enzyme
tration of calcium in intracellular stores, as well as desensitiz- for cGMP (Km=2.5µM),7 and this high affinity of vardenafil
ing cells to calcium; this effect decreases contractile tone in the for the PDE-5 catalytic site was independently verified in
smooth muscle and promotes vasodilatation (see Figure 32.2).4 direct binding studies using [3H]vardenafil in the absence
The level of cGMP in cells such as the smooth muscle cells of of the competing cGMP substrate.7
the corpus cavernosum and penile arteries is determined by a The exceptionally high affinity interaction between PDE-5
balance between its synthesis from GTP (by enzymes known as and vardenafil is provided by multiple structural features of
guanylyl cyclases) and its breakdown (by cGMP PDEs such as vardenafil that are absent in cGMP and that exploit additional
PDE-5).5 The action of PDE-5, which is highly abundant in contacts with amino acid side chains in the PDE-5 catalytic
penile vascular tissues, blunts or blocks cGMP elevation and site,8,9 by contacts that are formed with amino acids located in
the erectile response to erogenous stimuli (see Figure 32.2).6 close proximity to the catalytic site, and by influences external
The appropriate balance between cGMP synthesis and break- to the catalytic site (see below).10 Vardenafil is highly selective
down is critical for normal erectile function; many patients for inhibition of PDE-5 compared with other PDEs; it has a
suffering from ED have a biochemical imbalance in this pro- more than 15-fold lower potency for inhibition of the photo-
cess, either too little synthesis of cGMP or excessive hydrolysis receptor PDE-6 family, more than 130-fold lower potency
of cGMP, which can lead to ED. The therapeutic effect of for inhibition of the PDE-1 family, more than 300-fold lower

248
 Vardenafil: a biochemically potent phosphodiesterase type 5 inhibitor 249

potency for inhibition of the PDE-11 family, and more than has very low affinity for the PDE-5 catalytic site (about
1000-fold lower potency for inhibition of the PDE-2, PDE-3, 1-5mM) and rapidly dissociates from the catalytic pocket. In
PDE-4, PDE-7, PDE-8, PDE-9, and PDE-10 families.11 Owing contrast, when vardenafil binds to the PDE-5 catalytic site, it
to the effects of differences in the distribution of nitrogen and is not modified; therefore, its potency is preserved and disso-
carbon atoms in the bicyclic ring of vardenafil compared with ciation is very slow.7,12 Furthermore, following dissociation, it
the guanine of cGMP, some contacts may be stronger and, has the potential to rebind immediately to the PDE-5 catalytic
along with some ‘extra’ contacts, may contribute to the higher site (as shown by the double-ended arrow in Figure 32.4)
affinity of PDE-5 for vardenafil over cGMP (see below). since it is structurally intact. This characteristic is true of all
the PDE-5 inhibitors currently in clinical use for treatment of
ED. Therefore, the effect of vardenafil (as well as that of
cGMP and vardenafil following sildenafil and tadalafil) to block cGMP access is amplified by
interaction with PDE-5 catalytic site the fact that these features contribute to a longer occupancy of
the catalytic site by the inhibitors. Vardenafil does not interact
The fates of cGMP and vardenafil differ when each enters the with the allosteric cGMP-binding site in the regulatory domain
PDE-5 catalytic site. When cGMP enters the catalytic site, the of PDE-5 (see Figure 32.4) because this site is structurally very
cyclic phosphate ring is quickly hydrolyzed by the PDE-5 different from the PDE-5 catalytic site and is highly rigorous
catalytic machinery to produce 5′-GMP (Figure 32.4). 5′-GMP in its specificity for cGMP and closely related nucleotides.4
The topography of the allosteric cGMP-binding site excludes
vardenafil access.
O

NH
N O HCl
N N
Potency of vardenafil
O 3 H2O
Vardenafil is 10- to 40-fold more potent than either sildenafil,
N N S which was already in clinical use for treatment of ED when
O
vardenafil was licenced for use (Figure 32.5), or tadalafil,
Figure 32.1 Molecular structure of vardenafil hydrochloride which was introduced later.7 The higher potency of vardenafil
trihydrate. The vardenafil structure is depicted according to the for PDE-5 inhibition accounted, at least in part, for its lower
conformation described for sildenafil when bound to the fully range of dosing options (2.5 mg, 5 mg, 10 mg, and 20 mg)
active phosphodiesterase type 5 isolated catalytic domain. compared with that for sildenafil (25 mg, 50 mg, and 100 mg)

Penile vascular smooth

Guanylyl cyclase muscle cell
NO (inactive) GTP
Citrulline
NO guanylyl cyclase PDE-5
cGMP 5′-GMP
(active)

Inactive PKG
Activated PKG
NO
synthase ATP
Ca2+ Phosphoproteins Proteins
CaM
l-Arginine

Endothelial
Lowering of Ca2+
or neuronal Desensitization to Ca2+
cell

Erogenous stimuli

Vasodilation and erection

Figure 32.2 Nitric oxide (NO) and cGMP signaling in penile vascular smooth muscle. Tactile or psychogenic erogenous stimuli
promote increased release of NO from penile neurons and endothelial cells. NO binds to and activates the NO-sensitive guanylyl
cyclase, thereby promoting increased synthesis of cGMP. cGMP binds to and activates cGMP-dependent protein kinase (PKG),
which phosphorylates intracellular proteins. Phosphorylation of several proteins by PKG promotes lowering of intracellular calcium
(Ca2+), decreased contractile tone, vasodilation, and increased tumescence of penile tissues. PDE, phosphodiesterase; CaM, calcium/
calmodulin.
250 Textbook of Erectile Dysfunction

O
O
N Bicyclic
NH
Guanine ring NH
N O
N N
N NH2 N
O
O
Cyclic OH
phosphate S
ring O O N N
P O
O Ribose
OH

Piperazine ring

cGMP Vardenafil
(a) Km = 2.5 µM IC50 = 0.09 nM

cGMP Vardenafil

(b)

Figure 32.3 Comparison of the molecular structures of the natural substrate for phosphodiesterase type 5 – cGMP with that of the
competitive inhibitor vardenafil. (a) Stick models of cGMP and vardenafil. (b) Comparison of models of cGMP and vardenafil that
employ space-filling components that simulate the volume occupied by the atomic components of these compounds. IC50, half
maximum inhibitory concentration; Km, Michaelis constant for substrate affinity.

or tadalafil (5 mg, 10 mg, and 20 mg). The higher potency of to equal that in the plasma (peak plasma concentration
vardenafil may also account for its effectiveness in treating following vardenafil 20 mg was determined to be about 30 nM
patients with severe ED and those who had unsatisfactory of which about 1.5 nM is estimated to be free). As soon as any
results with sildenafil.13 For most patients, the recommended of the three inhibitors enters the cell, it is predicted to be
starting dose of vardenafil is 10mg to be taken about 1 hour bound immediately by PDE-5. The high affinity of interaction
prior to sexual activity, although certain medical conditions between PDE-5 and each of the inhibitors would tend to
may warrant a lower beginning dose (see below).11 sequester the inhibitor and maintain low cytosolic concentra-
As with all PDE-5-selective inhibitors, sexual arousal is tion; this effect would assist in maintaining a high gradient
required to increase cellular synthesis of cGMP and to allow between the plasma and cytosol, thereby favoring continued
for the action of vardenafil to enhance cGMP accumulation entry of the inhibitor until PDE-5 is saturated. As a result, the
by blocking its breakdown and thereby improve penile tumes- action of PDE-5 inhibitors that exhibit such high potency may
cence (see Figure 32.2).5 Despite the significantly higher be less influenced by plasma concentration than is thought.
inhibitory potency (IC50) of vardenafil for PDE-5 than that
for sildenafil or tadalafil (IC50 values of 0.09 nM, 3.7 nM, and
1.8 nM, respectively),7 the clinical efficacy, ease of use, and Pharmacokinetics
patient satisfaction for the three medications appears to be
similar.13–16 This would not be intuitively predicted, but the Vardenafil has proven to be an effective, safe, and reliable oral
comparable efficacy despite a lower dosing regimen (see treatment for ED in a broad spectrum of patients.1,17–22 In
above) may have explanations in the basic functional proper- 2003, a report from a multicenter, randomized, double-blind,
ties of PDE-5 and the higher affinity of the enzyme for vard- placebo-controlled study employing three vardenafil dosages
enafil. The inhibitor concentration in the cytosol is expected (5 mg, 10 mg, and 20 mg) in 580 patients (aged from 45 to
 Vardenafil: a biochemically potent phosphodiesterase type 5 inhibitor 251

Catalytic domain

Catalytic PDE-5 inhibitors

site

5′-GMP

cGMP

Allosteric
site

Regulatory
domain

Figure 32.4 Working model of the structure of phosphodiesterase (PDE) type 5. PDE-5 comprises two identical kDa monomers,
each of about 98 kDa. Each monomer contains a more carboxyl-terminal catalytic domain where breakdown of cGMP (shown as a
black ball) occurs and the product, 5′-GMP (shown as a black half-moon) is released. Each subunit also contains a more amino-
terminal regulatory domain that contains allosteric cGMP-binding sites that are biochemically and evolutionarily distinct from the
catalytic site. Vardenafil binds only to the catalytic site and inhibits catalysis by competing with cGMP for access to the catalytic
pocket. Unlike cGMP, vardenafil is not modified by the PDE-5 catalytic site.

over 65 years) with ED of varying severity resulting from is similar to the profile for sildenafil and tadalafil.24–28 In a
organic, psychogenic, or mixed etiologies indicated that vard- placebo-controlled study of 732 men, an erection sufficient
enafil treatment (all doses) improves reliability of achieving for successful intercourse was reported to occur in some
an erection sufficient for penetration, orgasmic function, and patients as early as 10 minutes after dosing with either 10mg
persistence of the erection for a period long enough for satis- or 20 mg, and about 50% of patients have a successful result
factory intercourse.19 Other placebo-controlled studies testing within 25 minutes after dosing.24 However, given the variation
the effectiveness of vardenafil in treatment of ED in large in the time of onset (10–60 minutes), first-time users are
groups of diverse patients reached similar conclusions.20–23 advised to take vardenafil an hour prior to initiating sexual
A recent study reported that vardenafil treatment for 12 of activity.26 Onset of action correlates well with the peak con-
26 weeks restores normal erectile function in a substantial centration, which occurs within 0.5–2 hours of administra-
percent of men with general ED irrespective of the severity, tion in the fasted state (see Table 32.1).26 Consumption of a
etiology, age, or duration of ED.18 high-fat meal preceding ingestion of the medication was
Vardenafil is rapidly absorbed, has a bioavailability of about shown to delay absorption substantially, by up to 1 hour, and
15%, and is extensively metabolized on the first pass through also to reduce the peak concentration, but a moderate-
the liver (Table 32.1). Vardenafil and its main metabolite fat meal has little or no effect and is not considered to be a
(N-desethyl vardenafil) are distributed throughout most body clinical concern.29
tissues and are highly (about 95%) adsorbed, albeit reversibly, The duration of the effect of vardenafil has not been exten-
to plasma proteins. Since vardenafil is distributed extensively sively studied. Typically, the pharmacological effectiveness of
in body tissues, it is expected that any tissue containing PDE-5 a medication wanes quickly as the medication is cleared from
has the potential to be affected by vardenafil as well as by the plasma.30 However, many drugs either act at cell surfaces
other PDE-5 inhibitors such as sildenafil, tadalafil, and udenafil. or act with relatively low affinities on target proteins inside
In the fasting state, onset of action following ingestion of cells. Vardenafil not only acts inside cells, it does so by binding
vardenafil is about 0.5–2 hours, with a median of 1 hour, which with very high affinity to PDE-5. Vardenafil is not believed to
252 Textbook of Erectile Dysfunction

Lower electronegativity Higher electronegativity

pKa = 4.2 pKa < 2.0
O O
N
NH NH
N O N O
N N
N

O O

N S N S
N N
O O

Vardenafil Sildenafil
IC50 = 0.09 nM IC50 = 3.7 nM

Figure 32.5 Comparison of the molecular structures of vardenafil and sildenafil. The two positions that differ in vardenafil and
sildenafil are indicated by the dotted circles. The pKa values shown here were experimentally determined.38 IC50, half maximum
inhibitory concentration; pKa, the acid dissociation constant.

randomized, double-blind, placebo-controlled, flexible-dose

Table 32.1 Pharmacokinetics of vardenafil
study of 383 men with ED treated with different dosages of
Parameter Vardenafil 10 mg Vardenafil 20 mg vardenafil (5 mg, 10 mg, or 20 mg) and asked to initiate sexual
activity 8 hours later, a significant number of patients reported
Area under the curve 32.6±1.59 74.5±1.82 that the effect of vardenafil to improve erections was still
(µg/hour/l) functional at a time (8–10 hours after dosing) when plasma
Cmax (µg/l) 9.05±1.63 20.9±1.83 vardenafil levels should have been less than 25% of the
Half-life (hours) 4.18±1.27 3.94±1.31 peak concentration, which is usually associated with optimal
pharmacological action.31 More rigorous analysis of this phe-
Tmax (hr) 0.92 (0.25–2.5) 0.66 (0.25–3.0)
nomenon is required to understand more fully the pharma-
Absolute 15 codynamics involved not only with vardenafil, but also with
bioavailability (%)
the other PDE-5 inhibitors used for the treatment of ED, since
Protein binding (%) 95 sildenafil and tadalafil also show persistence of action beyond
Mean steady-state 208 the time that would be predicted based on plasma clearance
volume of time.32,33
distribution (l) Vardenafil is metabolized primarily in the liver by cyto-
Effect of high-fat meals 18–50% chrome P4503A4 (CYP3A4) and to some extent by CYP3A5
on Cmax (%) and CYP2C9. The major circulating metabolite is produced
Site of metabolism Hepatic Hepatic by removal of the ethyl group from the vardenafil piperazine
ring. In plasma, the main metabolite is also found largely as
Contribution of — 7
metabolite to effect the glucuronidated form but the non-glucuronidated meta-
(%) bolite represents about 26% of the parent compound. The
main metabolite of vardenafil contributes to the bioactivity
Excretion (% of dose)
(about 7% of the pharmacological effect), is subject to further
Feces — 92 metabolism, and exhibits a similar selectivity profile among
Urine — 5 mammalian PDEs, albeit with a roughly 28% lower potency
Cmax, maximum concentration; Tmax, time to Cmax. Values compiled
for PDE-5 than vardenafil.11
from reference 26. Plasma clearance of both the parent compound and the
major metabolite occurs with a half-life of about 4 hours; the
major metabolites are primarily removed by extrusion into
be degraded within smooth muscle cells. Therefore, this the biliary duct and excretion in the feces, with a small
unusual mechanism could lead to trapping of vardenafil inside amount eliminated in the urine. Clearance is significantly
smooth muscle cells in the penis, which could extend its dura- slowed in patients suffering from hepatic insufficiency or
tion of action well beyond that predicted from its half-life in when vardenafil is taken along with other medications that are
the plasma. Thus, for intracellular-acting, high-affinity drugs competitively metabolized by the cytochromes; these include
such as vardenafil, the duration of action should depend on retonavir, indinavir, ketoconazole, itraconazole, and erythro-
intracellular half-life, not plasma half-life. Although it would mycin.11 In these situations, recommended dosage is reduced
be predicted that intracellular half-life of different drugs significantly and frequency of administration must be lessened.
would be proportional to their affinities for the receptor, other Co-administration of ritonavir and vardenafil was shown to
factors could mitigate this prediction. cause a 13-fold increase in peak concentration of vardenafil
The half-life of vardenafil in the plasma following oral and prolonged the half-life of vardenafil in plasma to 26 hours.
administration was determined to be about 4 hours in fasted Other factors such as aging also slow clearance and therefore
patients suffering from ED (see Table 32.1);25 however, in a warrant adjustment in the dosage protocol.
 Vardenafil: a biochemically potent phosphodiesterase type 5 inhibitor 253

Side-effects can produce pronounced systemic hypotension and tachycar-

dia, both of which can be life-threatening. Co-administration
Use of vardenafil for treatment of ED is well tolerated by most of vardenafil with various medications prescribed to lower
patients.1,14,20–22,34 Vardenafil is highly selective for PDE-5 blood pressure elicits only modest lowering of systemic blood
except for slight cross-reaction with PDE-6 (see below), and it pressure; however, caution is advised when vardenafil is co-
has not been shown to interact with other cellular proteins. administered with alpha-blockers, which are commonly pre-
This high specificity and affinity of vardenafil for PDE-5 is scribed for blood pressure control or treatment of benign
consistent with the limited number of side-effects that have prostatic hyperplasia.1 In addition, men who have conditions
been reported and with the low concentration of the inhibitor that predispose them to priapism (e.g. sickle cell anemia) or
required for improvement of erectile function. The most who have anatomical deformation of the penis should use
common side-effects, which are experienced by a small per- PDE-5 inhibitors, including vardenafil, with caution.
centage (<15%) of patients, include headache, facial flushing,
stuffy nose, dyspepsia, sinusitis, dizziness, and nausea; all of
these are typically mild to moderate in severity, transient, Mechanism of action
and infrequent as the basis for discontinuation of use of the
medication. Most of these effects are either constant during Vardenafil competes with cGMP for access to the catalytic
the course of the use of the medication or decline over time.19 site of PDE-5, thereby blocking breakdown of cGMP (see
Most of these common adverse effects are thought to be due Figure 32.4).5,7 It is highly selective for PDE-5 over other
to vardenafil inhibition of PDE-5 activity in the smooth PDEs, thereby restricting its action to tissues containing
muscle of the blood vessels or other smooth muscle, such as PDE-5 and other proteins that provide for cGMP signaling.
that which forms the sphincters and the wall of the gastroin- The selective and potent interaction of vardenafil with the
testinal tract. catalytic site of PDE-5 is most likely due to unique features in
The effect of vardenafil on systemic cardiovascular function both. Vardenafil potency for inhibition of PDE-5 (IC50) is
is modest and there have been few if any concerns regarding about 25,000-fold higher (IC50 = 0.09nM) than the affinity of
cardiovascular safety issues.1 Following administration of var- the substrate cGMP (Km = 2.5µM).7 The much higher affinity
denafil (20 mg), systolic and diastolic blood pressure declines of the PDE-5 catalytic site for vardenafil provides for the very
by 7mmHg and 8mmHg, respectively, and is accompanied by effective pharmacological action of this medication. Vardenafil,
a slight increase in heart rate (4 beats per minute). In some like sildenafil and tadalafil, does not interact with the allosteric
people, vardenafil, like sildenafil, causes a dose-related distur- cGMP-binding site on PDE-5; nor does it interact with allos-
bance of blue–green color discrimination; the effect is transient teric cGMP-binding sites either on the PKG, cGMP-gated
and most obvious within 1 hour of taking the medication.1,11 cation channels or on other cellular proteins.
The visual perturbation is thought to be due to the effect of This high selectivity for the catalytic site of PDE-5 is due
vardenafil to inhibit the catalytic activity of photoreceptor to the fact that this site is evolutionarily and biochemically
PDEs, which are members of the PDE-6 family and are highly distinct from cGMP-binding sites in proteins other than
homologous in amino acid sequence to the PDE-5 family. members of the PDE superfamily.4 To date, vardenafil has not
Non-arteritic anterior ischemic optic neuropathy, which been shown to potently interact with cellular proteins other
results in loss or decrease in vision, has been reported in a very than PDE-5. Therefore, the novel topography of the PDE-5
small number of patients taking PDE-5 inhibitors, including catalytic site and the unique chemical characteristics of the
vardenafil. However, the risk factors for ED and non-arteritic vardenafil molecule provide for highly selective and potent
ischemic optic neuropathy are very similar, and a causal role interaction. The very high affinity of PDE-5 for vardenafil is
of these medications in the few cases of the optic neuropathy provided by contacts within the catalytic site that are shared
is not established.35 by cGMP and other inhibitors. However, novel contacts that
are uniquely provided by the structure of vardenafil and its
effect on the protein exploit interactions that the other inhi-
Contraindications bitors and cGMP cannot make (see below).

In addition to the cautions described above regarding con-

comitant use with CYP3A inhibitors, the use of vardenafil Structural features that contribute
with nitrovasodilators, either regularly or intermittently, is
also contraindicated. This includes prescription medications to the higher potency of vardenafil
such as nitroglycerin and some recreational drugs (poppers) over sildenafil
that contain amyl nitrate and butyl nitrate. As with the
NO released from penile neurons or endothelial cells (see X-ray crystal structures of isolated PDE-5 catalytic domain in
Figure 32.2), NO released from nitroglycerin or certain rec- complex with vardenafil or sildenafil reveal a similar mode of
reational drugs increases guanylyl cyclase activity in vascular binding.8 Initially this result was puzzling since the potencies
smooth muscle and so leads to increased synthesis of cGMP;3 differ by 10- to 40-fold.7 This conundrum was recently
the action of these agents to increase production of cGMP resolved when our group demonstrated that in the isolated
therefore synergizes with the action of PDE-5 inhibitors such catalytic domain of PDE-5, vardenafil and sildenafil have
as vardenafil to block cGMP breakdown (see Figure 32.4), and similar potencies so it is not surprising that they share a
the resulting increase in cellular cGMP can be dramatic and ‘similar mode of binding’.10 The potency of sildenafil for
254 Textbook of Erectile Dysfunction

Gln817
PDE-5 holoenzyme
100
Inhibition of PDE activity

Water-bridge H
N
Phe820 H
O
O
(%)

Isolated catalytic domain H H H

50 N Hydrogen
Zn2+ O H O H N bond
N N
H O

Hydrophobic interaction
0
0 25 50
Vardenafil (nM)
Phenyl ring of
Figure 32.6 Comparison of inhibitory potency of vardenafil for Tyr612
phosphodiesterase (PDE) type 5 holoenzyme and the isolated
Figure 32.7 Cartoon depicting binding of vardenafil bicyclic
catalytic domain. Increasing concentration of vardenafil was
ring to the phosphodiesterase (PDE) type 5 catalytic site.
added to a PDE assay containing [3H]cGMP (0.4µM) as substrate
Vardenafil and sildenafil have been reported to have a similar
and the effect of vardenafil to inhibit hydrolysis of cGMP was
mode of binding in the catalytic site of PDE-5.8 Three key
determined.7
interactions are shown between PDE-5 catalytic site (hydrophobic
interactions with the phenyl rings of Phe820 and Tyr612), and a
PDE-5 inhibition is the same for PDE-5 holoenzyme and the bidentate hydrogen bond with the side chain of Gln817 and the
isolated catalytic domain; however, the potency of vardenafil bicyclic ring (imidazotriazinone ring) of vardenafil.38,39
is significantly greater for the holoenzyme than for the iso-
lated catalytic domain (Figure 32.6). Thus, it is clear that the
higher potency of vardenafil over sildenafil in the PDE-5 the polarization of electrons intrinsic to a particular purine
holoenzyme is provided by the influence of the regulatory such as cGMP or a purine-like molecule generates a charac-
domain on the catalytic site to optimize interaction with the teristic dipole moment that can differentially induce polariza-
unique chemical properties of vardenafil. The molecular tion in the aromatic side chains of certain amino acids. This
mechanism that provides for this effect is not known, but it is ‘polarizing power’ is influenced both by exocyclic substitutents
clearly of considerable importance in drug design. on a purine-like ring, such as the carbonyl oxygen of cGMP,
The structural features of sildenafil and vardenafil appear vardenafil, or sildenafil, and by nitrogens in the bicyclic ring. If
to be quite similar, but the greater potency of vardenafil and the polarizing power of vardenafil is greater than that of silde-
the novel requirement for the PDE-5 regulatory domain to nafil, this may induce greater polarization in the side chains of
exhibit higher potency indicates that there are substantial amino acids such as Phe-786, Phe-820, and Tyr-612 in the
differences. Sildenafil and vardenafil differ in having: PDE-5 holoenzyme, thereby enhancing hydrophobic interac-
tions between these residues and the vardenafil bicyclic ring.8,9
• an ethyl or methyl group appended to the piperazine The importance of each of the three most prominent amino
side chain; acid contacts (Gln-817, Phe-820, and Tyr-612) was quantified
• a carbon or nitrogen at position 2 in the 5-member using site-directed mutagenesis of the PDE-5 holoenzyme
ring; and (Figure 32.7); individual replacement of any of these by
• a carbon or nitrogen at position 3 in the 5-member ring. alanine causes significantly greater loss in vardenafil potency
than in sildenafil potency.9,11 Binding contact of inhibitor with
Differences are indicated in Figure 32.5 by the dotted-line Phe-820 or Tyr-612 involves hydrophobic interactions; the
circles. Analogs of vardenafil and sildenafil were used to show side chain of Phe-820 forms stacking interactions with the
that the potency difference is not due to the ethyl–methyl five-member ring of each of the inhibitors. If the polarizing
group appended to the respective piperazine rings.35 This indi- power of vardenafil substantially exceeds that of sildenafil, the
cates that the altered distribution of the carbon and nitrogen binding pattern in X-ray crystal structures may indeed be
atoms in the bicyclic ring systems of these inhibitors in com- similar, but a difference in the strength of those bonds could
bination with the influence of the PDE-5 regulatory domain still exist in the context of the holoenzyme.
provides for the difference in potency; the bicyclic rings are Vardenafil or sildenafil also contacts the hydroxyl of
more accurately described as an imidazotrazinone ring in Tyr-612 through a water molecule that contacts the nitrogen
vardenafil and a pyrazolopyrimidinone ring in sildenafil. at position N-3 or N-2 in the respective five-member ring (see
The variation in location of the nitrogen and carbon atoms Figure 32.7).8 This water molecule is hydrogen-bonded to the
in the respective bicyclic rings has an impact on the pKa Tyr-612 hydroxyl and another water to form a water-bridge
of titratable groups (see Figure 32.5), the distribution and with the zinc in the catalytic site. Differences in the strength of
density of electrons in the rings, and perhaps other features. this bond may also have an impact on potency. The electro-
In general, the influence of a strong dipole moment (or negativity of the nitrogen atom of the vardenafil 5-member
polarization) in purines contributes importantly to stacking ring (indicated by an arrow in Figure 32.5) was experimen-
interactions with phenylalanine or tryptophan in proteins;36 tally determined to be about 100-fold greater than that of the
 Vardenafil: a biochemically potent phosphodiesterase type 5 inhibitor 255

nitrogen in the same position of sildenafil.37 This clearly indi- It has proven to be highly effective and safe in a broad spec-
cates different patterns of charge distribution in these drugs trum of patients. Satisfaction in its effectiveness is strong, and
that could affect both the effectiveness of each to polarize side-effects are infrequent and typically mild. Its high bio-
catalytic site amino acids and to form strong hydrogen bonds chemical potency compared with the potencies of other com-
with the water-bridge. In addition, the nitrogen adjoining the mercial PDE-5 inhibitors is conferred by the regulatory
carbonyl oxygen in the six-member ring of the sildenafil bicy- domain influence on the catalytic domain of PDE-5, which
clic ring is about three-fold more electronegative than the brings about stronger contacts with amino acids in the cata-
homologous nitrogen in vardenafil. These differences refute lytic pocket. The high selectivity and potency of vardenafil
the concept that the chemical properties of these inhibitors for PDE-5 contributes importantly to its usefulness as a
are essentially the same. Nevertheless, in the absence of the medication for treatment of ED, and studies of the interaction
PDE-5 regulatory domain, these are not sufficient to provide between vardenafil and PDE-5 have provided new insights
for different potencies.10 that should be useful in the development of other potent
drugs.

Conclusion
Acknowledgments
Vardenafil continues to be the most biochemically potent
PDE-5-selective inhibitor in clinical use for treatment of ED. Supported by NIH DK40299 and DK58277.

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33 The Princeton Guidelines
for treatment
Graham Jackson

Introduction not to deny sexual activity or ED therapy based on risk but to

evaluate the risk and lower it if possible to facilitate sexual
With the increasing evidence linking erectile dysfunction (ED) intercourse or ED therapy. Closing the door to sexual activity
to coronary artery disease, a panel of experts was convened in prematurely does not constitute good medical practice – it is
Princeton in 1999 in order to create guidelines for treatment not a crime to be unsure of what to do, so referral is strongly
of ED in men with cardiac disease.1 Criteria for stratifying recommended.
men into low-risk, indeterminate-risk (also intermediate-risk)
and high-risk groups were developed based on the evidence
available at that time, and treatment strategies were recom- The man presenting with erectile dysfunction
mended in a practical clinical context. The guidelines were Atherosclerosis of the coronary arteries shares the same risk
well received, having a significant impact on the medical pro- factors as ED. All men presenting with ED and no cardiac
fession and lay community and dispelling the fear that wrongly history should have a cardiac history taken. Asking about
linked sex and the treatment of ED in cardiac patients with effort-induced chest pain or breathlessness should be comple-
potentially fatal consequences. mented with a check of the family history, smoking habits,
Over time, several landmark papers established that the link and any suggestion of hypertension. Is he overweight, what
between ED and coronary artery disease is endothelial dys- exercise does he take, and is he on any medication? More
function and, importantly, that the ED presentation may subtle signs include recent increased fatigue, falling asleep
occur 2–3 years ahead of a cardiac event.2,3 ED came to be easily watching television, irritability, and being unusually
recognized as a marker for silent coronary artery disease and short-tempered. Clinical examination is usually normal but
to be considered a ‘cardiovascular equivalent’.4 In response, in occasionally murmurs are heard, carotid or femoral bruits
2004 the Second Princeton Consensus Conference was con- detected, peripheral edema noted, and the blood pressure
vened and the panel revisited the treatment recommendations found to be raised (over 140/90 mmHg). Routine investiga-
and algorithms, updating them on the basis of the evidence tions should include a fasting glucose and lipid profile, and
accrued since 1999.5 These recommendations have been any evidence of the metabolic syndrome should be acted
presented and published but are briefly summarized in this upon with appropriate referrals. In the era of technology, ‘old-
chapter. fashioned clinical medicine’ remains the basis for directing
further tests.

Clinical management guidelines The cardiac patient

As the knowledge and evidence base associating ED with ED affects over 50% of cardiac patients but cardiologists and
coronary artery disease became firmly established, the second family doctors rarely ask about sex or ED.6,7 The Algorithm in
Princeton (Princeton II) paper focusing on cardiac risk con- Figure 33.1 and Table 33.1 offers practical guidelines but
cluded that ‘a man with ED and no cardiac symptoms is a clearly is useless if the subject is not raised by the healthcare
cardiac (or vascular) patient until proved otherwise’.5 This professional or patient. The importance of lifestyle modifica-
fundamental concept emphasizes the importance of evaluat- tion as part of the management was emphasized by the Princ-
ing the ED patient ‘beyond the penis’ but also challenges eton Panel (see Chapter 15) and by encouraging the patient to
cardiologists to consider sexual activity and ED as part of their contribute to his treatment, it establishes a contract between
routine patient evaluation. Just as there is more to sex than the healthcare professional and patient that should promote
an erect penis, there is more to ED evaluation than simply benefit.
restoring an erection.
The Princeton II Guidelines include an algorithm for evalu-
ating cardiac risk (Figure 33.1). The algorithm maintains the Cardiovascular response to sexual activity
low-, indeterminate-, and high-risk groupings, which are Several studies performed using ambulatory electrocardio-
expanded upon in Table 33.1. One of the key points here is graphy (ECG) and blood pressure monitoring have compared

257
258 Textbook of Erectile Dysfunction

Sexual enquiry

Clinical
evaluation

Low risk Indeterminate risk High risk

• Initiate or resume sexual Cardiovascular • Sexual activity

activity assessment and deferred until
or restratification stabilization
• Treatment of cardiac
for sexual dysfunction condition

Risk factors and coronary heart disease evaluation, treatment

and follow up for all patients with ED

Figure 33.1 The Princeton II algorithm for the evaluation of men with erectile dysfunction (ED).

the heart rate, ECG, and blood pressure responses to sexual dangerous arrhythmias, it will be safe to advise on sexual
activity with the responses to other normal daily activities.8 activity.1,9 If a patient is unable to perform an exercise test
The energy requirement during sexual intercourse is not because of mobility problems, a pharmacological stress test
excessive for couples in a longstanding relationship. The aver- should be utilized (e.g. dobutamine stress ECG). Advice on
age peak heart rate is 110–130 beats per minute and the peak METs in the clinical setting, and relating this advice to sexual
systolic blood pressure is 150–180mmHg. Expressed as a intercourse, should also include advice on avoiding stress, a
multiple of the metabolic equivalent (MET) of energy expen- heavy meal or excess alcohol consumption prior to sexual
diture expanded in the resting state (1 MET), sexual inter- intercourse.
course is associated with a work load of 2–3 METs before
orgasm and 3–4 METs during orgasm. Younger couples, who
are not usually the people we advise, may be more vigorous in Cardiac risk
their activity, expending 5–6 METs. The average duration of There is only a small risk of myocardial infarction associated
sexual intercourse is 5–15 minutes. Therefore, sexual inter- with sex. The relative risk of a myocardial infarct during the
course is not an extreme or sustained cardiovascular stress for 2 hours following sex is shown in Table 33.3.10,11 The baseline
patients in a longstanding relationship who are comfortable absolute risk of a myocardial infarction during normal daily
with each other. Casual sexual intercourse, which must be life is low – one chance in a million per hour for a healthy
separated from extramarital sexual intercourse with a long- adult and 10 chances in a million per hour for a patient with
standing ‘other partner’, may involve a greater cardiac work- documented cardiac disease. Therefore, during the 2 hours
load because of lack of familiarity and age mismatch (usually after sex, the risk increases to 2.5 in a million for a healthy
older men with a younger woman), with different activities adult and 25 in a million for a patient with documented
and expectations.9 cardiac disease; but, importantly, there is no risk increase in
By using our knowledge of MET equivalents in the clinical those who are physically active (physically fit equals sexually
setting we can advise on sexual safety by comparing sexual fit). Coital sudden death is very rare.
intercourse to other activities. Some of the daily activities and
MET equivalents are shown in Table 33.2.
Treating erectile dysfunction in patients with
cardiovascular disease
Exercise testing The updated Princeton consensus guidelines are summarized
Using METs, sexual intercourse is equivalent to 3–4 minutes in Table 33.1. It is recommended that all men with ED should
of the standard Bruce treadmill protocol. Where doubts exist undergo a full medical assessment (see Figure 33.1). Baseline
about the safety of sexual intercourse, an exercise test can physical activity needs to be established and cardiovascular
help guide decision-making. If a person can manage at least risk graded as low, intermediate, or high. Most patients with
4 minutes on the treadmill without significant symptoms, low or intermediate cardiac risk can have their ED managed
ECG evidence of ischemia, a fall in systolic blood pressure or in the outpatient or primary care setting.
 The Princeton Guidelines for treatment 259

Table 33.1 Risk from sexual activity in cardiovascular diseases: Second Princeton Consensus Conference

Low risk: typically implied by the ability to perform exercise of modest intensity without symptoms

Asymptomatic and fewer than three major risk factors (excluding sex)
Major risk factors for cardiovascular disease include age, male sex, hypertension, diabetes mellitus, cigarette smoking,
dyslipidemia, sedentary lifestyle, family history of premature coronary artery disease
Controlled hypertension
Beta-blockers and thiazide diuretics may predispose to erectile dysfunction
Mild, stable angina pectoris
Non-invasive evaluation recommended
Antianginal drug regimen may require modification
Post-revascularization and without residual ischemia
Exercise test may be beneficial to assess risk
Post-myocardial infarction (>6–8 weeks), but asymptomatic and without exercise test-induced ischemia, or post-revascularization
If post-revascularization or no exercise test-induced ischemia, intercourse may be resumed 3–4 weeks after myocardial
infarction
Mild valvular disease
May include selected patients with mild aortic stenosis
Left ventricular dysfunction (NHYA class II)
Most patients are low risk

Intermediate or indeterminate risk: evaluate to reclassify as high or low risk

Asymptomatic and three or more risk factors for coronary artery disease (excluding sex)
Increased risk for acute myocardial infarction and death
Exercise test may be appropriate particularly in sedentary patients
Moderate, stable angina pectoris
Exercise test may clarify risk
Myocardial infarction within previous 2–6 weeks
Increased risk of ischemia, re-infarction, and malignant arrhythmias
Exercise test may clarify risk
Left ventricular dysfunction or congestive heart failure (NYHA class II)
Moderate risk of increased symptoms
Cardiovascular evaluation and rehabilitation may permit reclassification as low risk
Non-cardiac atherosclerotic sequelae (peripheral arterial disease, history of stroke, or transient ischemic attacks)
Increased risk of myocardial infarction
Cardiological evaluation should be considered

High risk: defer resumption of sexual activity until after cardiological assessment and treatment
Unstable or refractory angina
Increased risk of myocardial infarction
Uncontrolled hypertension
Increased risk of acute cardiac and vascular events (e.g. stroke)
Congestive heart failure (NYHA class III, IV)
Increased risk of cardiac decompensation
Recent myocardial infarction (within 2 weeks)
Increased risk of re-infarction, cardiac rupture, or arrhythmias, but impact of complete revascularization on risk is unknown
High-risk arrhythmias
Rarely, malignant arrhythmias during sexual activity may cause sudden death
Risk is decreased by an implanted defibrillator or pacemaker
Obstructive hypertrophic cardiomyopathies
Cardiovascular risks of sexual activity are poorly defined
Cardiological evaluation (i.e. exercise testing and echocardiography) may guide patient management
Moderate-to-severe valve disease
Use vasoactive drugs with caution

NYHA, New York Heart Association.

260 Textbook of Erectile Dysfunction

intended to be a drug for stable angina).12 Because PDE-5 is

Table 33.2 Metabolic equivalent of task units (METs) present in smooth muscle cells throughout the vasculature
as a guide to relating daily activity to sexual activity and the nitric oxide (NO)–cGMP pathway is involved in the
regulation of blood pressure, PDE-5 inhibitors have a modest
Daily activity METs
hypotensive action. In healthy men a single dose of sildenafil
Sexual intercourse with established partner 100mg transiently lowered blood pressure by an average of
10/7mmHg, with a return to baseline at 6 hours post-dose.
Lower range (normal) 2–3
There was no effect on heart rate.12 Because NO is an impor-
Lower range orgasm 3–4 tant neurotransmitter throughout the vasculature and is
Upper range (vigorous activity) 5–6 involved in the regulation of vascular smooth muscle relax-
Lifting and carrying objects (9–20kg) 4–5 ation, a synergistic and clinically important interaction with
Walking 1.6 km (1 mile) on the level in 3–4 oral or sublingual nitrates can occur and a profound decrease
20 minutes in blood pressure can result. The mechanism involves a com-
bination of increased cGMP formation when nitrates activate
Golf 4–5
guanylate cyclase and decreased breakdown of cGMP as a
Gardening (digging) 3–5 result of the action of PDE-5 inhibitors. The concomitant
Do-it-yourself, wall-papering, etc. 4–5 administration of PDE-5 inhibitors and nitrates is thus con-
Light housework (e.g. ironing, polishing) 2–4 traindicated and this recommendation also extents to other
Heavy housework (e.g. making beds, scrubbing 3–6 NO donors such as nicorandil. Clinical guidelines recom-
floors, cleaning windows) mend that sublingual nitrate should be taken 12 hours after
the PDE-5 inhibitors sildenafil and vardenafil;5 tadalafil, which
has a longer half-life, ceases to react with nitrates only after 48
hours.13 Oral nitrates are not prognostically important drugs
and they can therefore be discontinued and, if necessary,
alternative agents substituted.14 After oral nitrate cessation,
Table 33.3 Relative risk of myocardial infarction and provided there has been no clinical deterioration, PDE-5
during the 2 hours after sexual activity: physically fit inhibitors can be used safely. It is recommended that the time
equals sexually fit interval before the use of a PDE-5 inhibitor use is five half-
lives, which equates to 5 days in the case of most popular
Patient type Relative risk (95% CI) once-daily oral nitrate agents.

All patients 2.5 (1.7–3.7)

Men 2.7 (1.8–4.0)
Women 1.3 (0.3–5.2) Observations
Previous myocardial infarction 2.9 (1.3–6.5)
The Princeton II guidelines emphasize the link between the
Sedentary life 3.0 (2.0–4.5) ED and vascular disease and strongly recommend a cardiovas-
Physically active 1.2 (0.4–3.7) cular risk assessment even when there are no cardiac symp-
toms. An exercise test will assess the functional ability of the
CI, confidence interval.
patient but a normal exercise ECG does not rule out subclini-
cal plaques, which may be vulnerable to rupture.15 The symp-
tomatic cardiac patient should have his therapy optimized to
allow for safe sexual activity. The cardiologist needs to be
involved as part of a multidisciplinary approach, which might
There is no evidence that treating ED in patients with car- include the urologist, the family doctor, and a specialized
nurse.16
diovascular disease increases cardiac risk; however, this is with
Due emphasis is given to lifestyle advice (increased exer-
the proviso that the patient is properly assessed and the couple
cise and weight loss) as well as drug therapy. There is reas-
or patient (self-stimulation may be the only form of sexual
surance concerning the cardiovascular safety of PDE-5
activity) are appropriately counseled. Oral drug therapy is the
most widely used because of its acceptability and effectiveness, inhibitors providing that drug interactions are remem-
bered, and there is no evidence that vacuum pumps, intra-
but all therapies have a place in management. The philosophy
is always to be positive during what, for many men and their cavernous injection therapy, or transurethral alprostadil are
partners, is an uncertain time. deleterious.
The Princeton Guidelines, by highlighting the link bet-
ween ED and coronary artery disease, are intended to help
Phosphodiesterase type 5 inhibitors to detect the cardiac patient before he has an event that will
trigger risk factor reduction benefits. In addition they offer
Hemodynamically, phosphodiesterase (PED) type 5 inhi- guidance on assessment and therapy in a positive and
bitors have mild nitrate-like actions (sildenafil was originally constructive way.
 The Princeton Guidelines for treatment 261

REFERENCES

1. Debusk R, Drory Y, Goldstein I, et al. Management of sexual 10. Moller JE, Mittleman A, MacLure M, et al. Determinants of myo-
dysfunction in patients with cardiovascular disease: the Princeton cardial infarction onset study investigators. Triggering myocardial
Consensus Panel. Am J Cardiol 2000; 86: 175–81. infarction by sexual activity: low absolute risk and prevention by
2. Solomon H, Man JW, Jackson G. Erectile dysfunction and the regular physical exercise. JAMA 1996; 275: 1405–9.
cardiovascular patient: endothelial dysfunction is the common 11. Müller J, Ahlbom A, Hulting J, et al. Sexual activity as a trigger
denominator. Heart 2003; 89: 251–3. of myocardial infarction: a case cross-over analysis in the Stock-
3. Montorsi P, Ravagnani PM, Galli S, et al. Association between holm Heart Epidemiology Programme (SHEEP). Heart 2001; 86:
erectile dysfunction and coronary artery disease: matching the 387–90.
right target with the right test in the right patient. Eur Urol 2006; 12. Gillies HC, Roblin D, Jackson G. Coronary and systemic haemo-
50: 721–31. dynamic effects of sildenafil citrate: from basic science to clinical
4. Jackson G. Erectile dysfunction: a marker for silent coronary artery studies in patients with cardiovascular disease. Int J Cardiol 2002;
disease. Eur Heart J 2006; 27: 2613–14. 86: 131–41.
5. Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunction and 13. Kloner RA, Hutter AM, Emmick JT, et al. Time course of the
cardiac risk (the second Princeton consensus conference). Am J interaction between tadalafil and nitrates. J Am Coll Cardiol 2004;
Cardiol 2005; 96: 313–21. 42: 1855–60.
6. Feldman HA, Johannes CB, Derby CA, et al. Erectile dysfunction 14. Jackson G, Martin E, McGing E, Cooper A. Successful withdrawal
and coronary risk factors: prospective results from the Massachusetts of oral long-acting nitrates to facilitate phosphodiesterase type 5
Male Aging Study. Prev Med 2000; 30: 328–38. inhibitor use in stable coronary disease patients with erectile
7. Kloner RA, Mullin SH, Shook T, et al. Erectile dysfunction in the dysfunction. J Sex Med 2005; 2: 513–16.
cardiac patient: how common and should we treat? J Urol 2003; 15. Montorsi F, Briganti I, Salonia A, et al. Erectile dysfunction preva-
170: S46–50. lence, time of onset and association with risk factors in 300 con-
8. Drory Y. Sexual activity and cardiovascular risk. Eur Heart J Suppl secutive patients with acute chest pain and angiographically
2002; 4 Suppl: H13–18. documented coronary artery disease. Eur Urol 2003; 44: 360–5.
9. Jackson G, Betteridge J, Dean J, et al. A systematic approach to 16. Solomon H, Man J, Wierzbicki AS, O Brien T, Jackson G. Erectile
erectile dysfunction in the cardiovascular patient: a consensus dysfunction: cardiovascular risk and the role of the cardiologist.
statement: update 2002. Int J Clin Pract 2002; 56: 633–71. Int J Clin Pract 2003; 57: 96–9.
34 Phosphodiesterase type 5
inhibitors: safety and adverse events
Konstantinos Hatzimouratidis and Dimitrios Hatzichristou

Introduction 6 hours after taking sildenafil and are rarely a reason for dis-
continuing treatment.7 In this review including 5 fixed- and 6
Erectile dysfunction (ED) is a highly prevalent disease, as well flexible-dose trials, placebo patients were more likely to drop
as a major men’s sexual concern.1,2 As the proportion of older out than treatment patients from treatment-related adverse
people in the population increases, it has been estimated that events (2% for sildenafil vs 2.3% for placebo, differences not
the worldwide prevalence of ED will double from 152 million statistically significant).
men in 1995 to 322 million men in 2025.3 Today, phospho- Long-term safety data from open-label extension studies
diesterase (PDE) type 5 inhibitors are considered the first- revealed very low rates of treatment-emergent adverse events
choice treatment for ED by both physicians and patients.4,5 (see Table 34.1).7 However, this population differed from
The safety of these drugs is becoming more important since those of the pooled double-blind studies in that it was self-
more than 30 million men are treated worldwide with a PDE-5 selected. Therefore, it is likely that the population included
inhibitor, especially in the primary care setting. This chapter mostly men who had previously experienced a good response
summarizes current knowledge on safety and adverse events to sildenafil. Post-marketing case series reported a higher
of PDE-5 inhibitors, providing clinical guidance on essential incidence of adverse events, especially for headache (9–39%),
topics related to drug interactions and contraindications. flushing (7–33%) and abnormal vision (5–11%).7 Patients may
tolerate sildenafil differently based on existing comorbidities.
Ischemic heart disease and hypertension are associated with
higher incidence of discontinuation rates caused by adverse
Adverse events and events than diabetes (3.6%, 2.3%, and 1.9% respectively).7
discontinuation rates Multiple studies have demonstrated that sildenafil is well
tolerated by elderly patients with ED, irrespective of comorbid
The currently available PDE-5 inhibitors (sildenafil, tadalafil, conditions. Rates of serious adverse events and discontinua-
and vardenafil) have been shown to be efficacious and safe tion of treatment owing to adverse events are similar between
treatment options for patients with ED. Being of the same placebo and sildenafil groups.8–11 The safety profile of sildena-
class of drugs, they share common side-effects, although fil remains unchanged in patients with spinal cord injury or
differences have been noticed in the reported frequency and depression treated with serotonin reuptake inhibitors.12,13
severity of these symptoms; therefore an analysis follows for
each of the three.
Tadalafil
The most frequent adverse events reported by patients on
Sildenafil tadalafil were headache, flushing, nasopharyngitis, and back
Sildenafil was the first commercially available PDE-5 inhibitor, pain or myalgia (Table 34.2).14 These adverse events were pri-
and its safety profile has been assessed in numerous studies.6–8 marily mild or moderate and generally self-limited over con-
The most commonly reported treatment-related adverse tinuous use of the drug. Only few patients discontinued
events are headache, facial flushing, dyspepsia, dizziness, rhin- treatment in each of the treatment groups (1.3% for placebo,
itis, and abnormal vision (Table 34.1).7 Adverse events are 1.6% for tadalafil 10mg, 3.2% for tadalafil 20mg), although
typically transient and mild to moderate, and they are due to the difference was significant between tadalafil and placebo
the vasodilatory effects of the medication; these include head- (p=0.026). The long-term safety and tolerability of tadalafil
ache, flushing, and nasal congestion. Dyspepsia is probably assessed in a 24-month extension trial (all patients started at a
secondary to relaxation of the smooth muscle of the gastro- dose of tadalafil 10mg but dose could be increased to 20mg or
esophageal sphincter. Visual disturbances (blurred vision, decreased to 5mg).15 No unexpected adverse event was
flashing lights, blue haze, and change in color perception) recorded. Serious adverse events occurred in 8.6% of patients
occur as a result of weak inhibition of PDE-6 in the retina. but no consistent pattern of serious adverse events was
They are coincident with peak plasma concentrations of assessed as causally associated with tadalafil administration.
sildenafil and are transient and fully reversible. None persisted The discontinuation rate because of adverse events was 6.3%,

262
 Phosphodiesterase type 5 inhibitors: safety and adverse events 263

Table 34.1 Drug-related adverse events and discontinuation rates associated with on-demand use of sildenafil

Adverse event 18 randomized, double-blind, placebo-controlled Open-label, 4-year extension trial

trials, lasting up to 6 months (fixed and flexible (3-year data, flexible dose, n=979)7
dose, n=5918)7

Placebo Sildenafil Sildenafil

Headache 3.3% 14.6% 0.9%
Flushing 1.9% 14.1% 0.4%
Dyspepsia 0.7% 6.2% 0.9%
Dizziness 1.1% 2.2% N/A
Rhinitis 0.2% 2.6% 0.3%
Abnormal vision 0.3% 5.2% 0.4%
Discontinuation as a result of 2.3% 2% 1%
treatment-related adverse events

Table 34.2 Drug-related adverse events and discontinuation rates associated with on-demand use of tadalafil

Adverse event 11 randomized, double-blind, placebo-controlled, parallel studies Open-label, 24-month

lasting 12 weeks14 extension trial15

Placebo (n=638) Tadalafil 10mg (n=321) Tadalafil 20mg Tadalafil (flexible dose)
(n=1143) (n=1173)

Headache 5% 12% 15% 15.8%

Dyspepsia 1% 7% 8% 11.8%
Back pain 2% 6% 5% 8.2%
Nasopharyngitis 4% 8% 2% 11.4%
Myalgia 1% 5% 3% 2.9%
Flushing 1% 3% 3% 3.6%
Nasal congestion 1% 3% 2% 3.6%
Limb pain 1% 3% 3% 2%
Discontinuation as a result 1.3% 1.6% 3.2% 3.1%
of treatment-related
adverse events

while 3.1% of the patients discontinued as a result of adverse Studies across different ethnic groups and various risk
events that were assessed by the investigator as being possibly factors revealed the same pattern of adverse events and dis-
related to tadalafil. continuation rates, without statistically significant differences
Visual disturbances are very rare since tadalafil clinically between groups.18–20 This was also the case in patients treated
lacks selectivity for PDE-6. Myalgia or back pain is a common in tertiary care academic centers where more severe ED and
adverse event related to tadalafil, in contrast to the other two ED-associated comorbidities are expected compared with
PDE-5 inhibitors but its pathophysiology is poorly under- patients treated in primary care centers.21 Finally, the safety
stood. Owing to the fact that tadalafil is also an inhibitor of pattern of tadalafil did not change when administered con-
PDE-11, an enzyme encountered also in the testis, safety con- tinuously (20mg, 3 times per week or 5–10mg daily) com-
cerns about sperm effects were raised. A study conducted in pared with on-demand use in general ED populations22–24 or
men older than 45 years revealed no effect on spermatogenesis in ED patients with diabetes mellitus.25
or reproductive hormones after chronic administration of
tadalafil (10mg and 20mg) for 6 months.16 Preliminary results
indicate that tadalafil may acutely (1–2 hours after adminis- Vardenafil
tration of a single 20mg dose) impair sperm motility in young, The most frequent adverse events reported by patients on vard-
infertile patients.17 However, there are no data showing that enafil were headache, flushing, and rhinitis, consistent with
this fact may be of any clinical significance. the vasodilatory properties of PDE-5 inhibitors (Table 34.3).26
264 Textbook of Erectile Dysfunction

Table 34.3 Drug-related adverse events and discontinuation rates associated with on-demand use of vardenafil

Adverse event Randomized, double-blind, placebo-controlled, Fixed-dose, 24-month extension trial27

flexible-dose study lasting 12 weeks26

Placebo (n=164) Vardenafil (n=157) Vardenafil 10mg Vardenafil

(n=272) 20mg (n=294)

Flushing 0% 11% 14% 20%

Headache 2% 10% 16% 20%
Rhinitis 1% 5% 10% 14%
Dyspepsia 0% 3% 4% 9%
Dizziness 1% 2% N/A N/A
Discontinuation as a result of 2% 3% 1.8% 2%
treatment-related adverse events

Discontinuation rates because of treatment-emergent adverse patients who received these agents as part of double-blind,
events were similar to those for placebo (2% for placebo vs 3% placebo-controlled trials or open-label studies, or compared
for vardenafil). Treatment-emergent adverse events were with expected rates in aged-matched populations of men.7,39
generally of mild-to-moderate intensity and rapidly decreased Analysis of pooled data from more than 120 clinical trials
during long-term treatment.27 During one 104-week study, found that sildenafil usage in men with ED did not increase
the incidence of treatment-emergent adverse events was great- the risk of myocardial infarction or cardiovascular death
est during the first 4 weeks of the study, and rapidly decreased within 6 or 24 hours after intercourse, or overall.40,41 Overall,
during long-term treatment, similar to the situation seen with the rate per 100 patient-years of myocardial infarction or
other PDE-5 inhibitors.27 Overall, 1.8% of patients in the cardiovascular death in men treated with sildenafil was similar
vardenafil 10mg group and 2% of patients in the vardenafil to that in men treated with placebo (0.91 vs 0.84) and was
20mg group discontinued treatment because of adverse slightly lower in open-label and extension studies (0.56).
events. Sildenafil also has a strong overall safety profile in men with
Visual disturbances are reported more rarely than with ED and comorbid cardiovascular disease. Pooled data from 37
sildenafil. Serious adverse events were infrequent, reported by double-blind, placebo-controlled trials of sildenafil showed
1–5% of patients receiving vardenafil 5–20mg and 3–5% of pla- similar adverse event profiles for the subset of men with
cebo recipients in short-term studies28–30 and in 11% and 13% comorbid cardiovascular disease and the overall ED popula-
of patients receiving vardenafil 10mg and 20mg, respectively, in tion enrolled in these clinical trials.39 Except for facial flushing
the 104-week study, but only one event (reduced visual acuity) (vasodilatation), each type of treatment-related cardiovascu-
was judged as possibly related to vardenafil treatment.27 lar adverse event (e.g. palpitations, tachycardia) occurred in
In the post-marketing surveillance study involving almost <1% of men, regardless of treatment assignment or comorbid
30,000 patients in Germany, adverse events were reported by condition. Similar results have been reported in prospective
only 1.4% of men.31 The incidence of adverse events with trials.42,43
vardenafil under ‘real-life’ conditions appears to be much Sildenafil does not adversely affect total exercise time or
lower than that seen in clinical trials.26 Similar results have time to ischemia during exercise testing in men with stable
been reported in other general ED populations,32,33 in aging angina. In fact it may actually improve exercise tests. While
men,34 in patients with diabetes mellitus35 and in patients with sildenafil causes a modest decrease in blood pressure in both
spinal cord injury.36 normal and hypertensive patients, it does not result in cardiac
strain. Sildenafil does not alter cardiac contractility, cardiac
output, or myocardial oxygen consumption, while it improves
Cardiovascular safety endothelial function.44–46
There is no evidence that treating ED with PDE-5 inhibitors
increases cardiac risk. ED and vascular disease share the same Tadalafil
risk factors and ED in otherwise asymptomatic men may be a
marker of silent vascular disease, especially coronary artery In clinical studies of tadalafil, the incidence of myocardial
disease. This has now been established to be the case and is infarction was low and similar to that seen with placebo. Myo-
discussed extensively in the second Princeton consensus.37,38 cardial infarction rates in 35 controlled clinical trials were 0.26
per 100 patient-years in tadalafil-treated patients and 0.41 per
100 patient-years in placebo-treated patients. In 8 open-label
Sildenafil studies, these rates were 0.36 and 0.33, respectively. These
Clinical trials and post-marketing data of sildenafil demon- rates were no higher than the myocardial infarction rate of
strated no increase in myocardial infarction rates either in 0.6 per 100 patient-years reported for an age-standardized
 Phosphodiesterase type 5 inhibitors: safety and adverse events 265

population (men under 75 years of age).47 In all trials, the threshold (i.e. ST-segment depression ≥1mm compared with
cardiac mortality rate was 0.12 per 100 patient-years com- baseline).58 As with the other two PDE-5 inhibitors, vardenafil
pared with 0.26 per 100 patient-years for an age-standardized also improves endothelial function.59–61
population.
The incidence of cardiovascular adverse events (including Phosphodiesterase type 5 inhibitors and
congestive heart failure, cerebrovascular events, hypotension, antihypertensive medications
and arrhythmias) was low and similar to that seen with
All PDE-5 inhibitors share mild-to-moderate vasodilator effects,
placebo.47 Observational studies confirmed this safety profile,
resulting in transient decreases in systolic and diastolic blood
reporting similar ischemic heart disease and myocardial infarction
pressures in healthy volunteers.50,62,63 Since hypertension is a
rates to those in the general male population.48 Finally, the
common risk factor in ED patients, it is important to determine
incidence rates of myocardial infarction and cardiovascular
if PDE-5 inhibitors potentiate the decreases in blood pressure
treatment-emergent adverse events were similar to those with
achieved with different classes of antihypertensive agents.
placebo even in cases of once-daily or 3 times per week dosing.49
The incidence of treatment-related adverse events for
Daily tadalafil administration in healthy men resulted in
patients taking sildenafil and antihypertensive medications
blood pressure decreases similar to those seen with placebo
was similar to that for sildenafil-treated patients not taking
administration. Single doses of 5mg and 10mg in men with
any antihypertensive agent (34% vs 38%) in 18 double-blind,
coronary artery disease resulted in small decreases of blood
placebo-controlled studies.7,64 The number of antihyperten-
pressure that were not associated with significant hypotensive
sive medications taken from among the five classes (diuretic,
symptoms.50 There is no evidence for QT prolongation
beta-blocker, alpha-1-blocker, angiotensin converting enzyme
induced by tadalafil. Tadalafil had no significant effect
inhibitor, and calcium-channel blocker) had no effect on the
on global myocardial blood flow at rest, during adenosine
adverse event profile of sildenafil even among patients taking
infusion, or during dobutamine infusion. Compared with
more than three different agents. Therefore, sildenafil is a well-
placebo, tadalafil significantly augmented myocardial blood
tolerated treatment for ED in patients taking concomitant
flow during increased workload in normal regions, with a
antihypertensive medication, including those on multi-drug
trend toward improving myocardial blood flow in poorly per-
regimens.
fused regions.51 Chronic administration of tadalafil improves
Tadalafil administration in patients receiving concomitant
endothelial function in men with or without cardiovascular
antihypertensive therapy may result in a reduction in blood
risk factors.52–54
pressure, which is, in general, mild and not likely to be of
clinical concern. In the phase 3 studies, no statistically signifi-
Vardenafil cant differences were observed between tadalafil and placebo
in the mean changes in blood pressure from baseline in
Vardenafil is associated with a very low risk for myocardial
patients taking ≥2 antihypertensive agents.65 The incidence
infarction, similar to that seen with placebo. In double-blind
rates of cardiovascular events in six phase 3 trials were similar
and open-label clinical trials, myocardial infarction occurred
in tadalafil-treated patients (3.7%) and placebo-treated
in 0.1% of 793 placebo-treated patients compared with <1%
patients (4.8%). Hypotension or postural hypotension was
of 1812 vardenafil-treated patients, with only 1 patient in each
not reported in any tadalafil-treated patient, compared with
group sustaining a myocardial infarction.55 In this analysis, 1
one report of each in the placebo-treated patients. Conse-
placebo-treated patient had a stroke, while no vardenafil-
quently, tadalafil is safe in patients receiving concomitant
treated patient had a stroke. Similarly, patients reporting
antihypertensive agents.
angina or chest pain included 2 (0.3%) in the placebo group
Vardenafil is associated with a low incidence of treatment-
and 1 (<0.1%) in the vardenafil-treated group.
emergent adverse events (21.2%) and discontinuation rates
The incidence of cardiovascular adverse events in double-
(2.1%) compared with placebo (16.4% and 1%, respectively)
blind, long-term, open label, and real-life studies was very low
in ED patients receiving antihypertensive agents.31 There were
(≤0.1% for individual events) and similar to that with
no significant changes in systolic and diastolic blood pressure
placebo.26,27,30–33 Only a few serious cardiovascular adverse
or heart rate between the vardenafil and placebo groups. The
events were reported but none was considered to be due to
average number of antihypertensives used per patient was
vardenafil. In a retrospective analysis of 17 clinical studies of
1.5 (range 1–4) in the vardenafil group and 1.4 (range 1–5)
vardenafil in men with ED, the incidence rates of drug-related
in the placebo group. Both the incidence of adverse events
dizziness was slightly higher in vardenafil-treated patients
and the ability to maintain an erection were unaffected by
than in placebo-treated patients (1.5% vs 0.4%), but without
stratification into distinct subsets according to the class of
additive effects by antihypertensive or alpha-blocker use.56
antihypertensive medication being received. Consequently, in
Vardenafil had only small effects on corrected QT intervals
hypertensive men treated with concomitant antihypertensive
that were not associated with absolute QT prolongation, and
medication, vardenafil is well tolerated, and does not signifi-
they are not considered clinically significant.57 There was no
cantly affect blood pressure.
evidence of long-term cardiovascular safety concerns accord-
ing to vital sign and electrocardiographic recordings during
2 years of treatment with vardenafil.27 Compared with placebo, Phosphodiesterase type 5 inhibitors and
vardenafil had no significant effect on mean total exercise alpha-adrenergic antagonists
time or time to first awareness of angina. Vardenafil 10mg Co-administration of PDE-5 inhibitors and alpha-adrenergic
(but not 20mg) significantly prolonged the time to ischemic antagonists may result in an additive drop of blood pressure
266 Textbook of Erectile Dysfunction

under certain conditions. Sildenafil labeling currently includes Establishing a causal relationship between NAION and a spe-
a precaution advising that sildenafil 50mg or 100mg should cific risk factor (including the use of a particular medication)
not be taken within a 4-hour window of an alpha-adrenergic is problematic since most patients with NAION have one or
antagonist (commonly used for the treatment of lower urinary more concurrent systemic or local risk factors that place them
tract symptoms and benign prostatic hyperplasia). In con- at risk for optic head ischemia. On 8 July, 2005, the FDA
trast, sildenafil 25mg may be taken at any time in relationship approved updated labeling for all three PDE-5 inhibitors,
to alpha-blocker administration.37 However, this precaution reflecting current knowledge of the possible association with
refers mainly to combination treatment with doxazosin. This NAION. At this time, it is not possible to determine whether
may not be the case when tamsulosin66 is used. The concomi- PDE-5 inhibitors were the cause of the loss of eyesight or
tant use of tadalafil with doxazosin may result in significant whether the problem is related to other factors such as high
hypotension and is not recommended.37 This may not be the blood pressure or diabetes, or to a combination of these prob-
case for tamsulosin67 or alfuzosin.68 Similarly, concomitant lems. The FDA advises patients to stop taking these medicines
use of vardenafil with terazosin resulted in hypotension (espe- and call a doctor or healthcare provider right away if they
cially when given to achieve simultaneous time to peak plasma experience a sudden or decreased vision loss in one or both
concentration). However, concomitant use of vardenafil 10mg eyes. Patients taking or considering taking these products
or 20mg with tamsulosin 0.4mg resulted in small asymptom- should inform their healthcare professionals if they have
atic reductions in standing blood pressure.69 ever had severe loss of vision, which might reflect a prior
In all cases, physicians must be cautious when prescribing episode of NAION. Such patients are at an increased risk of
both PDE-5 inhibitors and alpha-adrenergic antagonists. developing NAION again and PDE-5 inhibitors should not be
Patients should be stable on alpha-blocker therapy prior to considered until possible risk factors are optimized. Aspirin is
starting on a PDE-5 inhibitor, which must be initiated at the the only medication that shows some potential benefit in
lowest recommended dose, and dosing should be 3–4 hours reducing the frequency of second eye involvement in patients
apart from alpha-blocker administration.37,49 with NAION.75 Therefore, a reasonable and informed consent
should be provided by the clinician to patients regarding the
possible but low risk of NAION in association with PDE-5
Non-arteritic anterior ischemic inhibitors.73
optic neuropathy
The non-arteritic type of anterior ischemic neuropathy is not
due to inflammation of the arteries; rather, it results from Contraindications
transient poor circulation or loss of circulation in the capillar- Consistent with the effects of PDE-5 inhibition on the nitric
ies of the optic nerve head, causing infarction of the anterior
oxide (NO)–cGMP pathway, all PDE-5 inhibitors may poten-
optic nerve. It is a rare disorder (the annual incidence is 2.3 to tiate the hypotensive effects of nitrates. Therefore, the admin-
10.3 per 100,000).70,71 The pathophysiology of non-arteritic
istration of all PDE-5 inhibitors is contraindicated in patients
anterior ischemic neuropathy (NAION) is controversial. It is who are using any form of organic nitrates, either regularly or
postulated that decreased perfusion in the pial vasculature intermittently. Patients with known hereditary degenerative
(the capillaries feeding the optic nerve head) results in hypo- retinal disorders, including retinitis pigmentosa, were not
perfusion and ischemia of the optic nerve head. A vascular included in clinical trials, and PDE-5 inhibitor use in these
nature is suggested by the abrupt onset of symptoms typical of
patients is not recommended.
ischemia, the increased incidence in older age, and the strong
association with vascular risk factors. NAION onset is typi-
cally characterized by sudden painless monocular visual loss
that may progress over hours to weeks without any proven Other precautions
effective treatment.72–74
A total of 196 post-marketing reports of NAION in patients Several precautions exist in patient subpopulations and
using PDE-5 inhibitors (168 reports with sildenafil, 18 reports as a result of drug interactions.76–78 Renal insufficiency
with tadalafil, and 10 reports with vardenafil) had been alters the pharmacokinetics of PDE-5 inhibitors, increasing
received by the US Food and Drug Administration (FDA) as both the area under the curve (AUC) and the maximum
of June, 2007. Thirty-six of these cases appear to be of the plasma concentration. A starting oral dose of 25mg should
NAION subtype. In 26 cases, the loss of vision was described be considered for sildenafil in patients with severe renal
as continuing or permanent. Furthermore, five cases have insufficiency. No modifications are necessary in patients with
been reported in Canada.72,73 There are 17 NAION case reports mild or moderate renal insufficiency. The dose of tadalafil
published in association with sildenafil and three in associa- should be limited to 5mg not more than once daily in patients
tion with tadalafil.74 A few of the cases associated with sildena- with severe renal insufficiency or end-stage renal disease.
fil use and one case associated with tadalafil experienced A starting dose of 5mg not more than once daily is
temporary partial visual loss that became a fixed visual loss recommended for patients with moderate renal insufficiency;
upon rechallenging. No case reports have been published in the maximum recommended dose is 10mg not more than
association with vardenafil usage. once in every 48 hours. No dose adjustment is required
Based on the similar risk profiles for both NAION and ED, in patients with mild renal insufficiency. In patients with
it is not unexpected to observe NAION cases in men with ED. moderate or severe renal insufficiency, the AUC of vardenafil
 Phosphodiesterase type 5 inhibitors: safety and adverse events 267

was 20–30% higher than in normal subjects. Vardenafil Therefore, they should be administered to these patients
pharmacokinetics have not been evaluated in patients only after careful benefit–risk assessment and with caution.
requiring renal dialysis. Co-administration with aspirin does not prolong bleeding
In patients with hepatic cirrhosis (Child–Pugh score A time, relative to aspirin alone.
and B), a starting oral dose of 25mg should be considered for Both alcohol and PDE-5 inhibitors act as mild vasodilators.
sildenafil. Tadalafil dose should not exceed 10mg in these When mild vasodilators are taken in combination, blood-
patients, and use in patients with severe hepatic impairment pressure-lowering effects of each individual compound may
(Child–Pugh score C), is not recommended. Finally, a starting be increased. Regular alcohol consumption does not alter
dose of vardenafil 5mg is recommended for patients with pharmacokinetics of PDE-5 inhibitors. However, substantial
moderate hepatic impairment, and the maximum dose should consumption of alcohol (e.g. 5 units or greater) in combina-
not exceed 10mg. Vardenafil has not been evaluated in patients tion with a PDE-5 inhibitor can increase the potential for
with severe hepatic impairment. orthostatic signs and symptoms, including increase in heart
Drug interactions may play a significant role in the safety rate, decrease in standing blood pressure, dizziness, and
profile of PDE-5 inhibitors. Besides precautions already headache.
reported, Table 34.4 summarizes effects of PDE-5 inhibitors PDE-5 inhibitors should be used with caution in patients
on other drugs. Physicians must be aware of these effects, with anatomical deformation of the penis (such as angulation,
since dose and treatment modifications may be necessary. The cavernosal fibrosis, or Peyronie’s disease), or in patients
safety of PDE-5 inhibitors in patients with bleeding disorders who have conditions that may predispose them to priapism
and patients with active peptic ulceration is not documented. (such as sickle cell anemia, multiple myeloma, or leukemia).

Table 34.4 Effects of other drugs on phosphodiesterase (PDE) type 5 inhibitors

Study drug (dose Mechanism of Sildenafil Tadalafil Vardenafil

studied for each interaction
PDE-5 inhibitor)

Cimetidine (800mg, Non-specific CYP 56% increase in plasma N/A (nizatidine – another No effect
N/A, 400mg bd) inhibitor concentrations (50mg) H2 antagonist – has no
effect)
Erythromycin CYP3A4 inhibitor 182% increase in AUC N/A (would probably Three-fold increase in
(500mg tid, N/A, (100mg) increase tadalafil exposure) Cmax, four-fold
500mg bd) increase in AUC
Ritonavir (500mg P450 inhibitor 300% increase in Cmax No change in Cmax, 124% 13-fold increase in
bd, 200mg bd, (100mg), 1000% increase increase in AUC Cmax, 49-fold increase
800mg tid) in AUC (100mg) in AUC
Saquinavir (1200mg CYP3A4 inhibitor 140% increase in Cmax N/A (expected to increase N/A (expected to
tid, N/A, N/A) (100mg), 210% increase in tadalafil exposure) increase vardenafil
AUC (100mg) exposure)
Indinavir (N/A, N/A, N/A (expected to increase N/A (expected to increase Seven-fold increase in
800mg tid) sildenafil exposure) tadalafil exposure) Cmax, 16-fold increase
in AUC
Ketoconazole (N/A, CYP3A4 inhibitor N/A (expected to increase 22% increase in Cmax 4-fold increase in
400mg daily, 200mg (strong) sildenafil exposure) (20mg), 15% increase in Cmax, 10-fold increase
daily) Cmax (10mg), 312% increase in AUC
in AUC (20mg), 107%
increase in AUC (20mg)
Itraconazole CYP3A4 inhibitor N/A (expected to increase N/A (would probably N/A (would probably
(strong) sildenafil exposure) increase tadalafil exposure) increase vardenafil
exposure)
Grapefruit CYP3A4 inhibitor N/A (may give rise to N/A (would probably N/A (would probably
(weak) modest increases in increase tadalafil exposure) increase vardenafil
plasma levels) exposure)
Rifampin (N/A, CYP3A4 inducer N/A (expected to decrease 46% decrease in Cmax N/A (expected to
600mg daily, N/A) sildenafil exposure) (10mg), 88% decrease in decrease vardenafil
AUC (10mg) exposure)

CYP, cytochrome P450 isoenzyme; AUC, area under the curve; Cmax, maximum plasma concentration
268 Textbook of Erectile Dysfunction

There have been rare reports of prolonged erections for more Summary
than 4 hours and priapism (painful erections lasting longer than
6 hours) for this class of compounds.79–81 In the event that an Numerous clinical trials and post-marketing studies have
erection persists for longer than 4 hours, the patient should established that PDE-5 inhibitors have an excellent overall
seek immediate medical assistance. safety profile. Adverse events are typically transient, mild-to-
The safety and efficacy of combinations of PDE-5 inhibitors moderate in severity, and self-limiting with continuous use.
with other treatments for ED have not been studied in Despite early concerns, the cardiovascular safety of PDE-5
pre-marketing trials. However, there are data in the literature inhibitors is also excellent with the incidence rates of cardio-
supporting combination of PDE-5 inhibitors with intraure- vascular adverse events being similar to those with placebo.
thral alprostadil and intracavernosal injections in non- Furthermore, recent data show that PDE-5 inhibitors may
responders to PDE-5 inhibitors alone.82–84 Such combinations actually have a cardioprotective role. However, certain limita-
may increase side-effects and they are not recommended in tions and precautions exist. Physicians must be aware of these
everyday clinical practice. in order to treat ED patients safely and effectively.

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and open-label clinical trials of Tadalafil with as needed, three-times- anterior ischemic optic neuropathy. Population-based study in
per-week or once-a-day dosing. Am J Cardiol 2006; 97: 1778–84. the state of Missouri and Los Angeles County, California.
50. Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of tada- J Neuroophthalmol 1994; 14: 38–44.
lafil. Am J Cardiol 2003; 92: 37M–46M. 72. Hatzichristou D. Phosphodiesterase 5 inhibitors and nonarteritic
51. Weinsaft JW, Hickey K, Bokhari S, et al. Effects of tadalafil on anterior ischemic optic neuropathy (NAION): coincidence or cau-
myocardial blood flow in patients with coronary artery disease. sality? J Sex Med 2005; 2: 751–8.
Coron Artery Dis 2006; 17: 493–9. 73. Bella AJ, Brant WO, Lue TF, et al. Non-arteritic anterior ischemic
52. Caretta N, Palego P, Ferlin A, et al. Resumption of spontaneous optic neuropathy (NAION) and phosphodiesterase type-5 inhibi-
erections in selected patients affected by erectile dysfunction and tors. Can J Urol 2006; 13: 3233–8.
various degrees of carotid wall alteration: role of tadalafil. Eur Urol 74. Laties A, Sharlip I. Ocular safety in patients using sildenafil citrate
2005; 48: 326–31, discussion 331–2. therapy for erectile dysfunction. J Sex Med 2006; 3: 12–27.
53. Foresta C, Ferlin A, De Toni L, et al. Circulating endothelial 75. Salomon O, Huna-Baron R, Steinberg DM, et al. Role of aspirin in
progenitor cells and endothelial function after chronic Tadalafil reducing the frequency of second eye involvement in patients with
270 Textbook of Erectile Dysfunction

non-arteritic anterior ischaemic optic neuropathy. Eye 1999; 13: 81. Wilt TJ, Fink HA. Is antidepressant plus sildenafil a recipe for pria-
357–9. pism? Postgrad Med 2004; 116: 11–2.
76. Curran M, Keating G. Tadalafil. Drugs 2003; 63: 2203–12, discus- 82. McMahon CG, Samali R, Johnson H. Treatment of intracorporeal
sion 2213–14. injection nonresponse with sildenafil alone or in combination with
77. Keating GM, Scott LJ. Vardenafil: a review of its use in erectile triple agent intracorporeal injection therapy. J Urol 1999; 162:
dysfunction. Drugs 2003; 63: 2673–703. 1992–7, discussion 1997–8.
78. Langtry HD, Markham A. Sildenafil: a review of its use in erectile 83. Mydlo JH, Volpe MA, Macchia RJ. Initial results utilizing combina-
dysfunction. Drugs 1999; 57: 967–89. tion therapy for patients with a suboptimal response to either
79. King SH, Hallock M, Strote J, et al. Tadalafil-associated priapism. alprostadil or sildenafil monotherapy. Eur Urol 2000; 38: 30–4.
Urology 2005; 66: 432. 84. Nehra A, Blute ML, Barrett DM, et al. Rationale for combination
80. McMahon CG. Priapism associated with concurrent use of phos- therapy of intraurethral prostaglandin E (1) and sildenafil in the
phodiesterase inhibitor drugs and intracavernous injection therapy. salvage of erectile dysfunction patients desiring noninvasive
Int J Impot Res 2003; 15: 383–4. therapy. Int J Impot Res 2002; 14 Suppl 1: S38–42.
35 Diagnosis and treatment
of hypogonadism
Mathew Oommen, Levent Gurkan, Allen D Seftel, and Wayne JG Hellstrom

Introduction most subjects reported some symptoms of hypogonadism,

regardless of their testosterone levels.2 Signs of hypogonadism
As men go beyond the fourth decade of life, there is a gradual include anemia, muscle wasting (sarcopenia), reduced bone
decrease in serum testosterone levels. The US Food and Drug mass or bone mineral density, abdominal adiposity, and
Administration (FDA) estimates that 4–5 million men in the oligospermia or azoospermia.
USA suffer from true hypogonadism, with only 5% of these Frequently, the effects of age-related hypogonadism and
men actually being treated. Other sources estimate the range effective treatment modalities are not even discussed with
of hypogonadism in men above 40 years of age to be between patients, owing to a lack of comfort in discussing sexual issues
6.0% and 43.7%.1 by both patients and their primary care providers. Discussing
Hypogonadism can be due to testicular dysfunction (primary the symptoms and evaluating the signs of age-related hypo-
testicular failure, primary hypogonadism, hypergonadotropic gonadism openly and aggressively helps to change patients’
hypogonadism) or to central, hypothalamic–pituitary causes, perspective that certain conditions are meant to be accepted
which lead to hypogonadotropic hypogonadism (secondary as part of the aging process.
hypogonadism). Primary testicular failure can be a result of
the aging process but can also be caused by chemotherapy,
radiation therapy, congenital defects, and genetic disorders,
such as Klinefelter’s syndrome. Secondary hypogonadism is Diagnosis
characterized by decreased luteinizing hormone (LH) produc- Diagnosing age-related hypogonadism is not always a straight-
tion in the anterior pituitary. In addition to aging, known forward process. Frequently, hypogonadism is a diagnosis
causes include pituitary tumors, surgery, radiation, infections, of exclusion (physicians arrive at the diagnosis only after
trauma, inflammation, bleeding, genetic disorders, nutritional eliminating all other possibilities) because the symptoms are
deficiency, and hemochromatosis. Secondary hypogonadism rather vague and are of gradual onset. Further, there is no
may be associated with syndromes known as Kallmann’s, absolute consensus on what laboratory threshold values and
Prader–Willi, and Laurence–Moon–Biedl. other factors should be included in the formal definition of
While hypogonadism is defined as a low total serum testos- hypogonadism. Current models suggest using a combination
terone, symptomatic hypogonadism is characterized by low of patient history, questionnaire, physical examination, and
total serum testosterone together with clinical symptoms and specific laboratory values.
signs. Symptoms include:
• sexual dysfunction, such as reduced libido, erectile dys-
function (ED), diminished penile sensation, and difficulty Patient history
attaining orgasm, as well as diminished ejaculate with Often, questions dealing with family (relatives with hypo-
orgasm; gonadism), social history (smoking, heavy alcohol consump-
• reduced energy, vitality, or stamina; tion), medical history (history of depression, diabetes,
• depressed mood or diminished sense of well-being; hypothyroidism), sexual history (changes in sexual practices,
• increased irritability; ED, and desire), and changes in sleep and exercise patterns
• difficulty concentrating and other cognitive problems; and can direct a physician to an easy diagnosis. There is general
• hot flashes in some cases of acute onset. consensus that the diagnosis of hypogonadism must be not
Many authorities have supported the position that symptom- only on the basis of certain signs and symptoms (Table 35.1)
atic hypogonadism is a more realistic representation of the but also on the basis of low serum testosterone levels.
true hypogonadal state and thus look for a low serum testos-
terone level combined with one or more of the symptoms
noted above to confirm the diagnosis of true hypogonadism. Questionnaires used in the diagnosis of hypogonadism
The prevalence of hypogonadal symptoms was demon- Owing to the costly nature of laboratory tests, lack of defined
strated by a Swedish survey of men aged 55–75 years, in which coverage by insurance companies, and the uncertainties of

271
272 Textbook of Erectile Dysfunction

Laboratory tests
Table 35.1 Common signs and symptoms in
hypogonadism Assessing the prevalence of hypogonadism is difficult because
of the inconsistencies regarding which laboratory values are
Symptoms Signs used to define hypogonadism. The use of total testosterone,
bioactive testosterone (not bound to sex hormone-binding
Sexual dysfunction Anemia globulin) or free testosterone (not bound to sex hormone-
Diminished penile sensation Muscle wasting binding globulin or albumin) in various studies makes pool-
Difficulty attaining orgasm Reduced bone mass ing data from many studies difficult and inaccurate.
Reduced energy Abdominal adiposity Another issue is that symptoms may manifest themselves at
varying levels of testosterone in different patients. One study
Depressed mood Oligospermia
showed that testosterone levels that elicited symptoms in an
Difficulty concentrating individual patient were reproducible but the exact concentra-
tion that elicited symptoms varied between patients.5
According to the Second International Consultation on
standard laboratory assays, there has been a debate as to Erectile Dysfunction of the World Health Organization
whether other modalities besides a measurement of serum (WHO), a serum testosterone level should be obtained
testosterone can be used to make a diagnosis of hypogonad- between 8.00am and 11.00am, when testosterone levels typi-
ism, especially in the growing population of elderly males. The cally peak in healthy young men. The 2.5th percentile was
use of relatively non-invasive and cost-effective question- 251ng/dl for healthy men aged 40–49 years, 216ng/dl for ages
naires is becoming more accepted. When evaluated for speci- 50–59, 196ng/dl for ages 60–69, and 156ng/dl for ages 70–79.
ficity and sensitivity, current models such as the St Louis Corresponding 2.5th percentile values for free testosterone
University Androgen Deficiency in Aging Males (ADAM) were 5.3ng/ml, 4.2ng/ml, 3.7ng/ml and 2.2ng/dl, respectively,
questionnaire are highly sensitive but not very specific for the and corresponding values for bioavailable testosterone were
diagnosis of hypogonadism.3,4 However, surveys using some 99.7ng/ml, 79.8ng/ml, 69.7ng/ml, and 41.8ng/dl, respectively.
of the ADAM questions may guide the clinician in following Finally, the exact values and methods of obtaining the
the patient response to treatment. results vary between laboratories. For instance, one recent
The ADAM questionnaire asks the following questions. study showed that not only did assay types vary between
The response is considered positive if the answer is yes laboratories but even reference values for low testosterone
to question 1 or question 7, or yes to at least three other (130–450ng/dl) and high testosterone (486–1593ng/dl) had
questions. discrepancies.6 In the previously mentioned study, 23 of the
25 laboratory directors said they would welcome the esta-
1. Do you have a decrease in libido (sex drive)? blishment of uniform standards that were clinically relevant.
2. Do you have a lack of energy? A recent study has shown that analysis of saliva samples for
3. Do you have a decrease in strength and/or endurance? testosterone may yield comparable results to serum testoster-
4. Have you lost height? one analysis in the diagnosis of hypogonadism.7 Regardless,
5. Have you noticed a decreased enjoyment of life? more studies in this hot area of research are necessary before
6. Are you sad and/or grumpy? it can be considered as part of a standardized method for
7. Are your erections less strong? diagnosis of hypogonadism.
8. Have you noted a recent deterioration in your ability to
play sports?
9. Are you falling asleep after dinner? Treatment
10. Has there been a recent deterioration in your work
performance? Testosterone supplementation in hypogonadal men restores
testosterone levels and improves secondary sexual character-
It is generally recognized that questionnaires are at the very istics, sexual function, sense of well-being, muscle mass and
best an adjunct to, but not a replacement for serum testos- strength, and bone mineral density. Currently, there are many
terone measurements. As these types of questions and surveys formulations of testosterone with varying advantages and
evolve, the level of specificity will also improve, which, in disadvantages (Table 35.2).
turn, may make them a more integral part in the diagnosis of
hypogonadism.
Suggested regimens of replacement therapy
Suggested regimens of testosterone replacement therapy
include:8
Physical examination
A thorough but focused physical examination needs to be • testosterone enanthate or cypionate, 75–100mg by intra-
performed when evaluating a patient for hypogonadism. muscular injection weekly or 150–200mg administered
Particular attention is directed to secondary sexual charac- every 2 weeks;
teristics, gynecomastia, muscle atrophy, changes in body fat • testosterone patch, non-genital, one or two 5mg patches
composition, and testicular atrophy. Examination of the penis applied nightly over non-pressure-bearing sites such as the
and a digital rectal examination is also mandatory. back, chest, or upper arm;
 Diagnosis and treatment of hypogonadism 273

Table 35.2 Advantages and disadvantages of various testosterone formulations

Formulation Route of administration Advantages Disadvantages

Buccal adhesive Twice-daily dosing via Maintains a steady state of Irritation at the gum line
controlled-release patch testosterone
17-methyl testosterone Oral — Damages the liver; not
recommended for this use
Testosterone pellets Placed under the skin for 4–6 Infrequent physician visits Requires a procedure; pellets
months may extrude from skin
Testosterone undecanoate Intramuscular injection every Fewer physician visits required Injections may be painful
in oil 6–12 weeks for therapy
Non-genital testosterone Applied to non-pressure- Ease of application Irritation at the patch site
patch bearing sites
Scrotal testosterone patch Applied to the scrotum Non-invasive, painless Scrotum must be shaved for
application
Testosterone gel Daily skin application Less skin irritation compared Potential transfer of
with patches testosterone via skin contact
with partner or children

• testosterone gel, 5–10mg applied daily to dry intact skin Buccal patches
of the upper arm, back or chest; and Buccal testosterone comes as a tablet-shaped patch, which is
• buccal testosterone, 30mg patch applied twice daily to applied to the upper gum. It is a 30mg controlled-release
buccal mucosa. tablet, which is applied every 12 hours. It has been shown
to have good results in attaining eugonadal serum levels.11
Intramuscular preparations However, drawbacks include irritation at the gum line and a
Intramuscular injections such as testosterone cypionate and twice-daily dosing schedule.
enanthate are esterified compounds that are dissolved in
oil-based solutions.9 They can be given in varying doses Transdermal patches
ranging from 75mg to 400mg depending on the frequency
Current transdermal routes include daily patches that can be
of injections (75–100mg weekly, 150–200mg every 2 weeks,
placed on the appendages or torso as well as scrotal patches.
300–400mg every 3 weeks). Doses higher than 400mg have
They have been shown to provide an adequate clinical response
not been demonstrated to lengthen the eugonadal period.
and appropriately increase serum testosterone levels. The most
One drawback is the frequency of injections, which may be
common complaint is irritation at the site of patch placement.
unappealing to both physicians and patients.
The scrotal patch also increases levels of dihydrotestosterone
For patients who prefer longer intervals between injections,
secondary to high 5-alpha-reductase activity in scrotal skin.12
testosterone undecanoate in oil is being used in Europe
Another issue for some patients is the need for constant
(1000mg every 6–12 weeks). However, patients must be
shaving of the scrotal skin for better adherence.
willing to tolerate a slightly more painful, larger volume injec-
tion. A preparation currently undergoing trials in the USA is
testosterone undecanoate in castor oil, which may last as long Monitoring of men receiving testosterone therapy
as 14 weeks after an initial 6-week loading dose. The patient should be initially evaluated 3 months after treat-
ment starts and then annually to assess whether symptoms
Oral preparations have responded to treatment and whether the patient is
Though still prescribed by some clinicians, most authorities suffering any adverse effects.8
do not recommend 17-methyl testosterone in tablet form,
1. Obtain testosterone levels 2–3 months after initiation of
owing to known changes in liver function tests and the need for
testosterone therapy. Therapy should aim to raise serum
relatively large doses.10 However, capsules that contain testoster-
testosterone to within the normal range.
one undecanoate in oil are available in Europe and Canada and
2. Check hematocrit at baseline, at 3 months, and then
are given in a twice- or three-times-daily dosing regimen.
annually. If hematocrit is 54% or greater, stop therapy
until hematocrit decreases to a safe level. The clinician
Gels must evaluate the patient for hypoxia and sleep apnea,
Testosterone gels are applied to the skin in varying doses and then may reinitiate therapy at a reduced dose.
ranging from 5mg to 10mg daily. These preparations allow for 3. Measure bone mineral density of lumbar spine or femoral
steady states of testosterone and cause fewer adverse reactions neck after 1–2 years of testosterone therapy in hypo-
at application sites. A drawback is the potential risk of testos- gonadal men with osteoporosis or a history of traumatic
terone transfer via skin contact to the partner or children. fracture, consistent with the regional standard of care.
274 Textbook of Erectile Dysfunction

4. Perform a digital rectal examination and check the usually hormone-dependent initially and may be stimulated
prostate-specific antigen (PSA) level before treatment (at with any form of testosterone therapy. In a similar fashion,
baseline), at 3 months, and then in accordance with benign prostatic tissue also responds to testosterone therapy.
guidelines for prostate cancer screening depending on A thorough prostate evaluation needs to be performed prior
the age and race of the patient. One study showed that to initiation of replacement therapy.
parenteral testosterone replacement therapy in older
hypogonadal men increased the serum PSA level by a
mean of 0.96ng/ml over a mean treatment duration of Adverse effects of testosterone therapy
30.2 months.13 The adverse effects of testosterone administration must be dis-
5. Obtain urological consultation if there is: cussed with any patient contemplating replacement therapy.2
• an increase in serum PSA concentration of 1.4ng/ml
or greater within any 12-month period of treatment;
Adverse events for which there is evidence of
• PSA velocity of >0.4ng/ml/year using the PSA levels
association with testosterone administration
after 6 months of testosterone administration as the
reference (only applicable if PSA data are available for Patients should be notified that conditions such as increased
a period exceeding 2 years); acne, decrease in sperm production, possible decreased fertility
• any prostatic anomaly on digital rectal examination; rates, and elevations in the red blood cell count are possible.
• AUA or American Urological Association prostate There should also be a discussion about the increased like-
symptom score or International Prostate Symptom lihood of detecting subclinical prostate cancer and the growth
Score of 19 or more. of hormone-sensitive metastatic prostate cancer.
6. Evaluate formulation-specific adverse effects at each visit:
• buccal testosterone tablets – enquire about alterations Less common adverse events
in taste and examine the gums and oral mucosa for Patients should be notified of the remote possibility of
irritation;
side-effects such as gynecomastia, initiation of male pattern
• injectable testosterone – ask about fluctuations in baldness, and worsening of obstructive sleep apnea.
mood or libido and pain at the injection site;
• testosterone patches – examine for skin reaction at the
injection site; Medication-specific adverse effects
• testosterone gels – advise patients to cover the appli-
When the physician and patient are deciding on a form of
cation sites with a shirt and wash the skin with soap
testosterone therapy, formulation-specific effects should be
and water before having skin-to-skin contact, because
discussed. For instance, oral methyltestosterone, if used, can
testosterone gels leave a testosterone residue on the
damage the liver. Subcutaneous pellets can be extruded from
skin that can be transferred to a woman or child who
the skin. Intramuscular injections of testosterone can cause
might come in close contact; serum testosterone levels
problems such as fluctuations in mood, pain at the injection
are maintained when the application site is washed
site, and excessive erythrocytosis. Transdermal testosterone
4–6 hours after application of the testosterone gel.
patches can cause localized skin reactions. Transdermal
testosterone gels and creams can potentially be absorbed by
others via skin contact. Buccal testosterone patches can inter-
Contraindications to testosterone therapy fere with taste sensations and cause gum irritation.
Treatment with testosterone is effective for the aging hypo-
gonadal male. However, care must be taken during the initial
screening and subsequent treatment regimen to assure that Conclusion
the patient does not have or develop conditions that would
contraindicate initiating or continuing therapy. Conditions By choosing appropriate formulations of testosterone based
in which testosterone should not be administered include on factors such as ease of use, cost of medication, dosing
prostate cancer, breast cancer, prostate nodule without interval, preferred method of administration, and side-effect
biopsy-confirmed histology, elevated PSA without work-up, profile, the treatment of hypogonadism can improve the
erythrocytosis (hematocrit >50%), severe lower urinary tract quality of life for this greatly under-served patient population.
symptoms associated with benign prostatic hypertrophy, and The diagnosis and treatment of hypogonadism is continuing
unstable severe congestive heart failure (New York Heart to evolve as newer detection methods and medication formu-
Association class III or IV).2 Prostate and breast cancers are lations become available.

REFERENCES

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learned since the Institute of Medicine report and what lies ahead? 161–6.
Int J Clin Pract 2007; 61: 622–32. 3. Morley JE, Charlton E, Patrick P, et al. Validation of a screening
2. Gladh YM, Rahgozar M, Hammar ML, et al. Prevalence questionnaire for androgen deficiency in aging males. Metabolism
of symptoms possibly related to PADAM, in a Swedish 2000; 49: 1239–42.
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4. Tancredi A, Reginster J, Schleich F, et al. Interest of the Endocrine Society clinical practice guideline. J Clin Endocrinol
androgen deficiency in aging males (ADAM) questionnaire for Metab 2006; 91: 1995–2010.
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5. Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone thresh- term methyltestosterone. Lancet 1977; 6: 261.
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2004; 89: 3813–17. testosterone bioadhesive buccal system, striant, with a testosterone
6. Lazarou S, Reyes–Vallejo L, Morgentaler A. Wide variability in adhesive patch in hypogonadal males. J Clin Endocrinol Metab
laboratory reference values for serum testosterone. J Sex Med 2004; 89: 2039–43.
2006; 3: 1085–9. 12. Jordan W. Allergy and topical irritation associated with transdermal
7. Morley JE, Perry HM, Patrick P, et al. Validation of salivary testos- testosterone administration: a comparison of scrotal and nonscro-
terone as a screening test for male hypogonadism. Aging Male tal transdermal systems. Am J Contact Dermat 1997; 8: 103.
2006; 9: 165–9. 13. Gerstenbluth R, Maniam P, Corty E, et al. Prostate-specific antigen
8. Bhasin S, Cunningham G, Matsumoto AM, et al. Testosterone changes in hypogonadal men treated with testosterone replace-
therapy in adult men with androgen deficiency syndromes: an ment. J Androl 2002; 23: 922–6.
36 Central nervous system agents for
the treatment of erectile dysfunction
Julita Mir and Ricardo Munárriz

Introduction The PVN is also regulated by adrenocorticotropic hormone

(ACTH) and alpha-melanocyte stimulating hormone (alpha-
Although the central mechanisms involved in the regulation MSH). These melanocortin peptides can stimulate penile
of erectile physiology are not completely understood, recent erections after intra- or paraventricular administration
advances have allowed the development of promising central even after lesion of the nucleus, which suggests that ACTH
acting drugs. This chapter reviews the available data on may elicit penile erections through non-dopaminergic
apomorphine and melanocortins. mechanisms.5,15,16 Interestingly, intrathecal administration of
melanotan II (MT-II) was more effective in eliciting a penile
erection than central (ventricle) administration, which suggests
melanocortins modulate penile erections at the level of the
Central mechanism of spinal cord.17 Although melanocortin receptor type 4 (MC-4R)
penile erections is expressed in the nerve fibers and nerve endings in the penis,
intracavernosal administration of melanocortins (THIQ (1, 2,
Penile erections are elicited by local sensory stimulation of the 3, 4 tetrahydroisoquinoline), MT-II) did not change intra-
genital organs and by central psychogenic stimuli received by cavernosal pressures.18
or generated within the brain.1,2 Recently, specific regions of The melanocortin system includes melanocortin peptides,
the brain (inferior temporal cortex, right insula, right inferior melanocortin receptors, melanocortin antagonists, and two
frontal cortex, and left anterior cingulated cortex) activated by ancillary proteins (mahogany and syndecan-3); it is involved
visual evoked sexual arousal have been identified by positron in a variety of regulatory functions that include skin pigmen-
emission tomography.3 The medial preoptic area (MPOA) tation, steroidogenesis, satiety, analgesia, immunomodulation,
and the paraventricular nucleus (PVN) within the hypotha- energy and temperature homeostasis, and cardiovascular,
lamus appear to integrate visual (occipital area), tactile (thala- neuromuscular, and sexual function. There are five melano-
mus), olfactory (rhinencephalon), and imaginative (limbic cortin receptors (MCRs), which are G protein-coupled and
system) input and send neural projections to the lumbosacral linked to cAMP generation. MCR type 1 (MC-1R) is primarily
spinal cord through oxytocinergic pathways.4,5 More specifi- found in melanocytes where skin pigmentation is modulated
cally, the MPOA integrates sensory stimuli from higher brain by alpha-MSH.19 MCR type 2 (MC-2R) is expressed in the
centers with sexual motivation and copulatory behavior,6 adipose tissue and the adrenal gland, where it modulates
while the PVN plays a role in the erectile and ejaculatory steroidogenesis under the influence of ACTH. MC-4R is
responses.7,8 Dopamine and oxytocin are thought to play involved in sexual function and adipose homeostasis and
important roles in mediating the pre-erectile response in the satiety (see Table 36.1). Agouti and agouti-related protein are
MPOA and the PVN, respectively.9 natural melanocortin antagonists that play a role in appetite,
Electrostimulation of the PVN induces erections, while dam- obesity, and maybe in sexual function.
age of the nucleus disrupts the dopamine receptor mediated On the other hand, the nucleus paragigantocellularis (nPGi)
erectile responses.5,8 In addition, systemic dopamine receptor in the brain stem exerts an inhibitory effect on sexual arousal.20
agonist or direct administration into the PVN induces penile Nerves from the nPGi project to sacral segments of the spinal
erections while administration of dopamine receptor anta- cord and release serotonin. This has been postulated as the
gonist prevents erectile responses.10–12 These observations reason why specific serotonin reuptake inhibitors (SSRIs)
suggest that the PVN plays a critical role in the dopaminergic depress sexual function, more specifically delay or block ejacu-
control of penile erections. There are five subtypes of dopami- lation. Therefore, premature ejaculation has been successfully
nergic receptors which have been classified into D1-like (D1 managed with SSRIs. The locus caeruleus also exerts inhibi-
and 5) and D2-like (D2–4) receptors. The latter group is thought tory input via sympathetic nerves that interface with hypotha-
to be mainly responsible for erectile responses.10,13 D4 receptor lamic nuclei as well as with the spinal cord. Withdrawal of
agonists elicit penile erectile responses while D2 receptor stimu- sympathetic input because of suppressed activity of the locus
lation is responsible for the emetic effects of dopaminergic caeruleus during rapid eye movement sleep is thought to lead
drugs (Table 36.1).14 to episodes of nocturnal penile tumescence.21,22 The pudendal

276
 Central nervous system agents for the treatment of erectile dysfunction 277

Table 36.1 Receptor-binding affinities of apomorphine for dopamine receptor subtypes

Ki (nM) D1-like receptors D2-like receptors

D1 D5 D2 D3 D4

Dopamine 0.9–2340 < 0.9–261 2.8–474 4–27 28–450

Apomorphine 0.7–680 122–163 0.7–24 20–32 4
Effect on cAMP D1 and D5 increase cAMP D2, D3, and D4 decrease cAMP
Physiologic role Emesis Erections
Ki, binding affinity.

nerve, which is the afferent limb for reflexogenic erections,

Table 36.2 Melanocortin receptor localization and role
collects somatic sensation from the genital skin. The auto-
nomic nerve fibers that arise from the sacral parasympathetic Localization Effect
center (spinal cord levels S2–S4) make up the efferent limb
for this reflex, innervating the penile smooth muscle. Reflexo- MC-1R Melanocytes Skin pigmentation
genic and psychogenic erectile mechanisms probably act MC-2R Adrenal cortex and Steroidogenesis in
synergistically in the control of penile erection.1,23–29 adipose tissue response to ACTH
MC-3R Central nervous system Energy homeostasis
and other tissues
Apomorphine in sexual function MC-4R Neural tissues Sexual function
Hypothalamus Obesity
Apomorphine, a non-selective dopamine receptor agonist, is (MC-4R inactivation)
the first central-acting drug approved in Europe (2001) for Lean phenotype
the management of erectile dysfunction (ED) (Table 36.2).30 (MC-4R activation)
Only after sexual stimulation, apomorphine can stimulate D2 MC-5R Peripheral human Exocrine function
receptors since the PVN integrates sensory and imaginative tissues Sebaceous gland
input. Stimulation of D2 receptors increases oxytocinergic function
neural signaling, which stimulates sacral spinal centers, MC, melanocortin; MCR, melanocortin receptor; ACTH, adrenocorti-
resulting in increased parasympathetic stimulation and penile cotropic hormone.
erections.

Efficacy reported improvements in erectile function (from 15.9 to

Over 5000 men worldwide have received apomorphine SL 20.4), intercourse satisfaction (from 7.7 to 9.9), and orgasmic
(sublingual) in clinical trials. The first three phase 3 crossover domains (from 6.8 to 7.5) in the IIEF.32
studies (n=854; 2mg and 4mg doses) were conducted in men
with mild (25.9%), moderate [International Index of Erectile
Function (IIEF) 11–16; 36.8%], and severe (IIEF <10; 37.3%) Onset of action
ED.31 However, the majority of patients (74.1%) had moderate- Data from the first three phase 3 crossover trials show median
to-severe ED. The following comorbidities were reported in times to erection of 17.5 and 16.4 minutes for the 2mg and
these studies: hypertension (31%), coronary artery disease 4mg doses, respectively, for all men achieving erections suffi-
(16%), dyslipidemia (16%), diabetes (16%), benign prostatic cient for intercourse. However, the time to erection in the
hyperplasia (16%), alcohol use (63%), and smoking (16%). placebo group was 15 minutes. Thus, there was no significant
Combined data from these three crossover studies reported change in the timing of sexual response in comparison with
54.6% and 45.6% successful attempts in attaining erections placebo.
sufficient for intercourse for the 4mg and 2mg dose groups,
respectively, compared with baseline (26.8%) and placebo
(33.8%). Interestingly, partner’s responses were very similar Tolerability and safety
to patient’s reports (54% and 46% for the 4mg and 2mg Several clinical trials have documented the safety of apomor-
doses, respectively; concordance of 98%). Ability to have phine SL in ED patients with mild-to-moderate adverse
intercourse for the 4mg and 2mg dose groups were 50.6% and events.33–37 The most common reported adverse events were
41.5%, respectively, compared with baseline (25.7%) and nausea, headache and dizziness. Nausea was reported in 2.1%
placebo (31%).31 and 20.4% of men who took the 2mg and 4mg doses, respec-
Long-term studies (n=135; 6 months) reported rates of suc- tively, in the three first crossover studies. However, nausea
cessful erections (erections firm enough for intercourse) in 82.9– was reported as mild in the majority of patients (1.2% and
91.6% of all attempts. A more recent study by Kongkanand et al. 12.2% for the 2mg and 4mg doses, respectively) and rarely
278 Textbook of Erectile Dysfunction

resulted in trial drop-out or use of anti-emetics. Nausea is a subsequent study by the same investigators reported that
dose-related and improves with continued dosing.33,36,38 In the four of 19 injections were associated with severe nausea.39
forced-dose-escalation European clinical trial, 4.7% and 1.6%
of the 507 patients taking apomorphine SL and placebo,
respectively, dropped out of the trial as a direct result of PT-141
drug-related adverse events.33 Data from a double-blind cross- Efficacy
over comparison of apomorphine 3 mg and 4 mg documented Molinoff et al. demonstrated that administration of PT-141 to
an improved risk–benefit profile for the 3 mg dose base on a healthy men and patients with ED resulted in a rapid and
comparison of the incidence of nausea with a firm erection dose-dependent increase in penile responses.40 Subsequently,
enough for intercourse. However, the tolerability profile of Diamond et al. showed in a double-blind, placebo-controlled
apomorphine SL is enhanced when dose optimization is study that intranasal administration of PT-141 to healthy males
followed.34 and to sildenafil-responsive ED patients resulted in statisti-
cally significant erections when compared with placebo.41
More recently, Rosen et al. investigated the effects of subcuta-
Cardiovascular safety
neous administration of PT-141 (0.3–10mg) to healthy males
Data from the first three crossover studies reported no and to patients with ED who report an inadequate response to
deaths, myocardial infarction, cerebrovascular accidents, or sildenafil. The investigators showed a statistically significant
priapisms. However, 4 of 690 patients (0.6%) experienced increase in erectile responses in healthy men at doses greater
brief (approximately 60 seconds) and self-limited syncopal than 1.0mg in the absence of audio–visual–sexual stimulation.
episodes. Interestingly, 7 of the patients who suffered syncopal More importantly, patients with ED who reported inadequate
episodes continued to use the drug without further events. responses to sildenafil experienced statistically significant
In addition, Holter studies demonstrated no arrhythmias. penile erectile responses to subcutaneous administration
Apomorphine in patients with underlying conditions of 4mg or 6mg of PT-141.42 Diamond et al. investigated the
(i.e. hypertension, CAD, diabetes, and benign prostatic hyper- safety and efficacy of the co-administration of sub-therapeutic
plasia) was well tolerated.33 In addition, the cardiovascular doses of intranasal PT-141 (7.5mg) and sildenafil (25mg) to
safety of the concomitant use of apomorphine 5mg with angio- 19 patients with ED who responded to sildenafil or vardenafil.
tensin converting enzyme inhibitors, beta-blockers, diuretics, Co-administration of PT-141 and sildenafil resulted in signifi-
calcium-channel blockers, alpha-1-blockers, and nitrates was cantly greater erectile response (on RigiScan) than sildenafil
investigated by Fagan et al. They reported minimal changes in alone.43
blood pressure after repetitive orthostatic stress.38

Pharmacokinetics
Intranasal administration of intranasal PT-141 (4mg, 7mg,
Melanocortins in sexual function 10mg, and 20mg) resulted in peak plasma concentration
M-II38,39 and PT-14140–42 are synthetic melanocortin agonists, values of 14.9ng/mL, 90.1ng/ml, and 140.5ng/ml with a
which have been shown to be effective in the management of median time to peak concentration of 30 minutes and a half-
ED in humans. life of 1.85–2.09 hours.42

Tolerability and safety

Melanotan II PT-141 was safe and well tolerated in all clinical trials.40–43
Efficacy The most common adverse events were flushing and nausea.
In addition, no significant changes in vital signs, laboratory
A double-blind, placebo controlled crossover study with MT-II tests, electrocardiography, or physical examination were
of 10 men with ED using real-time RigiScan monitoring reported.41
reported that 8 of the 10 men developed clinically apparent
erections after MT-II administration. Mean duration of tip
rigidity (>80%) was 38 minutes and 3 minutes for MT-II and
placebo, respectively.38 In a subsequent study by Wessells et Novel central-acting drugs in
al., subcutaneous administration of MT-II to men with ED the treatment of erectile dysfunction
resulted in penile erections (mean rigidity score 6.9 out of 10)
without sexual stimulation. MT-II and placebo mean dura- Oxytocin
tion of tip rigidity (>80%) was 45.3 minutes and 1.9 minutes, When the oxytocin patent was revoked, the pharmaceutical
respectively. In addition, the level of sexual desire was signifi- industry lost interest in the potential role of oxytocin in the
cantly higher with MT-II administration.39 management of men with ED. However, early clinical investi-
gations showed that oxytocin was effective in men with
psychogenic ED.44–46 These observations were subsequently
Tolerability and safety supported by preclinical studies showing that oxytocin injec-
Transient nausea, stretching and yawning, and decreased tions to the PVN resulted in erectile responses in the rat
appetite were reported with MT-II administration.38 However, model.47
 Central nervous system agents for the treatment of erectile dysfunction 279

Glutamate model,51 led to several clinical trials in the use of trazadone in

Rampin et al. showed that glutamate released after genital the management of ED. However, poor efficacy has decreased
stimulation acts at AMPA and NMDA receptors.48 In addition the initial interest.52
Song et al. reported that hippocampal injection of glutamate
receptor agonists resulted in erectile activity. 49
Summary
Scientific advances in the understanding of central nervous
Hexarelin analogs system signaling and regulation of penile physiology has
Intraventricular or systemic administration of hexarelin allowed the development of the first central-acting ED drugs
analogs induces penile erectile activity in the rat model. (apomorphine, MT-II, PT-141). Based on the available
Melis et al. showed that two hexarelin analogs induced penile data, these drugs seem to be safe and effective in the manage-
erections by increasing central oxytocin transmission at the ment of men with ED. However, comparison trials between
level of the PVN.50 apomorphine and sildenafil have clearly favored the latter.53–55
On the other hand, co-administration of central-acting drugs
and PDE-5 inhibitors may result in better efficacy and tolera-
5-Hydroxytryptamine-2c agonist bility.43 Development of more selective dopamine receptor
The observation that a metabolite of trazadone (mCPP) is agonists, melanotonin agonists, or other novel central-acting
a 5-hydroxytryptamine (5-HT)-2c agonist and a 5-HT-1a drugs may result in better efficacy and decrease adverse
antagonist capable of inducing penile erections in the rat events.

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PT-141: a melanocortin agonist for the treatment of sexual dys- 53. Perimenis P, Markou S, Gyftopoulos K, et al. Efficacy of apomor-
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41. Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB. function. A comparative crossover study. Andrologia 2004; 36:
Double-blind, placebo-controlled evaluation of the safety, pharma- 106–10.
cokinetic properties and pharmacodynamic effects of intranasal 54. Eardley I, Wright P, MacDonagh R, Hole J, Edwards A. An open-
PT-141, a melanocortin receptor agonist, in healthy males and label, randomized, flexible-dose, crossover study to assess the
patients with mild-to-moderate erectile dysfunction. Int J Impot Res comparative efficacy and safety of sildenafil citrate and apomor-
2004; 16: 51–9. phine hydrochloride in men with erectile dysfunction. BJU Int
42. Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB. 2004; 93: 1271–5.
Evaluation of the safety, pharmacokinetics and pharmacodynamic 55. Porst H, Behre HM, Jungwirth A, Burkart M. Comparative trial of
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receptor agonist, in healthy male subjects and in patients with an apomorphine in erectile dysfunction--an open, randomized cross-
inadequate response to Viagra. Int J Impot Res 2004; 16: 135–42. over study with flexible dosing. Eur J Med Res 2007; 12: 61–7.
37 Intracavernosal therapy for
erectile dysfunction
Carsten Maik Naumann, Moritz Franz Hamann, Sascha Kaufmann,
Amr Al-Najar, Christof van der Horst, and Klaus-Peter Jünemann

Introduction In the same year, Hedlund and Andersson published their

findings on the relaxation effect of prostaglandin on human
The era of intracavernous drug administration had its onset penile tissue.5 But it was not until 1988 that Stackl et al.
in the early 1980s, now almost 30 years ago. It was on reported the effectiveness and safety of alprostadil in home
11 January 1980 that Virag placed an injection of 80mg self-injection therapy.6 In further studies by McMahon7 and
papaverine hydrochloride directly into the inferior epigastric Bennett and Barada,8 the use of a triple-drug combination of
artery, which was anastomosed to the cavernous body of the papaverine, phentolamine, and alprostadil was shown to be
penis in the course of a Michal I Operation. According to his as effective as alprostadil alone, which consequently became
reports, this procedure bestowed a 3-hour episode of firm the first drug approved in the USA by the Food and Drugs
erection upon the 46-year-old patient.1,2 To support these Administration for the treatment of ED.7,8 Since then, intra-
incidental findings, Virag subsequently carried out compre- cavernous injection of alprostadil has gained worldwide
hensive studies on the effects of vasodilatory drugs on the acceptance and became a first-line treatment option in ED.
erectile tissue of the penis. Two years later, in 1982, the metho- Combinations of papaverine, phentolamine, and alprostadil
dological option to achieve and maintain an erection by intra- still remain treatment options in patients in whom mono-
cavernous application of vasoactive agents was made known therapy has failed or who suffer from significant side-effects.
to the medical public. The ability to initiate erections via Up to 1998, ICI therapy was the only effective, non-invasive
local physiological mechanisms and without sexual stimula- treatment option in ED. But the introduction of phosphodi-
tion shook up the diagnostic procedures and treatment esterase (PDE) type 5 inhibitors to the field of ED treatment
modalities of erectile dysfunction (ED) at that time, and set has challenged self-injection treatment as the first-line option.
new standards.3 Today, it has generally been downgraded to a second-line
Recognizing the widespread therapeutic opportunities of option for the majority of ED patients. Nevertheless, ICI
this method, the following decade was devoted to directed maintains its important role in diagnostic procedures and also
clinical and basic research, investigating numerous pharma- in those patients where PDE-5 inhibitors are contraindicated
cological agents with respect to their suitability for intracaver- or have turned out to be ineffective.
nous injection (ICI) therapy. In principle, all agents that
promise smooth muscle relaxation, such as papaverine,
alpha-adrenergic antagonists, prostaglandins, vasoactive intes- Pharmacology
tinal polypeptide (VIP), calcitonin gene-related peptide, and
There are three main peripherally acting drugs for intra-
nitric oxide (NO) donors (lisidomine, sodium nitroprusside)
cavernous treatment of erectile dysfunction: PGE-1, papaver-
were submitted to pharmacological investigations. Since
ine, and phentolamine. PGE-1 was the first drug approved
most of the active substances never reached the stage of
and the only drug approved worldwide for intracavernous
official approval or were even accepted for off-label use, only
administration.9,10 While widely used, combinations of papa-
three groups of drugs are currently in use for ICI: papaverine,
verine and phentolamine have not received approval outside
alpha-adrenergic antagonists (phentolamine, moxisylyte) and
Europe for treatment of ED.8,11 These drugs have in common
prostaglandin-1 (PGE-1; alprostadil). Throughout these early
that they induce erection through an increase in corporal
studies, the enormous potential of auto-injection for home
smooth muscle relaxation. Direct ICI leads to a high local
use in patients with ED became evident. While some investi-
concentration of acting agents and results in a favorable
gators focused on single substances only, Zorgniotti and
combination of local effects and systemic side-effects.
Lefleur reported the application of a mixture of papaverine
and phentolamine, which was effective in 72% of patients
treated.4 In contrast to the initial office-based injection treat- Prostaglandin E-1
ment pursued by Virag and his colleagues, these patients were PGE-1 acts via specific extracellular receptor binding, which
instructed in the technique of auto-injection. in turn stimulates the intracellular enzyme adenylate cyclase.

281
282 Textbook of Erectile Dysfunction

This causes a rise in intracellular cAMP by conversion of reduce the dosage and accompanying side-effects of each
ATP. The rise in intracellular cAMP results in smooth muscle individual drug. The ‘Bimix’ of papaverine (general dosage
relaxation via a fall in cytoplasmic calcium concentration. 7.5–45mg) plus phentolamine (general dosage 0.25–1.5mg)
has been widely used and has shown a slightly lower success
rate of 61–71% than PGE-1 alone.4 The ‘Trimix’ of papaverine
Phentolamine (8–16mg), phentolamine (0.2–0.4mg) and PGE-1 (10–20µg)
Phentolamine is a non-selective alpha-1- and alpha-2-adreno- is associated with the highest available efficacy rate of 92%.8
receptor blocker. Erection is promoted by blockade of the
tonic sympathetic neuronal activity and an increased supply
of nitric oxide (NO) via a non-adrenergic, non-cholinergic Side-effects
effect on NO synthases (NOS).
The most frequent side-effect of PGE-1 is penile pain after
injection (13–80%), which occurs more frequently at doses
Papaverine above 15µg. Combination with sodium bicarbonate or pro-
Papaverine (general dosage 20–80mg) is a non-specific PDE caine reduces these pain sensations. Prolonged erections (for
inhibitor that causes increased intracellular levels of cAMP more than about 4 hours after injection) are a rare event with
and cGMP, which in turn results in smooth muscle relaxation PGE-1, with an estimated risk of 1%; this is due to a faster
via a fall in intracellular calcium concentration. decrease in local concentration than occurs with papaverine.16
Cavernosal fibrosis occurs in 7.5–11.7% of patients using
PGE-1, but usually heals up in 50%.17 Monotherapy with
Dose finding papaverine has been abandoned, owing to its hepatotoxic
The dose depends on the etiology of the ED, and it needs to be effects and a prolonged erection rate of up to 18%. The side-
estimated initially. Severe vasculogenic ED requires higher effects of phentolamine–papaverine in combination therapy
initial doses, while administration of smaller doses promises resemble those found in papaverine monotherapy, with
therapeutic success in neurogenic and psychogenic ED. priapism in 15% and fibrosis in 12%.14

Indications and contraindications

Technique of administration
Today, ICI of vasoactive substances is considered to be a
The drug is administered with a fine needle into the side of the second-line treatment, although it has been proved to be
shaft of the penis and gently massaged throughout the shaft highly effective in the treatment of ED. It can be used both in
for 30 seconds. Erection usually occurs within a period of diagnostic and therapeutic approaches.
10–15 minutes.

Pharmacotesting
ICI of vasoactive substances is a reliable procedure to differen-
Efficacy tiate between vasculogenic and non-vasculogenic ED. In gen-
The rationale for intracavernous treatment of ED is to gain eral, a full erection after 10–15 minutes rules out severe arterial
good local efficacy with small doses, leading to fewer systemic or venous insufficiency. In order to improve the response to
side-effects. Monotherapeutic approaches as well as combina- ICI, the patient is allowed to stimulate himself if a full erection
tion treatment options are available. In addition to an imme- is not achieved or lasts only for a short time. Failure after ICI
diate therapeutic success, an increase in spontaneous erections and stimulation is a good indicator for the presence of vascu-
as a result of improved penile circulation and oxygenation logenic ED. Color Doppler imaging provides further informa-
after long-term self-injection has been described.12,13 tion for distinguishing veno-occlusive dysfunction from arterial
insufficiency. Patients with needle phobia or anxiety may not
respond to this test.18
Monotherapy
PGE-1 (general dosage 5–40µg) is the main representative of Indications
a single treatment approach. It is the most effective substance Nowadays, PDE-5 inhibitors are first-choice agents in the
in monotherapy, with a reported efficacy rate of 70–75%.14 therapy of ED. Basically, ICI is indicated if PDE-5 inhibitors
Phentolamine used alone is associated with a poor erectile fail, are not tolerated, or are contraindicated.
response, as is the case for papaverine (with a reported success
rate of 31%15). The two substances are therefore mainly used
in combination treatment. Contraindications
Common contraindications include allergies against any of the
constituent drugs (alprostadil, phentolamine, or papaverine)
Combination treatment and the presence of hematological conditions such as hyper-
The basic aim of combination therapy is to combine the dif- coagulable states or sickle cell anemia, which can lead to pro-
ferent modes of pharmacodynamic actions and thereby to longed erections.
 Intracavernosal therapy for erectile dysfunction 283

Satisfaction All of these tend to be noted as early as 6 months after ini-

tiation of the treatment and tend to become even more nota-
Men who seek professional help for treating their ED generally ble in those receiving the treatment over a longer period
have a low level of satisfaction with their sex life and this in of time.24
turn is highly predictive of their overall psychological status.19 Some of the factors responsible for dissatisfaction with or
Consequently, successful treatment enhances the level of satis- rejection of ICI are the inability to achieve adequate penile
faction with their lives, particularly regarding the sexual quality rigidity, the drugs being too expensive, the association with
of life.20 pain, needle phobia, the lack of spontaneity, return of spon-
The efficacy rate for the use of ICI in treating ED varies, taneous erection, the absence of a sexual partner, and altera-
owing to a number of factors, including the type of agent used tion in the shape of the penis.21,25 Other factors can also relate
and the age of the patient.21 Furthermore, the level of educa- to the sexual partner; the most common reason for partner
tion is associated with the degree of acceptance for receiving dissatisfaction being the inability of the partner to achieve
such a mode of treatment. The efficacy can be reviewed with adequate penile rigidity. Among further reasons mentioned
regard to different aspects, one of which is the degree of satis- were the lack of sexual desire, the above-average duration of
faction of the patient and, not less importantly, the satisfac- the erection, deterioration in the general health condition of
tion of the sexual partner. The primary efficacy criterion, the partner, and a complicated procedure.21,25 Close initial
however, is the ability of the patient to achieve a rigid erection observation and monitoring of patients is very important in
sufficient for vaginal penetration and performance of sexual order to determine the degree of patient acceptance at an early
intercourse. The degree of efficacy tends to increase the longer stage, since the high drop-out rate is registered chiefly during
the period that the ICI has been applied. A rise in efficacy the initial period of therapy.26 The level of acceptance tends to
from almost 90% in the first year to almost 96% in the fourth be higher in those who accept the treatment over a longer
year has been described.22 period of time. Furthermore, the degree of satisfaction of
ICI has met patients’ expectations in terms of efficacy, the sexual partner, together with the partner’s degree of
ease of use, tolerance, and improved sex life. All of this willingness to help, plays an important role in the degree
should encourage physicians and patients to use ICI when of acceptance. Once the treatment is accepted, adequate
PDE-5 fails inhibitor therapy, is not well tolerated, or is training and detailed medical follow-up are crucial.
contraindicated.23
Age plays an important role in the satisfaction rate of the
patient. Patients aged between 25 and 40 years tend to have
a higher rate of dissatisfaction than those over 40 years.21 Non-responders to phosphodiesterase
Table 37.1 shows satisfaction rates with different ICI thera- type 5 inhibitor therapy
pies ranging between 80.3% and 91.4%, including patients
with partial and full satisfaction. In addition, ICI is associ- The therapy of ED is a multi-modal concept with different
ated with substantial improvements in several aspects of kinds of options. A fundamental change was introduced with
quality of life; the largest improvement being in mental and the development and approval of sildenafil. Sildenafil is the
social health, including anxiety, depression, and self-esteem. oral PDE-5 inhibitor with the longest clinical experience and

Table 37.1 Satisfaction rates of different agents in ICI therapy

Satisfaction Age (median) Number of Agent Instrument Symptom score

rate in years patients

Virag et al. 84.8% Not mentioned 615 Papaverine, papaverine– Not mentioned IIEF
199146 phentolamine, ceritine
Giuliano et al. 81% 24–72 144 Alprostadil Not mentioned Not mentioned
199447 (not mentioned)
Porst et al. 91.4% 22–70 (54) 162 Alprostadil–Alfadex Not mentioned Erection
199810 assessment
score 0–3
Purvis et al. 87.4% 23–93 (56) 766 PGE-1, Papaverine– D-penn/ Not mentioned
199921 phentolamine, ‘Trimix’ BD-injectors/
OM autoinjector
Shabsigh et al. 85.1%–89.6% 30–79 111 PGE-1 Not mentioned Not mentioned
200042 (not mentioned)
Alexander et al. 78.3% 21–86 (62.1) 596 PGE-1 Not mentioned IIEF, EDITS,
200723 DAN-PSS
IIEF, International Index of Erectile Dysfunction; DAN-PSS, Danish Prostatic Symptom Score; EDITS, Erectile Dysfunction Inventory of Treatment
Satisfaction; PG, prostaglandin; OM, Owen Mumford Ltd; BD, Becton Dickinson.
284 Textbook of Erectile Dysfunction

has proved highly popular since its introduction in 1998. a failure of monotherapy.37 Mydlo et al. were also able to
Today, sildenafil, as well as vardenafil and tadalafil, is an demonstrate an improvement in erectile function in 68% of
effective first-line oral treatment for ED. Sildenafil shows a the study group with combined therapy, consisting of intra-
high efficacy–safety profile, with success rates for all etiologies corporal injection of alprostadil and administration of an
of between 50% and 80%. Patients with severe organic ED oral PDE-5 inhibitor in men with a suboptimal response to
have a bias towards oral therapy because of its non-invasive monotherapy.38 Moreover, Mazo et al. have shown that the
approach. results of ultrasonographic measurements of post-occlusive
A strong preference for PDE-5 inhibitors has been demon- changes in the diameters of cavernosal arteries after vardenafil
strated even if this therapy produces lower cumulative response administration are significantly associated with the clinical
rates of 75% than intracavernosal injection therapy.27 The efficacy of the drug in patients with arteriogenic ED.39 ICI
high burden of ED is shown in the willingness to pay for the may be capable of predicting the response to oral therapy.40
treatment. The Cologne Male Survey has demonstrated that Most of the available data on the efficacy of sildenafil are
oral treatment of ED is the preferred option.28 Approximately based on questionnaires. By using cavernosometry and Dop-
40 million patients with ED worldwide have been treated suc- pler examination and by taking penile biopsies, Wespes et al.
cessfully with the three available PDE-5 inhibitors (sildenafil, have shown that severe vascular lesions and atrophy of the
tadalafil, and vardenafil).29 To be considered ineffective, each cavernous smooth muscle are mainly observed in sildenafil
drug has to be taken at least six to 10 times with a plateau for non-responders.33
satisfaction at around the eighth dose.27,30 Shabsigh et al. have shown that PGE-1 therapy can be used
In the text below the reasons for non-response are described effectively and safely in men in whom initial therapy with
for sildenafil, because the focus in the available literature is on sildenafil fails.41 It is also a good alternative for treatment of
this particular drug. For a long time it was maintained that ED when PDE-5 inhibitors are contraindicated, especially
there were no prognostic factors that might predict success or for patients with severe cardiovascular disease.41 Moreover,
failure with sildenafil. Penile erection requires intact vascular some patients refractory to sildenafil have responded to ICI.42
structure, endothelium, smooth musculature, and nerves. The Transurethral therapy with alprostadil (MUSE – medicated
limitation of PDE-5 inhibitors lies in the fact that a minimum urethral system for erection) is an alternative non-oral therapy
level of NO is necessary. If alterations are severe, they cannot for ED. Before the development of PDE-5 inhibitors, a com-
be compensated for by PDE-5 inhibition.31 Studies have dem- parative study of MUSE and ICI showed alprostadil to be the
onstrated that progression of endothelial dysfunction and ‘gold standard’ in the management of male impotence, owing
diminished cavernosal smooth muscle content are organic to the superior efficacy and fewer side-effects of self-injection
factors that lead to end-organ dysfunction and treatment fail- therapy.43 Hatzichristou et al. have evaluated the efficacy and
ure of PDE-5 inhibitors.32 Each patient was asked to take eight preference of sildenafil or ICI in a group of impotent men
doses of sildenafil with a maximum allowed dose of 100mg currently using ICI. Sildenafil was found to be highly effective
before being considered a sildenafil non-responder.33 Andro- in 74.8% of ICI responders, although oral therapy was
gen treatment in hypogonadic patients unresponsive to any preferred by 61.2%.44
PDE-5 inhibitor therapy seems to result in an improvement of If medical treatment fails, there are non-pharmacological
erectile function.34,35 Administration of sildenafil with testos- options such as the vacuum constriction device and penile
terone has resulted in significantly better improvement of implants. Penile prosthesis implantation is considered a last
erectile function and better arterial blood flow than sildenafil resort, if all other therapies fail. New therapeutic strategies,
alone in patients with low testosterone levels.36 Additional such as anti-serotoninergic substrates and growth hormones,
pharmaceutical products that lead to activation of, or an offer promising new prospects for the therapy of ED but
increase in, cGMP, as well as alpha-adrenoceptor antagonists, remain to be evaluated. In any case, therapy of ED should be
have also been used to treat ED. A combination of sildenafil performed in an individually suited way leading to a satisfying
with PGE-1 has led to an improvement in 47–100%, following sexual life for every man affected by erectile dysfunction.30

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14. Porst H. The rationale for prostaglandin E1 in erectile failure: a challenging to treat. Int J Impot Res 2004; 16: 40–2.
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19. Gheorghiu S, Godschalk M, Gentili A, Mulligan T. Quality of life 36. Aversa A, Isidori A, Spera G. Androgens improve cavernous
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25. Lehmann K, Casella R, Blchlinger A, Gasser T. Reasons for dis- acceptance of sildenafil citrate as treatment for erectile dysfunction.
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27. Schulman CC, Shen W, Stothard DR, Schmitt H. Integrated analysis 44. Hatzichristou D, Apostolidis A, Tzortzis V, et al. Sildenafil versus
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38 Invicorp in erectile dysfunction
Michael G Wyllie and W Wallace Dinsmore

Introduction impotence.7 However, this and other studies found that

phentolamine alone could not produce an erection. This is
Invicorp is a combination of vasoactive intestinal polypeptide thought to be due to the fact that phentolamine produces a
(VIP; aviptadil) and phentolamine mesylate for intracavern- modest increase in arterial inflow, but has no effect on venous
osal injection in the management of moderate-to-severe outflow. Sufficient arterial blood supply and a functional
erectile dysfunction. VIP is a naturally occurring 28-amino veno-occlusive mechanism are prerequisites for the attainment
acid neurotransmitter present in the male genital tract,1,2 and and maintenance of a functional erection (i.e. one allowing
phentolamine mesylate is a competitive, non-selective alpha-1- intromission).
and alpha-2-adrenoreceptor blocker. VIP has a potent effect
on the veno-occlusive mechanism, but little effect on arterial
inflow,3 whereas phentolamine increases arterial blood flow Vasoactive intestinal polypeptide
without showing any impact on the veno-occlusive mecha- Following the discovery of nerves possessing VIP immunore-
nism.4 Studies using VIP in combination with phentolamine activity in the male genital tract, a putative role for VIP
1mg or 2mg led to the development of Invicorp.5 Clinical in local nervous control of the smooth muscle activity in
studies have shown that Invicorp is effective in ≥80% of men the male urogenital tract was proposed.1 Shortly thereafter,
with erectile dysfunction (ED), including those who have Willis et al. suggested that VIP plays a role as a possible neuro-
failed to respond to other therapies, and it is associated with a transmitter involved in penile erection.2,8 VIPergic nerves are
very low incidence of penile pain and virtually negligible risk densely distributed in the penis, supplying the pudendal
of priapism. arteries and the cavernous smooth muscle cells, and VIP is
Invicorp may be used from an ampoule using a standard released when erection is induced.9 When applied exoge-
syringe, or via an autoinjector designed to reduce the usual nously, VIP mimics the action of that released endogenously,
anxieties of self-injection. Invicorp is approved and marketed displaying identical pharmacological characteristics.10
in Denmark and New Zealand and is prescribed on a named- The veno-occlusion resulting from the relaxation of smooth
patient basis in the UK. We estimate that there are over muscle appears to be under the control of VIP. In human
5.9 million men in the USA alone for whom oral ED drugs are corpus cavernous smooth muscle preparations, VIP has been
not a viable treatment option and for whom Invicorp may found to act as a relaxant both in terms of spontaneous
offer a safe and effective alternative. activity and for electrically pre-contracted tissue. These results
are supported by the findings of Junemann et al., who showed
that VIP has a potent effect on increasing venous outflow
Rationale for clinical development restriction.3 Ottesen et al. demonstrated that the concentration
of VIP in cavernous blood increased up to 20-fold during
The regulation of penile erection is thought to be under penile tumescence and erection, which they attributed to local
neural control.6 The contraction and relaxation of the smooth release of the peptide since they were unable to demonstrate a
muscle inside the tunica albuginea, which keeps the penis change in peripheral concentrations.9 VIPergic nerves were
flaccid when contracted and allows it to erect when relaxed, is found to be depleted in the corpus cavernosum of impotent
regulated by increased and decreased adrenergic tone, respec- and diabetes-related impotent men.11 It therefore seemed
tively. The concomitant release of neurotransmitters, including likely that a deficiency in VIP might be responsible for ED,
VIP, may also play a role in attainment and maintenance of and this led to several investigations of VIP per se as an
the relaxed state. In the contracted state, only blood required inducing agent for penile erection. A study was undertaken by
for nutrition is circulating, whereas during sexual excitement Wagner and Gertenberg looking at the effect of VIP (1–20µg)
the smooth muscle relaxes, arteries open, the cavernous in normal men.12 The study demonstrated that VIP alone will
muscles are stretched, and the cavernous space fills with induce tumescence but not erection in normal males in doses
blood. of up to 20µg, suggesting that VIP could be the transmitter
Virag et al. demonstrated that the smooth muscle relaxant involved in relaxation of the trabecular smooth muscle and is
papaverine and the alpha-adrenoceptor antagonist (alpha- involved to a lesser degree in the dilatation of the penile artery.
blocker) phentolamine, given by intracavernosal injection, The existence of a dual neurotransmitter system in the control
can be used to induce penile erection in the treatment of of erection was postulated by these authors.

286
 Invicorp in erectile dysfunction 287

As an agent for the treatment of erectile dysfunction, the and reduce the adverse reactions associated with the
use of low doses of up to 1.2µg of VIP administered intra- latter; and
cavernously was unsuccessful,9,13 and doses up to 60µg would • it provided the missing pharmacodynamic property (com-
not induce a useful erection, even with visual or tactile stimu- pared with VIP alone) required for penile erection – namely
lation in more severely impaired patients.12 Severe facial flush- its action on smooth muscle, increasing arterial inflow.
ing was also observed at doses of 60µg and it was concluded
that the optimum dose for further investigation would be It is also now known that phentolamine when used as an
30µg, which equates to 25µg of the formulation of Invicorp intracavernosal agent in combination significantly prevents
proposed for marketing, following adjustment in relation to suppression of rigidity due to stress.17
water and acetate content.12 The first reported use of the combination of VIP with
The normal erectile process requires there to be both an phentolamine was in 1989 though the authors used only either
adequate arterial inflow and an efficient veno-occlusive mech- VIP 2µg or 4µg with phentolamine 2mg and found the com-
anism. VIP is therefore not an effective monotherapy for ED, bination to be ineffective.18 Phentolamine, in doses between
but the rationale exists for combining VIP with a substance 0.5mg and 3mg, had been established as an effective agent in
known to exert an affect on the arterial in-flow. combination with papaverine.19 The work using higher doses
of VIP in combination with phentolamine 1mg on 2mg led to
the development of Invicorp.5 This early long-term study
Phentolamine mesylate included some dose ranging and demonstrated that phento-
Phentolamine mesylate is a competitive non-selective alpha-1- lamine 0.5mg in combination with VIP was insufficiently
and alpha-2-adrenoceptor blocker with a relatively short efficacious for most patients with non-psychogenic ED, but
duration of action. Following intravenous injection its onset that phentolamine 1.0mg appeared to give a generally more
of action is rapid, the hypotensive response peaking within satisfactory response, with phentolamine 2.0mg being gener-
5 minutes and lasting only 15–30 minutes. The ease with ally effective in those cases in which 1.0 mg was ineffective.
which endogenous catecholamines can displace phentolamine The results of further (unpublished) dose-finding studies led
from the alpha-receptors accounts for the short duration to the conclusion that the combination of VIP and phento-
of action. lamine is more effective than the individual components and
Phentolamine causes vasodilatation and a fall in blood that the higher dose combinations are more effective. This
pressure as a result of two pharmacological actions; alpha- observation was confirmed by the subsequent clinical studies
blockade and a direct action on vascular smooth muscle, of Invicorp, in which the higher dose has been shown to be
suggestive of beta-receptor agonism.14 The principal alpha- required by patients with more seriously impaired erectile
adrenoceptor blocking properties of phentolamine are due to function.5,20–24
its antagonistic effects, with almost equal efficacy, at both the The dose–response observation was endorsed by an in vitro
pre- (alpha-2) and postsynaptic (alpha-1) receptors. It is the study that examined the response of stimulated excised human
latter that mediate smooth muscle relaxation.15 and rabbit corpus cavernosal smooth muscle to increasing
In the dog model, intracavernous injection resulted in a doses of both VIP and phentolamine.25 VIP caused dose-
50–100% increase in arterial blood flow without showing any dependent relaxation in both rabbit and human cavernosal
impact on the veno-occlusive mechanism,4 and in humans, tissue strips. Furthermore, alpha-adrenergic blockade with
the intracavernous injection of phentolamine 5mg resulted phentolamine potentiated this VIP-induced relaxation in a
only in penile tumescence but not rigidity.16 Phentolamine is dose-dependent manner, demonstrating a synergistic effect
therefore not suitable as monotherapy. between the two compounds in the relaxatory response. The
in vitro study, together with the dose-ranging studies, endorse
the benefits of combining VIP and phentolamine in the treat-
Combining VIP and phentolamine ment of moderate-to-severe ED. The response to VIP per se
Invicorp was developed in Denmark by the inventors was minimal at the doses selected for the combination therapy,
Fahrenkrug, Ottesen, and Gerstenberg, all of whom were and variable at higher doses. The response to phentolamine
clinicians active in the field of ED. It was initially evaluated alone was minimal in all studies regardless of dose. Therefore,
clinically by Gerstenberg and Metz working in collaboration the combination of VIP and phentolamine for the treatment of
at two separate centers and developed further by Senetek non-psychogenic ED is based on valid therapeutic principles as
PLC (California, USA). required by the Committee for Proprietary Medicinal Products
A logical step in the search for an effective and safe treat- (CPMP) note for guidance on combination products.26 Each
ment for ED was to combine VIP, which has a potent effect on component has been shown to contribute to the effect, and
the veno-occlusive mechanism but little effect on arterial the level of efficacy of the combination has been shown to
inflow,3 with an agent that had the complimentary properties. be greater than that achievable by either of the components
Phentolamine was a good candidate in that: individually.

• it is a licensed drug with a long history of use and an excel-

lent safety record even at high intravenous doses; Current regulatory status
• its off-label use in combination with papaverine was well Invicorp is approved in Denmark, where it has been marketed
documented for the treatment of ED, for which it was found by Ardana Bioscience (London, UK) since December 2006,
to reduce the requirement for high doses of papaverine and it has been prescribed on a named-patient basis in the UK
288 Textbook of Erectile Dysfunction

since mid 1995. Regulatory filings are underway in other erection-facilitating agent and intracavernosal injection results
European countries to seek pan-European approval for in tumescence or semi-rigidity, with most patients gaining full
Invicorp under the Mutual Recognition Process. Additionally, rigidity only following visual or tactile stimulation.5 This has
Invicorp has been approved in New Zealand, where it has been resulted in reports from patients that the erection achieved
marketed by Douglas Pharmaceuticals (New Zealand) since with Invicorp is much more like the normal coital cycle than
June 2004. Safety concerns raised by the US Food and Drug the action of papaverine or papaverine and phentolamine
Administration in 1999 in relation to carcinogenicity observed combination.5
in animal models with a competitor’s phentolamine mesylate Injectable therapies for ED typically have a significant
product resulted in a clinical hold being placed on Invicorp.27 advantage over oral therapies in their rapid onset of action.
The clinical hold has since been lifted following the outcome The time from injection to onset of tumescence for Invicorp
of a long-term rodent study of Invicorp; the initial carcinoge- has been reported to be 0–5 minutes in 41% of patients and
nicity observed in animal models was deemed to have no rele- 5–10 minutes in 27% of patients.23 Reports of the duration of
vance as an indicator of carcinogenic risk in humans. Invicorp erection depend on the starting point of measurement and
has been licensed to Plethora Solutions plc (London, UK) for this has varied (i.e. from tumescence or full rigidity) but is
marketing within the USA, and this company is working typically within the range 30–240 minutes,5 although this may
towards marketing Invicorp in the USA by the end of 2009. vary depending on the etiology of the ED.21 Unlike the action of
papaverine (with or without phentolamine), which results in
full rigidity until the action of the drug subsides (despite ejacu-
Clinical outcomes lation), the rigid erection resulting from Invicorp injection
and stimulation subsides to semi-rigidity or tumescence in a
Dosing more natural manner after ejaculation, but with the potential
The initial prescribing dose is Invicorp 1 (VIP 25µg and for a new erection after further sexual stimulation.5
phentolamine 1mg), which can be increased to Invicorp 2
(VIP 25µg and phentolamine 2mg) if the effect is insufficient. Achievement of grade 3 erections
Invicorp is marketed either in ampoules or as a very user-friendly
Several clinical studies have been conducted in Europe, and
single-use pre-filled autoinjector device. In the autoinjector
the published data from two large placebo-controlled phase 3
the needle is not visible before injection, therefore reducing
patient anxiety. The pre-filled, single dose design also elimi- trials are summarized in Table 38.1.21,23 Both trials had iden-
nates the need for reconstitution and so eliminates dosing tical entry criteria (1-year history of predominantly non-
psychogenic ED based on medical history) and 84% of patients
errors. The needle is so small and the injection is so rapid that
(in both trials) responded with a grade 3 erection to either
the injection is virtually painless. Injection of the medication
does not commence until the correct needle depth has been Invicorp 1 or 2 during screening. This is similar to the 80%
response reported by McMahon in a smaller pilot study,24 who
reached, reducing the possibility of subcutaneous injection.
also noted a complete response in patients with ED of neuro-
genic or psychogenic etiology, 78% response in patients with
Erection-facilitating action: duration of erection and arteriogenic ED, and 33% response in patients with ED caused
time of onset by venous leakage. It is worth noting that only patients failing
Unlike other intracavernosal injections for ED, which result in to respond to Invicorp 1 in the screening or dose-titration
full rigidity regardless of sexual stimulation, Invicorp is an phase were tested with Invicorp 2; hence, although the success

Table 38.1 Efficacy of Invicorp in patients with a history of predominantly non-psychogenic ED

Screening phase Placebo-controlled phase

Grade 3 erections (n) Patients (n) Grade 3 erections per Active agent
per patient (n) injection (n) vs placebo
comparisons

Active Placebo

Sandhu et al. Invicorp 1 204/304 (67%) 188 1417/1886 (75%) 45/373 (11%) p<0.001
199923 Invicorp 2* 55/117 (47%) 50 257/386 (67%) 8/78 (10%) p<0.001
Total 255 (84%) 238 1674/2272 (74%) 53/451 (12%) p<0.001
Dinsmore et al. Invicorp 1 155/234 (65%) 91 655/877 (75%) 21/179 (12%) p<0.001
199921 Invicorp 2† 52/108 (48%) 14 92/140 (66%) 5/28 (18%) p<0.001
Total 197 (84%) 105 747/1017 (74%) 26/207 (13%) p<0.001
Only patients failing to respond to a test dose of Invicorp 1 in the clinic and at home went on to receive the test dose of Invicorp 2 in the screen-
ing phase. Patients who did not respond to either dose of Invicorp in the screening phase did not proceed to the placebo-controlled phase.
*4 and †6 subjects tested positive to Invicorp 1 but went on to test Invicorp 2 in error.
 Invicorp in erectile dysfunction 289

rate of Invicorp 2 at around 47% in both trials appears to be formulations have found lower incidences, although a review
lower than with Invicorp 1 per se (around 65% in both trials) of 20,000 patients over 15 years reported an overall incidence
it represents success in a harder-to-treat group of patients. of 24%.31 In contrast, penile pain after injection with Invicorp
The overall success rate of Invicorp in achievement of grade 3 is negligible. There was not a single report of pain following
erection is therefore similar to published rates for other intra- Invicorp injection (using autoinjectors) in one 6-month study
cavernosal therapies.28 including 236 men21 and with only 0.5% of injections in a
Importantly, treatment success is maintained when com- 12-month study in which 2061 injections were used,23 despite
pared with placebo over a 6-month21 or 12-month23 period, ‘pain’ being one of the options available to tick in a list of
with 74% of injections resulting in grade 3 erections (out of possible side effects in both trials. In a 120-patient trial in
a total of 3285 injections in both trials combined), with no which Invicorp was compared to PGE-1 (Caverject), Invicorp,
evidence of tachyphylaxis. both in ampoules and autoinjectors, produced erections
Invicorp also appears to be particularly successful in patients without discomfort in over 75% of patients compared with
who have failed to respond to other intracavernous injections. only 37% using Caverject. Other local adverse effects
A study designed to evaluate Invicorp in patients with ED reported following Invicorp use are bruising, bleeding at the
resistant to other intracavernosal agents (including prosta- injection site, and urethral bleeding, possibly related to injec-
glandin (PG)-E1 and papaverine–phentolamine) reported an tion technique, and all typically at an incidence of <8%
overall response rate of 67% (n=47).20 This was further sup- of injections, which are similar to rates reported for placebo
ported by results from a larger study where 73% (n=71) of injections.20,21,23
patients who withdrew from previous therapies because of It is well established that intracavernosal injection may cause
poor efficacy responded to Invicorp.23 Additionally, the lack cavernosal fibrosis, particularly in the case of papaverine. In a
of any reduced effect in older patients (aged over 60 years) in meta-analysis of the literature, including 15 retrospective
two trials suggests that this patient group, who may have more studies, fibrotic changes were observed in 5.7% and 12.4% of
advanced organic impairment, are equally likely to benefit patients after papaverine, and a mixture of papaverine and
from Invicorp use.21,23 This finding is supported by the reports phentolamine, respectively.28 Fibrosis has not been reported
of patients receiving Invicorp on a compassionate use basis, with Invicorp, even following long-term use,22,29 and it also
with an 85% success rate in a group of 410 patients treated in appears that there is no progression of pre-existing Peyronie’s
the UK over a 10-year period22 and 179 patients treated in plaques during or after Invicorp therapy.5
Denmark for up to 5 years.29 In the UK group, many patients The incidence of priapism following intracavernosal therapy
had a high degree of comorbidity (28% had hypertension, has been variously reported, possibly being influenced by
26% coronary heart disease, and 26% diabetes), 49 patients the dosage used, the etiology of ED in the patient population
were over the age of 75 years, and 89% of prescriptions were reported, and the criteria adopted for the definition of
for the higher dose; Invicorp 2. priapism by different authors. Incidences for PGE-1 have
varied between 0.07%32 and 1%,33 with papaverine and phen-
tolamine combination (bimix) carrying a relatively high risk
Patient-reported outcomes of priapism (lasting longer than 6 hours) of between 2% and
In two placebo-controlled trials, overall satisfaction with the >10%, depending on the dose used.28 The only reports of
drug and the autoinjector was assessed by the patients using a priapism in published trials using Invicorp are three occurring
follow-up questionnaire.21,23 A similar questionnaire was also in 5044 injections in two large studies,21,23 equivalent to an
completed by patients and their partners on quality of life. incidence of 0.06%. There was not a single report of priapism
Overall, ≥ 85% of patients were satisfied or very satisfied with occurring in patients who have been prescribed Invicorp on
the drug and ≥ 92% were satisfied or very satisfied with the a compassionate-use basis in the UK for over 10 years.22 The
autoinjector. In terms of improvements in quality of life, ≥ 81% risk of priapism occurring with Invicorp is therefore excep-
of patients and ≥ 76% of their partners stated that their lives tionally low.
had been improved or greatly improved by the treatment.

Safety and adverse events

Conclusion
Not surprisingly, given the vasoactive properties of the com- Invicorp is a highly safe and effective treatment for ED and,
ponents, facial flushing is the most commonly experienced unlike many other ED therapies, it has no known contraindi-
adverse event following use of Invicorp and (following cations. Invicorp has shown excellent results in a wide range
direct questioning) it is typically experienced after 33–50% of of patients, in many of whom other therapies have failed, and
injections,21,23 with no significant difference between Invicorp it appears to be particularly suited to patients with moderate-
1 and Invicorp 2, but it is rarely stated as a reason for discon- to-severe ED. Other significant advantages include a rapid onset
tinuation of treatment. Other systemic side-effects are tachy- of erection after stimulation, typically within 2–5 minutes;
cardia or palpitations, headache, and dizziness, all being natural termination of the erection after ejaculation; and a
reported in ≤ 2.2% of injections.21,23 When Invicorp has been favorable safety profile. While phosphodiesterase type 5
administered in the clinic, no changes were observed in blood inhibitors will undoubtedly remain the first-line treatment
pressure or pulse rate after the injections.5 for ED, Invicorp offers an effective and safe alternative for the
Intracavernosal injection with PGE-1 produces painful erec- estimated 5.9 million men in the USA alone for whom oral ED
tions in up to 30% of cases.30 More recent studies of modern drugs are not a viable treatment option.
290 Textbook of Erectile Dysfunction

REFERENCES

1. Larsen JJ, Ottesen B, Fahrenkrug J, Fahrenkrug L. Vasoactive 18. Kiely EA, Bloom SR, Williams G. Penile response to intracavern-
intestinal polypeptide (VIP) in the male genitourinary tract: concen- osal vasoactive intestinal polypeptide alone and in combination
tration and motor effect. Invest Urol 1981; 19: 211–13. with other vasoactive agents. Br J Urol 1989; 64: 191–4.
2. Willis EA, Ottesen B, Wagner G, Sundler F, Fahrenkrug J. Vasoac- 19. Zentgraf M, Baccouche M, Junemann KP. Diagnosis and therapy of
tive intestinal polypeptide (VIP) as a putative neurotransmitter in erectile dysfunction using papaverine and phentolamine. Urol Int
penile erection. Life Sci 1983; 33: 383–91. 1988; 43: 65–75.
3. Juenemann KP, Lue TF, Luo JA, et al. The role of vasoactive intes- 20. Dinsmore WW, Alderdice DK. Vasoactive intestinal polypeptide
tinal polypeptide as a neurotransmitter in canine penile erection: a and phentolamine mesylate administered by autoinjector in the
combined in vivo and immunohistochemical study. J Urol 1987; treatment of patients with erectile dysfunction resistant to other
138: 871–7. intracavernosal agents. Br J Urol 1998; 81: 437–40.
4. Juenemann KP, Lue TF, Fournier GR Jr, Tanagho EA. Hemodynamics 21. Dinsmore WW, Gingell C, Hackett G, et al. Treating men with
of papaverine- and phentolamine-induced penile erection. J Urol predominantly nonpsychogenic erectile dysfunction with intra-
1986; 136: 158–61. cavernosal vasoactive intestinal polypeptide and phentolamine
5. Gerstenberg TC, Metz P, Ottesen B, Fahrenkrug J. Intracavernous mesylate in a novel auto-injector system: a multicentre double-
self-injection with vasoactive intestinal polypeptide and phentol- blind placebo-controlled study. BJU Int 1999; 83: 274–9.
amine in the management of erectile failure. J Urol 1992; 147: 22. Hackett G, Larsen F. Clinical experience with Invicorp at Good Hope
1277–9. Hospital ED Clinic 1996–2006. J Sex Med 2007; 4 Suppl 2: 134.
6. Giuliano FA, Rampin O, Benoit G, Jasdin A. Neural control of 23. Sandhu D, Curless E, Dean J, et al. A double blind, placebo
penile erection. Urol Clin North Am 1995; 22: 747–66. controlled study of intracavernosal vasoactive intestinal polypep-
7. Virag R, Frydman D, Legman M, Virag H. Intracavernous injection tide and phenotolamine mesylate in a novel auto-injector for the
of papaverine as a diagnostic and therapeutic method in erectile treatment of non-psychogenic erectile dysfunction. Int J Impot Res
failure. Angiology 1984; 35: 79–87. 1999; 11: 91–7.
8. Willis E, Ottesen B, Wagner G, Sundles F, Fahrenkrug J. Vasoactive 24. McMahon CG. A pilot study of the role of intracavernous injection
intestinal polypeptide (VIP) as a possible neurotransmitter involved of vasoactive intestinal peptide (VIP) and phentolamine mesylate
in penile erection. Acta Physiol Scand 1981; 113: 545–7. in the treatment of erectile dysfunction. Int J Impot Res 1996; 8:
9. Ottesen B, Wagner G, Virag R, Fahrenkrug J. Penile erection: 233–6.
possible role for vasoactive intestinal polypeptide as a neurotrans- 25. Kim N. Potentiation of VIP-induced relaxation by phentolamine in
mitter. Br Med J (Clin Res Ed) 1984; 288: 9–11. corpus cavernosum. Int J Import Res 1998; 10: A327.
10. Dixon RL. Assessment of chemicals affecting the male reproduc- 26. Committee for Proprietary Medicinal Products for Human Use.
tive system. Arch Toxicol Suppl 1984; 7: 118–27. Note for Guidance on Fixed Combination Medicinal Products.
11. Gu J, Polak JM, Lazasides M, et al. Decrease of vasoactive intesti- 1996 [cited; CPMP/CWP240/95 (Available from: http://www.emea.
nal polypeptide (VIP) in the penises from impotent men. Lancet europa.eu/pdfs/human/qwp/015596en.pdf).
1984; 2: 315–18. 27. Keijzers GB. Aviptadil (Senatek). Curr Opin Investig Drugs 2001;
12. Wagner G, Gerstenberg T. Intracavernosal injection of vasoactive 2: 545–9.
intestinal polypeptide (VIP) does not induce erection in man per se. 28. Porst H. The rationale for prostaglandin E1 in erectile failure: a
World J Urol 1987; 5: 171–2. survey of worldwide experience. J Urol 1996; 155: 802–15.
13. Roy JB, Petrone RL, Said SI. A clinical trial of intracavernous vaso- 29. Gerstenberg T. Long term use of vasopotin in the treatment of
active intestinal peptide to induce penile erection. J Urol 1990; erectile dysfunction. Int J Imp Res 1995; 7: S5.
143: 302–4. 30. Jünemann K-P, Alken P. Pharmacotherapy of erectile dysfunction:
14. Dollery CT. Clinical pharmacology of calcium antagonists. Am J a review. Int J Impot Res 1989; 1: 71–93.
Hypertens 1991; 4: 88S–95S. 31. Junemann K, Manning M, Krautschick A, Alken P. 15 years of
15. Hoffman BB, Lefkowitz RJ. Alpha-adrenergic receptor subtypes. injection therapy in erectile dysfunction. Impot Res 1996; 8: 114.
N Engl J Med 1980; 302: 1390–6. 32. Porst H, Buvat J, Meuleman E, Michal V, Wagner G. Final
16. Blum MD, Bahnson RR, Poster TN, Carter MF. Effect of local alpha- results of a prospective multicenter-study with self-injection
adrenergic blockade on human penile erection. J Urol 1985; 134: therapy with PGE1 after 4 years of follow-up. Int J Imp Res 1996;
479–81. 8: D118.
17. Nagao K, Takanami M, Li P, et al. Effect of phentolamine methylate 33. Linet OI, Ogrinc FG. Efficacy and safety of intracavernosal alpros-
in preventing stress-induced suppression of erection. Jpn J Impot tadil in men with erectile dysfunction. The Alprostadil Study
Res 1995; 10: 159–60. Group. N Engl J Med 1996; 334: 873–7.
39 Vacuum systems for
erectile dysfunction
Audrey C Rhee and Ronald W Lewis

Introduction the USA. The first shipment of the ErecAid System® was in
February 1984, with subsequent addition of the Chaney or
Continual media attention and the breakdown of sexual Safe-T-ring. Table 39.1 details the current manufacturers who
taboos have led to the population’s increasing awareness of provide VS with a prescription or are covered by Medicare.
their sexuality and, subsequently, to higher sexual expecta- In 1998, the FDA approved the over-the-counter sales of
tions. Erectile dysfunction (ED) has burst forward not only vacuum therapy devices in the USA.
into the medical field, but also into our vernacular. This is due While the VS was initially seen as a simple gadget, the med-
to the increasingly vital aging population in conjunction with ical community was eventually swayed. Drs Roy Witherington
increases in the prevalence of certain chronic disorders (such and Perry Nadig pioneered its acceptance in publications of
as diabetes and peripheral vascular disease), and a decrease in the first scientific papers regarding the VS’s efficacy and
the stigma attached to impotence. utility.5,6 The VS was considered a mainstream treatment
The urologist’s arsenal for treatment of ED has exponen- option after Dr Tom Lue’s editorial in 1991 in the Journal of
tially increased in the past four decades. Options range from Urology, in which he stated that he recommended the vacuum
androgen therapy, phosphodiesterase (PDE) inhibitors, penile erection device as first-line treatment to all his patients when
prostheses, vacuum erection devices, and injection or trans- not contraindicated.7
urethral approaches. Therapy is individualized on the basis
of the patient’s medical history, manual dexterity, expecta-
tion, social situation, and economic circumstances. In the
modern age, two therapies have gained prominence as first- Mechanisms and principles
line therapy. They are PDE inhibitors and the vacuum erection
The vacuum erection device comprises three main components
system.1 The vacuum system (VS) offers patients a non-invasive,
(Figure 39.2):
safe, and reliable option.
1. The cylinder
2. The pump
Historical perspective 3. The tension or occlusion ring.

In 1874, a physician, John King, described applying negative The cylinder is usually made of clear plastic. They are provided
vacuum pressure to the penis for ED; however, once the glass in different sizes to accommodate the variance in penile length
cylinder was removed, the penis was unable to maintain an and girth. Another option is to use an internal cylinder to
erection.2 In 1917, Dr Otto Lederer, from Vienna, Austria, modify the diameter. Larger cylinders are available by select
issued a patent for his ‘surgical device’ to produce erections companies for the patient who has significantly greater penile
with a vacuum. The product was crude and difficult to use, circumference than the cylinder will permit or for the patient
and was not accepted by his medical peers.3 who has severe angulation from Peyronie’s disease and there-
In 1960, Geddings D Osbon Sr became frustrated when told fore has difficulty removing the cylinder once the erection has
by his family physician that the only option he had regarding been obtained. Some of the cylinder models taper out distally,
his impotence was abstinence.4 He devised a vacuum erection with a nipple-like extension to attach plastic tubing to a hand-
device from a standard bicycle pump, which he converted into held vacuum pump. Others have an open end at the distal
a negative pressure pump for his personal use. Mr Osbon con- aspect to permit direct attachment of the pump.
structed a conduit to the mouth at the end of the device that The pump design also varies. Some have a one-piece unit
produced the desired ‘mouth suction’. With this modifica- with a pump handle, while others have an outer pumping
tion, he was able to market his Youth Equivalent Device®, cylinder over an inner column. There is also a battery-
which was initially sold as a marital aid and then as a medical operated pump, which was designed for patients who lack
device called ErecAid System® (Figure 39.1). Eventually, in the manual dexterity or the strength to generate the hand-
October 1982 this device obtained approval by the Food pumping motion. A majority of these pumps have a safety
and Drug Administration (FDA) for the treatment of ED in feature: a pop-off vacuum valve, which is activated after a

291
292 Textbook of Erectile Dysfunction

Shave the base of the penis for maximum results

Lubricate

Generously coat penis with water soluble

lubricant such as K–Y jelly or a good face
lotion. NO VASELINE.
While cylinder is dry, double the rubber
band in place around base of cylinder. –
Now generously lubricate bands and base
Water soluble lubricant of cylinder. Lubricated bands will push
off more easily.

Vacuum

After lubricating penis, place

cylinder over penis and hold
against body with light pressure.
Place free end of flexible tubing
in your mouth, and suck on tubing
Apply suction
(like you would a thick milk shake)
to remove air and to create a vacuum
which pulls the blood down and engorges
Vacuum the penis with blood, thus producing the
erection-like state

Retaining band

Once the firmness you need is obtained, hold suction

to maintain it, by placing tougue over end of tubing or
use the clamp provided. Do not let the vacuum escape!
When firmness is satisfactory then push rubber band off
of base of cylinder onto base of penis. Release vacuum
Slide band off and remove cylinder.

Figure 39.1 Youth Equivalent Device, later renamed the ErecAid System®, required a mouth suction apparatus in order to develop
sufficient negative pressure.

Table 39.1 Current manufacturers in the USA that

provide vacuum systems with a prescription or are
covered by Medicare

Augusta Medical System – Augusta, GA

Timm Medical Technologies – Eden Prairie, MN
Pos-T-Vac Therapy System – Dodge City, KS

certain negative pressure is produced (300–350 mmHg).

Adequate rigidity is obtained after a vacuum pressure of
90 mmHg. Once sufficient engorgement of the penis has been
reached and the tension rings have been placed around the
base of the penis, the patient should then activate the release
mechanism which releases the negative pressure.
Tension prosthesis rings come in a variety of schemes.
Initially, Osbon manufactured elastic rings, which have since
been replaced by soft-latex rings made by Timm Medical. These Figure 39.2 Three main components of the vacuum system:
occlusion bands vary in size and tension (Figure 39.3a). Some cylinder, ring, and pump. Image depicts Pos-T-Vac Therapy
rings are molded with a urethral-sparing notch along the System.
 Vacuum systems for erectile dysfunction 293

(a) (b)

(c)

Figure 39.3 Tension rings. (a) Augusta Medical Systems Ultimate tension ring. (b) Timm Medical Technologies’ Obson ErecAid
Esteem Pressure-Point™ tension ring with urethral sparing notch. (c) Augusta Medical Systems SureRelease tension ring with tear-
apart feature.

inner curve of the ventral aspect of the ring (see Figure 39.3b). penis (see Figure 39.5b). The vacuum is then released (by
The notch helps to reduce ejaculatory obstruction while main- either a valve or a button) and the cylinder is removed from
taining pressure on the corpora cavernosa. The tension rings the penis (see Figure 39.5c). The patient is ready for inter-
should provide a tab or a string to facilitate its removal after course. The occlusion bands are to be left in place no longer
use. There is also a tear-apart ring available from Augusta than 30 minutes. If the user would like to proceed with inter-
Medical System called the SureRelease (see Figure 39.3c). course after 30 minutes, he must remove the ring, allow penile
The assembly of the apparatus can be performed by the detumescence to occur, and repeat the process all over again.
patient or his partner. The proximal end of the cylinder, the The average time to obtain an erection is 2–2.5 minutes.8,9
penis, and the constriction band (or bands) need to be well The results vary with the pumping device. Of 100 patients,
lubricated with water-soluble jelly. The tension ring is then 88% obtained optimum tumescence and rigidity in 30 seconds
placed along the proximal aspect of the cylinder; some to 2 minutes.8 Intermittent pumping may be necessary to
companies provide a loading cone to facilitate its placement obtain satisfactory rigidity to permit penetration (e.g. pumping
(Figure 39.4). The cylinder is then placed firmly over the for 1–2 minutes, releasing the pressure, and then resuming
flaccid penis (Figure 39.5a). The pubic hair may need to be pumping for 3–4 minutes).4
trimmed in order to obtain an adequate seal against the pubis. Vacuum erection is different from an erection obtained
One hand should be around the cylinder to press the appa- normally. Natural erections undergo a relaxation of the sinus
ratus against the skin at the base of the penis. With the other smooth muscle within the corpora cavernosa, entrapping
hand, the patient can then begin to pump by hand or by blood. Instead, with the VS, the negative pressure applied
activating the battery-powered model. Some devices allow the to the penis transmits passive engorgement of all the tissue
user to press the distal aspect of the cylinder against a table or compartments; in conjunction with the tension rings, the
a countertop to free one hand. Once adequate rigidity has venous outflow is prevented.10 Bosshardt et al. confirmed
been obtained, the pre-loaded tension rings are slipped off the these findings, reporting the presence not only of passive
proximal end of the cylinder and seated on the base of the mixed congestion of arterial and venous blood, but also that a
294 Textbook of Erectile Dysfunction

(a)

To vacuum pump

(b)

Figure 39.4 Loading cone provided by the Pos-T-Vac Therapy

System.

large component of the increase in penile diameter was extra-

tunical tissue.11 Notably, for some patients, the erections
(especially at the glans) obtained with the VS are larger than
their natural erections.4

(c)
Patient selection and contraindications
The VS has proven to be effective in treating ED in a variety
of men. In an era in which oral therapy is considered first-line,
men who are unable to take the medications or those who do
not tolerate them can greatly benefit from the VS. Also,
patients in whom other forms of treatment for ED have failed
should be offered VS, either alone or in conjunction with
other therapies. Furthermore, even though a patient does
respond appropriately to oral, injectable, or transurethral
treatments, he may not be able to afford the prescription. This
patient population is often able to accommodate a one-time
fee for the VS. Most importantly, the patient will need to be
motivated. Those who have an understanding, well-established
relationship are more likely to have long-term success with
the device than others.9,12,13
There are absolute and relative contraindications for the
use of the VS. An absolute contraindication is if both the
Figure 39.5 Assembly and use of the vacuum system. (a) The
patient and his partner lack the manual dexterity to use the
penis is placed into the cylinder, which is pressed firmly against
device.14 Also, patients with sickle cell disease should not be the pubis while the vacuum is applied. (b) After a satisfactory
offered VS for their ED given the increased likelihood of erection is obtained, the tension ring is slipped off the cylinder
developing priapism (i.e. sickle cell crisis).7 and seated onto the base of the penis and the cylinder may be
The relative contraindications include anticoagulant uses, removed. (c) The ring maintains the erection, but must be
Peyronie’s disease, and tight foreskin.15 Patients who have removed after 30 minutes.
 Vacuum systems for erectile dysfunction 295

capillary fragility should be adequately counseled that they are Similarly, men with organic erectile dysfunction have satis-
more prone to significant subcutaneous penile bleeding when factory response rates with the VS. Adequate erections are
using the VS. If a patient has severe angulation secondary to obtained in:
Peyronie’s disease, he may not be able to use the VS owing to
the distortion of the penis when placed into the vacuum • 70% of diabetic patients;27–29
cylinder. Furthermore, men with tight foreskin may have • 93% of patients with arterial insufficiency;30–32
discomfort if they do not obtain a circumcision prior to using • 70% of patients with venous leak;30–32 and
the constriction device. • approximately 100% of patients after radical retropubic
prostatectomy.23

Results One study suggested that, as the venous leakage became more
severe, the VS was found to be more efficacious than other
There are various publications assessing both the patient and therapies.33 Among patients who have had their penile pros-
partner satisfaction with the VS. They have proven to be thesis explanted, 11 of 14 patients (3 men were reluctant to
widely effective in the treatment of ED, even with the advent try the device) had satisfactory erections and successful inter-
of PDE inhibitors.16 Erections satisfactory for penetration are course with the VS.18 Ten of the 11 patients continued to use
obtained in approximately 90% of men.6,10,17–19 Likewise, the the vacuum system regularly.
frequency of intercourse and orgasms increased, according to Psychogenic erectile dysfunction was found to be effectively
its users.20,21 treated in combination with VS and psychotherapy. Wylie et al.
Dr Perry Nadig reported long-term results of using the VS. described a trial separating two groups of patients with
The patients were separated into two groups: group 1 (short- psychogenic ED, in which one group received both a VS and
term follow up of average of 1 month) and group 2 (long- psychotherapy while the other group had psychotherapy
term follow-up of average of 29 months).22 Regular use was alone.34 Improvement in erectile function was noted in both
69% in group 1 and 70% in group 2. The overall quality of the groups; however, a greater response was noted with combined
erection scored >90% regarding the rigidity of the erection, therapy, 84% vs 60%. Segenreich et al. had similar findings,
the length of the penis, and the circumference of the penis in noting that 32% of the patients eventually achieved normal
both groups. Another clear indication of patient and partner and spontaneous erections.12
satisfaction was if the men continued usage of the VS. Nadig Patients in whom single therapy has failed can greatly
found that regular use occurred in the majority of patients benefit from combination treatment. Ten men in whom indi-
who had used the device successfully for at least 3 months; vidual therapy of either VS or injection had failed were treated
thus indicating that the drop-out rate is highest in the first 3 with simultaneous injection and vacuum modalities.35 Penile
months.22 Long-term use by the patient may plateau to strength, circumference, and buckling pressure were the
50–69% after 2 years.9,23 end-points of the study. The study concluded that while the
In 1995, Dr Roy Witherington presented the largest and VS augmented the erectile response, combination therapy was
longest follow-up available on the external vacuum device.9 found to be cumbersome by 2 of the 10 patients.
The Impotence Resource Center of the Geddings Osbon Raina et al. describe using sildenafil with VS in post-
Foundation sent out a survey to its 34,777 registered owners prostatectomy patients. A statistically significant improve-
of the Osbon products. Of the 7075 (20.3%) owners who ment was found in both rigidity and satisfaction when
responded, 5847 were considered valid, and 76% of the comparing the VS versus the VS plus sildenafil in this set of
respondents remained continuous users, with 83.5% having patients.36 Moreover, 30% of the post-prostatectomy patients
sex as often as desired. Interestingly, after obtaining and using had a return of spontaneous erections 8 months after using
the VS, 65.4% reported improved self-image and 69.6% had combination therapy.
an improvement in their relationship with their partner. While it was clear that patients may achieve sufficient
Spinal cord injury (SCI) patients have reported similar erections, it became apparent that overall patient and partner
results as the general population, with improvement not satisfaction (including effects on quality of life and marital
only in the quality of their erections, but also in their sex relationship) with the VS needed to be evaluated. Turner et al.
lives and marital relationships.24 In a pool of 13 SCI patients, reported a drop-out rate of only 20% within a 12-month
92% were able to obtain an erection rigid enough for inter- period.21 They found from their interviews that both men and
course and all 13 men would recommend the VS to other their partners were pleased with improvements in erectile
SCI patients who suffered from erectile dysfunction.25 Of quality, increased partner arousal, increased frequency of
these 13 patients, two men developed sweating; none of the orgasm, and sexual satisfaction. The VS was also associated
seven patients with T5 lesions or higher developed auto- with a decrease in general psychiatric symptomatology for
nomic dysreflexia. Watanabe et al. reported findings consis- men, increased male self-esteem, and increased martial satis-
tent with other studies, in which 28 of 85 SCI patients faction.19 The same group evaluating the partners of ED
elected to use VS as their first-line therapy.26 Particularly for patients demonstrated that the women were equally pleased
this patient population with respect to decreased penile sen- with either the injection therapy or the VS.37 The partners
sation, there is an increased risk of ischemic injury if the reported statistically significant increases in frequency of
tension ring is left on for too long, and subcutaneous hemor- intercourse, sexual arousal, coital orgasm, and sexual satisfac-
rhage may develop if the patient uses anticoagulants and tion. Furthermore, they felt more at ease in their relationships
over-vigorous suctioning.25 and characterized sex as more leisurely, relaxed, and assured.
296 Textbook of Erectile Dysfunction

Side-effects and reasons for death of a partner or loss of libido.4,23 Another 11% of men,
after using the VS, reported the spontaneous return of their
discontinuing use erections.9
In Dr Nadig’s long-term evaluation of both group 1 (n = 161)
and group 2 (n = 115) (see above),23 men reported:
Expanded applications
• pivoting of base of penis (35% in group 1, 29% in group 2)
• bruising of the penis (32%, 32%) While there is a theory that the VS may cause Peyronie’s
• penile petechiae (32%, 38%) disease, there is some thought of using the device to aid in
• pain or swelling after device use (16%, 28%) treating penile curvature.40,42 Dr Lue describes a small set of
• pain with orgasm related to the tension device (19%, 19%) patients who had severe Peyronie’s disease with penile short-
• occasional numbness (48%, 49%) ening. These patients underwent a circular venous graft to
• increased climax or orgasm (38%, 50%) treat the curvature. Postoperatively, they were instructed to
• decreased climax or orgasm (23%, 23%). use the VS daily for 1 month after surgery for what the authors
termed chronic intermittent stretching of the penis. The study
Individual patients reported that the first five effects listed suggested that using the VS helped patients to regain penile
above occurred the majority of the time that the device length after grafting.
was used; however, it was considered a major issue by fewer Another possible application of the VS is penile rehabilitation
than 6% of the patients. Notably, Nadig has stated that the after prostatectomy.43 Patients were divided into two groups:
most frequent complaint of patients is the unnatural interrup- group 1 used the VS an average of 3.9 weeks after surgery at
tion of intercourse. Partners also reported the lack of sponta- time of follow-up (9 months), and group 2 was observed with-
neity and hesitation about initiating sex as a negative aspect out any erectile aids. Spontaneous erections returned for a
of using the VS.37 similar fraction of patients in both groups; however a slightly
In some cases, partners were not pleased with how the penis greater number of these patients (17% vs 11%) had erections
becomes slightly cold to touch and becomes bluish in color rigid enough for penetration. These results suggested a possible
due to cyanosis.4 Once the occlusion bands are placed, the benefit in early intervention for post-prostatectomy patients.
drop in penile blood flow results in a decrease in penile skin This topic continues to be debated, and more studies will need
temperature of about 1°C.11 to be performed.44,45
There are case reports of more serious side-effects of using
the VS. Skin necrosis and Peyronie’s disease have resulted
from misuse of the device.38–41 To date, there has been no direct Summary
evidence that proves that the VS causes Peyronie’s disease.
Fournier’s gangrene, urethral bleeding, and herniation of the ED has become a popular focus and topic between patients
scrotal tunica vaginalis have been also been reported as rare and urologists. With this in mind, it is vital to have available
complications. both invasive and non-invasive options for this patient popu-
Many patients discontinued use of the VS for reasons unre- lation. The vacuum system offers a safe therapy that has minor
lated to side-effects. Men reported not using the VS because or rare complications and is likely to remain a significant and
of changes in their relationships – for example, divorce or successful treatment option.

REFERENCES

1. Lewis RW. Sustaining the cure. In: Broderick GA, ed. Oral Pharma- the American Urological Association New York Section Meeting,
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2. King J. The American Family Physician/Domestic Guide to Health, spheric pressure on the simian penis. J Urol 1989; 142: 1087–9.
Division I. 1874: 384. 11. Bosshardt RJ, Farwerk R, Sikora R, et al. Objective measurement of
3. Lederer O. Specification of letter patent. United States Patent the effectiveness, therapeutic success and dynamic mechanisms of
Office No 1,225,341. 8 May, 1917. the vacuum device. Br J Urol 1995; 75: 786–91.
4. Lewis RW, Witherington R. External vacuum therapy for 12. Segenreich E, Israilov SR, Shmueli J, et al. Vacuum therapy
erectile dysfunction: use and results. World J Urol 1997; 15: combined with psychotherapy for management of severe erectile
78–82. dysfunction. Eur Urol 1995; 28: 47–50.
5. Nadig PW, Ware JC, Blumoff R. Non-invasive device to produce 13. Villeneuve R, Corcos J, Carmel M. Assisted erection follow-up with
and maintain an erection-like state. Urology 1986; 27: 126–31. couples. J Sex Marital Ther 1991; 17: 94–100.
6. Witherington R. Vacuum constriction device for management of 14. Levine LA, Dimitriou RJ. Vacuum constriction and external
erectile dysfunction. J Urol 1989; 142: 729–31. erection devices in erectile dysfunction. Urol Clin North Am 2001;
7. Lue TF. Editorial comment on clinical experience of vacuum 28: 335–41.
tumescence enhancement therapy for impotence. J Urol 1991; 15. Lewis RW, Barrett DM. Modern management of male erectile
145: 1112. dysfunction. AUA Update Series 1995; 14: 162–7.
8. Sidi AA, Becher EF, Zhang G, Lewis JH. Patient acceptance of and 16. Chen J, Mabjeesh NJ, Greenstein A. Sildenafil versus the vacuum
satisfaction with an external negative pressure device for impo- erection device: patient preference. J Urol 2001; 166: 1779–81.
tence. J Urol 1990; 144: 1154–6. 17. Baltaci S, Aydos K, Kosar A, et al. Treating erectile dysfunction
9. Witherington R. Long term follow up (2–21 years) of users of exter- with a vacuum tumescence device: A retrospective analysis of
nal vacuum devices for treatment of impotence. In: Proceedings of acceptance and satisfaction. Br J Urol 1995; 76: 757–60.
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18. Moul JW, McLeod D. Negative pressure devices in the explanted 33. McMahon CG. Nonsurgical treatment of cavernosal venous
penile prosthesis population. J Urol 1989; 142: 729–31. leakage. Urology 1997; 49: 97–100.
19. Turner LA, Althof SE, Levine SB, et al. Treating erectile dysfunction 34. Wylie KR, Jones RH, Walters S. The potential benefit of vacuum
with external vacuum devices: impact upon sexual, psychological devices augmenting psychosexual therapy for erectile dysfunction:
and marital functioning. J Urol 1990; 144: 79–82. a randomized controlled trial. J Sex Marital Ther 2003; 29:
20. Bodansky HJ. Treatment of male erectile dysfunction using the 227–36.
active vacuum assist device. Diabet Med 1994; 11: 410–12. 35. Chen J, Godschalk MF, Katz PG, et al. Combining intracavernous
21. Turner LA, Althof SE, Levine SB, et al. External vacuum devices in injection and external vacuum as treatment for erectile dysfunc-
the treatment of erectile dysfunction: a one-year study of sexual tion. J Urol 1995; 153: 1476–7.
and psychosocial impact. J Sex Marital Ther 1991; 17: 81–93. 36. Raina R, Agarwal A, Allamaneni SS, et al. Sildenafil citrate and
22. Nadig PW. Six years experience with the vacuum constriction vacuum constriction device combination enhances sexual satisfac-
device. Int J Impot Res 1989; 1: 55–8. tion in erectile dysfunction after radical prostatectomy. Urology
23. Cookson MS, Nadig PW. Long-term results with vacuum constric- 2005; 65: 360–4.
tion device. J Urol 1993; 149: 290–4. 37. Althof SE, Turner LA, Levine SB, et al. Through the eyes of women:
24. Denil J, Ohl DA, Smythe C. Vacuum erection device in spinal cord the sexual and psychological responses of women to their partner’s
injured men: patient and partner satisfaction. Arch Phys Med treatment with self-injection or external vacuum therapy. J Urol
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25. Lloyd EE, Toth LL, Perkash I. Vacuum tumescence: An option for 38. Ganem JP, Lucey DT, Janosko EO, et al. Unusual complications of
spinal cord injured males with erectile dysfunction. Spinal Cord Inj the vacuum erection device. Urology 1998; 51: 627–31.
Nurs 1989; 6: 25–8. 39. Meinhardt W, Kropman RF, Lycklama à Nijeholt AA, et al. Skin
26. Watanabe T, Chancellor MB, Rivas DA, et al. Epidemiology of cur- necrosis caused by use of negative pressure device for erectile
rent treatment for sexual dysfunction in spinal cord injured men in impotence. J Urol 1990; 144: 983.
the USA model spinal cord injury centers. J Spinal Cord Med 1996; 40. Hakim LS, Munarriz RM, Kulaksizoglu H, et al. Vacuum erection
19: 186–9. associated impotence and Peyronie’s disease. J Urol 1996; 155:
27. Price DE, Cooksey G, Jehu D. The management of impotence in 534–5.
diabetic men by vacuum tumescence therapy. Diabetic Med 1991; 41. Kim JH, Carson C. Development of Peyronie’s disease with the use
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28. Kaplan FJ, Levitt NS, Stevens PJ, et al. Non-invasive management 42. Lue TF, El-Sakka A. Lengthening shortened penis caused by
of organic impotence. S Afr Med J 1995; 85: 276–8. Peyronie’s disease using circular venous grafting and daily stretching
29. Wiles PG. Successful non-invasive management of erectile impo- with a vacuum erection device. J Urol 1999; 161: 1141–4.
tence in diabetic men. BMJ 1988; 296: 161–2. 43. Raina R, Agarwal A, Ausmundon S, et al. Early use of vacuum
30. Vrijhof HJ, Delaere KP. Vacuum constriction devices in erectile constriction device follow radical prostatectomy facilitates early
dysfunction: acceptance and effectiveness in patients with impo- sexual activity and potentially earlier return of erectile function.
tence of organic or mixed etiology. Br J Urol 1994; 74: 102–5. Int J Impot Res 2006; 18: 77–81.
31. Blackard CE, Borkon WD, Lima JS, et al. Use of vacuum 44. Mulhall JP, Morgentaler A. Penile rehabilitation should become
tumescence device for impotence secondary to venous leakage. the norm for radical prostatectomy patients. J Sex Med 2007; 4:
Urology 1993; 41: 225–30. 538–43.
32. Kolettis PN, Lakin MM, Montague DK, et al. Efficacy of the 45. Wang R. Penile rehabilitation after radical prostatectomy:
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occlusive dysfunction. Urology 1995; 46: 856–8. 1085–97.
40 Integrated sex therapy: a
psychosocial–cultural perspective
integrating behavioral, cognitive, and
medical approaches
Michael A Perelman

Introduction equation.1,5,8–11 Retrospectively, it seems intrinsically obvious

that if etiology is multifaceted, treatments must incorporate
After a decade-long dialogue between sex therapists and other that knowledge! Yet that viewpoint was not initially the
sexual medicine specialists the old idea of a biopsychosocial consensus within the sexual medicine community. Now there
model is being re-adopted as conventional wisdom. The etiol- is widespread recognition that simply restoring erectile func-
ogy of erectile dysfunction (ED) is thought to be due to a tion is often insufficient in helping patients or, especially,
dynamic combination of organic and psychosocial–cultural couples to resume a satisfying sex life.8–10 However, it was
factors (PSCFs). Yet, the relative contributions of these the examination of failure, and specifically non-responder
factors continue to be debated. Fortunately, few still clung to discontinuation rates, that helped to raise greater recognition
20th-century concepts, which reported that either of these of the multifaceted etiology of ED.9,12–14
factors typically accounted for 90% of the ED etiology.1,2 Following sildenafil’s launch, close to 90% of men who
This chapter is rooted in one sex therapist’s perspective sought medical assistance for ED were treated with phospho-
regarding the etiology, diagnosis, and treatment of ED. It diesterase (PDE) type 5 inhibitors alone, with little additional
summarizes clinicians’ adaptions of biopsychosocial models counseling at all. Approximately 70% of these men reported
to optimize ED treatment for men and their partners. These improvement in quality of life15 yet discontinuation rates
approaches were types of combination treatment, which itself appeared to approach 50%.16,17 Some men tried PDE-5
has a distinguished history in medicine. An ED chapter’s inhibitors out of curiosity and never intended long-term
audience would typically be urologists and primary care use. Others discontinued ED treatments as a result of a lack of
physicians (PCPs). However, this chapter’s concepts are appli- efficacy, a fear of side effects, cost, and overall poor health.
cable to all sexual dysfunctions (SD), expanding the intended Yet, there is no question that PSCFs were also major consid-
readership to a wider range of clinicians. erations. Both patient and partner PSCFs included mental
status (e.g. depression), loss of confidence, fear of failure,
unrealistic expectations, and performance anxiety. All of these
Etiology affected treatment outcome. In addition, unconventional
sexual arousal patterns (e.g. homosexuality, sadomasochism)
Both organic and PSCFs play a role in the etiology of sexual sabotaged treatment. Over time, there were reality-based
function and SD, and consequently in the diagnosis and alterations in a partner’s sexual desirability that also affected
treatment of ED.3–6 Omnipresent psychogenic components both arousal and orgasmic response. Perhaps the most impor-
exist in most potency problems. Anxiety may even exacerbate tant PSCFs interfering with reversing ED and establishing a
a mild organic situation into total deficit. The manifest deficit satisfying sex life were relationship issues.18 While partner
frequently exceeds the actual organic impairment even in pressure was a primary driver for seeking treatment, relation-
‘organically impotent’ men. Despite the degree of organic ship issues were frequent causes of treatment discontinuation
component, ED always has a psychogenic component – even and failure.19–21
if the ED was initially caused by illness, surgery, or other
treatment.7
Shifting sexual health care delivery patterns
Furthermore, this discontinuation phenomenon occurred
The importance of failure concurrent with shifting patterns in the health care delivery.
Immediately subsequent to sildenafil’s 1998 launch, mental PCPs became the principal providers for men complaining of
health professionals and others presented at meetings and ED. Rarely were sex therapists the first to see these men, as
published about the PSCF balance in the sexual medicine medicalization hit its apex by the end of the 20th century.1

298
 Integrated sex therapy 299

Unfortunately, the sexual history obtained by these PCPs factor (or more than one) dominating, while others recede in
during their brief office visits was usually end-organ-focused. importance.
Significant PSCFs to restoration of sexual health were fre- The double-arrow signs (↔) adjacent to the ‘psychosocial–
quently unexamined. These PSCFs represented an important cultural’ and ‘physiologic and organic’ factors in Figure 40.1
cause of non-response and treatment discontinuation.22 For represent the variable valences (weighting) of these compo-
treatment to be optimized, the complexity of these obstacles nent etiologic contributors. The physical factors that both
should be understood.4,9,23 These barriers to success could be inhibit (−) and excite (+) include, but are not limited to: ana-
managed as part of the treatment, yet too few clinicians felt tomical, endocrinological, and neurological factors. For
they had the necessary training or time.8,9 How might this instance, these neurological factors can be both activated and
complex etiology be conceptualized? deactivated, actively turning on or turning off like millions of
microswitching stations. The ‘mental’ factors include various
turn-ons (+) and turn-offs (−) in the realms of psychology
The Sexual Tipping Point® (cognition, emotions, behavior), social interactions (relation-
One depiction of the role that both biogenic and PSCFs ships), and culture (contextual zeitgeist). These forces interact
play in the etiology of sexual function and SD is The Sexual with each other in a unique way that influences the nature and
Tipping Point® (STP). This etiological model provides a foun- quality of sexual capacity and experience at any moment. The
dation for a fuller understanding of the interface between balance beam symbolizes the dynamic or continuously read-
PSCFs and the medical and surgical treatments of ED (Figure justing nature of the STP. ED is a negative balance of these
40.1).22 The mind and body both inhibit and excite sexual various complementary and opposing forces (‘turn off’),
response.24 PSCFs may simultaneously excite (turn on) or reflecting the fact that positive arousal (+) factors were not
simultaneously inhibit (turn off) sexual response. Recipro- sufficient, or were overwhelmed by the negative (−) factors,
cally, organic factors, also, both excite (turn on) and inhibit mitigating erection.
(turn off) sexual response. These factors combine dynamically
in a manner that predetermines a person’s sexual readiness
or capacity. The point at which the person’s ‘turn-ons’ are Treatment
meaningfully greater than their ‘turn-offs’ is their STP. There-
fore, sexual response may be inhibited or facilitated as a Besides raising consciousness regarding the multifaceted
result of a mixture of both PSCFs and organic factors. The nature of the etiology of ED, examination of non-responder
STP is the characteristic threshold for the expression of a and discontinuation data increased research on treatment
sexual response for any individual person, which may fluctu- optimization. Initially, urologists improved efficacy and
ate dynamically within and between individuals for any given ‘salvaged failures’ by revised dosing instructions to include
sexual experience.22 That threshold is determined by multiple diet and timing, as well as dose repetition and escalation
factors for a given moment or circumstance, with one strategies.12,13 Optimization efforts were continually refined;

– Physiologic & organic factors

+ Physiologic & organic factors

– Psychosocial – cultural factors

+ Psychosocial – cultural factors

"Turn on" "Turn off"

Excite (+) Inhibit (–)

faster & greater slower & less
response response
“Hot” “Not”

The
sexual
tipping point®

Dynamic
Dynamic process
Process

Figure 40.1 The Sexual Tipping Point®: The characteristic threshold for the expression of a sexual response for any person, that may
vary within and between sexual experience. ©2006 Michael A Perelman, from reference 3.
300 Textbook of Erectile Dysfunction

Brock et al. recently published results of a first-visit treatment physician worked alone (including the use of office physician
optimization program, which incorporated a tear-off sheet, extenders) or as part of a multidisciplinary team. Besides
a brochure, and a video used to standardize and optimize assessing all needed physical findings (by examination, labo-
dosing instructions for sildenafil-naïve men seeking ED ratory testing, and so on) the physician diagnosed the patient
treatment.25 as suffering from mild, moderate, or severe obstacles to
While these approaches resulted in some improvement, it successful restoration of sexual function and satisfaction. The
was soon recognized by sex therapists that treatment optimi- physician attempted to identify the PSCFs (cognitive, behav-
zation required a more sophisticated combination treatment ioral, relational, and contextual–cultural) that were predis-
that incorporated attention to PSCFs. In fact, it was postu- posing, precipitating, and maintaining the ED. The diagnosis
lated that combining sexual pharmaceuticals and sex therapy was dynamic and continuously re-evaluated as treatment
optimized treatment and required less medication, thus progressed. The clinician continued treatment or made refer-
improving risk–benefit ratios.9 rals based on progress obtained. Perelman categorized these
PSCFs obstacles as follows:4
Combination treatment • Mild – no significant or mild obstacles to successful
Combination treatment was not new, and sexual medicine was medical treatment
not the first specialty to use this approach. In many medical • Moderate – some significant obstacles to successful
specialties, including urology, combination treatment referred medical treatment
only to a multi-drug regimen.26 Yet psychiatry had demon- • Severe – substantial or overwhelming obstacles to success-
strated the benefit of combining both psychological and ful medical treatment.
pharmaceutical treatments for many conditions.27–29 Sexual
medicine had its own history of combination treatment. Sex While no objective data determined the criteria for diagnosing
therapists in the 1990s worked adjunctively with urologists, these three categories, they provided useful guidance. For
combining intracavernosal injection, intraurethral insertion, instance, ‘severe’ usually required psychotherapeutic and/or
and vacuum tumescence therapy.11,30 Case reports and con- psychopharmacologic intervention prior to the initiation of
sensus panels summarized the evidence and strengthened the sexual pharmaceutical treatment. The treatment matrix in
argument for combination treatment for ED.4,9,11,17,23,31–34 Both Table 40.1 suggested whether physicians treated by themselves
Althof and Perelman expanded upon these strategies and or sought collaborative assistance.
recommended a combination treatment approach for office Clearly a multidisciplinary team, including a sex therapist
practices to optimize treatment outcome and satisfaction.4,14 and multiple medical specialists, could treat almost every
Their synergistic conclusions were supported by limited case, although severe cases usually require a greater number
empirical evidence, yet their recommendations continue of office visits, with lower success rates, than moderate or
gaining adherents. mild cases. However, such a team was labor-intensive and
frequently economically and geographically unrealistic. Yet,
mild and/or moderate cases reflected common scenarios for
Who, what, when, where, and how? which a solo physician could successfully treat by combining
Two alternative models for combination treatment were sex counseling with sexual pharmaceuticals. Physician diffi-
gradually adopted. First, primarily PCPs, but also urologists, culty with either moderate or severe PSCFs would lead to
added some sex education and counseling to their therapeutic referral and presumably the use of the multidisciplinary team
armamentarium. ‘Sex counseling’ in this situation made use model.
of techniques to overcome PSCF obstacles to patients’ sexual
function and satisfaction.9 Physicians did this work themselves Sex counseling tips for physicians
or used various physician extenders within their offices.14,22 In PCPs adapted the STP model within a combination treat-
the second model, physicians collaborated with non-physician ment model, in which pharmacotherapy and brief sex coach-
sex therapists, resolving ED through a co-ordinated multi- ing were combined into a more satisfactory, efficacious
disciplinary team approach to treatment.4,23,35 This author treatment.4 ‘Sex coaching for physicians’ provided a compre-
respectfully acknowledges his many outstanding physician hensive discussion for non-psychiatrist physicians on incor-
sex therapist colleagues, but has used this language because porating counseling into their office practice to enhance ED
the majority of sex therapists are non-physicians. Treatment
format varied according to the preference and expertise of
those healthcare providers. Additionally, it was influenced by Table 40.1 Psychosocial–cultural factor (PSCF) severity
the PSCF severity of the ED and by patient preference. determines ED treatment management format
These models of combination treatment4,17,23 all suggested
guidelines for managing ED that expanded, but continued to Mild Moderate Severe
match, the type of treatment algorithm described in the ‘pro-
Physician sex Frequently Often Rarely
cess of care’ model and other step-change approaches.36,37 coach
Later, Perelman advocated a model of combination treatment
Multidisciplinary Frequently Frequently Frequently
for all SD.4,32,38–41
team
Perelman recommended that clinical expertise, as well
Adapted with permission from reference 4.
as the PSCF’s complexity, determine whether the treating
 Integrated sex therapy 301

treatment efficacy and satisfaction.9 The article highlighted on the particular patient, the discussion of last sexual experi-
the following key areas of combination treatment: ence and an elaboration on current functioning will inevitably
evoke information about previous approaches the patient
• a focused sex history (sex status); attempted. The effects of such treatments should be assessed.
• partner issues; Enquiries can be made about desire, fantasy, frequency of sex,
• sexual scripts and pharmaceutical choice; and effects of drugs and alcohol.
• follow-up and therapeutic probing to manage non- The clinician should briefly screen for obvious psycho-
compliance, weaning, and discontinuation; pathology that would preclude initiation of ED treatment.
• relapse prevention; and There is a statistically significant increase in depression for
• referral. individuals with ED, and the severity should be clarified. All
patients with major depression should be queried for suicide
risk. Treatment of ED may improve mild depression, while
Focused sex history depressive symptoms might alter the effect of therapy of ED.
A focused history integrates pychosexual and medical factors A clinician’s history-taking must parse out whether the ED
in a flexible manner and can be adapted by a PCP with only is causing depression or whether the depression and its
7 minutes’ consultation time available, or by a sex therapist treatment is causing the ED.9
with 45 minutes for a patient. Treatment for ED should be
started as soon as possible, with re-evaluations based on
patient response. The successful treatment of ED requires a Partner issues
specific dataset that provides answers to three key questions The sex status frequently leads to a brief review of the current
regarding diagnosis, etiology, and treatment: relationship, which should be assessed for contextual factors
and interpersonal relationship difficulties and for whether
1. Does the patient really have ED and what is the differen- the partner has female sexual dysfunction. In reality most
tial diagnosis? physicians lack the time for a thorough evaluation of all rela-
2. What are the underlying organic and/or PSCFs? tionship issues even if the partner joins the patient for the
• What are the organic factors? office visit, which itself is not typically the case. Sensitivity to
• What are the maintaining PSCFs (e.g. current cogni- partner issues on the part of the physician is critical. However,
tions, emotions, behaviors)? despite the exhortations always to interview the partner
• Are potential ‘deeper’ PSCFs present (e.g. incest, when treating men with ED, it is partner co-operation
sexual orientation confusion, addiction)? and participation that are the key variables – not necessarily
partner attendance at the office visits.9,43
3. Are the PSCFs severe enough to require pre-treatment, or Spending an extra few minutes with the patient during the
can these factors be bypassed or treated concurrently? evaluation visit and recognizing the importance of follow-up
and referral solves this potential conundrum.
Ask the man questions about himself, but also about his
Sex status examination partner and their relationship. Evaluation of his sexual func-
The sex status is the single most important diagnostic tool at tion must also capture information about her sexual function,
the clinician’s disposal and is consistent with the ‘review of attitudes, and behavior. What is her emotional readiness for
systems’ common to all aspects of medicine.9,42 The sex status treatment? When and how should treatment be introduced?
is a summation of the patient’s current sexual desire, arousal, The average man with ED waits 2–3 years before seeking assis-
and orgasmic capacity. The details of the physical and emo- tance. By then, a new sexual equilibrium has been established
tional circumstances surrounding the onset of difficulty are within the relationship that may be resistant to change. What
important for the assessment of both physical factors and is her desire for sex? What are her concerns regarding his
PSCFs. It is informative to assess if the ED was slowly pro- safety? What are her belief systems regarding the treatment
gressing with age, rather than an acute shift. Ascertain why processes that enable coitus? Her compliance may be affected
the patient is seeking assistance at that moment in time. ‘Tell by her perception of the treatment being artificial or mechan-
me about your last sexual experience.’ This request evokes ical: ‘Is it the sildenafil, or me?’ What is her health status (vag-
descriptions of insufficient stimulation, lack of desire or inal atrophy for example) and physical readiness for sex, her
arousal, fatigue, and negative thinking.9 When does anti-sex- capacity for lubrication, and her need for stimulation? We
ual thinking emerge? Is the patient anxious about sexual fail- know that the prevalence of ED increases with age.44 We know
ure early in the day before sex is even on the horizon? Is he that older men tend to have older, postmenopausal partners.
concerned about his partner’s thoughts or is he judging him- Female sexual dysfunction is often detected in the partners
self negatively? The mind is capable of derailing normal sexual of men with ED, including urogenital atrophy, dyspareunia,
arousal as well as interfering with the restorative benefit of lack of desire, and vaginismus, which may interfere with
sexual pharmaceuticals. To function sexually, men need sexy resumption of intercourse even once his sexual capacity is
thoughts, not only adequate friction. Assess if the last sexual restored.45,46
attempt was a typical experience. What were the differences Assess whether sexual relations were ever good with the
between this experience and earlier ones. Comparisons that current partner, what changed, and what is the patient’s view
will inform the clinician of numerous etiological issues, of causation. Whether or not the problem is partner-specific
including masturbation frequency and technique. Depending needs to be determined. If the problem is partner-specific, the
302 Textbook of Erectile Dysfunction

clinician must ascertain which of several categories are rele- to evoke it. Sometimes a referral for adjunctive treatment to a
vant: inadequate sexual technique, poor communication, sex therapist may be required.9
incompatible sexual script, or no physical attraction. Screen
for severe difficulties in the couple’s relationship through
inquiry. A reassuring, ‘No one’s relationship is perfect; what Weaning and relapse prevention
do you two argue about?’ can be helpful. Additionally, moni- Generally, the concept of relapse prevention has not been
tor the degree of acrimony when the patient describes his incorporated into sexual medicine. Yet ED’s progressive
complaints. For example, is the anger, hurt, or sadness a caus- pathology may play a role in altering the threshold for response
ative factor, or are they mild emotional frustrations of daily and in a potential re-emergence of dysfunction. Additional
life? follow-up sessions help the patient to stay the course and
Fortunately, many partners of both men and women are provide an opportunity for additional treatment.9,10 These
co-operative, which partially accounts for the high success concepts are derivative of an addiction treatment model in
rates of medical and surgical interventions. Indeed, most of which intermittent but continuous care is the treatment of
the co-operation goes unexplored. The co-operation is choice. Additionally, sex therapy concepts offer potential for
assumed, based on post hoc knowledge of success. In other minimizing dose and temporarily or permanently weaning
words, serendipitous matching of sexual pharmaceutical and the medication based on severity of PSCFs and organic risk
previous sexual script equaled success: ‘we did what we used factors. Over time, the progressive exacerbation of either
to do, and it worked’.9 Many of these partners are never seen organic factors (such as endothelial disease) or PSCFs may
by the treating physician, nor is their attendance necessary for have an adverse impact on a previously successful treatment
success.4 regimen. Most physicians’ initial response was to escalate
dose and provide alternative medications. However, these
processes may be modulated by sexual counseling, provided
Sexual scripts by the physician or through referral.
Understanding the couple’s ‘sexual script’ can help the
clinician to fine-tune pharmaceutical selection, leading to
better orgasm and sexual satisfaction, not merely improved Referral, consultation, collaboration?
erection.4 This transcends, ‘try it, you’ll like it’. Knowledge of The physician’s time crunch is manageable, if counseling of
pharmacokinetics (onset, duration of action, and so on) plus the ED patient is brief. With more severe PSCFs the modal
sexual script analysis helps to optimize treatment.47 Sexual choice was a simultanous initiation of ED treatment along
script in this situation refers to style and process of the with a referral to a mental health professional. The more
couple’s pre-morbid sex life. Instructions should focus severe the PSCFs, the less likely that patient–partner educa-
on returning to previously successful sexual scripts – as if tion will successfully augment treatment, in and of itself. Inev-
medication was not a necessary part of the process. Fitting the itably, a referral would be required, albeit not necessarily
right medication based on pharmacokinetics to the couple accepted.
will increase efficacy, satisfaction, and compliance, and
will improve continuation rates. Rather than changing the
couples’ sexual style to fit the treatment, try to fit the right
medication to the couple.4
Working together: a multidisciplinary
team approach
Follow-up and therapeutic probe Having a multidimensional understanding of ED does not
Healthcare professionals can increase their success by mandate a multidisciplinary approach. A solo practitioner may
scheduling follow-up on the day they prescribe. As with any question whether to collaborate within a multidisciplinary
therapy, follow-up is essential to ensure an optimal outcome. team or whether to provide combination treatment by himself
Initial failures examined at follow-up reveal critical informa- or herself. How does one decide? If one is not inclined to
tion. The pharmaceutical acts as a therapeutic probe, illumi- counsel or is uncomfortable, consider working conjointly
nating the causes of failure or non-response.9 Retaking a with a sex therapist.4 All clinicians should be encouraged
quick sex status provides a convenient model for managing to practice to their own comfort level. Indeed, some PCPs
follow-up. Other components of the follow-up visit include will not have the expertise to diagnose PSCFs adequately,
monitoring side-effects, assessing success, and considering quite apart from their ability or willingness to treat these fac-
whether an alteration in dose or treatment is needed. A con- tors. Awareness of their own limitations will appropriately
tinuing dialogue with patients is critical to facilitate success, prompt these physicians to refer their patients for adjunctive
prevent relapse, and differentiate treatment non-responders consultation.
from biochemical failures.
Partner co-operation must be anticipated before treatment,
and follow-up provides an opportunity to confirm whether In-house multidisciplinary team
or not such co-operation is present. If co-operation is not The concept of an in-house multidisciplinary team is a simple
present, the recognition of a need for contact with the partner one: sometimes two heads are better than one. Treatment may
should increase. If the partner’s support for successful resolu- require a multidisciplinary team in cases of severe dysfunction,
tion of the ED is not present, then active steps must be taken and such dysfunction may be recalcitrant to success even in
 Integrated sex therapy 303

this ideal circumstance. There are many models for working whom initial medical treatments have failed, as well as help
together. Team approaches and composition will vary accord- patients to adjust to ‘second- and third-line’ interventions.
ing to clinician specialty training, interest, and geographic They help to make patients receptive to trying again. Sex ther-
resources. Some physicians work alone, or have set up in- apists are equipped to resolve the intrapsychic and interper-
house multidisciplinary teams in which nurses, physician sonal blocks (resistance) to restoring sexual health.9,36 They
associates, and master’s level mental health professionals are trained to manage the most difficult cases involving pro-
provide the sex counseling. This approach has obvious cess-based trauma, which may be replicated in the current
advantages and disadvantages. relationship. Sex therapists working adjunctively with a PCP
Research evidence supporting a multidisciplinary combi- or urologist could provide all the sex counseling discussed
nation treatment approach is increasing in the areas of treat- above, as well as managing PSCFs with greater therapeutic
ment optimization, adherence, and continuation. Recently, depth. Sex therapists can enhance hope, facilitate optimism,
ED patients who received sildenafil and a structured educa- and maximize placebo response. There can be an increased
tion or counseling group treatment achieved higher rates individualization of treatment format, by fine-tuning thera-
of clinical success within the first 4 weeks of therapy than a peutic suggestions, as well as improving response to medica-
sildenafil-alone cohort. However, that study was limited to tion. Sex therapists have a sophisticated appreciation of
men with ‘psychogenic’ ED.48 For men with ‘psychogenic’ ED, predisposing (constitutional and prior life-experience) factors
meta-analysis has shown that men randomized to receive and precipitating factors triggering dysfunction, and factors
group therapy plus sildenafil showed significant improve- maintaining SD. Finally, sex therapists are skilled in using
ment of successful intercourse and were less likely than cognitive–behavioral techniques for relapse prevention. All
those receiving sildenafil only to drop out.35 Yet, it is hypoth- of these issues have an impact on the potential capacity for
esized here, that men with more moderate and severe ED successful restoration of sexual health.
of mixed etiology will benefit the most from combination
treatment, which will increase continuation and optimize
outcome. A sex therapist’s perspective
What is the sex therapist’s perspective? Patients who have SD
based on deep-seated psychosocial and emotional issues may
Virtual multidisciplinary team not be amenable to simple single-agent pharmacologic thera-
In cases of more severe PSCFs, patients will be ‘referred peutics, while patients who have physical issues related to age
out’ for psychopharmacology, cognitive–behavioral therapy, or illness are unlikely to be fully helped by sex counseling
and marital therapy in various permutations, provided by exclusively. Sex therapists working together with physicians
doctoral level mental health professionals. However, typically who prescribe pharmacologic agents may be able to help
clinicians refer within their own academic institution or patients previously untreatable by counseling methods alone.4
within their own professional referral network – a kind of Reciprocally, counseling will help a physician optimize the
‘virtual’ multidisciplinary team. Endocrine, gynecologic, or efficacy of pharmaceutical treatments within the context of an
urologic referrals for the patient or partner may also be individual patient’s own STP matrix.4
required. Occasionally, the ED patient consults a sex therapist first,
Whether the referral is physician or patient initiated, sex who then refers to the physician for evaluation and treatment
therapists are ready to effectively assist in educating the patient of organic components of the patient’s ED. Given the tremen-
about maximizing response. They re-motivate people in dous success of pharmaceutical advertising in driving patients

Integrated sex therapy:

counseling & medication
– Physiological & organic factors

– Psychosocial – cultural factors

"Turn off"
+ Physiological & organic factors

+ Psychosocial – cultural factors

Inhibit (–)
"Turn on" slower, difficult &
less response
“Not”
The
erectile tipping
Excite (+) point
faster, easier &
greater response
Dynamic process
“Hot”

Figure 40.2 The elegant solution for ED. ©2006 Michael A Perelman, PhD, from reference 4.
304 Textbook of Erectile Dysfunction

to seek treatment from their PCP, this scenario is now infre- pharmaceutical non-responders provides an emerging oppor-
quent. When the patient expects the sex therapist to ‘captain’ tunity to demonstrate the robust power of an Integrated Sex
the treatment, the physician will often prescribe a phosphodi- Therapy to assist patients successfully with sexual concerns
esterase type 5 inhibitor, but only function adjunctively. What when a pharmaceutical monotherapy or polyceutical approach
is the perspective of the sex therapist in such a situation, where has failed.
the patient has usually presumed there was a preponderance
of psychosocial–cultural etiology. Sex therapists must embrace
knowledge gleaned from colleagues in urology, endocrinol- Conclusion
ogy, neurology, cardiology, gynecology, primary care, and
family practice with the same enthusiastic fervor with which A biopsychosocial–cultural model of SD provides a compel-
we chastised them earlier for not appreciating our wisdom.49 ling argument for combination treatment integrating sex
Most sex therapists recognize and appreciate the advances therapy and sexual pharmaceuticals. Restoration of lasting
in biology, gene therapy, pharmaceuticals, and other areas and satisfying sexual function requires a multidimensional
of medical science. We are beginning to unite behind a new understanding of all of the forces that created the problem,
Integrated Sex Therapy (Figure 40.2). whether a solo physician approach or a multidisciplinary team
Sex therapists need to embrace our unique ability to man- approach is used. Each clinician needs to evaluate carefully his
age complex matrices of variables, which dynamically shift the or her own competence and interests when considering the
sexual equilibrium. This requires more time than the typical treatment of a man’s ED, so that regardless of the modality
prescribers of sexual pharmaceutical agents have available used, the patient receives optimized care. For the most part,
during an office visit. Fortunately, thoughtful examination neither sex therapy nor medical–surgical interventions alone
and sustained effort while still appreciating treatment dura- are sufficient to facilitate lasting improvement and satisfac-
tion is part of the sex therapist’s legacy. Sex therapists have tion for a patient or partner suffering from ED. There will be
multiple roles as educators and counselors, but our identity new medical and surgical treatments in the future and sex
will be re-stabilized and enhanced by our unique ability to therapy can complement all of these approaches. This author
treat successfully individuals and couples who suffer from is optimistic for a future in which a combination of sex coun-
more complex PSFCs. There are an extremely high propor- seling and sexual pharmaceuticals are the normative treat-
tion of patients who discontinue pharmaceutical agents pre- ment to restore patient and partner’s sexual function and
scribed for sexual difficulties. Examining discontinuation and satisfaction.

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41 Gene therapy in erectile
dysfunction: an update
Tamer Aboushwareb, Christian Gratzke, Karl-Erik Andersson, and
George J Christ

Introduction • neural growth factors for improved neuronal innervations;

• strategies for improved vascularity, to ensure adequate
Gene therapy has undergone significant evolution since the blood flow; and
completion of the human genome project and the advent of a • modulation of second messengers, receptors, and effectors
new age of molecular medicine.1 In fact, gene therapy and of arterial and corporal smooth muscle cell tone, to ensure
gene transfer were originally regarded primarily as treatment enhanced smooth muscle responses to endogenous
options for life-threatening diseases such as cancer and stimuli.
other acquired and hereditary disorders with few effective
treatment options. For such life-threatening applications, the The vast majority of work thus far has been directly or indi-
risk–benefit ratio intrinsic to gene transfer was considered to rectly focused on the NO–cGMP–G kinase pathway, given the
be acceptable. prominent role that this pathway is known to play in the erec-
However, the recent completion of the first phase I gene tile process. Below, we review each of these, as well as the only
transfer trial for erectile dysfunction (ED)2 has opened up new clinical data available, that is, gene therapy with the human
vistas for the potential application of gene transfer to diseases large-conductance, calcium-sensitive potassium (K) channel
and disorders that have substantial impact on quality of life. (or maxi-K).
As noted in a recent editorial by Dr Arthur Caplan,3 ED can be
considered a serious medical problem as judged by a variety of
relevant criteria. Moreover, it is well established that current Gene therapy strategies that modulate
treatment options are not effective in all patients, especially the nitric oxide–cGMP pathway
patients with moderate-to-severe disease. In this scenario, it
can be forcefully argued that gene therapy clearly represents As evident from numerous laboratory investigations, as well
an ethical course of research for the treatment of ED.3 as the clinical success of sildenafil and other phosphodiesterase
Not surprisingly, the increased molecular understanding (PDE) type 5 inhibitors, it is clear that the nitrergic system
that has accompanied the genomic technological revolution plays a critical role in the normal erectile process. Thus, the
has provided important benefits for the improved under- NO synthetic pathway and biochemical cascade seems a logi-
standing, diagnosis and treatment of ED. Since the seminal cal molecular target for gene therapy.5,10,11,13–15 The approaches
preclinical publications in this area of research,4–6 many differ- tried thus far are quite diverse and are reviewed below. The
ent groups have become involved in the pursuit of gene ther- rationale is that increased expression of an important endog-
apy and transfer as effective treatment modalities for ED.4,5,7–14 enous smooth muscle relaxant–vasodilator will assist with the
In fact, a Medline search using the text words: ‘gene therapy diminished erectile response (i.e. relaxation) characteristic of
and erectile dysfunction’ revealed 99 hits, with nearly half of ED in many impotent patients.
these being review-type articles;46 all of these reports date from
the past decade.
With this backdrop in mind, the goal of this chapter is to Gene therapy with nitric oxide
provide a timely review of the preclinical strategies and recent synthase isoforms
clinical safety data that have resulted from this decade-long
research effort. In short, the strategies thus far employed have The strategy thus far has been to target one of the NO synthase
interrogated numerous distinct molecular targets in physio- (NOS) isoenzymes known to be present in the penis. The
logically relevant erectile pathways. A schematic depiction rationale for this is that, as elsewhere in the body, NOS is
of the approaches tried thus far is shown in Figure 41.1. None- responsible for synthesizing NO from L-arginine and molecu-
theless the diversity of targets can be grouped into a few more lar oxygen in the penis. There are three known NOS isoforms,
general categories. They are: and they have all been targeted:
• modulators of the nitric oxide (NO)–cGMP–G kinase • neuronal NOS [nNOS; penile neuronal NOS (PnNOS)
pathway for provision of improved erectile stimulus; in rats];16
306
 Gene therapy in erectile dysfunction: an update 307

Nerves

BDNF
Blood vessel CGRP
nNOS
SOD GDNF
Endothelial cell

eNOS Arginase
VEGF Smooth muscle cell MSC

iNOS PDE-5
PKG1 RhoA KATP
Maxi-KCa

Figure 41.1 Illustration of many of the molecular targets that have been the object of preclinical gene transfer and gene therapy
studies to date. BDNF, brain-derived neurotrophic factor; nNOS, neuronal nitric oxide (NO) synthase; CGRP, calcitonin gene-related
peptide; GDNF, glial-derived neurotrophic factor; iNOS, inducible NO synthase; PKG1, cGMP-dependent protein kinase 1; PDE,
phosphodiesterase; SOD, superoxide dismutase; VEGF, vascular endothelial-derived growth factor; eNOS, endothelial NO synthase;
MSC, mesenchymal stem cell.

• endothelial NOS (eNOS);10,11,17 and protein kinase 1 (PKG1) is probably the most important
• inducible NOS (iNOS), found in macrophages and smooth effector target for cGMP to mediate its effects on erectile
muscle cells.5,14 function. Consistent with this supposition, in rats with STZ-
induced diabetes and ED, erectile function was enhanced by
The effects observed with iNOS transfection appear as early gene transfer (Ad) of protein kinase 1-alpha.
as 2 days post-injection,14 and have now been shown to last In recent years, PnNOS (the penile-specific variant of
for up to 10 days after a single injection.5 In both cases, there nNOS) was transfected in rats using a ‘gutless’ (i.e. replication
was a statistically significant increase in the cavernous nerve incompetent) Ad vector, as well as a plasmid.13 The main goal
stimulated intracavernous pressure (ICP) response in animals of these studies was two-fold:
receiving the gene therapy treatment. Similar observations
have been made utilizing an adenovirus (Ad)–eNOS vector • to increase transfection efficiency and reduce the immu-
(i.e. a physiologically significant effect on the nerve-stimulated nogenic potential by using a modified Ad vector; and
ICP response was observed within 1 day of transfection).11 • to reduce the required viral load by increasing the transfec-
Importantly, the pharmacological responses to intracaver- tion efficiency with electroporation techniques.
nous injection of zaprinast (a cGMP PDE inhibitor) and
acetylcholine were also enhanced; again, this may indicate Comparisons with naked DNA plasmids were made in parallel.
that gene therapy can be combined with more traditional In these studies, statistically significant, and apparently physi-
forms of pharmacological therapy.18 Further supporting this, ologically relevant, in vivo effects were observed for up to
it was shown that over-expression of eNOS and cGMP in 18 days after a single injection of either plasmid–PnNOS or
combination with sildenalfil significantly increased the peak Ad–PnNOS (i.e. elevated nerve stimulated ICP responses were
ICP in the streptozotocin (STZ)-induced diabetic rat.18 More- observed). Furthermore, expression of the beta-galactosidase
over, subsequent studies by these same investigators have reporter gene was observed for up to 56 and 60 days post-
shown that the duration of Ad/eNOS gene therapy can be injection with plasmid and Ad, respectively. Thus, electropo-
extended for up to 5 days (note that longer time points were ration (i.e. application of electrical current across the injection
not examined).10 In addition, expression of the reporter site) was shown to increase both the apparent transfection
gene, beta-galactosidase using the same Ad vector lasted for efficiency and the duration of the effect of both plasmid and
up to 60 days. adenoviral-mediated gene transfer techniques.
One possible way of enhancing the effect of NO is to inhibit The main limitation to these studies with NOS gene trans-
the arginase pathway, since arginase is an enzyme competing fer may well be the relatively short duration of the physiolog-
with NO for the substrate L-arginine. By using the arginase ical effect, although it appears that the in vivo effects may be
inhibitor 2(S)-amino-6-boronohexanoic acid together with significant at later time points with a greater number of exper-
an adeno-associated virus encoding an antisense sequence to imental observations (i.e. up to 30 days, consistent with the
arginase I in the aging B6/129 mouse, Bivalacqua et al. found statistical significance of the beta-galactosidase expression
that endothelial and erectile functions could be improved, as data).13 The explanation for the relatively short duration
reflected by significant improvements of the responses to cav- of efficacy is undetermined, but may be related to either
ernous nerve stimulation.17 It is known that cGMP-dependent the presence of even the ‘gutless’ viral vector or perhaps tight
308 Textbook of Erectile Dysfunction

Table 41.1 Summary of published preclinical gene therapy studies in rats

Vector used Gene target Physiological end-points Duration of effect*

Adenovirus5 iNOS Increased ICP to NS At least 10 days

14
Adenovirus iNOS Increased ICP to NS 2 days
Adeno-myoblast14 Increased resting ICP
Adenovirus13 pNOS Increased ICP to NS ≤18 days
Plasmid 13
pNOS Increased ICP to NS ≤18 days
Adenovirus11 eNOS Increased ICP to NS, Ach and 1 day
Zapranist
Adenovirus10 eNOS Increased ICP to NS 5 days
18
Adenovirus eNOS+sildenafil Increased ICP to NS
Adenovirus42 eNOS+mesenchymal stem cells Increased ICP to NS 21 days
32
Adenovirus VEGF Increased ICP to NS 8 weeks
33
Adenovirus Ang1+VEGF165 Increased ICP to NS 8 weeks
31
Adeno-associated virus VEGF+AAV-BDNF Increased ICP to NS 4 months
Adeno-associated virus8 BDNF Increased ICP to NS 8 weeks
Herpes simplex26 GDNF Increased ICP/BP to NS 4 weeks
Herpes simplex27 NT3 Increased ICP to NS
Adeno-associated virus12 Rho A Increased resting ICP, 1 week
Increased ICP to NS
Adenovirus9 CGRP Increased ICP to NS 5 days
Naked DNA pc hSlo (maxi-K channel) Increased ICP to NS ≥3–4 months†
DNA 3.12,4,40,42,43
cDNA40 KATP channel Increased ICP/BP 1 week
cDNA 35
VIP Increased ICP to NS ≥ 2 weeks
Antisense oligonucleotides7 PDE V Increased cGMP in cultured ≤1-6 h
human corporal smooth
muscle cells
Adenovirus19 SOD Increased SOD activity and 1 day
cGMP levels
ICP, intracavernous pressure response; NS, nerve stimulation; Ach, acetylcholine; DCNF, brain-derived neurotrophic factor; CGRP, calcitonin
gene-related peptide; iNos, inducible nitric oxide (NO) synthase; pNOS, penile NOS; eNOS, endothelial NO synthase; VEGF, vascular endothelial-
derived growth factor, Ang1, angiotensin 1; AAV–BDNF, adeno associated virus–brain derived neurotrophic factor; BDNF, brain-derived neurotrophic
factors; NT3, neurotrophin 3; VIP, vasoactive intestinal peptide, PDE phosphodiesterase; SOD, superoxide dismutase.
*
Duration of effect refers to the latest time point at which a physiologically significant increase in the ICP response was measured.
†
The most recent data from our group indicate that the physiological effect on ICP lasts for up to 6 months in the aged rat model, and up to
4 months in an experimentally diabetic rat model. Also note that an increased ICP to NS refers to a statistically significant increase over that
observed in an untreated age-matched control rat. In general, the responses observed in the gene therapy treated rats were similar to those observed
in young animals.

cellular regulation of the gene product. While no adverse age-related ED as a result of enhanced inactivation of NO by
immunologic, histologic or circulatory effects were observed, oxidative stress in the aging penis.19–21 Although NO is rapidly
the potential long-term side effects of over-expression of the diffusible from nerves or endothelial cells to the neighboring
pleiotropic cytokine product (i.e. NO) are not known. Lastly, smooth muscle cells for the induction of smooth muscle relax-
the possibility of priapism seems to be a real concern with this ation, it can be scavenged by its interaction with superoxide
approach, particularly with respect to iNOS (see Table 41.1). anion (O2−) within vessel walls or corporal sinusoids to form
the toxic molecule peroxynitrite (ONOO−).22,23 The increased
levels of O2− in the endothelium and smooth muscle of aging
Superoxide dismutase gene corpora cavernosa may cause the decrease in NO bioavail-
therapy for ED ability observed in the aging penis. To test this hypothesis
Bivalacqua et al. examined the effect of adenoviral gene
Another gene transfer approach may provide a solution transfer of extracellular (EC) superoxide dismutase (SOD) to
for the reduced NO bioavailability that may contribute to the penis on O2− levels and erectile function in the aged rat.
 Gene therapy in erectile dysfunction: an update 309

Intracavernosal injection of Ad–cytomegalovirus (CMV) rats were examined in functional studies, and corporal tissue
EC-SOD (an adenoviral vector containing the EC-SOD under was harvested for histological analysis.
the control of CMV promoter) into aged rats resulted in a Briefly, these studies demonstrate that the AAV–BDNF
significant increase in erectile responses to cavernosal nerve treated group had a significantly elevated nerve stimulate ICP
stimulation, acetylcholine, and zaprinast to a magnitude response, which correlated with a significant increase in the
similar to young rats.19 In vivo adenoviral gene transfer of number of NOS-positive nerve fibers observed. However, it
EC-SOD to the penis resulted in higher expression of EC-SOD should be pointed out that the time course and magnitude of
mRNA and protein, higher SOD activity and cGMP levels, the measured ICP response was relatively modest or blunted
and lower nitrotyrosine staining. (50–60cmH2O), compared with that observed in the other
These data provide evidence in support of the hypothesis gene therapy studies reported in this chapter (which were
that ED associated with aging is related in part to an increase generally more immediate and in the 60–100cmH2O range).
in cavernosal O2− formation. Intracavernosal EC-SOD gene This may be a reflection of the intrinsic complexities of neu-
transfer reduces O2− formation, restores age-associated erec- ronal regrowth, and it is conceivable that the magnitude of the
tile function and may represent a novel therapeutic strategy increase in ICP may not be sufficient to produce an erection
for the treatment of ED.19 in this model. Nonetheless, these important initial studies do
open the door to the possibility of affecting the ‘driving force’
for erection by manipulating the innervation density. Such a
Antisense oligonucleotide therapy possibility has been previously documented on both theoreti-
cal and practical grounds,25 and it would represent a real step
with phosphodiesterase type 5 forward in the understanding and treatment of ED.26,27
Kato et al. used gene transfer with herpes simplex virus
A study was published in Chinese in 2002 indicating that
vector (HSV) expressing glial-cell-line-derived neurotrophic
transfection of cultured human corporal smooth muscle
factor (GDNF) in rats in which the cavernous nerve was bilat-
cells with antisense oligonucleotides might also be possible.7
erally injured using a clamp and dry ice.26 They found that at
While the critique of this entire paper is limited here to the
4 weeks after nerve injury, rats treated with HSV–GDNF had
abstract, it seems worth including in this review, because of its
a significant recovery of erectile function compared with rats
potential implications to the field. In that regard, antisense
treated with control vector or untreated rats. The same HSV
oligonucleotides directed to the PDE-5 isoforms was used.
was used by Bennett et al. to deliver neurotrophin-3 (NT3) to
The rationale is that the antisense oligonucleotides will
rats with STZ-induced diabetes and ED.27 They found that
base-pair with or bind to the PDE-5 mRNA and prevent
NT3 vector injected directly into the cavernous nerve sheath
translation of the protein. If true, this strategy would be
increased the mean number of nNOS-positive neurons and
expected to reduce the amount of the PDE-5 isozyme
produced a significant increase in the maximal ICP induced
available and, therefore, to increase the half-life of cGMP.
by electrical stimulation of the cavernous nerve, and they
Consistent with such a possibility, the authors reported
concluded that NT3 gene therapy may be applicable for the
increased cGMP accumulation levels 1–6 hours after transfec-
treatment of diabetes-associated ED.
tion, as detected with an enzyme-linked immunosorbent assay
(ELISA).7 Another study was recently conducted evaluating
the value of pSilencer2.1-U6-PIN-shRNA gene therapy and
concluded that it was more effective than the antisense pro- Strategies for improved vascularity:
tein inhibitor of NOS (PIN) mRNA in ameliorating ED in the gene therapy with vascular
aged rat, thereby suggesting that PIN is indeed a physiological
inhibitor of nNOS and nitrergic neurotransmission in the endothelial-derived growth factor
penis.24
An insufficient vascular supply is thought to be responsible, at
least in part, for the etiology of some ED. While it seems that
in many cases, sufficient corporal smooth muscle relaxation
Gene therapy with (i.e. intracavernous injections) can overcome this deficit,
neurotrophic factors nonetheless there is a rational basis for expecting that an
increased blood flow will aid recovery of erectile function and
The concept behind this therapeutic approach is that increas- capacity. Thus, the strategy here is to use an angiogenesis
ing the number of nerves, and thereby altering the supply side strategy to increase the vascularity of the penis to provide an
of the erectile effector equation, will restore erectile capacity. increased blood flow component to the erectile process. While
This approach would be of specific interest to address neuro- the number of patients whose ED is solely related to decreased
pathic changes that accompany age, diabetes, or radical pros- vascularity may be small, a technique that could produce
tate surgery. Lue et al. examined the ability of brain-derived more subtle increases in vascularity might prove to be pro-
neurotrophic factor (BDNF) gene therapy to restore the phylactic. Moreover, this approach is also quite distinct from
cavernous nerve-stimulated ICP response in a rat model of those described above, and is therefore worthy of consider-
neurogenic impotence.8 After undergoing a bilateral nerve- ation. In fact, vascular endothelial-derived growth factor
damage procedure (i.e. nerve freezing), rats received an intra- (VEGF) gene transfer techniques are currently being applied
cavernous injection of adeno-associated virus (AAV) vector to the treatment of other ischemic cardiovascular diseases
containing the BDNF gene. At 4 and 8 weeks post-injection, such as myocardial ischemia.28
310 Textbook of Erectile Dysfunction

In addition, another recent study has characterized the ICP response to a level equivalent to that of young animals.9
VEGF isoforms present in the corpora of humans and rats.29 This effect lasted for up to 5 days, although longer time points
Furthermore, consistent with the aforementioned observa- were not examined. As such, the precise duration of the effects
tions, the direct intracorporal injection of VEGF in a rat model of this therapy is unknown, but it nonetheless appears that
of vascular insufficiency had restorative effects on the nerve- this may represent an attractive therapeutic possibility. The
stimulated ICP response,29–33 and has clearly provided ‘proof potential long-term side-effects, if any, are also not known.
of concept’ for this approach.19 Importantly, there were no detectable effects of CGRP over-
However, Dr Lue and colleagues were the first to expression on resting ICP or blood pressure in this series of
provide preclinical data supporting a potential role for experiments.
VEGF gene transfer to the amelioration of ED. In two Vasoactive intestinal polypeptide (VIP) is another endoge-
different studies, the San Francisco group illustrated the nous smooth muscle cell relaxing agent that has long been
ability of an AAV–VEGF construct to mitigate the degree of thought to be a potentially important neurotransmitter for
ED observed in rodent models of atherosclerosis and veno- penile erection. In a recent investigation Shen et al. injected
occlusive dysfunction. In both instances, intracavernous pcDNA3/VIP naked DNA intracorporally in STZ-diabetic
injection of AAV–VEGF was associated with detectable rats after 10 weeks of established diabetes.35 In short, the
remodeling of the penile erectile tissue, and corresponding nerve-stimulated ICP responses were significantly elevated
enhancements in the cavernous nerve stimulated ICP response in the STZ-diabetic rats that received the VIP cDNA to levels
(Table 41.1). that appear sufficient to restore penile erection in this animal
In another recent study, Ryu et al. showed that combina- model. Importantly, elevated levels of VIP were found only
tion gene transfer with angiogenic factors, in this case, in the penile erectile tissue, and not in liver, kidney, or aorta.
angiopoietin-1 and VEGF, may provide an even more favor- These effects lasted up to 14 days post-injection, the last
able outcome for the treatment of atherosclerosis-related time point examined. Taken together, these two preclinical
ED.33 While details of the time course and magnitude of the studies certainly document that modulation of the cAMP
increased or altered vascularity observed at the histological pathway is also a potentially effective strategy for the treat-
level are still lacking, taken together these data are consistent ment of ED.
with the supposition that gene-based approaches using
angiogenic factors may be useful in the treatment of ED. The
potential pleiotropic actions of this cytokine on multiple
cell types (as mentioned for NO above) may provide a signifi- Gene therapy of RhoA: alterations
cant clinical barrier.34 Certainly then, this would also be con- in calcium sensitization
sidered to be in the supply-side category of gene transfer
techniques. Calcium sensitization refers to the ability of corporal smooth
muscle cells to maintain a tonic contraction in the face of
near-resting intracellular calcium levels. Presumably the
RhoA–Rho-kinase pathway plays a major role in this process.
Modulation of second messengers, In fact, calcium-sensitization mechanisms represent an
receptors, and effectors of arterial important component to the tonic contraction of corporal
and corporal smooth muscle cell smooth muscle, and thus, flaccidity.12 In a first attempt to
target this system using gene-based approaches, the investiga-
tone: gene therapy with modulators tors transfected the corpora with a dominant-negative mutant
of the cAMP pathway of RhoA. The goal was to increase competition between the
endogenously expressed RhoA isoforms and the nonfunc-
While NO is clearly a major modulator of erectile capacity tional RhoA mutant. In these studies both endogenous RhoA
and function in the normal penis, it is well known that and Rho-kinase expression were unaltered by the presence of
other vasorelaxants are also present and potentially relevant to the RhoA mutant. As expected, transfection with the RhoA
erectile function. Among the possible suspects, calcitonin mutant using an AAV vector (see Table 41.1 for details) was
gene-related peptide (CGRP) has long been hypothesized to associated with a decreased phosphorylation of the regulatory
be such a compound. CGRP is an effector of erectile capacity subunit of the myosin light-chain phosphatase, consistent
by virtue of its ability to produce a receptor-mediated increase with a decrease in calcium sensitization (i.e. an inhibition of
in intracellular cAMP levels, and a concomitant cellular hyper- an inhibition), nominally anticipated to produce a lower
polarization via increased K+ channel activity. The therapeutic degree of corporal smooth muscle cell tone. In line with the
rationale applied here is similar to that described above suspected mechanism of action, there was an approximately
for the NO cascade, and involves increasing expression of two-fold increase in basal ICP and, moreover, a significant
CGRP in order to enhance the cAMP-mediated relaxation increase in the cavernous nerve-stimulated ICP response (the
response in aged rats, thus ameliorating the age-related decline ICP:blood pressure ratio approximated unity at the highest
in the nerve-stimulated ICP response. Using an adenoviral- levels of stimulation). No effects were observed on mean arte-
mediated delivery system, Bivalacqua et al. were able to docu- rial pressure, and there was no evidence of an inflammatory
ment that over-expression of CGRP reversed the age-related response or other side-effects at the 1-week time point in these
decline in CGRP and cAMP concentrations in the rat corpora, initial studies. The efficacy and side-effect profile of longer
and moreover, produced an increase in the nerve stimulated time points are currently unknown. Nonetheless, this report
 Gene therapy in erectile dysfunction: an update 311

clearly shows the importance of this pathway to the erectile Cell-based gene therapy
process, and moreover, indicates that genetic modification of
this pathway can produce quite robust and physiologically All of the approaches described thus far involve genetically
relevant alterations in erectile function and capacity. modifying the extant cells in the corpora. Another possibility
is the re-implantation of genetically modified cells into the
corpus cavernosum. The strategy here is to ‘seed’ the penis
with cells having the desired, genetically modified, physiolog-
Gene therapy with ical characteristics. Wessells and Williams have established
potassium channels the feasibility of utilizing autologous transplantation of
endothelial cells into the corpus cavernosum of the rat.44 The
K+ channels provide an important mechanism for the regula- next step would be to endow these cells with the desired
tion of corporal smooth muscle cell tone36–40 and, moreover, genetic characteristics ex vivo, prior to their re-implantation
represent a convergence point for mediating the effects of a in vivo. A similar approach, also in the rat model, has docu-
wide array of endogenous neurotransmitters, neuromodula- mented the feasibility of using iNOS adenoviral-transfected
tors, and hormones. Thus, K+ channels represent an attractive myoblasts as the delivery vehicle.14 In this latter instance,
therapeutic target for the treatment of ED.36 Thus far the increases in the nerve-stimulated ICP response were observed
majority of data and efforts derive from gene transfer with the (Table 41.1). In this scenario, the newly seeded cells provide
alpha-, or pore-forming, subunit of the human large conduc- an additional reservoir or supply of endogenous vasorelax-
tance, calcium-sensitive K+ channel (KCa or maxi-K channel), ants. With the currently contemplated approaches then, the
referred to here as hSlo.36,41 In this regard, while the KCa chan- end-result should be a diminished baseline corporal smooth
nel represents the primary focus of our efforts to date, unpub- muscle cell tone or an enhanced supply of vasorelaxants (or
lished data from our group also indicate that gene transfer both).
with the alpha-subunit of another important K+ channel sub- Bivalacqua et al. have shown the same experience with cell-
type, namely Kir6.236 might also restore diminished erectile based therapy utilizing the endothelial cells both alone and
capacity in the aged rat model. ex-vivo gene modified with eNOS.45 They illustrated that the
Consistent with this supposition, another recent report has results obtained from both techniques were statistically better
also utilized a similar strategy with the metabolically regulated than controls up to 21 days post-transplantation; however,
K+ channel (i.e. KATP).40 The rationale behind ion channel gene the ex vivo modified cells have shown improvement to the
therapy is based on the tight link between K+ channel activity, erectile function as early as 7 days post-transplantation. Most
transmembrane calcium flux through voltage-dependent recently, intracavernous injection of e-NOS-modified synge-
calcium channels, and corporal smooth muscle cell tone.4,36–39 nic rat mesenchymal stem cells (bone marrow) was docu-
Specifically, over-expression of hSlo in corporal smooth mus- mented to improve the erectile response in aged rats at 7 days
cle cells is presumed to increase the hyperpolarizing ability of and 21 days after injection.45 This increase in erectile function
the syncytial corporal smooth muscle cell network, and by so was associated with increased eNOS protein, NOS activity,
doing, increase the responsiveness of the erectile apparatus to and cGMP levels. These results suggest that combining the
a nominally diminished supply of endogenous smooth muscle cell-based therapy and gene transfer therapy may be a suitable
relaxants (a similar rationale would apply to the KATP chan- alternative for future work.
nel). In any case, the physiological end-point is restoration of Questions remain concerning the long-term viability of
a degree of corporal smooth muscle relaxation sufficient to autologously transplanted cells in the corpus cavernosum.
result in normal penile erection. The evidence consistent with Certainly, this is another exciting approach that would open
this supposition has been recently reviewed.4,36–39 Of note is up additional therapeutic possibilities, and would fall into the
the fact that the gene product, namely, the maxi-K channel, supply-side category of gene transfer techniques.
apparently exhibits little or no activity in the corporal smooth
muscle cell during flaccidity4,36,37 but becomes robustly acti-
vated by the endogenous erectile second messenger pathways Human clinical data
during tumescence.
Consistent with the fact that hSlo has little impact on The ultimate goal of all of these approaches is to apply the
baseline corporal smooth muscle activity, no evidence for findings to improve the treatment of ED in humans. In this
the possibility of priapism (i.e. increased resting ICP) has regard, the first human clinical trial of gene transfer for the
been observed in our preclinical work to date, nor in the treatment of ED has recently been completed.2 In this semi-
recently completed phase 1 clinical trial.2 Moreover, as with nal dose-escalation safety study 11 patients with moderate-to-
other gene therapy approaches discussed in this chapter, severe ED were given a single-dose corpus cavernosum
there is apparently no pathologic effect on corporal tissue injection of hMaxi-K, a ‘naked’ DNA plasmid carrying the
histology or architecture (i.e. no inflammatory or immune human cDNA encoding hSlo (for human slow-poke), the
response), or on mean arterial blood pressure. Another gene for the alpha-, or pore-forming, subunit of the human
advantage of this gene therapy approach is the apparent lon- smooth muscle maxi-K channel. More specifically, 3 patients
gevity of exogenous gene expression. Published reports indi- were each given hMaxi-K 500 µg, 1000 µg, and 5000 µg, and
cate that the physiologic effects of a single intracorporal 2 patients were given hMaxi-K 7500 µg, and followed for
injection of hSlo–pcDNA (‘naked DNA’) can last for up to 6 months. As always, the primary end-point of this phase 1
4–6 months.42,43 study was safety. Importantly, no serious adverse events or
312 Textbook of Erectile Dysfunction

dose-related adverse events attributed to gene transfer were Conclusion

observed for any patient at any dose during any study visit.
Moreover, no clinically significant changes from baseline Clearly, all of the preclinical data collected to date are very
were seen in physical evaluations (general and genitourinary) encouraging, and the work of Melman and colleagues55 is
or in hematology, chemistry, or hormone analyses. There equally ground breaking and encouraging in the clinical
were no cardiac events, as determined by repeated electrocar- arena. As one looks to the future, from a clinical standpoint,
diograms, and no plasmid was detected in the semen of some of the major advantages of further advancing gene-based
patients at any time after the injections. In addition, second- treatments for ED are:
ary efficacy end-points were measured using the Interna-
• the potential for restoration of normal organ function
tional Index of Erectile Function (IIEF) scale, with patient
in the absence of the necessity for any other form of
responses validated by partner responses. In this regard, one
therapy;
patient at each of the two highest doses of hMaxi-K (i.e.
• elimination of the need to ‘plan’ for sex (i.e. it would
5000 µg and 7500 µg doses) had apparently sustained improve-
represent an ‘on-demand’ therapy); and
ments in erectile function as indicated by improved IIEF
• the possibility of combination therapy with currently
erectile function domain scores over the length of the study.
existing pharmacological approaches.
In fact, these patients reported erectile function category
improvements that were highly clinically significant and This approach would reduce the required doses of oral
maintained throughout the 24 weeks of study. While efficacy medications, thus increasing their efficacy and nominally
conclusions cannot be drawn from results of a phase 1 trial decreasing their side effect profile.
without a control group, these initial safety data are indeed As discussed in detail elsewhere, for any and all of the
encouraging and, furthermore, these indications, albeit pre- aforementioned reasons, the continued preclinical and clini-
liminary, of effectiveness suggest that hMaxi-K gene transfer cal success of gene therapy and transfer would represent a
may be a viable approach to the treatment of ED. Clearly huge step forward in the treatment of ED in particular.24,46–55
further clinical investigation is both required and justified. Lastly, the success of any gene therapy protocol would open
Nonetheless, these exciting data represent a major step toward the door to the possibility of new treatments for a wide range
bringing the age of molecular medicine to bear on the of human smooth muscle disorders (e.g. urinary incontinence,
treatment of ED. irritable bowel disorders, asthma, premature labor).

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42 Stem and endothelial progenitor cells
in erectile biology: future therapeutic
applications and potential biomarker
for erectile dysfunction
Trinity J Bivalacqua, Travis D Strong, Hunter C Champion, and
Arthur L Burnett

Background development of new approaches, including gene and cell-

based therapies for the treatment of ED.14 Therapeutic strate-
The Massachusetts Male Aging Study (MMAS), a substantial gies for ED that aim at rejuvenating dysfunctional cells
epidemiological survey that quantified the prevalence of erec- (endothelium) or replacing lost or critically damaged cells
tile dysfunction (ED) in a non-institutionalized population of (nerves, smooth muscle) would be of immense value. Addi-
men in the Boston area, revealed that 52% of 1290 men aged tionally, early diagnosis with the use of biomarkers for high-
40–70 years had some degree of ED.1 Additional studies have risk ED patients has been advocated in order to select patients
estimated that the worldwide incidence of ED will increase that are at greatest risk for cardiovascular disease as well
from 152 million men in 1995 to 322 million men by the year as patients who would benefit most from PDE-5 inhibitor
2025.2 Vascular disease is a major cause of ED, and several therapy.
cardiovascular risk factors such as smoking, aging, hyperlipi-
demia, diabetes, and hypertension are strongly correlated to
ED.3,4 Injury to the cavernous nerves during pelvic surgeries Fundamentals of cell-based therapies
(e.g. radical prostatectomy, radical cystoprostatectomy) is the for erectile dysfunction
cause of an appreciable number of ED cases as well.5
In order to achieve penile tumescence, smooth muscle The long-term goal for the treatment of any disease process is
within the corporal sinusoids must relax and dilate. In the to identify molecular correlates involved in the pathophysiol-
flaccid state, the contractile machinery of penile smooth ogy of disease, and use this information to develop novel and
muscle is tonically activated, thus decreasing luminal space more effective therapeutics. Gene and cell-based therapies
and prohibiting engorgement.6 Nitric oxide (NO) is now provide attractive therapeutic possibilities for the treatment of
understood to be a key mediator in diminishing penile ED because selective genes of interest that are involved in
smooth muscle tone by increasing the production of cGMP neural degeneration and penile vascular dysfunction can
(Figure 42.1).7,8 In turn, cGMP activates a cGMP-dependent be targeted.14,15 In most men only a small alteration in the
protein kinase (PKG), which phosphorylates and activates balance between contracting and relaxing stimuli can cause
downstream promoters of vasodilatation.9 Upon neurogenic significant effects on corporal and penile vascular smooth
stimulation, NO is released from nitrergic axons and acts muscle tone.15 Thus, transfer of a therapeutic gene product
to initiate an erection.10 As engorgement begins, shear into the penis via non-viral and viral vectors, as well as
stress within the penile vasculature activates the production cells alone or genes modified ex vivo, may restore impaired
of endothelial-derived NO, a critical component in the erectile function. Using gene and cell-based therapies, erectile
maintenance of erection.11 function can be modulated and potentially restored by
Basic science research on erectile physiology has focused on altering the physiological supply and demand of the erectile
the pathogenesis of ED and has provided convincing evidence apparatus.
that ED is predominately a disease of vascular etiology. Phos- Recently, the emerging concept of the use of stem cells
phodiesterase (PDE) type 5 inhibitors are first-line pharmaco- for the treatment of severe neurogenic and penile vascular
therapies for the treatment of ED because of their high efficacy dysfunction has gained substantial attention.16–22 This
rate in a diverse population of patients.12,13 Although PDE-5 approach has so far yielded encouraging results for treating
inhibitors are effective, these oral medications have failed in both vasculogenic and neurogenic ED. By rejuvenating
certain disease states, such as diabetes, post-prostatectomy or replacing defective penile tissues with stem cells, it is con-
ED, and severe vascular dysfunction. This has resulted in the ceivable that cell-based therapies could result in permanent

314
 Stem and endothelial progenitor cells for erectile dysfunction 315

comprising all three embryonic layers: endoderm, mesoderm,

L-Arginine
and ectoderm.26 Embryonic stem cells are the most widely
acknowledged example of pluripotent cells. Lineage-restricted
potency (and loss of unlimited self-renewal) is a feature of
eNOS nNOS multipotent, tissue-resident stem cells such as hematopoietic
stem cells residing in the bone marrow.27 With yet more lim-
ited differentiation potential, the term ‘progenitor cells’ is
NO loosely used in the literature to refer to cells capable of becom-
ing one or a small number of related cells.28

Guanylate cyclase
Definition of endothelial progenitor cells
In 1997, the apparent detection of endothelial progenitor
GTP cells (EPCs) circulating within human blood was identified.
cGMP PKG Asahara et al. showed that under specific culturing conditions
peripheral blood mononuclear cells (PBMCs) enriched for
GMP
CD34+ could ostensibly differentiate into endothelial-like
cells.29 Consistent with mature endothelial cells, these cells
expressed the endothelial markers CD31, CD34, vascular
PDE-5 Penile endothelial growth factor receptor 2 (VEGFR2, Tie-2), and
erection eNOS and formed vessel-like structures in Matrigel.29 These
data suggested the existence of a population of circulating,
bone-marrow-derived (BMD) cells that can differentiate into
Figure 42.1 Molecular determinants of the nitric oxide (NO) mature endothelial cells under particular stimuli.
signal transduction pathway involved in normal erection By methods that are still becoming elucidated, BMD EPCs
physiology. NO is synthesized upon sexual stimulation by the are stimulated by various cytokines to emigrate from the bone
catalytic actions of neuronal NOS (nNOS) and endothelial NOS
marrow to sites of tissue stress such as occurs in hypoxia.30
(eNOS) from its precursor L-arginine and diffuses locally to
Within the hypoxic vasculature, EPCs bind to the endothe-
corporal smooth muscle cells, where it activates guanylate
cyclase, which then converts 5′-GTP to 3′,5′-cGMP. In turn, lium in an antigen-dependent manner and secrete angiogenic
cGMP activates cGMP-specific protein kinase 1 (PKG), which factors, incorporate themselves within the endothelium, or
acts through downstream effectors to produce erection. perhaps extravasate into the extracellular matrix and form
Degradation of cGMP occurs by the catalytic action of blood vessels de novo.31 The discovery of EPCs circulating
phosphodiesterase (PDE) type 5, after which GTP is reformed. within the blood spurred a very rapid, and greatly premature
to some, advancement to clinical trials.32 A litany of clinical
trials has provided evidence that either unfiltered PBMCs or
functional restoration. Such a potential outcome stands in PBMCs enriched for EPC characteristics can, in some cases,
stark contrast to current therapies, which require continuous increase neoangiogenesis, improve endothelial function, and
intervention. Stem cell-based therapy may also offer an option positively affect clinical outcomes.33 Since ED is often a mani-
for those men with presentations of ED unresponsive to festation of endothelial dysfunction in the penis, the use of
currently available medications (PDE-5 non-responders). EPC as a therapeutic intervention or as a potential biomarker
has been advocated (see below).
Definition of stem cells
Because cell senescence and degeneration increases with time,
older people are acutely prone to cell loss and consequent
Preclinical evidence for the use of
disease.23 In this cell population, pharmacological agents may cell-based therapies for vasculogenic
be largely ineffectual at stimulating the inherent regenerative erectile dysfunction
capacity of the failing tissue. It is evident that in many condi-
tions an alternative to drug therapy is needed, which focuses Gene therapy, although effective in animal models of ED as a
on the transplantation of healthy donor cells or the restora- more lasting approach, carries substantial risks of random
tion of tissue-resident stem cells, which may then repopulate transgene expression and inflammatory effects.34 As a result,
and functionally improve compromised tissues. the most likely application for gene-based therapies may be
Stem cells are by definition capable of self-renewal, differ- the ex vivo manipulation of cells prior to transplantation.
entiation into one or more phenotypes, and functional repro- Gene- and cell-based therapies may thus act synergistically.
duction of the damaged tissue.24 The differentiation capacity With or without concurrent genetic modifications, cell-based
of stem cells falls along a gradient of potency. Restricted to approaches may offer significant benefits over both in vivo
early development, totipotent cells are those with the capacity gene therapy and pharmacological agents (Table 42.1).
to differentiate into not only all the cells of an organism, but Cell-based therapies can be used to replace dysfunctional or
also the extra-embryonic tissues.25 Pluripotent stem cells are dying cells in a way that may obviate the need to comprehend
capable of giving rise to every cell phenotype of the adult, thus the subtle pathological deviations in molecular pathways
316 Textbook of Erectile Dysfunction

Table 42.1 Comparisons among current treatment strategies for erectile dysfunction

Pharmacotherapy Gene therapy Cell-based therapy

Efficacy Effective in a diverse population of Effective in animal Effective in animal models

patients, but ineffective for an appreciable models
population (diabetes, post-radical
prostatectomy, severe vasculogenic
erectile dysfunction)
Duration of Ephemeral Moderate duration Potentially extensive duration
effect (weeks to months) (months to years)
Invasiveness Oral, sublingual, intracavernous, Intracavernous or Intracavernous or intravenous
intrauretheral intravenous delivery delivery; intravenous drug
delivery to mobilize endogenous
stem cells
Risks Relatively minor Random transgene Unregulated cell division;
expression; unintended phenotypic
inflammatory differentiation
response

Table 42.2 Summary of recent efforts involving stem cell treatment for erectile dysfunction

Stem cell type and Source of cells Model of Donor cell Functional
reference erectile dysfunction differentiation improvement?

Neural embryonic stem Syngeneic embryonic Bilateral cavernosal Not determined, but Yes (3 months)
cells16 stem cells nerve crush in rats neurons suspected
Muscle-derived stem Skeletal muscle of Bilateral cavernosal Not determined, but Yes (2 and 4 weeks)
cells17 syngeneic females nerve transection in donor cells found in
rats smooth muscle
Mesenchymal stem Syngeneic bone Aged rats Endothelial, smooth Yes (1 and 4 weeks)
cells18 marrow muscle
Mesenchymal stem Fetal human spinal None; young, Endothelial, smooth Not determined
cells19 vertebrae healthy rats muscle

leading to ED. To a significant degree, cell-based therapies risk of vasculogenic ED.1–4 The systemic vasculature is fre-
treat comprehensive molecular pathologies of the damaged quently taxed by endothelial dysfunction, a complex condi-
tissue, and therefore an understanding of the precise nature of tion that may not be fully reversible through treatment with
the dysfunction may not be critical. The new cells, being pharmacological agents. In patients with hypertension and
functional simulacra to the healthy native tissue, will conceiv- atherosclerosis, endothelial dysfunction of the penile vascula-
ably take over the proper function of the damaged cells. In the ture is often the primary cause of ED.35,36 If the penile endothe-
case of ED, these cells could functionally replace damaged lial cells are compromised, then replacing these cells with stem
endothelial cells, smooth muscle cells, or neurons. Clearly, it or progenitor cells may be a viable therapeutic option. Two
is an oversimplification to discount the need to probe the stem or progenitor cell populations – mesenchymal stem cells
molecular underpinnings of ED, but much of the promise of and endothelial progenitor cells – have been evaluated for
cell-based therapies lies in their well-documented abilities either treating or predicting vasculogenic ED.
either to wholly replace damaged cells or to secrete factors
in a paracrine fashion that somehow repair dysfunctional
cells, seemingly irrespective of the specific pathophysiology. Mesenchymal stem cells
Although stem cell-based approaches for treating ED are new, Mesenchymal stem cells (MSCs) are intermixed within the
the few pioneering studies have reported very promising bone marrow stroma in a sparse population of multipotent
results, some documenting long-term functional improve- stem cells with the unique capacity to differentiate into
ment (Table 42.2). Reviewed below are the known studies that mesodermal tissues such as osteoblasts, chondrocytes, and
have explored the potential for using stem or progenitor cells adipocytes.37 MSCs have the additional ability of differentiat-
in the treatment of ED (Figure 42.2). ing into non-mesodermal phenotypes such as neurons, lung
The natural aging process and diseases of the cardiovascu- epithelial cells, and hepatocytes.38–40 MSCs have been isolated
lar system (such as diabetes, hypertension, hypercholester- in a number of other tissues and organs, including placenta,
olemia, dyslipidemia, and atherosclerosis) greatly increase the cord blood, and adipose tissue.41 The presence of MSCs in a
 Stem and endothelial progenitor cells for erectile dysfunction 317

(a)
Intracavernosal
BDNF injection Glia?
ESCs NESCs
neurons

(b)

Intracavernosal injection
of unaltered cells Neurons?
MDSCs Smooth
muscle?

(c)
With or without Intracavernosal
eNOS transfection injection
Smooth
MSCs Modified muscle and
MSCs endothelial
cells

(d)

Transfection with Intracavernosal Smooth

v-myc Immortal injection muscle and
MSCs
MSC line endothelial
cells

(e)

Genetic Intracavernosal or
modification? Modified systemic injection? Endothelial
EPCs
EPCs cells?

Figure 42.2 Schematic of recent studies considering the use of stem cells to treat erectile dysfunction (ED). (a) Embryonic stem cells
(ESCs) isolated from blastocysts underwent directed differentiation into neural embryonic stem cells (NESCs). NESCs were then
injected into the corporal bodies in a rat model of neurogenic ED in which the cavernosal nerves were bilaterally crushed.16 (b)
Muscle-derived stem cells (MDSCs) were isolated from adult striated muscle and injected into the corporal bodies shortly before
bilateral cavernosal nerve transection in a rat model of neurogenic ED.17 (c) Mesenchymal stem cells (MSCs) were isolated from bone
marrow of syngeneic rats and either left unaltered or transfected with endothelial nitric oxide synthase (eNOS). The cells were then
injected intracavernosally in an aged model of vasculogenic ED.18 (d) MSCs were isolated from human fetal spinal vertebrae and
rendered immortal. These cells were then injected into young, healthy rats to assess the capacity of MSCs to adopt appropriate
phenotypes.19 (e) Hypothetical schematic for using EPCs to treat ED, with or without transfection. Conceivably, donor EPCs could be
injected systemically or locally within the corpora cavernosa.

number of different organ systems has led some to contend fusion into heterokaryons with resident cells, and the release
that these cells may exist within virtually every postnatal of paracrine growth factors.45,46 Allogeneic MSCs can often
organ.41 escape the notice of the immune system because of their lack
The combined attributes of multipotency, robust prolifera- of HLA class II.47
tion ex vivo, and amenability to genetic manipulation have The documented multipotency, high engraftment, and
inspired many researchers to study the potential clinical appli- immune suppression of MSCs make them an intriguing source
cations of MSCs. In animal experiments, MSCs have shown for cell-based therapy for ED. Given the right environment,
the capacity to home to damaged tissues, and they apparently MSCs have the established capacity to differentiate into diverse
differentiate into the necessary mature phenotypes.42,43 Clini- cell types and thus conceivably may be able to replace dam-
cal applications are being presently undertaken or are immi- aged or dysfunctional tissues of the penis. MSCs can success-
nent for several common maladies such as heart disease and fully repair vascular diseases and insults in vivo, suggesting the
neurological diseases (e.g. amyotrophic lateral sclerosis).44 possibility that this stem cell population may be effective in
The method by which MSCs improve the regeneration of replacing or rejuvenating the dysfunctional analogous tissues
various tissues has been ascribed to direct differentiation, within the penis.48,49
318 Textbook of Erectile Dysfunction

Currently, little is known about the effect of MSC-based through the increase in physiological response and relevant
therapy on erectile physiology. Recently, Bivalacqua et al. molecular markers in an animal model of vasculogenic-related
assessed the potential for MSCs alone or when transfected ED.18,21,22 Finally, the lack of immune response suggests the
with endothelial nitric oxide synthase (eNOS) to differentiate safety of allogeneic MSC cell-based therapy for ED.18 Further
into new endothelial and smooth muscle cells, as well as their studies are clearly warranted and are ongoing.
effect on penile endothelial-derived NO bioavailability and
erectile physiology (see Figure 42.2).18 Rat MSCs (rMSCs)
were isolated, expanded ex vivo, and transfected with eNOS.21,22
Aged rats, known to have diminished NO bioavailability and Preclinical evidence for the use of
resultant vasculogenic ED, were injected intracavernosally
with vehicle, rMSCs alone (with or without transfected lacZ), cell-based therapies for neurogenic
or rMSCs transfected with eNOS. Seven and 21 days later, erectile dysfunction
engraftment, differentiation, eNOS expression and activity,
and erectile responses were assessed. Seven days following For neurogenic ED caused by iatrogenic intervention (e.g.
injection of lacZ-transfected rMSCs, rMSCs had adhered to a after radical prostatectomy), trauma, diabetes, or neurological
number of cell types in the penis, including the vascular disease, cell-based therapies may offer a novel way of regener-
endothelium and smooth muscle cells. After 21 days, the cells ating neural signaling. Chronically axotomized peripheral
had engrafted within the corporal sinusoids and had begun nerves frequently result in poor regeneration, possibly caused
expressing endothelial and smooth muscle antigens that were by apoptosis of the involved neurons, Schwann cells, and
not previously expressed in vitro, such as eNOS, CD31, and smooth muscle and endothelial cells.50 Oral pharmacotherapy
smooth muscle myosin heavy chain (SM-MHC). Seven days is unlikely to resurrect all these tissues effectively. For such
after intracavernous injection, penises obtained from rats trans- scenarios, cell-based therapy may be the most promising
fected with rMSC expressing eNOS had higher levels of eNOS approach.
protein/activity compared to vehicle or rMSCs alone. Erectile
responses were demonstrably higher in the rats treated with
eNOS-transfected rMSCs than vehicle and rMSCs alone. After Embryonic stem cells
21 days penises obtained from rats treated with rMSCs alone Embryonic stem cells (ESCs) are pluripotent cells derived
and eNOS-transfected rMSCs expressed higher levels of eNOS from the inner cell mass of blastocysts or from single
protein and activity and cGMP compared with vehicle. At both blastomeres.51–55 In the laboratory, ESCs have been coaxed to
7 and 21 days, no inflammatory response or fibrosis was docu- differentiate into a vast number of mature cells, originating
mented, highlighting the ability of allogeneic rMSCs to modu- from all three embryonic germ layers, including cardiomyo-
late the immune response. By mechanistically connecting cytes, hepatocytes, endothelial cells, keratinocytes, insulin-
improved physiological responses and enhanced endothelial- secreting cells, and neurons, to name just a few.51–54 ESC
derived NO bioavailability following rMSC injection, this therapy has lagged, however, partly owing to immunogenicity,
study has provided strong support for the potential therapeu- the teratogenic risks of transplanting pluripotent cells, and
tic use of MSCs to treat vasculogenic-related ED by improving innumerable ethical issues related to harvesting ESCs.26,55
endothelial-derived NO biosynthesis in the penis via direct ESCs were the first group of stem cells to be evaluated
differentiation of the MSCs as well as unknown local para- for treating neurogenic ED associated with cavernous nerve
crine mechanisms. injury (see Figure 42.2).16 Isolated ESCs from rat blastocysts,
In the ensuing paper, Song et al. assessed the potential of which were directed to differentiate into neural embryonic
immortalized human MSCs to differentiate into endothelial stem cells (NESCs), were utilized. Three months following
and smooth muscle cells within the corpora cavernosa of rats NESC injection to the major pelvic ganglion (MPG) or crura,
(see Figure 42.2).19 Human MSCs (hMSCs) were isolated from tests of erectile response were performed. After the 3-month
fetal spinal vertebrae and immortalized through the introduc- interval, erection physiology measurements demonstrated
tion of the v-myc oncogene. The immortalized human MSCs a significant decline in erectile response in bilateral nerve
were injected into the corpora cavernosa of young rats and the crush groups compared with sham. The experimental groups
corpora cavernosa were collected after 2 weeks. Prior to injec- receiving a NESC injection in either the crura or MPG exhib-
tion, cultured hMSCs did not express the endothelial markers ited significantly improved erectile responses. NESCs therapy
CD31 and vWF or the smooth muscle markers desmin, cal- groups showed significantly higher neurofilament expression
ponin, or smooth muscle actin (SMA). Two weeks after injec- compared with vehicle in both the MPG and dorsal cavernous
tion, however, immunofluorescence revealed that many of the nerve. Crural or MPG injection of NESCs yielded no differ-
injected hMSCs began expressing the endothelial and smooth ence between neurofilament expression in the experimental
muscle cell antigens. This study emphasized the differentia- and sham groups in both the MPG and dorsal cavernous
tion capacity of hMSCs in young, healthy rats; physiological nerve. This study revealed that ESCs directed along a neural
measurements of erectile function were not collected. lineage are able to exert some neuroprotective effects. Whether
In combination, these early studies suggest that syngeneic the NESCs differentiated into new neurons, glia, or transiently
and allogeneic MSCs have the capacity to differentiate into secreted neurotrophic factors is unknown. The authors could
endothelial and smooth muscle cells after being injected into not identify transplanted cells within the cavernosa, suggesting
the corpora cavernosa of rats. MSC-derived endothelial cells that perhaps these cells acted in a paracrine manner. Additional
within the corpora cavernosa also appear to be fully functional studies are clearly necessary to determine the mechanisms
 Stem and endothelial progenitor cells for erectile dysfunction 319

involved in neuronal regeneration or protection after ESC- In this study, MDSCs assisted in the regeneration of nerves,
based therapy in models of cavernous nerve injury. and the authors concede that it is uncertain exactly how the
MDSCs exert their neuroprotective effects, but they offer the
possibility of direct differentiation into cells with neuronal
Muscle-derived stem cells phenotypes. Such a finding would be very interesting because
When skeletal muscle is enzymatically degraded into its MDSCs are primarily used in basic and clinical research for
constituent cells, these cells proliferate robustly, maintain their muscle-regenerating capacity rather than their ability to
long-term self-renewal capability, and express myogenic and protect or differentiate into neuronal cells.
stem cell antigens.56 These early myogenic precursors, termed There are potential drawbacks to stem cell (MSC, ESC,
muscle-derived stem cells (MDSCs), are capable of adopting MDSC)-based therapies for ED. As a general caveat, stem cell
phenotypes of vastly diverse cell types.57 In urological tissues, treatments hold the risk of unintended differentiation, along
MDSCs have been transplanted with surprising efficacy into with the ensuing complications. If the differentiation pathway
the smooth muscle of damaged bladder and urethra, resulting is not thoroughly controlled, stem cells injected into the
in functional recovery of muscle control and diminished penis may very well differentiate into ectopic fibroblasts or
incontinence.58 Remarkably, the innervation of these tissues osteoblasts, thus potentially creating a significantly worse
improved, suggesting direct differentiation into neural cells or situation.59 As a result, it is critical for the researcher to evalu-
the secretion of neurotrophic factors or both.58 Recently, Kim ate such rogue differentiation by determining the presence of
et al. isolated MDSCs from skeletal muscle, and these enriched unintended phenotypes. In addition, inflammation and graft
MDSCs were then transfected with lacZ and injected into both rejection with allogeneic cells may be a formidable hurdle to
corpora cavernosa immediately prior to bilateral cavernosal overcome. Autologous and allogeneic stem cell approaches
nerve transection in a rat model.17 Rats undergoing sham sur- to treating ED are likely to differ from each other in several
gery (bilateral cavernous nerve transection plus no therapy) respects, each having unique benefits and drawbacks
demonstrated markedly lower erectile responses as well as (Table 42.3). Further research is required to determine in
decreased cavernosal expression of the pan-neuronal marker which scenarios one cell source would be a better option than
PGP 9.5, at 2 and 4 weeks after surgery. Experimental groups the other.
receiving bilateral injections of 1 × 106 MDSCs (into each
corporal body) had demonstrably greater erectile responses
and cavernosal protein gene product (PGP) 9.5 expression Endothelial progenitor cells
compared with the sham surgery group. Further histology
revealed the presence of lacZ-containing cells integrated as potential biomarker for
within the smooth muscle cells. erectile dysfunction
The significance of this study is the apparent identification
of a readily accessible cell population for cell-based ED ther- Innumerable studies have shown strong epidemiological
apy. Clearly, this is an intriguing study deserving of further associations between ED and cardiovascular disease, and
exploration. Owing to their multipotency, not to mention others have suggested ED as an independent risk factor for
their robust proliferation and high engraftment, MDSCs major cardiovascular events.1–4 Linking ED and cardiovascu-
may prove to be a preferred source for cell-based ED treatment. lar disease appears to be the pathological phenomenon of

Table 42.3 Comparisons between allogeneic and autologous sources for potential stem cell treatment for erectile
dysfunction

Allogeneic (banked centrally) Autologous

Pros • Donor cells would be functionally normal (i.e. free • Histocompatibility effectively guaranteed
from endothelial dysfunction) • Certain prospective cell populations may grow robustly
• Demonstrated in animal models to differentiate ex vivo, providing abundant donor cells in a limited time
appropriately and improve erectile physiology (e.g. MSCs and late outgrowth EPCs)
• Genetic modifications possible • Genetic modifications possible
• Centralized cell bank would provide expedited
treatment
Cons • Histocompatibility concerns • Donor cells may be susceptible to original conditions
• Quality of cells varies by donor leading to tissue failure
• Replicative senescence limits extensive expansion • Cell extraction potentially difficult and/or painful
• Karyotypic and phenotypic changes during growth • Lack of viable stem cells in those populations most in
• Unregulated cell growth a possibility, particularly need of treatment (e.g. elderly and those with chronic
with donor cells derived from ESCs disease)
• Time needed to grow cells ex vivo in sufficient numbers
may be excessive
MSCs, mesenchymal stem cells; EPCs, endothelial progenitor cells.
320 Textbook of Erectile Dysfunction

endothelial dysfunction, a condition characterized by reduced response to PDE-5 inhibitor therapy for the treatment of
NO bioavailability and a concomitant increase in vascular vasculogenic ED.
tone, as well as other phenotypic changes to the corporal
smooth muscle.60 Endothelial dysfunction is believed to be a
clinically silent harbinger of impending cardiovascular disease Conclusion
and is notably present in at-risk patients, such as those with
hypertension, diabetes, and dyslipidemia.60 Despite the recent evidence demonstrating a reduced number
Because both the incidence of ED and low circulating EPCs of EPCs in people with ED, it is currently unclear if circulating
are independently correlated to an increased risk of cardiovas- EPCs will serve as an independent biomarker of ED. One may
cular disease, several recent efforts have been made to mea- conclude that low EPCs can be strongly correlated with global
sure the association between ED and circulating EPC levels. endothelial dysfunction of the peripheral vasculature. Recent
One of the intentions of these studies is to determine whether evidence evaluating circulating EPCs in ED patients may cor-
circulating EPC levels can accurately predict ED and thus relate well with penile vascular dysfunction in a select group
serve as a readily available diagnostic biomarker for incipient of patients, although a definitive conclusion that low EPCs are
endothelial dysfunction (see Figure 42.2). In the first study of specifically diagnostic or predictive of imminent ED cannot
its kind, Foresta et al. found significantly lower levels of circu- be made at this time. However, there is sufficient evidence to
lating EPCs within those having ED, though not necessarily suggest that decreased mobilization of EPCs to PDE-5 inhibi-
having known cardiovascular risk factors.61 In another study, tor stimulus portends a poorer response to this form of ther-
Baumhäkel et al. showed that circulating EPCs were dimin- apy and may serve as a surrogate marker to determine severity
ished in patients with both ED and high risk for cardiovascu- of ED symptomatology. Rather than diagnosing or foretelling
lar disease, and decreased EPCs served as an independent ED, the greatest benefit of EPCs may be in their direct thera-
predictor of ED.62 peutic potential. If EPCs turn out to be a natural reservoir
In a further study, which included ED patients with or of incipient endothelial cells, then cell-based therapies aimed
without known cardiovascular risk factors, Foresta et al. noted at delivering EPCs to the dysfunctional corpora cavernosa
a significant increase in both EPCs and brachial artery will be likely to yield significant improvements in erectile
flow-mediated dilatation (a clinical measure of endothelial response.
function) after 3 months’ treatment with tadalafil (a PDE-5 Research into stem cell and progenitor cell therapy for ED
inhibitor).63 The results of this study may be interpreted to is currently at an early stage. Nevertheless, the therapeutic
suggest a possible link between the restoration of circulating success of the pioneering studies suggests that this approach
EPCs and improved endothelial function. In a subsequent may offer an effective, long-lasting treatment option, or
study, patients with ED and varying intima media thicknesses potentially a possible curative treatment regimen for severe
of the carotid artery were given the oral PDE-5 inhibitor ED. The observation that distinct stem cell populations have
vardenafil in a single 20mg dose.64 Circulating EPC numbers exhibited milieu-dependent differentiation and functional
increased in all test and control groups 4 hours after PDE-5 recovery in models of ED implies that a variety of cell-based
inhibitor treatment, though those with higher grades of approaches may prove efficacious for both vasculogenic and
carotid intima media thickness had significantly lower increases neurogenic-mediated penile vascular dysfunction. However,
in EPCs than the control group.64 The authors interpreted as we encountered in our early experience with gene therapies
these results as suggesting that people with more significant for ED, it will take extensive preclinical evidence before any
cardiovascular risk factors and endothelial dysfunction may cell-based therapy can be utilized in human clinical trials.
deficiently mobilize EPCs under PDE-5 inhibitor stimulus. Acknowledgments: This work was funded from a grant
Thus diminished EPC mobilization may be a surrogate test from the American Urological Association Foundation and
for a patient’s capacity for endothelial regeneration and the Astellas Foundation.

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26. Hoffman JA, Merrill BJ. New and renewed perspectives on embry- 50. Furey MJ, Midha R, Xu QG, et al. Prolonged target deprivation
onic stem cell pluripotency. Front Biosci 2007; 12: 3321–32. reduces the capacity of injured motoneurons to regenerate.
27. Spangrude GJ, Heimfeld S, Weissman IL. Purification and Neurosurgery 2007; 60: 723–32.
characterization of mouse hematopoietic stem cells. Science 1988; 51. Bin Z, Sheng LG, Gang ZC, et al. Efficient cardiomyocyte differen-
241: 58–62. tiation of embryonic stem cells by bone morphogenetic protein-2
28. Weissman IL, Anderson DJ, Gage F. Stem and progenitor cells: combined with visceral endoderm-like cells. Cell Biol Int 2006;
origins, phenotypes, lineage commitments, and transdifferentia- 30: 769–76.
tions. Annu Rev Cell Dev Biol 2001; 17: 387–403. 52. Cai J, Zhao Y, Liu Y, et al. Directed differentiation of human
29. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative embryonic stem cells into functional hepatic cells. Hepatology
progenitor endothelial cells for angiogenesis. Science 1997; 275: 2007; 45: 1229–39.
964–7. 53. Rufaihah AJ, Haider HK, Heng BC, et al. Directing endothelial
30. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell traf- differentiation of human embryonic stem cells via transduction
ficking is regulated by hypoxic gradients through HIF-1 induction with an adenoviral vector expressing the VEGF(165) gene. J Gene
of SDF-1. Nature Med 2004; 10: 858–64. Med 2007; 9: 452–61.
31. Ceradini DJ, Gurtner GC. Homing to hypoxia: HIF-1 as a mediator 54. Jiang W, Shi Y, Zhao D, et al. In vitro derivation of functional
of progenitor cell recruitment to injured tissue. Trends Cardiovasc insulin-producing cells from human embryonic stem cells. Cell Res
Med 2005; 15: 57–63. 2007; 17: 333–44.
32. Leor J, Marber M. Endothelial progenitors: a new Tower of Babel? 55. Nussbaum J, Minami E, Laflamme MA, et al. Transplantation of
J Am Coll Cardiol 2006; 48: 1588–90. undifferentiated murine embryonic stem cells in the heart: teratoma
33. Dzau VJ, Gnecchi M, Pachori AS, et al. Therapeutic potential formation and immune response. FASEB J 2007; 21: 1345–57.
of endothelial progenitor cells in cardiovascular diseases. Hyper- 56. Deasy BM, Jankowski RJ, Huard J. Muscle-derived stem cells:
tension 2005; 46: 7–18. characterization and potential for cell-mediated therapy. Blood
34. Tan PH, Tan PL, George AJ, et al. Gene therapy for transplantation Cells Mol Dis 2001; 27: 924–33.
with viral vectors—how much of the promise has been realized? 57. Jankowski RJ, Deasy BM, Huard J. Muscle-derived stem cells.
Expert Opin Biol Ther 2006; 6: 759–72. Gene Ther 2002; 9: 642–7.
35. Musicki B, Burnett AL. eNOS function and dysfunction in the 58. Huard J, Yokoyama T, Pruchnic R, et al. Muscle-derived cell-
penis. Exp Biol Med (Maywood) 2006; 231: 154–65. mediated ex vivo gene therapy for urological dysfunction. Gene Ther
36. Bivalacqua TJ, Usta MF, Champion HC, et al. Endothelial dysfunc- 2002; 9: 1617–26.
tion in erectile dysfunction: role of the endothelium in erectile 59. Vernet D, Nolazco G, Cantini L, et al. Evidence that osteogenic
physiology and disease. J Androl 2003; 24: S17–37. progenitor cells in the human tunica albuginea may originate from
37. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential stem cells: implications for Peyronie’s disease. Biol Reprod 2005;
of adult human mesenchymal stem cells. Science 1999; 284: 73: 1199–210.
143–7. 60. Watts GF, Chew KK, Stuckey BG. The erectile-endothelial dysfunc-
38. Kopen G, Prockop D, Phinney D. Marrow stromal cells migrate tion nexus: new opportunities for cardiovascular risk prevention.
throughout forebrain and cerebellum, and they differentiate into Nat Clin Pract Cardiovasc Med 2007; 4: 263–73.
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61. Foresta C, Caretta N, Lana A, et al. Circulating endothelial pro- 63. Foresta C, Ferlin A, De Toni L, et al. Circulating endothelial progenitor
genitor cells in subjects with erectile dysfunction. Int J Impot Res cells and endothelial function after chronic Tadalafil treatment in sub-
2005; 17: 288–90. jects with erectile dysfunction. Int J Impot Res 2006; 18: 484–8.
62. Baumhäkel M, Werner N, Böhm M et al. Circulating endo- 64. Foresta C, Caretta N, Lana A, et al. Relationship between vascular
thelial progenitor cells correlate with erectile function in damage degrees and endothelial progenitor cells in patients with
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2184–8. expression in the bone marrow. Eur Urol 2007; 51: 1411–17.
43 Mechanical, malleable, and soft
semi-rigid penile implants for
erectile dysfunction
John J Mulcahy

Introduction flaccid as the segments separated. Cable breakage, difficulty in

cylinder selection, and problems with activation–deactivation
Reliable penile implants were first introduced over 35 years resulted in a short market life for this device. The intention
ago, in the early 1970s. At the same time the Scott three-piece was to provide a prosthesis that gave the rigidity of the
inflatable model1 and Small–Carrion model2 were introduced. malleable rods but with superior bendability for positioning
These were soon followed by the Finney Flexirod device3 and during intercourse and easy downward positioning without
the Jonas malleable device.4 In the early days of penile implant spring back.
placement, the semi-rigid rods outsold their inflatable coun- The successor to the Omniphase implant was the Duraphase
terparts by a 3:1 margin. Experienced implanters were in short implant. This implant, also sold by Dacomed Corporation,
supply and most urologists felt more comfortable inserting contained the same polysulphone segments without the
the simpler devices with parts contained completely within activation–deactivation switching mechanism. The device was
the erectile bodies. There were problems unique to the inflat- easy to insert, provided reasonably good rigidity, and was easy
able implants such as leaks, cylinder aneurysms, and tubing to conceal without the spring-back seen with the malleable
kinks, which were not seen with the rod-like devices. With implants. It became a very popular member of the semi-rigid
time urologists gained experience in placing hydraulic pros- rod category of penile prostheses, but cable breakage and
theses and successfully managing their associated complica- segment wear necessitated replacement of many of these
tions. The manufacturers attended to wear areas by reinforcing devices sooner than was anticipated.7
or eliminating them and soon the market shifted toward a
preference for the inflatable implants, owing to the better
quality of erection and the more flaccid resting state that Dura II prosthesis
they afforded. In the mid-1980s, American Medical Systems The material of the Duraphase implant was changed in an
introduced the Hydroflex implant5 and later the Dynaflex attempt to increase the mechanical reliability. The segments
implant and Surgitek Corporation marketed the Flexiflate were changed from polysulphone to high-molecular-weight
device.6 Each of these was composed of paired hydraulic cyl- polyethylene, which was five times more durable. The cable
inders, one placed in each corporal body. Fluid was trans- was redesigned with smaller and more numerous strands,
ferred between parts of the cylinder by a distal pumping which in bench testing showed no fatigue after 8 million
mechanism to give alternating rigidity and flaccidity. Early bends. This improved cylinder was named the Dura II pros-
mechanical failure, patient difficulties in learning the mechan- thesis (Figure 43.1). It had numerous vendors over the suc-
ics of inflation–deflation, suboptimal rigidity, spontaneous ceeding decade and is now sold by American Medical Systems.
deflation, and low market share led to the demise of both The body segments are held together by a cable attached to
devices by the late 1990s. fixed posts at each end by a spring. A polytetrafluoroethylene
sleeve covers the segments, and the entire device is covered by
a silicone membrane to prevent adherence to body tissues.
Mechanical penile implants There are two diameters available, 10mm and 12mm. Each
cylinder in both widths is 13cm long, and proximal and distal
Omniphase and Duraphase implants tips can be added by attaching these to the body with a set
In 1984 Dacomed Corporation introduced the Omniphase screw. The segments of the body are positioned at the bend
prosthesis. This consisted of two rod-like cylinders composed angle of the penis. A grid combining glans–pubis distance and
of a series of polysulphone segments that articulated in a ball- total corporal length determines which size proximal and dis-
and-socket arrangement held together by a central cable tal tips are to be used to make sure the segments are posi-
attached to a spring. Bending the cylinders would alternately tioned for optimal bendability. When measuring glans–pubis
shorten and lengthen the cable, thus allowing the rods to distance, the distal point should be at the proximal one-third
become taut as the segments abutted against each other or of the glans. The proximal end of the measuring tool should

323
324 Textbook of Erectile Dysfunction

Figure 43.1 Dura II penile implant. (With permission of

American Medical Systems, Minnetonka, MN, USA.)

Figure 43.2 AMS 650 penile implant. (With permission of

rest without pressure against the skin of the pubis. In the American Medical Systems, Minnetonka, MN, USA.)
heavy-set patient, this may be a considerable distance from
the pubic bone, but it is the most accurate way of determining
the best location of the segments for complete and easy bend-
ing of the device. If a discrepancy in intracorporal length
between the two sides is observed, the difference in cylinder
length should be adjusted by using proximal tips of different
sizes or using proximal tips of the longer size and trimming
the proximal tip of the cylinder to be inserted on the shorter
side. This will ensure symmetric bending of the device. The
Dura II cylinders can actually be bent more than the limits of
the corporal anatomy will allow.
This is the prosthesis of choice for patients with little or no
manual or mental dexterity as it can be positioned upward or
downward with the motion of one finger. Patients with a very
broad penis will achieve suboptimal axial rigidity during pen-
etration for intercourse with the Dura II since there is room
laterally for the cylinders to shift. The shortest cylinder
implantable is 14cm. The proximal tip can be omitted but the Figure 43.3 Genesis penile implant. (With permission of
distal tip must be attached. Hence patients with a very short Coloplast, Minneapolis, MN, USA.)
penis or with considerable scarring from removal of a previ-
ous implant may not be candidates for this prosthesis. The
longest length of this implant if the largest proximal and distal
tips are attached is 31cm. A recent report with mean follow-up extenders can be applied as sizing dictates (Figure 43.2). The
of 5.7 years showed no mechanical defects in the device placed AMS 600M is a narrower version with the same basic design
in 94 patients.8 with a 9.5mm girth and an outer jacket, which, if left in place,
provides an 11.5mm diameter. The lengths supplied are 12cm,
14cm, 16cm and 18cm, and rear tip extenders can be applied
Malleable implants as needed in increments of 0.5cm.

Malleable rod implants have a tendency towards spring-back

and are difficult to position in a directly dependent position. Genesis implant
They also require some manual dexterity to bend up and The Genesis, sold by Coloplast, is basically the Accuform
down as desired. They do, however, give good intrinsic axial malleable prosthesis manufactured by Mentor Corporation to
rigidity and the newer models have been virtually free of which a hydrophilic coating has been added (Figure 43.3).
mechanical failure (i.e. wire breakage). When the implant is placed in an antibiotic solution, the solu-
tion adheres to the implant and is delivered into the wound,
where it elutes into the tissues surrounding the implant. Early
AMS 650 and 600M reports about other implants with this antibiotic coating have
American Medical Systems manufactures two variations of a shown a significant reduction in the incidence of implant
malleable rod implant with a spiral stainless steel wire as the infection. This is the only semi-rigid rod implant with an anti-
central core surrounded by a solid silicone covering. The AMS biotic coating. The Genesis comes in 9.5cm, 11cm, and 13mm
650 basic implant has an 11mm girth and is surrounded by a girths, and each girth size is 22cm in length. The length can be
silicone jacket, which, if left in place, is 13mm in girth. It is trimmed and a proximal cap added as needed for appropriate
provided in 12cm, 16cm, and 20cm lengths, and rear tip sizing to the length of the corporal body. The core of the
 Mechanical, malleable, and soft semi-rigid penile implants for erectile dysfunction 325

cylinder is double-braided silver wire, which is surrounded by Surgical approach

silicone.
There are a number of other malleable rod implants that A number of incisions have been used for the placement of the
are manufactured and used locally in certain countries. The semi-rigid rod implants: subcoronal, penoscrotal, infrapubic,
Jonas prosthesis in Germany and the Silmed prosthesis in dorsal penile, and perineal. The last-named two are seldom
Brazil are examples of these. used for reasons of cosmesis and difficult access. A very
convenient incision to place any semi-rigid cylinder is the
ventral penile approach with local anesthesia (Figure 43.4).11
Soft semi-rigid implants A penile block using lidocaine 1% without epinephrine is
The Small–Carrion and Finney implants that were popular in placed circumferentially at the base of the penis. A tourniquet
the 1970s are no longer manufactured. They were composed is then placed snugly around the base of the penis and 25ml of
mostly of silicone and in many cases the support of the erec- lidocaine 1% is injected intracorporeally as if performing
tion for vaginal penetration was suboptimal. In addition, the an artificial erection. Bupivacaine, although longer acting
penis was difficult to conceal as it tended to point outward than lidocaine, should not be used intravascularly as it may be
when the patient was standing. Silicone semi-rigid rods are cardiotoxic in large doses. After 2 minutes the tourniquet
still manufactured and used locally in some countries. The is released, allowing the anesthetic to flow proximally to
Shah prosthesis in India and the Virilis (Subrini) implant in anesthetize both corporal bodies.
France (and Italy) are examples of these. The Virilis implant A midline skin incision is made on the proximal half of the
has been used in patients with Peyronie’s disease to help ventral penile shaft and carried down to the corpus spongio-
straighten the erection. The patient’s natural tumescence sum (Figure 43.5). A vein retractor pulls the foreskin at the
helps give additional girth and support with the silicone rods distal aspect of this incision toward the glans penis. Buck’s
in the corporal bodies acting as splints.9 fascia and areolar tissue are dissected from the tunica
albuginea about two-thirds of the way down the shaft of the
penis. Two stay sutures are placed on each side of the corpus
Preoperative preparation spongiosum at this location. These will be used to hold open
the corporotomy and as reference points for corporal mea-
Patients are encouraged to bathe the genital region with a surements. A 3cm incision is made between the stay sutures,
strong soap for 3 days prior to the procedure. The urine and the plane of dissection is developed under the tunica dis-
should be sterile, and in the case of patients at high risk tally to the subglandular area and proximally to the ischial
for infection, such as those with indwelling catheters or tuberosities using Metzenbaum scissors. Dilators starting at
those with neurogenic bladders, prophylactic antibiotics are size 8 or 9 are passed in each direction.
given for a week beforehand. The skin of the genital area is
inspected for sites of infection and these are eliminated
before the procedure.
Systemic antibiotics are started after the intravenous line
has been placed, before the induction of anesthesia. This will
provide tissue levels of the antibiotic while the wound is open
during the surgery, and the systemic antibiotics are contin-
ued for up to 24 hours afterward. A number of regimens have
been recommended. The organisms associated with prosthetic
infections are staphylococcal skin contaminants and Gram-
negative rods. Although antibiotics are commonly used in
conjunction with prosthetic surgery, no study has been per-
formed that demonstrates their effectiveness in preventing
intra-operative acquired infections. Many infectious disease
specialists recommend against their frequent use because they
can promote the development of resistant organisms. In addi-
tion the practice is costly and can also lead to the development
of allergies to the drugs used. However, frequent irrigation
of the wound with an antibiotic solution is a very important
feature in reducing wound infections.
The patient’s genital area is shaved and thoroughly pre-
pared with a strong antiseptic solution. If phimosis is present,
circumcision should be performed prior to the implant pro-
cedure (not simultaneously). The incidence of infection asso-
ciated with penile implant is low (1–2%). In the event of
infection the implant may be removed, the wound thoroughly
cleansed with a series of antiseptic solutions, and a new
implant inserted (during the same surgery), with success rates Figure 43.4 Ventral penile incision for placing semi-rigid rod
in eradicating the infection in the range of 85%.10 implants.
326 Textbook of Erectile Dysfunction

Figure 43.5 Proximal penile shaft skin incision. Figure 43.7 Vein retractor lifting the distal end of the
corporotomy over the end of the rod.

less discomfort. If cylinders are too long, an ‘S’ configuration

or snake-like appearance, with spring-back during ventral
bending, will be noted.
Once the appropriate length and width have been deter-
mined the cylinders are removed from the sterile package and
appropriate tips or extenders are applied. The cylinder is
inserted proximally to the ischial tuberosities. A vein retractor
is then used to pull the distal end of the corporotomy over the
exposed end of the rod (Figure 43.7). The rigid cylinders need
not be bent using this technique. The wound is then closed in
three layers: corporotomy, subcutaneous tissues, and skin.
The advantages of this incision include preservation of the
foreskin in the uncircumcised patient, and the avoidance of
overlapping suture lines.
Figure 43.6 Width sizing of semi-rigid rod implants. The
thumb is apposed to the index finger between the two dilators.
Postoperative care
The patient is discharged from the recovery room on the day
All semi-rigid cylinders come in two or more fixed width of surgery or from the hospital the following day. Antibiotics
sizes, and the question arises as to which size to use. The are continued for 24 hours until the wound is sealed. Cathe-
decision should be made before opening the sterile package ters or drains are left in place at the discretion of the surgeon.
containing the device and possibly contaminating two sets if The penis is usually kept pointing upward or positioned in the
the first one is not the right size. To determine which size of crease of the leg to avoid friction of the head against the
two would be a better fit, place two dilators of the smaller size undergarments. Use of the penis for intercourse is usually
simultaneously side by side into the corporal bodies, first resumed 5–6 weeks after implantation.
proximally and then distally. The surgeon’s thumb should
then be apposed to his or her index finger on the shaft of the
penis between the two dilators (Figure 43.6). Slight separation Reliability and troubleshooting
of the dilators between the fingers would indicate an ideal fit
of that width cylinder. If no separation is found, a snug fit The durability of the Dura II implant has been superior to that
with that size cylinder would result. If the thumb can easily of its precursor, the Duraphase, with no mechanical failure
touch the index finger between the dilators, a relatively loose reported in 85 patients at a mean follow up of 5.7 years.8 If
fit will be achieved with that size of paired rods. The corporal segment wear were to occur, little or no tension would remain
cavities should be dilated one size wider than the cylinder on the springs attached to the fixed posts, the segments
width to be inserted to allow easy passage of the device in both would become loose, the rods would lose their rigidity, and
directions. the penis would appear floppy. Wire breakage of the malleable
The corporal length is then measured in both directions rods is very unusual, but cases have been reported.12,13 If
with a stay suture used as a reference point, and the two these mechanical problems occur, the cylinders can easily be
dimensions added to give the total corporal length. For all of replaced by a surgical approach similar to that used for their
the semi-rigid rods, inserting a rod length about 0.5cm shorter insertion. The ventral penile approach using a penile block on
than the total corporal length will give better bendability and an outpatient basis is commonly used.
 Mechanical, malleable, and soft semi-rigid penile implants for erectile dysfunction 327

Special considerations There the ratio is about 95% hydraulic implants and 5% mal-
leable or mechanical implants. In the rest of the world the
Erectile dysfunction (ED) is a common sequela of spinal cord ratio is closer to 50% rods and 50% inflatable implants, owing
injury and other neurologic diseases. Penile implants have to cost considerations. Kearse et al., in a multicenter evalua-
been used successfully to restore erectile ability in these condi- tion of the Dura II prosthesis up to 2 years after implantation,
tions. In a study of 245 neurologically impaired patients in noted no mechanical failures and patient satisfaction rates in
whom a variety of penile implants was placed, the distal ero- the range of 80%.15 Fallon and Ghanem found overall satisfac-
sion rate for semi-rigid rod prostheses was 18%, while the ero- tion of about 90% in a series of 142 patients with either an
sion rate with hydraulic implants was much lower.14 The need inflatable or malleable implant.16 Eighteen percent of the rod
for catheter placement in this group with an always-firm group and 6% of those with an inflatable device believed that
implant next to the fossa navicularis could contribute to a they had chosen the wrong prosthesis. Twenty-six percent
pressure-associated erosion. This group also has diminished thought that their prosthesis did not meet expectations in that
sensitivity in the penis and might not appreciate the friction it was too short or not stiff enough. Eighty percent of partners
and accompanying pain as the firm implant and penis con- were happy with the results. Krauss et al. completed a pro-
tinually rub against the undergarments. A hydraulic prosthe- spective study of 19 malleable implant recipients and their
sis is recommended for patients in this category and, if they partners and found that 85% of patients and 70% of partners
are manually impaired, the partner should be instructed in the were pleased with the function of the device.17 A total of 92%
operation of the pump. of patients and 90% of partners indicated that they would
If a proximal perforation of the corporal body occurs dur- choose the implant surgery if faced with the same option
ing placement of a semi-rigid rod implant, the area must be again. The size of the penis postoperatively was a major disap-
secured to prevent proximal migration of the rod in the post- pointment to many patients, although with time and acclima-
operative period. A ramrod effect will occur, and as the cylin- tization to the new device this became less of a concern. In a
der moves back and forth it will broaden the perforated area previously cited long-term study of the Dura II implant, 76%
and soon be palpable in the buttocks. A suture sling placed as reported satisfactory rigidity and 87% reported satisfactory
the rod is inserted into the corporal body will solve this prob- ease of concealing the device.8 Eighty-seven percent of patients
lem. A 3–0 proline suture with double swedged-on needle is reported that the prosthesis improved their quality of life,
placed through the proximal tip of the cylinder or through the 85% would undergo the implant surgery again, and 88%
rear tip extender. The cylinder is then positioned in the cor- would recommend the Dura II prosthesis to a friend. In a
poral body and each needle at the end of the sling suture is study from the Middle East of 50 patients with an AMS 650 or
brought through the tunica albuginea at the midpoint of the Mentor Accuform malleable implant, 70% of patients and
corporotomy. The corporotomy is closed and the suture of 57% of partners were satisfied with the prosthesis. Dislike for
the sling is tied snugly over the corporotomy. If the rod needs the device was the most common reason for dissatisfaction of
to be removed in the future, the sling suture is cut as the cor- patients with the device, while a sense of unnaturalness was
porotomy is re-opened and the proline suture is easily pulled the reason for the partners.18
out of the wound. If a proximal perforation occurs during
placement of a hydraulic cylinder, the input tube will act as a
buttress to prevent proximal migration if it exits the corporo- Conclusion
tomy as it comes off the cylinder.
Mechanical, malleable, and soft semi-rigid penile implants
continue to play a significant role in the management of ED.
Ease of insertion, low malfunction rate, lower cost, and sim-
Satisfaction plicity of the operation has made them a popular choice in
many circumstances. Satisfaction rates in the range of 70–80%
Penile implants have seen consistent improvement in the are consistently higher than those of other less invasive treat-
numbers placed in recent years following the precipitous ments. The predictable and reliable results which these devices
decline in numbers with the arrival of the phosphodiesterase afford add to the patient’s confidence in his ability to perform
type 5 inhibitors in 1998. About 20,000 are being placed annu- sexually. His overall outlook on life, productivity, and body
ally worldwide, with about 80% of these being in the USA. image are consequently enhanced.

REFERENCES

1. Scott FB, Bradley WE, Timm GW. Management of erectile impo- 5. Mulcahy JJ. The Hydroflex penile prosthesis. Urol Clin North Am
tence: use of implantable inflatable prosthesis. Urology 1973; 2: 1989; 16: 33–8.
80–2. 6. Stanisic TH, Dean JC. The Flexiflate and Flexiflate II penile pros-
2. Small MD. Small–Carrion penile prosthesis: a report on 160 cases theses. Urol Clin North Am 1989; 16: 39–43.
and review of the literature. J Urol 1978; 119: 365–8. 7. Mulcahy JJ. The Omniphase and Duraphase penile prostheses.
3. Finney RP. New hinged silicone penile implant. J Urol 1977; 118: Urol Clin North Am 1989; 16: 25–31.
585–7. 8. Ferguson KH, Cespedes RD. Prospective long term results and
4. Jonas U, Jacobi GH. Silicone-silver penile prosthesis: description quality of life assessment after Dura II penile prosthesis placement.
of approach and results. J Urol 1980; 123: 865–7. Urology 2003; 61: 437–41.
328 Textbook of Erectile Dysfunction

9. Grasso M, Lania C, Fortuna F et al. Evaluation of post-operative 14. Zermann DH, Kutzenberger J, Sauerwein D, et al. Penile prosthetic
residual function of the corpora cavernosa after soft penile prosthe- surgery in neurologically impaired patients: long term follow up. J
sis implant for Peyronie’s disease. Arch Ital Urol Androl 2006; 78: Urol 2006; 175: 1041–4.
49–52. 15. Kearse WS, Sago AL, Perets SJ, et al. Report of a multicenter evalu-
10. Mulcahy JJ. Long term experience with salvage of infected penile ation of the Dura II penile prosthesis. J Urol 1996; 155: 1613–6.
implants. J Urol 2000; 163: 481–2. 16. Fallon B, Ghanem H. Sexual performance and satisfaction with
11. Wahle GR, Mulcahy JJ. Ventral penile approach in unitary penile prostheses in impotence of various etiologies. Int J Impot
component penile prosthesis placement. J Urol 1996; 149: Res 1990; 2: 35–42.
537–8. 17. Krauss DJ, Lantinga LJ, Carey MP, et al. Malleable penile prosthesis
12. Lockyer R, Gingell C. Spontaneous breakage of malleable prosthe- in the treatment of erectile dysfunction: a prospective study of
sis. Int J Impot Res 1999; 11: 237. postoperative adjustment. J Urol 1989; 142: 988–91.
13. Lee WH, Xin ZC, Choi YD, et al. Spontaneous breakage 18. Salama N. Satisfaction with the malleable penile prosthesis
of malleable penile prosthesis. Int J Impot Res 1998; 10: among couples from the Middle East: is it different from that
255–6. reported elsewhere? Int J Impot Res 2004; 16: 175–80.
44 Inflatable penile prostheses in erectile
dysfunction (including penile shaft
re-modeling in Peyronie’s disease)
Daniel Yachia

Introduction Its advantages include the fact that it has no tubing or

external components; in addition, the implant procedure is
The concept of implanting a penile prosthesis for the easy. However, there are difficulties associated with activating
management of erectile dysfunction (ED) is based on a two separate distal pumps; it provides less rigidity than the
natural anatomical component found in several species (e.g. semi-rigid or multi-component devices; occasional buckling
dogs), the os penis or baculum, which supports and maintains and deflation has been experienced during intercourse; and it
the penis in erection. For men who are non-responders to has less flaccidity (when deflated) than the multi-component
oral ED treatment, in whom vacuum erection devices have devices. Furthermore, it is limited to the small-to-average-sized
failed, or who have contraindications for using intracavern- penis because of the inadequate rigidity in large or long penile
osal or intraurethral pharmacotherapy, insertion of a penile sizes.
prosthesis remains a very satisfactory and effective treatment
alternative.
An ideal penile prosthesis should create a normal-looking Two-component inflatable prostheses
penis in its erectile and flaccid state. The nearest to this
ideal is the inflatable penile prosthesis (IPP), which was devel- The two-component inflatable penile prostheses, Ambicor
oped to mimic the natural hydraulic event of the erection (American Medical Systems) and Mark II (Mentor)
(therefore providing a more natural erection and detumes- (Figure 44.2), have a pair of erectile cylinders and a pump in
cence). These prostheses are composed of two inflatable cylin- the scrotum that acts as a reservoir, holding 15–20 ml of liquid
ders, a reservoir, and a pump mechanism. When an erection (Figure 44.3). These prostheses are mostly used in patients in
is desired, the pump is activated and fluid (saline) is trans- whom an abdominal reservoir cannot be implanted. They
ferred from the reservoir into the cylinders. By activating are activated by squeezing the pump and deactivated by simul-
the deflation valve, detumescence is induced. Current IPPs taneously squeezing the pump and bending the penis. They
come in self-contained or in multi-component (two-piece or are simple to inflate and deflate. However, they cannot
three-piece) configurations. enhance penile girth and their flaccidity is less than the
three-component prostheses because of fluid remaining in
the cylinders. In large penises, the rigidity that they create is
Self-contained inflatable restricted because of the limited volume of fluid contained in
penile prosthesis the reservoir.

Dynaflex (American Medical Systems) is a self-contained

penile prosthesis that is made of two individual cylindrical Three-component
elements, each one containing the operating elements for acti- inflatable prostheses
vation and deactivation (Figure 44.1a). The reservoir is at the
rear end of each cylinder, the mid-part of the cylinder con- The three-component prostheses, Ultrex, CX, and CXN
tains the inflatable chamber, and the distal end of the prosthe- (American Medical Systems) and Alpha–1 Titan (Mentor)
sis has the pump (at the level of the glans penis). When each have two erectile cylinders, a reservoir at the Retzius space and
pump is activated, 2–4 ml of saline is added to the inflation a small pump in the scrotum which transfers the liquid from
chamber and rigidity is achieved (see Figure 44.1b). Deflation the reservoir to the cylinders and back (Figures 44.4 and 44.5).
is carried out by bending the penile shaft 55° or more. This These prostheses produce the most natural-appearing
activates the deflation valve and returns part of the liquid to the erection. Because of the large amount of liquid held in the
reservoir (see Figure 44.1c). This prosthesis is a compromise reservoir they create a good rigidity even in large penile sizes.
between the semi-rigid prostheses and the multi-component Upon deflation, good flaccidity is achieved since the liquid in
devices. the cylinders is completely returned to the reservoir.

329
330 Textbook of Erectile Dysfunction

Rear reservoir

Fluid passageway

Inflation chamber

Deflation valve

Inflation pump

(a) (c)

(b)

Figure 44.1 Self-contained prosthesis. (a) Components of the self-contained prosthesis. Pressure to the pump at the glans area
moves liquid from the rear reservoir to the inflation chamber to erect the prosthesis. (b) In the erect state. (c) In the flaccid state.

(a) (b)

Figure 44.2 Two-component inflatable prostheses from (a) American Medical Systems and (b) Mentor.

Recent penile prostheses have an antibiotic coating to reduce not only for reaching an accurate diagnosis, but also for
the risk of infection and safety valves to prevent involuntary medicolegal reasons. The preoperative evaluation is covered in
erection by autoinflation or involuntary deflation. Chapter 45.
In addition to the pre-operative evaluation, when the
decision for a penile prosthesis implantation is being made, it
is recommended that all available prosthesis options are
The surgery presented to the patient and the partner, including costs and
the risk–benefit profile of each type of implant: have the
Preoperative evaluation patient or the couple as decision-making partners.
Since penile prosthesis implantation is an invasive proce- As with every mechanical device the penile prostheses also
dure, a basic evaluation of the ED etiology is important have their ‘wearing-out’ time and mechanical dysfunctions,
 Inflatable penile prostheses in erectile dysfunction 331

which may necessitate a surgical repair.1,2 These issues

should be discussed and documented in order to prevent
future medicolegal problems.

Pre-operative preparation
Prevention of infection is the most important part of this sur-
gery.3 This can be achieved by proper preoperative prepara-
tion of the patient; the use of intra-operative, wide-spectrum
systemic antibiotics and intra-operative local antibiotic irriga-
tions; and pre- and postoperative wide-spectrum antibiotic
coverage.
These preparations are performed in a step-wise fashion
starting with the patient taking a shower with an antiseptic
soap (e.g. Betadine) the evening before and on the morning of
surgery (to decrease the bacterial colony count on the skin);
parenteral administration of cefazolin 1g and gentamicin
160 mg 30–60 minutes before surgery. After the patient has
been anesthetized and positioned on the operating table, the
genitalia are shaved (using hair clippers). The genitalia, thighs,
Figure 44.3 The pump of the two-component prosthesis acts inguinal folds and abdomen are then cleaned with iodine
also as the reservoir of the liquid to inflate the cylinders. scrub for 10–15 minutes prior to the same area being painted

(a) (b)

Figure 44.4 Three-component inflatable penile prostheses: (a) Ultrex and (b) Titan.

(a) (b)

Figure 44.5 (a) Placement of the three-component prosthesis. (b) X-ray view of the contrast-filled three-component prosthesis in
erect shape. Note the collapsed reservoir. Contrast solutions are not used any more for filling the inflatable prostheses.
332 Textbook of Erectile Dysfunction

with non-alcoholic iodine solution. The patient is then draped. Handling the prosthesis
Members of the team who scrubbed and draped the patient After completing the dilatation, the length of each corpus is
change their gloves and wash away residual powder from the measured separately with the measuring device and the proper
new gloves with saline. length prosthesis is chosen. After removing the inflatable
prosthesis from its packing tray, all of the components are
visually inspected and the air suctioned out. The cylinders,
Surgical approach to the corpora cavernosa and reservoir, and pump are checked for integrity by filling them
dilatation of the corpora cavernosa with isotonic saline solution and removing it several times.
The penoscrotal approach is the ideal ventral corporeal approach It is recommended that all the components of the pros-
for the implantation of self-contained or multi-component thesis be kept immersed in an antibiotic solution (e.g.
penile prostheses. It also provides an excellent approach to the gentamicin 160 mg in 500 ml of saline) from the time of
dorsal side of the corpora cavernosa for incising Peyronie’s removal from the packaging until implantation.
disease plaques when this procedure is combined with pros-
thesis implantation. The steps involved in the implantation of
an IPP are shown in Figure 44.6. Insertion of inflatable prostheses
A 5–6cm long midline skin incision is made. Through After dilating the corpora, the tip of the inflatable cylinder is
this incision, at the level of the penoscrotal angle, the corpus attached to a Furlow or Keith inserter with a suture. Then the
spongiosum and corpora cavernosa are identified and pre- inserter is advanced from the corporotomy incision toward
pared. A pair of parallel stay sutures are applied to the tunica the glans. When the tip of the inserter reaches the tip of the
albuginea of each corpora to allow their opening for dilatation corpus, its needle is advanced to pass through the glans and
of the cavernous tissues with Hegar type dilators. If a septal the inserter is removed. By pulling the suture, the tip of the
perforation occurs during dilatation, the direction of the cylinder is pulled until it sits snugly at the tip of the distal
dilatation is diverted laterally to enter the proper corporeal corpus. Then the proximal end of the cylinder is manually
space. In the event of urethral perforation, some surgeons placed through the corporotomy incision toward the crus.
prefer to stop the procedure and drain the bladder either with When necessary, rear tip extenders are used to add length
a small-caliber urethral catheter or suprapubicly. If during to the cylinders to fit them to the length of the corpora
dilatation, difficulty in inserting the large-caliber dilators is (Figure 44.8). When the cylinder sits satisfactorily in the
felt, the use of long blunt-tipped scissors can be helpful for corpus the suture at its tip is removed. The same maneuvers
increasing the dilatation. The scissors are inserted closed into are repeated for inserting the second cylinder.
the corpus and the blades are gently opened in the 12 o’clock It is recommended that the pump and the reservoir be
and 6 o’clock position for performing the dilatation. Care implanted according the manual preference of the patient. In
should be taken not to open the blades toward the septum or left-handed patients they are implanted at the left scrotum
the urethra since this may cause perforation. As with the (with the reservoir to the left side of the Retzius space) to
semi-rigid prosthesis implantation, if one of the cavernous allow its easy manipulation. To allow easy access to the patient,
bodies is severely fibrosed, it is recommended that one the pump is inserted in a sub-dartos pouch created at the
cylinder be implanted in the contralateral corpus and that anterior face of the scrotum. The abdominal reservoir is
the fibrotic corpus be abandoned. Inadequate dilatation inserted into the Retzius space through a tunnel created
of the corpora can cause unnatural-looking erections, espe- through the transversalis fascia at the level of the external
cially when an inflatable prosthesis is used. Dilatation not inguinal ring. Proper insertion of the reservoir into the
reaching the tip of the corpora can cause insertion of a shorter Retzius space is important for reducing the risk of spontane-
cylinder than needed, resulting in ‘drooping glans’ or penile ous inflation of the cylinders. After it has been positioned, the
asymmetry. reservoir is filled with 60–100 ml of saline and its tube
Dilatation of the proximal corpora also should be done clamped.
carefully to prevent perforation of the crura. Perforation of After the pump has been implanted, the tubes from the
the crus can cause early backward migration of the cylinder. cylinders and the reservoir are trimmed to length and
When a crural tear occurs, there is a need to perform a ‘wind- connected to the pump.
sock’ repair using a Goretex or Dacron vascular graft, closed Before the incision is closed, the functioning of all the com-
at one end. This ‘wind-sock’ is inserted toward the torn crus ponents of the prosthesis are tested by inflating and deflating
and fixed to the tunica albuginea with non-absorbable fine the cylinders, and leaks at the connections are checked.
sutures. Then the proximal end of the cylinder is inserted into
the ‘wind-sock’. An alternative is to insert the rear part of
the cylinder into the ‘wind-sock’ and then insert them
together into the proximal corpus and fix the graft to the
Inflatable penile prosthesis
tunica albuginea at the proximal level of the corporotomy implantation for the repair of
incision (Figure 44.7). Peyronie’s disease curvature
From the incision stage of the procedure, and throughout
the entire procedure, the open tissues should be frequently Only about 10% of the Peyronie’s disease curvatures need to
irrigated with an antibiotic solution (e.g. gentamicin 160 mg be surgically corrected.4 Surgical intervention is required
diluted in 500 ml of saline). when coital function is impaired. Surgical procedures for the
 Inflatable penile prostheses in erectile dysfunction 333

(a) (b) (c)

(d) (e) (f)

(g) (h) (i)

Figure 44.6 Steps for implanting an inflatable penile prosthesis. (a) Penoscrotal incision. (b) Preparation of the corpora cavernosa.
(c) After its dilatation the length of the corpus cavernosum is measured. (d) The suture to help pull the inflatable cylinder into the
corpus cavernosum is passed through the tip of the cylinder. (e) The pulling suture is thread through the Furlow or Keith inserter to
attach the tip of the cylinder to the inserter. With its needle retracted, the inserter will be advanced toward the glans. (f) When the
tip of the inserter reaches the tip of the corpus cavernosum, the needle is pushed forward to pass through the glans. (g,h) The inserter
is removed and the proximal end of the cylinder is inserted toward the crura.
334 Textbook of Erectile Dysfunction

(j) (k) (l)

(m) (n)

(o) (p)

Figure 44.6 (Continued) (i,j) The distal part of the cylinder is inserted into the distal corpus cavernosum and the distal cylinder is
pulled toward the glans by pulling the suture. (k) The incision of the tunica albuginea is closed using absorbable sutures. (l) The
implantation site for the scrotal pump is prepared in the scrotum. (m, n) The implantation site for the reservoir is prepared at Retzius
space by blunt finger dissection and the use of a blunt dissector. (o) All the tubing between the cylinders and the pump is connected,
and the pump is connected to the reservoir. (p) At the end of the procedure, the pump is activated to inflate the cylinders.
 Inflatable penile prostheses in erectile dysfunction 335

(a) (b)

Figure 44.7 (a) A crural tear and (b) the use of a ‘wind-sock’ to repair the tear.

• penile prosthesis implant with or without plaque manipu-

lations (i.e. without incisions or corporoplasty).

Patients with calcified plaques invading the cavernous

tissues and with impaired erectile capacity who do not
respond to pharmacotherapy are the best candidates for penile
prosthesis implantation. Penile prosthesis implantation alone
or combined with corporeal reshaping is needed when penile
angulation is severe.5–13
The use of semi-rigid penile prosthesis implants for the
correction of penile deformations caused by Peyronie’s
plaques was proposed almost 30 years ago. This was almost
immediately followed by the use of IPPs to restore erection
and straighten the penis in Peyronie’s disease.14,15 The effect
of penile prosthesis implantation in Peyronie’s disease
patients is double: by splinting the curved corpora the
deformity is straightened, and by restoring erection and
providing a straight penis comfortable penetration becomes
possible.
In these patients, after implanting the prosthesis the
cylinders are inflated to observe the degree of straightening
Figure 44.8 After the measurement of the corpus cavernosum achieved. In mild residual curvature the penis can be manu-
has been taken, the length of the cylinder can be adjusted by ally straightened. In order to achieve a good straightening
using rear tip extenders. in a severely deformed penis it is recommended to add
plaque incisions to the inflatable prosthesis implantation.
Single or multiple transverse incisions can be performed
repair of Peyronie’s disease are divided into three major using electrocautery (cutting current), with the prosthesis
groups: in situ (cutting current incises tissue but cannot cut silicone
rubber) (Figure 44.9). These transverse incisions can be left
• plaque surgery (incision or excision of the plaque and open.
grafting or incision through the plaque); The surgical wound is irrigated again with an antibiotic
• corporoplasty; and solution and closed in two layers using fine absorbable sutures.
336 Textbook of Erectile Dysfunction

(a) (b)

(c) (d)

Figure 44.9 In Peyronie’s disease curvature, after the components of the inflatable prosthesis have been implanted, the cylinders
are inflated to achieve straightening of the penis. In cases of residual curvature, the dorsal neurovascular bundle is carefully dissected
and elevated. One or more releasing transverse incisions at the most convex part of the shaft completely straightens the curvature.
If a single incision (a, b) cannot straighten the shaft, additional incisions are done to achieve complete straightening (c, d).

A non-compressing dressing is applied. At the end of the may continue for a further 2–3 weeks. Driving is not allowed
procedure the prosthesis is left in a semi-inflated–semi-rigid for 2–3 weeks.
state. Sexual activity can be resumed no sooner than 6 weeks after
implantation, and only if there is no pain. In the case of con-
tinuing pain or severe soreness, sexual activity is delayed for
Postoperative period another 2–4 weeks. At this stage the patient is instructed how
to activate and deactivate the prosthesis. The patient’s partner
It is best to do the procedure with a short hospitalization period also is trained how to operate the penile prosthesis in order to
or as day-care in order to reduce the risk of hospital-acquired create co-operation between the partners and to decrease
infections. The patient is prescribed oral wide-spectrum anti- partner’s rejection of the procedure. This also helps in cases
biotics for a period of 2 weeks. Since almost all patients have in which the patient lacks the manual dexterity for activating
pain after penile prosthesis implantation, oral analgesics or the prosthesis.
even oral narcotics are prescribed for the painful period. The Complications of penile prosthesis implantation and their
initial painful period of 2–3 weeks turns into soreness, which management are discussed in Chapter 45.

REFERENCES

1. Levine LA, Estrada CR, Morgentaler A. Mechanical reliability 4. Carson CC, Hodge GB, Anderson EE. Penile prosthesis in Peyronie’s
and safety of and patient satisfaction with the Ambicor inflatable disease. Br J Urol 1983; 55: 417–21.
penile prosthesis: results of a two center study. J Urol 2001; 166: 5. Raz S, DeKernion JB, Kaufman JJ. Surgical treatment of
932–7. Peyronie’s disease. A new approach. J Urol 1977; 117:
2. Milbank AJ, Montague DK, Angermeier KW, et al. Mechanical 598–601.
failure of the American Medical Systems Ultrex inflatable penile 6. Pryor JP. Surgical treatment of Peyronie’s disease using the Nesbit
prosthesis: before and after 1993 structural modification. J Urol technique. Prog Reprod Biol Med 1983; 9: 98–103.
2002; 167: 2502–26. 7. Goldstein M, Laungani G, Abrahams J, Waterhouse K. Correction
3. Mulcahy JJ, Austoni A, Barada JH, et al. The penile implant for of adult penile curvature with a Nesbit operation. J Urol 1984;
erectile dysfunction. J Sex Med 2004; 1: 98–109. 131: 56–86.
 Inflatable penile prostheses in erectile dysfunction 337

8. Coughlin PWF, Carson CC III, Paulson DF. Surgical treatment of 12. Yachia D. Modified corporoplasty for the treatment of penile
Peyronie’s disease. The Nesbit procedure. J Urol 1984; 131: 282–5. curvature. J Urol 1990; 143: 80–2.
9. Nesbit RM. Congenital curvature of the phallus: report of three 13. Small MP. Peyronie’s disease and penile implantation. J Urol 1978;
cases with description of corrective operation. J Urol 1965; 93: 119: 579.
230–2. 14. Furlow WL. Peyronie’s disease and penile implantation. J Urol
10. Kelâmi A. Congenital penile deviation and its treatment with 1978; 120: 647.
Nesbit-Kelâmi technique. Brit J Urol 1987; 60: 261–3. 15. Furlow WL, Knoll DL. Implantation of the inflatable penis prosthe-
11. Lemberger RJ, Bishop MC, Bates CP. Nesbit’s operation for sis in patients with Peyronie’s disease: an evaluation of sixty-seven
Peyronie’s disease. Brit J Urol 1984; 56: 721–3. patients. J Urol 1988; 137: 402A.
45 Inflatable penile prostheses
Culley C Carson III

Introduction the second group of penile implants, which are inflatable.

These devices have undergone multiple revisions and new
Although the problem of erectile dysfunction (ED) has been designs between the early prosthetic devices and the currently
recognized since ancient times, adequate treatment has been available inflatable penile prostheses. The initial device
available only since the second half of the 20th century. In the consisted of four components, including an inflation pump,
early 20th century, attempts to design surgical procedures to deflation pump, reservoir, and two implantable cylinders. The
provide rigidity of the penis for sexual activity and to recreate current device has combined the inflation and deflation pump
the os penis of lower animals was unsuccessfully attempted by into a single pump.
a variety of surgeons. The first attempts at penile prosthesis There are currently two varieties of hydraulically inflatable
implantation were in the 1930s, when Bogaras described the penile prostheses, including two-piece and three-piece inflat-
use of a tailored section of rib cartilage to produce penile able penile prostheses. Early three-piece inflatable penile pros-
rigidity, in a fashion similar to that provided by the os penis theses were widely used, with excellent erections and a
of walruses, squirrels, and other animals.1 These tailored physiologically flaccid-appearing penis between uses. Mechan-
grafts, however, were unsatisfactory, and cartilage reabsorp- ical malfunction rates in these early devices, however, were
tion, infection, extrusion, and progressive angulation resulted reported in excess of 60% of cases.9,10
in abandonment of this procedure. Bergman et al., in 1948, Current inflatable prosthetic devices, however, have a
reported the use of a rib graft with similar complications.2 greatly improved mechanical reliability.11–13 These current
Development of newer synthetic materials in the 1950s devices (Table 45.1) are multiple-component inflatable penile
and 1960s propelled the advancement of prosthetic devices in prostheses, of which two- and three-piece models are avail-
the treatment of a variety of medical conditions, including able. There were single-rod inflatable penile prostheses, which
ED. Early reports by Goodwin et al. in 1952 suggested that have been termed the ‘hydraulic hinge’ penile prostheses.
synthetic materials could produce satisfactory results when Because these latter prostheses did not provide a significant
implanted into the penis for ED.3 The era of modern penile increase in penile girth and are frequently limited in flaccidity,
prosthetic devices began with the development of silicone- and because their reliability was poor, these devices have been
based prosthetic materials in the late 1960s as a result of the removed from the market.
space program.4 In 1968, Lash et al. reported on 28 patients
using single silicone prosthetic devices with good results,5 and
in 1972 Pearman designed a single silicone silastic prosthetic Current penile implants
rod placed beneath Buck’s fascia in 126 patients (Figure 45.1).6
Although these devices increased the success of penile pros- Two three-piece inflatable penile prostheses are currently
thesis implantation, their placement beneath Buck’s fascia available from American Medical Systems (Minnetonka, MN,
provided little stability, significant discomfort, and a non- USA) as the AMS 700 CX InhibiZone and the LGX (formerly
physiological penile shape. Extrusion rates were also high with Ultrex) InhibiZone prostheses, and the Titan prosthesis is
these initial attempts at penile prosthesis design. available from Coloplast (Minneapolis, MN, USA) (Figure 45.2).
The AMS cylinders are available as 700 CX, 700 CXR, and 700
LGX. The cylinder design consists of a three-layer construc-
tion, with an inner layer of silicone, middle layer of limited-
Types of penile prostheses expansion woven Dacron mesh in the CX cylinders and
middle layer of woven Dacron–Lycra in the LGX cylinders,
Modern penile prosthetic devices were first developed in the with an outer layer of silicone to prevent tissue adherence
early 1970s, when Scott et al.,7 together with Small et al.,8 from the middle-layer mesh.14,15 Whereas the CX cylinders
reported the implantation of penile prosthetic devices into the have controlled expansion capabilities, the LGX cylinders
corpora cavernosa to fill the corpora cavernosa and to provide permit girth expansion to 18mm and elongation by as much
a physiologically functional erection with good cosmetic as 20% in length to allow increased filling of the corporal
results. The development of semi-rigid rod prostheses for bodies and possible axial expansion. A paralyne coating has
which the Small–Carrion device is a prototype, has been previ- been added between the three layers to diminish the fabric
ously described (see Chapter 43). Scott et al., in 1973, described separation and ultimately decrease cylinder aneurysm.16,17

338
 Inflatable penile prostheses 339

The prosthetic cylinders of the Coloplast Titan and Alpha-1 single-layer silicone, although the currently available triple-
prostheses are constructed of Bioflex material that expands layer silicone prostheses appear to have durability equivalent
to 20mm in girth without axial elongation. As a result of its to that of Bioflex cylinders.18 Aneurysmal dilatation is rare with
single-layer design, more rigid wall, and resilient construc- both of these cylinder designs but has been reported.17,19–21
tion, the Bioflex material appears to be more durable than Similarly, other design changes over the past 20 years,
including replacement of stainless steel connectors with
plastic connectors, addition of non-kinked tubing, single-
design construction, Teflon cylinder input sleeves, and
multiple-layer cylinders, have improved the longevity of these
devices. Because the cylinder portion of the inflatable system
functions at significantly higher pressure than the reservoir
portion, most complications occur where pressure mainte-
nance is important. Therefore, strengthening or eliminating
connectors, strengthening cylinder materials, and input tubes
has decreased mechanical malfunction rates from more than
30% to less than 5%. Estimated life of these implants is 12–15
years, which is longer than for almost any other human
implanted prosthesis.12
Subsequent to investigations that identified the efficacy of
coating prostheses with a combination of rifampin and mino-
cycline to inhibit bacterial growth, American Medical Systems
Figure 45.1 Pearman penile prosthesis placed beneath Buck’s developed a new penile prosthesis coating that received
fascia through dorsal penile incision. approval in the USA from the Food and Drug Administration
in May, 2001. In the InhibiZone™ prosthesis, tissue-contacting
surfaces are impregnated with quantifiable doses of rifampin
Table 45.1 Currently available penile prostheses and minocycline that elute into the area surrounding the
prosthesis post-operatively.22 Both drugs elute initially at high
Semi-rigid rods rates, with a significant drop-off in rifampin after day 1 and
AMS 600 (AMS) in minocycline by day 7. The Coloplast Corporation has
Malleable (Coloplast) developed a coating called Resist and applied it to their Titan
inflatable penile prostheses. This concept is that a hydrophilic
Inflatable
coating on the Bioflex surface will decrease bacterial adher-
700 CX Inhibizone (AMS) ence that precedes biofilm formation.23,24 Further, the coating
700 LGX Inhibizone (AMS) will absorb antibiotics of the surgeon’s choice and permit
Titan (Coloplast) these to elute from the implant for 1–3 days after implanta-
Ambicor (AMS)
tion to decrease bacterial adherence. This concept has been
evaluated in vitro and has promise for reducing infections.
Mechanical A large multicenter trial has confirmed the reduction in
DuraII (AMS) prosthesis-associated infections with the Resist coating.24
The three-piece inflatable penile prostheses continue to be
AMS, American Medical Systems
the most satisfactory prostheses while they remain functional.

(a) (b)

Figure 45.2 Multiple-component inflatable penile prostheses. (a) AMS 700 LGX Plus penile prosthesis. (Courtesy of American
Medical Systems, Minnetonka, MN, USA. Illustration by Michael Schenk.) (b) Alpha-1 penile prosthesis. (Courtesy of Coloplast
Corporation, Minneapolis, MN, USA.)
340 Textbook of Erectile Dysfunction

These prosthetic devices produce the most natural-appearing who have undergone significant radical pelvic exenteration
erection in girth and length, and impart satisfactory rigidity procedures, as well as patients with surgically implanted
and excellent flaccidity for optimal concealment. They also vascular prostheses, may benefit from two-piece devices.
have advantages for many patients with complex penile
implantations, since the flaccid position removes pressure
from the corpora cavernosa and decreases the possibility of Patient selection
erosion in these highly difficult implantations. Pressure within
the corpus cavernosum is reflected upon the layers of the Although there are a variety of penile prosthesis designs
tunica albuginea. The thinnest portion of the tunica albuginea currently available for implantation, not all patients with ED
appears to be the ventral aspect, which lacks longitudinally are candidates for penile prosthesis implantation. Careful
directed outer bundles of collagen and corresponds to the area counseling of patients before penile implant procedures avoids
of most common penile prosthesis extrusion.25 In difficult many of the problems with postoperative dissatisfaction.
situations, such as in patients who have had previous extru- Despite careful counseling, however, many patients enter
sion or infection, in patients with severe diabetes or peripheral penile prosthesis procedures with expectations that cannot be
neuropathy, or in patients with severe corpus cavernosum met by penile prosthesis surgery. Complaints about decreased
fibrosis or reconstruction, the inflatable penile prosthesis may penile length compared with the pre-implant state, decreased
be the optimum choice.24,26,27 To improve ease of surgical penile sensation, and ‘coolness’ of the penis and glans penis,
implantation and to remove a portion of the prosthesis placed as well as chronic pain and partner dissatisfaction, are among
within the abdominal region, two-piece prostheses were those that patients may voice despite adequate surgical
designed (Figure 45.3). implantation and satisfactory mechanical functioning. Fortu-
Currently available is the AMS Ambicor prosthesis. The nately, these complaints are unusual and more than 90% of
previously available Uniflate 1000 (Surgitech) is still encoun- patients report satisfaction with their prostheses.15,28 Many
tered in patients implanted with these devices in the early patients who are dissatisfied with their penile prostheses
1990s.28 Because the Ambicor two-piece inflatable prosthesis will benefit from sexual counseling or continued counseling
eliminates the separate reservoir, additional fluid is available assistance from the implanting surgeon to be sure that they
by a combination of proximal cylinder and pump reservoir. are able to operate the device satisfactorily and understand
Although these devices provide adequate erection in many its use.29
patients, the limited reservoir capacity decreases flaccidity and Most patients’ dissatisfaction results from difficulty with
may, in some patients, diminish rigidity.28 These prostheses functioning and unrealistic expectations.15 Discussions with
are especially difficult to deflate in patients with small penises patients should include the concept that penile prostheses do
and frequently provide inadequate rigidity for patients with not create normal erections but only support the penis for
longer penises. In these devices, instead of cycling to full sexual activity. Penile prosthesis surgery brings about the abil-
inflation, 15–20ml of fluid is transferred and at least 5–10ml ity to resume sexual functioning and vaginal penetration, but
of fluid remains within the cylinders between uses. This dif- decreased penile sensation, length, and engorgement may
ference in cycled volume may decrease flaccidity and be objec- result in some patients. Furthermore, patients should be made
tionable to some patients. Although they are less optimal than aware of the possibility of mechanical malfunction, infection,
three-piece devices, these two-piece implants may be ideal for and other common complications that may compromise the
patients in whom reservoir placement is difficult or contrain- results of their penile implant. Patients should also be advised
dicated. Such patients as renal transplant recipients and those that a penile prosthesis will not improve libido or ejaculation.
Patients frequently report delayed or difficult ejaculation
initially following penile prosthesis surgery. This delay is
primarily a result of inadequate preparation, stimulation and
psychological adjustment to the prosthesis. Most patients
require 3–6 months of prosthesis use, with careful attention to
perpetual stimulation, before ejaculation routinely returns to
preoperative levels.28,30 Mulhall et al. used the standardized
instruments – the International Index of Erectile Function
(IIEF) and the Erectile Dysfunction Inventory of Treatment
Satisfaction (EDITS) questionnaires – to evaluate the results
of penile implants.30 They showed a slow increase in these
indices but excellent function at 6–12 months. Because the
prosthesis neither improves nor detracts from preoperative
ejaculatory ability, patients must be counseled regarding
their preoperative ejaculatory ability before a prosthesis
placement.
Once the discussion and demonstration of penile implant
Figure 45.3 Two-piece Ambicor inflatable penile prosthesis. varieties has been carried out, patients can be counseled about
(Courtesy of American Medical Systems, Inc., Minnetonka, MN, the most appropriate penile prosthesis for their individual
USA. Illustration by Michael Schenk.) use. Patients may choose a specific prosthetic type based on
 Inflatable penile prostheses 341

their needs and preferences. Younger patients with normal

manual dexterity often choose a three-piece inflatable penile
prosthesis because appearance in the flaccid position is
important, particularly for patients who wear stylish, form-
fitting, athletic clothing or who shower in public at a health
club or other athletic facility. For these patients, implantation
of a semi-rigid rod penile prosthesis requires a significant
lifestyle change and they are better served with an inflatable-
type prosthesis. Similarly, patients with Peyronie’s disease,
secondary implantation, or significant peripheral neuropathy
(such as occurs in severe diabetes) are best served with an
inflatable penile prosthesis because interior tissue pressures
are diminished between uses and the possibility of extrusion
is diminished.31,32 For patients in whom the convenience of
Figure 45.4 Deflation of AMS 700 CX implant.
inflation and deflation are not important, the risks of mechan-
ical malfunctions may outweigh the disadvantage of a mal-
leable penile prosthesis. Such patients as paraplegics who
require an external urinary collection device, those with rates. Carson et al. reviewed more than 700 patients with
inadequate manual dexterity, or those with significant obesity primary penile implants and demonstrated no difference in
may be better served with a malleable or mechanical penile infection with scrotal or infrapubic surgical approach.11
prosthesis. Device cost may be a concern for patients without
insurance coverage, and these patients may choose a less costly
malleable implant. Infrapubic approach
Surgical implantation of a multipiece inflatable penile
prosthesis is by the infrapubic approach (see Figure 45.4),
which begins with a (usually) horizontal incision one finger-
Surgical implantation breadth above the pubic symphysis. In obese patients, how-
of penile prostheses ever, a midline incision may facilitate dilatation by improving
exposure of the corpora cavernosa. Similarly, if a patient
Surgical implantation of penile prostheses can be carried out has a previously healed midline incision, this incision can
using a variety of surgical approaches and incisions. Multiple- again be used for the infrapubic approach to penile prosthesis
piece prostheses can be implanted by the infrapubic or peno- implantation. After incision of the subcutaneous tissue, the
scrotal approaches. Although individual surgeons have a section is continued to the rectus fascia. The rectus fascia is
variety of rationales for their choice of approach, there does incised horizontally and dissected cephalad for approximately
not appear to be any clear advantage in patient satisfaction or 2–3cm. A midline separation of the rectus muscles is carried
outcome of either of the two approaches.11,33 Patient anatomy out and, with sharp and blunt dissection, a pouch is created
may dictate the appropriate choice: patients with previous beneath the rectus muscles to insert the inflatable reservoir
abdominal surgical procedures, in whom reservoir placement comfortably without compression. This step is eliminated by
is difficult, may be better served with an infrapubic approach, the use of a two-piece penile prosthesis.
whereas patients with massive obesity may be better The dissection is then carried out over the corpora cavernosa.
approached through a penoscrotal incision. Two-piece devices Sharp and blunt dissection is begun on either side of the fun-
(because no separate reservoir is present) are best implanted diform ligament, identifying the dorsal neurovascular bundle.
through a penoscrotal incision. The infrapubic approach is It should be noted that the dorsal nerves of the penis lie
usually carried out with a horizontal incision approximately approximately 2–3mm lateral to the deep dorsal vein. Once
one finger-breadth above the symphysis pubis, allowing Buck’s fascia has been dissected free from the tunica albug-
implantation with an easily concealed incision once the inea, the shiny white tunica albuginea is fixed with two paral-
pubic hair regrows (Figure 45.4). In patients with significant lel traction sutures.
obesity or a previous midline incision, however, a midline A corporotomy incision is then carried out between
incision carried out to the base of the penis facilitates the traction sutures and the corpora cavernosa entered.
exposure of the corpus cavernosum and improves the ability The corporotomy incision can be carried out with scalpel or
for corpus cavernosum dilatation. Because the penoscrotal electrocautery. Metzenbaum scissors are then used carefully
approach requires differentiation of the corpora cavernosa to initiate the tunnelling of the corpora cavernosa, gently
from the corpus spongiosum during resection, initial place- spreading the cavernosal tissue both proximately and distally
ment of a Foley catheter is preferred. until the ischial tuberosities and crura are encountered, and
The infrapubic approach allows more direct dissection distally palpating the glans penis to identify the most distal
of the corpora cavernosa; however, because of the dorsal aspect of dilatation. Hagar dilators can be used (size 9–14F), or
neurovascular bundle, injury is possible, resulting in decreased Brooks or Pratt dilators can be used (Figure 45.5). If fibrosis
distal penile sensation in some patients. The choice of surgical is encountered, Rosillo cavernotomes can be used to dilate
approach does not appear to have an impact on infection and lyse fibrosis to size 12. Once dilatation has been adequately
342 Textbook of Erectile Dysfunction

and adipose tissue in this area is dissected free using sharp and
blunt dissection to expose the dartos fascia, which is thor-
oughly cleaned to allow pump placement. Following develop-
ment of a subcutaneous pouch for the pump, the pump is
positioned in the most dependent portion of the scrotum and
temporarily fixed into position using a Babcock clamp. The
inflatable reservoir is then placed in the previously constructed
subrectus pocket and filled with an appropriate volume of
normal saline or water and radiographic contrast medium.
Tubing connection is carried out using quick connectors or
suture tie plastic connectors. The snap-on connectors are used
for the Mentor prosthesis. In a ‘re-do’ prosthesis, in which a
residual tubing segment is connected to a new device piece,
suture tie plastic connectors must be used. Connection is
carried out by tailoring tubing to eliminate excessive length
but to allow for adequate pump positioning. Rubber-shod
clamps are used to compress the tubing, and the ends of
the tubing, once tailored, are flushed with inflation fluid to
Figure 45.5 Brooks corporal dilators.
eliminate small particles and blood clots.
After connection, the adequacy of the connection is tested.
All rubber-shod clamps are removed and the device is inflated
and deflated on multiple occasions to ensure adequate loca-
carried out bilaterally, the Furlow insertion tool is introduced tion, placement, and erection (Figure 45.4).
or is used to measure the length of the corpora cavernosa, Following testing, thorough irrigation with antibiotic
using a traction suture as a central point of reference. The solution is carried out, and the rectus fascia is closed
proximal and distal measurements are added together to with interrupted sutures. The wound is then closed in
identify total corporal length and obtain appropriate-sized the standard fashion with two layers of subcutaneous tissue
inflatable cylinders. A length slightly less than this measure- and a subcuticular skin suture. A dry sterile dressing is applied,
ment is usually selected to permit comfortable positioning of a Foley catheter is placed if necessary, and an ice pack
the cylinders. Rear tip extenders of size 1cm, 2cm, or 3cm, or is applied. Suction drains may be used at the surgeon’s
combinations thereof, are placed on the proximal cylinder discretion.
end to adjust length. Postoperatively, patients are instructed to maintain their
Once the measurement has been obtained, interrupted or penis in an upward position for 4–6 weeks. Tight underwear
running sutures can be placed for later corporotomy closure. and athletic supports are not used, in an effort to maintain the
The advantage of pre-placed sutures is the elimination of pump in its most dependent position.
suture needles close to the area of the inflatable cylinder,
diminishing the possibility of cylinder damage during cor-
porotomy closure. Other methods of corporotomy closure Penoscrotal approach
include running sutures with or without a locking technique. Two- and three-piece inflatable penile prostheses can be
Once the interrupted sutures are placed in the cavernostomy implanted by a transverse or vertical penile scrotal incision
incision, cylinders are positioned within the dilated corpora (Figure 45.6). This approach has distinct advantages in obese
cavernosa using the inserting tool with a distal needle to pull patients and is widely used for routine penile prosthesis
the cylinders into position. Once the cylinders are positioned, implantation. An incision is begun in the upper portion of the
it is essential to visualize each one within the corpus caverno- scrotum following placement of a Foley catheter. The Lone
sum to ensure that no kinking is seen and that complete prox- Star (Lone Star Instrument Company, Houston, TX, USA)
imal and distal seating has taken place. The cavernostomy retractor facilitates exposure with this incision. Once the skin
incision should be placed proximal enough to allow easy incision has been carried out, the dissection is continued lat-
exit of the input tube and to minimize contact between the eral to the corpus spongiosum and urethra to expose the cor-
cylinder and the input tube. Closure of the corpus caverno- pora cavernosa. Incision and closure of the corpora cavernosa
sum incision is carried out with traction on the cylinder place- are similar to those described previously for the infrapubic
ment suture to maintain it in a flat non-kinking position incision. Pump placement is likewise in the most dependent
and to ensure adequate seating. Following placement of the portion of the scrotum just above the dartos fascia, with
cylinder and closure of the corporotomy incision, cylinder position maintained using a Babcock clamp. The dissection
inflation can be tested by placing fluid in each of the cylinders for reservoir placement, however, can be carried out with a
through the input tubes using 60ml syringes and then gently second separate infrapubic incision but is more commonly
inflating the prosthesis to identify any abnormalities in performed through the penoscrotal incision. The scrotal skin
position, any curvature, or any other sizing problems. incision is retracted to the area of the external inguinal ring,
A finger is then placed in the most dependent portion of the and dissection is carried out medial to the spermatic cord. The
scrotum lateral to the testicle on the right or left side. The transversalis fascia is identified and punctured sharply
finger is then pushed to the area of the external inguinal ring using index finger or a Kelly clamp placed against the pubic
 Inflatable penile prostheses 343

tubercle. Dissection is carried out using a blunt dissection. have had success with local anesthesia.34,35 Candidates for
Dilatation is carried out with the index finger after incision of local anesthesia must be carefully selected, as corporal dilata-
the transversalis fascia and with gentle blunt dissection using tion, even after infusion of local anesthetic agents, may be
a large Kelly clamp. The reservoir balloon is then positioned somewhat uncomfortable. The author prefers general and
over the index finger and placed in the perivesical space. regional anesthesia, since patients are less likely to move dur-
Inflation of the reservoir is carried out with care that no back- ing surgery and describe the implantation procedure as more
pressure of fluid is observed. If refilling of the syringe occurs, satisfactory in post-operative interviews.
the reservoir should be removed and further reservoir pocket
dissection must be carried out. Once the reservoir is placed
and inflated, and the tubing connected as previously described, Peri-operative care
the device is tested in inflation and deflation (Figure 45.7).
Scrotal closure is carried out with a subcuticular suture in the Peri-operative antibiotic treatment is critical in reducing the
standard fashion. incidence of peri-operative infection and prosthetic removal.
An initial peri-operative dosage of an agent effective against
the most common infectious pathogens should be adminis-
Anesthesia tered 1–2 hours prior to surgery and continued for 48 hours
postoperatively.36,37 An aminoglycoside with a first-generation
The choice of anesthesia for penile prosthesis implantation cephalosporin, a cephalosporin alone, vancomycin, or a fluo-
varies with surgeon and patient preference. Although roquinolone are appropriate choices for prophylaxis of the
the majority of penile prostheses are placed with general, most common infections from Staphylococcus epidermidis.36,38
spinal, or epidural anesthesia, some implanting surgeons Patients are discharged with 7 days of continued antibiotic
therapy. The penile prosthesis remains deflated for 4 weeks
while healing occurs. Prior to activation, the patient is advised
to retract the pump into his scrotum on a daily basis. Tight
underwear and athletic supports are avoided to maintain
pump position. A return office visit for activation of the device
is carried out once discomfort has resolved. Patients are
advised to inflate and deflate the device on a daily basis to
allow tissue expansion around the prosthesis. Most patients
can then begin use of their device immediately. Satisfaction
has been show to increase over 6–12 months. Patients should
be encouraged to continue device cycling on a regular basis
during the first year.30

Post-operative complications
The most worrisome postoperative complication is infection.
Fortunately, this complication occurs in fewer than 5% of all
Figure 45.6 Penoscrotal incision with a Scott retractor for patients. Peri-operative prosthetic infections can, however,
penile prosthesis insertion. occur at any time in the postoperative period in patients with

(a) (b)

Figure 45.7 (a) A surgeon inflating an AMS inflatable penile prosthesis placed through an infrapubic approach. (b) Prosthesis
deflation.
344 Textbook of Erectile Dysfunction

penile or other prosthetic devices. Patients continue to be at risk treating these prostheses with an exchange protocol including
for hematogenously seeded infections from gastrointestinal, systemic antibiotics for 24–48 hours using vancomycin to
dental, or urological manipulations as well as from remote target Staphylococcus epidermidis. The suspected infected
infections. Patients must be counseled to request antibiotic prosthesis is then removed and a combination of vancomycin
cover if remote infections occur.39 Most infections of prostheses and protamine used for antibiotic irrigation prior to implan-
are caused by Gram-positive organisms such as Staphylococcus tation of a new prosthesis. Patients are maintained on vanco-
epidermidis, but Gram-negative organisms such as Escherichia mycin and parenteral antibiotics for 1 week. These authors
coli and Pseudomonas spp. are also common culprits.36,38 Severe also recommend an initial trial of oral antibiotic therapy using
gangrenous infections with a combination of Gram-negative long-term antibiotics. Following initiation of antibiotics, pain
and anaerobic organisms have also been identified and suppression should suggest continuing antibiotics for 10–12
frequently result in significant disability and tissue loss.40–42 weeks. If pain fails to resolve or rapidly returns after antibiot-
Patients at increased risk for peri-operative infections ics, however, surgical intervention is appropriate. Parsons
include those with diabetes, patients undergoing penile et al. recommend ciprofloxacin 500 mg twice daily for 10–12
straightening procedures or circumcision with prosthetic weeks, a regimen with an approximately 60% success rate.48
implantation, patients with urinary tract bacterial colonization, Cephalosporins are also useful with cephalexin or cephradine
and immunocompromised patients such as post-transplant 500 mg four times daily for 10–12 weeks, with success rates
patients and patients undergoing prosthesis revision or of 25–30%. The findings of Licht et al. make it unlikely that
replacement.38,43 Although these patients are at increased risk, intraoperative Gram staining in suspected penile prosthesis
the risk of infection continues to be less than 5% and is less infection will be accurate.47
than 1% in studies of newer antibiotic-coated implants.44 If a grossly infected penile prosthesis is encountered,
Spinal cord injury patients have also been reported to have an surgical intervention along with antibiotics is of critical
especially increased risk of infections, with rates as high as importance. Salvage surgery or prosthesis removal with sub-
15% being reported.45 Because of a decrease in sensation, an sequent re-implantation are current alternatives for surgical
increased risk of extrusion of semi-rigid prostheses has been intervention. In patients with prosthesis infections that do not
reported in this group of patients. Diabetic patients with poor include significant necrosis, diabetics with significant puru-
glycemic control may be evaluated with glycosylated hemo- lence, rapidly developing infections or significant cylinder
globin studies to enhance diabetic control prior to prosthesis erosion, salvage procedures can be successfully performed.
implantation and, perhaps, to decrease the possibility of It is important to choose patients carefully and to carry out
infection.46 The results of these studies themselves, however, rigorous surgical technique. Initially, peri-operative antibiot-
do not predict higher infection risk in diabetic patients. ics are administered and all portions of the penile prosthesis
Penile prosthesis infections can be divided into clinically as well as any additional foreign bodies are removed and
apparent and sub-clinical penile prosthesis infections. Clini- wound cultures are obtained. Irrigation is then carried out in
cally apparent penile prostheses can be diagnosed from symp- all areas where the penile prosthesis resided. This is best per-
toms such as new onset of penile pain, erythema and induration formed using a red rubber catheter to direct irrigation fluid
overlying a prosthesis part, fever, drainage, and ultimately into all pockets in a stepwise fashion. Mulcahy et al. recom-
device extrusion. While most of these infections occur in the mend a sequence of irrigating solutions including kanamycin
early peri-operative period, late device infections have been 80 mg/l and bacitracin 1 g/l in normal saline followed by half-
documented.39 Most infections within the first 24 months’ strength hydrogen peroxide, half-strength providone–iodine
follow-up, however, are probably infections caused by bacte- solution, 5 liters of pressurized normal saline containing van-
rial colonization at the time of surgery, with symptoms and comycin 1 g and gentamicin 80 mg, half-strength providone–
signs beginning later. These infections are most often associ- iodine, half-strength hydrogen peroxide, and finally another
ated with Staphylococcus epidermidis on culture. Bacteria can, kanamycin–bacitracin solution.49 Following irrigation, gloves,
however, be cultured from asymptomatic penile prostheses instruments and drapes are changed and a new sterile pros-
and artificial urinary sphincters without evidence of infection. thesis is inserted. Patients are treated peri-operatively with
Licht et al. report low colony counts of Staphylococcus epider- antibiotics, including ciprofloxacin 500 mg twice daily for
midis from as many as 40% of uninfected penile prostheses 4 weeks. Antibiotics can be modified on the basis of culture
and 36% of artificial urinary sphincters cultured at the time of and sensitivity results. Brant et al. report successful salvage in
revision for mechanical malfunction.47 Of these low colony 10 of 11 patients (91%) with a 21.3 month mean follow-up.
count colonizations, fewer than 10% – all with high colony Nine of 12 patients’ principal pathogen was Staphylococcus
counts – eventually went on to penile prosthesis infection. epidermidis.50 Because of the high rate of bacterial colonization
Sub-clinical prosthetic infections occur more frequently. of revision implants, Henry et al. have shown that modified
These infections, which most often manifest themselves by salvage procedures with antibiotic-coated implants can dra-
chronic prosthesis-associated pain, are difficult to diagnose matically lower infection risk to levels of original implants.38
and even more challenging to treat. Device pain or migration They showed a colonization risk as high as 70% in replace-
strongly suggests that sub-clinical infection is present, requir- ment for mechanical problems.
ing antibiotic therapy and frequently prosthesis removal and The most common complication of penile prosthesis func-
replacement. Parsons et al. have documented pain resolution tion is mechanical malfunction.11,28,51 Mechanical malfunction
by prosthesis removal with antibiotic irrigation and substitu- has declined from rates as high as 61% to levels below 5%
tion of a new prosthetic device in a group of patients with since the 1970s (Figure 45.8). Aneurysmal dilatation of inflat-
prolonged isolated pain.48 They have been 90% successful in able cylinders, both American Medical Systems and Mentor,
 Inflatable penile prostheses 345

associated with these prostheses is cylinder erosion through

100
skin or urethra.53 Prosthesis fracture or breakage has been
reported, and patients may return, 6–8 years after implanta-
tion, with complaints of decreased rigidity of their semi-rigid
80 rod, indicating fracture of central prosthetic cylinder wires.54
These wire fractures cannot usually be appreciated radio-
Percentage survival

graphically unless the prosthesis is put on stretch once it has

60 been explanted. Replacement of these devices is indicated
when patients note decreased rigidity. Prosthesis extrusion or
erosion is most common in patients with diabetes and spinal
40
Prostheses cord injury, especially those requiring urinary management
1P1742a with catheter placement or condom collection.
20 AMS 700 Post-implantation, use of periurethral alprostadil or phos-
AMS 700 CX phodiesterase type 5 inhibitors has been show to enhance the
results for some patients.55,56 Alprostadil may be helpful with
0 intromission and ultimate prosthesis function in patients with
0 12 24 36 48 60 72 84 96 108 120
poor glans engorgement.56
Time (months)

Figure 45.8 Penile prosthesis survival of different American Conclusion

Medical System penile prosthesis models (Kaplan–Meier curve):
1P1742a, AMS 700, and AMS 700 CX. The implantation of inflatable penile prostheses is commonly
performed throughout the world. This successful procedure
restores erectile function in most men in whom implantation
tube kinking, reservoir leakage, and pump malfunction have is carried out. The knowledge of the types of prostheses avail-
been limited by device modifications. Fluid leak, however, able, together with their advantages, disadvantages, and
continues to be a problem for many inflatable penile prosthe- implantation techniques, is necessary for the skilled prosthetic
ses. These mechanical malfunctions require replacement of management of ED. Careful discussion of these factors and
the leaking portion of the inflatable portion of the prosthe- the potential risks optimizes patient satisfaction. Patients
sis.52 If a non-functioning prosthesis has been in place more should be allowed to choose prostheses from each of the clas-
than 4 years, however, the author usually replaces the entire sifications of prostheses available. With careful patient selec-
device in order to reduce further mechanical malfunction. tion, prosthesis choice, and with currently available reliable
Semi-rigid rod penile prostheses are associated with few prosthetic devices, the urologist can expect excellent patient
mechanical problems, and the most common complication and partner satisfaction with low morbidity.

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46 Design, development, and use of
questionnaires and surveys in the
evaluation and management of sexual
dysfunction: erectile dysfunction
Glen W Barrisford and Michael P O’Leary

Introduction satisfaction were determined to be best measured and evalu-

ated by patient and partner ‘self reporting’. The question-
As of 1995 approximately 152 million men worldwide were naires in this discussion will all have the option of being
estimated to have been afflicted with some degree of male self-administered (patient–partner reporting). Second, sexual
sexual dysfunction. By the year 2025, that number is expected dysfunction was subdivided into a number of ‘domains’. Each
to climb to over 322 million men.1 Sexual dysfunction is of these domains is a specific component of sexual dysfunc-
known to have an impact on men of all ages and freely crosses tion and is evaluated by a subgroup of questions within a given
all cultural and national boundaries.2 Given the vast global survey. For example, a survey with 20 questions may allocate
impact of the problem, a large-scale period of intense clinical five questions to each of the following domains: erectile func-
investigation has been under way since the late 1970s. tion, ejaculatory function, sexual interest, and satisfaction. The
Presently, we are reaping the benefits of this work by way of domain-specific approach allows the clinician to hone in more
an improved understanding of the normal and abnormal specifically on the problem. Lastly, it was assumed that all
physiology of male sexual function. patients who would be completing questionnaires would have
Prior to the interest established by urologists, sexual dys- sexual dysfunction. An assumption or expectation of dysfunc-
function had been a discipline that had largely fallen within tion universally existed. Therefore, the questions and surveys
the practice of psychiatric professionals. A large portion of were designed with this assumption in mind. It was O’Leary
the historic sexual dysfunction literature can be found in psy- who suggested that a questionnaire be designed in a ‘non-
chiatric publications.3–5 As one might expect, early work evaluative’ way so that the function and the impact of that
attributed psychogenic etiologies to many sexual disorders. function could be measured autonomously.9 This was a major
Means to assess level of dysfunction were developed by the advance in the evolution of male sexual function surveys. By
creation of comprehensive questionnaires. These surveys were using these building blocks, concise surveys were designed
aimed at evaluating the scope of the problem within the with the intention of obtaining maximum information with
framework of established psychiatric disease.6–8 The detailed minimal expenditure of office and staff time.
nature of these questionnaires proved to be too cumbersome The remainder of the discussion here addresses the specific
for the efficient evaluation of patients in the urologic clinic.9 tools available to the urologist to evaluate male patients with
Focused but comprehensive surveys were needed by urolo- concerns regarding sexual dysfunction.
gists. Previously established work was built upon in an effort
to create more appropriate questionnaires. Three basic
principles were incorporated from the psychiatric literature Addressing dysfunction
and were used as the foundation for contemporary urologic
sexual dysfunction surveys: Sexual dysfunction can often be an exasperating problem for
patients and partners. Anxiety and embarrassment can ham-
1. Sexual dysfunction and satisfaction are effectively per the discussion between patient and clinician. As a conse-
measured by patient and partner ‘self-reporting’. quence, male sexual dysfunction is a problem that has largely
2. Sexual dysfunction can be subdivided into a number of gone under-diagnosed and frequently goes untreated. The
subsets or ‘domains’. clinician should aim to initiate this discussion and offer the
3. The ‘existence of dysfunction’ had been assumed by patient an opportunity to address any concerns. One way
most surveys – the idea of creating surveys without to ease into this discussion is to present the patient with a
assumptions built in was established. questionnaire to review and complete prior to meeting with
The most important lesson learned from the psychiatric the clinician. This allows the patient to consider concerns that
sexual dysfunction experience was that performance and might otherwise go unaddressed once face-to-face with the

347
348 Textbook of Erectile Dysfunction

physician. The patient can critically evaluate personal concerns that used for the assessment of pain levels in post-operative
regarding performance and satisfaction in a number of domains patients.
(erectile and ejaculatory function, desire, satisfaction, and Heiman14 and Quirk et al.15 have defined essential criteria
bother). Those patients with an interest in having a more for validated instruments:
extensive discussion can complete the surveys accordingly.
• reliability;
• test–retest reliability;
• internal consistency;
Defining male sexual dysfunction • test validity;
Male sexual dysfunction can be categorized into a number of • concurrent validity;
domains. The most classically recognized domains are: desire, • divergent validity;
erectile and ejaculatory function, orgasmic function, satisfac- • sensitivity;
tion, and bother. Surveys are generally designed to address • specificity;
each of these entities as a separate component. However, • capacity; and
many of these domains overlap and are interdependent. For • receiver operating characteristics (ROC).
example a person with erectile difficulty may require intense
stimulus to achieve and maintain an erection. The intense Reliability is often referred to as an ‘inverse measurement
of error’.16 To be reliable implies that a survey yields the same
stimulation may secondarily result in premature ejaculation.
The erectile and ejaculatory function may subsequently affect or comparable results in different clinical experiments or
desire, patient–partner satisfaction, and bother. statistical trials. Therefore, a survey with high reliability is
considered to provide consistent information.
The test–retest reliability applies when a given survey is
repeatedly applied to the same population over a period of
Initial evaluation several weeks. Thus, the test–retest reliability is a measure-
ment of the stability of the factors over time. Similarly, the
The initial evaluation of a patient presenting with sexual internal consistency refers to the uniformity of an item within
dysfunction includes a complete medical, sexual, and psycho- a domain.
social history and a complete physical examination. Upon Test validity, concurrent validity, and divergent validity are
obtaining the history, the physician should make every effort values that measure the degree to which a test will actually
to provide a comfortable and supportive setting, the assurance measure what it is intended to measure. Sensitivity is the
of confidentiality, and the avoidance of judgementalism. The ability of a given test to differentiate between people with and
patient should be allowed to feel in control of the discussion. without dysfunction. Specificity is a measure of discriminat-
Under these circumstances patients will tend to provide more ing between people that are not affected by the disease or
complete explanations and allow the introduction of sensitive condition. Capacity refers to the ability of a given instrument
topics into the discussion.10 Additional diagnostic and labora- to detect changes in the conditions measured with the advent
tory evaluation will be directed by the findings of the history of treatment.
and physical examination. Receiver operating characteristics curves (ROC curves)
have been used in the analysis of a given instrument to assess
the ability to correctly classify a patient’s status based upon a
score in a given domain. Alternatively stated, the ‘area under
Development of surveys the curve’ (AUC) is an appraisal of the discriminant ability of
In an effort to create questionnaires with statistical value, a given questionnaire.16
efforts have been made to develop ‘validated’ surveys. The Various additional statistical measurements have been
term ‘validated’ was originally used in the discipline of psy- applied to validated questionnaires. However, the preceding
chometrics.11 Psychometrics is a branch of psychology that represents the nucleus of essential items applied to most
deals with the design, administration, and interpretation of surveys in use.
quantitative tests for the measurement of psychological vari-
ables such as intelligence, aptitude, and personality traits.12
When creating a survey, a condition of interest is selected. Validated surveys
Subsequently, a complete battery of items is developed to
describe all aspects of the chosen condition. At this point a A number of surveys have been developed and validated
formal statistical process is used to narrow the survey into a secondary to the increased interest in the field of male sexual
workable questionnaire. Once this is completed the question- dysfunction. In an effort designed to review and examine
naire is tested in populations with the condition of interest in rigorously the available surveys, the Second International
an effort to validate the survey. To be validated means that the Consultation on Sexual Dysfunction (Paris) prepared spe-
questionnaire accurately measures what it intends to measure. cific guidelines with respect to the use of a select group of
Responses on individual questions may be scaled indepen- validated instruments.10 The scope of the recommendations
dently (from 0 to 5). This is known as a Likert scale.13 Alterna- included surveys used to evaluate both sexes. This discussion
tively, a visual analog scale can be used by having the patient considers only those relevant to the evaluation of male sexual
mark on a line between 0 and 10. This method is similar to dysfunction.
 Design, development, and use of questionnaires and surveys 349

Among validated surveys, a two-tiered system was devel- Golombok–Rust Inventory of Sexual Satisfaction
oped. Those in the top echelon consisted of ‘highly recom- The Golombok–Rust Inventory of Sexual Satisfaction (GRISS)7
mended’ surveys, and those in the second tier were considered is a 28-item survey that is designed to evaluate the existence
‘additional recommended’ surveys. The stratification was based and severity of sexual problems among individuals or couples.
upon reliability; internal consistency; number of domains When given as a combined survey for couples it consists of 56
evaluated; ease; duration, and mode of transmission; discrim- items. In the combined survey 12 domains are evaluated, with
inative validity; sensitivity; and specificity. All of the question- two being common to both sexes while the other 10 consist of
naires recommended were self-administered. However, a five that are specific to each sex. The 28-item male version
number of the surveys could be administered during a clinical evaluates the five domains of premature ejaculation, erectile
interview (CI) as well. A detailed review of this two-tiered dysfunction, avoidance, non-sensuality, and dissatisfaction.
system follows here. In addition, a discussion of ‘additional The two additional common domains are frequency of sexual
valuable’ instruments is included. This consists of a number contact and non-communication. The survey is reported
of surveys that have been deemed to be highly useful for clini- with an aggregate score that summarizes the sexual function
cians based upon the authors’ own rigorous review of the and relationship quality. This survey can be administered in
remaining sexual dysfunction surveys.17 15 minutes. The range of internal consistency is 0.61–0.83,
while the test–retest reliability ranges from 0.47 to 0.82. Nor-
mal values have been established, and versions are available
Highly recommended surveys in English and Dutch.

Change in Sexual Function Questionnaire

The Change in Sexual Function Questionnaire (CSFQ)18 International Index of Erectile Function
is a survey that can be administered in CI or self-report (SR) The International Index of Erectile Function (IIEF)23 was
formats. The CI version contains 36 items while the SR primarily designed to evaluate erectile function and quality.
version contains 14 items. They can be completed in 20 and It is a 15-item survey that can be completed in approximately
5 minutes, respectively. Versions have been created for use 15 minutes. The origin of this survey lies within the initial
with men or women. This particular questionnaire is tailored clinical trials of sildenafil.24,25 However, those trials offered
to address five domains of dysfunction: sexual desire and wide exposure and use, leading to the current popularity of
interest, sexual desire and frequency, sexual pleasure, sexual the IIEF so that it is now one of the most common surveys
arousal and excitement, and orgasm completion. In its used in clinical practice. Five domains are evaluated: erectile
original form this survey was designed to detect alterations in function, orgasmic function, sexual desire, sexual satisfaction,
sexual function secondary to the administration of medica- and overall satisfaction. The internal consistency ranges from
tion or changes related to illness. The CSFQ is appropriate 0.73 to 0.95 and the test–retest reliability from 0.64 to 0.84.
for both heterosexual and homosexual men. This survey Standardized cut-off values are available for comparison.
carries a satisfactory reliability (0.64–0.80), and values that Severe erectile dysfunction (ED) is noted at scores 6–10, mod-
have been considered ‘acceptable’ for the concurrent and erate ED at scores 11–16, mild-to-moderate ED at scores
discriminative validity.18,19 This survey was noted to be par- 17–21, and mild ED at scores 22–25.26 Scores in the range of
ticularly useful in demonstrating changes in sexual function 26–30 represent normal sexual function. This survey has been
secondary to antidepressant medications.20 Normal values validated and is available in 32 languages.
have been established and can be used for comparison. Vali- The erectile function of the IIEF is referred to as the IIEF-6.
dated versions exist in English and Spanish,21 but translated This six-item mini-survey can be completed in less than
versions have been established with linguistic validation in 10 minutes. It carries an internal consistency of 0.92–0.99 and
French, German, Dutch, Italian, Swedish, Finnish, and French a test–retest reliability of 0.64. This survey has most often
Canadian.10 been used in clinical trials. A score of 25 or greater represents
normal erectile function. The sensitivity and specificity are
Derogatis Interview for Sexual Functioning 89% and 93%, respectively.
The Derogatis Interview for Sexual Functioning (DISF)22 can
be administered in a CI version or a SR (DISF-SR) version
and is applicable for both men and women. The main Recommended surveys
objective of this survey is to evaluate the current sexual
function of the patient. Twenty-five items address five Arizona Sexual Experience Scale
domains of interest: sexual cognition and fantasy, sexual The Arizona Sexual Experience Scale (ASEX)27 is another SR
arousal, sexual behavior and experiences, orgasmic function, survey that can be administered to men and women. This
and sexual desire/relationship. This test is designed to be five-item questionnaire addresses five domains of male sexual
interpreted at three tiers: individual items, individual function: sexual drive, sexual arousal, erectile function, orgas-
domains, and the summary (total score). This survey can mic function, and sexual satisfaction. The ASEX is scored
be completed in approximately 15 minutes. The DISF-SR from 5 to 30 and can be completed in 5–10 minutes. A higher
carries a test–retest reliability of 0.8–0.9, and an internal con- score indicates a greater degree of sexual dysfunction. The
sistency of 0.74–0.8. This survey has been validated and is internal consistency is 0.81 and the test–retest reliability is
available in 10 languages. 0.69–0.84. A score of 11 or less indicates the absence of sexual
350 Textbook of Erectile Dysfunction

dysfunction. Sensitivity and specificity are 100% and 52%, an excellent screening tool to identify men who may warrant
respectively. A number of clinical trials have incorporated this further discussion on the topic of sexual dysfunction. The
survey as a primary tool. sensitivity and specificity are 96% and 88%, respectively.
Although this survey has no established consistency or reli-
ability, the survey has an established cut-off point. Men
Brief Male Sexual Function Inventory who score less than 21 are considered to have ED, and the
The Brief Male Sexual Function Inventory (BSFI)9 is another degree of ED is measured along a spectrum using the total
SR survey that was initially designed to evaluate male sexual score: 1–7 suggests severe ED, 8–11 moderate ED, 12–16 mild-
dysfunction. It was modeled after the American Urological to-moderate ED, and 17–21 mild ED.
Association (AUA) Symptom Index for benign prostatic
hyperplasia. It was validated in a similar fashion.11,28 The AUA
symptom index is familiar to most urologists and served as an The Male Sexual Health Questionnaire
excellent model upon which to design a sexual dysfunction The Male Sexual Health Questionnaire (MSHQ)36 is a 25-item
survey. The BSFI is an 11-item questionnaire that evaluates survey that addresses the three domains of erectile function,
five domains and takes approximately 10 minutes to com- ejaculation, and sexual satisfaction. This survey can be com-
plete. The domains are sexual drive (two items), erectile func- pleted in approximately 20 minutes and has been used in the
tion (three items), ejaculation (two items), perception of a clinical setting to evaluate male sexual dysfunction. The inter-
problem (three items), and overall satisfaction (one item). nal consistency ranges from 0.84 to 0.93 and the test–retest
The internal consistency is 0.62–0.95 and the test–retest reli- reliability from 0.85 to 0.94. Neither cut-off points nor
ability varies from 0.79 to 0.89. Although no cut-off points normal values have been established for the MSHQ.
have been developed at this time, it has been widely used in
clinical trials.
The Sexual Encounter Profile
The Sexual Encounter Profile37–39 has gained widespread
Derogatis Sexual Functioning Inventory popularity as a measure in clinical trials used to assess the
The Derogatis Sexual Functioning Inventory (DSFI)6 is a effectiveness of erectogenic medications, most notably tadala-
245-item survey that requires approximately 90–120 minutes fil. This survey consists of five items and can be completed in
to complete and address 10 domains of function. Although less than 5 minutes. This survey appears commonly in phar-
this survey is an extensive, complete survey it is not practical maceutical company literature to support product efficacy.
for the outpatient setting given the time required to complete However, to the best of our knowledge this survey has not
the survey. It is most often used in the evaluation of couples been validated. The two most commonly studied questions
and does not possess normal values or cut-off points. include SEP question 2: ‘Were you able to insert your penis
into your partner’s vagina?’ and SEP question 3: ‘Did your
erection last long enough for you to have successful inter-
course?’ Although the statistical significance of this survey
Additional valuable surveys has not been clearly demonstrated, it warrants mention here
Self-Esteem and Relationship Questionnaire given the likelihood that the urologist will encounter it in
pharmaceutical literature.
The Self-Esteem and Relationship Questionnaire (SEAR)29 is a
14-item survey that addresses the three domains of sexual
relationship, self-esteem, and overall relationship. It was orig-
inally developed with the objective of measuring confidence,
Conclusion
self-esteem, and the quality of sexual relationships in men At one time sexual dysfunction was largely considered a dis-
with ED.29,30 This survey can be completed in approximately ease of psychogenic origin. As a consequence it became a
15 minutes and is often utilized in clinical trials.31–34 The clinical interest among the psychiatric profession. However,
internal consistency is 0.76–0.93 and the test–retest reliability the past 30 years of research has spawned a large interest in
is 0.57–0.79. Presently no norms or cut-offs have been estab- understanding the organic etiology of sexual dysfunction. As
lished for comparison. a result, we now have a greater understanding of the anatomy
and physiology of male sexual function. This body of knowl-
edge, coupled with pharmacological innovation and the
The Sexual Health Inventory for Men development of validated questionnaires, has exponentially
The Sexual Health Inventory for Men (SHIM)35 is another increased the interest in male sexual dysfunction in the uro-
brief survey that is often used in clinical trials but also has logic community. These developments have allowed the iden-
found a place in the urologic clinic. In our practice at the tification of patients with organic sexual dysfunction, and
National Naval Medical Center, patients complete both have simultaneously provided a means to measure the response
the SHIM and AUA symptom score while waiting to see the to therapy. The vast number of surveys available is a clear
urologist. This is a five-item survey that is essentially a short- demonstration of the rising clinical and research interest.
ened version of the IIEF,23 which addresses the domains of Although only a small number of surveys have been discussed
erectile function and intercourse satisfaction. This survey in this chapter, it is our goal to expose the reader to a useful
can be easily completed in less than 10 minutes and serves as cross-section of instruments. This exposure will allow the
 Design, development, and use of questionnaires and surveys 351

clinician or researcher to select a tool most useful for their ED, the IIEF-6 would be preferred. Familiarity with an array
specific needs. of validated surveys is useful because no single instrument is
Validated surveys have sustained rigorous statistical review universally applicable.
with respect to the most common measures. Although many Validated surveys have strived to be brief and self-reported
surveys do not possess established cut-off points or normal while addressing the main domains of male sexual dysfunc-
values, the many measures of each survey can be used for tion. However, they are not intended to replace a complete
comparison. For example, a survey with an internal consis- history and physical examination, appropriate laboratory
tency of 10% can not possess the same statistical strength as evaluations, or physician judgement and experience. Although
one with 90%. Conversely, it is important to understand that these surveys can help to identify dysfunction they fail to offer
surveys are imperfect tools with strengths and weaknesses in etiologic origin. Validated surveys carry many imperfections,
different areas. Selection of a survey must begin with the ques- which prevents them from providing the ultimate solution
tion of the purpose. If one is seeking a screening tool to be to male sexual dysfunction. However, their appropriate devel-
used in the outpatient clinic to assess for the presence of male opment and use provides another tool for the clinician to
sexual dysfunction, the BSFI9 might be a better choice than guide the evaluation and management of men with sexual
the IIEF.23 However, if a patient presents with a complaint of dysfunction.

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1. Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in 19. Clayton AH, McGarvey EL, Clavet GJ, Piazza L. Comparison of
erectile dysfunction between 1995 and 2025 and some possible sexual functioning in clinical and nonclinical populations using the
policy consequences. BJU Int 1999; 84: 50–6. changes in sexual functioning questionnaire (CSFQ). Psychophar-
2. Kandeel FR, Koussa VK, Swerdloff RS. Male sexual function and its macol Bull 1997; 33: 747–53.
disorders: physiology, pathophysiology, clinical investigation, and 20. Bobes J, Gonzalez MP, Bascaran MT, et al. Evaluating changes in
treatment. Endocr Rev 2001; 22: 342–88. sexual functioning in depressed patients: sensitivity to change of
3. Reynolds CF 3rd, Frank E, Thase ME, et al. Assessment of sexual the CSFQ. J Sex Marital Ther 2002; 28: 93–103.
function in depressed, impotent, and healthy men: factor analysis 21. Bobes J, Gonzalez MP, Rico-Villandemoros F, et al. Validation of
of a brief sexual function questionnaire for men. Psychiatry Res the Spanish version of the changes in sexual functioning question-
1988; 24: 231–50. naire (CSFQ). J Sex Marital Ther 2000; 26: 119–31.
4. Sherbourne C. Social functioning: sexual problems measures. In: 22. Derogatis LR. The Derogatis Interview for Sexual Functioning
Stewart A, Ware J, eds. Measuring Functioning and Well Being: (DISF/DISF-SR): an introductory report. J Sex Marital Ther 1997;
the Medical Outcomes Study Approach. Durham, NC: Duke 23: 291–304.
University Press, 1992: 194–204. 23. Rosen RC, Riley A, Wagner G, et al. The International Index of
5. Masters W, Johnson V. Human Sexual Inadequancy. Boston: Little Erectile Function (IIEF): a multidimensional scale for assessment of
Brown and Co, 1970. erectile dysfunction. Urology 1997; 49: 822–30.
6. Derogatis LR, Melisaratos N. The DSFI: a multidimensional 24. Cappelleri JC, Rosen RC. A comparison of the International Index
measure of sexual functioning. J Sex Marital Ther 1979; 5: of Erectile Function and erectile dysfunction studies. BJU Int 2003;
244–81. 92: 654.
7. Rust J, Golombok S. The GRISS: a psychometric instrument for 25. Rosen RC, Cappelleri JC, Gendrano N 3rd. The International Index
the assessment of sexual dysfunction. Arch Sex Behav 1986; 15: of Erectile Function (IIEF): a state-of-the-science review. Int J Impot
157–65. Res 2002; 14: 226–44.
8. Fineman KR, Rettinger HI. Development of the male function 26. Cappelleri JC, Rosen RC, Smith MD, et al. Diagnostic evaluation of
profile/impotence questionnaire. Psychol Rep 1991; 68: 1151–75. the erectile function domain of the International Index of Erectile
9. O’Leary MP, Fowler FJ, Lenderking WR, et al. A brief male sexual Function. Urology 1999; 54: 346–51.
function inventory for urology. Urology 1995; 46: 697–706. 27. McGahuey CA, Gelenberg AJ, Laukes CA, et al. The Arizona Sex-
10. Rosen R, Hatzichristou D, Broderick G, et al. Clinical evaluation ual Experience Scale (ASEX): reliability and validity. J Sex Marital
and symptom scales: sexual dysfunction assessment in men. In: Ther 2000; 26: 25–40.
Lue T, ed., et al. Sexual Medicine: Sexual Dysfunctions in Men and 28. Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological
Women. Paris: Health Publications, 2004: 175–220. Association Symptom Index for Benign Prostatic Hyperplasia. The
11. O’Leary MP, Barry MJ, Fowler FJ Jr. Hard measures of subjective Measurement Committee of the American Urological Association.
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148: 1546–8, discussion 1564. 29. Cappelleri JC, Althof SE, Siegel RL, et al. Development and valida-
12. The American Heritage Dictionary of the English Language, tion of the Self-Esteem and Relationship (SEAR) questionnaire in
4th ed. Boston: Houghton Mifflin, 2007. erectile dysfunction. Int J Impot Res 2004; 16: 30–8.
13. Likert R. A technique for the measurement of attitudes. Archives of 30. Althof SE, Cappelleri JC, Shpilsky A, et al. Treatment responsive-
Psychology 1932; 140: 44–53. ness of the Self-Esteem and Relationship Questionnaire in erectile
14. Heiman JR. Issues in the use of psychophysiology to assess female dysfunction. Urology 2003; 61: 888–92.
sexual dysfunction. J Sex Marital Ther 1976; 2: 197–204. 31. Althof SE, O’Leary MP, Cappelleri JC, et al. Sildenafil citrate
15. Quirk FH, Heiman JR, Rosen RC, et al. Development of a sexual improves self-esteem, confidence, and relationships in men with
function questionnaire for clinical trials of female sexual dysfunc- erectile dysfunction: Results from an international, multi-center,
tion. J Womens Health Gend Based Med 2002; 11: 277–89. double-blind, placebo-controlled trial. J Sex Med 2006; 3: 521–9.
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17. Barrisford GW, O’Leary MP. Male Sexual Dysfunction: Validated esteem and relationship questionnaire following treatment with
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18. Clayton AH, McGarvey EL, Clavet GJ. The changes in sexual 2005; 8: S54–60.
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subjects on the self-esteem and relationship questionnaire. J Sex 37. Brock GB, McMahon CG, Chen KK, et al. Efficacy and safety of
Med 2006; 3: 274–82. tadalafil for the treatment of erectile dysfunction: results of inte-
34. O’Leary MP, Althof SE, Cappelleri JC, et al. Self-esteem, confidence grated analyses. J Urol 2002; 168: 1332–6.
and relationship satisfaction of men with erectile dysfunction treated 38. Costa P, Buvat J, Holmes S, et al. Predictors of tadalafil efficacy in
with sildenafil citrate: a multicenter, randomized, parallel group, men with erectile dysfunction: the SURE study comparing two dos-
double-blind, placebo controlled study in the United States. J Urol ing regimens. J Sex Med 2006; 3: 1050–8.
2006; 175: 1058–62. 39. Rubio-Aurioles E, Porst H, Eardley I, Goldstein I. Comparing
35. Cappelleri JC, Rosen RC. The sexual health inventory for men vardenafil and sildenafil in the treatment of men with erectile
(SHIM): a 5-year review of research and clinical experience. Int J dysfunction and risk factors for cardiovascular disease: a random-
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47 Assessment of male
ejaculatory disorders
Raymond C Rosen, Stanley E Althof, and Tara Symonds

Introduction orgasmic function, sexual desire, intercourse satisfaction,

and overall satisfaction);7
Prevalence and impact of ejaculatory disorders • the Brief Sexual Function Inventory (11 items that focus
Orgasmic and ejaculatory disorders in men are highly on sexual drive, erection, ejaculation, perceptions of prob-
prevalent,1 although less well understood or recognized than lems in each of these areas, and overall satisfaction);8 and
erectile dysfunction (ED). Epidemiological studies have shown • the International Continence Society Sex Questionnaire
that both premature ejaculation (PE) and ejaculatory dys- (four items assessing erectile function, ejaculatory function,
function (EjD) are common in men.2–4 Recent studies have pain or discomfort during ejaculation, and the extent that
shown that about 30% of men in each age category have pre- urinary symptoms spoil the patient’s sex life).9
mature ejaculation, whereas the prevalence of EjD increases to
The Danish Prostate Symptom Score Sex questionnaire has
more than 50% in the 70 and over age group.4 Studies have
also been used to assess erection, ejaculation, pain or discom-
shown that at least half of men over age 60 with benign pros-
fort during ejaculation, and the bothersomeness of each of
tatic hyperplasia (BPH) and lower urinary tract symptoms
these items.10
have decreased or absent ejaculation.4,5 Additionally, EjD is
In this chapter we describe new PRO instruments that
commonly seen after pelvic or prostate surgery, and is a
specifically focus on disorders of ejaculation, both rapid and
reported side-effect of various medicines (e.g. alpha-blockers,
delayed. These new instruments will undoubtedly contribute
such as tamsulosin, and selective serotonin reuptake
significant new information to our understanding of these
inhibitors).5 One recent study showed a significant degree of
disorders. We will begin by discussing PE, and recent assess-
bother or psychological distress associated with delayed or
ment measures of that dysfunction. We then consider EjD and
absent orgasm or ejaculation in men,3 as has also been demon-
one new measure for assessing this disorder.
strated with PE.6 Unfortunately, in contrast to PE, few treat-
ments have been described for EjD. Clinically, the condition
is largely unrecognized.

Instruments for assessing male sexual function Definitions of premature

Patient self-assessment questionnaires are necessary and impor- ejaculation and problems with the
tant tools in assessing sexual function in a clinical setting.
Validated questionnaires, also known as patient-reported
current definitions
outcomes (PROs) play an integral role in the diagnosis and A universally accepted definition of PE remains to be esta-
treatment of male sexual dysfunctions. They are used to: blished. To date there are at least eight definitions of PE
offered by different professional organizations or resear-
• identify or diagnose men who suffer from sexual problems;
chers (Table 47.1).1,11–17 All but one were derived from the
• assess the severity of the dysfunction;
consensus opinion of experts, or from clinical wisdom; only
• measure improvement or satisfaction with treatment;
that of Waldinger et al.17 is the by-product of scientific data
• examine the impact of the dysfunction on the person’s
collection from a large observational study from the general
quality of life (e.g. relationship satisfaction, mood, sexual
population. All but two definitions13,17 suffer from excessive
confidence); and
vagueness, lack of precision and undue subjectivity on
• study the impact of the dysfunction on the partner and his
the part of the diagnostician. For example, let us examine
or her quality of life.
the definition of PE from the American Psychiatric
The most widely used PROs in the assessment of male Association:11
sexual function include:
• Persistent or recurrent ejaculation with minimal sexual
• the International Index of Erectile Function (IIEF; 15 items; stimulation before, on or shortly after penetration, and
five domains of male sexual function: erectile function, before the person wishes it.

353
354 Textbook of Erectile Dysfunction

Table 47.1 Definitions of premature ejaculation

Definition Offered by

Persistent or recurrent ejaculation with minimal sexual stimulation, before, on or American Psychiatric Association11
shortly after penetration and before the person wishes it. The condition must also
cause marked distress or interpersonal difficulty and cannot be due exclusively to
the direct effects of a substance.
For individuals who meet the general criteria for sexual dysfunction, the inability to International Statistical Classification of
control ejaculation sufficiently for both partners to enjoy sexual interaction, manifest Disease, 10th ed16
as either the occurrence of ejaculation before or very soon after the beginning of
intercourse (if a time limit is required, before or within 15 seconds) or the
occurrence of ejaculation in the absence of sufficient erection to make intercourse
possible. The problem is not the result of prolonged absence from sexual activity.
The inability to control ejaculation for a ‘sufficient’ length of time before vaginal European Association of Urology
penetration. It does not involve any impairment of fertility, when intravaginal (Guidelines on Disorders of
ejaculation occurs. Ejaculation)12
Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly International Consultation on
after penetration, and before the person wishes it, over which the sufferer has little Urological Diseases1
or no voluntary control, which causes the sufferer and/or his partner bother or
distress.
Ejaculation that occurs sooner than desired, either before or shortly after penetration, American Urological Association
causing distress to either one or both partners. (Guideline on the Pharmacologic
Management of Premature
Ejaculation)15
The man does not have voluntary, conscious control, or the ability to choose in Metz and McCarthy14
most encounters when to ejaculate.
The Foundation considers a man a premature ejaculator if he cannot control his Masters and Johnson13
ejaculatory process for a sufficient length of time during intravaginal containment to
satisfy his partner in at least 50 percent of their coital connections.
Men with an IELT of less than 1 minute (belonging to the 0.5 percentile) have Waldinger et al.17
‘definite’ premature ejaculation, while men with IELTs between 1 and 1.5 minutes
(between 0.5 and 2.5 percentile) have ‘probable’ premature ejaculation. In addition,
an additional grading of severity of premature ejaculation should be defined in terms
of associated psychological problems. Thus, both definite and probable premature
ejaculation need further psychological subclassification in nonsymptomatic, mild,
moderate, and severe premature ejaculation.
IELT, intravaginal ejaculatory latency time

• The disturbance causes marked distress or interpersonal control, poor sexual satisfaction, and distress.21,22 Recent pub-
difficulty. lications of observational data in men with and without PE
• The PE is not due exclusively to the direct effects of a have clarified the answer to this controversy.23–25
substance. The data suggest that the diagnosis of PE should be multi-
dimensional and include clearly defined thresholds of IELT,
How would a clinician objectively define ‘minimal sexual the man’s perceived control, sexual satisfaction, and distress.
stimulation’ or ‘shortly after penetration’ or ‘before the person Perceived control, sexual satisfaction, and distress can be
wishes’ or ‘marked distress or interpersonal difficulty’? One assessed via brief self-administered questionnaires with vali-
clinician’s interpretation of this definition is likely to differ dated cut-off points. There remains some controversy as to
from another clinician’s interpretation. the IELT threshold necessary to diagnose PE; further data
Despite the convincing criticisms leveled at the eight defi- analysis will probably resolve this debate.
nitions of PE (excessive vagueness, imprecision, and subjec-
tivity) there is significant overlap among them. Four common
factors emerge from the proposed definitions: intravaginal Patient-reported outcomes for
ejaculatory latency time (IELT), perceived control, distress, and premature ejaculation
interpersonal difficulty (related to the ejaculatory dysfunction).
Given these common factors, the issue becomes whether a Table 47.2 lists the PROs available to identify or diagnose men
diagnosis of PE should be uni-dimensional,18–20 based primarily with PE and PROs for detecting change when treating men
on a defined IELT threshold, or multi-dimensional, utilizing with PE. The psychometric properties of each measure are
a defined IELT threshold and the variables of perceived lack of described as well. Table 47.3 was compiled by reviewing the
 Table 47.2 Psychometric properties of measures of premature ejaculation

Instrument Population Factor analysis Reliability Validity Responsiveness MID Diagnostic tests

Internal Test–retest Convergent– Known- Sensitivity/ Positive &

consistency divergent groups Specificity negative
predictive
value

CIPE n = 169; Mean IELT: 1.6 (SD 1.2) × × × ×
× ×

minutes; 61% lifelong; 39%
acquired
Single-Item Two groups: n = 1587; n = 166 n/a n/a
×

× × ×
PROs DSM-IV clinician diagnosis;
DSM-IV clinician diagnosis plus
IELT 2 minutes >50% intercourse
episodes
IPE Study 1: n = 147 lifelong PE;




× × × ×
DSM-IV clinician diagnosis. IELT
mean 1.92 (SD 2.98) minutes.
Study 2: n = 939 acquired or lifelong
PE; DSM-IV clinician diagnosis,
IELT mean 3.9 (SD 37.4) seconds
MSHQ-EjD n = 1245 US men; n = 179




× × × ×
homosexual or bisexual men;
n = 6909 US men with lower
urinary tract symptoms and benign
prostatic hyperplasia; no details on
PE status within these samples
PEDT n = 292; IELT 66 (SE 1.78) seconds;



× ×
×
n = 309 self-reported PE; IELT 279.4
(SE 19.22) seconds
MID, minimum important difference; PE, premature ejaculation; CIPE, Chinese Index of Premature Ejaculation; Single-Item patient-reported outcomes (PROs), Control, Sexual Satisfaction, personal distress
and interpersonal difficulty; IPE, Index of Premature Ejaculation; MSQ, Male Sexual Quotient; MSHQ-EjD, Male Sexual Health Questionnaire-Ejaculatory Dysfunction; PEDT, Premature Ejaculation Diagnos-
tic Tool. SE, standard error; SD, standard deviation; DSM, Diagnostic and Statistical Manual; ✓, feature demonstrated; ×, feature not demonstrated.
Assessment of male ejaculatory disorders 355
356 Textbook of Erectile Dysfunction

Table 47.3 Psychometric properties of premature ejaculation measures

Instrument Population Factor Reliability Validity Responsiveness

analysis

Internal Test–retest Convergent Known

consistency or divergent groups
CIPE n = 169; mean IELT 1.6 × × × ×
×
(SD 1.2) minutes; 61%
lifelong; 39% acquired
Single-item Two groups: n = 1587; n = n/a n/a
×


PROs 166 DSM-IV clinician
diagnosis plus IELT, 2
minutes > 50% intercourse
episodes
IPE Study 1: n = 147 lifelong PE;




×
DSM-IV clinician diagnosis.
IELT mean 1.92 (SD 2.98)
minutes. Study 2: n = 939
acquired or lifelong PE;
DSM-IV clinician diagnosis;
IELT mean 3.9 (SD = 37.4)
seconds
MSHQ-EjD n = 1245 US men; n = 179




×
homosexual or bisexual men;
n = 6909 US men with lower
urinary tract symptoms or
benign prostatic hyperplasia;
no details on PE status
within these samples
PEDT n = 292; IELT 66 (SE 1.78)




×
seconds; n = 309 self-
reported PE; IELT 279.4 (SE
19.22) seconds
PE, premature ejaculation; CIPE, Chinese Index of Premature Ejaculation; IPE, Index of Premature Ejaculation; MSHQ-EjD, Male Sexual Health
Questionnaire-Ejaculatory Dysfunction; PEDT, Premature Ejaculation Diagnostic Tool. ✓, feature demonstrated; ×, feature not demonstrated

literature, and only those measures for which the reliability without PE, the sensitivity and specificity of the AIPE was
and validity is documented have been included. 0.98 and 0.88, respectively. No information regarding reliabi-
lity, treatment responsiveness, and meaningful differences is
available. The limitations of the tool are that it is only in Arabic,
Patient-reported outcomes to identify it was based on a relatively small sample of subjects, and impor-
or diagnose premature ejaculation tant psychometric parameters have yet to be determined.
There are three measures available to diagnose PE. The first, The third PRO, the Premature Ejaculation Diagnostic Tool
the Chinese Index of Premature Ejaculation (CIPE) has five (PEDT) is a five-item measure that evaluates difficulty in
items, which assess perceived time to ejaculation from intro- delaying ejaculation, ejaculating before the person wishes,
mission, ability to prolong intercourse time, sexual satisfaction, ejaculating with little stimulation, frustration related to ejacu-
partner satisfaction, and anxiety or depression related to sexual lating prematurely, and concerns about partner being sexually
activity.26 This measure does not appear to have had any unfulfilled.27,28 The items have good reliability and validity.
psychometric analyses conducted before the scoring system Additionally, the PEDT has excellent sensitivity and specificity
to diagnose absence or presence of PE. Although further val- and makes an ideal diagnostic tool.
idation appears necessary, the CIPE may be used to identify The limitation to using questionnaires in busy clinical prac-
men with PE, although it is not recommended as an outcome tices is the time required to have the patient complete the
measure. measure and the time necessary to score the PRO and make
The Arabic Index of Premature Ejaculation (AIPE) is a the diagnosis. However, all three measures are brief and are
seven-item self-report measure that assesses sexual desire, quickly completed and scored. They are less intrusive and
erectile function, ejaculation time and control, and mood. burdensome than asking patients to time lovemaking, and
Comparing the scores of clinician-diagnosed men with and they provide an immediate decision regarding diagnosis.
 Assessment of male ejaculatory disorders 357

Patient-reported outcomes for determining latency time.34 In the rat, postsynaptic 5-HT-1A and 5-HT-2C
treatment effects receptors appear to play a role in ejaculatory behavior.33 Based
There are five measures developed to assess the impact of on the results of animal studies, Waldinger suggested that
treatment on men with PE. A summary of the development hyposensitivity of 5-HT-2C receptors or hypersensitivity of
and validation of each PRO is given in Table 47.3. 5-HT-1A receptors (or both) may be responsible for prema-
The Premature Ejaculation Profile (PEP) contains four ques- ture ejaculation in humans.34
tions assessing perceived control over ejaculation, satisfaction
with sexual intercourse, personal distress related to ejaculation,
and interpersonal difficulty related to ejaculation.24 Each item Male Sexual Health Questionnaire
has been validated and has shown robust psychometrics. An To address the need for an instrument to assess specific
assessment of the items’ convergent and divergent validity aspects of ejaculation in older men, a new self-administered
needs to be considered, as does a criterion for showing a questionnaire, the 25-item Male Sexual Health Questionnaire
meaningful change such as minimum important difference (MSHQ), was recently developed and validated.35,36 The
(MID) or responder definition. MSHQ, which has domains for erection (three items), ejacu-
The advantage of the PEP is its brevity. However, this may lation (seven items), and sexual satisfaction (six items), pro-
also be a limitation since each domain (control, satisfaction, vides a more in-depth assessment of ejaculatory function and
distress, and interpersonal difficulty) consists of only one sexual satisfaction than the IIEF and other instruments. The
question, which may have an impact on the reliability of the ejaculation domain of the MSHQ assesses loss of ejaculation,
items and limit the sensitivity of each domain. delayed ejaculation, the force of the ejaculation, the amount
The Index of Premature Ejaculation with three domains of semen ejaculated, pleasure associated with ejaculation, and
covering control, sexual satisfaction, and distress, has also pain or discomfort during ejaculation. In validation studies,
shown strong psychometric properties.28 Responsiveness has the three domains of the MSHQ demonstrate a high degree of
yet to be shown and a minimal important difference/responder internal consistency, test–retest reliability, and construct
definition needs to be defined. validity as well as the ability to differentiate between men with
There are other measures mentioned in the literature; lower urinary tract symptoms and sexual dysfunction and
however, validation data are very sparse or non-existent. The healthy men.35,36
PEQuest was developed to investigate cognitive and partner- Of the three domains of the MSHQ, the ejaculation domain
related factors in PE.30 However, apart from information has the most significant correlation with severity of lower
about how it was developed, there is limited information given urinary tract symptoms. Linguistic validation studies of the
as to its validation. The Yonsei-Sexual Function Inventory-II MSHQ have been completed. The MSHQ is also being used
was similarly developed to assess various factors related to PE to assess sexual function in a national survey of US men. A US
(performance anxiety, patient and partner satisfaction, sexual observational BPH Registry is collecting data on patient out-
desire, and overall sexual function) but, again, there is no comes and the relationship of lower urinary tract symptoms
validation information in the literature to defend the mea- and BPH with sexual dysfunction37 and data from placebo-
sures used to assess outcome in PE clinical trials.31 controlled clinical trials of the effects of treatment with alfu-
zosin 10mg (on demand) on sexual function in men with
lower urinary tract symptoms and BPH. The results of these
studies will provide valuable new information on EjD in the
Ejaculatory dysfunction general population of men and specifically in those men with
BPH and lower urinary tract symptoms.
A less widely understood or recognized problem in men is
EjD. This refers to the loss of force or volume or to delay or
complete absence of ejaculation. This problem is highly age-
related, like ED, and is commonly reported in older men or Male Sexual Health Questionnaire –
men who have benign or malignant prostate disease. The Short Form
emission and ejaculation of semen can take place with or
without the subjective experience of orgasm. An abridged four-item MSHQ for assessing EjD – MSHQ-
The physiologic and pathophysiologic mechanisms of ejacu- EjD Short Form – with three ejaculatory function items and
latory function are not well understood, although current one ejaculation bother item has recently been developed.38
studies of neurophysiological measures are under way. This new screening measure demonstrates a high degree of
Emission (i.e. deposition of seminal fluid and sperm from internal consistency, reliability, and construct validity,
the distal epididymis, vas deferens, seminal vesicles, and pro- together with an ability to discriminate between men with
state gland into the posterior urethra) and ejaculation (i.e. no lower urinary tract symptoms or mild symptoms and those
expulsion of seminal contents through the urethral meatus) with moderate-to-severe symptoms. This four-item question-
are controlled by the sympathetic and somatic nervous naire adheres to the measurement properties for patient-
systems. Both emission and ejaculation involve contractile administered outcome instruments as described in draft
processes.32 Central serotoninergic neurotransmission may guidance issued in 2006 by the US Food and Drug
also play a role in ejaculation.33 Interestingly, the stimulation Administration,17 and it should provide healthcare profes-
of different serotonin (5-hydroxytryptamine, 5-HT) receptor sionals with an easy-to-use instrument for assessing EjD in
subtypes can result in an increase or decrease in the ejaculatory everyday clinical practice.
358 Textbook of Erectile Dysfunction

Overall, the topic of ejaculatory dysfunction (EjD) has been anticipated, will contribute substantially to the development
neglected in comparison with other common male disorders, of new management approaches in the coming years. We
notably ED and PE. In part, this may be due to the lack of anticipate that these new PRO scales will be used increasingly
available treatments for EjD. However, the recent availability in preference to stop-watch or other objective measures, since
of a validated questionnaire measure (MSHQ) for assessing they more accurately reflect the patient’s and partner’s views
components of EjD, and the recent publication of a brief, of the sexual problem and area of greatest distress. In the PE
screening tool (MSHQ-Short Form) could raise awareness and literature, this has been shown to be the domain of ejaculation
stimulate research or practice in this area. Based on the results control. For EjD, it is the loss of force and volume of ejacula-
of the Multinational Survey of The Aging Male (MSAM-7),4 tion that causes maximum distress for patients. Sensitive and
men with problems of ejaculatory dysfunction were almost as reliable PRO scales such as those described in this chapter
bothered as men with ED by the presence of this problem. are the optimal means for assessing these effects.
Specifically, more than half the men in that study with EjD Further studies are needed to characterize fully the psycho-
reported being bothered by the problem. Since loss of ejacula- metric properties of the scales described in this chapter. Cross-
tory function is a common result following prostatectomy cultural studies are urgently needed, and further studies of
surgery, the scale may have particular benefit in assessing EjD treatment sensitivity would enhance our understanding of
prior to or following prostatectomy surgery. Additionally, the each of these measures. The clinical utility of these measures
scale may be of value in assessing the response to treatment also needs to be further addressed, in addition to the profile
in sexually active men being treated with alpha-blockers or of responses in patients with chronic medical or psychiatric
5-alpha-reductase inhibitors. conditions. Medication effects also need to be more fully
investigated.
In summary, ejaculatory problems (PE, EjD) are highly
Future directions prevalent and potentially bothersome sexual problems in
men. Greater attention has been given to erection problems in
Ejaculatory disorders (PE, EjD) have received less attention recent years, although studies have indicated that ejaculatory
than ED in both the clinical and research literature in recent problems may be almost as common and a potential source of
years. As a result, measurement approaches are less developed, distress for many men and their partners. New questionnaires
and adequate PROs for PE and EjD have only recently and validated assessment tools have been developed, and these
become available. The availability of these new measures, it is are recommended for clinical and research purposes.

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48 Clinical trial design for
erectile dysfunction
Michael G Wyllie

Introduction phase of the drug trials process addresses different and specific
areas of investigation or groups of questions, the outcomes of
It is estimated, from 2001–2002 data, that erectile dysfunction which support subsequent phases. It is essential that clinical
(ED) was self-reported by one in five men in the USA.1 trials be conducted in compliance with the most recent stan-
However, the prevalence may be higher, since the rate of ED dards of Good Clinical Practice (GCP). These standards
identified by the International Index of Erectile Dysfunction ensure that the design, conduct, performance, monitoring,
five-item index (IIEF-5)2 has been shown to be nearly twice auditing, recording, analyses, and reporting of clinical trials
that of self-reported ED.3 During the past 20 years there has are performed to common standards and provide assurance
been fundamental change in the way in which ED is treated that the data and reported results are credible and accurate,
and also the attitudes of both the medical profession and the and that the rights, integrity, and confidentiality of trial
general population to this condition. Prior to 1995, when the subjects are protected.
first treatment for ED (intracavernosal alprostadil) was
approved in the USA by the Food and Drug Administration, Phase 1 trials
treatment of ED had been limited to psychotherapy and
Phase 1 trials are usually conducted in healthy young volun-
vacuum tumescence devices, and many considered the
teers and may be followed by the same study performed in
condition to be an inevitable consequence of the aging pro-
older volunteers. As these trials are the first time the drug is
cess. However, further understanding of the physiology of
administered to humans, it is important that suitable precau-
erectogenesis and the pathophysiology of ED has resulted in
tions are incorporated into the study design to ensure the
the development of effective therapies with different modes of
safety of the volunteers and subjects. Such trials are usually
application: intracavernosal injections, intraurethral adminis-
conducted in a hospital or a clinical research unit where
tration, and oral therapies. The launch of the first oral agent
adverse events and any toxicity can be carefully monitored
(sildenafil) in 1998, a decade ago, has not only increased the
and managed.
awareness and acceptance of ED as a treatable condition but
The overall objectives of phase 1 trials are the evaluation of
has also resulted in the diagnosis and treatment of ED by pri-
tolerability, safety, and pharmacokinetics, and they usually
mary care physicians, where previously it had been the domain
involve single and multiple dose studies.
of the urological specialist. Thus, it is important that not only
Dose selection for phase 1 studies is based on the results of
the urologist but also the general practitioner should be famil-
preclinical toxicological, toxicokinetic, and safety studies in
iar with the interpretation of clinical trials for ED so that they
animals and previous in vitro studies. The initial dose selected
are able to make informed decisions in treatment planning
(extrapolated to humans) is usually much lower than the
and in offering the appropriate therapy.
no-observed-adverse-effect level (NOAEL) and the toxic dose
Although the market for products to treat ED has now been
in animal models. The initial dose is often then escalated (in
established, there are various agents in development, both
increments of 2: one-fold, two-fold, four-fold and so on)
oral and other (e.g. nasal, inhaled or intracavernosal). Regula-
either using the same group of volunteers or a new cohort,
tory approval is based on the indication and need for the drug,
until a maximally tolerated dose is reached, thus establishing
the therapeutic outcomes, and the adverse events profile. For
a dose range with regard to tolerability.
non-life-threatening conditions such as ED, the risk–benefit
Safety assessments such as vital signs, electrocardiography,
profile of the drug is important, especially for patients with or
clinical observations, and reported and observed adverse
receiving medication for cardiovascular disease. This chapter
events should be regularly and frequently monitored and
seeks to outline the current acceptable methodologies for ED
recorded throughout these trials. Blood and urine samples are
clinical trials and also to provide guidance on the evaluation
also taken at frequent intervals to study the pharmacokinetics
of data for these trials.
of the drug and its metabolites in humans (including maxi-
mum plasma concentration, time to maximum plasma con-
Rationale and design of clinical trials centration, the average plasma concentration, area under the
concentration–time curve, and elimination half-life). It is
Development of drugs for ED, or indeed any indication, important that these pharmacokinetic parameters are deter-
requires a carefully phased and progressive approach. Each mined for single and multiple doses of different strengths, but
360
 Clinical trial design for erectile dysfunction 361

also other variables that may affect the pharmacokinetics of progression to the second stage in which a further 25 or so
the drug and its metabolites are examined (e.g. age, dosing patients are recruited.
with or without food, and frequency of dosing). The meta- Assessment of efficacy may involve both objective mea-
bolic pathway of the drug in humans may also be established sures, such as penile tumescence determined by Rigiscan or
during these phase 1 studies, which could be indicative of duration of certain degrees of rigidity, or subjective measures,
potential drug interactions or special precautions needed in such as daily diaries, patient-reported outcomes, IIEF,5 and
compromised patients such as those with renal or hepatic quality-of-life questionnaires. Shortened versions of these
impairment. subjective measures may be employed as the outcomes from
In phase 1 trials of drugs intended for the treatment of ED, phase 2 studies do not serve as ‘pivotal’ data and so time and
it is often difficult to undertake any preliminary efficacy cost can be reduced.
assessments as these are often distracting (e.g. use of the Rigi- It may also be appropriate to investigate more specific safety
scan device with visual sexual stimulation) and may interfere issues in small groups of patients such as special populations,
with more critical objectives of this phase, namely the assess- drug interactions and selected organ system risks (e.g. cardio-
ment of tolerability, safety, and adverse events. vascular, neurological, liver, eye).
Thus, on completion of phase 1 the following outcomes During phase 2, it is important to explore a wide range
should be achieved: the determination of an initial dose range of doses and establish the lowest effective dose and the maxi-
in terms of safety, the pharmacokinetic profile of the drug and mally tolerated dose and doses at which toxicity is apparent,
its metabolites, and the identification of commonly occurring allowing calculations of the potential benefit–risk ratio.
side-effects. Phase 2 studies are becoming an important decision-
making stage in drug development for ED. Early identification
of a positive safety profile (in particular in terms of cardiovas-
Phase 2 trials cular risks) is beneficial since this is becoming an increasingly
The objectives of phase 2 trials are to characterize the significant issue with regulatory authorities, especially in
preliminary efficacy of the drug and to evaluate safety the treatment of conditions that are not associated with mor-
further. bidity.6 In addition, the safety and efficacy results of phase II
These studies are conducted in larger groups (ranging studies are indicative of those expected in the larger, more
from 25 to several hundred) and in patients with ED. These time-consuming and costly phase 3 trials and may be impor-
study populations may also include men in high-risk groups tant in deciding whether or not to progress with the drug’s
(e.g. those with comorbid hypertension or diabetes) or patients development.
who are ‘treatment-resistant’. Early indications of efficacy
and safety in these patient subgroups are useful for decision-
making and the planning of phase 3 trials. Phase 3 trials
Trial designs used in phase 2 are similar in scope to those The objective of phase 3 trials is to establish the body of
in phase 3 but have shorter treatment periods and smaller evidence, both for efficacy and for safety, that will provide the
numbers of patients. Crossover designs are more commonly basis of regulatory approval for the drug.
used in this phase since these have the advantages of allowing Phase 3 trials for ED are usually multicenter, randomized,
the patient to act as his own control, giving intra-individual double-blind, and placebo-controlled. The simplest design
comparison and thus reducing sample size and expenditure commonly employs parallel arms of fixed dose in which
(Figure 48.1). A two-stage design may also be incorporated,4 each patient is exposed to one treatment condition only and
which provides an early decision-making point in terms of the inter-group comparisons are made at various time points
response level. If the response level is low in the first stage (Figure 48.2). Efficacy may be assessed by analysis of inter-
(15–25 patients) then the study may be terminated early, group differences following treatment or change relative to
reducing the number of patients exposed to the drug. A high baseline. The duration of such trials is usually 12 weeks, which
or acceptable response level in the first stage will then justify is deemed sufficient time to predict efficacy over a reasonable
Outcome evaluation

Outcome evaluation

Active Active
Randomization

treatment treatment
Patients
Baseline
reporting
assessment
ED

Placebo Placebo

Screening Treatment phase 1 Crossover Treatment phase 2

Figure 48.1 Crossover design commonly used in phase 2 erectile dysfunction (ED) trials.
362 Textbook of Erectile Dysfunction

1 month 12 weeks 6 months

Randomization
Active treatment

Patients
Baseline
reporting Active treatment
assessment
ED

Placebo

Screening Controlled treatment phase Open-label extension

Figure 48.2 Parallel arm design commonly used in phase 3 erectile dysfunction (ED) trials.

dosing period and not so long as to result in excessive P450 liver isoenzyme that may be critical to a drug’s elimina-
drop-out of placebo patients. tion). Pharmacodynamic drug interactions are unrelated to
Crossover designs may also be used, with the advantage of the pharmacokinetic interactions but are those in which the
reducing patient variability, although this may result in a bias combined physiological effect may produce a clinically mean-
towards a positive outcome and be insufficient as a basis for ingful event, such as lowering of blood pressure or increase in
regulatory approval. With the crossover design, consideration heart rate. For investigation of both of these types of drug
should also be given during the planning and analysis of interactions, the end-points will be pharmacodynamic, such
the data to carry-over effects or sequence effects between as vital signs, effects on cognitive function and sedation, or
treatment phases. more specific measures such as prolongation of the corrected
There should be a baseline assessment period prior to QT interval, QT dispersion, and shape of the T wave on
randomization, during which baseline measures are obtained electrocardiogram.
and patients can be screened and their eligibility assessed. Special population studies may also be relevant in phase 3,
Baseline periods are usually treatment-free but could include again considering that ED patients tend to be older and
single-blind placebo treatment to determine potential patient to have comorbid conditions (e.g. diabetes, cardiovascular
compliance or to identify patients who are most susceptible disease), may have impaired renal or hepatic function, may
to ‘placebo effects’. The controlled treatment period is often have undergone prostatectomy or pelvic radiation therapy, or
followed by an open-label extension (6 months to 2 years) may have spinal cord injury, multiple sclerosis or depression.
during which longer-term safety data can be collected. It should be noted that special population studies are often
The choice of the primary efficacy end-point (or end- powered to assess safety rather than efficacy.
points) is important for phase 3 trials, and reliable, sensitive,
and validated measures that produce suitable data for clear
analysis should be used. Recent ED trials have employed a Phase 4 studies
combined end-point consisting of the erectile function (EF) Phase 4 studies are those conducted after approval, when the
domain of the IIEF and questions 2 and 3 of the Sexual drug has been marketed, they may be requested by regulatory
Encounter Profile (SEP) diary (ability to penetrate and ability bodies or performed voluntarily. The reasons for undertaking
to maintain erection to completion of intercourse). The use of these trials are various and diverse. They afford the opportu-
this end-point has been shown to give reliable, reproducible nity to assess longer-term safety, to address specific safety
and comprehensible data that have proved acceptable to issues that did not prevent approval, and to assess further effi-
regulatory authorities, and it is also sensitive enough to detect cacy and safety in patient subgroups or special populations.
small treatment effects. Comparator trials of efficacy with competitor products
Regulatory authorities may also require that any specific or already on the market may also be conducted and may pro-
potential safety issues are addressed at this stage, such as vide useful data for marketing claims. Similarly, studies that
special patient populations and drug interactions, especially address health economic issues (e.g. overall drug benefit or
since tolerance of any risk associated with ED drugs is low. comparative costs) or quality-of-life issues may provide
Many men with ED are middle-aged and have comorbid con- supportive marketing information. Marketing studies should
ditions for which they take concomitant medications. There be conducted and analyzed with the same rigor as the pivotal
are two categories of drug interaction that should be consid- phase 3 studies.
ered: pharmacokinetic and pharmacodynamic drug interac-
tions. Pharmacokinetic drug interactions are those in which a
concomitant medication may affect the bodily exposure to the Selection of study populations
investigational drug. For example, inhibition of the metabolic
pathway of the ED drug by a concomitant drug would result As previously mentioned, phase 1 trials are conducted in small
in raised serum levels of active metabolites, thus potentiating numbers of healthy volunteers. For all other phases in which
the effect of the ED drug (e.g. inhibition of a cytochrome patients with ED are studied, and especially in phase 3, the
 Clinical trial design for erectile dysfunction 363

selection of the study population is of utmost importance Inclusion and exclusion criteria
since this will determine the value of the data. In phase 3, studies are usually conducted in ED patients, and
The study population should be representative of the over- inclusion criteria generally capture patients who are 18 years
all patient population for whom the drug is intended. This of age or older (there is usually no upper age limit), hetero-
will allow prediction of the utility of the drug in ‘real life’ once sexual, and in a stable monogamous relationship with a part-
marketed, and is of particular importance for ‘pivotal’ phase 3 ner who is willing to support participation in the trial. Men
trials. It is also important for the purpose of these trials that must specifically complain of ED, which is defined as ‘a con-
ED is well defined and characterized so that the data can sistent difficulty in achieving and/or maintaining an erection
be easily interpreted by both the regulatory authorities and sufficient for sexual intercourse’, and their ‘dysfunction’
prescribing physicians in the future. should have a negative impact on their satisfaction or enjoy-
Patients with various degrees of ED severity should be ment of the overall sexual experience. Their ED should be a
included. Based on the data from the Massachusetts Male consistent rather than a transient problem and it is generally
Aging Study (MMAS),7 two-thirds of ED patients in the USA accepted that it should be of a minimum of 3 months’ dura-
with erectile failure have moderate or severe ED. Disease tion. Some trials include a ‘run-in’ period during which base-
severity is usually categorized using the EF domain of the line ED can be assessed (rather than relying on patient history)
IIEF, which has a score range of 6 to 30. A score of <10 indi- and patients whose ED is not significant in terms of being
cates severe ED, 10–16 moderate ED, 17–24 mild ED and consistent (e.g. >75% of attempts) can be excluded at this
≥25 no ED. Although it may be considered that those with stage. Commonly employed exclusion criteria for recent trials
severe ED may be more treatment-resistant and those with in ED are shown in Table 48.1.
milder disease may only have a small or modest response to
the drug, these patient groups are representative of the gen-
eral population and should be included even though clear
demonstration of efficacy with these patients may be more Table 48.1 Typical exclusion criteria employed in
difficult. erectile dysfunction trials
The incidence of comorbidities in the general population
should be represented in the ED study population (e.g. diabe- Patients with penile deformities (e.g. Peyronie’s disease) or
tes, coronary artery disease, hypertension, hyperlipidemia, penile implants
and tobacco use). In the MMAS, the incidence of hypertension Patients with predispositions to priapism (e.g. sickle cell
was 33%, of coronary artery disease 16%, and of diabetes 9%, disease, blood dyscrasias, multiple myeloma)
and previously most large-scale trials have recruited such Patients with untreated hypogonadism
representative populations. However, the incidence of
Patients with uncontrolled diabetes (elevated glycosylated
comorbidites does not give an indication of their nature of
hemoglobin levels)
severity (e.g. the type of diabetes or the presence of diabetic
complications). Patients with significant baseline liver dysfunction (baseline
aspartate aminotransferase or alanine aminotransferase
In defining patient populations, disease etiologies should
levels > three times the upper limit of normal)
also be considered. Many patients with ED have comorbidi-
ties or predisposing factors that are contributory to the Patients with significant baseline renal dysfunction (serum
etiology of their disease (e.g. diabetes, hypertension, hyper- creatinine values <2.5mg/dl) or those on dialysis or post
renal transplant
lipidemia, atherosclerosis, tobacco use, genitourinary dis-
orders, neurological disorders, endocrinopathies, depression) Patients with a history of HIV infection
or they may have ED of a psychogenic etiology. However, many Patients with drug, alcohol, or substance abuse within 6
of these conditions often co-exist, and classifying etiology months of study initiation
as ‘organic’, ‘psychogenic’, or ‘mixed’ can create unrealistic Patients who have participated in another study for the
subgroups that may confound the interpretation of the results. treatment of ED within 30 days of study initiation
Additionally, the assignment of etiology from the patient’s Patients who have partners who are nursing or pregnant
history without investigation (nocturnal penile tumescence or or who wish to become pregnant during the course of the
vascular studies) may also contribute to ambiguity in such study
classifications. Patients who are unable to provide informed consent
Patients in ‘special populations’ (e.g. post-prostatectomy
Patients with uncontrolled psychiatric disorders, such
patients, spinal cord injury patients, men with more severe
as psychosis, manic depressive disorders, or chronic
ED, patients in whom other therapies have failed) should also depression
be studied in smaller trials, which may provide useful results
Patients for whom sexual activity may put them at risk of a
that support the larger ‘pivotal’ trials.
cardiovascular event, such as those with:
The selection of the ‘representative’ study population is
achieved by careful consideration and balancing of inclusion • unstable angina
and exclusion criteria. However, patients whose health may be • uncontrolled hypertension (systolic pressure
compromised by the study drug or by participation in sexual >170mmHg or diastolic pressure <100mmHg)
• a history of myocardial infarction, life-threatening
activity should not be included, although the exclusion crite-
cardiac arrhythmias, or stroke (within 6 months of study
ria should not be so stringent as to restrict patient recruitment
initiation)
to the study.
364 Textbook of Erectile Dysfunction

It is also important to consider the contraindications for interpret the clinical relevance of very small point changes
drugs of a similar class or mode of action as the investigational from baseline scores for individual domains. It is also interest-
agent (e.g. the exclusion of patients using nitrate therapy in ing to note that although so widely used as a trial end-point,
trials of a phosphodiesterase type 5 inhibitor). the IIEF has only been validated for use with all 15 questions
and not just the two items of the EF domain.
An abridged version of the IIEF questionnaire (consisting
of five items) has been developed (the Sexual Health Inventory
Outcome assessments for Men) to allow for more rapid diagnosis of ED and assign-
ment of severity.2
Currently the primary end-points of most ED trials are Patient diaries (per-event questionnaires) are used to
patient-reported outcomes of sexual function. This represents complement retrospective questionnaires and have been
a shift from the development of earlier ED drugs, for which widely used in phase 3 trials. The SEP is one such six-item
objective or ‘physiological’ outcomes were used as primary instrument; it has undergone some validation and shows
end-points. a good degree of correlation with regard to the erection
and intercourse satisfaction ratings with the measures of
the IIEF.9
Physiological measures Quality-of-life questionnaires have been used as secondary
Physiological measures continue to have a role in phase 2, end-points, but because most of these generalized instru-
proof-of-concept studies, in which the pharmacodynamic ments tend to address patients whose health is more compro-
effect of the drug is established. The blood flow through the mised than that of the ED patient (e.g. those with cognitive
cavernosal arteries can be assessed using ultrasonography, but and physical impairment), the results have not been regarded
the most commonly used method is the Rigiscan device as important by regulatory authorities. However, more dis-
(Timm Medical Technologies) which measures radial rigidity ease-specific quality-of-life questionnaires have been devised
of the penis via two loops placed at the base and tip of the and, although they continue to be used as secondary end-
penile shaft and is used with visual sexual stimulation. Tests of points, the outcomes may provide support for long-term
this nature do have limitations in that they are intrusive and risk–benefit evaluation.
‘artificial’ and there is also some contention as to whether
radial rigidity is indicative of the axial rigidity required for
intromission.8 There may also be some difficulty in defining Safety assessments
clinically meaningful rigidity (and duration of erection),
though it is generally accepted that a 55% rigidity at the base Safety evaluation and monitoring of clinical adverse events is
(as measured with Rigiscan) is sufficient for intercourse. fundamental and routine in ED clinical trials and should be
Although this and other methods of penile plethysmography conducted in the ‘per-protocol’ population and include data
may be considered to have their drawbacks, they do provide from placebo-treated patients. It should also be noted that in
objective measurements of tumescence and data that may be most trials, the size of the patient population is selected to
used to support other outcome variables. demonstrate efficacy end-points and thus may be underpow-
ered to assess reliably the frequency of side-effects.
Two methodologies for collecting adverse events data are
Patient-reported outcome measures commonly used: symptom checklists and structured inter-
The most commonly used measures are self-administered views. The use of specific questions (checklists) to prompt the
questionnaires (e.g. IIEF) and patient diaries (e.g. SEP). Other reporting of particular or expected adverse events is not used
patient-reported response variables include structured inter- in phase 3 and more ‘open’ questions are commonly employed.
views, global questions regarding symptom improvement, Symptom checklists have the advantage of standardizing
and quality-of-life questionnaires. reporting within and between trials, but the structured inter-
The IIEF is currently the ‘gold standard’ in ED clinical view will allow for the recording of unexpected adverse
trials, since it has been extensively validated2 and has been events.
found to be reliable, responsive (in terms of sensitivity Data may be reported as either per-patient incidence or per
and specificity), easy to use, and has been translated and administration. The per-patient incidence has been widely
re-validated in many languages. The IIEF consists of 15 ques- used in most previous ED trials and is useful in giving an indi-
tions and assesses sexual function in five domains (erectile cation of the probability of a patient experiencing that side-
function, orgasmic function, sexual desire, intercourse satis- effect, whereas the per-administration incidence will indicate
faction, and overall satisfaction). The EF domain score whether the adverse event consistently occurs. Adverse events
(maximum score 30 points) is a commonly used primary are reported as mild, moderate, or severe, and they are also
end-point, although some trials have used questions 3 and 4 classified as being possibly, probably, or definitely related to
of the EF domain (maintenance of erection on penetration the study medication. Such classification of causality is
and maintenance of erection to completion of intercourse) as assigned by the study investigator and as such is subjective in
stand-alone primary end-points. The IIEF may also be used to nature; thus care should be taken in the comparison of adverse
stratify patients according to their baseline severity of ED and events profiles from different trials.
then demonstrate change within these groups. Drawbacks of Controlled trials of 1–2 years’ duration and long-term
the questionnaire are that it is retrospective (relating to the follow-up in phase 4 provide invaluable evidence for the
previous 4-week time period) and that it may be difficult to overall clinical adverse events profile of a drug. The occurrence
 Clinical trial design for erectile dysfunction 365

Table 48.2 Guidance notes for the interpretation of clinical trials in ED

Trial design Crossover design Patient acts as own control giving low patient variability
There may be a potential carry-over effect of treatment to the next study phase
This design may lead to a bias towards positive outcomes
Baseline measures A no-treatment, run-in phase allows determination of baseline severity of ED
Single-blind, A run-in including single-blind, non-active treatment allows for indication of treatment
run-in compliance and screening for patients susceptible to placebo response
Duration Most phase 3 ED trials are a minimum of 8 weeks’ treatment – most often 12 weeks
Patient Age A patient population with a mean age of >50 years may lead to overestimation of efficacy
populations and underestimation of adverse events and hemodynamic effects
‘Responders’ Including ‘responders’ (especially to agents of the same therapeutic class) may exclude
patients with more severe ED and not be representative of the general population
Ethnicity Most ED trials to date have enrolled 85% white patients. Care should be taken in
extrapolating such data to other ethnic populations (e.g. Black, Asian, Hispanic)
Baseline severity A study population with two-thirds of patients having moderate-to-severe ED is thought to
be representative of the general population
Data from trials in patients with lesser baseline ED severity should be interpreted with
caution
Etiology If etiology of a patient’s ED has been assigned by history and physical examination,
without further investigations, then such diagnoses and assignment of etiology may not be
accurate
Comorbidities The incidence of comorbidities (e.g. diabetes, coronary artery disease, hypertension,
hyperlipidemia and tobacco use) in a study population should be similar to that of the
general population
Incidence of comorbidities should be used only as a general comparison since it does not
give information on the severity of the comorbidity
End-points Primary Primary end-points should be assessed at baseline, during treatment, and at the end of
treatment
The EF domain of the IIEF and the SEP event log (questions 3 and 4) are the most widely
used primary end-points
Secondary Global questions of efficacy and quality-of-life questionnaires tend to be used as
secondary end-points
Physiological Objective measures of tumescence (e.g. Rigiscan) are more commonly used as end-points
in phase 2 trials
Adverse Methods Symptom checklist allows standardized reporting within and across trials
events Open questioning allows information on unexpected side-effects to be captured
Patient population Patient numbers for most phase 3 trials are selected to demonstrate efficacy end-points
and may be underpowered to assess frequency of side effects reliably
Safety analyses should be conducted in the ‘per-protocol’ population to capture
withdrawals due to adverse events
The side-effect profile in placebo-treated patients should also be presented for
comparison
Incidence of Data are usually presented as per-patient incidence, which indicates the probability of a
adverse events patient experiencing the side effect. However, this does not give an indication of the
consistency of the side-effect (e.g. whether it is likely to occur with every administration)
Severity and Adverse events are usually described as being possibly, probably, or definitely related to
causality the investigational agent. These categories are usually investigator-assigned and caution
should be exercised when making inter-trial or inter-agent comparisons
ED, erectile dysfunction; EF, erectile function; IIEF, International Index of Erectile Function; SEP, Sexual Encounter Profile

of a low incidence of adverse events that are medically signifi- Data analysis and
cant should also be considered as these may only be apparent
in studies of large sample size. Alternatively, it may be appro- statistical considerations
priate to conduct trials designed to address specific safety
It is important that a biostatistician is consulted both in the
issues, such as the drug’s effect on cardiovascular parameters,
design and data analysis of clinical trials in ED (in particular
vision, and cognitive functioning, or drug interactions.
phase 3 trials). Such an expert can advise on issues such as
366 Textbook of Erectile Dysfunction

sample size and power, the statistical model, the optimum standardized it is preferable to use several measures of efficacy,
design to employ (having considered the trial objectives), and including quantitative measures (e.g. number of successful
whether the use of covariate analyses might be appropriate. attempts of intercourse) and qualitative measures (e.g. global
For analysis of efficacy outcomes, the intention-to-treat satisfaction).
(ITT) population should be considered – that is, data from all The use of covariate analyses may be appropriate when dif-
randomized patients should be included. If the data from only ferences in baseline characteristics of study groups exist. Such
those patients completing the study are analyzed, then a bias analyses include the degree of ED, age, duration of ED, and
in results may be induced. However, the ITT principle should other demographic characteristics.
not be applied to the analysis of adverse events, where
withdrawal from the study may have been due to side-effects
or an adverse event. Interpretation of clinical trials
The magnitude of treatment effect in ED trials may be
described using various measures, such as the group mean Interpretation of clinical trials for ED requires careful consid-
change from baseline or the percentage of responders in active eration of study design, study populations and enrolment,
versus control groups. Use of the latter requires prior defini- efficacy end-points and side-effect profiles.9 Although it is
tion of a ‘responder’, and there are currently no widely agreed tempting to compare outcomes of different trials, only the
defining criteria of an ED responder. The definition of a data from head-to-head comparator trials should be consid-
responder is also confounded by the fact that no normative ered meaningful. Some of the key points that should be con-
data exist for what is considered ‘acceptable’ sexual perfor- sidered when evaluating the results of a clinical trial in ED are
mance in differing age groups. Thus, since this measure is not shown in Table 48.2.

REFERENCES

1. Saigal CS, Wessells H, Pace J, Schonlau M, Wilt TJ. Predictors and 5. Rosen RC, Riley A, Wagner G, et al. The International Index of
prevalence of erectile dysfunction in a racially diverse population. Erectile Function (IIEF): a multidimensional scale for assessment of
Arch Intern Med 2006; 166: 207–12. erectile dysfunction. Urology 1997; 49: 822–30.
2. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM. Develop- 6. Wyllie MG. Clinical trials for aspiring dummies (and urologists).
ment and evaluation of an abridged, 5-item version of the Interna- BJU Int 2007; 99: 939–40.
tional Index of Erectile Function (IIEF-5) as a diagnostic tool for 7. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB.
erectile dysfunction. Int J Impot Res 1999; 11: 319–26. Impotence and its medical and psychosocial correlates: results of
3. Wu CJ, Hsieh JT, Lin JS, et al. Comparison of prevalence the Massachusetts Male Aging Study. J Urol 1994; 151: 54–61.
between self-reported erectile dysfunction and erectile dysfunc- 8. Udelson D, Park K, Sadeghi-Nejad H, et al. Axial penile buckling
tion as defined by five-item international index of erectile forces vs Rigiscan radial rigidity as a function of intracavernosal
function in Taiwanese men older than 40 years. Urology 2007; 69: pressure: why Rigiscan does not predict functional erections in indivi-
743–7. dual patients. Int J Impot Res 1999; 11: 327–37; discussion 337–9.
4. Simon R. Optimal two-stage designs for phase II clinical trials. 9. Mulhall JP. Deciphering erectile dysfunction drug trials. J Urol
Control Clin Trials 1989; 10: 1–10. 2003; 170: 353–8.
49 Sexual function in
congenital anomalies
CRJ Woodhouse

Introduction patients can now live a normal life and, in the past 20 years,
can expect to have a normally working bladder. Although it
All of the problems that are commonly seen in an andrology has always been recognized that the penis required recon-
clinic may be the result of the major congenital genitourinary struction as well, a good functional result for sexual inter-
anomalies (Table 49.1). Surprisingly, most of those affected course was not always achieved. The exstrophy patient now
have a rather better sex life than might be expected. Further- grows up in normal society and has the same sexual and
more, the recent advances in the management of male infertil- reproductive aspirations as his peers. My clinical impression
ity will be of particular benefit to those whose testes are normal is that their libido is as high as that of other adolescents. It is
but whose ejaculatory function is compromised by their a matter of priority to reconstruct the genitalia to allow
anomaly or its reconstruction. normal intercourse to take place. (In this section, the terms
Gross as some of these abnormalities are, very few ‘exstrophy penis’, and ‘exstrophy pelvis’ encompass the same
commonly cause erectile failure. The main exception is severe anomalies in epispadiac patients.)
myelomeningocele. General sexual function may be compro-
mised for six possible reasons.
Genital anatomy in exstrophy
1. The penis may be grossly malformed (e.g. exstrophy,
The anatomy of the exstrophy pelvis and penis is obviously
micropenis).
abnormal, the details of which have been investigated clini-
2. The penis may be a little deformed but the patient’s
cally, by cavernosography, computerized tomography (CT),
perception may so exaggerate the deformity that sexual
and magnetic resonance imaging (MRI), by experimental
function is impaired (e.g. hypospadias).
models and by dissection.1
3. Obstructive lesions of the bladder outlet may cause
The visible part of the penis (Figure 49.1) is short – not, as
back pressure on the prostate, leading to ejaculatory
might be thought, because most of the penis is buried in the
failure and seminal abnormalities (e.g. posterior urethral
perineum. However, the penis is longer if the divarication of
valves).
the pubic bones is 3cm or less and it is shorter if the divarica-
4. Developmental failure may impair hormonal or ejacula-
tion is 4cm or more.2 In the past, surgical apposition of the
tory function (e.g. prune belly syndrome).
pubic bones was said not to lengthen the visible penis. Some
5. Penile innervation may be incomplete (e.g. spina bifida)
evidence suggests that the visible penis is longer if the pelvic
or destroyed by pelvic surgery.
ring is closed.3 Osteotomies performed in infancy may
6. Embarrassment about some aspect of the general abnor-
be more effective in producing a normal penis, at least in
malities may prevent the formation of a partnership in
childhood.
which intercourse can take place (e.g. an external urinary
MRI investigation of the normal and the exstrophy penis
diversion).
has established that, whatever the condition of the pelvic ring,
Whatever the anomaly, it should always be assumed that erec- the exstrophy penis is short but broad. The total corporeal
tile function and intercourse are desired and possible until length was 60% greater in normal subjects (16.1cm, versus
proved otherwise. It is astonishing how severe handicaps can 10.1cm in exstrophy).4 Most of this deficiency was in the
be overcome and how small a penis is necessary for apparently anterior or exophytic part of the penis (12.3cm for normal
satisfactory intercourse. subjects versus 6.9cm for exstrophy). The posterior penis was
much the same length in both (3.9cm versus 3.2cm). The cor-
poreal diameter was 1.0cm in normal men and 1.4cm in
exstrophy men. The abnormalities may be exaggerated by the
Penile malformations recession of the supra pubic area (Figure 49.2), absence of the
mons pubis, and the normal size of the scrotum.
Exstrophy and epispadias The prostate is present. In the initial dissection in the
Reconstructive surgery of the basic bladder problems of the neonate it is detached from the penile urethra and remains in
exstrophy–epispadias complex has progressed so much that its normal relationship to the bladder base. In adult men

367
368 Textbook of Erectile Dysfunction

Table 49.1 Literature review of sexual function in men with a small penis.

Reilly and Miller and Money Husmann26 Wisniewski Bin-Abbas Van Seters Total
Woodhouse24 Grant27 et al.22 et al.23 et al.25 and Slob28

n 20 19 9 20 13 8 3 92
Gender identity 0 2 0 0 0 0 2%
disorder
Erections 20 15 9 20 13 3 95%
Heterosexual 20 6 19 10 3 —
Homosexual 0 3 1 0 —
Bisexual 1 2 —
Regular sexual 15 6 12 6 3 60%
intercourse
Psychological 6 9 5 6 0 35%
problems
Blank entries indicate that there were no specific data in the paper

Figure 49.1 Adult flaccid exstrophy penis. Figure 49.3 Dorsal chordee in exstrophy.

the prostate is of normal weight for age but lies completely

behind the urethra. The veru montanum (which is normally
positioned) is a useful landmark for surgery in later life.
The shape of the erect penis depends on the initial recon-
struction. In the natural state, the erect epispadiac penis has a
tight dorsal chordee (Figure 49.3). Cavernosography in these
cases shows that the site of the maximum curvature is at the
point where the corpora emerge from the perineum.5 The
degree of chordee is variable. In some the angle is such
that sexual intercourse is possible either in the conventional
position or in one that brings the female introitus in more
direct apposition to the penis.
A more complex deformity occurs when one or both of the
corpora are damaged in the initial surgery so that they fail to
fill completely. If one corpus fails to fill on erection it acts as a
Figure 49.2 Exstrophy penis, illustrating the recession in the ‘bow-string’ on the other and causes lateral deviation in addi-
mons area (arrowed). tion to the dorsal chordee (Figure 49.4).5 If both corpora are
 Sexual function in congenital anomalies 369

Figure 49.4 Operative photograph to show the artificial

erection of an exstrophy penis deviating 90° to the right (head is
at the top). Figure 49.6 Distribution of pubic hair in exstrophy.

Awareness of the erectile problems and appropriate recon-

struction in infancy may improve the function in adults. The
techniques for children reviewed by Snyder do produce a
short but normal penis with a normal angle of erection.7
Indeed, Perovic et al. have reported that the penis in infants is
similar in length to that of normal boys although slightly dif-
ferent in appearance (see Figure 49.3).8 Even in adolescents
and adults correction of chordee can be successful and will
give a little increase in length.9
In adult exstrophy patients, the pubic area is nearly always
recessed from the uncorrected divarication of the pubic bones.
The pubic hair lies on either side of the midline (Figure 49.6).
Many exstrophy patients find the appearance distressing and
try to hide it from their partner. It is most important, either in
infancy or in adolescence, to rotate hair-bearing flaps of skin
and fat to cover the midline defect.

Sexual function
There is no reason, special to exstrophy, why the erections
should not be normal. Even where both corpora are rudimen-
tary, penile tumescence occurs. Exstrophy patients presenting
Figure 49.5 Exstrophy penis, which is small with the corpora
detached from the inferior pubic rami.
with impotence should be investigated in the same manner
as other males. The only difference is that there is no cross-
circulation between the corpora. Therefore, if intra-corporeal
rudimentary, the visible or exophytic part of the penis is prostaglandin is to be used, each corpus will have to be injected
normal except that it is a little higher than usual on the abdo- individually. Occasional boys appear to have suffered damage
men (Figure 49.5). On cavernosography the corpora appear to to the erectile nerves during pelvic dissection and report life-
have no attachment to the pubic rami. Erection is very limited long inadequate or absent erections. They respond to small
and the penis unstable. In one of my patients the whole of one doses of standard medication such as sildenafil.
corpus and the exophytic part of the other is missing so that Much the commonest problem, however, is fear of rejec-
there is no visible penis at all. The evidence suggests that tion by a partner because of the obvious penile anomalies.
the corpora are of equal size at birth and are damaged at the Unfortunately, there is no easy solution. In my experience, the
primary (and revision) reconstructive surgery.6 most important part of management is not to raise false
370 Textbook of Erectile Dysfunction

expectations from surgery. Chordee and other erectile below the normal stretched length. Thus it ranges from 1.75cm
deformities can be corrected but there is no surgical means of to 2.7cm at birth.19,20 Growth curves have been constructed
producing the long, normal penis for which they hope. It is from which the normal penile lengths can be derived at any
better to use knowledgeable and sympathetic counseling to age.21 The andrologist may be asked to see a neonate or adult
help the adolescent establish a durable relationship in which with a small penis for whom endocrine treatment is impossi-
normal sex takes place. Boys with exstrophy are unlikely to be ble or has failed. The questions that then arise are what use
successful with ‘one-night stands’, though patients reported will the present organ be, can it be made any bigger and, in an
by Ben-Chaim et al. were said to have random and short-term extreme case, should a sex re-assignment be made?
relationships.10
Orgasm is normal. About 75% of men with exstrophy will
have some ejaculation, occasionally as much as 5ml. Although Sexual function with a small penis
poor or absent ejaculation may follow genital reconstruction, There is now a considerable literature on sexual function in
complete absence of ejaculation is rare but the emission that men with a small penis (Table 49.1). At first sight, it may
does occur may be slow and may continue over several hours appear to be self-contradictory. However, there is a strong
after orgasm. Some patients describe a more or less continu- selection bias. Papers derived from psychology units inevita-
ous urethral discharge of semen-like fluid.4,11,12 bly describe a high incidence of psychological problems22,23
It has been suggested that patients who had early urinary but those that come from more general clinics give a picture
diversion have better ejaculation than those who have been of male sexual behavior that is close to normal.24–26 The most
reconstructed (particularly if the reconstruction was unsuc- striking features of all series are the strength of male gender
cessful). Most authors who have specifically addressed the identity (98%) and a potency rate of 95%. Not surprisingly,
point have results that appear to support this conclusion. the two reported cases of gender identity disorder were from
Evidence from the literature as a whole is inconclusive. In sev- a psychology unit.
eral papers it is difficult to work out which patients were In the 20 adults reported by Reilly and Woodhouse, all
diverted and which were not, or whether the ejaculation was had heterosexual interests, erections, and orgasms, and 11 of
anything like normal.13 12 had ejaculates. The mean age of sexual debut was 16.4 years
With or without surgical correction, the men appear to (range 13.5–20) while the normal is 16.2. All claimed to find
have a normal libido. They form stable partnerships with intercourse enjoyable though their partners’ views were
normal girls and have normal family life. Hensle reported that unknown. One patient had a wife and a mistress. The partner-
60 of 77 adult males were cohabiting with a sexual partner ships were stable and long-lasting, a situation that some
and a further 8 had a regular sexual relationship (personal patients attributed to the extra attention that had to be paid to
communication). About a half of men who are trying to will intercourse because of the short penis. Although vaginal pen-
be able to father a child.14 etration was usual, there was an experimental attitude to posi-
tions and methods. One patient was the father of a child.24
Cloacal exstrophy It seems safe to conclude that even the possession of the
very small penis illustrated in Figure 49.7 is compatible with a
Cloacal exstrophy is a very rare and extreme form of exstrophy
normal male role, especially with proper parental support.
involving the intestinal tract as well as the bladder and genita-
lia. Many patients have an associated spina bifida as well. The finding of a micropenis at birth should not, on its own,
be grounds for re-assignment to female.
There were no reported survivors before 1960. The early survi-
vors now are reaching adulthood and the limited data on long-
term outcomes are fuelling much ethical debate at present. Hypospadias
Initially, standard advice was that 46,XY infants should be
There are few major subjects in urology that are so difficult to
re-assigned as female. Cases have been cited where refusal of
review than the adult sexual consequences of hypospadias.
such advice by the parents has resulted in poorly adjusted
Data on adults who were born with hypospadias are few and
adolescents who commit sexual offences. In a series of eight
often imprecise. Adult patients who now are available for out-
males with cloacal exstrophy only one achieved successful
comes analysis were operated on in the 1970s. Much of the
vaginal intercourse. Two were impotent and three required
intensive psychiatric counseling.15 About two-thirds of pedi- evidence cited in this chapter comes from surgery that is even
older. Techniques have changed and surgical results have
atric urologists still accept this recommendation.16 However,
recently there has been a reaction against this policy because improved. However, against this must be set the rise in patient
expectations that has come with greater education. Consider-
of the observation that at least a third of children who had
ing the large number of boys who are operated for hypospa-
been re-assigned as female subsequently re-adopted the male
dias and the small number that present themselves in adult
sex.17 Some are living as successful males and there has been at
life with complications, it is reasonable to believe that the
least one reported pregnancy. Psychological reviews suggest
majority of patients have had a good enough result not to seek
that the broad problems of cloacal exstrophy are more impor-
revision surgery.
tant than the single issue of sexual function.18

The small penis Appearance

It is generally agreed that a small penis must have normal There is a wide range of size and appearance of the normal
anatomy but be more than 2.0 or 2.5 standard deviations penis. Like other human features there is a variation in that
 Sexual function in congenital anomalies 371

Table 49.2 The features of the genital perception

score described by Mureau et al.32

Correctable features Uncorrectable features

Glans shape Penile size
Position of meatus Penile thickness
Scars Glans size
Scrotum
General appearance
All the features are scored, but for the purposes of Figure 49.8, they
are divided into surgically correctable and uncorrectable items

score was 3.2 and the surgeons’ was 3.5 (Figure 49.8b). Much
of the dissatisfaction seems to have been related to the circum-
cised appearance in a society where circumcision is unusual
and is perceived to shorten the penis.32
It seems likely, therefore, that surgeons can reliably correct
those abnormal features of the hypospadiac penis that are
amenable to reconstruction: chordee, the hooded prepuce
Figure 49.7 A 46,XY adult male born with a micropenis (especially if the circumcised appearance is acceptable) and
(diagnosis undetermined). the position of the meatus. Features related to the size of the
corpora or the glans, are not correctable.
which is considered normal or beautiful. It has been estab- Size may be a cause of dissatisfaction. The hypospadiac
lished, however, that the meatus is not always at the tip of the penis is often said to be short. In part this may be because of
penis. Thirteen percent of apparently normal men have a the circumcised appearance, especially in countries where
hypospadiac meatus and in a further 32% it is in the middle infant circumcision is unusual. However, where a formal
third of the glans. Most of these men thought they were nor- measurement has been made, 20% of hypospadiac penises
mal, all voided normally and had sexual intercourse.29 It could, were below the 10th centile. The finding was most marked
therefore, be said that minor degrees of hypospadias, espe- in the adolescents, with four of seven being below the 10th
cially if there is no chordee, do not greatly matter to men or centile (Figure 49.9).32 The numbers of patients in each age
to their partners. group, especially the post-pubertal group, were small and the
For men who have had surgery for hypospadias, there is results must be taken with care.
often disagreement with the surgeon on the success of the
operation. Up to 80% of adolescents are dissatisfied with their
penile appearance, though only 38–44% sufficiently so to Chordee
want further surgery.30,31 There is a difference in results Hypospadias repairs currently in use put great emphasis
depending on the attitude of the community to circumcision: on correction of chordee, recommending frequent intra-
in countries where childhood circumcision is routine, results operative artificial erections to check that the penis is straight.
are perceived to be better than in those where it is uncom- Older repairs were much less successful in this regard, and
mon. When there is a direct comparison between the opinions at long-term follow up 20% or more had residual chordee
of the patient and the surgeon, there is almost no agreement. (Figure 49.10). As with strictures, it is very important to
Mureau et al. have introduced the helpful concept of the confirm that the man actually has significant symptoms from
‘Genital Perception Score’ (GPS).32 Eight features of the penis the chordee. The bend may be sufficient to prevent inter-
are scored from one to four, giving an overall range of eight course and therefore demand correction. There is also a group
to 32 with the highest score being the best result (Table 49.2). of men for whom the bent appearance, even if not a physical
This allows a numerical comparison between observers and impediment to penetration, is an emotional cause of sexual
helps to identify areas of concern for the patient. It is impor- dysfunction. It is interesting that in Summerlad’s late review,
tant to note, however, that three of the eight features were 13 patients were thought, objectively, to have chordee,
concerned with penile size, which cannot be altered by of whom only 8 had symptoms, while 2 of 47 complained
surgery. The authors asked patients and their surgeons to give of curvature that was not confirmed on examination.33 Recent
a GPS for the surgical result. Surgeons gave a mean score results have been better, with only 18% of men having
of 29.1 and the patients gave a mean of 25.1, a difference that significant chordee.30
is statistically significant (Figure 49.8a). For the uncorrectable, Chordee can occur many years after an apparently success-
size-related features, the patients gave a mean satisfaction ful repair, either at the site of the original operation or remote
score of 3.1 (out of 4) while the surgeons gave a score of 3.9. from the site of the hypospadias. In a group of 34 men referred
For the features related to the surgical result, the patients’ for alleged recurrent chordee, 22 were identified who had
372 Textbook of Erectile Dysfunction

32 4
28
24 3
20
Score

Score
16 2
12
8 1
4
0 0
(a) Surgeon Patient (b) Correctable Uncorrectable

Figure 49.8 (a) Histogram to show the Genital Perception Score (GPS) for all eight features of the corrected hypospadiac penis by
the surgeon and the patient. Maximum score is 32. The difference between the scores of the surgeon and the patient is significant
(p<0.001). (b) Histogram to show mean GPS scores (maximum score 4) for features of hypospadias that are correctable by surgery
and those that are not. It is seen that there is little difference between patient (red) and surgeon (yellow) for the correctable
features.

80 Sexual intercourse
60 Problems, both physical and emotional, with sexual inter-
<10th percentile course, have been reported. The ‘physical causes’ include soft
40
Average
glans, poor ejaculation, tight skin, and pain. ‘Emotional
20 >90th percentile causes’ are small size, poor appearance, and the anxieties from
the physical causes.30 The difficulties in assessing these claims
0
9–12 13–15 16–18 lie partly in the fact that similar problems are found in many
n = 16 n = 10 n=7 adolescents (with or without genital anomalies) and partly
that hypospadiac men appear to have intercourse in much
Figure 49.9 Histogram to show the percentage of patients with
the same way as everybody else. All reported series record
stretched penile length by age compared to normal percentiles.
that most men have sexual intercourse, even though the
Data from J Urol 1996; 155: 703–60.32
quality and quantity may be difficult to decipher from the
data. Figures for successful intercourse range from 77% to
90%,30,35,36 Curiously, frequency of sexual intercourse does
not seem to be related to the success of the repair, though
it is probably related to the degree of severity of the original
hypospadias.
Nowhere in medicine is it more necessary to have control
patients than in the assessment of adolescent sexual function.
The greatest difficulty lies in the identification of a satisfactory
control group to compare with the hypospadiac patient.
Without controls it is impossible to know whether the myriad
of sexual problems that have been identified are caused by the
hypospadias. There is no group that mirrors all of the features
of hypospadias, but infant circumcision, herniorrhaphy, and
appendicectomy have all been used. Two studies have shown
that there was no difference in the number of sexual episodes
or their perceived quality between patients with hypospadias
Figure 49.10 Operative photograph of an artificial erection and controls (herniorrhaphy patients and circumcision
showing incompletely corrected chordee. patients, respectively).31,37,38 This was despite the observation
that the patients with hypospadias had significantly more
erectile problems, such as curvature, shortness, and pain, than
adequate initial surgery, confirmed by intra-operative erec- the controls.37 There was no significant difference in the ages
tion and reported absence of chordee during follow-up. All at which boys started masturbating, necking, or having sexual
had had proximal, or even penoscrotal, chordee and all had intercourse. Hypospadiac men described themselves as more
had a tubularized free-graft urethroplasty. The chordee sexually inhibited than controls who had had a hernia repair
developed during puberty, from 12–18 years of age. The (24% vs 1.8%).31
median age of presentation was 21 years and a mean of The quality of sexual satisfaction may be different when the
17 years after the original surgery. Although in two-thirds of hypospadiac man has suffered complications since there is a
cases, the urethra was shortened and fibrosed, division of the correlation between more complications, dissatisfaction
urethra did not correct the chordee in all cases. Disproportion with the surgical outcome, and dissatisfaction with sexual
of the corpora was present in 68% of men, with or without performance.39
short urethra.34 The cause of this late deterioration is Men with major complications in the surgical outcome
unknown. often have physical difficulty with intercourse. Apart from
 Sexual function in congenital anomalies 373

Figure 49.12 Operative photograph of a hypospadias repaired

in childhood by the Dennis Brown buried-strip method. Note
that the meatus is not terminal and the urethra is baggy.

Figure 49.11 An unsuccessfully reconstructed hypospadiac

Meatus with
penis (hypospadiac cripple). sound inserted

chordee, tight scarred skin makes penetration painful and

may even tear with intercourse (Figure 49.11). Matters may
be worsened if balanitis xerotica obliterans (BXO) has
developed.
Distal urethra
In the patients with most severe hypospadias there is a with no
considerable overlap with intersex abnormalities, especially spongiosal
androgen insensitivity syndromes. In one series of posterior tissue
hypospadias, 13 of 42 men had a major intersex anomaly.
All had severe hypospadias (usually perineoscrotal) and
micropenis.40 None of the 13 patients had sperm in their
ejaculate. Even with hypospadias as severe as this intercourse
still occurs. In a series of 19 patients born with ambiguous Figure 49.13 An unoperated penis with glanular hypospadias,
genitalia, subsequently determined to be caused by perineal showing the deficiency of the spongiosus in the distal urethra.
hypospadias alone, it was reported that 63% had had inter-
course. However, only 4 had a regular partner.27 Less good
figures were given in the series of Eberle et al.: although 25 Psychological aspects of sexual intercourse
of 42 reported satisfactory erections, masturbation, and ejacu- Emotional satisfaction with intercourse is particularly difficult
lation, few had sexual intercourse. Nine of 42 were married to measure, and series without controls are valueless. Most
and 3 had children but only 6 had a stable relationship.40 teenagers, exploring their sexuality, have anxieties that are
unrelated to any penile abnormality though a penis that is
perceived to be abnormal may get the blame. Penile size is a
Ejaculation source of considerable anxiety in many adolescents. Limited
The first, or prostatic, phase of ejaculation is normal in men research is available on the relationship of penile size to sexual
with hypospadias. The next stage is the expulsion of the semen satisfaction. Men with micropenis and with epispadias have
by the bulbospongiosus muscle. In proximal hypospadias, this intercourse that is satisfactory to themselves, though the opin-
muscle is likely to be absent. It is, therefore, not surprising to ions of their partners have not been investigated (see above).
find that ejaculation is unsatisfactory in 63% of men with An investigation of women with multiple sexual partners has
severe hypospadias even though orgasm is normal in most.27 suggested that intercourse with an uncircumcised penis gives
Poor surgical results from the distal urethroplasty may cause greater pleasure than a circumcised one.41
a baggy urethra (Figure 49.12) or even a diverticulum, further As there is no realistic means of enlarging the penis in
slowing the ejaculation. The reconstructed urethra lacks hypospadias, it seems wise to help the patient to make the best
the support of corpus spongiosum. Even in the unoperated use of that which he has, rather than embark on surgery for
hypospadiac penis it is apparent that the urethra for some lengthening, which has a most uncertain outcome. If the com-
distance proximal to the meatus consists of little more than parative trials of Mureau et al.31 and Aho et al.37 are correct,
skin (Figure 49.13). In more general reviews most authors hypospadiac boys are not greatly different from their peers in
state that ejaculation is normal. However, by asking the right their sexual activity and enjoyment.
questions, Bracka found that 33% had ‘dribbling ejaculation’ There is conflict over the effect of the success of the repair.
and 4% were dry.30 Bracka made the interesting observation that those who were
374 Textbook of Erectile Dysfunction

satisfied with the results of their repair had a sexual debut at a Before deciding on treatment, it is essential to establish
mean of 15.6 years old, while those who were dissatisfied had what the patient hopes to achieve from surgery. With limited
a debut at 19 years old.30 On the other hand, it has been objectives, such as enlargement of the meatus, simple, local
reported that in a group of boys whose ‘curative repair’ was surgery will suffice. For complete reconstruction, the same
delayed beyond 12 years old, 50% had their sexual debut techniques may be used as in children. Unfortunately, the
before the definitive surgery.42 It could be said that the complication rate of around 33% is much higher than that
experience of intercourse, acknowledged by the authors to be seen in younger patients.44 Wound healing seems to be slower
less satisfactory, drew attention to the shortcomings of the and the infection rate higher, than in children. BXO should be
repair. treated by complete excision of all affected tissue as a first pro-
cedure. Reconstruction should be undertaken only when
healing is complete, all edema has settled, and it is clear that
Fertility all BXO tissue has successfully been removed.45
It seems probable that boys with uncomplicated hypospadias Careful discussion with the patient about objectives and
are normally fertile. There have been no studies of a large possible outcomes is essential. Couples may seek advice on the
cohort of hypospadiac patients. There is no excess of patients inheritance of hypospadias. There is an increased risk of
with hypospadias in infertility clinics. In an apparently hypospadias if the father or one of his first-degree relatives has
unselected group of 169 hypospadiac men, 50% were found hypospadias. It is difficult to determine an exact figure since
to have a sperm count below 50 million/ml and 25% had the subject may not be discussed within the family. In a review
below 20 million. More than half of those with the lowest of 430 patients with hypospadias, 21% had another affected
sperm counts had associated anomalies, such as undescended family member. It should also be noted that hypospadias is
testes, which might have accounted for the poor result.30 the most common congenital anomaly in boys conceived by
In a detailed study of 16 hypospadiac men, true oligo- intra-cytoplasmic sperm injection, with a relative risk of 3.0.46
astheno-teratozoospermia was found only in the 2 patients
with perineal hypospadias; low counts were seen in 1 of 3 with
glanular and in 2 of 6 with penile hypospadias, but other Obstruction and disorders
parameters were normal. With two minor exceptions of
slightly elevated luteinizing hormone (LH), all the patients of development
had normal hormone profiles.43
Posterior urethral valves
A congenital urethral valve causes obstruction to bladder
New adult patients outflow and, in most boys, some consequent damage to the
From time to time a man will present with hypospadias who kidneys. However, the back-pressure also causes dilatation of
has had no previous surgery. Most often BXO will have caused the prostate (Figure 49.15). Little is known of the conse-
a stricture (Figure 49.14). Occasionally, a man will present quences of the prostatic damage or other factors on sexual
with an unconnected symptom and the hypospadias will be a function and fertility. There is a very wide spectrum of severity
chance finding. Even an uncomplicated hypospadiac meatus in boys with posterior urethral valves, ranging from death
may not be large enough to accept a conventional cystoscope in utero or in early infancy to such minor symptoms that diag-
or resectoscope. The distal urethra is often fragile with no nosis is only made in childhood. There is also a selection bias
supporting corpus spongiosum and may easily be damaged by in patients volunteering to be investigated, since those that are
instrumentation (see Figure 49.13). fertile will see little point in providing semen samples.

Bladder with several

diverticula

Bladder neck

Dilated prostatic
urethra

Level of valve

Figure 49.14 Unoperated coronal hypospadias with balanitis Figure 49.15 Cystogram of an infant born with a posterior
xerotica obliterans. urethral valve.
 Sexual function in congenital anomalies 375

Work from my own unit has shown that abnormal semen adult populations.38,56 Those adolescents who seek medical
and poor ejaculation occurs in up to 50% of boys. The semi- attention for sexual dysfunction without neurologic or struc-
nal abnormality is characterized by lack of liquefaction, low tural etiology are likely to have a psychological or psychiatric
sperm count, poor motility, and high pH (up to 9.5).47 Puri problem. The very fact that the presentation is with impo-
et al. had similar findings except that no patient (out of 5) tence is a measure of the seriousness of the underlying condi-
had oligozoospermia; 4 had abnormal sperm agglutination. tion. Further questioning may reveal that some of these
Hormone profiles were normal except that 5 of 9 had hyper- adolescents are simply seeking a prescription for phospodi-
prolactinemia, which contributes to slow ejaculation.48,49 esterase type 5 inhibitors such as sildenafil. The fastest grow-
The effect on fertility is unknown but up to a third of ing group of sildenafil users is young men aged 18–45 years.57
my patients appear to have some difficulty in achieving Non-psychological causes of ED in adolescents are the same
paternity. The dilated posterior urethra means that inadequate as in adults, including endocrine disorders (diabetes, hyper-
pressure is established at the beginning of orgasm, resulting in prolactinemia, hypogonadism), fibrosis caused by priapism in
less forceful (or absent) ejaculation.47 Serum prostate-specific sickle cell disease, and trauma, such as posterior urethral dis-
antigen has been found to be normal in all of the small num- ruption. Management is the same as for adults.
ber of young men in whom it has been measured.50 Holmdahl
and Sillen asked their patients about paternity but did not do
any semen analyses.51 They found that 11 of 13 men who were
not uremic had produced 18 children between them (one with Disorders of pelvic innervation
the help of intra-cytoplasmic sperm injection). None of 6 ure-
Myelomeningocele
mic men were fathers. They concluded that uremia was the
cause of infertility.51 Although uremia is certainly a cause of Spinal abnormalities, especially myelomeningocele, are prob-
impaired fertility, it does not cause the seminal abnormalities ably the only strictly physical cause of congenital erectile fail-
that are well documented. ure. Even the most crippled spina bifida patient has sexual
desires. Normal sexual intercourse is quite possible even when
life is spent in a wheelchair. Those with minimal neurological
Prune belly syndrome defect are probably normal. Those who are grossly abnormal
Prune belly syndrome is a rare syndrome that consists of are often assumed to be ‘asexual’ though this may be a cover
bilateral undescended testes, absence of muscle in the anterior for our unwillingness to tackle a difficult subject. In investi-
abdominal wall (which gives it the name), and variable abnor- gating sexual function, there is a difference between theory
malities of the upper urinary tracts. It is probably due to and practice and between findings in adolescents and adults.
a mesenchymal developmental defect but could be due to In practice, sexual activity is more common than would be
transient urethral obstruction in utero. About a third of expected from theory or from investigating the adolescent
babies die in utero or in the first few weeks of life, but the alone.
remainder grow up normally, though often with impaired
renal function.
In the 1950s and 1960s it was felt that the testes were so Sexual development
abnormal that fertility and malignancy need not be consid- Patients with severe congenital disabilities often fail to develop
ered. Orchiopexy was, therefore, delayed either until a major normal sexuality because of lack of privacy and because of
reconstruction was performed or until late childhood. It was dependence on others for normal daily living. They have low
not surprising, therefore, to find that the testes could just social and sexual confidence. Surprisingly, however, even
about produce sufficient hormones to maintain masculinity those who can walk and whose spina bifida is ‘hidden’ also
but only at the price of high pituitary drive: serum testoster- have major sexual problems. They will have uncertain bladder
one levels in adulthood are usually in the normal range but and bowel control, which leads to an unwillingness to mix
serum LH levels are two or three times normal.52 Men with with their peers on an equal basis. It is most important not
prune belly syndrome were thought to be inevitably sterile to imagine that an apparently minor level of neurological
and testicular biopsies showed Sertoli cells only. disability means that sexuality is normal.58 The physical
It has now become apparent that some germ cells are pres- aspects of sexual function that depend on the brain are gener-
ent and so the outlook is not so bleak. There have been reports ally intact, while those which depend on the spinal cord will
of sperm in the semen. There has been at least one pregnancy be damaged in line with the neurological level.
using intra-cytoplasmic sperm injection and resulting in When children are brought up in the mainstream of
twins, one of whom was normal though the other had multi- education and integrated in school, the social results are
ple anomalies. There have also been three reported cases of excellent. In a study to compare 11 dimensions of self-image
germ cell neoplasia.53–55 in adolescents with spina bifida with those of their peers,
there was no difference in 10. Unfortunately, the 11th was
the dimension of sexuality, which was significantly below
Disorders of perception normal.59
Adolescents with spina bifida are often ignorant of even
Impotence in adolescents very straightforward aspects of sexuality that should be
Erectile dysfunction (ED) is rare in adolescents, although the taught within the family. The ordinary facts of reproductive
incidence of sexual dysfunction is greater than 50% in some life often are not given. It is not surprising, therefore, that
376 Textbook of Erectile Dysfunction

they have very little sexual contact. Dorner interviewed 63 spina over-protective parents. It could, therefore, be said that 88%
bifida teenagers and their families. Seventy percent of the of those with realistic prospects were married or had a steady
patients had moderate or severe handicap. It was found that partner. Many of the patients were severely handicapped and
sexual discussion with peers was inhibited. Twenty-three incontinent, which seemed no bar to their achievements.65
percent did not know how babies were conceived. Few patients
understood anything of contraception. Only 18 patients
had ‘dated’.60 This paper was published in 1977. The lack Impotence
of education in patients who had grown up in the 1960s, a Impotence responds to the conventional management, such
period of great sexual openness and freedom, was worrying as intra-corporeal injection.64 Sildenafil may be used with
enough. Sadly, matters have not greatly improved. In a paper appropriate dose reduction. In the only trial to date in this
published more than 20 years later, 93% of adolescents group, dose escalation was used with patients as their own
expressed a wish to have education in sexual issues but only controls. Eighty percent of men responded to a dose of 50mg.
39% had received it and only 5% felt that they had adequate Although one patient subsequently responded to 100mg, it
knowledge.61 was recommended that such a high dose should not be used
in spina bifida. Five of the 11 responders in the series were
wheelchair-bound.65,66
Erection and ejaculation
In assessing sexual potential it is important to remember that
erections are often reflex and not necessarily a sexual response. Fertility
Diamond et al.62 related erections to the neurological defect No figures are available for the overall incidence of infertility
but pointed out that many observed erections could have been in males. However, it is interesting to note that in the study
purely reflex in origin. In a series of 52 post-pubertal males, of 49 adults with spina bifida quoted above, 16 men and
70% claimed to have erections, in most cases supported by 15 women were married or had a regular partner. Ninety
parental observation. Erections occurred in all patients with percent of co-habiting couples had children. Success in part-
a positive anocutaneous reflex and in 64% of those with a nership and fertility were said to be unrelated to continence
negative reflex and a sensory level at or below the sympathetic or mobility.67
outflow (T10–L2). Only 14% of males with higher lesions The bigger issue, however, is the risk of the offspring having
and absent reflex had erections.63 With a rather more detailed a neural tube defect (NTD). Combined series have shown
sexual history, Cass et al. showed that orgasm and ejaculation an increased risk of NTD to be as high as 4% in the offspring
occurred in 7 of 9 men with a level at L3 or below. Only 3 men of spina bifida patients. The risk is the same whether the
with higher levels were studied and, although 2 of them had affected parent is male or female, but daughters have a 1 in 13
ejaculations, only 1 had sexual sensation.64 incidence while the risk for sons is only 1 in 50.65,68
One of the great medical success stories of the past 30 years
has been the discovery of the prophylactic role of folic acid.
Sexual activity In a double-blind, placebo-controlled trial involving 1195
A recent study from the Netherlands has shown that, in prac- women with high-risk pregnancy (previous birth of a child
tice, sexual activity in adolescents with spina bifida is limited, with NTD or an affected parent), there were 6 affected fetuses
especially in those with hydrocephalus (Figure 49.16).63 The in the treated group versus 21 in the untreated group.69 Even
situation improves as the patients get older. In a review of 49 before the discovery of the protective effects of folic acid, the
adults it was found that 9 had steady partners and 22 were overall incidence had been falling. In a recent study from
married. Nine had fathered 23 children. Of the others, 10 were the UK, it was shown that the incidence of NTD started to
under 20 years old, 2 were mentally handicapped, and 2 had fall about 18 years before the use of folic acid began to rise.

100
No hydrocephalus n=22
With hydrocephalus n=42
80

60

40

20

0
Masturbation Sexual intercourse Sexual Partner (ever) Satisfaction
in the past year intercourse ever

Figure 49.16 Histogram to show levels of sexual activity in adolescent males born with spina bifida. Data from Arch Phys Med
Rehabil 2005; 86: 979–87.
 Sexual function in congenital anomalies 377

The incidence fell from about 225 per 100,000 live births to man would not be satisfactory. As it was easier to create a
about 48 per 100,000 live births between 1972 and 1990. The vagina by surgery than a penis, there was some pressure to
number of sales of folic acid was less than 100,000 per year re-assign as female. It is not surprising, therefore, that there
until 1990, rising to 1.2 million per year by 1996.69 has been an unwillingness to raise infants with abnormal or
However, the main protection against the conception ambiguous genitalia as males.
of a baby with an NTD defect is to give the partners of There is now a greater understanding of sexuality. It seems
men with spina bifida folic acid 5mg per day for at least likely that the brain is the main determinant of sexuality.
3 months before a planned conception.70 In spite of this pro- Particularly where the brain has been exposed to androgens
phylaxis, there remains a small risk of an affected pregnancy. in utero, it is most probable that the infant will exhibit male
At least one cause appears to be an inborn error of folic acid sexual traits. The main exception to this is in complete andro-
metabolism, which was found in 16 women who gave birth gen insensitivity. In this condition, the fetus is 46,XY and the
to two successive babies with myelomeningocele in spite of testes are present. However, there are no androgen receptors
prophylaxis.71 in the genitalia or in the brain. The phenotype is, therefore,
In those with higher lesions, it might be thought that largely female, and androgenization of the brain does not
infertility would be due to the impotence. Although this is occur. There has also been greater understanding of female
undoubtedly true in part, a small study has identified another sexuality. The vagina is not a passive organ in intercourse but
problem. In 10 impotent males with spina bifida, all were one that is at least as active as the penis.76
found to be azoospermic on analysis of semen obtained by Attitudes to sex of rearing have also been influenced by
electro-ejaculation. On testicular biopsy, all had Sertoli cells the prospects for fertility. Even very complex problems of
only.72 Poor semen quality has also been reported in men with infertility can be solved by reproductive technology.
acquired spinal lesions using electro-ejaculation, especially if There must be a re-evaluation of previously held truths.
ejaculation is infrequent.58 Those with DSD must be helped to achieve what is possible
with the structures available. It is a mistake to amputate sexu-
ally sensitive organs without a definite medical reason. Fur-
Disorders of sexual development thermore, it is naïve to think that female sexuality is so simple
that inadequate male genitalia can be ‘cured’ by reassignment
Patients raised in the male sex of sex: there is no evidence to show that the outcome of this
The conditions covered by the terms ‘intersex’ and ‘hermaph- policy is satisfactory. Indeed, evidence is emerging to suggest
roditism’ have been re-named ‘disorders of sexual develop- that the outcome is poor: many people with ambiguous geni-
ment’ (DSD).73 Infants with any DSD present one of the talia would prefer to keep what they have rather than have bits
greatest challenges that the pediatrician can face. In consider- reconstructed to produce a copy of a specific sex.77
ing the sexual outcome in these and other men with gross In spite of the theoretical evidence, little is known of the
genital anomalies, it is important to remember that there is consequences of raising poorly androgenized babies with DSD
no ‘right answer’. Even with the most careful counseling in the male sex. It is all very well to say that intercourse and
and psychological care, 39% of children have been shown to even fertility are possible, but quite another to have a ‘normal’
develop one or more general psychological disorders, regard- man. Nonetheless, in the absence of a ‘right answer’, the
less of the sex of rearing. Psychological intervention from same criteria should be applied to potentially male as to
birth reduces but does not abolish the problem.74 potentially female babies. It is unacceptable to say that a baby
There has been a lack of enthusiasm to raise babies with will make an unsatisfactory man and therefore it will be raised
ambiguous genitalia in the male sex. This has been in part female.
because of the apparent success in raising them as girls, par- The question then arises as to whether a proper penis can
ticularly until around 6 years old, and partly because of their be made. The early management of any case of DSD is that of
poor success as boys. In the 1960s, Money, amongst others, the underlying condition. With endocrine correction there
championed the view that even totally normal boys could be may be some growth of the penis. Once the boy has passed
raised in the female sex providing the decision was made early puberty further growth of the penis is unlikely. Dihydrotes-
enough and constantly reinforced. tosterone cream has been used to stimulate penile growth.
At a simple level, lessons can be drawn from babies with Both the penis and prostate show rapid growth. In a series of
abnormal but clearly masculine genitalia. Reference has 22 children there was a mean increase in length of 53% in the
already been made to classical and to cloacal exstrophy. In the first month and a further 18% in the second month of treat-
classical form, sexual function as a male has been satisfactory ment. The series included 4 boys who had failed to respond to
and fertility is possible. However, in a very gross form known testosterone treatment.78 Late treatment of a 12-year-old and
as cloacal exstrophy and discussed above, the penis may be so a 17-year-old boy have been reported, but the responses were
rudimentary that sexual intercourse as a male may be impos- poor.79 Until recently, this preparation has been unobtainable
sible. The genotype is 46,XY and the testes are histologically in many countries. It is now becoming available again and it
normal. Even into early adolescence, there has been consider- may be hoped that further studies on its efficacy will confirm
able success in raising the male cloacal exstrophy patients as its value.
girls.75 Furthermore, in the small number raised as males, the Surgical enlargement of the penis is limited by the inability
psychological problems have been overwhelming and there to make erectile tissue. It is possible to gain length by releasing
have been reports of criminal behavior. In men with micro- the corpora from the pubic bone by dividing the suspensory
penis, there has been a tacit assumption that intercourse as a ligament but at the price of some loss of erectile stability.
378 Textbook of Erectile Dysfunction

If the penis is completely absent, a new penis can be formed in those with varicoceles compared with controls. As most
from skin flaps using the techniques developed for sex reas- of testicular bulk comprises the seminiferous tubules, their
signment. Good technical results have been reported in boys damage will be reflected in reduced testicular size. If, as has
with micropenis using both groin flaps and a microsurgical been suggested, the main damaging agent is increased ambi-
transfer of a forearm flap.80,81 The microsurgical technique is ent temperature, it is possible that both testes may be affected
claimed to allow return of sensation and even, with time, of and so size differential may not be apparent. Ligation of vari-
erogenous sensation. No attempt was made to insert prosthe- cocele may reverse the abnormalities and allow catch-up
ses for erection and there is no report on the sexual results. growth of a hypotrophic testis.87–89
A technique has been described to make a phallus from a In one study of boys between 17 and 19 years of age there
skin flap, using the technique for female-to-male sex reassign- was no significant difference in sperm concentration between
ment, and to ‘piggy-back’ it onto the natural penis. The man those who had or did not have a varicocele. Varicocele was
then has his own sexual satisfaction from his small natural associated with reduced motility and an increased number
penis and can penetrate his partner’s vagina with the recon- of abnormal forms, which was just significant.90 In another
structed part. The results in patients are reported to be good study, standard semen analysis showed no difference between
with very careful selection.82,83 In my own very limited experi- boys with and without varicocele, but there was more DNA
ence of the procedure, the appearance is odd and I am doubt- fragmentation in those with varicocele. DNA fragmentation
ful if it can be justified except in those with a very rudimentary may be a marker of sperm function, but there is no standard
natural penis. test in clinical use, and the research tests are expensive and
As a general rule, a small penis with natural erections should difficult.91
not be sacrificed, but should be used as the basis for sexual In the main, however, abnormalities that have been found
function. Every effort should be made to help men to have in adolescents are related to differences in testicular and
sexual satisfaction and to this end a knowledgeable sexual varicocele size. Although a definition of significant hypotro-
therapist is invaluable. Surgery on the penis is often poor phy has been made as a greater than 20% difference in size,
treatment for problems that lie in the brain. Only if all else two studies from Boston have found no evidence of progres-
fails, and the man is very clear about the likely outcomes, sion in hypotrophy with sequential follow-up and no correla-
should surgery be done to create a large but sexually insensate tion with grade of varicocele.92,93 However, detailed semen
penis. analysis did show significant differences with increasing
degree of hypotrophy. Fifty-seven boys at Tanner V were
assessed by one or more analyses. Those with >20% reduction
Adolescent varicocele in volume had lower concentration and less good motility
than those with <20% reduction. Fifty-nine percent of boys
Varicoceles are not congenital in origin. However, they have had sperm counts of less than 10 million, with 77% having
been diagnosed in adolescents for many years. The prevalence poor motility.
data shown in the Table 49.3 go back to 1966. The absence of When the volume reduction was less than 20% there was
varicocele before the age of 11 suggests that puberty must play only a trend to impaired semen analysis. With a volume reduc-
a part in their initiation. By 19 years old, a prevalence of up to tion of 10–20%, only 11% had sperm counts <10 million and
19% makes them common and it might be expected that urol- 67% showed normal motility. With a reduction <10%, none
ogy clinics would overburdened with young men complaining had such low counts and 85% had normal motility. There was
of scrotal abnormalities. It would seem to be a rare problem no relationship between any of the parameters and the grade
in the UK even now and is seldom seen in general clinics. of varicocele.94
However, the literature from the rest of the world is full of None of the available tests, including semen analysis, is of
papers on the subject – at least 20 in 2006 alone. value in predicting future fertility. There has been no study
If varicocele invariably caused significant damage to overall comparing operated and non-operated patients with proven
testicular function, the incidence of male factor infertility fertility as an outcome measure. At present, the most that
would be considerably higher than is the case. Abnormalities can be said is that varicocele is associated with structural
of tubular histology and function are found more commonly changes in the testes. Success in treatment may be measured
by reversal of these changes.
Varicocele repair has resulted in a significant increase in
testicular volumes and consistency. Testicular catch-up
Table 49.3 Prevalence of varicocele and associated
growth has been found in 53–90% of adolescents.88,95–98 It is
testicular hypotrophy by age
noteworthy that when follow-up into adulthood has been
Age Prevalence of Prevalence of possible, the total testicular mass (i.e. the volume of both tes-
varicocele hypotrophic testis tes added together) has been the same in operated patients
and normal controls and significantly larger than in men
Under 11 years 0 0 newly presenting with varicocele in adulthood.88 Studies sug-
11–14 years 6–8% 7.3% gest that varicocele repair in older adolescents significantly
15–19 years 11–19% 9.3% increases sperm parameters, especially motility and total
84
motile sperm count.95,96,99 Repair probably has positive effects
Data from JAMA 1966; 198: 1121–2, Scand J Urol Nephrol 1971;
on Leydig cell function by improving serum testosterone
5: 27–32,85 and BJU Int 2000; 86: 490–386
level.89,96,100
 Sexual function in congenital anomalies 379

Evidence that paternity is affected by varicocele ligation in grade 3 varicocele with no testicular hypotrophy, presence
adolescence is limited. It has been shown that operated of varicocele in a solitary testis, poor semen analysis in a
patients are fertile but there were no controls in the series and Tanner V adolescent (preferably confirmed on two speci-
so the fate of unoperated patients is not known.101 It is striking mens), and the rare conditions of pain or intra-testicular
that even studies with long-term follow-up make little or no varicocele.
mention of paternity. It is interesting to note, however, that when relatively non-
Current recommendations for adolescent varicocele invasive treatment is advocated, the criteria for surgery have
repair are based on the findings of persistently impaired tes- been lowered. In a series from Austria of 88 adolescents and
ticular growth. The main indication for surgery is testicular children, 94% were treated by antegrade sclerotherapy for
hypotrophy (<2ml or <20%) on the affected side. As growth varicoceles with equal-sized testes.102
may vary between the testes, the difference in size should be The boys and their families must be aware of the uncertain-
confirmed by two measurements 12 months apart. Relative ties about the significance of varicocele and the indications for
indications for varicocele repair are a soft testis, bilateral surgery.

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62. Diamond DA, Rickwood AMK, Thomas DG. Penile erections in in pubertal boys prevents testicular growth arrest. J Urol 1997;
myelomeningocele patients. Br J Urol 1986; 58: 434–8. 157: 1456–7.
 Sexual function in congenital anomalies 381

89. Çayan S, Kadýo lu A, Orhan I, Kanirali E, Tefekli A, Tellalo lu S. 96. Çayan S, Acar D, Ülger S, Akbay E. Adolescent varicocele repair:
The effect of microsurgical varicocelectomy on serum follicle long-term results and comparison of surgical techniques accord-
stimulating hormone, testosterone and free testosterone levels in ing to optical magnification use in 100 cases at a single university
infertile men with varicocele. BJU Int 1999; 84: 1046–9. hospital. J Urol 2005; 174: 2003–6.
90. Paduch DA, Niedzielski J. Semen analysis in young men with 97. Lemack GE, Uzzo RG, Schlegel PN, Goldstein M. Microsurgical
varicocele: preliminary study. J Urol 1996; 156: 788–90. repair of the adolescent varicocele. J Urol 1998; 160: 179–81.
91. Bertolla RP, Cedenho AP, Hassun Filho PA, Lima SB, Ortiz V, 98. Greenfield SP, Seville P, Wan J. Experience with varicoceles in
Srougi M. Sperm nuclear DNA fragmentation in adolescents with children and adolescents. J Urol 2002; 168: 1684–8.
varicocele. Fertil Steril 2006; 85: 625–8. 99. Lenzi A, Gandini L, Bagolan P, Nahum A, Dondero F. Sperm
92. Diamond DA, Zurakowski D, Atala A, et al. Is adolescent varico- parameters after early left varicocele treatment. Fertil Steril 1998;
cele a progressive disease process? J Urol 2004; 172: 1746–8. 69: 347–9.
93. Alukal JP, Zurakowski D, Atala A, et al. Testicular hypotrophy does 100. Silveri M, Adorisio O, Pane A, Colajacoma M, de Gennaro M.
correlate with grade of varicocele. J Urol 2005; 174: 2367–70. Subinguinal microsurgical ligation: its effectiveness in pediatric and
94. Diamond DA, Zurakowski D, Bauer SB, et al. Relationship of adolescent varicocele. Scand J Urol Nephrol 2003; 37: 53–4.
grade of varicocele and testicular hypotrophy to semen parameters 101. Salzhauer EW, Sokol A, Glassberg KI. Paternity after adolescent
in adolescents. J Urol 2007; 178: 1584–8. varicocele repair. Pediatrics 2004; 114: 1669–70.
95. Çayan S, Akbay E, Bozlu M. The effect of varicocele repair on 102. Zaupa P, Mayr J, Hollwarth ME. Antegrade scrotal sclerotherapy
testicular volume in children and adolescents with varicocele. for treating primary varicocele in children. BJU Int 2006; 97:
J Urol 2002; 168: 731–4. 809–12.
50 Veno-occlusive impotence and
erectile dysfunction: treatment
and outcomes
Aksam A Yassin and Farid Saad

Introduction and biological substrates for penile erection. Metabolic factors

are substantial in this concern.4
The physiological process of erection may be viewed as inter- Step 1 in the diagnostic procedure of ED patients is the
play between three integral and inter-related processes:1 history, laboratory findings, physical examination, and basic
ultrasound. For the management of VOD it is necessary to
• sinusoidal relaxation; investigate (step 2) using non-invasive or less invasive proce-
• arterial dilatation; and dures to evaluate the cavernosal competence or properties
• venous compression. [intracavernosal injection (ICI), Doppler or color duplex ultra-
sound, and corpus cavernosum electromyography (CC-EMG)].
In approximately 20–30% of patients with erectile dysfunc-
In step 3, it is important to evaluate penile structure and caver-
tion (ED) failure is due to dysfunction of the veno-occlusive
nosal venous circulation [cavernosography and cavernosom-
system.2 Several pathological conditions can contribute to
etry, also magnetic resonance imaging (MRI)]. The data from
veno-occlusive dysfunction (VOD), including:
these three steps should provide adequate information to
• congenital ectopic veins; determine the proper treatment.
• congenital or acquired insufficiency of cavernosal tissues
or the tunica albuginea (or both);
• post-traumatic or iatrogenic fistulae; Clinical management of patients with
• shunts to spongiosal body or the glans penis;
• lack of neurotransmitters; and veno-occlusive dysfunction
• metabolic abnormalities, which can lead to alteration in
The introduction of modern diagnostic methods and equip-
penile microanatomy with consequences to biology and
ment, as well as better understanding of metabolic disorders
function.
affecting the penis, such as the impact of testosterone defi-
Flaccidity of the trabecular smooth muscle of the corpus cav- ciency4 on erectile tissue function, has drastically enhanced
ernosum of the penis plays an important role in erectile func- our understanding of the pathology of VOD, increased the
tion. Under conditions of excessive adrenergic tone or efficiency of the diagnosis of venous leakage, and facilitated
impaired neurovascular status, following sexual stimulation the choice of the right surgical or conservative options for
phosphodiesterase (PDE) type 5 inhibitors act to enhance treatment.5
nitric oxide (NO)-mediated smooth muscle relaxation, result-
ing in improved penile erection in men with ED.3 Better man-
Surgical procedures
agement of ED and treatment outcomes in VOD depends on
greater understanding of the physiology and pathophysiology Venous ligation
of the penis. Such deeper knowledge of the physiology and Venous ligation has been known for more than 12 decades.
pathophysiology depends on the knowledge of the microanat- Raymond et al., in 1895, developed a procedure to ligate
omy or the normal and pathological histology. Alteration in penile veins for management of VOD in ED patients. This was
tissue structure can lead in turn to changes in biology and followed by a large number of surgical procedures.6 More
subsequently in function. After years of experience with penile recently, the use of duplex ultrasound with intracavernosal
venous surgery, and its disappointing short- and long-term injection has provided a better indication of venous leak, but
results, we started to understand the mechanisms of VOD not cavernosometry and cavernosography are most relevant diag-
only as a ‘pipeline’ concept, such as in venous anomalies, or nostic procedures for evaluating the venous leak pattern. This
venous valve insufficiency, either congenital or acquired, but can also lead to better patient selection for this surgery.
also as a consequence of different factors leading together to Wespes et al. investigated penile ligature–resection of the
veno-occlusion. It is the interplay of several microanatomical deep dorsal vein and concluded that resection of the deep

382
 Veno-occlusive impotence and erectile dysfunction: treatment and outcomes 383

dorsal vein can restore penile erection in about 50% of well- VOD, treated by means of retrograde embolization of the
selected patients with cavernous venous leakage.7 Good prog- internal pudendal vein. Embolization in angiographically
nostic factors are in relatively young patients: primary erectile identified pathological venous leakage might have represented
dysfunction with intact arterial flow, normal hormone levels, a promising alternative to surgical isolation and antegrade
normal CC-EMG and flow-to-maintain <50 ml/minute. The embolization of the deep dorsal penile veins.18 However, this
failure rate is 30–50%. Success is taken to include those patients method has not gained recognition as a routine therapeutic
who can then obtain an erection with pharmacological agents approach, owing to the limited number of patients and the
who were unable to do so prior to surgery.8–10 absence of long-term follow-up data. There is also another
Despite the mediocre long-term results of the surgical important consideration, in that changes in metabolic factors
procedure and lack of preoperative predictive factors, it is dif- could affect the microanatomy of penile structures, causing
ficult to believe that venous leak surgery could be offered to alteration of erectile substrates.
well-selected patients in whom the only other available alter-
native would be a prosthetic device.
Penile prosthesis implantation
Cakan et al. concluded that long-term success for unselected
patients undergoing deep penile venous ligation is disappoint- The introduction of ICI therapy in the early 1980s, and later
ing; however, careful patient selection significantly improves the oral PDE-5 inhibitors, led to more limited indications
long-term results.11 The standard surgical procedure has a low for penile implant surgery. This type of surgery is indicated
morbidity rate. An incision of 3.8cm on the proximal dorsal when there is a lack of success with conservative therapies
site of the penis is normally sufficient. Superficial veins are (including PDE-5 inhibitors, ICI, and vacuum device) or
first double-ligated and resected. After Buck’s fascia has been when the patient refuses other surgical procedures. An abso-
opened, sparing the neurovascular bundle, the dorsal profound lute indication for implant surgery is the severest ED with
veins with the circumflex veins must be resected and ligated. progressive venous leakage, Peyronie’s disease, or spongio-
Generic complications include hematoma formation, infec- cavernosal reflux. Patient consent must be given in the
tion, and necrosis. Possible specific complications include knowledge of detailed information about the irreversible nature
penile edema, deviation, and shortening. Extension of surgery of the procedure and its potential complications, such as infec-
to include the crural veins, spongiolysis, and closure of spon- tion, hematoma formation, edema, rejection, pain, iatrogenic
goicavernosal shunts, showed no additional advantages but injuries, scars and deviation, as well as the potential need for
higher morbidities.12 re-operation.12

Conservative approaches
Penile revascularization or arterialization
Long-term treatment with phosphosdiesterase
Arterialization with the deep dorsal veins, presented by Virag type 5 inhibitors
et al. in 1981, showed an improvement in both arterial perfu-
The effects of PDE-5 inhibitors are very well established in
sion and the therapeutic basis of VOD.13 Anafarta et al. believed
numerous animal models and clinical studies. In addition to
that anastomosis of the inferior epigastric artery to the deep
enhancing the smooth muscle relaxation, PDE-5 inhibitors
dorsal penile vein and ligation of the vein proximally in cases
appear to play a role in ameliorating age-related changes in
of venous leakage resulted in a low success rate, probably
erectile tissues, such as fibrosis.
owing to a pancavernosal alteration in corporal tissue compli-
Ferrini et al. reported in an animal model that long-term
ance.14 Current therapy, while effective in circumventing vascu-
treatment with vardenafil prevented corporal veno-occlusive
logenic ED, is relatively ineffective in permanently reversing
dysfunction (CVOD) after radical prostatectomy by preser-
the condition.15 An exact preoperative diagnosis is most essen-
ving smooth muscle content and inhibiting corporal fibrosis,
tial. In patients with arteriogenic impotence, identification of
possibly by its effect on inducible NO synthase (iNOS).19
concomitant corporeal veno-occlusive dysfunction diagnosed
Normalization of the dynamic infusion cavernosometry, as
by preoperative dynamic infusion cavernosography and caver-
assessed by the drop rate and smooth muscle–collagen ratio
nosometry may be helpful, not only in planning a more phy-
was noted. The authors stated that long-term continuous
siological surgical procedure but also in predicting long-term
treatment with sildenafil ameliorates age-related erectile dys-
results. Overall, fewer than 50% of patients had good postop-
function and the underlying corporal fibrosis in the rat.20
erative results with median follow-up of 24 months (range
These data demonstrate that long-term PDE-5 inhibitor treat-
19–56 months).16 Hauri’s method of arterial–venous shunt
ment corrected CVOD in the aged rat and partially reversed
between inferior epigastric artery and the penile profound
the age-related fibrosis and loss of smooth muscle cells (SMCs)
dorsal veins was published in 1984. He reported positive
in the corpora cavernosa, without affecting levels of oxidative
results, especially in patients younger than 55 years with two
stress markers, transforming growth factor-beta-1 or the Rho
or fewer comorbidities.17
kinase inhibitor protein tyrosine phosphatase, nonreceptor
type 11 (PTPN-11). They speculate that similar effects may be
achieved with this regimen in men.20 The effects of PDE-5
Venous embolization inhibitors on endothelial progenitor cells can explain the
Parona, in Italy, was the first person documented, in 1873, as endothelial recovery seen with long-term treatment. Vardenafil
performing a sclerosis of the penile dorsal vein.6 More recently, had been found to increase circulating progenitor cells in
a German group presented a subset of four patients with humans.21
384 Textbook of Erectile Dysfunction

Intracavernosal injection therapy Traish et al. have demonstrated that androgens are critical
In the past 25 years, ICI therapy has led to better understanding for maintaining the corpus cavernosum smooth muscle
of the pathophysiology of ED. Use of color duplex Doppler responsivity, the fibroelastic properties of the corpus caver-
as a clinical screening method (to eliminate concomitant nosum, and the endothelial cell function, especially with
arterial disease) is the primary diagnostic tool.22 In step 3 reference to NO synthesis.29,30 Thus, androgens have a role
(see above), cavernosometry, pharmacocavernosometry, and in maintaining the integrity of penile tissues and structures,
pharmacocavernosography can add very valuable informa- improving the response of the cavernosal nerve, smooth
tion on intracavernosal pressure and pattern of venous leak. muscles and fibroelastic elements (Figure 50.2).31 Androgen
In 21% of patients with VOD, erectile function can be improved deprivation in animal models, either following surgical or
with pharmacological injection therapy to enable a sufficient medical intervention, produced significant changes in the
erection for intercourse.23,24 In non-responders to monotherapy tunica, as demonstrated by electron microscopy techniques.32
with papaverine or prostaglandin E1, a mixture of vasoactive Androgens modulate PDE-5 expression and activity. The
agents as Trimix or in combination with forskolin can improve current model of androgen action on the erectile structures
responsiveness.24 proposes that penile tissue remodeling provides the link
Other authors have presented excellent results of four-drug to veno-occlusive manifestations. Rogers et al. demonstrated
intracavernous therapy for ED caused by CVOD, diagnosed that androgen deprivation results in VOD.33 Furthermore,
by dynamic infusion cavernosometry–cavernosography (flow- Traish et al. noted that androgen deprivation in the animal
to-maintain erection >10ml). Patients who were not consi- model results in the accumulation of adipocytes in the
dered suitable candidates for surgery underwent self-injection penile subtunical area of the corpus cavernosum.34 This
therapy. A vasoactive mixture composed of papaverine hydro- pathology was suggested as a potential mechanism for VOD in
chloride 12.1mg/ml, prostaglandin E1, 10.1 micrograms/ml, androgen deficiency. (Figure 50.3).35 The infiltration of the
phentolamine mesylate 1.01mg/ml, and atropine sulfate trabecular tissues by adipocytes in diabetic and testosterone
0.15mg/ml was used. After dose titration of the drug mixture, deficient dogs (Figure 50.4) and in rats suggest that this
54 patients (95%) were able to obtain sustained rigid erections pathological process may contribute to VOD.34,35 In humans,
that guaranteed satisfactory sexual activity and 69% were testosterone therapy improves erectile function in men with
satisfied using the mixture. The association of the drugs used hypogonadism.36
with different mechanisms of action caused a synergism that A number of clinical observations supporting a role for
potentiated the therapeutic activity and reduced side-effects testosterone in erectile function and in the treatment of ED
by decreasing the total drug dose.25 have been reported.36–45 There is considerable emerging clinical
evidence for the management of ED with only testosterone
therapy in hypogonadal patients.36–38
Androgen treatment A link between testosterone and ED was inferred from
Erectile function is a complex neurovascular process that observations of hypogonadal patients with ED who did not
requires input from central and peripheral nervous systems, respond to PDE-5 inhibitor therapy but improved with tes-
as well as the endocrine system.26–28 The erectile response is tosterone treatment. The number of circulating endothelial
dependent on the structural integrity of the penile tissue progenitor cells is reduced in hypogonadal men and is
vascular bed and on the fibroelastic properties of cavernosal increased by testosterone treatment.39 Recently, Yassin et al.
tissue. Androgens are critical for maintaining the physiological presented a case report on a dramatic improvement in penile
function of erectile tissue.28–32 In preclinical studies Shabsigh venous leakage with testosterone administration.36,37,40,41 A
et al. reported that castration causes apoptosis, adversely detailed report was published on a series of case reports of
affecting smooth muscle content and penile hemodynamics 12 hypogonadal men with low plasma testosterone (total
and leading to VOD. Testosterone therapy reverses these struc- plasma testosterone <8nmol/l) and severe ED with varying
tural, biochemical, and physiological changes (Figure 50.1).30 comorbidities, such as diabetes mellitus type 1 or 2, metabolic

(a) (b)

Figure 50.1 (a) Apoptosis in the penis of a castrated rat. (b) Replenishment with testosterone after castration causes new DNA
synthesis. From World J Urol 1997; 15: 21–6.56
 Veno-occlusive impotence and erectile dysfunction: treatment and outcomes 385

C V

Figure 50.2 Effect of castration and androgen substitution on trabecular smooth muscle and connective tissue content in the corpus
cavernosum. C, Castrated; V, Vehicle; T, Testosterone therapy. From Endocrinology 1999; 140: 1861–8.31

Testosterone modulates adipocyte accumulation

in the penile corpus cavernosum

Control Castrated

(a) (b)

Figure 50.3 Testosterone modulates adipocyte accumulation in the subtunical region in the penile corpus cavernosum. From
reference 41.

syndrome with possible related hypertension, dyslipidemia,

and obesity (Table 50.1).41 These patients did not respond to
oral PDE-5 inhibitor therapy or maximal dosage of ICI with
alprostadil. All patients underwent the standard administra-
tion of 1000mg single-dose long-acting injectable testoster-
one undecanoate at the start, repeated at 6 weeks and then
every 12 weeks over a study period of longer than 6 months;
subsequently, long-term follow-up procedures were carried out.
All patients underwent dynamic infusion pharmacocaver-
nosography at baseline, after 3 months, and after reporting
improvement in erectile function following the treatment
with testosterone. No residual venous leakage could be
detected as early as 3–5 months in 5 patients (Figures 50.5,
Figure 50.4 Diabetes promotes adipocyte accumulation or 50.6, 50.7, 50.8).41
fat distribution in the penile corpus cavernosum in the canine These 5 patients reported significant improvement in
model. erectile function compared with baseline within 12–21 weeks
386 Textbook of Erectile Dysfunction

of androgen treatment, as evidenced by clinically relevant

Table 50.1 Patients’ characteristics
increase in their erectile function (EF) domain (questions
Patients’ characteristics, All subjects Non-respond- 1–5 plus question 15) of the International Index of Erectile Func-
demography and comor- (n=13) ers (n=7) tion (IIEF) when compared with baseline values (Table 50.2).
bidities Pharmacocavernosography and repeat radiological studies in
Mean age 58 66 patients who reported improvement in erectile function did
not show veins draining the corporal bodies (see Figures 50.5,
Age range 39–73 52–73
50.6, 50.7, 50.8). All patients noted improvement in the sexual
Mean age ± SD (years) 58.3 ± 9.7 59.9 ± 9.1 desire domain. Notably, a sixth patient exhibited improved
ED severity erectile function and absence of venous leakage after 11.5
Mild and moderate 2 0 months of treatment (see Figure 50.6); therefore, this patient
Severe 11 7
was considered to be a late responder to the study therapy (see
Table 50.2). The remaining 7 patients with persistent venous
Mean IIEF erectile 12 7
leakage are still under follow-up observation. Currently, these
function domain
patients are entering the 24th month of the therapy. Plasma
ED etiology testosterone levels and other biochemical markers were moni-
Organic 13 (100%) 6 tored in long-term follow-up for efficacy and safety evalua-
Psychogenic 0 0 tion of the therapy. The results are summarized in Table
Mixed 0 0
50.3.
In a recent report by Kurbatov et al. 19 hypogonadal men
Total serum
(testosterone level <12nmol/l), aged 32–56 (44±8.3) years,
testosterone
non-responders to PDE-5 inhibitors and with venous leakage
≤2.0ng/ml 7 3 from corpora cavernosa (demonstrated by sophisticated and
2.1–3.4ng/ml 6 3 impressive MRI methods) were treated with testosterone.46 A
Mean IPSS 15 19 total of 13 of the 19 patients (68.4%) had restored sexual
activity (Figure 50.9).
Smokers (%) 8 5
We can suggest or hypothesize that penile venous leakage
Comorbidities could be a metabolic disorder that can be reversible in some
Metabolic syndrome 10 0 cases with testosterone replacement, rather than a purely
Type I diabetes 3 2 physical lesion. This hypothesis should be tested in further
Type II diabetes 7 1 studies. We propose that the standard monotherapy with tes-
tosterone produces structural remodeling processes of the
Hypertension 7 4
penile tissues, ultimately leading to venous leakage correction
Dyslipidemia 7 4 and significant improvement of symptomatic ED.
BPH/LUTS 8 5
Non-defined etiology 1 0
SD, standard deviation; ED erectile dysfunction; IIEF, International
Index of Erectile Function; IPSS, International Prostate Symptom Vacuum devices
Score; BPH, benign prostatic hyperplasia; LUTS, lower urinary tract Vacuum devices are a non-invasive, successful, and cheap
symptoms. From reference 41.
therapy and they have good acceptance. In 1974, Osbon

(a) (b)

Figure 50.5 X-ray of a 56-year-old patient with type 2 diabetes, metabolic syndrome and erectile dysfunction at baseline; initial
testosterone level 1.8 ng/ml, and non-responder to phosphodiesterase type 5 inhibitors or alprostadil 20 µg. (b) Cavernosography
12 weeks after initiation of testosterone treatment. There are no signs of venous leakage. From Andrologia 2006; 38: 34–7.40
 Veno-occlusive impotence and erectile dysfunction: treatment and outcomes 387

(a) (b)

Figure 50.6 (a) A 63-year-old patient with type 1 diabetes, metabolic syndrome, and severe hypogonadism at baseline; initial
testosterone level 1.07ng/ml, and non-responder to phosphodiesterase type 5 inhibitors or alprostadil 20 µg. Abnormal cavernosography
showing venous leakage in the superficial and deep veins. (b) Absence of venous leakage evident by cavernosography after
4.5 months on testosterone undecanoate, with better ‘penile composition’ and corporal opacification. From J Sex Med 2006; 3:
727–35.41

(a) (b)

Figure 50.7 (a) Cavernosography of a 61-year-old patient with metabolic syndrome and type II DM; initial testosterone level
2.1 ng/ml, and non-responder to phosphodiesterase type 5 inhibitors or alprostadil 20 µg. (b) Control dynamic infusion pharmaco-
cavernosography (DIPC) after 21 weeks of therapy with injectable testosterone undecanoate: testosterone level 5.1ng/ml, with better
penile corporal opacification. After combination with 50mg sildenafil the VOD of superficial veins had no negative effect on erectile
quality. From J Sex Med 2006; 3: 727–35.41

delivered the commercial system to the US market.47 The The ring must be removed after intercourse, and should
principle is to force blood flow into the penis by means of not be in place for longer than half an hour. Advantages
vacuum induction by inserting the penis in a vacuum cylin- are its possible application in ED due to all etiologies, its
der. With a restriction rubber ring placed at the base of ease of use, and its very low side-effect profile. Potential dis-
the penis, venous outflow can be prevented so erection can advantages are retrograde or decreased ejaculation as a
take place and be maintained. This method has a high success result of the restriction ring, skin bleeding, coldness and
rate48–50 and it is well accepted in older patients with a personal extreme penile congestion, and occasionally decreased erection
preference for this device or with severe comorbidities. during sexual intercourse.
388 Textbook of Erectile Dysfunction

(a) (b)

Figure 50.8 (a) A 52-year-old patient with type 2 diabetes and hypertension; initial testosterone level 1.81ng/ml, and non-responder
to phosphodiesterase type 5 inhibitors or intra-cavernosal injection with alprostadil 20–30 µg. (b) Cavernosography after 11.5 months
of treatment with testosterone undecaoate injections. No signs of venous leakage; Interational Index of Erectile Function score 24
(questions 1–5 and 15).

Table 50.2 International Index of Erectile Function scores of erectile function (EF) and sexual desire (SD) in
early and late responders (six patients) compared with non-responders at baseline and at 12, 30, and 46 weeks
follow-up

Baseline Week 12 Week 30 Week 46

Responders (n=6)
Early responders:
(N=5)
EF 8.0 (±0.00) 23.4 (±0.80) 24.4 (±0.40)
SD 4.0 (±0.00) 8.0 (±0.00) 8.0 (±0.00)
Late responders:
(N=1)
EF 7.0 (±0.00) 4.0 (±0.00) 17.0 (±0.00) 24.0 (±0.00)
SD 4.0 (±0.00) 7.0 (±0.00) 7.0 (±0.00) 7.0 (±0.00)
Non-responders (n=6)
EF 6.71 (±1.21) 10.28 (±2.11) 11.28 (±2.70) Follow-up in progress
SD 4.0 (±0.00) 7.42 (±0.52) 7.85 (±0.15)
From reference 41.

Future directions there may be an endocrine mechanism behind the disorder.

Estradiol plasma concentrations were significantly higher in
Tan et al. proposed that ED is the most common symptom venous leakage patients compared with controls, suggesting
in hypogonadal subjects.51 The percentage of patients with that the steroid environment, in particular the estradiol level,
testosterone deficiency and ED ranges between 12% and 36%. can influence venous vascular tone (via vascular endothelial
We found, from screening an ED population, that 18.3% are growth factor or NO), thus affecting venous leakage.54
identified as hypogonadal.52 Guay et al. reported that 37% of Recently, it has been shown that there are a reduced number
their ED patients had had hypogonadism.53 In functional of circulating endothelial progenitor cells in hypogonadal
insufficiency of veno-occlusion, it has been hypothesized that men, suggesting that hypotestosteronemia may be associated
 Veno-occlusive impotence and erectile dysfunction: treatment and outcomes 389

Table 50.3 Follow-up protocol and measurements at baseline and regular check-ups at 3, 6, and 12 months
afterwards
Late responder (n=1) follow-up protocol Baseline 3 months 6 months 12 months
Abdominal girth (cm) 121 116 115 107
Prostate sonogram ± TRUS (ml) 48/15 48/16 46/16
Blood pressure (mmHg) 130/80 125/75 130/80 125/86
IIEF
EF 7.0 4.0 17.0 24.0
SD 4.0 7.0 7.0 7.0
AMS 55 49 38 36
IPSS 16 14 14 14
PSA (free) 0.81 1.15 1.16
Testosterone 1.81 4.54 4.9 5.2
SHBG
DHT 196 88 76
DHEA-sulfate
CRP
CBC
Leucocytes 8.6 6.0 6.0
Erythrocytes 4.2 5.85 5.04
Thrombocytes 115 197 152
Hemoglobin 12.8 14.7 14.0
Hematocrit (%) 40 46 44
Glycosylated hemoglobin 7.8 6.7 6.8 6.6
Blood glucose 145 130 120 116
Lipids
Cholesterol 316 257 161 188
HDL 38 na na 47
LDL 70 na 55 55
Triglycerides 468 368 244 220
TRUS, transrectal ultrasound; IIEF, International Index of Erectile Function; AMS, Aging Male Symptoms Score; IPSS, International Prostate Symptom
Score; PSA, prostate-specific antigen; SHBG, sex hormone-binding globulin; DHT, dihydrotestosterone; HDL, high-density lipoprotein;
LDL, low-density lipoprotein. From reference 41.

(a) (b)

Figure 50.9 MRI of venous leak in a hypogonadal man (a) before and (b) after 21 weeks of treatment with injectable long-acting
testosterone undecanoate.
390 Textbook of Erectile Dysfunction

with low numbers of these cells.55 The fact that testosterone in evaluating the effect of novel therapeutic approaches to
therapy results in an increase in these cells, through a possible treat VOD (e.g. androgens, PDE-5 inhibitors, or a combina-
direct effect on the bone marrow, suggests a profound role for tion of both).46 We will have to await further preclinical
androgens in erectile function.39 Newer diagnostic methods, research outcomes to judge whether other novel approaches,
such as duplex ultrasound or MRI of the penis, which can such as gene therapy, will be effective in managing this specific
detect and visualize venous leakage in patients, may be useful pathology of ED.

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phy (DICC). Multi-institutional study. Urology 1993; 41: 445–51. effective for the treatment of erectile dysfunction in diabetic men.
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4. Shabsigh R, Rajfer J, Aversa A, et al. The evolving role of testoster- role in management of vasculogenic impotence resistant to standard
one in the treatment of erectile dysfunction. Int J Clin Pract 2006; 3-agent pharmacotherapy. J Urol 1997; 158: 1752–8.
60: 1087–92. 25. Montorsi F, Guazzoni G, Bergamaschi F, et al. Four-drug intra-
5. Sasso F, Gulino G, Basar M, Alcini A, Alcini E. Could standardized cavernous therapy for impotence due to corporeal veno-occlusive
cavernosometry be helpful in therapeutic management of veno- dysfunction. J Urol 1993; 149: 1291–5.
occlusive dysfunction? J Urol 1996; 155: 150–4. 26. Traish AM, Guay AT. Are androgens critical for penile erections in
6. Das S. Early history of venogenic impotence. Int J Impot Res 1994; humans? Examining the clinical and preclinical evidence. J Sex
6: 183–9. Med 2006; 3: 382–404.
7. Wespes E, Delcour C, Preserowitz L, et al. Impotence due to 27. Traish AM, Goldstein I, Kim NN. Testosterone and erectile func-
corporeal veno-occlusive dysfunction: long-term follow-up of tion: from basic research to a new clinical paradigm for managing
venous surgery. Eur Urol 1992; 21: 115–19. men with androgen insufficiency and erectile dysfunction. Eur
8. Petrou S, Lewis RW. Management of corporal veno-occlusive Urol 2007; 52: 54–70.
dysfunction. Urol Int 1992; 49: 48–55. 28. Shabsigh R. Testosterone therapy in erectile dysfunction and
9. Lewis RW. Results of surgery for veno-occlusive disease. J Sex hypogonadism. J Sex Med 2005; 2: 785–92.
Marital Ther 1991; 17: 129–35. 29. Traish A, Kim N. The physiological role of androgens in penile
10. Berardinucci D, Morales A, Heaton JP, Fenemore J, Bloom S. Surgi- erection: regulation of corpus cavernosum structure and function.
cal treatment of penile veno-occlusive dysfunction: is it justified? J Sex Med 2005; 2: 759–70.
Urology 1996; 47: 88–92. 30. Shabsigh R, Raymond JF, Olsson CA, O’Toole K, Buttyan R. Andro-
11. Cakan M, Yalçinkaya F, Demirel F, Ozgunay T, Altug U. Is dorsal gen induction of DNA synthesis in the rat penis. Urology 1998; 52:
penile vein ligation (DPVL) still a treatment option in veno-occlusive 723–8.
dysfunction? Int Urol Nephrol 2004; 36: 381–7. 31. Traish AM, Park K, Dhir V, et al. Effects of castration and androgen
12. Stief CG, Hartmann U, Hoefner K, et al. Erectile Dysfunction: replacement on erectile function in a rabbit model. Endocrinology
Diagnostics and Therapy. Stuttgart, Germany: Springer, 1997. 1999; 140: 1861–8.
13. Virag R, Zwang G, Dermange H, Legman M. Vasculogenic impo- 32. Lu YL, Shen ZJ, Wang H, et al. Ultrastructural changes of
tence: a review of 92 cases with 54 surgical operations. Vasc Surg penile tunica albuginea in diabetic rats. Asian J Androl 2004; 6:
1981; 15: 9–15. 365–8.
14. Anafarta K, Aydos K, Yaman O. Is deep dorsal vein arterialization 33. Rogers RS, Graziottin TM, Lin CS, Kan YW, Lue TF. Intracavernosal
an alternative surgical approach to treat venogenic impotence? vascular endothelial growth factor (VEGF) injection and adeno-
Urol Int 1997; 59: 109–12. associated virus-mediated VEGF gene therapy prevent and reverse
15. Siroky MB, Azadzoi KM. Vasculogenic erectile dysfunction: venogenic erectile dysfunction in rats. Int J Impot Res 2003; 15:
newer therapeutic strategies. J Urol 2003; 170: S24–29; discussion 26–37.
S29–30. 34. Traish AM, Toselli P, Jeong SJ, Kim NN. Adipocyte accumulation
16. Cookson MS, Phillips DL, Huff ME, Fitch WP 3rd. Analysis of in penile corpus cavernosum of the orchiectomized rabbit: a
microsurgical penile revascularization results by etiology of impo- potential mechanism for veno-occlusive dysfunction in androgen
tence. J Urol 1993; 149: 1291–5. deficiency. J Androl 2005; 26: 242–8.
17. Hauri D. [The trigone]. Urologe A 1983; 22: 425–30. 35. Traish AM, Munarriz R, O’Connell L, Goldstein I. Effects of medi-
18. Basche S, Eger C, Elsebach K, Ulshofer B. [Veno-occlusive dys- cal or surgical castration on erectile function in an animal model.
function as a cause of erectile impotence: therapy of venous leak J Androl 2003; 24: 381–7.
with retrograde embolization of the internal pudendal vein]. Vasa 36. Yassin AA, Saad F. Improvement of sexual function in men with
2003; 32: 47–50. [in German] late-onset hypogonadism treated with testosterone only. J Sex Med
19. Ferrini MG, Davila HH, Kovanecz I, et al. Vardenafil prevents 2007; 4: 497–501.
fibrosis and loss of corporal smooth muscle that occurs after 37. Yassin AA, Saad F. Treatment of sexual dysfunction of hypogo-
bilateral cavernosal nerve resection in the rat. Urology 2006; 68: nadal patients with long-acting testosterone undecanoate (Nebido).
429–35. World J Urol 2006; 24: 639–44.
20. Ferrini MG, Kovanecz I, Sanchez S, et al. Long-term continuous 38. Greenstein A, Mabjeesh NJ, Sofer M, et al. Does sildenafil com-
treatment with sildenafil ameliorates aging-related erectile dys- bined with testosterone gel improve erectile dysfunction in hypo-
function and the underlying corporal fibrosis in the rat. Biol Reprod gonadal men in whom testosterone supplement therapy alone
2007; 76: 915–23. failed? J Urol 2005; 173: 530–2.
21. Foresta C, Lana A, Cabrelle A, et al. PDE-5 inhibitor, Vardenafil, 39. Foresta C, Caretta N, Lana A, et al. Reduced number of circulating
increases circulating progenitor cells in humans. Eur Urol 2007; endothelial progenitor cells in hypogonadal men. J Clin Endocrinol
51: 1411–17. Metab 2006; 91: 4599–602.
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40. Yassin A, Saad F. Dramatic improvement of penile venous leakage venous leakage in patients with veno-occlusive erectile dysfunc-
upon testosterone administration. A case report and review of tion. Int J Impot Res 2008; 20: 192–8.
literature. Andrologia 2006; 38: 34–7. 47. Walden TB. Osbon Erec Aid. J Urol 1986; 136: 689.
41. Yassin AA, Saad F, Traish A. Testosterone undecanoate restores 48. Levin EI. Vacuum-constriction therapy in association of erectile
erectile function in a subset of patients with venous leakage: dysfunction and premature ejaculation. Urologiia 2002; 6: 37–41.
a series of case reports. J Sex Med 2006; 3: 727–35. [in Russian]
42. Kalinchenko SY, Kozlov GI, Gontcharov NP, Katsiya GV. Oral 49. Lewis RW, Witherington R. External vacuum therapy for erectile
testosterone undecanoate reverses erectile dysfunction associated dysfunction: use and results. World J Urol 1997; 15: 78–82.
with diabetes mellitus in patients failing on sildenafil citrate therapy 50. Blackard CE, Borkon WD, Lima JS, Nelson J. Use of vacuum
alone. Aging Male 2003; 6: 94–9. tumescence device for impotence secondary to venous leakage.
43. Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. Androgens Urology 1993; 41: 225–30.
improve cavernous vasodilation and response to sildenafil in 51. Tan RS, Philip PS. Perceptions of and risk factors for andropause.
patients with erectile dysfunction. Clin Endocrinol (Oxf) 2003; 58: Arch Androl 1999; 43: 97–103.
632–8. 52. Yassin A, Saad F. Erectile dysfunction, metabolic syndrome,
44. Yassin A, Saad F, Diede HE. Testosterone and erectile function hypogonadism are intertwined. J Urol 2007; 177: 288.
in hypogonadal men unresponsive to tadalafil: results from 53. Guay AT, Perez JB, Jacobson J, Newton RA. Efficacy and safety of
an open-label uncontrolled study. Andrologia 2006; 38: sildenafil citrate for treatment of erectile dysfunction in a popula-
61–8. tion with associated organic risk factors. J Androl 2001; 22: 793–7.
45. Rochira V, Balestrieri A, Madeo B, Granata ARM, Carani C. Erratum in: J Androl 2002; 23: 113.
Sildenafil improves sleep-related erections in hypogonadal men: 54. Mancini1 A, Milardi1 D, Bianchi1 A, Summaria V, De Marinis L.
evidence from a randomized, placebo-controlled, crossover study Increased estradiol levels in venous occlusive disorder: a possible
of a synergic role for both testosterone and Sildenafil on penile functional mechanism of venous leakage. Int J Impot Res 2005; 17:
erections. J Androl 2006; 27: 165–75. 239–42.
46. Kurbatov DG, Kuznetsky VY, Kitaev SV, Brusensky VA. Magnetic 55. Shabsigh R. The effects of testosterone on the cavernosal tissues
resonance imaging as a potential tool for objective visualization of and erectile function. World J Urol 1997; 15: 21–6.
51 Penile fracture: evaluation
and management
Osama KZ Shaeer and Kamal ZM Shaeer

Introduction Rupture of the tunica mostly occurs on the ventral aspect of

the penis, particularly if a coital injury is the cause.3 This can
‘Fracture of the penis’ is the term describing traumatic be explained both by the mechanism of injury (direction of
rupture of the tunica albuginea of the corpus cavernosum,1 the arm of force) and by the sturdy nature of the dorsal aspect
secondary to blunt trauma inflicted when the penis is in the of the penis in comparison with the ventral aspect. The tunica
erect state, most commonly during sexual activity. The conse- albuginea is thicker dorsally than ventrally, and is less liable to
quent pain and swelling is usually the cause of presentation; stretch beyond its limit in the erect state, thus preventing the
however, despite a consistent and classical clinical picture, erect penis from bending ventrally. It is therefore less liable to
many controversies surround the guidelines for optimal rupture. The dorsal aspect is further supported by the neuro-
management. vascular bundle. In case of overwhelmingly forceful ventral
Penile fracture is by far the most commonly reported blunt bending, the dorsal vessels are more liable to snap than is the
injury to the penis,2 although an exact incidence cannot be dorsal tunica albuginea, and the resulting pain usually brings
stated. Penile fracture was reported in 183 publications the traumatic force to a stop, protecting the dorsal tunica
between 1996 and 2001, discussing a total of 1331 cases.3 from further development of pressure. Accordingly, ventral
Variation in prevalence according to geographic distribution bending of the erect penis is less likely than dorsal bending,
is evident, mostly on account of diversity of sexual cultures and thus ventral rupture is more likely than dorsal rupture.
and practices. The vast majority of the 1331 cases reported Nevertheless, though it is rare, dorsal rupture of the tunica
came from the Middle East; namely Iran, Morocco, Turkey, albuginea does occur.5
Egypt, and Saudia Arabia. The USA and Canada came second Injury of the urethra is widely reported as a complication of
in rank.3 Patients were mostly in the fourth decade, with the penile fracture, occurring in up to 38% in one case series,8
age range between 12 and 82 years.3 and ranging from partial injury to complete disruption.3 A
clear variation in the incidence of urethral injuries has been
noticed in correlation with the modality of trauma, being
higher in coital injuries. This was explained by the higher
Pathogenesis magnitude of force with coital trauma in comparison with
Erection is a prerequisite to rupture of the tunica albuginea manipulation injuries.5
in response to blunt trauma or bending, since the high intra- If surgical repair is not undertaken, the defect usually
corporal pressure in the erect state stretches the tunica to heals by secondary intention, and the hematoma becomes
its limit, thinning it out and rendering it fragile. Forceful organized and encapsulated. The healed tear in the tunica
bending at this state will lead to a surge of intracorporal albuginea is relatively weak and is therefore liable to aneurys-
pressure that stretches the already taut tunica beyond its limit, mal dilatation and may be the site of venous leakage, resulting
causing it to rupture. Bending an erect penis can cause pres- in erectile dysfunction (ED).10 The neglected hematoma may
sure to increase from 180 mmHg to 1500 mmHg.4 In contrast, lead to abscess formation or deformity.11
a flaccid penis will bend and yield in response to blunt trauma Although fracture of the penis implies rupture of the corpus
with relatively no rise in intracorporal pressure. cavernosum, the resultant hematoma may be exacerbated fur-
Rupture of the tunica albuginea is usually painful as well as ther by associated injuries, such as rupture of the superficial
audible (a snapping sound). Blood contained in the corpus vessels of the penis or tears in Dartos muscle or in Buck’s
cavernosum gushes out, resulting in immediate detumescence, fascia, which is firmly adherent to the tunica albuginea.12
and formation of a hematoma. Edema of penile skin follows.
The tear in the tunica albuginea is mostly unilateral5
though bilateral tears have been reported.6 The tear is usually Etiology
transverse or oblique;5 nevertheless, longitudinal tears are also
encountered.7 Rupture usually occurs in the proximal shaft8 Traumatic event
but has also been described in the distal third of the penis and, Penile fracture is the result of blunt trauma or bending force
rarely, in the crus.9 applied to the erect penis. The causative incident is almost

392
 Penile fracture: evaluation and management 393

always related to sexual activity, whether coital or non-coital. of the hematoma declines, probably owing to detumescence
In coital mishaps, the erect penis accidentally propels into the and pain-induced vasoconstriction, both of which arrest the
partner’s perineum or pubis. This event can occur in any sex- bleeding.21 Distribution of the hematoma depends in part on
ual position, but is more liable to occur in the female domi- the integrity of fascial layers of the penis. If Buck’s fascia is
nant position, the so-called reverse coitus.7 Variation intact, ecchymosis is confined within Buck’s fascia over the
in the traumatic event is noticeable in different geographic tear, and the patient has a well-defined collection and the
regions. The previously mentioned coital injuries are the so-called eggplant deformity.22 When Buck’s fascia is compro-
main cause of fracture penis in the USA and Europe.8 In con- mised, the collection seeps to Colles’ fascia, in which case
trast, in the Middle East, non-coital injuries (primarily during extravasation is diffuse and assumes a ‘butterfly’ pattern over
masturbation) are relatively more common.1 This can be the perineum, scrotum, and lower anterior abdominal wall.23
attributed to religious and social prohibition on pre-marital In cases of early presentation, this distribution may be masked
and extra-marital sex, with possible consequent inclination to by edema.21 It should be noted that the hematoma does not
masturbation until marriage. necessarily coincide with the defect. If Buck’s fascia is torn,
In addition to aggressive masturbation, non-coital fractures blood may proceed to Colle’s fascia and assume a wide, non-
are caused by intentional bending of the erect penis to induce specific distribution.21 Patients may have angulation of the
detumescence. The latter is a cultural habit reported in some penis, commonly away from the site of rupture. Deviation in
Middle Eastern countries, where it is referred to as taqaandan this early stage is caused by hematoma and edema.24
or qolenj shekestan (meaning ‘to click’ or ‘to snap’). The erect The defect may be palpable over the fracture site, referred
penis is pushed forcibly downwards, upwards, or laterally to to as the ‘rolling sign’.25 The tenderness encountered and the
achieve detumescence or pleasure, in many cases habitually.13 overlying swelling and edema may prevent palpation of the
Other rare incidents and modalities of trauma have been defect without causing significant discomfort to the patient.
reported, including attempts at manual correction of a con- This sign is best elicited under anesthesia.17 Injury of the urethra
genital chordee,14 attempts to tuck an erect penis into is not uncommon, and usually manifests itself by bleeding
underwear,15 falling from the bed onto an erect penis during from the urethral meatus5 or frank hematuria.15 Retention of
sleep,16 rolling over in bed during nocturnal tumescence,14 urine and a weak stream are possible presentations. Bleeding
and masturbating with the tubing of a vacuum cleaner.17 from the urethra does not necessarily imply rupture of the
urethra. In some cases with meatal bleeding, ascending urethro-
graphy excludes urethral rupture, while urethroscopy demon-
Predisposing factors strates mucosal injury rather than frank rupture.17
To date, factors predisposing to penile fracture have been
ambiguous. An association was noted with Peyronie’s plaques
in four penile fracture cases. This was theoretically explained Late presentation and complications
by aberrant elasticity and deviation of the penis in the erect
state, both rendering the penis more prone to trauma upon If a fractured penis is neglected, the initial manifestations,
sexual activity.18 In addition to Peyronie’s disease, fibrosclerosis namely edema and hematoma, subside gradually. Patients with
of the tunica albuginea and chronic cell infiltrates were delayed presentation usually report the classic history but also
observed in five cases of fracture penis.19 Periurethral inflam- complain of the resulting complications, such as ED,10 penile
mation, as occurs in gonococcal urethritis, was also noted in deviation,11 and a palpable mass,1 erectile dysfunction,10 or
association with penile fracture.20 penile deviation.11 ED is caused by possible venous leakage at
the site of the healed tear.10 Deviation may be caused by
contracture of scar in the tunica albuginea or by organization
Clinical picture of the hematoma. Contrary to the initial early deviation that
follows fracture, late deviation may be towards the ipsilateral
The unique and classical clinical picture notorious to fracture side of the healing tear and hematoma, the opposite side of the
of the penis may suffice in many instances for a clinically initial earlier deviation. Less frequently, patients may present
based diagnosis without resorting to investigations.17 Presen- with poor urinary stream, urinary retention,9 a urethro-
tation may be early or late, depending on the extent of injury cavernous, or a urethrocutaneous fistula.26
that is the motivation to seek urgent medical assistance if
significant, availability of specialized medical expertise, as well
as other social circumstances. Atypical presentation
In rare incidents, the characteristic story of penile fracture is
Early presentation not evident. The relationship of the onset to sexual activity
Blunt trauma to the erect penis sufficient to cause rupture may not be reported, commonly on account of embarrass-
of the tunica albuginea results in a tell-tale cascade of ment, and less frequently because of a failure to correlate the
events: acute pain mostly during sexual intercourse, a charac- sexual act with the symptoms on the part of the patient. Frac-
teristic popping or snapping sound, immediate detumescence, tures close to the pubic insertion of the corpora may result in
progressive swelling, and ecchymosis. scrotal and perineal pain, and a totally normal penis, and may
Initially, the ecchymotic swelling increases progressively, as be misdiagnosed and managed as epididymo-orchitis. The
does edema of the penile skin. After a brief period, progression correct diagnosis may be reached by cavernosography.7
394 Textbook of Erectile Dysfunction

Recurrent fracture Ultrasonography

Penile refracture following surgical repair of an initial instance The defect in the tunica albuginea may be palpated directly or
has been described in a few case reports.27–29 In one case, its site deduced from the overlying hematoma. Amidst tense
refracture occurred 10 weeks after repair of the initial fracture, edema and tenderness, it can be difficult to determine the site
and was associated with extension into the urethra, unlike of the hematoma and more importantly the site of the defect
the initial fracture, in which there was no urethral injury. in the corporeal bodies by palpation. Both the hematoma and
Refracture was attributed to early resumption of sexual activ- defect can be delineated by ultrasonography34 without causing
ity, specifically vigorous intercourse. This emphasizes the patient discomfort. Ultrasonography is fast, reliable, and non-
importance of abstinence following repair. Non-absorbable invasive. However, a contradictory opinion is that ultrasonog-
sutures have been suggested as a measure taken to avoid raphy may fail to localize the exact site of the tear (as checked
refracture.29 by surgical exploration) and may fail to diagnose multiple
tears.21 Instead, it gives provisional information about the
probable site of the tear, by demonstrating the hematoma.
Differential diagnosis
Cavernosography
Several conditions may simulate fracture of the penis. Rupture
Cavernosography is capable of accurately demonstrating the
of the deep dorsal vein is one of the most common. In one
site and number of defects in the tunica albuginea. It can also
study, 2 out of 21 cases with the classic picture of fracture
diagnose some of the possible complications such as a caver-
penis had intact corporeal bodies and a ruptured deep dorsal
no-urethral fistula.6 Despite its value and accuracy, some
vein.30 Less commonly reported are rupture of the dorsal
authors believe that cavernosography will unnecessarily delay
penile artery and non-specific Dartos bleeding.12
surgery.21 The same information issued by cavernosography
A rare entity is ruptured Mondor’s disease of the penis.
can be obtained upon surgical exploration, which is in many
Mondor’s disease is thrombosis of the superficial dorsal vein
cases inevitable. Furthermore, cavernosography has been
of the penis, usually related to trauma, including sexual
reported to yield false negative results in some cases, as
intercourse. Thrombophlebitis may occur on top, rendering
checked by surgical exploration, where a tunical breach found
the vessel wall fragile and prone to rupture upon coital
upon exploration is not demonstrated in the cavernogram.6
trauma. Ruptured Mondor’s disease therefore exhibits a similar
Cavernosography cannot exclude vascular injuries that may
sequence of events to those of a fractured penis: acute pain and
be the underlying pathology, rather than disruption of the
a popping sound during coitus. A recent history of a painful,
tunica albuginea, thus giving a misleading indication for
firm, cord-like structure on the dorsum of the penis, possibly
conservative management.30
extending to the inguinal region, may be suggestive.31
The painful and invasive nature of this examination and the
Considering that rupture of the corpus cavernosum occurs
possible complications (including infection and allergy to
mostly ventrally, a hematoma oriented on the dorsal aspect of
the dye used) may discourage its application. It is my opinion
the penis should raise questions as to other possibilities. Imag-
that cavernosography may be reserved for decision-making in
ing, especially cavernosography, may discriminate between
ambiguous cases with atypical presentation, such as those
the aforementioned possibilities. In many situations, surgical
with crural rupture manifesting with scrotal pain and a nor-
exploration alone can reveal the underlying pathology.
mal penis,7 cases of late presentation and non-progressive
course where conservative management is a possible option,
and cases with suspicion of a caverno-urethral fistula, in which
Investigations cavernosography is the diagnostic modality of choice.35

Diagnosis of penile fracture may be established solely on

clinical grounds considering the characteristic sequence of Urethrography
events and the possibility of directly palpating the defect in Retrograde urethrography is well indicated in cases with
the tunica albuginea. Exclusive dependence on clinical hematuria or difficult micturition. Nevertheless, urethrogra-
impression is advocated by some authors, based on the phy has demonstrated urethral tears in cases of penile fracture
experience that radiological assessment contributes little to with neither meatal bleeding nor micturition problems. It is
decision-making,32 especially with surgical exploration being not yet agreed whether this justifies routine application of
inevitable in the opinion of the majority. In addition, investi- urethrography for cases with penile trauma.6
gations are subject to availability of expertise and equipment, On the other hand, urethrography may give false negative
which may be an obstacle. Considering the invasive nature results. Bleeding from the urethra may be on account of injury
of some of the diagnostic tools, patient disapproval may of the urethral mucosa rather than because of a frank tear.
be encountered.33 Mucosal injury is diagnosed by urethroscopy rather than
On the other hand, investigations can help to ascertain the urethrography.17
diagnosis, localize the site and number of breaches in the
tunica, identify the presence of associated complications, and
exclude other possible diagnoses. This in turn may influence Urethroscopy
the treatment plan and whether a conservative or surgical Exploration of the urethral mucosal surface following fracture
approach is undertaken. of the penis has demonstrated injury of the mucosa despite a
 Penile fracture: evaluation and management 395

negative urethrogram.17 Flexible cystoscopy is more suitable Another review reported complication rates of 40.7% and
for this purpose but cannot be advocated for routine use. 8.2%, respectively.42 Complications issuing from conservative
treatment included pain, ED, urethral stenosis, and persistent
hematoma.41 In favor of conservative treatment is the shorter
Magnetic resonance imaging hospital stay and lower physical burden.33
Accuracy of magnetic resonance imaging (MRI) has been veri- No clear-cut guidelines have been proposed for patient
fied by several reports,36,37 one of which ascertained its superio- selection to receive conservative treatment or surgery. While
rity over ultrasonography and cavernosography in ambiguous patient rebuttal of surgery is an absolute indication for con-
cases.37 Despite its accuracy, MRI cannot be recommended for servative therapy, other indications include milder cases
routine use in the diagnosis of fractured penis considering the without major progressive tissue swelling, without urinary
time and cost involved. It can be a valid option in vague cases complications,41 without deformity, without an extracorpo-
where clinical examination and the aforementioned investi- real source of bleeding and with intact corporeal bodies as
gations neither confirm nor exclude a defect in the tunica confirmed by imaging techniques.43 Cases with delayed pre-
albuginea, and conservative treatment is strongly considered. sentation and promising clinical condition may also be candi-
To sum up, imaging is a useful adjunct to clinical diagnosis, dates for the conservative approach.
especially in cases with atypical presentation or those in which
conservative treatment is an option to be considered. Never-
theless, surgical exploration is still the gold standard for the Principles of surgical repair
evaluation and management of suspected penile fracture, and The procedure should be performed under antibiotic
whenever indicated, it should not be delayed awaiting the coverage. Palpation of the defect and imaging techniques such
availability of a diagnostic measure. as cavernosography and urethrography may guide the surgical
plan, and can be performed intra-operatively under anesthe-
sia. A trial at urethral catheterization may commence the
Treatment procedure.44 If this fails, options are cystoscopy and catheter-
ization along a guidewire, or suprapubic cystostomy. Some
Prior to intervention, adequate patient counseling is manda- authors recommend a cautious approach to catheterization
tory, and so is a written informed consent. The mainstay so as to reduce the risk of infection and further trauma to
in the management of suspected fracture of the penis is imme- the urethra.1
diate surgical exploration.38 Nevertheless, controversy still Several incisions have been proposed for exploring the
exists. Some experts advocate delayed repair. Others recom- penile shaft, the most popular of which is the circumferential
mend conservative treatment in selected cases. Each of these subcoronal degloving incision.44 The hematoma is evacuated
opinions has its rational basis. and ‘bleeders’ in Buck’s or Dartos layers are ligated. The three
corporeal bodies are inspected for defects. This may be assisted
by injection of methylene blue or saline into the corpora and
Choice of treatment through the meatus. The irrigation fluid flows back from the
Most authors advocate urgent surgical intervention for defect (if present), facilitating identification.21 When a defect
cases of suspected penile fracture.38 Unintentional delay of the in the tunica albuginea of the corpora cavernosa is encoun-
repair up to 48 hours (depending on the time of presentation) tered, the edges are freshened and sutured ‘water-tight’ in the
was not associated with exceptional difficulty or exaggerated direction of the defect. In the case of a longitudinal defect, if
complications in comparison with immediate repair.39 narrowing is anticipated, the edges are approximated trans-
Intentional delay for 7–12 days has been suggested, allowing versely.45 In some instances, a transverse defect in the tunica
resolution of edema and organization of the hematoma, may proceed medially behind the corpus spongiosum. In such
in which case the hematoma would be clearly palpable and cases, subtle mobilization of the spongiosum may assist full
would then be taken as a guide for an incision at the site of exposure and repair. The shaft should be explored for a sec-
the tear in the tunica albuginea.40 There are reports of ond defect. This, as well as competence of the repair, can be
successful outcome with this approach, without significant checked by repeating the previously mentioned transcorpo-
complications.10 Nevertheless, the site of the hematoma may real irrigation.21
be misleading, since it does not always lie over the tear.21 Continuous sutures are more ‘water-tight’. Relaxing inter-
Moreover, delayed repair may lead to prolongation of rupted sutures across the continuous suture line will support
morbidity and possibly a heavier psychological impact. the latter and help prevent dehiscence upon future erections.
As to conservative treatment, its advocates base their opin- Interrupted stitches are adopted by some authors, especially
ion on experience with patients who were not operated upon, in cases of penile refracture.29,44 Absorbable41 or non-absorb-
either because of patient disapproval of surgical intervention able14 suture materials are a matter of personal preference. If
or because of delayed presentation. This subset of patients did non-absorbable stitches are to be used, the knots should be
exhibit a higher rate of complications in comparison with inverted.14 Non-absorbable suture materials were recom-
those who were operated upon, but the complications mended following some instances of penile refracture.27
were not significant enough in frequency and magnitude Although no clearly definitive information is available, it
to rule out conservative treatment completely.41 A review seems that the type of suture material used is not critical,
of the literature reported complication rates of 29% and 0% much the same as with abdominal fascial closures.29 I
for conservative and operative approaches, respectively.15 recommend slowly absorbable suture materials such as
396 Textbook of Erectile Dysfunction

polydioxanone, to maintain a good balance between the through edematous skin. A horizontal semicircular incision
virtues of the two. on the ventral aspect of the distal penis has been proposed,
As to urethral injuries, an indwelling catheter may suffice preferably in the area that suffers edema the least. This incision
for a tiny defect to heal. Suprapubic cystostomy is also a is more secure to gaping upon erection, and the shaft can be
possible resort if catheterization fails. Larger defects should delivered through it.21 A direct longitudinal incision over the
be formally repaired by freshening and suturing the edges, presumed site of fracture may provide simple direct access, but
preferably in two layers, and diverting urine for a sufficient may also be misleading since the hematoma does not always
period postoperatively. An end-to-end anastomosis may be coincide with the defect,21 and may give poor cosmetic result.
necessary in the rare cases of complete transection of the A high scrotal midline raphe incision avoids the excessive
urethra.46 dissection in the process of degloving and is relatively concealed
The utility of a drain is controversial,3 since its value in with better cosmetic outcome. It can also be a route for a pro-
drainage may be compromised by the possibility of intro- ximal degloving procedure. A suprapubic incision gives access
ducing infection. The penis should be dressed in the vertical to the three corporeal bodies and is away from the edematous
position to decrease edema. Dressing should be snug but area. However, access to the ventral aspect of the penis is
never tight enough to cause skin necrosis.3 Postoperative anti- more difficult in comparison with the subcoronal incision.
biotic coverage and analgesia are prescribed. The use With several options for the incision, none is unanimously
of antierectogenic drugs for the convalescence period is adopted, or ideal for all situations.3
controversial.47
The catheter is usually removed on postoperative day 2
unless urethral injury is suspected. Dressing is removed on Principles of conservative treatment
postoperative day 7.44 Abstinence from sexual activity for an Conservative treatment comprises cold compresses, pressure
adequate period of time is important to avoid penile refrac- dressings, and anti-inflammatory drugs. Antibiotics are used
ture. Although the healing time of tunical tissue is not known, empirically in some cases although no evidence exists as to
it seems appropriate for patients to remain sexually abstinent their value.1 The use of sedatives and estrogens to suppress
for a minimum of 6 weeks and to refrain from high-impact erection during convalescence is probably unnecessary.47 Fur-
sexual activity thereafter.29 thermore, it has been suggested that the presence of erections
The choice of incision for the repair of penile fracture is after a penile fracture reduces the patient’s anxiety about
probably a matter of custom or preference.3 A subcoronal cir- impotence and may have an overall beneficial psychological
cumferential degloving incision is one of the most popular, effect.1 Although patients with urethral injuries are not rec-
allowing excellent exposure of the three corpora48 but it may be ommended for conservative treatment, those who do decline
complicated by lymphedema.3 It is my experience that the surgery may receive a suprapubic cystostomy or a transure-
postoperative erections may pull on the suture line and result thral catheter, which should be left in place for 1–6 weeks
in gaping in some cases, especially with the sutures tearing under antibiotic prophylaxis.41

REFERENCES

1. El-Sherif AE, Dauleh M, Allowneh N, Vijayan P. Management of 13. Zargooshi J. Trauma as the cause of Peyronie’s disease: penile
fracture of the penis in Qatar. Br J Urol 1991; 68: 622–5. fracture as a model of trauma. J Urol 2004; 172: 186–8.
2. Hunter W, Layron L. Penile and genital injuries. Urol Clin North 14. Zargooshi J. Penile fracture in Kermanshah, Iran: report of 172
Am 2006; 33: 117–26. cases. J Urol 2000; 164: 364–6.
3. Eke N. Fracture of the penis. Br J Surg 2002; 89: 555–65. 15. Nicolaisen GS, Melamud A, Williams RD, McAninch JW. Rupture
4. Penson DF, Seftel AD, Krane RJ, et al. The hemodynamic of the corpus cavernosum: surgical management. J Urol 1983; 130:
pathophysiology of impotence following blunt trauma to the erect 917–19.
penis. J Urol 1992; 148: 1171–80. 16. Abulata KA, Awad RA. Fracture shaft of penis. Non-surgical treat-
5. Asgari MA, Hosseini SY, Safarinejad MR, Samadzadeh B, Bardideh ment of three cases. J R Coll Surg Edinb 1983; 28: 266–8.
AR. Penile fractures: evaluation, therapeutic approaches and long 17. Mydlo JH. Surgeon experience with penile fracture. J Urol 2001;
term results. J Urol 1996; 155: 148–9. 166: 526–8.
6. Mydlo JH, Hayyeri M, Macchia RJ. Urethrography and caverno- 18. Minor TX, Brant WO, Rahman NU, Lue TF. Approach to manage-
sography imaging in a small series of penile fractures: a compari- ment of penile fracture in men with underlying Peyronie’s disease.
son with surgical findings. Urology 1998; 51: 616–19. Urology 2006; 68: 858–61.
7. Pruthi RS, Petrus CD, Nidess R, Venable DD. Penile fracture of the 19. De Rose AF, Giglio M, Carmignani G. Traumatic rupture of the
proximal corporeal body. J Urol 2000; 164: 447–8. corpora cavernosa: new physiopathologic acquisitions. Urology
8. Fergany AF, Angermeier KW, Montague DK. Review of Cleveland 2001; 57: 319–22.
Clinic experience with penile fracture. Urology 1999; 54: 352–5. 20. Thompson RF. Rupture (fracture) of the penis. J Urol 1954; 71:
9. Naraynsingh V, Raju GC. Fracture of the penis. Br J Surg 1985; 72: 226–9.
305–6. 21. Shaeer O. Methylene blue-guided repair of fractured penis. J Sex
10. Hinev A. Fracture of the penis: treatment and complications. Acta Med 2006; 3: 349–54.
Med Okayama 2000; 54: 211–16. 22. Nudell DM, Morey AF, McAninch JW. Penile trauma. In: Graham
11. Mansi MK, Emran M, el-Mahrouky A, el-Mateet MS. Experience SD Jr, ed. Glenn’s Urologic Surgery, 5th edn. Philadelphia:
with penile fractures in Egypt: long-term results of immediate surgi- Lippincott Williams and Wilkins; 1998, 599–600.
cal repair. J Trauma 1993; 35: 67–70. 23. Lee J, Singh B, Kravets FG, et al. Sexually acquired vascular inju-
12. Armenakas NA, Hochberg DA, Fracchia JA. Traumatic avulsion of ries of the penis: a review. J Trauma 2000; 49: 351–8.
the dorsal penile artery mimicking a penile fracture. J Urol 2001; 24. Naraynsingh V, Maharaj D, Kuruvilla T, Ramsewak R. Simple
166: 619. repair of fractured penis. J R Coll Surg Edinb 1998; 43: 97–8.
 Penile fracture: evaluation and management 397

25. Gross M, Arnold TL, Peters P. Fracture of the penis with associated penile fracture with atypical clinical findings. J Urol 1996; 155:
laceration of the urethra. J Urol 1977; 117: 725–7. 1924–7.
26. Wang CN, Huang CH, Chiang CP, et al. Recent experience of 38. Jack GS, Garraway I, Reznichek R, Rajfer J. Current treatment
penile fracture (1989–1993). Gaoxiong Yi-Xue Ke Xue Za Zhi options for penile fractures. Rev Urol 2004; 6: 114–20.
1995; 11: 654–9. 39. Cummings JM, Parra RO, Boullier JA. Delayed repair of penile
27. Katan S, Yaussef A, Onuora V, Patil M. Recurrent ipsilateral frac- fracture. J Trauma 1998; 45: 153–4.
ture of the penis. Injury 1983; 24: 685–6. 40. Naraynsingh V, Ramdass MJ, Thomas D, Maharaj D. Delayed
28. Punekar SV, Kinne JS. Penile refracture. BJU Int 1999; 84: 183–4. repair of a fractured penis: a new technique. Int J Clin Pract 2003;
29. Eggener SE, Stern JA, Smith ND, Gonzalez CM. Penile refracture: 57: 428–9.
case report. J Trauma 2003; 55: 793–4. 41. Muentener M, Suter S, Hauri D, Sulser T. Long-term experience
30. Karadeniz T, Topsakal M, Ariman A, Erton H, Basak D. Rupture of with surgical and conservative treatment of penile fracture. J Urol
the deep dorsal vein of the penis. Br J Urol 1996; 77: 279–81. 2004; 172: 576–9.
31. Ganem JP, Kennelly MJ. Ruptured Mondor’s disease of the penis 42. Bennani S, el Mrini M, Meziane F, Benjelloun S. Traumatic rupture
mimicking penile fracture. J Urol 1998; 159: 1302. of the corpus cavernosum. 25 case reports and literature review.
32. Anselmo G, Fandella A, Faggiano L. Fractures of the penis: thera- Ann Urol 1992; 26: 355–9.
peutic approach and long-term results. Br J Urol 1991; 67: 509–11. 43. Philp T, Collin J. The fractured shaft: an unusual penile injury.
33. Mydlo JH, Gershbein AB, Macchia RJ. Nonoperative treatment of Br J Surg 1983; 70: 93.
patients with presumed penile fracture. J Urol 2001; 165: 424–5. 44. El-Taher AM, Aboul-Ella HA, Sayed MA, Gaafar AA. Management
34. Hoekx L, Wyndaele JJ. Fracture of the penis: role of ultrasonography of penile fracture. J Trauma 2004; 56: 1138–40.
in localizing the cavernosal tear. Acta Urol Belg 1998; 66: 23–5. 45. Karadeniz T, Topsakal M, Ariman A, Erton H, Basak D. Penile frac-
35. Seftel AD, Matthews LA, Herbener TE, Spirnak JP. Corpus ture: differential diagnosis, management and outcome. Br J Urol
cavernosum-spongiosum fistula after blunt pelvic trauma: success- 1996; 77: 279–81.
ful resolution with digoxin. J Urol 1996; 156: 1769. 46. Orvis BR, McAninch JW. Penile rupture. Urol Clin North Am 1989;
36. Rahmouni A, Hoznek A, Duron A, Colombel M, et al. Magnetic 16: 369–75.
resonance imaging of penile rupture: aid to diagnosis. J Urol 1995; 47. Tan LB, Chiang CP, Huang CH, Chou YH, Wang CJ. Traumatic
153: 1927. rupture of the corpus cavernosum. Br J Urol 1991; 68: 626–8.
37. Fedel M, Venz S, Andreessen R, Sudhoff F, Loening SA. The 48. Levine FJ, Goldstein I. Vascular reconstructive surgery in the man-
value of magnetic resonance imaging in the diagnosis of suspected agement of erectile dysfunction. Int J Impot Res 1990; 2: 59–61.
52 Risks, complications, and
outcomes of penile lengthening and
augmentation procedures
Hunter Wessells and Jack W McAninch

Introduction erect length is mentioned as motivation by others.15,16 It

is unlikely that these procedures will go away; rather, with
Elongation of the penis has been contemplated since antiquity,1 improvements in technique, they may become routine
but only since 1971 has it been carried out as a reconstructive cosmetic surgical procedures.
surgical technique for congenital and acquired shortening of
the penis.2–6 Cosmetic penile enlargement began with girth
enhancements in Miami in the late 1980s, but it was the Technique
Chinese surgeon Long who in 1990 described division of
the suspensory ligament and penile skin advancement as a The detail in this section on techniques is meant to give the
cosmetic procedure to increase penile length.7,8 Since then, reader enough familiarity with the methods of penile enlarge-
over 10,000 men have undergone penile lengthening and girth ment to allow patient counseling and to guide reconstruction
enhancement, although no peer-reviewed paper has reported of failed operations. The authors’ experience with penile
a reliable description of the techniques or results. The risks, lengthening comes not in physically normal men, but only in
both cosmetic and medical, have never been described by the those men with traumatic loss of penile length.
proponents of the operations, and the complication rate is
unknown.9 Interest in the procedures remains intense,8 despite
action by the California Medical Board against one of the Penile lengthening
major proponents.10 A full understanding of penile enlarge- Early reports of penile lengthening describe division of the
ment is therefore necessary for urologists and plastic surgeons, suspensory ligament and mobilization of the proximal crura
who may be called upon to treat the complications of these off the inferior pubic rami. Because of the risk of injury to the
procedures. This chapter reviews the indications, techniques, neurovascular structures of the penis, cosmetic surgery for
risks, complications, and results of penile lengthening and penile lengthening relies on division of the suspensory liga-
girth enhancement, and discusses considerations in the recon- ment and skin flap advancement to increase the pendulous
struction of failures. penile length. The corpora cavernosa, fused along the distal
three-quarters, are attached to the pubic symphysis by the
suspensory ligament; this structure, a condensation of Buck’s
Indications fascia, maintains penile position during coitus.17
Division of the ligament can be accomplished through a
Penile lengthening procedures have traditionally been reserved variety of infrapubic incisions, but the technique is straight-
for patients who suffer severe shortening of the penis as a forward. By dissecting just below the pubic bone, hugging the
result of epispadias, trauma, Peyronie’s disease, or failed penile periosteum, the relatively broad, dense fibrous tissue can be
implant. The definition of micropenis in the neonate is estab- released while avoiding injury to the cavernous arteries and
lished as greater than 2.5 standard deviations below normal, nerves. The more superficial fundiform ligament is encoun-
or 2.5cm stretched length.11 In adults, controversy exists as to tered prior to identification of the suspensory ligament, but
the definition of a penis small enough for lengthening.12,13 It is does not contribute to the position of the penis.
unclear whether the flaccid or erect length is an appropriate Choice of incision is more important from the perspective
guideline, or whether normal men should be considered for of skin flap advancement and wound healing than exposure of
the procedure, since even men with the smallest most deformed the suspensory ligament. Long described an M-shaped skin
penises can have appropriate sexual relationships.14 incision, while Roos developed an inverted VY flap for skin
However, despite such arguments, penile enlargement sur- advancement, which was ‘modified for the Western male’ to
gery continues unabated for esthetic reasons and to improve deal with problems of angulation (Figure 52.1).18,19 Rosenstein
self-esteem. Anecdotally, most men desire increase in flaccid has the distinction of popularizing the inverted V flap in the
length and girth in response to a ‘locker room’ mentality, but USA and of starting the risky but profitable industry of penile

398
 Risks, complications, and outcomes of penile lengthening and augmentation procedures 399

(a) (b)

Figure 52.1 (a) Inverted VY plasty and release of suspensory ligament for penile lengthening. (b) Intended outcome. With permission
from J Urol 1996; 156: 1617–20.9

Girth enhancement
Enlarging the girth of the penis may be esthetically desirable if
penile length is also increased, thus maintaining the normal
aspect ratio of the penis.22 Two methods have been proposed
to enhance penile girth – injection of harvested autologous
liposuction specimen and surgical placement of a dermal-fat
composite free graft around the penis.
Injection of liposuctioned fat from the abdominal wall or
inner thighs was popularized by Rosenstein, but has several
potential pitfalls.20 The harvested fat is injected into the dartos
fascia through several small incisions at the base or corona.
Distribution of fat may be irregular, or the fat may migrate in
the early postoperative period, leading to nodular deposits of
fat with resultant penile deformity (see Complications, below).
Human fat grafts lose weight and volume over time, with as
little as 10% remaining after 1 year.23,24 Thus re-absorption of
fat is also likely, causing loss of girth and, if not uniform,
(a) (b)
penile distortion.
Figure 52.2 Double-Z-plasty skin advancement. (a) Initial In an attempt to provide a more uniform and persistent
incision. (b) After skin closure. girth augmentation, combined grafts of dermis with attached
fat have been placed between the twin graft beds of the dartos
fascia and Buck’s fascia. The dermal surface of the graft is
placed facing up towards the dartos for a smooth contour, and
enlargements.8,20 This incision has several drawbacks: these theoretically each side of the graft undergoes neovasculariza-
include poor healing at the intersection of the limbs of the tion from its respective fascial covering.
inverted Y owing to excess tension; advancement of hair- Harvest sites for these dermal grafts may be from the groin
bearing skin onto the shaft, resulting in ‘scrotalization’ of the or bilateral gluteal creases. Grafts of 1.0cm thickness are con-
penis; and dog-ears on the scrotal margins. Experience in treat- sidered ideal.15 The harvesting is more time-consuming and
ing complications of the VY plasty led Alter to adopt a double- requires closure of the donor site, but graft-take and cosmetic
Z-plasty to expose the suspensory ligament and advance skin appearance are considered to be superior. The graft is sutured
onto the penile shaft without tension (Figure 52.2).21 He also at the corona and base of the penis and anchored on either
advocates the insertion of autologous or synthetic material to side of the urethra, to avoid a fully circumferential graft that
fill the dead space created by release of the ligament, prevent- may contract and cause constriction. Placement of the graft
ing re-attachment of the penis in its original location. may be achieved by inverting the penis through the infrapubic
400 Textbook of Erectile Dysfunction

incision used for penile lengthening; if only girth enhance-

ment is desired, a circumferential incision below the corona is
sufficient.
More recently, an alternative technique for girth enhance-
ment has been undertaken by Austoni et al., described as cor-
poplastic augmentation surgery.25 Increase in the diameter of
the erect penis is achieved by enlarging the albuginea of the
corpora cavernosa, by means of bilateral venous grafts. The
albuginea are incised longitudinally from the glans to the
pubis, along the lateral aspect of each corpus cavernosum, and
a saphenous vein graft is placed. Nine months postoperatively
the increase in penile diameter in the erect state was between
1.1cm and 2.1cm (p<0.01) in the 39 patients reported. There
was no significant increase in diameter of the flaccid penis.

Theoretical risks
No operation is without risk, especially when the technique is
not standardized or described in the literature. In 1996, excel-
lent descriptions of penile enlargement procedures were pub-
lished by Alter, which allowed better understanding of the
surgery and were intended to reduce the incidence of
complications.15,21 Significant bleeding from the procedure is
rare, although in 1992 a Miami lounge singer died after penile
enlargement while on anticoagulation.8 Other potential risks
of penile augmentation include infectious complications,
downward deflection of the penis due to release of the sus-
pensory ligament,26 resorption of fat grafts, and injury to the
neurovascular bundle with resultant erectile dysfunction or Figure 52.3 Scrotalization of penile shaft skin after penile
penile numbness. Failure to increase penile length or girth is a lengthening via inverted VY flap advancement. With permission
notable possibility as well. from J Urol 1996; 156: 1617–20.9

Complications formation. Wound infections requiring hospitalization,

abscess formation, and wound separation also have been
Rosenstein, in 1995, reported postoperative problems of pain, described.
discharge, edema, dehiscence, flap loss, phimosis, paraphimo- Girth enhancement using autologous fat injection can lead
sis, and infection. Long-term fat loss and encapsulation were to irregular residual fat nodules that cause patients to seek
also reported and, in 10% of patients, additional surgery was treatment (Figure 52.5). Some have undergone repeat
necessary.20 Another source of information on complications ‘touch-up’ injections in an attempt to smooth the contour.
is reports of patients seen by other physicians after penile Difficulty with intromission may occur, owing to excessive fat
augmentation surgery.9,27 deposits on the shaft, as well as a decrease in shaft sensation
Dissatisfaction with the cosmetic result is the most com- over especially large nodules. Complete loss of the graft over
mon complaint and may be due to lengthening or girth aug- time may occur.
mentation. These cases represent only a small percentage of Sexual function may be impaired by the development of
men who have undergone penile augmentation; the denomi- erectile dysfunction (ED), loss of penile sensation as a result
nator is unknown and thus a verifiable complication rate may of neurological injury, painful erections, ventral penile deflec-
never be available.9 tion, or failure to address pre-existing ED.9
The most common complaint related to lengthening proce-
dures is scrotalization of the penile shaft, in which the advance-
ment of hair-bearing skin onto the penis after VY plasty leads Results
to an undesirable result (Figure 52.3). The skin advancement
can also lead to a picture of phimosis; circumcision should be Interpretation of results is difficult, since most practitioners of
undertaken with caution, since later reversal of the VY plasty penile enlargement do not use standardized techniques to
may not be possible, owing to lack of shaft skin.27 A thick, measure length before and after surgery. Ideally, flaccid length
hypertrophic scar, most prominent at the apex of the Y-plasty, from penopubic skin to meatus, stretched length, and erect
is another frequent complaint (Figure 52.4). It is the authors’ length would be measured by a single observer. Rosenstein
opinion that this relates to excess tension caused by inade- reported a mean increase in length of 2.1 inches (5.3cm), but he
quate mobilization of the lateral skin flaps rather than keloid did not specify whether flaccid or erect and, most importantly,
 Risks, complications, and outcomes of penile lengthening and augmentation procedures 401

(a) (b)

Figure 52.4 Patients with poor cosmetic outcome of skin incision. (a) Hypertrophic scar. (b) Scrotal dog-ears and scrotalization
incompletely reversed by the original surgeon. With permission from J Urol 1996; 156: 1617–20.9

(a) (b)

Fat lump

(c)

Figure 52.5 Patients with irregular deposition of autologous fat harvested with liposuction and injected into the penis. (a) Excessively
broad base. (b) Nodule of fat caused by shifting in the early postoperative period. (c) Sonographic appearance of fat deposit. With
permission from J Urol 1996; 156: 1617–20.9
402 Textbook of Erectile Dysfunction

based measurements on photographs of the patients.20 Long To support the use of these procedures to increase self-
reported a mean increase in length of 3.8cm, but the measure- esteem, a validated questionnaire should be developed to
ments were taken in the operating room immediately after measure this construct and to show that penile augmentation
surgery, which makes their interpretation suspect. Bondil and increases self-esteem in a statistically significant manner.
Delmas preformed a study in cadavers and found that penile
length after release of the suspensory ligament alone was
increased by 0.5cm, while addition of a skin advancement Correction of complications
increased the gain in length to 1.6 cm.28
Li et al. conducted a study in 42 patients undergoing divi- The two main complaints that lead patients to seek reversal of
sion of the penile suspensory ligament between 1998 and their penile augmentation are scrotalization of the penile shaft
2005, which objectively assessed the increase in stretched and irregular fat deposits. Since 1994, the authors have oper-
penile length.29 The mean increase in stretched penile length ated on 20 men to correct these complications, and Alter has
was 1.3±0.9cm, and the only technique in which there was reconstructed another 17 men.27,30 The successful correction
significant gain in length was that involving placement of a of these penile deformities is very challenging, both from a
silicone buffer to prevent ligamentous re-attachment. In some technical point of view and because of the demanding nature
motivated patients who performed postoperative stretching of the patient population. These men have suffered disfigur-
with penile weights, a vacuum constriction device, or a penile ing genital complications from surgery that they themselves
stretcher device a gain of up to 3cm was achieved. The overall requested. As a result, many have to resolve shame, guilt, and
patient satisfaction rate was 35% but it was lower in the sub- self-recrimination before they can seek help. Once it has been
group of 27 men (64%) with penile dysmorphic disorder.29 determined that the patient desires correction of the deformi-
Division of the suspensory ligament can certainly give the ties, choosing the timing of the procedure becomes one of the
appearance of greater penile length, but often with only mod- key decisions for the surgeon. To avoid tissue ischemia and
est results. However, the increase in penile length achieved is flap loss, the authors advise waiting at least 6 months until all
often not to a degree that the patient finds satisfactory, and the edema and induration has resolved.
men with penile dysmorphic disorder often have unrealistic Reversal of the VY plasty will usually correct scrotalization
expectations. of the penis and any dog-ears. Patients should expect to lose
Likewise, girth enhancement using autologous fat place- any gain in length from the original operation, and if they are
ment can increases penile circumference, but the exact amount not willing to accept this risk the procedure should not be
of increase and durability are unproven. The technique of undertaken. Paucity of shaft skin may prevent a complete
cavernosal augmentation with saphenous vein has given reversal, but in most men, opening up the full extent of the Y
promising results for increasing erect penile diameter, but incision allows mobilization and re-attachment of the apex of
may be considered experimental and a somewhat invasive the flap, re-creating the inverted V (Figure 52.6). If penile
procedure and should not be preformed in men with ‘locker deflection or instability has occurred, formal re-attachment of
room syndrome’. the tunica albuginea to the pubis should be performed with an

(a) (b)

(c)

Figure 52.6 Reversal of deformity shown in Figure 52.3. (a) Incision through original scar. (b) Re-approximation of apex of flap into
a V. (c) Final result after 3 months. With permission from J Urol 1996; 156: 1617–20.9
 Risks, complications, and outcomes of penile lengthening and augmentation procedures 403

absorbable suture. When the inferior skin flap is being effectiveness of these procedures are not impressive. No clear-
advanced back up to the superior aspect of the Y, dermal cut indications have been developed, although guidelines for
sutures should be placed from beneath the flap to the pubis or what is considered a normal adult penile length have been
Scarpa’s fascia in order to anchor the proximal aspect of the proposed.13,22
shaft skin, thus recreating the penopubic skin junction. A Division of the suspensory ligament is a straightforward
multilayer closure and closed suction drainage are recom- technique that has been used along with other methods to
mended. Resection of irregular fat deposits should not be con- increase penile length. Nevertheless, complications from skin
sidered easy, since the fat is extremely adherent to the penile advancement maneuvers are devastating to patients, who
shaft skin. If care is not taken, the penile skin can be devascu- expect results without risk. Likewise, girth enhancement can
larized and may slough. Patients should be counseled that it increase circumference, but the simpler technique of autolo-
may not be possible to remove all the fat in a single procedure, gous fat injection should be considered discredited at the
and that a staged approach may be indicated. If reversal of the present time. A significantly higher level of skill is needed to
VY incision is planned, the fat can be removed through that perform successful dermal-fat grafting or corpoplastic aug-
incision by inverting the penis. When fat excision alone is mentation, but long-term and substantial data on this tech-
desired, a distal incision can be performed below the corona: nique are not yet available.
a partial circumference incision may be preferable to retain as Treatment of complications should be undertaken with
much collateral blood supply as possible. caution, after allowing the existing wounds to mature,
Complications occur rarely with reversals. Of the authors’ by reversal of the VY-plasty and resection of aberrant fat
20 patients, one developed a hematoma and another devel- deposits.
oped significant induration and edema of the penile skin, Penile augmentation is an unregulated cosmetic procedure
which took 6 months to resolve; this was attributed to embar- that is not reimbursed by insurance companies; nevertheless,
rassment of the skin circulation after resection of fat. Alter it must be efficacious if it is to be performed. Comparisons
reported one hematoma and one inadequate reversal in between penile enlargement and breast augmentation are not
25 reconstructive operations.27 appropriate, since breast augmentation, for all its potential
risks, does increase the size of the breast in a statistically sig-
nificant fashion. The results of penile lengthening and girth
Conclusion enhancement are unproven, whereas the complications are
well described, implying that a risk–benefit analysis cannot be
Penile augmentation techniques have been described in carried out. For these reasons, the authors consider penile
reputable publications, but supporting data to prove the augmentation to be still experimental.31

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accused of gross negligence. San Francisco Chron, 1996: A5. 25. Austoni E, Guarneri A, Cazzaniga A. A new technique for augmen-
11. Aronson I. Micropenis: medical and surgical implications. J Urol tation phalloplasty: albugineal surgery with bilateral saphenous
1995; 155: 4–14. grafts: three years of experience. Eur Urol 2002; 42: 245–53.
12. Bondil P, Salti A, Sabbagh R, et al. Is the erect penile length 26. Kropman RF, Venema PL, Pelger RC. Traumatic rupture of the sus-
<7cm a reliable guideline for penile lengthening? Int J Impot Res pensory ligament of the penis. Case report. Scand J Urol Nephrol
1995; 7: S58. 1993; 27: 123.
404 Textbook of Erectile Dysfunction

27. Alter GJ. Reconstruction of deformities resulting from penile 29. Li C-Y, Kayes O, Kell D, et al. Penile suspensory ligament division
enlargement surgery. J Urol 1997; 157(Suppl 4): 362. for penile augmentation: indications and results. Eur Urol 2006;
28. Bondil P, Delmas V. Is the section of the suspensory ligament of 49: 729–33.
penis really efficient for penile lengthening? Preliminary results of 30. McAninch JW. Unpublished data, 1997.
an anatomical study. Int J Impot Res 1995; 7: S32. 31. Sharlip ID. Personal communication, 1995.
53 Peyronie’s disease: evaluation and
review of non-surgical therapy
Frederick L Taylor and Laurence A Levine

Definition for ED, such as dyslipidemia, hypertension, atherosclerotic

disease, a history of tobacco use, and diabetes, should be
Peyronie’s disease (PD) is a psychologically and physically queried. The patient’s baseline erectile function should be
devastating disorder that is manifest by a fibrous inelastic scar assessed using a validated questionnaire. Although a validated
of the tunica albuginea, resulting in palpable penile scar in PD questionnaire is still in development, the International
the flaccid condition and causing penile deformity, including Index of Erectile Function (IIEF) may be used to gauge the
penile curvature, hinging, narrowing, and shortening, and patient’s baseline sexual function.
painful erections. In spite of multiple treatment options The objective evaluation begins with the physical examina-
offered since François de la Peyronie described PD in 1743,1 tion. Although the focus should be on the genital examina-
this disorder remains a considerable therapeutic dilemma tion, an examination of the hands and feet is appropriate
even to today’s practicing physicians. given the patient’s history. Measurement of penile length is
critical, since the loss of penile length is not only a known
complication of PD, but is also a source of great concern
among patients. The penis should be measured stretched in its
Evaluation of the patient with flaccid state dorsally from pubis to corona or meatus. Note
that the suprapubic fat pad should be compressed during
Peyronie’s disease measurement. Objective evaluation of curvature is best per-
Thorough evaluation of the PD patient is essential not only formed using penile duplex ultrasound after pharmacologic
to diagnose the disease correctly, but also to guide treatment. stimulation to produce a full erection equal to or better than
Currently, no universally accepted standardized evaluation the patient’s at home. Simple erection induction in the office
for PD exists, nor has a validated questionnaire been devel- will allow objective assessment of deformity. Duplex ultra-
oped. A suggested guideline for initial evaluation of the PD sound will allow assessment of vascular flow rates, the degree
patient, including history, physical examination, and imaging of curvature as measured with a protractor, the presence and
analysis, has been recommended2 and is outlined below. location of any Peyronie’s plaque (or plaques), and the pres-
The subjective assessment begins with the patient interview. ence of any hinge effect. In addition, plaque calcification can
History should be focused on the onset and duration of be assessed. Autophotography should not be used as the sole
symptoms, the patient’s presenting signs and symptoms, means for curvature measurement, as this modality can be
and the presence or absence of pain. It is particularly useful to inconsistent and inaccurate.
elucidate whether the patient continues to experience pain The final portion of the PD evaluation is objective assess-
at the time of the initial evaluation, since this may represent ment of the patient’s erectile capacity and penile sensation.
a man in the acute phase of the disease. Pain may be present During duplex ultrasound the patient should be asked to
with palpation or erection or during coitus, and these settings grade their pharmacologic erection compared with home
should be differentiated since they may indicate different erections. In addition, biothesiometry is recommended to
etiologies or degrees of acute inflammation. The patient’s assess penile sensation. Using the distal phalanx of the index
subjective curvature deformity should be noted. It should also fingers as positive control and the ventral surface of bilateral
be noted that up to 90% of men with PD may present with thighs as negative control, the point at which vibratory sensa-
diminished rigidity. In our experience, up to 50% of men with tion is appreciated should be measured on the midshaft bilat-
ED and PD have reported the onset of ED preceding PD. It is erally and on the glans.
also important to know what, if any, prior PD therapies
the patient has undergone, as this may help to guide future
treatment. A detailed past medical and sexual history should Non-surgical therapy for
be part of the initial evaluation of every man with PD. Medical Peyronie’s disease
history should focus on personal or family history of wound-
healing disorders, including Dupuytren’s contracture, which Since the first description of PD in the literature, physicians
is reported in up to 20% of patients with PD. Any risk factors have been searching for medical therapy options with little

405
406 Textbook of Erectile Dysfunction

confirmed success. Consistent successful medical therapies Kadioglu et al. treated 60 patients with PD using colchicine
continue to evade the practicing urologist, although current 1mg twice daily, with a mean follow-up of 11 months.14 They
research into the molecular pathophysiology of PD may one found significant improvement in pain in 95% of men; how-
day lead to a medical cure. Several non-surgical options, how- ever, 30% of patients reported improved curvature while 22%
ever, are currently available and may stabilize or reduce defor- of patients reported worsened curvature.14 Safarinejad per-
mity and improve sexual function. The evaluation of their formed a randomized, placebo-controlled trial of colchicine
efficacy has been compromised by clinical trials that are small in 2004 with 84 men.15 It was found that colchicine is no better
and, in most cases, without any placebo control. Data out- than placebo at improving pain, curvature angle, or plaque
comes are difficult to interpret in the absence of a validated size as measured by ultrasound.
questionnaire, and in a disease in which spontaneous improve- Colchicine is not recommended by the authors owing to its
ment has been noted in 5–12% of patients.3–6 Below, the non- lack of demonstrated efficacy in placebo-controlled trials. The
surgical options for treatment of the pain and curvature of agent is also associated with gastrointestinal distress, includ-
PD, including oral, topical, intralesional, external energy, and ing diarrhea, and rarely with aplastic anemia.
combination therapies, are presented (Table 53.1).
Potassium aminobenzoate
Oral therapies Potassium aminobenzoate is a member of the vitamin B
Vitamin E complex that is believed to increase the activity of monoamine
oxidase in tissues, thereby decreasing local levels of serotonin
Vitamin E was the first oral therapy to be described for the
and thus possibly decreasing fibrogenesis. Potassium amino-
treatment of PD.7 Vitamin E is a fat-soluble vitamin that is
benzoate is used for other conditions, including scleroderma,
metabolized in the liver and excreted in bile and is thought to
have antioxidant properties in humans. Oxidative stress and dermatomyositis, and pemphigus. Zarafonatis and Horrax
first described the use of potassium aminobenzoate for the
the production of reactive oxygen species (ROS) is known to
treatment of PD,16 and a subsequent European study pub-
be increased during the acute and proliferative phases of
lished in 1978 reported a 57% improvement rate with 9%
wound healing, since it is neutrophils and macrophages that
produce these ROS,8 and the inflammatory phase of wound complete resolution in a pooled cohort of 2653 patients.17
This study, however, did not include a control or placebo group.
healing has been shown to be prolonged in patients with PD.9
In 1999, Weidner et al. published a randomized, placebo-
Thus, a biochemical rationale does exist for vitamin E use.
Gelbard et al. compared vitamin E therapy to the natural his- controlled trial of potassium aminobenzoate 3g orally, four
times per day for 1 year, in 103 men.18 The only significant
tory of PD in 86 patients; no significant differences were found
between the two groups in terms of curvature, pain, or the difference found between the two groups was plaque size,
which was not shown and has not been shown to correlate
ability to have intercourse.5 In 1983, Pryor et al. performed a
double-blind, placebo-controlled, crossover study evaluating with a decrease in penile curvature. A 2005 follow-up study,
also by Weidner et al., suggested that the use of potassium
vitamin E for the treatment of PD in 40 patients.10 No signifi-
amionobenzoate may protect against progression of PD
cant improvements were noted in plaque size or penile curva-
ture. More recently, Safarinejad et al. published a double-blind, plaques.19 Potassium aminobenzoate is expensive, and has low
tolerability owing to gastrointestinal side-effects. It is also not
randomized trial of vitamin E with or without proprionyl-L-
carnitine (PLC) for the treatment of early PD. Patients were recommended by the authors because of a lack of evidence
randomly assigned to receive vitamin E, PLC, vitamin E plus regarding its efficacy in the treatment of PD.
PLC, or placebo.11 No significant improvement in pain, cur-
vature, or plaque size was noted in any active treatment group Tamoxifen citrate
compared with placebo.11 Tamoxifen is a non-steroidal antiestrogen that acts by com-
In the opinion of the authors, vitamin E is not recom- peting with estrogen binding sites in target tissues. In addi-
mended for the treatment of PD since there is no evidence of tion, tamoxifen affects the release of transforming growth
benefit in placebo-controlled trials. factor (TGF)-beta from fibroblasts and blocks TGF-beta
receptors, thus potentially reducing fibrogenesis.20,21 In 1992,
Ralph et al. investigated tamoxifen in 36 patients with recent-
Colchicine
onset PD (duration less than 4 months).20 Eighty percent of
Colchicine is an anti-gout medication that inhibits fibrosis the patients reported a reduction in pain, 35% reported a sub-
and collagen deposition primarily by inhibiting the inflamma- jective reduction in curvature, and 34% reported a decrease in
tory response through inhibition of neutrophil microtubules.12 plaque size. A follow-up study in 1999 by Teloken et al. failed
Colchicine has been used both as primary oral therapy for PD to show any statistically significant difference between tamox-
as well as in combination with other modalities. Akkus et al. ifen and placebo, and there was a reported increase of alopecia
administered an escalating dose of colchicine in a non- in the active treatment group.22
randomized, non-placebo-controlled fashion to 19 patients We do not recommend the use of tamoxifen.
with PD over a 3–5 month period.13 Thirty-six percent of the
patients noted a reduction in curvature, and 63% noted an
improvement in the palpable plaque. Seventy-eight percent of Carnitine
the patients who were experiencing painful erections at the Carnitine is a naturally occurring metabolic intermediate.
time of treatment initiation had resolution of this symptom.13 Carnitine facilitates the entry of long-chain fatty acids into
 Peyronie’s disease: evaluation and review of non-surgical therapy 407

Table 53.1 Non-surgical therapies for Peyronie’s disease

Treatment Mechanism of action Comments

Oral
Vitamin E Antioxidant that theoretically reverses or Limited side-effects, low cost. Efficacy not
stabilizes pathologic changes in the tunica proven
albuginea
Colchicine Inhibits fibrosis and collagen deposition Mixed reports of efficacy in non-controlled trials.
through inhibition of neutrophil microtubules Single randomized, controlled trial failed to
show benefit. May cause gastrointestinal
disturbances, including severe diarrhea
Potassium aminobenzoate Member of the vitamin B complex, thought Significant reduction in plaque size, but not
to increase the activity of monoamine curvature. Expensive, and difficult to tolerate due
oxidase, thereby decreasing local serotonin to gastrointestinal side-effects
levels, which may contribute to fibrogenesis
Tamoxifen May reduce release of transforming growth Efficacy not proven. Side-effects may include
factor-beta from fibroblasts and may block alopecia
transforming growth factor-beta receptors,
resulting in diminished fibrogenesis
Carnitine Believed to inhibit acetyl co-enzyme A Efficacy not proven, and more investigation is
needed
L-Arginine Amino acid substrate in the formation of Improvement in plaque size and collagen–
nitric oxide, which is thought to be lacking fibroblast ratio in a rat model. Well tolerated
in PD tissue
Pentoxifylline Non-specific phosphodiesterase inhibitor that Improvement in plaque size and collagen–
may reduce collagen levels in PD plaques fibroblast ratio in a rat model
Topical
Verapamil Increases extracellular matrix collagenase When administered topically the drug does not
secretion and decreases collagen and appear to penetrate into the tunica albuginea
fibronectin synthesis and secretion; decreases
fibroblast proliferation
Intralesional
Corticosteroids Anti-inflammatory and cause reduction in Treatment with corticosteroids is discouraged by
collagen synthesis the authors. Effects are unpredictable, and may
cause atrophy and distortion of tissue planes
Collagenase Breakdown of collagen Statistically significant improvement in curvature
has been noted in men with mild-to-moderate
disease
Verapamil Increases extracellular matrix collagenase Controlled and non-controlled trials show
secretion and decreases collagen and promise as improvements in plaque volume,
fibronectin synthesis and secretion; decreases pain, and curvature have been reported
fibroblast proliferation
Interferons Decrease the rate of proliferation of Recent encouraging results with reports of
fibroblasts in Peyronie’s plaques in vitro, improvement in curvature and pain. Dosing
reduce production of extracellular collagen, regimens and side-effect profiles yet to be
and increase production of collagenase determined
External energy
Penile ESWT ESWT-induced inflammatory response with No statistically significant improvement noted in
resultant plaque lysis, improved vascularity, curvature, plaque size, or pain
and the creation of contralateral scarring
Electromotively Effect of verapamil and corticosteroids Objective improvements of plaque size and
administered verapamil with discussed above. Electric current itself may curvature have been noted. Adverse effects
or without dexamethasone have some beneficial effect on wound include erythema at electrode site
healing

(Continued)
408 Textbook of Erectile Dysfunction

Table 53.1 (Continued)

Treatment Mechanism of action Comments

Combination therapy
Vitamin E plus colchicine Discussed above. Synergistic effect possible Improvements in curvature and plaque size have
been noted
ESWT with intralesional Discussed above. Synergistic effect possible Significant improvement in plaque size
verapamil injection compared with placebo
Intralesional verapamil with Discussed above. Synergistic effect possible Statistically significant subjective improvement
oral carnitine or tamoxifen in curvature, plaque size, and erectile function
in patients treated with carnitine and
intralesional verapamil
Penile traction devices
FastSize® penile extender Chronic traction forces may trigger scar Early results demonstrate reduction of curvature,
remodeling and formation of new connective increase in length, and improvement in hinge
tissue effect. Side-effects were limited to mild
discomfort with the device
PD, Peyronie’s disease; ESWT, electroshock wave treatment

muscle mitochondria, which are then used as energy substrate. to have increased cAMP levels and reduced collagen levels
Carnitine is also thought to inhibit acetyl co-enzyme A, which compared with controls. In addition, pentoxyfilline given
may aid in the repair of damaged cells. Biagiotti and Cavallini orally to a TGF-beta-1-induced PD rat model resulted
examined the use of carnitine for PD in 2001.23 Forty-eight in decrease in PD plaque size and in the collagen–fibroblast
men were divided into two groups to receive either tamoxifen ratio. Brant et al. reported a single case report of successful PD
20mg twice daily for 3 months or acetyl-L-carnitine 1g twice treatment using pentoxifylline alone.25
daily for 3 months. Overall, the men taking carnitine saw Further studies are required to make a definitive examina-
greater improvement in curvature and had statistically sig- tion of pentoxifylline for the treatment of PD; however its
nificant improvement in pain. In addition, the patients taking known biochemical effect and early animal-model success
carnitine reported far fewer side-effects than the patients make it an attractive option for oral therapy.
taking tamoxifen.
More study is needed to elucidate the role of carnitine in
the treatment of PD. Topical therapies
Verapamil
L-Arginine Interest in topical verapamil for the treatment of PD followed
its success as an intralesional agent (see below). It does not
L-Arginine is an amino acid that, when catalyzed by nitric
appear, however, that tunica albuginea tissue concentrations
oxide synthase (NOS), combines with oxygen ultimately to
of verapamil are achievable through topical application. In
form nitric oxide (NO). It is known that inducible NOS
2002 Martin et al.26 demonstrated that application of 0.5mg
(iNOS) is expressed in the fibrotic plaques of PD, and that
of a 40mg/ml verapamil gel to the penile shaft at 10 p.m. the
long-term suppression of iNOS exacerbates tissue fibrosis.24
night before and 5 a.m. the morning of scheduled PD surgery
In 2003, Valente et al. reported that L-arginine, given daily in
failed to result in measurable levels of the drug in the tunica
the drinking water of a rat model with TGF-beta-1-induced
albuginea. Of note, urine levels of verapamil obtained at the
PD plaques, resulted in an 80–95% reduction in plaque size and
same time as the tissue samples did demonstrate verapamil
in the collagen–fibroblast ratio.24 In addition, L-arginine was
concentration consistent with systemic absorption. A recent
found to be antifibrotic in vitro. This suggests that L-arginine, as
three-arm trial without a known placebo demonstrated ben-
a biochemical precursor of NO, may be effective in reducing
efit with topical verapamil,27 but this study was significantly
PD plaque size.
compromised.28 Thus the use of verapamil as a topical agent
Further human trials are needed before this agent can be
for PD is not recommended.
strongly recommended.

Pentoxifylline Intralesional therapies

Pentoxifylline is a non-specific phosphodiesterase (PDE) inhib- Corticosteroids
itor. Valente et al. found that normal human and rat tunica The powerful anti-inflammatory effect of corticosteroids led
albuginea, as well as PD plaque tissue, express PDE-5A-3 and to their early investigation as agents for intralesional therapy
PDE-4A, PDE-4B, and PDE-4D.24 In their in vitro study, PD of PD. In 1954, Bodner et al. reported improvement in
fibroblasts were cultured with pentoxifylline and were found 17 patients treated with intralesional hydrocortisone and
 Peyronie’s disease: evaluation and review of non-surgical therapy 409

cortisone.29 In 1975, Winter and Khanna showed no differ- consecutive patients with PD.40 Follow-up was at an average
ence between patients treated with dexamethasone injections of 5.2 months after completion of the sixth injection. Eighteen
and the natural history of the disease.30 In 1980, Williams and percent of patients (n=17) were found to have improved
Green published a prospective study using intralesional tri- curvatures (average improvement 12°), 60% (n=56) had
amcinolone.31 All patients were observed for 1 year after study stable curvature, and 22% (n=21) had increased curvature
enrollment; during that time only 3% of patients reported (average increase 22°). All patients with pre-treatment penile
improvement. Triamcinolone was administered every 6 weeks pain had improvement at follow-up. The authors suggest that
for 36 weeks; 33% of patients reported subjective improve- these data support intralesional verapamil for the stabilization
ment, particularly in pain and plaque size.31 of PD.
Currently, the use of intralesional corticosteroids is dis- It may be that six injections provide stabilization but are
couraged because of the side-effects of local tissue atrophy, insufficient to accomplish reduction of curvature. Currently,
fibrosis, immune suppression, and lack of objective measures we recommend a trial of six injections, with injections occur-
of benefit. ring at 2-week intervals. If no improvement is noted by the
patient, the therapy may be terminated, the verapamil dose can
be increased to 20mg, or interferon injections may be offered.
Collagenase If improvement is reported, another six injections are given.
Collagenase was first studied in vitro by Gelbard et al. in We consider verapamil to be contraindicated in patients with
1982.32 A subsequent clinical trial by that group demonstrated ventral plaques or extensive plaque calcification.
subjective improvement in 64% of patients within 4 weeks of
treatment.33 A decade after their initial study, they published
Interferons
their findings of a double-blind trial in 49 men.34 Statistically
significant improvement in curvature was noted in the Duncan et al. reported in 1991 that interferons decrease
collagenase-treated group; however, maximal improvement the rate of proliferation of fibroblasts in Peyronie’s plaques
ranged from 15–20° and was only seen in the patients with in vitro, reduce the production of extracellular collagen, and
curvatures of less than 30° and plaques of less than 2cm increase the activity of collagenase.41 Initial studies performed
in length. Larger-scale controlled trials of collagenase are by Wegner et al. demonstrated low rates of improvement,
currently in development. but a high incidence of side-effects, including myalgias and
fever.42,43 In 1999, Ahuja et al. reported on 20 men who
received 1×106 units of interferon-alpha-2b every other week
Verapamil for 6 months.44 One hundred percent of patients reported
Verapamil is a calcium-channel blocker that has been shown softening of plaque, 90% of men presenting with pain had
in in vitro studies to inhibit local extracellular matrix produc- improvement, and 55% had a subjective reduction in plaque
tion by fibroblasts, to reduce fibroblast proliferation, to size. Dang et al. administered 2×106 units to 21 men, twice
increase local collagenase activity, and to affect the cytokine weekly for 6 weeks and found objective curvature improve-
milieu of fibroblasts.35,36 In 1994, Levine et al. reported on ments in 67%, and improvement in pain in 80%.45 Seventy-one
14 men who underwent a dose-escalation trial of intra- percent of patients reported improvement in ED symptoms.
lesional injections of verapamil every other week for 6 months.37 In 2006, Hellstrom et al. reported on a placebo-controlled,
Significant improvement in plaque-associated narrowing multicenter trial of 117 patients who underwent injections of
was noted in all patients, and curvature was improved 5×106 units every other week for a total of 12 weeks.46 Average
in 42%.37 curvature in the treatment group improved by 13° compared
The first randomized, single-blind trial of intralesional with 4° in the placebo arm, and 27% of patients in the treat-
verapamil was published in 1998.38 Significant differences ment group had measured improvement compared with 9% of
were noted in terms of erection quality and plaque volume. A the saline group. Pain resolution was noted in 67% of the treat-
trend towards improvement in curvature was also noted. As a ment patients compared with 28% of the placebo group.
follow-up, Levine and Estrada reported on 156 men enrolled Interferon therapy requires further investigation to deter-
in a prospective non-randomized trial of PD men with a mean mine adequately its efficacy, dosing regimens, and side-
follow-up of 30.4 months.39 A local penile block was per- effect profiles before its routine use in PD patients can be
formed with 10–20ml bupivicaine 0.5%, followed by injection recommended.
of verapamil 10mg diluted in 6ml sterile normal saline (total
volume 10ml) into the Peyronie’s plaque using between one
External energy therapies
and five skin punctures, but with multiple passes through the
plaque. The goal is to leave the drug in the needle tracks but Penile electroshock wave therapy
not to tear or disrupt the plaque. Injections were administered Local penile electroshock wave therapy (ESWT) has been sug-
every 2 weeks for a total of 12 injections. Eighty-four percent gested to be helpful. Various hypotheses about its mechanism
of patients with pain achieved complete resolution, 62% were of action exist, including direct damage to the plaque result-
found on objective measurement to have improved curvature ing in an inflammatory reaction with increased macrophage
ranging from 5° to 75° (mean 30°), and only 8% of patients reaction leading to plaque lysis, improved vascularity result-
had measured worsening of curvature. ing in plaque resorption, and the creation of contralateral
More recently, Bennett et al. administered six intralesional scarring of the penis resulting in ‘false’ straightening.47 Hauck
injections (verapamil 10mg in 5ml) every 2 weeks to 94 et al. randomized 43 men to ESWT or oral placebo for
410 Textbook of Erectile Dysfunction

6 months.48 No significant effect was noted in terms of curva- therapy group.59 A follow-up study by the same investigators
ture, plaque size, or subjective improvement in sexual func- involving 481 patients demonstrated a 49% improvement
tion or rigidity. More recent work from a German group in plaque size among those treated with the combined
randomized 102 men to ESWT or to receive sham shocks.49,50 therapy.60
There was no statistically significant difference found between
the groups for plaque size, improvement of deformity, or
Intralesional verapamil with oral carnitine or tamoxifen
sexual function post-treatment. ESWT is not currently
recommended as therapy for PD. In 2002, Cavallini et al. randomized 60 men to receive intra-
lesional verapamil plus oral carnitine or intralesional vera-
pamil plus oral tamoxifen.61 Statistically significant subjective
Iontophoresis improvements in curvature, plaque size, and erectile function
Iontophoresis involves the transport of ions through tissue were found in the carnitine group. No difference in improve-
by means of an electric current. Several studies have investi- ment of pain was found between the two groups.
gated the efficacy of topically applied verapamil with or
without dexamethasone with enhanced penetration using Penile traction devices
iontophoresis.51–54 In 2002, Levine et al. confirmed that vera- The use of tissue expanders has long been a mainstay of treat-
pamil was found within the exposed tunica albuginea by
ment in the orthopedic, oral–maxillofacial, and plastic surgi-
examining surgically retrieved tunica albuginea from patients
cal fields. It is well documented that gradual expansion of
after a single intra-operative exposure during plaque incision
tissue results in the formation of new bone and connective
and grafting surgery.55 Di Stasi et al. recently reported on a
tissue. Recently, initial work has been done to evaluate the
prospective, randomized study of 96 patients treated with
efficacy of a penile extender device for the treatment of PD. A
verapamil 5mg plus dexamethasone 8mg using iontophoresis pilot study of 10 patients at our institution found that daily
versus lidocaine 2% delivered electromotively.54 Forty-three
application of the FastSize Medical® device for 2–8 hours per
percent of patients in the verapamil–dexamethasone group
day for 6 months resulted in a 33% measured improvement in
noted objective improvement in plaque size and curvature; no
curvature (ranging from 10° to 45° improvement and resulting
changes were noted in the lidocaine group. In 2005, Greenfield in an improvement in average curvature from 51° to 34°), an
et al. reported on the use of verapamil 10mg versus saline
increase in flaccid stretched penile length ranging from 0.5cm
iontophoresis.56 Patients were assessed using papavarine-
to 2.0cm, and an improvement in hinge effect in all those with
induced erections prior to and 1 month after treatment. Sixty-
advanced narrowing or indentation. No patients noted recur-
five percent of patients in the verapamil group demonstrated rence or worsening of curvature during 6 months of follow-up,
improvement in curvature compared with 58% in the saline
and there was no incidence of local skin changes, ulceration,
group. Mean curvature improvement was 9.1° in the treat-
loss of sensation, or worsening of curvature. Long-term and
ment group compared with 7.6° in the saline group,56 which is larger studies are indicated.62
clearly not as robust a response as reported with intralesional
verapamil injections. The authors suggested that the electric
current itself may have some beneficial effect on wound Conclusion
healing, which is known and supported in the dermatologic
literature.57 Investigation into iontophoresis is ongoing. PD remains a treatment dilemma, in part owing to the lack of
a clear understanding of its pathophysiology. It is hoped that,
with further basic science research and properly conducted
Combination therapy
clinical trials, novel treatments will emerge. Currently we do
Vitamin E and colchicine not believe that oral therapy alone provides any real benefit
A placebo-controlled study by Preito Castro et al. randomized with respect to correction of deformity, since it appears
45 patients to receive vitamin E plus colchicine or ibuprofen.58 unlikely that an adequate concentration of any agent will
Statistically significant improvements in curvature and plaque reach the relatively hypovascular and hypocellular plaque, and
size were noted in the group treated with vitamin E plus placebo-controlled trials have not demonstrated benefit. On
colchicine compared with the group receiving ibuprofen. the other hand, injection of verapamil or interferon-alpha-2b
Patients in the vitamin E plus colchicine arm reported a has been shown to provide, at a minimum, stabilization of
greater decrease in pain, although this did not reach statistical plaque and deformity progression, and it may improve sexual
significance. function as well. The newest non-invasive, non-surgical treat-
ment with prolonged traction poses a novel approach based
upon proven principles of tissue remodeling, and there have
Penile electroshock wave therapy with intralesional been encouraging preliminary results. We feel that it is possi-
verapamil injection ble to achieve a synergy with combination therapy using med-
In 1999, Mirone et al. prospectively examined two groups of ical treatment (oral and injection) with its potential chemical
PD patients; one group was treated with ESWT, while the effects, and the mechanical effects of traction therapy. This
other received ESWT plus perilesional verapamil injections.59 combination may result in the best chance for a non-surgical
A 52% improvement in plaque size by ultrasound was noted in reduction in deformity with improvement in sexual function.
the ESWT-only group compared with 19% in the combination- Further studies will clearly be necessary.
 Peyronie’s disease: evaluation and review of non-surgical therapy 411

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485–90. 1081–2.
4. Williams JL, Thomas GG. The natural history of Peyronie’s disease. 29. Bodner H, Howard AH, Kaplan JH. Peyronie’s disease: cortisone–
J Urol 1970; 103: 75. hyaluronidase–hydrocortisone therapy. J Urol 1954: 400–3.
5. Gelbard MK, Dorey F, James K. The natural history of Peyronie’s 30. Winter CC, Khanna R. Peyronie’s disease: results with dermo-jet
disease. J Urol 1990; 144: 1376–9. injection of dexamethasone. J Urol 1975; 114: 898–900.
6. Kadioglu A, Tefekli A, Erol B, et al. A retrospective review of 31. Williams G, Green NA. The non-surgical treatment of Peyronie’s
307 men with Peyronie’s disease. J Urol 2002; 168: 1075–9. disease. Br J Urol 1980; 52: 392–5.
7. Scott WW, Scardino PL. A new concept in the treatment of 32. Gelbard MK, Walsh R, Kaufman JJ. Collagenase for Peyronie’s
Peyronie’s disease. South Med J 1948; 41: 173–7. disease experimental studies. Urol Res 1982; 10: 135–40.
8. Sikka SC, Hellstrom WJ. Role of oxidative stress and antioxidants 33. Gelbard MK, Linkner A, Kaufman JJ. The use of collagenase in the
in Peyronie’s disease. Int J Impot Res 2002; 14: 353–60. treatment of Peyronie’s disease. J Urol 1985; 134: 280–3.
9. Gholami SS, Gonzalez-Cadavid NF, Lue TF, et al. Peyronie’s 34. Gelbard MK, James K, Riach P, Dorey F. Collagenase vs. placebo
disease: a review. J Urol 2002; 169: 1234–41. in the treatment of Peyronie’s disease: a double blind study. J Urol
10. Pryor JP, Farell CF. Controlled clinical trial of vitamin E in 1993; 149: 56–8.
Peyronie’s disease. Prog Reprod Biol 1983; 9: 41–5. 35. Roth M, Eickelberg O, Kohler E, et al. Ca2+ channel blockers
11. Safarinejad MR, Hosseini SY, Kolahi AA. Comparison of vitamin E modulate metabolism of collagens within the extracellular matrix.
and propionyl-L-carnitine, separately or in combination, in Proc Natl Acad Sci U S A 1996; 93: 5748–482.
patients with early chronic Peyronie’s disease: a double-blind, 36. Mulhall JP, Anderson MS, Lubrano T, et al. Peyronie’s disease cell
placebo controlled, randomized study. J Urol 2007; 178: culture models: phenotypic, genotypic and functional analyses.
1398–403. Int J Impot Res 2002; 14: 397–405.
12. Furst DE, Ulrich RW. Chapter 36. In: Katzung B, ed. Lange Pharma- 37. Levine, LA, Merrick PF, Lee RC. Intralesional verapamil injection
cology, New York: McGraw-Hill, 2007. for the treatment of Peyronie’s disease. J Urol 1994; 151: 1522–4.
13. Akkus E, Carrier S, Rehman J, et al. Is colchicine effective in 38. Rehman J, Benet A, Melman A. Use of intralesional verapamil to
Peyronie’s disease? A pilot study. Urology 1994; 44: 291–5. dissolve Peyronie’s disease plaque: a long term single-blind study.
14. Kadioglu A, Tefekli A, Koksal T, et al. Treatment of Peyronie’s Urology 1998; 51: 620–6.
disease with oral colchicine: long term results and predictive param- 39. Levine LA, Estrada CR. Intralesional verapamil for the treatment of
eters of successful outcome. Int J Impot Res 2000; 12: 169–75. Peyronie’s disease: a review. Int J Impot Res 2002; 14: 324–8.
15. Safarinejad MR. Therapeutic effects of colchicine in the manage- 40. Bennett NE, Guhring, P, Mulhall JP. Intralesional verapamil
ment of Peyronie’s disease: a randomized double-blind, placebo- prevents the progression of Peyronie’s disease. Urology 2007; 69:
controlled study. Int J Impot Res 2004; 16: 238–43. 1181–4.
16. Zarafonetis CJ, Horrax TM. Treatment of Peyronie’s disease with 41. Duncan MR, Berman B, Nseyo UO. Regulation of the proliferation
potassium para-aminobenzoate (potaba). J Urol 1959; 81: 770–2. and biosynthetic activities of cultured human Peyronie’s disease
17. Hasche-Klunder R. [Treatment of Peyronie’s disease with para- fibroblasts by interferons-α, β,and γ. Scand J Urol Nephrol 1991;
aminobenzoacidic potassium (POTOBA) (author’s transl)]. Urologe 25: 89–94.
A 1978; 17: 224–7. [in German] 42. Wegner HE, Andreson R, Knipsel HH, et al. Treatment of Peyronie’s
18. Weidner W, Schroeder-Printzen I, Rudnick J, et al. Randomized disease with local interferon-α-2b. Eur Urol 1995; 28: 236–40.
prospective placebo-controlled therapy of Peyronie’s disease (IPP) 43. Wegner HE, Andresen R, Knipsel HH, et al. Local interferon-α-2b
with Potaba (aminobenzoate potassium). J Urol 1999; 6: 205. is not an effective treatment in early-stage Peyronie’s disease. Eur
19. Weidner W, Hauck EW, Schnitker J. Potassium paraaminobenzoate Urol 1997; 32: 190–3.
(Potaba) in the treatment of Peyronie’s disease: a prospective, placebo- 44. Ahuja S, Bivalacqua TJ, Case J, Vincent M, Sikka SC, Hellstrom WJ.
controlled, randomized study. Eur Urol 2005; 47: 530–5. A pilot study demonstrating clinical benefit from intralesional
20. Ralph DJ, Brooks MD, Bottazzo GF, et al. The treatment of interferon alpha 2B in the treatment of Peyronie’s disease. J Androl
Peyronie’s disease with tamoxifen. Br J Urol 1992; 70: 648–51. 1999; 20: 444–8.
21. Colletta AA, Wakefield LM, Howell FV, et al. Anti-oestrogens 45. Dang G, Matern R, Bivalacqua TJ, et al. Intralesional interferon-α-2b
induce the secretion of active transforming growth factor beta from injections for the treatment of Peyronie’s disease. South Med J
human fetal fibroblasts. Br J Cancer 1990; 62: 405–9. 2004; 97: 42–6.
22. Teloken C, Rhoden EL, Grazziotin TM, et al. Tamoxifen versus 46. Hellstrom WJ, Kendirici M, Matern R, et al. Single-blind, multi-
placebo in the treatment of Peyronie’s disease. J Urol 1999; 162: center placebo-controlled parallel study to assess the safety and
2003–5. efficacy of intralesional interferon-α-2b for minimally invasive
23. Biagiotti G, Cavallini G. Acetyl-L-carnitine vs. tamoxifen in the oral treatment for Peyronie’s disease. J Urol 2006; 176: 394–8.
therapy of Peyronie’s disease: a preliminary report. BJU Int 2001; 47. Levine LA. Review of current nonsurgical management of
88: 63–7. Peyronie’s disease. Int J Impot Res 2003; 15: S113–20.
24. Valente EG, Vernet D, Ferrini M, et al. L-Arginine and phosphodi- 48. Hauck EW, Altinkilic BM, Ludwig M, et al. Extracorporeal shock
esterase (PDE) inhibitors counteract fibrosis in the Peyronie’s wave therapy in the treatment of Peyronie’s disease. First results of
fibrotic plaque and related fibroblast cultures. Nitric Oxide 2003; a case-controlled approach. Eur Urol 2000; 38: 663–9.
9: 229–44. 49. Hatzichristodoulou G, Meisner C, Liske P, Stenzl A, Lahme S.
25. Brant WO, Dean RC, Lue TF. Treatment of Peyronie’s disease with Efficacy of Extracorporeal Shock Wave Therapy (ESWT) in patients
oral pentoxifylline. Nat Clin Pract Urol 2006; 3: 111–15. with Peyronie’s disease (PD): first results of a prospective, random-
26. Martin DJ, Badwan K, Parker M, et al. Transdermal application ized, placebo-controlled, single-blind study. Abstract presented at
of verapamil gel to the penile shaft fails to infiltrate the tunica Annual Meeting of the American Urological Association, Atlanta,
albuginea. J Urol 2002; 168: 2483–5. GA, 20–25, May 2006.
412 Textbook of Erectile Dysfunction

50. Hatzichristodoulou G, Meisner C, Stenzl A, Lahme S. Efficacy of 56. Greenfield JM, Shah SJ, Levine LA. Verapamil vs. saline in electro-
extracorporeal shock wave therapy on plaque size and sexual motive drug administration (EDMA) for Peyronie’s disease: a dou-
function in patients with Peyronie’s disease: results of a prospective, ble blind, placebo controlled trial. J Urol 2007; 177: 972–5.
randomized, placebo-controlled study. Abstract presented at 57. Ojingwa JC, Isseroff RR. Electrical stimulation of wound healing.
Annual Meeting of the American Urological Association, Anaheim, J Invest Dermatol 2003; 121: 1–12.
CA, 19–24, May 2007. 58. Preito Castro RM, Leva Vallejo ME, Regueiro Lopez JC, et al. Com-
51. Riedl CR, Plas E, Engelhard P, et al. Iontophoresis for treatment of bined treatment with vitamin E and colchicines in the early stages
Peyronie’s disease. J Urol 2000; 163: 95–9. of Peyronie’s disease. BJU Int 2003; 91: 522–4.
52. Montorsi F, Salonia A, Guazzoni G, et al. Transdermal electromo- 59. Mirone V, Palmieri A, Granata AM, et al. Ultrasound-guided
tive multi-drug administration for Peyronie’s disease: preliminary ESWT in Peyronie’s disease plaques. Arch Ital Urol Androl 2000;
results. J Androl 2000; 21: 85–90. 72: 384–7.
53. Di Stasi SM, Giannantoni A, Capelli G, et al. Transdermal electro- 60. Mirone V, Imbimbo C, Palmieri A, et al. Our experience on
motive administration of verapamil and dexamethasone for the association of a new physical and medical therapy in patients
Peyronie’s disease. BJU Int 2003; 91: 825–9. suffering from induration penis plastica. Eur Urol 1999; 36:
54. Di Stasi SM, Giannantoni A, Stephen RL, et al. A prospective, ran- 327–30.
domized study using transdermal electromotive administration of 61. Cavallini G, Biagiotti G, Koverech A, et al. Oral propionyl-L-
verapamil and dexamethasone for Peyronie’s disease. J Urol 2004; carnitine and intraplaque verapamil in the therapy of advanced
171: 1605–8. and resistant Peyronie’s disease. BJU Int 2002; 89: 895–900.
55. Levine, LA, Estrada CR, Show W, et al. Tunica albuginea tissue 62. Levine L, Newell M, Taylor F. Penile traction therapy for treatment
analysis after electromotive drug administration. J Urol 2003; 169: of Peyronie’s disease: a single center pilot study. J Sex Med 2008;
1775–8. 5: 1468–73.
54 Surgical treatment of
Peyronie’s disease
Culley C Carson III

Introduction waiting at least 12 months from the stabilized PD before

considering any surgery.5 They suggest that many men with
Peyronie’s disease (PD) is an incurable chronic condition that stable disease for less than 6 months may have curvature
affects middle-aged men and often results in penile deformity recurrence postoperatively.
with loss of coital function. Scar-like plaques form between The choice of a surgical procedure depends upon patient
layers of the thick fibrous tunica albuginea, often as a result of needs and preferences (Figure 54.1) Counseling of patients
coital trauma. These plaques may result in penile curvature, should be based on the function and type of penile deformity
hour-glass deformity, and erectile dysfunction (ED) caused by and quality of erection. Three surgical categories are used for
veno-occlusive incompetence, or they may be asymptomatic. PD patients:
The condition occurs in approximately 3.2% of men over
age 40. Caucasians are at highest risk and the mean age is • tunica lengthening procedures;
57.4 years.1 Presentation includes penile pain with erection, • tunica shortening procedures; and
ED, inability to have intercourse secondary to penile defor- • implantation of penile prosthesis with or without modeling.
mity, and a palpable plaque. The putative etiology of PD is
coital trauma to the penis with subtunical bleeding and Penile prosthesis implantation is reserved for men with
inflammation, ultimately leading to fibrosis of the tunica Peyronie’s disease and refractory ED or men who prefer this
albuginea, usually in the dorsal aspect. This fibrosis produces method of treatment. Men with satisfactory erectile function
dense scar or plaque formation.2 with or without supportive medications are candidates for
Non-surgical treatment for PD has included oral medica- straightening procedures using either tunica lengthening or
tions, topical agents, intralesional injections, extracorporeal shortening operations. Tunica shortening procedures include
shockwave lithotripsy, and ultrasound.3 Most patients prefer plication techniques such as the Nesbit or Kelami proce-
non-surgical intervention prior to selecting a surgical proce- dures, and tunica lengthening procedures include plaque
dure despite the small number of successes with medication. incision or excision and grafting such as the Horton–Devine
Ultimately treatment is designed to improve coital function operation.
and result in satisfactory, comfortable erection for both patient
and partner.
Patient evaluation for surgery
Surgery for Peyronie’s disease Evaluating a patient’s erectile status is important in selecting
appropriate surgical alternatives. Potency may be determined
PD improves and even resolves spontaneously in fewer than by sexual history, a PDE-5 inhibitor take-home test, a phos-
13% of men, progression is seen in 40%, and no change phodiesterase (PDE) type 5 inhibitor, or intracavernosal injec-
in 47%.4 Surgery is recommended for patients with stable tion or Doppler ultrasound examination. Patient photographs
PD and poor coital function. PD includes both an active and may also be helpful in counseling patients before surgery. A
stable phase. The active phase occurs with the onset of PD and strong history of rigid erections is one of the best determi-
follows closely the traumatic event. Many men, however, do nants for choosing to proceed with a straightening procedure.
not recall specific trauma. The early, active phase lasts 12–24 Because many men with PD have avoided coitus for many
months and is often characterized by painful erections, a months, they are uncertain of their potency. Indeed, severe
changing plaque, and the development of penile curvature or curvature may preclude intromission and patients may not
other deformity during erection. The later, quiescent or stable appreciate the quality of their erection or the presence of
phase is characterized by stable penile deformity, resolution of veno-occlusive dysfunction. In these men, a home trial of
penile pain, and in some men the onset of ED. Surgery should PDE-5 inhibitors with sexual stimulation and subsequent
be avoided during active plaque change, since the penile follow-up history of the quality of erections is helpful in
deformity changes and may resolve enough for some men to choosing the best surgical procedure for the individual patient.
resume normal coital function. Montorsi et al. recommend When erection quality is still unclear or ED is likely, Doppler

413
414 Textbook of Erectile Dysfunction

Peyronie’s disease
+
symptoms

Quiescent disease for 6–12 months

Progressive +
disease Functional impairment

Medical treatment Surgery

Potency

Not certain

Intracavernosal
Phosphodiesterase type 5
injection or
inhibitor take-home test
Doppler ultrasound

Yes No

Inflatable penile
Tunica lengthening or prosthesis
shortening surgery

Short penis Adequate length Plaque incision

Penile modeling
Curve >45° Curve <45° or graft
Hour-glass deformity

Plication
Plaque incision
Nesbit procedure
or graft
Modified Nesbit
procedure

Figure 54.1 Algorithm for the surgical treatment of patients with Peyronie’s disease.7

penile blood flow studies may be helpful in identifying Tunica lengthening procedures are best chosen for men with
abnormalities in penile hemodynamics, plaque location and good erectile function, penile shortening, curvature of >45°,
size, presence of calcification, and degree of curvature.5 Large or hour-glass deformity. Tunica shortening procedures suc-
calcified plaques are poor prognostic indicators for spontane- ceed most often in men with good erectile function, adequate
ous resolution of PD or resolution with non-surgical meth- penile length, or curvature of <45°. Figure 54.1 shows the
ods. Montorsi et al. suggested that Doppler studies show algorithm for selecting treatment for Peyronie’s disease.7
sub-clinical penile abnormalities and aberrant communicat- Penile prosthesis implantation is best chosen for men with
ing vessels that could contribute to postoperative ED if dam- poor or absent erections or because of patient choice.
aged during surgery.6 Severe reduction in blood flow or severe Preoperative counseling should include discussions of the
veno-occlusive ED should suggest that prosthesis implanta- patient’s and partner’s expectations, alternatives, treatments,
tion would be the most successful choice. Digital photography and the risks, complications, and potential outcomes of
at the time of erection with in-office injection or at home by surgery. The most frequent complications of straightening
patients can be valuable in determining the severity of PD, procedures include: penile shortening, glans hypoesthesia,
planning surgery, and counseling patients and partners. ED, recurrent curvature, hematoma, and graft contraction.
 Surgical treatment of Peyronie’s disease 415

Figure 54.3 Dissection of Buck’s fascia with dorsal penile

nerve visible in dissected layer.

Figure 54.2 Penile curvature prior to surgical treatment.

Most patients will require the use of a PDE-5 inhibitor post- foreskin, owing to the increased risk for preputial edema,
operatively for penile rehabilitation. postoperative phimosis, or preputial necrosis. An artificial
erection is again induced and, if the penis is straight, Buck’s
fascia and the skin are closed. If extensive dissection has been
Tunica shortening required, a small subcutaneous drain such as the TLS® drain
may be used for 12–24 hours to diminish edema. If not ade-
Plication procedures quately straight, subsequent plications or tunica incision or
The Nesbit procedure was first described in 1965 for correcting excision and closure are necessary.
congenital penile curvature caused by corporal disproportion.8 A penile block is administered using long-lasting bupivic-
Pryor and Fitzpatrick first reported its use in the treatment of aine and a non-pressure dressing and an ice pack are applied.
patients with PD.9 Plication procedures require that the tunica Patients may be discharged home on the same day after this
opposite the Peyronie plaque and penile curvature is excised operation. They should avoid sexual activity for 6 weeks.
or plicated (or both) in order to straighten the penis. After an Yachia modified the Nesbit procedure, making single or
artificial erection is obtained with normal saline using the multiple 1–1.5cm longitudinal incisions along the convex side
Gittes technique or with injection of a vasoactive agent into of the tunica, which are subsequently closed horizontally,
the corpora cavernosum, an initial circumcising incision is applying the Heineke–Mikulicz principle. Yachia felt his mod-
created followed by degloving of the penis to the location of ification would reduce injury to the neurovascular bundle and
maximal curvature. A ventral penile incision may be used for so reduce glans hypoesthesia, though this complication is still
ventral exposure in very proximal dorsal curvature. Longitu- possible.11
dinal penile shaft incisions should be avoided because postop- The author of this chapter prefers a longitudinal incision
erative scarring may be painful or unsightly or even produce with horizontal closure in the Heineke–Mikulicz technique
further curvature. Buck’s fascia is dissected from the tunica because tunical deformities and palpable suture lines appear
albuginea in patients with dorsal curvature, or it is dissected to be fewer. Planning the tunical incision is facilitated by
off the dorsal neurovascular bundles for ventral curvatures. placing an Allis clamp to straighten the penis before perform-
An artificial erection is induced and the point of maximum ing the incision. Licht and Lewis compared the Nesbit, modi-
curvature is marked on the convex side of the penis. A 5–10mm fied Nesbit, and tunical incision with grafting and found
transverse ellipse on the tunica albuginea may be excised in the highest satisfaction rates (83%) and lowest ED rates (0%)
the classic Nesbit procedure (approximately 1mm for every with the modified Nesbit procedure.12 Recent studies show
10° of curvature). patient satisfaction rates for the Nesbit procedure of 75–88%
Rehman et al. modified this technique by using a partial- and rates of complete straightening of 61.9–82.1%.9,12–15 Simi-
thickness shaving of the tunica to avoid possible bleeding and lar rates of satisfaction (78–83%) and straightening (93%)
cavernosal injury.10 Alternatively, a longitudinal incision can have been found with Yachia’s modification to the Nesbit
be carried out at the location of the curvature and closed procedure.11,16,17
horizontally in the Heinike–Micwlicz fashion. Despite these high satisfaction and successful straightening
Next, the tunica is closed ‘water-tight’ and horizontally outcomes, penile shortening remains difficult with the Nesbit,
using interrupted or running, locking, non-absorbable, braided modified Nesbit, and other plication procedures. In a study
sutures with buried knots. Non-absorbable sutures are prefer- involving 359 men, Pryor reported shortening of <1cm in
able for maintaining correction during healing, as absorbable 86.6% of men, between 1–2cm in 8.6% of men, and >2cm in
sutures are more likely to break, causing recurrence of curva- 4.7% of men.13 Similarly, in another large study of 157 men
ture. A circumcision is recommended in men with redundant with PD, Savoca et al. reported shortening of <1.5cm in 86%
416 Textbook of Erectile Dysfunction

examined. If the penis is straight using another artificial

erection, the knots are completed and buried, ideally under
minimal tension. The Buck’s fascia is then re-approximated
with absorbable suture, and the skin closed.
A penile block is administered with bupivacaine, a non-
compressive dressing, and an ice pack is applied. Patients may
be discharged on the same day of surgery.
Gholami and Lue report that 85% of patients maintained a
straight erection while 15% suffered curve recurrence in a
study of 124 patients at a mean follow-up of 2.6 years.18 Forty-
one percent of patients in their series reported shortening
(from 0.5cm to 1.5cm), causing sexual dysfunction in 7% of
patients. Twelve percent reported bothersome knots, 11%
erectile pain, 9% penile indentation, 6% glans hypoesthesia,
and 6% worsened ED.18 Results vary for plication procedures,
Figure 54.4 Outline of plaque incision. with straightening rates ranging from 57% to 85% and satisfac-
tion rates ranging from 58% to 82%.18,20–24 Cahall et al. reported
significantly poorer outcomes than Gholami and Lue, with
57% of patients reporting deterioration in their quality of life,
55% severe penile shortening, 48% glans hypoesthesia, and
of men and of 1.5–3 cm in 14% of men.14 Pryor suggests 34% bothersome suture knot nodules.18,21
that the degree of penile shortening rarely precludes sexual
activity, only occurring in 1.7% of men in his study.13 Analysis
of other studies shows that the range for reported sexual Tunica lengthening procedures
dysfunction secondary to shortening is 1.3–11.9% for the
Nesbit and modified Nesbit procedures.12–15,17 Plaque incision or excision with placement of grafts has been
Complications with the procedures include curve recurrence used successfully for patients with severe penile curvature, for
(7.7–10.6%), ED (0–22.9%), penile indurations or narrowing complex or hour-glass deformity, and in men with a short-
(0–16.7%), suture granuloma (0–1.9%) and glans hypoesthe- ened penis from PD. In 1950, Lowsley and Boyce first reported
sia (0–21.4%).10–17 Glans hypoesthesia is common postopera- a series in patients with PD who underwent plaque excision
tively, though it frequently resolves after several months. with a fat graft, but there was no report of success.25
Various materials have since been used including dermis,26
temporalis fascia,27 vein,6,28–31 cadaveric or bovine pericar-
Tunica albuginea plication dium,32–34 dura mater,35 synthetic material,12 and porcine small
Plication of the tunica albuginea is the least invasive technique intestine submucosa (SurgiSIS®).36 The ideal graft should be
for correction of PD, and it is often performed using only pliable, easy to handle, and packaged in various sizes, have
local anesthetic. Gholami and Lue describe a 16-dot plication good tensile strength, a low inflammatory response, a low
method using multiple plication sutures with a high patient patient morbidity, a low risk of disease transmission, and low
satisfaction rate.18 Following induction of an artificial erec- cost.37
tion, a ventral longitudinal or circumcising incision is per- The author prefers porcine SurgiSIS® Biograft (Cook Uro-
formed. Longitudinal incisions are reserved for uncircumcised logical, Spencer, IN). SurgiSIS® is processed into a reliably
men desiring to keep their foreskin and are best carried out on packaged, acellular matrix, consistent in thickness and com-
the ventral aspect of the penis. Buck’s fascia is incised medial pliance. One drawback to the use of SurgiSIS® is that some
to the neurovascular bundle and an intravascular space devel- religions may not accept a porcine graft material and patients
oped bluntly between the dorsal vein and arteries. Nerve fibers should be made aware of the origin of the graft material. While
travel lateral to these dorsal arteries, and plication sutures may some surgeons have had less satisfactory results, my experi-
be placed in the developed space. For men with a dorsal cur- ence with SurgiSIS® has been equivalent to or exceeded that
vature, a ventral longitudinal incision is made down to Buck’s with other grafts.38,39
fascia overlying the corpus cavernosum. Synthetic materials, such as Dacron and Gore-Tex, may
After the center of the curve and entry and exit sites for the cause severe postoperative inflammation leading to fibrosis
plicating sutures have been marked, sutures are placed 2mm and post-correction curvature. Licht and Lewis reported poor
lateral to the corpus spongiosum. Two or three pairs of 2–0 patient satisfaction with synthetic grafts.12 Sampaio et al.
braided permanent polyester sutures are placed through the report that 95% of men achieved a straight penis using cadav-
tunica albuginea (four entry and exit points per suture). Van eric dura mater;35 however, this material has not been widely
der Horst et al. found that polytetrafluoroethylene sutures accepted because of concerns for prion and slow virus trans-
result in significantly less patient complaints of discomfort mission. Cadavaric pericardium has been widely used with
than polypropylene sutures (13% vs 52%) when a similar good postoperative results and excellent intra-operative tissue
plication technique is used.19 The sutures are gradually tied handling. Although prion transmission is rare, the media
with one surgical knot placed and subsequent clamping. Once have increased the concern regarding cadaveric human tissues
all plications are partly tied and clamped, the erect penis is and prion transmission. Use of vein grafts is well documented
 Surgical treatment of Peyronie’s disease 417

The chosen graft material is cut approximately 20% larger

than the measured defect and sutured to the tunica albuginea
with a running locking 4–0 polyglycolic acid suture (PDS).
Suture placement takes up approximately 3–5mm of graft
size on each side. Tisseal® (Baxter Healthcare, West Lake
Village, CA) can be applied by spray under the graft for fur-
ther adherence of the graft material to the underlying corporal
tissue. After the graft has been sutured in place and Tisseal®
applied, an artificial erection is induced to check straightening
and, when necessary, plications are placed on the contralateral
side of the penis to correct any residual curvature. Large resid-
ual curves may require a second incision and grafting. After
straightening has been achieved, Buck’s fascia and the skin are
closed.
A penile block is injected, a fine suction drain is kept
Figure 54.5 Graft sutured in place.
beneath the skin overnight, a non-compression dressing is
applied, and the patient is discharged that day or the following
morning. Ice is maintained on the operative site for 48–72
with good results ranging from 60% to 95% in terms of hours.
straightening and from 88% to 92% in terms of satisfaction,6,28– Patients are discharged home on nightly diazepam for 2
31
although these procedures carry the risk of harvest site weeks following surgery to prevent nocturnal erections, and
infection and lymphatic leak and they require longer opera- amyl nitrite may be used as needed to prevent erections for
tive time. Previously, deep dorsal penile vein has been used, that same period. Patients are advised to avoid sexual activity
but more recently vein grafts have used saphenous vein. Use for 6 weeks following surgery for adequate healing. If patients
of vein requires creation of a patchwork graft to fill larger experience mild curvature recurrence in the postoperative
tunical defects. Although I prefer SurgiSIS®, no material has period, a vacuum erection device (VED) may be employed for
emerged as the clearly superior graft.39 10 minutes twice daily without the constriction ring once the
The incision–excision straightening procedure begins with patient has recovered from the discomfort of surgery. This
an artificial erection to assess penile curvature, as previously postoperative VED use is successful for mild-to-moderate
described. For dorsal plaques, a circumcising incision and curvature. Many patients will require a phosphodiesterase
degloving of the penis is performed. Ventral plaques may be (PDE) type 5 inhibitor for 3–9 months after surgery to assist
accessed via a circumcising or a direct ventral incision longi- with ‘penile shock’ from surgery.
tudinally over the plaque. Dorsal penile incisions should be Reported satisfaction and straightening rates vary widely.
avoided. The neurovascular bundles, located lateral to the Complications include worsening ED, with most studies
deep dorsal vein of the penis, should be carefully dissected off reporting 0–15%,6,12,28–36 though this often takes up to 6 months
the underlying tunica albuginea. The plaque can be approached to improve and may require assistance with a vacuum device
through the bed of the deep dorsal vein with venous ligation or PDE-5 inhibitors. Since this ‘penile shock’ is expected in
1cm proximal and distal to the maximum curvature. The deep most patients, the author uses a PDE-5 inhibitor for 6–9
dorsal vein is excised between these ligatures. Buck’s fascia can months following surgery. Other complications include penile
also be incised at the 3 o’clock and 9 o’clock positions and shortening (0–40%), glans and penile hypoesthesia (0–16.7%),
dissected off the tunica albuginea to retract the neurovascular curve recurrence (0–16.7%), and hematoma.6,12,28–36
structures from the plaque and curvature. Buck’s fascia and Although the risk for increased penile shortening is
the contained dorsal penile nerves are then carefully dissected less with these procedures than with plication procedures,
off the tunica albuginea using sharp dissection. A relaxing patients still need to be warned of this outcome. PD itself will
H-shaped incision is then made in the plaque with subsequent cause shortening and may increase this complaint. Yurkanin
grafting, a technique described by Lue and El-Sakka.40 Egydio reported average penile lengthening of 2.1cm in the flaccid
describes an incision using ‘tripod-shaped forks of 120°’ penis in men with PD.30 Interestingly, over half the patients in
to produce a geometrically optimal relaxing tunical defect this study reported subjective shortening.
for easy graft suturing.41 This incision may also be termed a
‘Mercedes–Benz incision’ and it provides enhanced curvature
correction for severe curvature, especially if associated with an Penile prosthesis implantation
hour-glass deformity at the location of the curvature.
Larger or calcified plaques may require complete excision. Severe ED and PD is best treated with implantation of
The measurement of graft size can be estimated by measuring an inflatable penile prosthesis. The tunica lengthening and
the convex and concave portions of the erect penis and using the shortening procedures discussed above may provide a straight
difference for the first graft size estimate. After the curvature penis, though a complete loss of erectile function will result
has been incised or the plaque excised, measurements are from surgery in some patients.
taken from the corners of the tunical incision. It is important Montorsi et al. found that implantation of a semi-rigid
to raise flaps of tunica at the H- or Y-shaped incision to allow prosthesis in men with PD had very poor 5-year patient (48%)
for full straightening. and partner (40%) satisfaction rates despite a high satisfaction
418 Textbook of Erectile Dysfunction

urethral perforation in four patients. Carson described the

technique in 30 patients, 28 of whom suffered no complications
from modeling and all of whom had good penile straighten-
ing at a mean follow-up of 31.4 months.47 The remaining
2 patients in this study required plaque incision and grafting.
Chaudhary et al. reported the use of modeling in 28 of
46 patients undergoing prosthesis implantation for PD. The
remaining 18 patients achieved adequate straightening merely
with the prosthetic implantation.43 Furthermore, a recent
study showed slightly higher patient (88% vs 81%) and
partner (80% vs 72%) satisfaction rates for modeling com-
pared with corporoplasty with insertion of inflatable penile
prosthesis.34 AMS 700CX InhibiZone® (American Medical
Systems, Minnetonka, MN) and Coloplast Titan® (Coloplast,
Minneapolis, MN) prostheses are best suited for patients with
PD since these higher-pressure cylinders provide adequate
rigidity to straighten the penis across the Peyronie’s plaque.
AMS Ultrex cylinders are less likely to provide adequate
platform for modeling.48
Complications of inflatable penile prosthesis implantation,
such as infection and device breakdown, are no more com-
mon in men with PD than in others undergoing penile pros-
Figure 54.6 Post-correction artificial erection. thesis implantation. As mentioned above, 4 of 138 patients in
Wilson and Delk’s study suffered urethral perforation, possibly
linked to modeling, though none of the patients in Carson’s or
Chaudhary’s series experienced urethral injury.43,45,47 Regard-
rate (90%) at 3 months.42 Complaints included poor erection less, all men undergoing prosthetic implantation should
quality and girth with erections, unnatural sensation, and be warned before surgery of the risks for infection, device
partner pain. Meanwhile, these and other authors report good malfunction, urethral injury, penile shortening, and recurrent
results with inflatable penile prosthesis, with patient satisfac- curvature.
tion rates ranging from 75% to 93%.34,43,44
Following penile prosthesis implantation, patients with
continued curvature should be treated with modeling, plaque Conclusion
incision and grafting, or a modified Nesbit procedure. Wilson
and Delk first described modeling in a large, 138-patient ret- Peyronie’s disease is an incurable, sexually debilitating disease
rospective study.45,46 Prior to pump placement in the scrotum, resulting in penile deformity, coital failure, and significant
the cylinders are distended maximally and the connector psychological stress for many men and their partners. Urolo-
tubing to the pump is clamped to prevent excessive back- gists have an opportunity to help men suffering from PD to
pressure. Additionally, digital pressure is placed over the cor- improve their lives and the lives of their partners.
porotomy incisions to protect the suture lines. The penis is Appropriate treatment should be individualized and tailored
bent manually directly opposite the curve for 90 seconds. This to the patient’s expectations, disease history, physical examina-
results in plaque splitting and often an audible crack. Wilson tion findings, and erectile function. After medical therapy is
and Delk reported this technique as being successful in 118 considered and the PD has stabilized, surgical correction is an
of 138 patients, avoiding plaque incision and grafting.45 excellent option for patients with functional impairment from
They also reported that modeling was associated with greater their PD. Outcomes are excellent, with expected return to
postoperative pain and swelling and was possibly related to normal sexual function following PD treatment.

REFERENCES

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disease: results of a large survey. BJU Int 2001; 88: 727–30. 2006; 67: 166–9.
2. Devine CJ Jr, Somers KD, Jordan SG, Schlossberg SM. Proposal: 6. Montorsi F, Salonia A, Maga T, et al. Evidence based assessment
trauma as the cause of the Peyronie’s lesion. J Urol 1997; 157: of long-term results of plaque incision and vein grafting for
285–90. Peyronie’s disease. J Urol 2000; 163: 1704–8.
3. Gholami SS, Gonzalez-Cadavid NF, Lin CS, Rajfer J, Lue TF. 7. Tornehl CK, Carson CC. Surgical alternatives for treating Peyronie’s
Peyronie’s disease: a review. J Urol 2003; 169: 1234–41. disease. BJU Int 2004; 94: 774–83.
4. Gelbard MK, Dorey F, James K. The natural history of Peyronie’s 8. Nesbit RM. Congenital curvature of the phallus: report of three cases
disease. J Urol 1990; 144: 1376–9. with description of corrective operation. J Urol 1965; 93: 230–2.
5. Schaeffer E, Jarow JJ, Vrablic J, Jarow J. Duplex ultrasonography 9. Pryor JP, Fitzpatrick JM. A new approach to the correction of the
detects clinically significant anomalies of penile arterial vascula- penile deformity in Peyronie’s disease. J Urol 1979; 122: 622–3.
 Surgical treatment of Peyronie’s disease 419

10. Rehman J, Benet A, Minsky LS, Melman A. Results of surgical 30. Yurkanin JP, Dean R, Wessells H. Effect of incision and saphenous
treatment for abnormal penile curvature: Peyronie’s disease and vein grafting for Peyronie’s disease on penile length and sexual
congenital deviation by modified Nesbit plication (tunical shaving satisfaction. J Urol 2001; 166: 1769–72; discussion 1772–3.
and plication). J Urol 1997; 157: 1288–91. 31. Adeniyi AA, Goorney SR, Pryor JP, Ralph DJ. The Lue procedure:
11. Yachia D. Modified corporoplasty for the treatment of penile an analysis of the outcome in Peyronie’s disease. BJU Int 2002; 89:
curvature. J Urol 1990; 143: 80–2. 404–8.
12. Licht MR, Lewis RW. Modified Nesbit procedure for the treatment 32. Egydio PH, Lucon AM, Arap S. Treatment of Peyronie’s disease
of Peyronie’s disease: a comparative outcome analysis. J Urol by incomplete circumferential incision of the tunica albuginea
1997; 158: 460–3. and plaque with bovine pericardium graft. Urology 2002; 59:
13. Pryor JP. Correction of penile curvature and Peyronie’s disease: 570–4.
why I prefer the Nesbit technique. Int J Impot Res 1998; 10: 33. Chun JL, McGregor A, Krishnan R, Carson CC. A comparison
129–31. of dermal and cadaveric pericardial grafts in the modified Horton–
14. Savoca G, Trombetta C, Ciampalini S, et al. Long-term results with Devine procedure for Peyronie’s disease. J Urol 2001; 166:
Nesbit’s procedure as treatment of Peyronie’s disease. Int J Impot 185–8.
Res 2000; 12: 289–93. 34. Usta MF, Bivalacqua TJ, Sanabria J, et al. Patient and partner satis-
15. Syed AH, Abbasi Z, Hargreave TB. Nesbit procedure for disabling faction and long-term results after surgical treatment for Peyronie’s
Peyronie’s curvature: a median follow-up of 84 months. Urology disease. Urology 2003; 62: 105–9.
2003; 61: 999–1003. 35. Sampaio JS, Fonseca J, Passarinho A, Cristino J, Mendes J.
16. Daitch JA, Angermeier KW, Montague DK. Modified corporoplasty Peyronie’s disease: surgical correction of 40 patients with relaxing
for penile curvature: long-term results and patient satisfaction. incision and duramater graft. Eur Urol 2002; 41: 551–5.
J Urol 1999; 162: 2006–9. 36. Knoll LD. Use of porcine small intestinal submucosal graft in the
17. Sulaiman MN, Gingell JC. Nesbit’s procedure for penile curvature. surgical management of Peyronie’s disease. Urology 2001; 57:
J Androl 1994; 15: 54S–6S. 753–7.
18. Gholami SS, Lue TF. Correction of penile curvature using the 37. Kadioglu A, Sanli O, Akman T, et al. Graft materials in Peyronie’s
16-dot plication technique: a review of 132 patients. J Urol 2002; disease surgery: a comprehensive review. J Sex Med 2007; 4:
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19. van der Horst C, Martinez Portillo FJ, Melchior D, et al. Polytetra- 38. Breyer BN, Brant WO, Garcia MM, Bella AJ, Lue TF. Complica-
fluoroethylene versus polypropylene sutures for Essed-Schroeder tions of porcine small intestine submucosa graft for Peyronie’s
tunical plication. J Urol 2003; 170: 472–5. disease. J Urol 2007; 177: 589–91.
20. van der Drift DG, Vroege JA, Groenendijk PM, et al. The plication 39. Carson CC. Surgical treatment of Peyronie’s disease. Can J Urol
procedure for penile curvature: surgical outcome and postopera- 2006; 13: 28–33.
tive sexual functioning. Urol Int 2002; 69: 120–4. 40. Lue TF, El-Sakka AI. Venous patch graft for Peyronie’s disease. Part
21. Chahal R, Gogoi NK, Sundaram SK, Weston PM. Corporal plica- I: technique. J Urol 1998; 160: 2047–9.
tion for penile curvature caused by Peyronie’s disease: the patients’ 41. Egydio PH, Lucon AM, Arap S. A single relaxing incision to correct
perspective. BJU Int 2001; 87: 352–6. different types of penile curvature: surgical technique based on
22. Thiounn N, Missirliu A, Zerbib M, et al. Corporeal plication for geometrical principles. BJU Int 2004; 94: 1147–57.
surgical correction of penile curvature. Experience with 60 patients. 42. Montorsi F, Guazzoni G, Bergamaschi F, Rigatti P. Patient-partner
Eur Urol 1998; 33: 401–4. satisfaction with semirigid penile prostheses for Peyronie’s disease:
23. Geertsen UA, Brok KE, Andersen B, Nielsen HV. Peyronie curva- a 5-year followup study. J Urol 1993; 150: 1819–21.
ture treated by plication of the penile fasciae. Br J Urol 1996; 77: 43. Chaudhary M, Sheikh N, Asterling S, Ahmad I, Greene D.
733–5. Peyronie’s disease with erectile dysfunction: penile modeling over
24. Nooter RI, Bosch JL, Schroder FH. Peyronie’s disease and inflatable penile prostheses. Urology 2005; 65: 760–4.
congenital penile curvature: long-term results of operative 44. Montorsi F, Guazzoni G, Barbieri L, et al. AMS 700 CX inflatable
treatment with the plication procedure. Br J Urol 1994; 74: penile implants for Peyronie’s disease: functional results, morbidity
497–500. and patient-partner satisfaction. Int J Impot Res 1996; 8: 81–5,
25. Lowsley OS, Boyce WH. Further experiences with an operation for discussion 85–6.
the cure of Peyronie’s disease. J Urol 1950; 63: 888–902. 45. Wilson SK, Delk JR 2nd. A new treatment for Peyronie’s disease:
26. Devine CJ Jr, Horton CE. Surgical treatment of Peyronie’s disease modeling the penis over an inflatable penile prosthesis. J Urol
with a dermal graft. J Urol 1974; 111: 44–9. 1994; 152: 1121–3.
27. Gelbard MK. Relaxing incisions in the correction of penile 46. Wilson SK. Surgical techniques: modeling technique for penile
deformity due to Peyronie’s disease. J Urol 1995; 154: 1457–60. curvature. J Sex Med 2007; 4: 231–4.
28. El-Sakka AI, Rashwan HM, Lue TF. Venous patch graft for Peyronie’s 47. Carson CC. Penile prosthesis implantation in the treatment of
disease. Part II: outcome analysis. J Urol 1998; 160: 2050–3. Peyronie’s disease. Int J Impot Res 1998; 10: 125–8.
29. Backhaus B, Muller S, Albers P. Corporoplasty for advanced 48. Montague DK, Angermeier KW, Lakin MM, Ingleright BJ. AMS
Peyronie’s disease using venous and/or dermis patch grafting: new 3-piece inflatable penile prosthesis implantation in men with
surgical technique and long-term patient satisfaction. J Urol 2003; Peyronie’s disease: comparison of CX and Ultrex cylinders. J Urol
169: 981–4. 1996; 156: 1633–5.
55 Priapism
Rajeev Kumar and Ajay Nehra

Introduction Priapism is principally classified into two types: low-flow

priapism and high-flow priapism. This classification is based
Priapism is a pathological penile erection that persists in the on the status of arterial flow into the corpora cavernosa
absence of sexual stimulation. It is a relatively poorly under- during the priapic state and is instrumental in deciding the
stood condition and is a medical emergency if ischemic, management strategy.
because of its attendant pain and the associated complication
of permanent erectile dysfunction (ED). Despite significant
advances in the understanding of the physiology of normal
erection and pathophysiology of ED, the infrequent occur-
Low-flow (ischemic) priapism
rence of this condition, the paucity of basic research, and Ischemic priapism is the more common of the two types of
the lack of controlled trials of therapeutic options has led to priapism. This is characterized by a low or absent blood flow
priapism being considered an enigma. into the penis along with pain in acidotic corpora. The prin-
cipal abnormality is an imbalance between arterial inflow and
venous outflow from the penis. Persistent inflow with a
History decreased outflow leads to accumulation of blood within the
cavernosal sinusoids along with progressively increasing tissue
The term ‘priapism’ is derived from Priapus, one of the many pressure. As the pressure rises, it may approach or surpass the
mythological characters in Greek history. Modern medical systolic arterial pressure, with subsequent stasis of pooled
awareness of the condition can be safely attributed to blood resulting in hypoxia and acidosis. The condition is
Hinman, who, in an article in 1914, described the condition similar to a compartment syndrome.
as a thrombosis of the corporal veins and further attempted
to describe the etiology as arising out of mechanical or ner-
vous causes.1 He believed the majority of cases were due to Pathogenesis
mechanical causes resulting either from local factors (such as Priapism is a phenotypic manifestation of an underlying
pelvic infections, perineal injuries and penile tumors), or dysfunction of normal cavernosal enzymes and proteins.
from blood dyscrasias. These descriptions remain valid even Champion et al. conducted a series of experiments using
today. transgenic mice with deficiency of endothelial nitric oxide
synthase (eNOS) and neuronal NOS (nNOS) in varying com-
binations to evaluate their tendency for priapism.4 They found
Epidemiology increased episodes of priapism in mutants homozygously
negative for eNOS. This was associated with a decrease in the
The incidence of priapism varies depending upon the popula- activity of phosphodiesterase (PDE)-5A protein. They con-
tion being studied. Eland et al. reviewed the data of all cluded that mice deficient in eNOS could not break down the
men enrolled with the Integrated Primary Care Information cGMP released after stimulation of the cavernosal nerve
database in the Netherlands.2 This study of 145,071 males because of decreased activity of PDE-5, and eNOS restoration
with 341,133 person-years of follow-up is one of the most could reverse this trend. This whole phenomenon may be the
comprehensive epidemiologic publications for this condition. result of super-sensitization to cGMP after an erectile stimu-
They reported an overall incidence of 1.5 cases per 100,000 lus. The same group further evaluated the role of Rho-kinase
person-years with an increase to 2.9% in men above 40 years in the causation of priapism and noted decreased RhoA–Rho
of age. Intracavernosal therapy for ED was attributed to kinase-mediated contraction of the cavernosal smooth muscle
0.6 per 100,000 person-years. This incidence is higher than the cells in eNOS deficient mice.5
0.34–0.52 per 100,000 persons reported by Kulmala et al.3 This combination of increased excitatory neurotransmitters
from Finland, and this may be due to the increased use of along with decreased contractile response may be the cause of
intracavernosal therapy for ED. There are further variations in priapism in a number of patients. Tissue hypoxia seems to be
the incidence depending on the ethnicity and prevalence the principal factor responsible for the morbidity associated
of certain underlying medical conditions such as sickle cell with ischemic priapism and has been the focus of research
disease, in which the incidence may be as high as 42%. into the pathogenesis of this condition. Accumulation of toxic

420
 Priapism 421

metabolites is evident within 4 hours after onset of the erec- Evliyaoglu et al. induced priapism in rats using a vacuum
tion.6 Within 12 hours, there is interstitial edema, which pro- constriction device and measured the corporeal tissue for
gresses to endothelial platelet adherence and necrosis of the lipid peroxidation using malondialdehyde (MDA) levels
cavernosal smooth muscle cells.7 These cells are then replaced with a thiobarbituric acid assay.12 They noted a higher level
by fibroblasts, resulting in permanent ED. The platelet aggre- of MDA in the rats subjected to priapism compared with
gation and thrombus formation is supported by experimental control rats. They further reported a decrease in MDA levels
findings of reduced prostacyclin [prostaglandin (PG)I-2] pro- in rats pre-treated with allopurinol prior to induction of
duction and reduced nitric oxide (NO) levels in hypoxic tis- priapsim.13
sue, both of which are known to be antiplatelet aggregation Tissue hypoxia may also upregulate TGF-beta, a cytokine
agents.8,9 that can induce conversion of cavernosal tissue into
The fact that corporal damage is evident as early as 4 hours fibrosis.14 The overall data from these studies help define
after the onset of the erection highlights the importance of a potential pathogenic mechanism for ischemic priapism
early recognition and management for this condition, partic- (Figure 55.1).
ularly since the outcome of delayed management may be Erection is under neural control, and penile stimulation-
permanent ED. Prolonged anoxia decreases the ability of induced erections are reflex in nature, mediated by the sacral
the corporal smooth muscle to respond to alpha-agonists. parasympathetic nerves. The sympathetic nervous system is
Broderick et al. used isolated rabbit corpus cavernosum to believed to be responsible for mediating detumescence.
evaluate smooth muscle tone and contractility.10 They found Patients with lumbar canal stenosis and cauda equina syn-
that anoxia not only eliminated spontaneous smooth muscle drome may develop priapism, and this may be the result of
contractility but also led to a poor contractile response to parasympathetic hyperactivity resulting from increased
alpha-agonists. They concluded that these findings partly intrathecal pressure within the lumbar canal, particularly
explained the clinically poor response to alpha-agonists in during walking, when these symptoms often tend to first
delayed presenting cases of ischemic priapism. occur.15
An initial episode of priapism may tend to self-perpetuate.
Lin et al. isolated the cavernous smooth muscle cells from
rats and cultured it in anoxic or hypoxic states to simulate Etiology
priapism.11 They found a significantly decreased expression The etiology of low-flow priapism changed significantly
of PDE-5 in the tissue subjected to hypoxia as well as in the following the advent of intracavernosal therapy for the manage-
corpus cavernosal tissue of rats whose internal pudendal ment of ED and is now likely to change again with the decreas-
arteries had been ligated. Decreased PDE-5 levels would pre- ing use of these injections and increasing use of oral drug
dispose to prolonged action of cGMP, resulting in further therapies. The American Foundation for Urologic Disease
priapism. Thought Leader Panel (AFUD-TLP) classification of priapism
Ischemia may also affect smooth muscle function by increas- etiology is given in Table 55.1.16 This classification primarily
ing peroxidation of the lipid content of cell membranes. relates to low-flow priapism.

Predisposed patient (eNOS deficiency)

Decreased PDE-5 activity Decreased Rho-kinase activity

Decreased cGMP breakdown Poor cavernosal smooth muscle contractions

Stimulus Increased cGMP Poor response to alpha-agonists

Priapism

Ischemia
Increased TGF-beta Reduced PGI, NO
Acidosis

Platelet aggregation
Fibrosis
thrombosis

Erectile dysfunction

Figure 55.1 Pathogenesis of priapism. eNOS, endothelial nitric oxide synthase; PDE, phosphodiesterase; TGF, transforming growth
factor; PGI, prostaglandin I; NO, nitric oxide.
422 Textbook of Erectile Dysfunction

stasis may set up a cycle of sickling and sludging along

Table 55.1 Etiology of priapism
with acidosis.28 Dysregulation of the PDE-5 and Rho-kinase
Drug-induced enzymes may also be contributory to the etiology of priapism
in the sickle cell population. As a part of their study on
Hematologic
the priapic activity of eNOS- and nNOS-deficient mice,
Sickle cell disease and other hemoglobinopathies Champion et al found similar defects in mice carrying the
Thrombophilia states (protein C and other thrombophilia, sickle cell genotype.4
lupus) Francis proposed a theory of large-vessel occlusion as
Hyperviscosity states (hyperleukocytosis, polycythemia) being responsible for the priapism in patients with sickle cell
Idiopathic anemia.29 Abnormal adhesive and pro-coagulant properties of
the red blood cells may lead to endothelial damage, intimal
Centrally mediated
proliferation, and thrombosis.
Others
From Int J Impot Res 2001; 13 Suppl 5: 539–43.
Priapism caused by medications other than drugs for
erectile dysfunction
Apart from ED therapy, a large number of medications have
Drug-induced priapism been associated with the occurrence of priapism. The most
Virag introduced intrapenile injections of vasoactive sub- common among these are the antipsychotic group of drugs
stances as therapy for ED in 1982.17 All agents used in these and antihypertensive medications. Some of these medications,
therapies have the potential to cause priapism and, in fact, such as trazodone, are used off-label as therapy for premature
account for the largest proportion of patients with ischemic ejaculation and presumably an extension of this effect may
priapism. In a series of 207 cases of priapism, 21% were attrib- manifest as priapism. Both the typical and atypical antipsy-
uted to these injections.18 Papaverine was one of the initial chotic group of drugs may be associated with priapism. Some
agents used and is associated with the highest priapism rate of the antipsychotic medications that have been shown to
of about 5%. This rate has been as high as 17% in one series.19 cause priapism are chlorpromazine, risperidone, clozapine,
The more commonly used agent – PGE-1 – is associated with thioridazine, ziprasidone, and quetiapine.30–33
priapism in less than 1% of patients. PGE-1 used trans- Priapism may occur many years after the initiation of
urethraly has an even lower incidence of priapism, <0.3%.20 antipsychotic medication, and therefore a constant awareness
The oral PDE-5 inhibitor drugs are much safer, with needs to be maintained even if there have been no side-effects
extremely rare reports of priapism following their use. Sildena- in the initial years of drug use.34,35 The alpha-adrenergic antag-
fil citrate, abused in the absence of ED, has been reported to onist action of these medications may be responsible for their
cause priapism.21 pro-priapism activity.30 It is recommended that patients with
a prior history of priapism should be given drugs with lower
anti-alpha-adrenergic action, and all patients receiving such
Priapism secondary to hematologic conditions medication should be warned of these potential side-effects.
Priapism may occur with any condition that predisposes to Androgens, such as androstenedione used for athletic per-
hyperviscosity of the blood. Rheologic abnormalities that have formance enhancement, may also lead to priapism, as may the
been reported to be associated with priapism are thalassemia, use of testosterone or gonadotropin therapy in hypogonadal
thrombophilia, hemoglobin Olmsted, unstable hemoglobin men.36–40 Drug abuse, particularly of cocaine, is also associated
Perth, protein C, and Leiden factor V.22–25 with an increased risk of priapism, which may result from the
Sickle cell disease is one of the most common underlying corporeal smooth muscle relaxant effects of this drug.
conditions predisposing to priapism. An abnormality in one
or two genes coding for the S hemoglobin results in this dis-
ease, which may be seen in upto 0.15% of the black American Priapism caused by other medical conditions
population. Sickle cell trait is even more widely present. Sub- A number of systemic disorders have been associated with the
jects with sickle cell trait or sickle cell anemia are especially occurrence of priapism. However, most of these associations
prone to developing priapism. Priapism is uncommon in pre- are anecdotal and include amyloidosis, Henoch–Schönlein
pubertal boys but may occur in up to 42% of men with sickle purpura, and glucose phosphate isomerase deficiency.41–43
cell anemia.26 Mantadakis et al. surveyed children and adoles- Systemic malignancies may also be associated with priapism
cents with sickle cell anemia for the incidence of priapism and though the reason for this occurrence is not known.
found an alarmingly high actuarial probability of 89% of hav- A rebound hypercoagulable state may occur after cessation
ing at least one episode by the age of 20 years.27 Patients with of anticoagulant therapy. This is believed to result, in part,
sickle cell anemia suffer from the sickling of their red blood from the platelet aggregation induced by the antiplatelet anti-
cells in the presence of decreased oxygen tension in the blood. bodies. Priapism has been reported to occur after use of both
Sickled cells are less ‘deformable’ and find it difficult to navi- heparin and low-molecular-weight heparin.44–46 Singhal et al.
gate narrow vessels and sinusoids and tend to obstruct such reviewed 3337 patients in 93 dialysis units for the prevalence
vessels, further promoting stasis and sickling. This is often of priapism.47 Seventeen episodes were noted to occur, all
manifested as painful ‘crises’ in long bones. A similar phe- either during or up to 7 hours after dialysis. Heparin was
nomenon may occur in the penile tissue, where hypoxia and believed to be responsible for these events since none occurred
 Priapism 423

in patients receiving heparin-free peritoneal dialysis. Eleven of Table 55.2 Low-flow versus high-flow priapism
their patients were receiving simultaneous androgen therapy,
and two patients had sickle cell trait. High-flow Low-flow priapism
Intermittent ischemic priapism may also occur in patients priapism
with certain neurologic conditions such as lumbar spinal canal Duration of Often long – Usually short –
stenosis. Baba et al. reported on seven patients who presented symptoms weeks or hours
with intermittent claudication and priapism during walking months
and had radiologic evidence of some degree of cauda equina Pain Negligible Persistent
compression.15 They recommended surgical decompression
Medical history Perineal trauma Erectile dysfunction
as a possible solution to these symptoms.
therapy,
antipsychotic
medication, drug
High-flow priapism abuse,
hemoglobinopathy
High-flow priapism is a relatively uncommon form of Penile rigidity Usually partial, Complete,
priapism that results from increased flow of well-oxygenated, compressible non-compressible
arterial blood into the corpora. The normal inflow control Doppler Good flow Poor arterial flow
exerted by the helicine arteries is absent or diminished. The ultrasonography
increased inflow is usually well handled by the venous
Blood gas Well Poor oxygen
outflow, and there is no ischemia of the corporal tissue. There
analysis oxygenated saturation
is little or no pain, and the blood gas analysis of the aspirated (corporeal
blood shows normal oxygen saturation. blood)
These patients often have a history of perineal trauma.
Priapism is typically noticed a few days after the trauma, often
following a natural erection. The erection is painless, less rigid
than a normal erection, and becomes more rigid with arousal. examination is performed to determine the degree of rigidity,
Cycling may be the inciting traumatic event. The initial trauma any associated injury (if traumatic in origin), and abdominal
results in injury to the arterial wall that necroses completely malignancy.
over time.48 Increased arterial pressure during a natural erec- Laboratory investigations aid in the diagnosis but are not
tion causes the weakened arterial wall to rupture and present mandatory. The AFUD guidelines on the management of pria-
as priapism at a time remote from the original injury. pism suggest a urine toxicology screen for cocaine metabolites,
Bastuba et al. believe that this type of priapism results from screening for psychoactive substances, and a complete blood
an arteriolacunar fistula wherein the ruptured artery opens counts with platelet count and differential counts in all patients,
directly into the lacunar spaces of the cavernosal tissue, with an optional reticulocyte count, and urinalysis.16 A com-
bypassing the helicine arteries. The high flow results in shear plete blood count can help to identify infections and hemato-
stress of the adjacent areas. This causes increased smooth logic conditions such as platelet abnormalities, leukemia, or
muscle relaxation and trabecular dilatation through release of sickle cell disease. Patients with sickle cell disease may also have
nitric oxide and activation of cGMP. Unlike the situation in an elevated reticulocyte count, which can be confirmed through
low-flow priapism, there is no transformation of the trabecu- hemoglobin electrophoresis. More rapid tests for sickle cell
lar smooth muscles into fibroblasts even after prolonged peri- disease, such as the Sickledex test or peripheral smear exami-
ods, and therefore these patients are unlikely to develop ED as nation, may be more appropriate in the emergency setting.50
a direct consequence of the priapism.49 Blood gas analysis of the cavernosal blood would reveal
hypoxic, dark blood with a very low oxygen pressure
(<30mmHg) and pH <7.25 in ischemic priapism.50 In non-
ischemic priapism, these values resemble those of arterial
Management blood. Color Doppler ultrasonography would reveal little or
absent flow in the cavernosal arteries and the corpora caver-
Diagnosis and evaluation nosa in ischemic priapism and normal-to-high velocities in
Priapism is a medical emergency. It is important to realize the non-ischemic priapism. Additionally, the ultrasonogram may
potential long-term complications that may result from it and reveal an aneurysm of the cavernosal artery or an arterio-
to initiate therapy early to prevent these occurring. Differenti- venous fistula in high-flow priapism. Patients with high-flow
ating high-flow from low-flow types is important because they priapism that fails to respond to conservative measures may
require different management and also have differing potential require penile arteriography for the identification of the vas-
complications. This differentiation can usually be achieved cular abnormality. This may be accompanied by embolization
through the history and physical examination (Table 55.2). of the aneurysm or fistula.
A clear history will usually help to identify the type and
cause of priapism. Specific issues that should be enquired
about are perineal trauma, medications (both prescription Management of low-flow priapism
and non-prescription), drug abuse, previous episodes of Therapeutic goals in the management of priapism are to allevi-
priapism, and medical comorbidities. A focused physical ate pain and fear, abort the erection, maintain detumescence,
424 Textbook of Erectile Dysfunction

and prevent long-term complications, particularly ED. These phenylephrine include epinephrine (10–20 µg per dose)
goals are achieved through attempts at reducing the arterial and ephedrine (50–100mg per dose). Despite their alpha-
inflow and increasing the outflow from the corpora. Local selectivity, use of these agents should be accompanied by
measures within the corpora should be accompanied by cardiac monitoring. These agents may induce release of
definitive therapy for the underlying medical condition. The endogenous norepinephrine with consequent cardiac and
American Urologic Association (AUA) guidelines on the vascular side-effects. This mandates a close watch for features
management of priapism stress the importance of concurrent such as headache, bradycardia, hypertension, and cardiac
systemic and local management in patients with underlying arrhythmia. Resolution rates following the use of these agents
systemic diseases.50 They note a resolution rate of only up to is higher (43–81%) than with aspiration or irrigation alone
37% in sickle cell patients with priapism who did not receive (24–36%).50
local therapy.50 Failure of aspiration and drug instillation would be an
Management of ischemic priapism must proceed in a step- indication to begin a more extensive cross-irrigation using a
wise fashion depending upon the degree of response to each second 21-gauge needle in the opposite corpora for efflux of
intervention. Figure 55.2 is modified from the AFUD panel the irrigant solution and alpha-adrenergic agonist drugs may
guidelines16 and defines the algorithm for evaluation and be added to the irrigant solution or instilled after achievement
management of priapism. of detumescence.
Oral terbutaline, a beta-adrenergic agonist, has been used
to induce detumescence in patients who develop an erection
Medical management during anesthesia. This observation led to its use in priapism
Conservative measures for the erection include ice compresses and was found to be successful in up to a third of patients
and ejaculation. However, these are sufficient in only a minor- with early presentation, particularly those with intracorpo-
ity of patients. In fact, Burnett believes that‘ lack of ejacula- real prostaglandin-induced priapism.52 Priyadarshi reported
tion’ as a cause of priapism is only a myth.51 Pain management that 42% of patients with a pharmacologically induced erec-
may be achieved through either local penile or systemic anal- tion had detumescence with oral terbutaline compared with
gesia. This could include dorsal nerve block, penile block, or 15% of patients receiving a placebo.53 However, in a prospec-
oral conscious sedation in children. tive, blind, controlled trial of 24 patients with prolonged
Primary medical management involves corporeal aspira- erections, Govier et al. found no benefit of terbutaline over
tion to remove the collected blood and achieve detumescence, placebo.54
and instillation of an alpha-adrenergic agonist drug to induce Methylene blue is an inhibitor of cGMP and may induce
smooth muscle contraction and maintain the detumescence. smooth muscle contraction. It has been used in the manage-
Aspiration can be performed using a 21- or 22-gauge butterfly ment of priapism as a replacement for alpha-adrenergic ago-
needle inserted into the corpora. A pure alpha-adrenergic nist drugs. Hubler et al. described five patients in whom
stimulant such as phenylephrine is diluted to a concentration intracavernosal injection of methylene blue 100mg helped to
of about 0.5mg/ml and 0.5–1ml of this solution is administered achieve detumescence.55 Methylene blue may be specifically
repeatedly at intervals of 5–7 minutes for up to 1 hour through useful in patients with priapism secondary to intracavernosal
the butterfly needle to achieve detumescence. Alternatives to drug therapy.56,57

Erection >4 hours

History and physical examination

Painful Painless
recent onset Long duration
No trauma Cavernous blood gas an Doppler ultrasound Perineal trauma
Rigid Non-rigid

Ischemic Non-ischemic

Analgesia, treat underlying condition Observe, treat underlying condition

Aspiration, alpha-agonist agent Arteriographic embolization

Irrigation, alpha-agonist agent Surgical ligation

Distal shunt

Proximal shunt Follow-up and (?) recurrence prevention

Figure 55.2 Evaluation and management of priapism.

 Priapism 425

Surgical interventions recurrent (stuttering) priapism in 42% of men with sickle cell
First-line therapies such as aspiration and irrigation are anemia.61 Recurrent episodes of ischemic priapism are likely
found to be most effective if used early, ideally within the first to predispose to corporeal fibrosis.22 Levine et al. reported this
12 hours of the initiation of the erection. If these are initiated form of priapism in six men with no hemoglobinopathy and
beyond 72 hours, they have limited efficacy, and while they no other underlying abnormality.62 They believe that even one
may relieve pain, they do not help preserve potency.16 episode of ischemic priapism may lead to an abnormality in
If conservative and medical management measures fail to the normal regulation of tumescence and detumescence, pre-
achieve detumescence, surgical procedures may be needed. disposing to recurrent episodes of ischemic priapism. One of
The principle behind these procedures is to create a shunt the potential reasons for this dysregulation may be depletion
between the corpora cavernosa, and the corpora spongiosa in the expression of the PDE-5 enzyme.
since in most cases, priapism affects only the corpora cavern- Stuttering or recurrent priapism may recur multiple times
osa, and the venous drainage from the spongiosa is intact. during the same day or once every few months. Each episode
Creation of a shunt diverts the blood from the cavernosa into needs to be evaluated and treated independently. Addition-
the spongiosa, causing detumescence. ally, a number of preventive strategies have been attempted
The Winter procedure is one of the simplest first-line for these patients.
surgical interventions used for patients in whom medical Oral therapies to prevent recurrence have been based on
management fails. It creates a shunt between the glans penis hormonal manipulation to suppress endogenous testosterone
and the corpora cavernosa using a tru-cut needle.58 The needle action. The hormonal agents used include diethylstilbesterol,
is passed through the glans and fired into the cavernosa, thus antiandrogens, and gonadotropin-releasing hormone agonists.
excising a small length of the two tissues to create a shunt. An While these agents show a variable degree of success, they
alternative to this is the Ebbehoj procedure, in which a similar cause significant side-effects such as loss of libido, gyneco-
shunt is obtained using a sharp triangular scalpel blade.59 mastia, and premature closure of epiphyseal plates in children.
Another, more formal, distal shunt is the El-Ghourab proce- An alternative to hormonal agents is the self-administration
dure, in which, through an incision at the corona, the tips of of injectable alpha-adrenergic agonist drugs. The patient is
the two corpora are excised to create a communication.59 taught the injection technique and is instructed to self-inject
Proximal shunts are more formidable surgical procedures. when a priapism episode begins. This is particularly useful in
The Quakles shunt is a cavernospongiosal shunt in which an children, in whom hormonal manipulation is contraindicated.
anastomosis is created between the cavernosal bodies and the Levine et al. used oral phenylpropanolamine and found that it
spongiosum.60 It is important to place these shunts carefully significantly reduced both the incidence of recurrences as well
so as to avoid urethral injury. Venous drainage may also be as the need for repeated use of injectable phenylephrine
enhanced by creating direct cavernovenous anastomosis. The during the acute episode.62
Grayhack shunt drains the corpora into the saphenous vein Bivalacqua and Burnett describe an interesting therapeutic
while the cavernopenile dorsal vein shunts it to the dorsal vein option for the prevention of recurrent priapism based on their
of the penis. experimental data on the pathogenesis of priapism.63 They
There are no clear data on the efficacy of one shunting pro- believe that constant administration of PDE-5 inhibitors to
cedure over the other. The distal shunts are easier to perform men with an episode of priapism may help to restore the activ-
and should be attempted first before progressing to the proxi- ity of PDE-5 in deficiency of this enzyme. This deficiency
mal shunts. The AUA panel found success rates varying from may have been the primary reason for these men’s predisposi-
66% to 77% for these procedures.50 Common complications tion to priapism, and restoration of normal activity may pre-
of these procedures are ED and urethral injury. ED may result vent recurrent episodes. The authors validated their theory
from the corporal ischemia-induced fibrosis or as a result of while using PDE-5 inhibitors as oral preventive therapy in
excessive shunting if the shunt remains patent for a prolonged four patients with recurrent priapism, refractory to standard
period. Urethral injuries are more likely to occur in the therapy. One patient had hemoglobin SS disease, two had
proximal shunts. hemoglobin SC disease, and one had no major medical
problems. All four used either sildenafil citrate or tadalafil at
varying doses and noted a decreased incidence of recurrent
Sickle cell disease episodes, and all retained their erectile function.64
Patients with underlying sickle cell disease should be hydrated,
alkalinized, and started on oxygen therapy along with local
Management of high-flow priapism
measures for priapism. These are general measures for sickling
crises at any site and help to increase the arterial oxygen satura- The majority of patients with high-flow priapism present with
tion and decrease the tendency of the red blood cells to sickle. a varying degree of delay after the initial trauma. Early presen-
Additional therapeutic options include hyper-transfusion in tation can often be treated with ice compresses, which may
an attempt to increase the hemoglobin concentration and induce a spasm of the ruptured vessel, resulting in spontane-
reduce the levels of hemoglobin S. ous resolution. Occasionally, conservative measures may also
work in patients with a typical, delayed-onset priapism.65
Aspiration and irrigation or use of alpha-adrenergic agonist
Recurrent priapism drugs has no role in achieving detumescence.
Patients with sickle cell hemoglobinopathies may suffer Most patients with delayed-onset, high-flow priapism will
from recurring episodes of priapism. A Jamaican study found not have a spontaneous resolution and require intervention.
426 Textbook of Erectile Dysfunction

Arteriography with selective embolization of the internal Direct surgical exploration with excision or ligation of the
pudendal artery branches may be necessary. This therapy, aneurysm or fistula is a choice of last resort, with a high risk
though minimally invasive, is associated with a risk of arte- of ED.
riogenic impotence. Steers and Selby described injection of
methylene blue followed by embolization as a successful
option for such patients.66 The use of bioabsorbable material, Summary
such as autologous blood clot and gels, may be preferable to
permanent embolization coils as these may result in a higher Priapism represents an acute state. Prompt diagnosis and dif-
incidence of permanent ED.50 In patients where a pseudo- ferentiation between ischemic and non-ischemic priapism is
aneurysm has formed and is visible using a trans-perineal indicated since treatment strategies are different, and ischemic
Doppler probe, a direct puncture of the pseudoaneurysm priapism represents an emergency state. Patients and partners
with injection of embolizing material may also be attempted. should be counseled since long-term sequelae may occur.

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49. Spycher MA, Hauri D. The ultrastructure of the erectile tissue in 2006; 7: 497–502.
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50. Montague DK, Jarow J, Broderick GA, et al. American Urological oral phosphodiesterase 5 inhibitor therapy alleviates recurrent
Association guideline on the management of priapism. J Urol priapism. Urology 2006; 67: 1043–8.
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56 Phosphodiesterase type 5 inhibitor
therapy for priapism
Trinity J Bivalacqua, Biljana Musicki, Hunter C Champion, and
Arthur L Burnett

Introduction in the pathogenesis of priapism and, therefore, mechanism-

based therapies are limited.
Priapism is defined as an erectile disorder in which erection Low-flow (ischemic) priapism is more prevalent than
persists uncontrollably without sexual purpose.1,2 The precise high-flow (non-ischemic) priapism.8 Low-flow priapism is a
mechanisms involved in the development of priapism are condition whereby there is a persistent, painful erection. The
poorly characterized, and therefore medical management of patient often presents late because of embarrassment. Failure
priapism represents a monumental therapeutic challenge to to recognize this as an emergency and instigate immediate
urologists. The disorder is associated with functional and treatment may lead to corporal tissue ischemia or anoxia,
structural pathologic changes at the microscopic and macro- fibrosis, and long-term ED. High-flow priapism commonly
scopic level of the corpora cavernosa that manifest themselves follows an episode of trauma to the perineum or the genitalia
in corporal fibrosis or necrosis and ultimately erectile dys- resulting in increased flow through cavernosal arteries leading
function (ED).3,4 Certain patient populations are more afflicted to the formation of arteriocavernous shunts and resulting
by this disorder, in particular men with sickle cell disease in increased arterial flow into the cavernous tissue.8 Often this
(SCD), in whom the prevalence rate is approximately 30–45% is successfully treated with selective embolization without
and the rate of resultant ED in men with sickle cell disease can long-term sequelae. Treatment modalities for men with recur-
be as high as 59%.5,6 rent ischemic priapism are largely reactive and do not address
Priapism is probably a result of disturbances in the mecha- the underlying pathobiology of the disease state. Therefore,
nisms governing erectile physiology, specifically those relating mechanism-based therapies are warranted.
to regulatory control of penile detumescence and to initiation The overall incidence of priapism ranges from 0.34 to
and maintenance of penile flaccidity. During a single episode 1.5 cases per 100,000 person-years.9,10 These values may actually
of priapism, blood fails to drain from the corporal sinusoids, be higher because the previous studies included only pro-
resulting in prolonged painful erection. The pain associated longed erections that necessitated medical intervention. Addi-
with priapism is perceived to be a consequence of tissue tionally, the estimation of incidence rates of priapism also
ischemia and increased pressure generated within the corporal depends on the population of patients under study. One cate-
bodies. This condition frequently results in erectile failure, gory of patients with a high prevalence of recurrent priapism
and therefore prompt management is indicated. Prolonged is men with SCD. The lifetime probability for the develop-
corporal ischemia lasting more than 24 hours results in vary- ment of clinically significant priapism is as high as 42% in
ing degrees of irreversible penile fibrosis with endothelial men with SCD.5 SCD refers to a spectrum of disorders in
and smooth muscle cell destruction.3,7 Therefore, the natural which a major proportion of hemoglobin arises from a beta-
sequelae of untreated ischemic priapism or recurrent (stutter- globin gene variant, manifested as a substitution of valine for
ing) priapism is global penile fibrosis with significant impair- glutamic acid at position 6 in the beta-globin protein.11 How-
ments in erectile mechanisms resulting in an overall rate of ED ever, patients whose red cells contain almost exclusively
ranging between 30% and 59% in this patient population.5,6 hemoglobin S have remarkably variable clinical courses. This
Conventional treatments are largely reactive and are usually is particularly true for the adult SCD population, in which a
administered after a single episode of priapism has already wide disparity in types of end-organ damage is observed.12
occurred.8 Current therapies offered for this condition are In a selected group of sickle cell patients that suffer from
often administered too late during an episode of priapism and priapism, 29% could not have or maintain normal erections,
also do not always achieve the true objective, which is to suggesting that a large percentage of sickle cell patients with
reduce the occurrences of priapic events and restore normal recurrent priapism suffer from significant ED.5,13 Priapism
erectile function. Few therapies focus on the prevention of secondary to SCD is reported to account for as many as 23%
priapic events in selected patient populations because little of adult cases and 63% of pediatric cases.14
is known about the true pathophysiology of this disorder. Little is known about the pathological processes and genetic
Limited attention has been placed on the mechanisms involved risk factors that contribute to the occurrence of priapism in

428
 Phosphodiesterase type 5 inhibitor therapy for priapism 429

men with SCD, and the precise mechanism of priapism in L-Arginine

patients with SCD remains elusive. Therefore, the identifica-
tion of genetic variables or molecular mechanisms that
nNOS eNOS
pre-condition the sickle cell penile vasculature to respond
abnormally to any degree of an erectogenic stimulus is unclear.
If we are able to identify precise signaling pathways associated NO

with SCD-associated priapism, we may effectively identify and

treat patients at increased risk.
Guanylate cyclase
A more complete understanding of the pathogenesis of
priapism will help to gear new therapeutic modalities that
target disease-specific molecular mechanisms. Current thera- GTP
cGMP PKG
pies are non-preventative and largely reactive in the face of an GMP
acute event. This reflects a clear lack of consensus on the best
treatment of this condition, owing to a limited understanding
Penile
of the causes of this disease state. Ideally, a useful therapy for PDE-5
erection
recurrent priapism should meet objectives of efficacy, safety,
and ease of administration, as well as preservation of normal
sexual function. Therefore, as clinicians we must change the Figure 56.1 The molecular determinants of the nitric oxide
concept of treatment of priapism to develop increasingly (NO) signal transduction pathway involved in normal erection
preventative forms of therapy to supersede reactive manage- physiology. NO is synthesized upon sexual stimulation by the
catalytic actions of neuronal NOS (nNOS) and endothelial NOS
ment. Preventative or possibly corrective strategies for pria-
(eNOS) from its precursor L-arginine. It diffuses locally into
pism should ideally also relate to the pathophysiologic basis corporal smooth muscle cells, whereby it activates guanylate
of the disorder. This can only occur if we have a clear under- cyclase, which then converts 5′-GTP to 3′,5′-cGMP. In turn,
standing about the pathogenic basis of priapism. Recent basic cGMP activates cGMP-specific protein kinase (PKG), which acts
science investigations have focused on determining molecular through downstream effectors to produce erection. Degradation
derangements in the penis that may be involved in the final of cGMP occurs by the catalytic action of phosphodiesterase
consequences of ischemic priapism.15 This chapter reviews (PDE) type 5, after which GTP is reformed.
new discoveries focused on precise molecular mechanisms
involved in low-flow priapism and it presents our initial
experience with the use of phosphodiesterase (PDE) type 5 cyclase, thus elevating intracellular levels of corporal
inhibitors to prevent recurrent priapism. smooth muscle cGMP.19–22 Increases in cGMP activate cGMP-
dependent protein kinases (PKG) to reduce intracellular levels
of calcium and promote smooth muscle relaxation. Prime
Physiology of penile erection regulatory control of penile vasorelaxant actions is exerted by
PDE-5, the predominant PDE expressed in the corpus
The nitric oxide (NO)–cGMP system is recognized as the main cavernosum.19–22
neurovascular functional control system of penile erection Hydrolysis of cGMP into the non-reactive 5′-monophos-
(Figure 56.1).16–18 NO is generated by NO synthase (NOS) phate in the erectile bodies is specifically controlled by PDE-
isoforms, which oxidize the terminal guanidino nitrogen of 5.23,24 PDE-5 is in turn regulated by the amount of cGMP in
L-arginine to form NO and the amino acid L-citrulline. The the cell as well as the actions of PKG and other associated
constitutively activated endothelial NOS (eNOS) and neuronal signal transduction pathways. The binding of cyclic nucleotides
NOS (nNOS) isoforms have been demonstrated to have pro- to non-catalytic sites may alter the activity of the enzyme in a
minent roles for producing physiologically relevant levels of typical allosteric control mechanism. In addition, the enzyme
NO in the penis required for the erectile response.18 eNOS is itself may be phosphorylated though the action of protein
localized to the endothelium of the penile vasculature and sinu- kinases, with presumed changes in its activity state. Steady-state
soids while nNOS is localized to terminal nerve endings of the concentrations of cGMP are maintained by a balance between
autonomic nerves supplying the penis. Although nerve- the synthetic activity of the cyclases and the degradative action
derived NO has been well established in erectile physiology, of the PDEs. The activity of the PDEs appears to be much
endothelium-derived NO has become increasingly recognized higher than that of the cyclases. Thus, slight manipulations of
as exerting a critical role in the process of penile erection. the level of cGMP, either through increases in cyclase activity
Current concepts for the physiology of penile erection hold or decreases in PDE hydrolytic activity, may lead to profound
that psychogenic and neuronal impulses initiate erection changes in cellular function and thus affect normal penile
via nNOS function, whereas blood flow-related mechano- vascular homeostasis.
inductive mechanisms via eNOS facilitate maximal erection.18 The penile vascular endothelium is a source of vasorelaxing
The physiological manner of eNOS activation occurs through factors such as NO and vasoconstrictor factors such as Rho-
calcium-independent phosphorylation of eNOS.18 Upon its kinase. The RhoA–Rho-kinase signal transduction pathway has
release, NO acts within corporal smooth muscle cells to cause been shown to influence erectile function in vivo through an
tissue relaxation by its downstream signal transduction path- array of mechanisms, including phosphorylation of the myosin
way effectors. NO activates the soluble form of guanylate binding subunit of myosin light chain (MLC) phosphatase
430 Textbook of Erectile Dysfunction

RhoA Oxidative stress

Rho-kinase
Nitric oxide
Anoxia Priapism
imbalance
MLC phosphatase-P
(inactive)
PDE-5 dysregulation
MLC MLC-P
MLC kinase Figure 56.3 General overview of the proposed mechanisms
involved in the pathogenesis of priapism. PDE,
phosphodiesterase.
Relaxation Contraction

Figure 56.2 The RhoA–Rho-kinase pathway involved in penile necrosis as well as destruction of the endothelial lining.3 Until
smooth muscle contraction. Activation of G protein coupled recently, there has been little understanding of the precedent
receptors activates RhoA. RhoA-activated Rho-kinase phos- pathogenesis of this disorder as it relates to corporal smooth
phorylates and inhibits myosin light chain phosphatase (MLC muscle biology and biochemical regulation of the erectile
phosphatase-P). Inhibition of MLC phosphatase increases myosin responses in priapism.
light chain phosphorylation (MLC-P), which promotes the actin-
Our laboratory has recently sought to identify a role for
myosin cross bridge cycling rate, resulting in smooth muscle
NO–cGMP as well as for RhoA–Rho-kinase signaling in the
contraction. Dephosphorylation of MLC promotes corporal
smooth muscle relaxation. pathophysiology of priapism.30,31 In the penis, vascular smooth
muscle cells are continuously subjected to the action of basally
released NO from the vascular endothelium or vasoconstrictor
factors such as RhoA–Rho-kinase.25–28 Endothelium-derived
resulting in increased myosin phosphorylation (Figure 56.2).25–27
NO can regulate the vascular tone in the penis by controlling
RhoA, a member of the Ras low-molecular-weight GTP-
the downstream targets of NO (cGMP, PKG, or PDE-5) as
binding proteins, mediates agonist-induced activation of
well as other signaling pathways (RhoA–Rho-kinase). Recently,
Rho-kinase.27 The exchange of GDP for GTP on RhoA and
we have shown that eNOS−/− mutant mice have an exagger-
translocation of RhoA from the cytosol to the membrane are
ated erectile response to cavernous nerve stimulation and
markers of its activation, and enable the downstream stimula-
have phenotypic changes in erectile function consistent with
tion of various effectors such as Rho-kinase, protein kinase N,
priapism.30 In this initial observation, we demonstrated
phosphatidylinositol (PI) 3-kinase, and tyrosine phosphory-
that recurrent priapism is a manifestation of defective PDE-5
lation (Figure 56.2). Numerous studies have established an
regulatory function in the penis, resulting from altered
important role for RhoA and Rho-kinase in cellular responses,
endothelial NO–cGMP signaling in the organ.30 We then
including the contraction of smooth muscle cells, regulation of
showed that chronic endothelial NO deficiency in eNOS−/−
eNOS, and control of penile vascular function.25–28 Rho-kinase
mutant mice also influences other signaling molecules in the
exerts contractile effects in the penis by calcium-independent
penis, in particular the RhoA–Rho-kinase system, which is
promotion of MLC kinase or the attenuation of MLC phos-
known to exert significant contractile effects in the penis.31
phatase activity and by reduction in endothelial-derived NO
Therefore, we have concluded that episodes of priapism are
production (see Figure 56.2).26–28
a direct result of decreased NO bioavailability in the penis,
which downregulates PDE-5 expression or activity. When
PDE-5 is reduced, cGMP accumulates in the corporal
Role of dysregulation of smooth muscle in response to an erectogenic stimulus in
phosphodiesterase type 5 in priapism vivo, rendering the penile vasculature uncontrollably dilated.
During this molecular phenomenon, cGMP is ‘unchecked’,
In principle, ischemic priapism consists of an imbalance and therefore, the corporal bodies are more completely dilated
between vasoconstrictive and vasorelaxatory mechanisms, thus because cGMP is not degraded because of the loss of expres-
predisposing the penis to hypoxia and acidosis (Figure 56.3). sion of PDE-5 (Figure 56.4). Similar findings were shown
In vitro studies have demonstrated that when corporal smooth in vitro using aorta and corpus cavernosum from eNOS−/−
muscle strips and cultured corporal smooth muscle cells are mutant mice, in which electrical field stimulation, acetylcho-
exposed to hypoxic conditions, alpha-adrenergic stimulation line, and sodium nitroprusside caused constant corporal
fails to induce corporal smooth muscle contraction; these data vasodilation.32
suggest that anoxia significantly impairs corporal smooth In priapism contexts, the cyclic nucleotide cGMP is pro-
muscle contractility.7 In an experimental animal model, lipid duced in low steady state amounts under the influence of
peroxidation, an indicator of injury induced by reactive oxygen priapism-related destruction of the vascular endothelium and
species (ROS; oxidative stress), occurs in the penis during and thus reduced endothelial NO activity; this situation thereby
after ischemic priapism (see Figure 56.3).29 To date, the over- downregulates the set point of PDE-5 function (secondary
whelming majority of reports on the pathophysiology of pria- to altered cGMP-dependent feedback control mechanisms).
pism have been directed toward the sequelae of ischemia of The initial events that lead to destruction of the vascular
the penile vascular bed. Chronic anoxia and ischemia of pria- endothelium may be related to long-term intermittent episodes
pism result in severe smooth muscle damage and widespread of ischemia or genetic alterations. Under these conditions,
 Phosphodiesterase type 5 inhibitor therapy for priapism 431

(a)
Endothelium or nitrergic nerve terminal Corporal smooth muscle

Normal GTP
penile
nNOS
erection
L-arginine NO Guanylate PDE-5
eNOS
cyclase

cGMP
(b)

Priapism GTP
nNOS
L-arginine NO Guanylate PDE-5
eNOS
cyclase

cGMP

Figure 56.4 Schematic diagram showing the molecular determinants of the nitric oxide (NO) signal transduction pathway involved
in normal erectile physiology (a; as described in Figure 56.1) and priapism (b). For priapism pathophysiology, because of downregulated
endothelial NO bioactivity (such as eNOS inactivation or elevated reactive oxygen species), PDE-5 is thereby downregulated.
Accordingly, cGMP is not degraded and so accumulates, causing an excessive erectile tissue vasorelaxant response.

when NO is neuronally produced in response to an erecto- Effect of phosphodiesterase

genic stimulus or during sleep-related erectile activity, cGMP
production surges in a manner that leads to excessive erectile type 5 inhibitors on recurrent
tissue relaxation because of basally insufficient functional ischemic priapism
PDE-5 to degrade cGMP (see Figure 56.4). Additionally,
reduced Rho-kinase activity in concert with PDE-5 dysregula- The goals of any form of therapy for recurrent priapism are
tion may contribute to the susceptibility of corporal tissue the prevention of priapic events, safety, and maintenance of
to excessive relaxation via two distinct molecular mechanisms normal sexual function. Medical pharmacotherapy that
(enhanced vasorelaxation by uninhibited cGMP and less accomplishes these objectives for the treatment of recurrent
contractile effects of Rho-kinase) during priapism. We further stuttering priapism has remained elusive. Various purported
validated this hypothesis by demonstrating that transgenic medical therapies, such as baclofen, digoxin, and terbutaline,
sickle cell mice also have significant reductions in penile have drawn interest, mostly because they offer non-invasive
NO–cGMP signaling leading to deficient PDE-5 expression or management options, but in general their mechanisms of
activity, as a result of which they manifest enhanced erectile action are not well established and their clinical efficacies have
responses and recurrent priapism.33 We have further shown not been sufficiently demonstrated.4,8,15 This has been largely
that excessive ROS signaling, particularly superoxide anion, in due to a lack of a clear understanding of the etiologies involved
the penis also contributes to decreased endothelium-derived in priapism. Recent evidence from our laboratory has shown
NO bioactivity and further exacerbates the severe endothelial that eNOS-/-mutant mice and transgenic sickle cell mice have
dysfunction observed in the penile vasculature, with resultant cellular and molecular changes in the NO–cGMP–PDE-5 axis
PDE-5 dysregulation.33 Importantly, if sickle cell mice or in the penis that causes priapism (see Figure 56.3).30,31,33 PDE-5
eNOS-/-mutant mice are treated with the PDE-5 inhibitor dysregulation resulting in excessive corporal vasodilatation
sildenafil, endothelium-derived NO biosynthesis and eNOS represents the key component and the final convergence point
activity increase, with subsequent restoration of PDE-5 that causes aberrant cellular signaling in the penis. Therefore,
enzyme activity to ‘normal’ levels. These precise molecular we have proposed the use of PDE-5 inhibitors as a preventative
alterations lead to reduction in priapic activity in the sickle strategy for this disorder.34,35 Long-term, continuous use of a
cell mouse penis.33 PDE-5 inhibitor in priapism contexts causes PDE-5 to become
Taken together, these data demonstrate that priapism is a upregulated and thus normally expressed and active, which
direct result of NO imbalance resulting in aberrant molecular enables the enzyme to degrade cGMP effectively. Although this
signaling, PDE-5 dysregulation, and reductions in Rho-kinase proposal would immediately seem illogical based on the know-
activity, translating into enhanced corporal smooth muscle ledge that PDE-5 inhibitors exert erectogenic effects, we iden-
relaxation. Moreover, the use of PDE-5 inhibitor therapy to tified a scientific basis for using these agents to treat priapism
restore NO–cGMP signaling and PDE-5 activity in the penis in a manner unassociated with eliciting on-demand, sexually
provide important preclinical evidence that pharmacothe- stimulated responses. When applied according to a long-term
rapy that is targeted at precise molecular mechanisms dosing regimen unassociated with erection stimulatory condi-
involved in priapism and that restores penile vascular homeo- tions, we found that these agents alleviated recurrent priapism
stasis may represent ideal preventative therapy for patients episodes without affecting normal erectile capability.34,35
suffering from ischemic priapism, especially SCD-associated Our initial clinical results demonstrate that chronic daily
priapism. PDE-5 inhibitor therapy significantly reduced the degree and
432 Textbook of Erectile Dysfunction

amount of priapic events in a selected group of patients (with and no significant side-effects have occurred to lead to treat-
SCD-associated stuttering priapism and idiopathic priapism), ment discontinuation.
suggesting that daily PDE-5 inhibitor therapy may be used as Before initiation of any PDE-5 inhibitor pharmacotherapy
a preventative strategy for priapism.34,35 All patients were for the treatment of recurrent priapism, we recommend coun-
confirmed to have recurrent ischemic priapism without iden- seling, consent, and documentation of the treatment plan as
tifiable pharmacologic, traumatic, or neoplastic disease asso- basic procedures in implementing this management program.
ciations based on clinical history, physical examination, It is also suggested that patients be provided with contact
laboratory testing, and penile diagnostics. Patients were information for therapeutic direction or urologic intervention
informed in detail regarding the goals and requirements of the at any time. They should be made aware that the treatment
therapeutic protocol. Of note, patients were informed that may not be effective, and standard interventions for the
nitrate drug use for any indication constitutes an absolute development of any major priapism episode may still be
contraindication. They were further counseled that this treat- required. A precise follow-up schedule is also advocated to
ment should not forfeit alternative interventions for priapism monitor use of the therapy and to ensure safety.
such as hormonal therapies, penile aspiration and irrigation,
penile shunts, or penile prosthesis surgery, which could be
implemented in the event that PDE-5 inhibitor treatment was
unsuccessful. Instructions for use of PDE-5 inhibitors were Perspective
that the medication should be used in the morning a few
Prevention and corrective treatment of recurrent ischemic
hours after awakening from nighttime sleep under conditions
priapism must be addressed with therapies that may avert the
of complete penile flaccidity, and patients were instructed to
natural history of this disease process. Further elucidations of
abstain from any form of sexual activity or excitement within
the molecular changes that occur in priapism are paramount
8 hours of dosing. Instructions were given that if the medica-
to continue with future mechanism-based therapies for pria-
tion is missed on any morning, dosing for that day should be
pism. At this time, defective signaling of the NO–cGMP–
omitted. In our initial series, the treatment approach was
PDE-5 axis has been found to represent a likely major
determined to be the use of the short-acting PDE-5 inhibitor
molecular mechanism underlying priapism. Our scientific
sildenafil citrate in an oral dose of 25mg daily, with options to
investigations support a molecular basis for using PDE-5
increase to 50mg daily to improve efficacy or alternatively to
inhibitor therapy in settings of recurrent ischemic priapism.
switch to tadalafil at an oral dose of 5–10mg three times weekly
Based on our early observations using this therapy, we offer
for convenience.
several caveats. Patients presenting early in the disease course
It should be noted that the treatment effect is not immedi-
(mild-to-moderate priapism, recurrent priapism of less than
ate, such that patients may require cavernous self-injections
4 hours’ duration) should be targeted because they appear to
with the alpha-1-adrenergic agent phenylephrine on an interim
benefit most from this therapy. In our experience, men with
basis or re-treatments of penile decompression via irrigation
severe priapism with evidence of fibrosis and subsequent ED
and sympathomimetic injections under urologic supervision
are unlikely to benefit from PDE-5 inhibitor therapy to curtail
in the emergency room setting as needed. We have also
priapism episodes.
employed anti-androgenic therapy acutely, tapering this form
Multi-center, randomized, double-blind, placebo-controlled
of therapy in combination with PDE-5 inhibitor treatment.
clinical trials are planned to validate this medical intervention
From our preclinical results in the transgenic sickle cell mouse
for priapism and to fully characterize its therapeutic profile in
it takes 2–3 weeks of chronic daily dosing of a PDE-5 inhibitor
this context. These results would provide a critical step in
to upregulate the PDE-5 gene and thus influence normal
introducing an effective, secondary prevention program for
penile vascular homeostasis and so abate priapism (Bivalacqua
patients with recurrent priapism. We are enthusiastic about
et al., unpublished data).
our initial experience and are hopeful that this form of therapy
After initiation of daily PDE-5 inhibitor therapy, most
may help men with recurrent priapism. However, the applica-
patients will see changes in the occurrence of their priapic
tion of PDE-5 inhibitors for the treatment of priapism remains
events after 2 weeks of therapy. In our experience, after 1 month
investigational at present, and more work is needed to esta-
of therapy and titration of dose, if there is no response then
blish optimal parameters (i.e. optimal dose, optimal dosing
most patients may discontinue therapy. However, such goals
schedule) for their use in this context.
as maximizing the dose of sildenafil or tadalafil and concur-
rently ensuring medication compliance should be met before
any conclusion of the success or failure of the therapy can be
ascertained. Conclusion
Additionally, we have found that several patients believed
their recurrent priapism was cured after long-term therapy Early diagnosis and management of priapism are necessary to
with PDE-5 inhibitors, and therefore they stopped treatment. prevent and reverse its final pathological and clinical out-
Some of these patients experienced priapism recurrences and comes. A better understanding of the molecular mechanisms
after PDE-5 inhibitor therapy was re-initiated, their priapic involved in its pathogenesis will undoubtedly offer new
activity once again declined on therapy. Importantly, in our avenues for future medical intervention. The development of
initial series, all men preserved sexual function and the men a mechanism-based therapy based on a better understanding
did not have any enhanced or increased frequency of priapic of the true pathophysiology of this disease has been established
episodes. The medication has been tolerated by all patients, with the use of PDE-5 inhibitors.
 Phosphodiesterase type 5 inhibitor therapy for priapism 433

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9. Kulmala R, Lehtonen T, Tammela TL. Priapism, its incidence and 27. Jin L, Burnett AL. RhoA/Rho-kinase in erectile tissue: mechanisms
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10. Earle CM, Stuckey BGA, Ching HL, et al. The incidence and 28. Linder AE, Webb RC, Mills TM, et al. Rho-kinase and RGS-
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57 Augmentation of phosphodiesterase
type-5 inhibitor response
with testosterone
Antonio Aversa

Introduction treating the symptoms of ED in patients for whom treatment

with T or sildenafil alone has failed.7 Thus, the poor respon-
Erectile dysfunction (ED) is defined as the persistent inability siveness of some older men to PDE-5 inhibitors might be due
to achieve and maintain an erection adequate for satisfactory to a concomitant T deficiency.
sexual performance.1 The aging process in men is accompa- This chapter provides the reader with concepts for under-
nied by a progressive decline in serum testosterone (T) levels2 standing the molecular basis for T physiology in the erectile
and the various illnesses occurring in mid- to late adult life tissues and its relevance to the regulation of the PDE-5 path-
as well as birth cohort differences or environmental effects way. Clinical trials using combination therapy in hypogonadal
may further contribute to reduce circulating T independently and eugonadal men with ED are reported, with particular
of age.3 The use of androgen measurement in the evaluation attention to pros and cons regarding cardiovascular and pros-
of ED has shown that up to 35% of adults presenting with ED tate safety issues. Practical suggestions for the identification of
have reduced or borderline circulating androgen levels.4 the ideal candidate who would benefit from combination
A recent study, the first ever exploring the epidemiology of therapy are also given.
androgen deficiency based on longitudinal observations from
the Massachusetts Male Aging Study, estimated an incidence
of approximately 481,000 new cases per year in US men
40–69 years old.5 This has prompted many physicians to pre-
Role of testosterone in human
scribe T preparations to men suffering from ED even though erectile physiology
a causal relationship between altered levels of androgens and
erectile function has not yet been established. Molecular basis of testosterone regulation of
Overt hypogonadism is defined as inadequate gonadal erectile function
function manifested by deficiencies in gametogenesis or the T, either directly or subsequent to its conversion into 5-alpha-
secretion of gonadal hormones (or both). It may be related to dihydrotestosterone (DHT), exerts important physiological
a primary testicular disorder or pituitary disease, and may actions on muscle, bone, prostate, bone marrow, skin, liver,
occur as a consequence of advancing age (late-onset hypogo- and the central nervous system. In penile tissue, the action of
nadism or testosterone deficiency syndrome), or it may be T is probably mediated via its conversion into 5-alpha-DHT
concomitant with a chronic medical disorder, such as type 2 by the enzyme 5-alpha-reductase. Androgen receptors (ARs)
diabetes and the metabolic syndrome. The majority of experts are present within vascular endothelium and smooth muscle
in the field agree that T levels below 200 ng/dl (7 nmol/l) are cells. Thus, arterial functions may be directly subject to T influ-
abnormal and levels above 400 ng/dl (13 nmol/l) are normal. ence and, most likely, two independent pathways of T-induced
However, a significant proportion of men with androgen levels effects within the vessel wall can be assumed (i.e. genomic and
between 200 ng/dl and 400 ng/dl may show signs of and com- non-genomic).8
plain of symptoms of androgen deficiency (i.e. osteoporosis, The classical pathway of androgen action involves steroid
sexual dysfunction, fatigue, sleep and mood disturbances, binding to the AR, a ligand-activated transcription factor act-
changes in body composition).6 Reduced T levels determine an ing on the genome.9 The genomic action of AR is modulated
imbalance of body mass distribution, decreasing muscle mass by a large variety of co-regulators, which are proteins that
and increasing fat mass, in particular at the abdominal level. fine-tune target gene expression by enhancing (co-activators)
It has been reported that monotherapy with T for the treat- or restraining (co-repressors) transcription.10 Although T cir-
ment of ED may be of limited effectiveness and may be most culates throughout the body, the factors responsible for varia-
promising in young patients with hypogonadism and without tion in tissue androgen sensitivity remain to be further
vascular risk factors for ED. A number of laboratory and clarified. The intensity of expression of the single human AR
human studies have shown that the combination of T and a partly defines androgen sensitivity, but AR is almost ubiqui-
phosphodiesterase (PDE) type 5 inhibitor is more effective in tously expressed to some degree in tissues. Further biological

434
 Augmentation of phosphodiesterase type-5 inhibitor response with testosterone 435

determinants of tissue androgen sensitivity, including the Effects of androgens on protein expression and
functional AR polymorphisms as well as tissue distribution enzymatic activity of phosphodiesterase type 5
and regulation of AR co-regulators, androgen metabolic PDE-5 is the predominant enzyme responsible for cGMP
enzymes, and non-genomic mechanisms, remain to be better hydrolysis in vascular and trabecular smooth muscle. The
defined so that their net integrated effects can be understood activation of PDE-5 terminates NO-induced, cGMP-mediated
more precisely. Androgen sensitivity could be modulated by a smooth muscle relaxation, thus resulting in the restoration of
functional polymorphism of the AR that influences the basal smooth muscle contractility and penile flaccidity. It is
strength of the genomic signal transduced from its interaction known that two alternative promoters regulate transcription
with an androgen as a bound ligand. One such functional AR of three PDE5 isoforms, A1, A2, and A3.14 A clear-cut physi-
polymorphism is the exon 1 triplet trinucleotide gluatamine ological significance for these isoforms has not been demon-
CAG (polyglutamine) whereby the repeated length is inversely strated. Figure 57.1 shows the presence of a consensus sequence
correlated with androgen sensitivity in men with prostate for the androgen receptor in the 5-flanking region of the
cancer.11 human PDE-5A promoter, thus suggesting that androgens
There is now considerable evidence for rapid, non-genomic could regulate PDE-5 expression.15
effects of steroids, including androgens. Non-genomic steroid Morelli et al. have further investigated this regulation,
action is distinguished from genomic effects by demonstrating that in cavernous tissue from male-to-female
trans-sexual people, chronic exposure to estrogens and to the
• rapid onset (seconds to minutes) that is faster than genomic anti-androgen cyproterone acetate significantly reduced
mechanisms; PDE-5 mRNA and protein expression as well as cGMP hydro-
• insensitivity to inhibition of RNA and protein synthesis; lysis.16 These findings are consistent with previous observa-
• inability of steroids to access the nucleus (either covalently tions showing that responsiveness to PDE-5 inhibitors was
linked to impermeable membrane macromolecules or in reduced in hypogonadal rabbits and humans17 and restored
cells lacking a nucleus); and by T administration, further supporting the concept that T is
• inability to be blocked by classical antagonists, owing to necessary for a full PDE-5 inhibitor responsiveness.18–21 Also,
different steroidal specificity from classical cognate nuclear Zhang et al. performed studies in castrated rats in which acute
receptors. or chronic administration of PDE-5 inhibitor was given with
or without androgen supplementation.22 They found that
As for other steroids, non-genomic androgen effects charac- both acute and chronic use of PDE-5 inhibitors was ineffec-
teristically involve the rapid induction of conventional second tive in improving the penile erection response in castrated rats
messenger signal transduction cascades, including increases in and that the erectile response was restored following andro-
cytosolic calcium and activation of protein kinase A, protein gen treatment only. While these observations may appear
kinase C, and mitogen-activated protein kinase (MAPK), counterintuitive to what we have learned about PDE-5 expres-
leading to diverse cellular effects, including smooth muscle sion and activity, they do suggest an important physiological
relaxation, neuromuscular and junctional signal transmission, control mechanism and homeostasis between NO production
and neuronal plasticity.12 Most non-genomic effects involve a and NO signal termination and give a basic rationale for the
membrane receptor, and putative binding sites are described critical role of T not only for NOS activity, but also in modu-
for all major classes of steroids, including androgens. lating PDE-5 activity.
The effects of androgens on penile tissues in experimental
models demonstrated that androgen deprivation induces:

• smooth muscle cell degeneration (apoptosis) and adipose Testosterone monotherapy and
tissue deposition with associated fibrosis of the corpus erectile dysfunction
cavernosum;13
• reduction in the expression of endothelial nitric oxide Clinical studies examining T monotherapy for the treatment
synthesis (eNOS) and neuronal nitric oxide synthase of hypogonadal ED have generally yielded positive results
(nNOS); on both sexual desire and erectile function, although many
• decrease in arterial inflow and increase in venous outflow limitations and pitfalls may be evidenced in each study.23–26
in the corpus cavernosum; In contrast, other authors have demonstrated that T supple-
• enhanced response to mediators of vasoconstriction and mentation may be ineffective for treating hypogonadal ED
smooth muscle contraction such as alpha-adrenergic and may determine decreased vascular reactivity.27 Encouraging
agents; data have come from recent meta-analyses, confirming a
• a decrease of nitric oxide (NO)-mediated smooth muscle positive role for T supplementation in erectile function. Jain
relaxation during sexual stimuli; and et al. demonstrated a 57% efficacy for T replacement therapy
• down-regulation of expression of PDE-5.6 in patients with ED and hypogonadism, ranging from 64%
for primary hypogonadism to 44% for secondary hypogonad-
This last aspect seems to be crucial in determining meta- ism.28 In another meta-analysis by my group, T treatments
bolic and structural imbalance in the corpus cavernosum, in hypogonadal men moderately improved the number of
resulting in venous leakage and ED; this suggests a rationale nocturnal erections, sexual thoughts and motivation, the
for combination therapy with PDE-5 inhibitors plus any number of successful intercourses, scores of erectile function,
T preparation. and the overall satisfaction compared with placebo; whereas
436 Textbook of Erectile Dysfunction

T SMC

HSP
HSP

HSP

HSP
AR

AR
PDE-5A gene
AR ARE A1 A3 A2

Exon 1 Exon 2/21

A1

A3 Three isoforms
PDE-5 protein
A2

Figure 57.1 Schematic representation of the promoter of the phophodiesterase (PDE) type 5A human gene and its regulation by
testosterone (T). Androgen-responsive elements (ARE) are located on human PDE-5A gene. PDE-5A2 isoform is the most abundantly
expressed, while PDE-5A3 is confined to tissues with smooth muscle cell components and its expression is correlated with the
smooth muscle cell content in penile tissue. SMC, smooth muscle cell; AR, androgen receptor; HSP, heat shock proteins (in the
circle, ligand-activated AR and heat-shock protein complex are shown; in the rectangle, dephosphorylated, inactiave HSP form is
shown). Reproduced with permission from Eur Urol 2006; 50: 940–7.41

T had no effect on erectile function in eugonadal men. In this reported that plasma T concentration was related to erection
study, a cut-off T value of 288 ng/dl (10 nmol/l) failed to pre- entity as evaluated by duplex ultrasound scanning of the penis;
dict the effect of treatment. By contrast, the presence of risk in that study, 52 men with ED and no known vascular risk
factors for vasculogenic ED, comorbidities, and short evalua- factors were investigated in a double-blind correlation analysis.
tion periods were associated with greater T effects in hypogo- We noted a direct correlation between corporeal resistive index
nadal but not in eugonadal men. Meta-regression analysis also values and free-T, a relationship that was maintained after
showed that the effects of T on erectile function, but not adjusting for age, sex hormone-binding globulin (SHBG),
libido, were inversely related to baseline T concentration.29 level and estradiol level. We concluded that men with ED and
Given the multifactorial nature of the pathophysiology of low free T may have an impaired relaxation of the penile
ED, it is not expected that T monotherapy will be highly effec- smooth muscle, thus providing clinical evidence for the
tive in the treatment of all patients with ED if baseline cut-off importance of androgen in regulating erectile function.32 In a
values are not chosen correctly. In general, T monotherapy for subsequent study, we performed a prospective, randomized,
the treatment of ED is efficacious in men with hypogonadism placebo-controlled pilot study in 20 men with ED in whom
when it is the sole cause of ED; but is often not efficacious in sildenafil 100 mg treatment failed on six consecutive attempts
men with ED who show signs of hypogonadism and other and had free T levels falling into the lower quartile of the lower
comorbidities such as vascular disease and neuropathy. range.16 One month after treatment with transdermal T
patches and sildenafil on demand, we found significantly
increased scores in the erectile function domain of the Inter-
national Index of Erectile Function (IIEF). These clinical
Combination therapy and observations suggest a critical role for T in human erectile
erectile dysfunction function. More importantly, in all patients there was a strong
direct correlation between resistive index values and free T
Preclinical investigations reported by Traish et al.30 and Zhang levels. Again, this relationship was maintained also when
et al.22 provided convincing evidence that PDE-5 inhibitors adjusted for age, SHBG level, and estradiol level. These results
are ineffective in improving erectile function in androgen- indicate that in men with ED, low free T may correlate inde-
deficient animals and that the re-administration of androgen pendently of age with the impaired relaxation of the cavern-
facilitates PDE-5 inhibitor action. As already outlined, T may ous smooth muscle cells.
directly control the expression and activity of PDE-5 in human These findings were then confirmed by other authors’ clin-
corpus cavernosum.15 Androgen deficiency or hypogonadism ical studies. Shamloul et al. have shown a similar enhanced
reduce the cavernosal expression of PDE-5 mRNA, protein, response to sildenafil after T gel treatment in aging men;18
and enzyme activity, and T supplementation restores PDE-5 also, Greenstein et al. demonstrated that combined treatment
expression and activity,15,31 which represents the substrate for with sildenafil and T gel has a beneficial effect on ED in
the inhibitory action of PDE-5 inhibitors. hypogonadal patients in whom treatment with T supplement
The author was the first to investigate the effect of T on alone failed.33 The corollary has been shown that decreasing T
peripheral erectile mechanisms in a clinical setting. My group levels impair the effectiveness of PDE-5 inhibitor treatment.34
 Augmentation of phosphodiesterase type-5 inhibitor response with testosterone 437

In another randomized, placebo-controlled, double-blind, et al. with an oral T preparation in reversing ED associated
parallel-group, multicenter study, 75 hypogonadal or border- with type 2 diabetes in patients in whom sildenafil therapy
line hypogonadal men (18–80 years old) with confirmed lack alone had failed.17
of response to sildenafil monotherapy and morning serum Other convincing evidence comes from clinical investiga-
total T of 400 ng/dl or less, were randomized to receive a daily tional studies in men with ED and chronic renal insufficiency-
dose of 1% T gel or 5g placebo gel as adjunctive therapy to associated hypogonadism. In these men, intramuscular
sildenafil 100 mg during a 12-week period. T-treated subjects monthly injections of testosterone cypionate combined with
had significant improvement in erectile function compared oral sildenafil 50–100 mg once or twice weekly have been more
with those who received placebo.35 Similar trends were observed successful than T alone, owing to the combined pathogenesis
for improvements in orgasmic function, overall satisfaction, (i.e. vascular and hormonal), and such therapy may be benefi-
total IIEF score, and percentage of IIEF responders. The cial in this group of patients.36 Similar results were reported by
authors concluded that T-gel taken with sildenafil may be Tas et al. in a population of uremic patients unresponsive to
beneficial in improving erectile function in hypogonadal men T or erythropoietin alone.37 They concluded that the combi-
with ED who are unresponsive to sildenafil alone.35 Greenstein nation of erythropoietin plus sildenafil may salvage up to 50%
et al. evaluated the efficacy of T gel alone in hypogonadal ED of patients with ED while T treatment (alone or in combina-
patients with comorbidities, reporting a beneficial effect on tion with erythropoietin) would not be preferred in this
erection in most patients (63%); in the remaining patients, population, owing to the possibility of fluid retention.37
whose condition did not improve satisfactorily with T gel Finally, Yassin et al. investigated the efficacy of tadalafil in
treatment alone, the addition of sildenafil brought normaliza- combination with T gel for the treatment of tadalafil-refrac-
tion in erectile function scores. tory ED in hypogonadal patients.38 They demonstrated that a
Further striking evidence supporting combined therapy combination therapy with T and tadalafil is an effective means
comes from the study by Rosenthal et al., who evaluated in a subset of hypogonadal patients who do not respond to
whether combination therapy with T gel and sildenafil was tadalafil alone in the long-term. T monotherapy effects were
effective in achieving adequate potency in subjects with low- negligible at 4 weeks but became clinically relevant between 4
normal serum T levels.20 Despite the absence of a placebo arm, and 10 weeks of treatment and were similar to those obtained
the study demonstrated that none of the men initially unre- by combination therapy, thus suggesting that T-induced
sponsive to sildenafil alone, was supplemented with T alone, remodeling of penile tissue structure is a process that may
was able to achieve normal erectile function. Successive addi- require a longer period of T administration than 4 weeks. It
tion of sildenafil made most of the men (92%) capable of can be argued that if patients are unresponsive to androgen
penetrating their partners during intercourse. alone or PDE-5 inhibitors alone, a prolonged combined use of
Furthermore, the efficacy of oral T preparations has been both may improve erectile function, especially when ED has a
investigated by Hwang et al. in a series of hypogonadal patients multifactorial pathogenesis (Table 57.1).
unresponsive to sildenafil alone.19 One-third of hypogonadal Despite these clinical studies, the Endocrine Society have
patients with ED who failed to respond to sildenafil responded recently published a position paper in which a panel of experts
to T alone, and another one-third responded to sildenafil again concluded that very low-quality evidence exists in prescribing
after normalization of T. They concluded that in hypogonadal T therapy in older men with unequivocally low T levels for
patients with ED, androgen supplementation represents the treating their ED, while this therapy remains an option in those
first-line therapy. Similar results were obtained by Kalinchenko men with lower T levels to improve libido.39 In the opinion of

Table 57.1 Randomized controlled trials assessing the effects of combined therapy with testosterone plus
phosphodiesterase type 5 inhibitors in men unresponsive to monotherapy for erectile dysfunction
Authors n/hypogonadism PDE-5 inhibitor response at Efficacy/adverse events
baseline
Aversa et al.17 20/No Sildenafil failure 80%/none
Kalinchenko et al. 18
120/Yes Sildenafil failure 70%/none
Shabsigh et al. 35
75/Yes Sildenafil failure 70%/NA
Chatterjee et al.36 12/Yes NA 100%/none
19
Shamloul et al. 40/No Sildenafil failure Improved/none
Greenstein et al.33 49/Yes NA 63%/18% skin irritation
Hwang et al. 20
32/Yes Sildenafil failure 57%/none
Rosenthal et al. 21
24/Yes Sildenafil failure 92%/1% headache
Tas et al.37 23/Yes NA 50%/none
Yassin et al. 38
69/Yes Tadalafil failure 65%/none
Overall patients 428/368 70% failure 50–100%/1–18%
PDE, phosphodiesterase; NA, not applicable
438 Textbook of Erectile Dysfunction

No response
PDE-5 inhibitor failure

Re-challenge PDE-5
inhibitor with daily Re-challenge with
dosing for 1 month highest dosages
Treatment
No response salvage
Two samples 1 week
apart for
Normal Abnormal
total and free
testosterone Evaluate

Prolactinoma Primary or secondary Abnormal

hypogonadism FSH, LH
PRL
High PRL
Normal
Treatment with long-acting
Treatment with testosterone injections Treatment with testosterone gels
dopamine plus PDE-5 inhibitor for 3 months plus PDE-5 inhibitor
agonists

Every 3 months Every 1 month follow-

follow-up: up for 3 months
DRE, RBC, PSA, DRE, RBC, PSA,
hematocrit, estradiol hematocrit, estradiol, DHT

Figure 57.2 Diagnostic algorithm for the management of PDE-5 inhibitor failures in the treatment of ED. PDE, phophodiesterase;
DRE, digital rectal examination; RBC, red blood cell count; PSA, prostate-specific antigen; FSH, follicle stimulating hormone; LH,
luteinizing hormone; DHT, dihydrotestosterone.

the author, when serum T falls into the so-called uncertain clotting and fibrinolysis (plasminogen inhibitors, von
zone (between 8 nmol/l and 13 nmol/l) and comorbidities are Willebrand factor). Endothelial dysfunction can be defined
present in male ED outpatients, PDE-5 inhibitors represent as an abnormal response leading to a reduction in the bio-
first-line therapy for treating ED. However, higher rates of availability of NO and impaired vasodilatation, and it plays a
failure with PDE-5 inhibitors are reported in such cases, so major role in the development of atherosclerosis and acute
that combination therapy may ‘salvage’ up to one-third of coronary syndromes and ED.43 The degeneration of endothelial
patients who would otherwise be candidates for investigative integrity promotes adverse events leading to atherogenesis,44
surgery procedures or penile implants.40 This approach has such as infiltration of the vessel wall by macrophages loaded
proven to be effective and safe in terms of overall satisfaction with oxidized lipoproteins.
and intercourse satisfaction for the patients,41 without any Recent animal and in vitro studies have further documented
long-term side-effects on prostate size and prostate-specific that T up-regulates the expression of arterial AR mRNA and
antigen (PSA) values in the hypogonadal patients.42 However, is associated with an inhibitory effect on neo-intimal plaque
the lack of clinical trials designed to investigate the safety of formation.45 T has a relatively rapid vasorelaxant effect in iso-
this combination therapy in the long term means that this lated rabbit coronary artery and aorta and porcine coronary
option cannot be recommended in large ED populations. artery. Other studies have suggested that T may play a role in
Figure 57.2 shows a proposed diagnostic flowchart for use vascular protection and remodeling responses to vascular
during standard office evaluation of the patient not respond- injury by stimulating endothelial replication and inducing
ing to PDE-5 inhibitors. In the opinion of the author, it is endothelium-dependent vascular relaxation.46 Additionally,
noteworthy that any treatment for ED should be initiated positive acute hemodynamic effects of T on coronary vaso-
with T whenever clinical and biochemical T deficiency symp- motion and stress-test-induced ischemia were reported.47
toms occur, whilst PDE-5 inhibitors are co-administered for Nonetheless, interpretations of the effects of pharmacolog-
immediate relief of the complaint of ED. In all remaining ical doses of androgens on arterial compliance, and flow-
cases, a challenge with PDE-5 inhibitors alone is always mediated dilatation in particular, must also be treated with
recommended. circumspection because, at physiological concentrations, ben-
eficial, neutral, and detrimental effects on vascular reactivity
can be observed.48
Combination therapy and Historically, the link between plasma T levels and increased
improvements in endothelial function risk of coronary artery disease (CAD) has been attributed, at
least in part, to the unfavorable effect of the hormone on lipid
Normal vascular endothelium is essential for the synthesis metabolism and fibrinolysis. CAD represents one of the most
and release of substances affecting vascular tone (NO), cell common and costly atherogenic diseases in the Western world
adhesion (endothelins, interleukins), and the homeostasis of and is more common in men aged 30–50 years than in women
 Augmentation of phosphodiesterase type-5 inhibitor response with testosterone 439

of similar age; an observation that has often suggested harm- therapy. Furthermore, because of its effect on the potentiation
ful effects of androgens on the coronary circulation. Recent of endothelium-dependent cavernosal relaxations, chronic
studies suggest that blood T concentrations are consistently treatment with sildenafil could be of particular benefit in
lower among men with cardiovascular disease and angina49 patients with CAD-related ED, in which cavernosal endothe-
and have demonstrated that T treatment may have beneficial lial dysfunction occurs.59
effects on the coronary vasculature.50 Moreover, the presence
of reduced T levels is associated with increased risk of CAD,
visceral obesity, insulin resistance, low levels of high-density Combination therapy and the prostate
lipoprotein cholesterol (HDL-C), elevated triglycerides, elevated
low-density lipoprotein cholesterol (LDL-C), and impaired plas- Even if T administration is proven to prevent or reverse the
minogen activator inhibitor (PAI) 1 and Lp(a) lipoprotein age-related declines in some functions, there is reason to
hemostasis.51 This is supported by reports that T replacement wonder if it will also exacerbate T-dependent diseases to which
in males with idiopathic hypogonadotrophic hypogonadism is elderly men are particularly prone. Giving T to the aging male
associated with decreased cardiovascular risk and that natural with ED may sometimes cause an exacerbation of benign pro-
androgens may inhibit atherosclerosis in men.52 static hyperplasia (BPH), a T-dependent disease. Symptoms,
The wide use of PDE-5 inhibitors by patients with ED and predominantly urinary outflow obstruction, may worsen. The
CAD yielded a considerable number of independent studies symptom score should be assessed and, if warranted by the
investigating the cardiovascular safety and functional role of symptoms, the urine flow rate and the ultrasound post-void
PDE-5–cGMP–NO pathway in the cardiovascular system. bladder residual urine should be measured.
However, such clinical studies have been conducted only Because prostate cancer is, at least to some degree,
with ‘on-demand’ modality of administration. Recent animal T-dependent, it seems theoretically likely that the risk of pros-
studies provide strong evidence for a direct protective effect of tate cancer is less in hypogonadal men than eugonadal men
chronic PDE-5 inhibitor use against cardiomyocites necrosis and the risk increases to normal, but not above, when T is
and apoptosis through an NO-signaling pathway mecha- replaced. By contrast, it has been reported that prostate cancer
nism.53 Ancillary studies from my group show an influence of may be more aggressive in hypogonadal men, so that a para-
4 weeks of daily PDE-5 inhibitor administration on endothe- doxical protective effect of T administration can be hypothe-
lial function in men with a wide ED etiology.54,55 In these stud- sized in those patients.60 It seems prudent, nonetheless, to
ies, chronic PDE-5 inhibitor administration was able screen hypogonadal men for prostate cancer before beginning
to improve both flow-mediated dilatation and surrogate T replacement and to monitor them for prostate cancer
markers of endothelial function, thus opening a new scenario during treatment, just as one would monitor a eugonadal
for use of this class of drug. These promising results led my man. It has been demonstrated that serum T within the
group to speculate about a possible synergistic effect of the normal range is unrelated to prostate cancer incidence.
combined use of T plus PDE-5 inhibitors in the treatment of Recently, a suggestion that intraprostatic androgen activity
many diseases associated with ED (CAD, diabetes, obesity) in may increase and that serum estrogens may decrease the risk
which hypogonadism plays an important pathophysiological of prostate cancer occurrence has been raised,61 even if the
role. contribution of each one remains unknown. Once T supple-
Endothelial dysfunction is in turn associated with many of mentation in hypogonadal patients is commenced, a PSA
the risk factors for both CAD and ED (e.g. dyslipidemia, heart increase of ≥0.75 ng/ml per year over 2 years represents a bio-
failure, diabetes mellitus, and cigarette smoking). Some of chemical marker for androgen supplementation withdrawal.62
the drugs that have been shown to have a beneficial effect on For this reason, PSA may represent an indirect biochemical
morbidity and mortality in cardiovascular conditions such as marker of androgenic function during replacement therapy
the angiotensin converting enzyme inhibitors in heart failure and should be repeated at least every 3 months. As shown in
and hydroxymethyl-glutaryl co-enzyme A reductase inhibi- Table 57.1, no serious treatment-emergent adverse events
tors in ischemic heart disease, have additionally been shown caused by combination therapy with T plus PDE-5 inhibitors
to improve endothelial function. Furthermore, evidence is in hypogonadal men with ED have been reported at the
becoming available to suggest that measures of endothelial moment.
dysfunction might have value as prognostic factors for Another intriguing matter of debate is represented by the
cardiovascular event rates. recent demonstration of positive immunostaining for NOS
In this view, emerging data are now providing convincing within the bladder and the prostate,63 which has raised the
evidence that PDE-5 inhibitors may be used in a daily fashion hypothesis of possible improvements in lower urinary tract
to reverse endothelial dysfunction in patients with heart fail- symptoms (LUTS) following administration of PDE-5 inhibi-
ure56 and patients with type 2 diabetes.57 A possible concern tors. The role of PDE-5 inhibitors for treating BPH is only
for tachyphylaxis with PDE-5 inhibitors has arisen with the poorly understood; reportedly, various PDE isozymes are
suggestion that daily dosing may salvage poor responders to expressed in the prostate and there are some clues that non-
on-demand sildenafil therapy. Previous work with human specific PDE inhibition can relax human prostate tissue.64 In
cavernous smooth muscle cells in culture led to reports an animal model of bladder outlet obstruction, it has been
that tachyphylaxis could occur following repeated exposure clearly shown that inhibition of PDE-5 leads to reduction
to extremely high concentrations of sildenafil (25mM).58 of the irritative symptoms of BPH in vivo.65 Another pioneer
Behr-Roussel et al. have hypothesized that chronic sildenafil animal study demonstrated that PDE-5 regulates bladder
treatment could help salvage poor responders to sildenafil smooth muscle tone, strongly limiting the NO–cGMP signaling,
440 Textbook of Erectile Dysfunction

and that PDE-5 inhibitors may be a possible therapeutic option respond adequately to first-line treatment with PDE-5 inhibi-
for bladder dysfunction by ameliorating irritative LUTS.66 tors unless T levels are sufficient for intact penile machinery.
Anecdotally some patients cite improvement in LUTS while Clinical trials have shown that T supplementation with newer
using sildenafil. In a clinical study carried out in men with preparations (intramuscular long-acting agents) can rapidly
prostate symptom scores on the International Prostate Symp- increase levels of T and improve sexual function and mood in
tom Score (IPSS) >10, 60% of the men who were using men with hypogonadism.70 Currently there is no basis for
sildenafil twice weekly for their ED also improved IPSS score, large-scale T replacement therapy in older men, unless they
and 35% had at least a 4-point improvement in their score.67 have symptomatic T deficiency. However, identification of
The authors hypothesized that the effect of the medication sub-populations who may benefit from T augmentation of
might have been mediated through bladder neck or prostatic PDE-5 inhibitor responsiveness may be clinically useful in
smooth muscle relaxation. Preliminary reports on the use of order to maximize benefits other than sexual performance
daily tadalafil in men with moderate-to-severe LUTS due itself. The recent finding reporting that T replacement therapy
to BPH have shown that after 6 and 12 weeks of treatment, reduces insulin resistance and improves glycemic control in
a significant improvement of obstructive and irritative hypogonadal men with type 2 diabetes71 is full of clinical extra-
symptoms occurs when compared with placebo.68 If the reduc- sexual implications. Accordingly, improvements in glycemic
tion in prostate symptom scores was related to the improve- control, insulin resistance, cholesterol levels, and visceral adi-
ment in obstructive symptoms, this would be in agreement posity together represent an overall reduction in cardiovascu-
with the anti-proliferative effect of PDE-5 inhibitors on lar risk that has been reported as an addition to benefits
prostate stromal cells.66 deriving from PDE-5 inhibitor daily use also. Altogether, these
Taken together, these results open a new scenario for the data need to be validated in large population-based studies.
patients using combination therapy with T and PDE-5 inhib- Finally, it is mandatory that in the clinical setting, the age-
itors, thus suggesting more benefits on the prostate and blad- related decline of serum T should be confirmed twice, along
der outlet and obstruction symptoms after continuous use, with measurement of SHBG. The bioavailable T (plasma or
even in the presence of mild BPH symptoms at baseline. calculated) is currently not routinely recommended, owing to
the many difficulties of measurement; however, the occur-
rence of free testosterone levels below 0.250 nmol/l may
Conclusion directly determine failure in men with ED in their clinical
response to PDE-5 inhibitors so that its evaluation should
ED is extremely common and it is now well established that it always be performed. For these reasons, I do strongly recom-
can have a significant impact on the quality of life and self- mend measurement of plasma T alterations in all ED patients,
esteem of sufferers. It is often associated with aging and can be in order to verify the possibility of adding T-containing
a symptom of late-onset hypogonadism. Although low T lev- preparations if late-onset hypogonadism is diagnosed, and to
els do not necessarily cause ED and are not frequently reported maximize the effects of oral PDE-5 inhibitors, thus enabling
in ED patients,69 a proportion of men (20–30%) may not successful treating of the sexual dysfunction.

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20. Hwang TS, Chen HE, Tsai TF, Lin YC. Combined use of androgen 15: 99–105.
and sildenafil for hypogonadal patients unresponsive to sildenafil 41. Greco EA, Spera G, Aversa A. Combining testosterone and PDE5
alone. Int J Impot Res 2006; 18: 400–4. inhibitors in erectile dysfunction: basic rationale and clinical
21. Rosenthal BD, May NR, Metro MJ, et al. Adjunctive use of Andro- evidences. Eur Urol 2006; 50: 940–7.
Gel (testosterone gel) with sildenafil to treat erectile dysfunction in 42. El-Sakka AI, Hassoba HM, Elbakry AM, Hassan HA. Prostate spe-
men with acquired androgen deficiency syndrome after failure cific antigen in patients with hypogonadism: effect of testosterone
using sildenafil alone. Urology 2006; 67: 571–4. replacement. J Sex Med 2005; 2: 235–40.
22. Zhang X, Morelli A, Luconi M, et al. Testosterone regulates PDE5 43. Gori T, Sicuro S, Dragoni S, et al. Sildenafil prevents endothelial
expression and in vivo responsiveness to tadalafil in rat corpus dysfunction induced by ischemia and reperfusion via opening of
cavernosum. Eur Urol 2005; 47: 409–16. adenosine triphosphate-sensitive potassium channels: a human in
23. Skakkebaek NE, Bancroft J, Davidson DW, Warner P. Androgen vivo study. Circulation 2005; 111: 742–6.
replacement with oral testosterone undecanoate in hypogonadal 44. Ross R. Atherosclerosis – An inflammatory disease. N Eng J Med
men: a double blind controlled study. Clin Endocrinol (Oxf) 1981; 1999; 340: 115–26.
14: 49–61. 45. Hanke H, Lenz C, Hess B, et al. Effect of testosterone on plaque
24. Bancroft J, Wu FC. Changes in erectile responsiveness during development and androgen receptor expression in the arterial
androgen replacement therapy. Arch Sex Behav 1983; 12: vessel wall. Circulation 2001; 103: 1382–5.
59–66. 46. Chou TM, Sudhir K, Hutchison SJ, et al. Testosterone induces
25. Carani C, Zini D, Baldini A, et al. Effects of androgen treatment in dilatation in canine coronary conductance and resistance arteries
impotent men with normal and low levels of free testosterone. in vivo. Circulation 1996; 94: 2614–19.
Arch Sex Behav 1990; 19: 223–34. 47. Rosano GM, Leonardo F, Pagnotta P, et al. Acute anti-ischemic
26. Boyanov MA, Boneva Z, Christov VG. Testosterone supplementa- effect of testosterone in men with coronary artery disease. Circula-
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androgen deficiency. Aging Male 2003; 6: 1–7. 48. Wu FC, von Eckardstein A. Androgens and coronary artery disease.
27. Zitzmann M, Brune M, Nieschlag E. Vascular reactivity in hypogo- Endocr Rev 2003; 24: 183–217.
nadal men is reduced by androgen substitution. J Clin Endocrinol 49. Rosano GMC, Sheiban I, Massaro R, et al. Low testosterone levels
Metab 2002; 87: 5030–7. are associated with coronary artery disease in male patients with
28. Jain P, Rademaker AW, McVary KT. Testosterone supplementation angina. Int J Impotence Res 2007; 19: 176–82.
for erectile dysfunction: results of a meta-analysis. J Urol 2000; 50. Wynne FL, Khalil RA. Testosterone and coronary vascular tone:
164: 371–5. implications in coronary artery disease. J Endocrinol Invest 2003;
29. Isidori AM, Giannetta E, Gianfrilli D, et al. Effects of testosterone 26: 181–6.
on sexual function in men: results of a meta-analysis. Clin Endo- 51. Elbers JM, Giltay EJ, Teerlink T, et al. Effects of sex steroids
crinol (Oxf) 2005; 63: 381–94. on components of the insulin resistance syndrome in transsexual
30. Traish AM, Munarriz R, O’Connell L, et al. Effects of medical subjects. Clin Endocrinol (Oxf) 2003; 58: 562–71.
or surgical castration on erectile function in an animal model. 52. Tripathy D, Shah P, Lakshmy R , Reddy KS . Effect of testoste-
J Androl 2003; 24: 381–7. rone replacement on whole body glucose utilization and
31. Traish AM, Park K, Dhir V, et al. Effects of castration and androgen other cardiovascular risk factors in male with idiopathic hypo-
replacement on erectile function in a rabbit model. Endocrinology gonadotrophic hypogonadism. Horm Metab Res 1998; 30:
1999; 140: 1861–8. 642–5.
32. Aversa A, Isidori AM, De Martino MU, et al. Androgens and penile 53. Kukreja RC, Salloum F, Das A, et al. Pharmacological precondi-
erection: Evidence for a direct relationship between free testoster- tioning with sildenafil: basic mechanisms and clinical implica-
one and cavernous vasodilation in men with erectile dysfunction. tions. Vascul Pharmacol 2005; 42: 219–32.
Clin Endocrinol (Oxf) 2000; 53: 517–22. 54. Aversa A, Greco EA, Bruzziches R, et al. Relationship between
33. Greenstein A, Mabjeesh NJ, Sofer M, et al. Does sildenafil com- chronic tadalafil administration and improvement of endothelial
bined with testosterone gel improve erectile dysfunction in hypo- function in men with erectile dysfunction: a pilot study. Int J
gonadal men in whom testosterone supplement therapy alone Impot Res 2007; 19: 200–7.
failed? J Urol 2005; 173: 530–2. 55. Aversa A, Bruzziches R, Vitale C, et al. Chronic sildenafil in men
34. Guay AT, Perez JB, Jacobson J, Newton RA. Efficacy and safety with diabetes and erectile dysfunction. Expert Opin Drug Metab
of sildenafil citrate for treatment of erectile dysfunction in a Toxicol 2007; 3: 451–64.
population with associated organic risk factors. J Androl 2001; 22: 56. Zhao TC, Xi L, Chelliah J, et al. Inducible nitric oxide synthase
793–7. mediates delayed myocardial protection induced by activation
35. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H. Random- of adenosine A1 receptors: evidence from gene-knockout mice.
ized study of testosterone gel as adjunctive therapy to sildenafil in Circulation 2000; 102: 902–7.
hypogonadal men with erectile dysfunction who do not respond to 57. Aversa A, Vitale C, Volterrani M, et al. Chronic administration of
sildenafil alone. J Urol 2004; 172: 658–63. sildenafil improves markers of endothelial function in men with
36. Chatterjee R, Wood S, Mc Garrigle HH, et al. A novel therapy with type 2 diabetes. Diabet Med 2008; 25: 37–44.
testosterone and sildenafil for erectile dysfunction in patients on 58. Lin G, Xin ZC, Lue TF, Lin CS. Up and down-regulation of
renal dialysis or after renal transplantation. J Fam Plann Reprod phosphodiesterase-5 as related to tachyphylaxis and priapism.
Health Care 2004; 30: 88–90. J Urol 2003; 170: S15–18.
37. Tas A, Ersoy A, Ersoy C, et al. Efficacy of sildenafil in male 59. Behr-Roussel D, Gornya D, Mevela K, et al. Chronic sildenafil
dialysis patients with erectile dysfunction unresponsive to erythro- improves erectile function and endothelium-dependent caver-
poietin and/or testosterone treatments. Int J Impot Res 2006; 18: nosal relaxations in rats: lack of tachyphylaxis. Eur Urol 2005; 47:
61–8. 87–91.
38. Yassin AA, Saad F, Diede HE. Testosterone and erectile function 60. Algartè-Genin M, Cussenot O, Costa P. Prevention of prostate
in hypogonadal men unresponsive to tadalafil: results from an cancer by androgens: experimental paradox or clinical reality.
open-label uncontrolled study. Andrologia 2006; 38: 61–8. Eur Urol 2004; 46: 285–95.
442 Textbook of Erectile Dysfunction

61. Chen C, Weiss NS, Stanczyk FZ, et al. Endogenous sex hormones 67. Mulhall JP, Guhring P, Parker M, Hopps C. Assessment of
and prostate cancer risk: a case-control study nested within the the impact of sildenafil citrate on lower urinary tract
Carotene and Retinol Efficacy Trial. Cancer Epidemiol Biomarkers symptoms in men with erectile dysfunction. J Sex Med 2006; 3:
Prev 2003; 12: 1410–16. 662–7.
62. Rhoden EL, Morgentaler A. Risks of testosterone-replacement 68. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil
therapy and recommendations for monitoring. N Engl J Med 2004; relieves lower urinary tract symptoms secondary to benign prostatic
350: 482–92. hyperplasia. J Urol 2007; 177: 1401–7.
63. Chertin B, Rolle U, Solari V, Cascio S, Puri P. The role of nitric 69. Buvat J, Lemaire A. Endocrine screening in 1,022 men with erectile
oxide in bladder urothelial injury after bladder outlet obstruction. dysfunction: clinical significance and cost-effective strategy. J Urol
BJU Int 2004; 94: 392–9. 1997; 158: 1764–7.
64. Uckert S, Oelke M, Stief CG, et al. Immunohistochemical distribu- 70. Morales A, Nieschlag E, Schubert M, et al. Clinical experience with
tion of cAMP- and cGMP-phosphodiesterase (PDE) isoenzymes in the new long-acting injectable testosterone undecanoate. Report
the human prostate. Eur Urol 2006; 49: 740–5. on the educational symposium on the occasion of the 5th World
65. Tinel H, Stelte-Ludwig B, Hütter J, Sandner P. Pre-clinical evidence Congress on the Aging Male, 9–12 February 2006, Salzburg, Austria.
for the use of phosphodiesterase-5 inhibitors for treating benign Aging Male 2006; 9: 221–7.
prostatic hyperplasia and lower urinary tract symptoms. BJU Int 71. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone
2006; 98: 1259–63. replacement therapy improves insulin resistance, glycaemic
66. Filippi S, Morelli A, Sandner P, et al. Characterization and func- control, visceral adiposity and hypercholesterolaemia in hypo-
tional role of androgen-dependent PDE5 activity in the bladder. gonadal men with type 2 diabetes. Eur J Endocrinol 2006; 154:
Endocrinology 2007; 148: 1019–29. 899–906.
58 Phosphodiesterase type 5 inhibitors
for the treatment of women’s
sexual dysfunction
Salvatore Caruso, Agnello Carmela, and Lucia Di Mari

Introduction with the complicity of a medical community that was ignorant

of the true female sexual physiopathology.
Female sexual disorder (FSD) has been attracting much atten- Historically the psychological and biomedical approaches
tion over the past few decades, producing new research in were opposed, and sometimes they clashed. The former
epidemiology, pathophysiology, and pharmacotherapy. This affirmed that it would be reductive to treat a woman affected
interest, paradoxically, was stimulated when scientific research by sexual dysfunction pharmacologically; the latter, instead,
defining the efficacy of sildenafil, an inhibitor of phospho- considered women’s problems as a therapeutical opportunity.
diesterase (PDE) type 5, a drug that was experimentally used On the other hand, today, sexual psychotherapists understand
in cardiology, but found ‘by chance and unexpectedly’ to the importance of an integrative approach and try to use
cause side-effects, producing an erection in the test subjects.1 short-term therapy aimed at stimulating behavioral change.6
This raised the question of whether a vascular medication The behavioral divergence in the field of the sexual life
such as a PDE-5 inhibitor could also be efficacious for FSD.2 between men and women seems to be more subtle today. Men
However, there were some difficulties, namely the lack of are now treated with drugs or psychotherapy for certain events
definite diagnostic procedures, the lack of a widely accepted that were once considered as being part of the female world
classification of FSD,3 as well as the anatomical aspects such as only: fear, dyspareunia, hypoactive desire, and even headaches
the biological mechanism of sexual excitement and of orgasm are just some of these problems. As a demonstration of how
that were also not well defined.4 Moreover, it became increas- the somatic component can influence the generation of unease
ingly evident that FSD can have an organic basis occurring or sexual dysfunction, the most recent classifications focus on
secondarily to medical problems, even if risk factors for FSD the concept of stress.7 According to these, a condition of
are both psychological and physiological.5 ‘unease’ is considered a disorder whenever it produces stress
Consequently, FSDs have only recently gained the attention for the woman who suffers from this condition.
of medical research groups, who have begun to categorize it, In current concepts of FSD, there are both biomedical and
defining possible etiologies for the problems and describing physiological factors, among which are reduction in vaginal
potential therapeutic approaches. Clinicians also began to and clitoral blood flow, previous gynecological operations,
consider a possible role for sildenafil in treating female sexual alterations of the pelvic floor caused by childbirth, and dis-
arousal disorder (FSAD). orders secondary to hormonal alterations.8 Magnetic resonance
Sildenafil revolutionized sexology, which had, until the 1990s, imaging has shown that during female sexual arousal changes
generally used only empirical treatment; in fact, the treatment occur in the anterior vaginal wall, through gradual filling of
for erectile dysfunction was often rudimentary and fundamen- the bladder, and involving the clitoris.9 It is accepted that the
tally of the medical–surgical type, while psychotherapeutic clitoris plays a functional role during sexual arousal.10–17 All of
methods were used for female sexual disorders. these aspects make up the biological pathways that could be
The considerations that led to diametrically opposite treated with drugs.
treatment for men and women were based on clinical specula- A better understanding of the structures and substances
tion, more or less scientific, since female sexuality had always involved in normal sexual function, as well as age-related
been defined as more complex than that of males, the latter changes, can help practitioners to evaluate and appropriately
being considered simpler and more essential, based on coital to manage women with FSD proactively. The continued quest
capacity – the quality of the erection – and on the procreative to understand female sexual function and dysfunction requires
capacity – the quality of seminal liquid, two aspects that are more education and research on the treatment of underlying
quantifiable and evident. The ignorance of female pathophy- medical conditions and the use of pharmacologic therapies.18,19
siology produced further difficulties in treatment, because it Sexual arousability largely depends on the sympathetic
was easier to define female sexuality as being more complex and nervous system, and the non-adrenergic/non-cholinergic
less accessible than male sexuality, and thus psychological. (NANC) neurotransmitters [i.e. vasoactive intestinal poly-
The heirs of the Freudian culture managed female sexology peptide (VIP) and nitric oxide (NO)] are involved in smooth

443
444 Textbook of Erectile Dysfunction

muscle relaxation and enhancement of genital blood flow, difficulty in achieving orgasm, decreased vaginal lubrication,
while various hormones may influence female sexual and dyspareunia, also improved significantly.
function.20–22 The major findings of a double-blind, cross-over, placebo-
Today there are no drugs approved for the treatment controlled study in premenopausal women with normal ovula-
of FSD,23 though there have been independent studies and tory cycles and normal levels of steroid hormones, affected by
studies supported by pharmaceutical companies to look at the FSAD but without hypoactive sexual desire disorder (HSDD)
efficacy and safety of drugs that act on peripheral or central were that subjects may benefit from treatment with sildenafil,
sexual pathways. To date, among the known PDE-5 inhi- showing improvements in arousal and, indirectly, in orgasm,
bitors, sildenafil has been the most studied drug to treat and in frequency and enjoyment of sexual intercourse.33 The
FSAD. Thus sildenafil is used here to stand for the category of various hormonal levels could explain the differences in the
PDE-5 inhibitors. results from other studies in postmenopausal women, which
have shown little or no improvement. These negative results
could be due to the low ovarian steroid levels that first need to
Sildenafil and female sexual arousal disorder be treated before beginning sildenafil therapy.
The introduction of sildenafil24 for the treatment of men
affected by erectile dysfunction represented a major advance Postmenopausal studies
in the understanding and management of the neurovascular
Another open-label, non-randomized study in postmeno-
mechanisms of sexual response. In the female corpus caver-
pausal women with sexual dysfunction, based on history,
nousum, the release of NO from the NANC nerves or the
found that, overall, only 18.1% had a significant therapeutic
endothelium activates guanylyl cyclase and increases intra-
response to sildenafil, while clitoral discomfort and hyper-
cellular cGMP levels. cGMP modulates intracellular calcium
sensitivity occurred in 21%.34 Side-effects included headache,
and, in turn, regulates smooth muscle contractility and erectile
dizziness, and dyspepsia. The data suggest that sildenafil is
function.21 PDE-5 plays an important physiological role by
well tolerated in postmenopausal women with sexual dysfunc-
regulating the intracellular levels of cyclic nucleotides.25
tion, but overall sexual function did not improve significantly,
Sildenafil is able to inhibit cGMP hydrolysis by high-affinity
although there were changes in vaginal lubrication and clitoral
selective PDE-5 inhibition in intact cells and in soluble extracts
sensitivity. It should be noted that insufficient vaginal engorge-
of human clitoral corpus cavernosum smooth muscle cells.26
ment and insufficient clitoral erectile function in postmeno-
PDE-5 has also been found in clitoral and vaginal tissue.27,28
pausal women results from organic vasculogenic dysfunction
Clinical trials suggest that sildenafil could be an effective
caused by pathophysiological variations in endogenous
treatment for iatrogenic sexual dysfunction,29,30 on the basis of
hormones, such as low levels of estrogen. An important point
the observations that human clitoral corpus cavernosum
to remember also when treating postmenopausal women
smooth muscle tone may be regulated by synthesis and release
with FSDA is that they also need an adequate testosterone
of NO,31 and that this pathway is dependent on PDE-5 activity.
level to receive benefits from sildenafil treatment.
Researchers in the sexual field have hypothesized that sildenafil
In a randomized trial of sildenafil in postmenopausal
could have beneficial clinical effects on women affected by
women with FSDA who were receiving estrogen but not andro-
sexual arousal disorders.
gen therapy, no significant improvement in sexual arousal was
In a clinical setting, sildenafil was shown to enhance genital
found.35 To assess efficacy, patients completed the global effi-
blood flow and vaginal and clitoral engorgement in women
cacy questions, the Life Satisfaction Checklist, an event log of
affected by FSAD. Several studies have been performed over
sexual activity, and a 31-item sexual function questionnaire.
the past few years, in premenopausal or postmenopausal
To assess safety, adverse event data were recorded. Estro-
women with FSAD, and in healthy women without sexual
genized and estrogen-deficient women were diagnosed with
dysfunction in order to study female sexual pathways, and
FSAD, but it was the primary presenting symptom in only 46%
finally, on subjects with psychotropic-induced sexual dys-
and 50% of the women, respectively. It was concluded that any
function, and on premenopausal women with diabetic-
genital physiological effect of sildenafil was not perceived as
induced FSAD. A closer examination of these studies follows,
improving the sexual response in these women with a broad
and they are summarized in Table 58.1.
spectrum of sexual dysfunction that included FSAD. Estro-
genized postmenopausal women with FSAD and orgasmic
impairment diagnosed only on the basis of clinical assessment
Premenopausal studies did not benefit from sildenafil. However, photoplethysmo-
A pilot study on the effect of sildenafil on subjective and graphy could have a predictive value: those women showing
physiologic parameters of the female sexual response evalu- low vaginal pulse amplitude response benefited from sildenafil
ated its safety and efficacy for use in women with FSAD.32 compared with women with a higher response. Thus, estro-
Physiologic measurements, including genital blood flow, vaginal genized women diagnosed with acquired FSAD may be a hete-
lubrication, intravaginal pressure–volume changes, and genital rogeneous group and the photoplethysmography might be
sensation, were recorded before and after sexual stimulation at useful in their further characterization.36 It is well known that
baseline and following administration of sildenafil 100 mg. hormone replacement therapies usually improve vaginal epi-
Post-stimulation physiologic measurements showed signifi- thelial thickness and engorgement in postmenopausal women,
cant improvements. Subjective complaints of sexual function, but they can also decrease serum androgen levels as a result
including low arousal, low desire, low sexual satisfaction, of a decrease in LH-driven ovarian stromal steroidogenesis,37
 Phosphodiesterase type 5 inhibitors for the treatment of women’s sexual dysfunction 445

Table 58.1 Efficacy of sildenafil in treating women with sexual dysfunction and in healthy women

Authors Problem Number and type of Type of study Measurement Sildenafil Female sexual
patients dosage response

Berman et al.32 FSAD 48 premenopausal Prospective Physiologic 100 mg Improvement

33
Caruso et al. FSAD 51 premenopausal Double-blind, PEQ 25–50 mg Improvement
cross-over,
placebo-controlled
Kaplan et al.34 Sexual 30 postmenopausal Non-randomized, IFSF 50 mg Insufficient
disorders open-label response
Basson et al.35 FSAD 577 estrogenized Randomized, GEQ and 10–100 mg Not effective
and 204 control placebo-controlled SFQ
Postmenopausal
Berman et al.38 FSAD 202 Double-blind, FIEI 25, 50, Improvement
postmenopausal placebo-controlled 100 mg
treated with
estrogen and/or
androgen
Caruso et al.39 Healthy 50 premenopausal Double-blind, PEQ 50 mg Improvement
women cross-over,
placebo-controlled
Laan et al.40 Healthy 12 premenopausal Randomized, Physiologic 50 mg Enhancing vaginal
women placebo-controlled engorgement
Caruso et al.49 Type 1 30 premenopausal Prospective, Clitoral 100 mg Improvement of
diabetic open-label color (single clitoral blood flow
women Doppler dose)
with FSAD sonography
Caruso et al.50 Type 1 31 premenopausal Double-blind, PEQ and 100 mg Improvement of
diabetic cross-over, color sex and clitoral
women placebo-controlled Doppler blood flow
with FSAD sonography
FSAD, female sexual arousal disorder; PEQ, personal experience questionnaire; IFSF, international female sexual function, GEQ, global efficacy
questions; SFG, sexual function questionnaire; FIEI, female intervention efficacy index.

thus, sexual arousal in these woman, and other aspects of study were that sildenafil can improve general sexual behavior.
female androgen-dependent sexuality, are unlikely to be The benefits that the sildenafil group felt were mainly in the
improved by treatment with sildenafil. vagina and clitoris, confirming the peripheral genital target
Sildenafil efficacy in postmenopausal women with FSAD of PDE-5 inhibitors. This study thus showed that both the
who either had normal estradiol and free testosterone concen- qualitative (arousal, satisfaction and orgasm) and quantita-
trations or were receiving estrogen or androgen replacement tive (multiple orgasm) aspects of sexuality are significantly
therapy (or both) was studied in a double-blind, placebo- improved with respect to the pre-test baseline values. The
controlled trial.38 Women with FSAD without HSDD had a majority of the adverse events associated with the use of silde-
significantly greater improvement in sexual arousal, orgasm, nafil were related to vasodilatation (such as headache), to gas-
intercourse satisfaction, and overall satisfaction with their trointestinal events (with nausea), or to minor visual effects.
sexual life during sildenafil intake compared with those taking Each of these adverse events reflects the well-known pharma-
placebo, while no efficacy was shown for women with cological properties of sildenafil, and they usually increase in
concomitant HSDD. incidence with increasing drug dose. The study suggested that
sildenafil acts on different sexual pathways in healthy women,
improving their sexual experience; when sildenafil was given
Efficacy studies in healthy women to these healthy women having a normal vasodilatory function,
To determine changes in female sexual pathways caused by the PDE-5 inhibitor increased this activity.
sildenafil, and to verify the safety of the drug, a randomized, Sildenafil was also found to be effective in enhancing vaginal
double-blind cross-over, placebo-controlled study was con- engorgement during erotic stimulus conditions in healthy
ducted in premenopausal women asymptomatic for sexual women without sexual dysfunction but it was not associated
disorders, with normal ovulatory cycles and with normal with an effect on subjective sexual arousal.40 Women without
steroid levels.39 Sildenafil improved arousal, orgasm, and sexual dysfunction were randomly assigned to receive either
enjoyment compared with placebo. The major findings of the sildenafil or placebo. Subjective measurements of sexual
446 Textbook of Erectile Dysfunction

arousal were assessed after participants had been exposed index, peak systolic velocity, and end-diastolic velocity of
to erotic stimuli. Vaginal vasocongestion was recorded the clitoral arteries 1 hour and 4 hours after sildenafil adminis-
continuously during baseline, neutral, and erotic stimuli. tration. One hour after the drug intake, the mean resistance
At the end of each session, subjects were also asked to spec- index was significantly lower and the mean pulsatility index,
ify which treatment they suspected they had received. Signi- mean peak systolic velocity, and mean end-diastolic velocity
ficant increases in vaginal vasocongestion were found with of the clitoral arteries were significantly greater compared
sildenafil treatment compared with placebo. There were no with both the baseline readings and the readings 4 hours
differences between treatments on subjective sexual arousal after sildenafil. These homodynamic changes observed sono-
experience. Analyses by ‘suspected treatment received’ found graphically showed that sildenafil is able to improve the
that significantly stronger sexual arousal and vaginal wetness clitoral blood flow of premenopausal women with type 1
were reported for the treatment that was believed to be diabetes.
sildenafil. The results obtained from this study led to a second pro-
spective study, which had a double-blind, cross-over, placebo-
controlled design.50 Thirty-two premenopausal type 1 diabetic
Women with psychotropic-induced sexual dysfunction women affected by FSAD participated in the study. Efficacy
Women reported significant improvements in all domains of was assessed subjectively to quantify arousal, desire, orgasm,
sexual functioning and in overall sexual satisfaction after enjoyment of sexual activities, and frequency of sexual relation-
sildenafil treatment.41 Significant improvements were reported ships; and objectively by translabial color Doppler ultrasound
regardless of psychotropic medication type. However, patients to measure the changes in clitoral arteries. Flowmetric values
taking selective serotonin reuptake inhibitors reported less of the clitoral arteries were significantly higher compared
improvement in arousal, libido, and overall sexual satisfaction with baseline and placebo.
than did other patients, whereas patients taking benzodia-
zepines reported significantly more improvement in libido
and overall sexual satisfaction.41 Conclusion
Patients who had normal premorbid sexual function and
who had developed sexual dysfunction, particularly anor- FSD is a combination of problems with both biological and
gasmia, with or without other sexual disturbances (i.e. loss psychological components. It is multifactorial in etiology and
of libido, lubrication difficulties, uncomfortable or painful includes couple problems and behavioral, and sociocultural
intercourse) while being effectively treated with an anti- aspects.
depressant or mood stabilizer were treated with sildenafil.29 Sildenafil seems to be more effective in premenopausal
The subjects showed improvement in the presenting condition, women with FSAD than in postmenopausal women. This
usually depression, anxiety, or both. Patients took sildenafil could be explained by the important role played by sexual
and reported a complete or very significant reversal of their steroids in genital trophism. In fact, the best response to
sexual dysfunction. This included return of effective duration sildenafil was in women affected by genital arousal dysfunction.
and intensity of adequate arousal, lubrication, and orgasmic From these studies, it can be seen that women with other
function.29 sexual dysfunctions, such as HSDD, do not benefit from
sildenafil. Consequently, defining specific subgroups of women
is the first step in treating this dysfunction.
Diabetic women with seasonal affective disorder From the studies that have been carried out using PDE-5
The sexual function of women with diabetes has received little inhibitors, it can be seen that these drugs are potentially useful
attention in clinical research even though diabetes has recently in treating women with FSAD. We are at the beginning of a
been shown to increase the risk of female sexual dysfunction.42–46 new era in treating FSD, and the development of new drugs in
Changes in sexual genital pathways, such as diminished this field can only improve the situation.
clitoral sensation, vaginal dryness, vaginal discomfort, orgasmic There are currently potential therapeutic options for the
dysfunction, and dyspareunia, might be the mechanisms that treatment of FSD, including both hormonal and non-hormonal
cause damage to the vascular and autonomic nervous systems,47 pharmacological therapies. However, sex therapists are dis-
as well as causing alterations in the production and efficacy of covering that integrating adjunctive use of drugs with sex
NO.48 The most commonly reported sexual problem in women therapy can accelerate the therapeutic process and improve
with diabetes is genital arousal disorder.45 To date, only two outcome. As new pharmaceuticals are developed and approved
studies have been performed with diabetic women affected by for women, opportunities for medical and non-medical sex
FSAD, using sildenafil, the results of which are reported therapies will increase.51 To date, the results of the studies on
below. women affected by sexual dysfunction who received drug
A study was performed to verify whether sildenafil was treatments are still discordant, and this could be a result of the
effective in modifying clitoral blood flow in premenopausal multifactorial aspects of female sexual dysfunction.52 Specific
diabetic women.49 Thirty women affected by type 1 diabetes subgroups obviously need to be diagnosed for the treatment
treated with insulin therapy participated in a prospective of female dysfunctions.53 Finally, we are beginning to consider
open-label clinical study. Each woman received a single oral sexual dysfunction treatment in an integrative setting, rather
dose of sildenafil 100 mg. Translabial color Doppler ultrasono- than symptomatic therapy, so that more recent drugs, such as
graphy was used to measure the resistance index, pulsatility PDE-5 inhibitors, may be useful.
 Phosphodiesterase type 5 inhibitors for the treatment of women’s sexual dysfunction 447

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3. Leiblum SR. Definition and classification of female sexual dis- 191–5.
orders. Int J Impot Res 1998; 10 Suppl 2: S104. 29. Nurnberg HG, Lauriello J, Hensley PL, et al. Sildenafil for sexual
4. Pfaus JG. Neurobiology of sexual behaviour. Curr Opin Neurobiol dysfunction in women taking antidepressants. Am J Psychiatry
1999; 9: 751–8. 1999; 156: 1664.
5. Davis AR. Recent advances in female sexual dysfunction. Curr 30. Rosenberg KP. Sildenafil. J Sex Marital Ther 1999; 25: 271–9.
Psychiatry Rep 2000; 2: 211–14. 31. Burnett AL, Calvin DC, Silver RI, Peppas DS, Docimo SG.
6. Balint M, Ornstein PH, Balint E. Focal Psychotherapy: An Example Immunohistochemical description of nitric oxide syntheses isoforms
of Applied Psychoanalysis. London: Tavistock Publications, 1972. in human clitoris. J Urol 1997; 158: 75–8.
7. Basson R, Berman J, Burnett A, et al. Report of the international 32. Berman JR, Berman LA, Lin H, et al. Effect of sildenafil on subjec-
consensus development conference on female sexual dysfunction: tive and physiologic parameters of the female sexual response in
definitions and classification. J Urol 2000; 163: 888–93. women with sexual arousal disorder. J Sex Marital Ther 2001; 27:
8. Goldstein I. Female sexualarousal disorder: new insights. Int J 411–20.
Impot Res 2000; 12: S152–7. 33. Caruso S, Intelisano G, Lupo L, Agnello C. Premenopausal women
9. Schulz WW, van Andel P, Sabelis I, Mooyaart E. Magnetic reso- affected by sexual arousal disorder treated with sildenafil: a double-
nance imaging of male and female genitals during coitus and blind, crossover, placebo-controlled study. Br J Obstet Gynaecol
female sexual arousal. BMJ 1999; 319: 1596–600. 2001; 108: 623–8.
10. Sadeghi-Nejad H, Moreland RB, Traish AM, et al. Preliminary 34. Kaplan SA, Reis RB, Kohn IJ, et al. Safety and efficacy of sildenafil
report on the development and characterization of rabbit clitoral in postmenopausal women with sexual dysfunction. Urology 1999;
smooth muscle cell culture. Int J Impot Res 1998; 10: 165–9. 53: 481–6.
11. Levin RJ. The physiology of sexual function in women. Clin Obstet 35. Basson R, McInnes R, Smith MD, Hodgson G, Koppiker N. Efficacy
Gynaecol 1980; 7: 213–52. and safety of sildenafil citrate in women with sexual dysfunction
12. Park K, Goldstein I, Andry C, et al. Vasculogenic female sexual associated with female sexual arousal disorder. J Womens Health
dysfunction: the hemodynamic basis for vaginal engorgement Gend Based Med 2002; 11: 367–77.
insufficiency and clitoral erectile insufficiency. Int J Impot Res 36. Basson R, Brotto LA. Sexual psychophysiology and effects of
1997; 9: 27–37. sildenafil citrate in oestrogenised women with acquired genital
13. Goldstein I, Berman JR. Vasculogenic female sexual dysfunction: arousal disorder and impaired orgasm: a randomised controlled
vaginal engorgement and clitoral erectile insufficiency syndromes. trial. BJOG 2003; 110: 1014–24.
Int J Impot Res 1998; 10(Suppl 2): S84–90. 37. Casson PR, Elkind-Hirsch KE, Buster JE, et al. Effect of postmeno-
14. Van Turnhout AA, Hage JJ, van Diest PJ. The female corpus pausal oestrogen replacement on circulating androgen. Obstet
spongiosum revisited. Acta Obstet Gynecol Scand 1995; 74: Gynecol 1997; 90: 995–8.
767–71. 38. Berman JR, Berman LA, Toler SM, Gill J, Haughie S. Safety and
15. Baskin S, Erol A, Li YW, et al. Anatomical studies of the human efficacy of sildenafil citrate for the treatment of female sexual
clitoris. J Urol 1999; 162: 1015–20. arousal disorder: a double-blind, placebo controlled study. J Urol
16. Ingelman-Sundberg A. The anterior vaginal wall as an organ for 2003; 170: 2333–8.
the transmission of active forces to the urethra and the clitoris. 39. Caruso S, Intelisano G, Farina M, Di Mari L, Agnello C. The function
Int Urogynecol J Pelvic Floor Dysfunct 1997; 8: 50–1. of sildenafil on female sexual pathways: a double-blind, cross-
17. Toesca A, Stolfi VM, Cocchia D. Immunohistochemical study of over, placebo-controlled study. Eur J Obstet Gynecol 2003; 110:
the corpora cavernosa of the human clitoris. J Anat 1996; 188: 201–6.
513–20. 40. Laan E, van Lunsen RH, Everaerd W, et al. The enhancement
18. Bancroft J. The medicalization of female sexual dysfunction: the of vaginal vasocongestion by sildenafil in healthy premeno-
need for caution. Arch Sex Behav 2002; 31: 451–5. pausal women. J Womens Health Gend Based Med 2002; 11:
19. Walton B, Thorton T. Female sexual dysfunction. Curr Womens 357–65.
Health Rep 2003; 3: 319–26. 41. Salerian AJ, Deibler WE, Vittone BJ, et al. Sildenafil for psychotropic-
20. Argiolas A. Neuropeptides and sexual behaviour. Neurosci Biobehav induced sexual dysfunction in 31 women and 61 men. J Sex
Rev 1999; 23: 1127–42. Marital Ther 2000; 26: 133–40.
21. Hauser-Kronberger C, Cheung A, Hacker GW, et al. Peptidergic 42. Park K, Ahn K, Chang JS, et al. Diabetes induced alteration of
innervation of the human clitoris. Peptides 1999; 20: 539–43. clitoral haemodynamics and structure in the rabbit. J Urol 2002;
22. Marthol H, Hilz MJ. Female sexual dysfunction: a systemic over- 168: 1269–72.
view of classification, pathophysiology, diagnosis and treatment. 43. Boulton AJ, Selam JL, Sweeney M, et al. Sildenafil citrate for the
Fortschr Neurol Pshychiatr 2004; 72: 121–35. treatment of erectile dysfunction in men with type II diabetes
23. Furcroy JL. Female sexual dysfunction: potential for pharmaco- mellitus. Diabetologia 2001; 44: 1296–301.
therapy. Drugs 2003; 63: 1–12. 44. Koch P, and Young E. Diabetes and female sexuality: a review of
24. Boolell M, Gepi-Attee S, Gingell JC, Allen MJ. Sildenafil, a novel literature. Health Care Women Int 1988; 9: 251–62.
effective oral therapy for male erectile dysfunction. Br J Urol 1996; 45. Enzlin P, Mathieu C, Vanderschueren D, et al. Diabetes mellitus
78: 257–61. and female sexuality: a review of 25 years’ research. Diabet Med
25. Moreland RB, Goldstein I, Traish A. Sildenafil, a novel inhibitor of 1988; 15: 809–15.
phosphodiesterase type 5 in human corpus cavernosum smooth 46. Buvat J, Lemaire A. Sexuality of the diabetic woman. Diabetes
muscle cells. Life Sci 1998; 62: 309–18. Metab 2001; 27: S67–75.
26. Park K, Moreland RB, Goldstein I, Atala A, Traish A. Sildenafil 47. Erol B, Tefekli AS, Ozbey I, et al. Sexual dysfunction in type II
inhibits phosphodiesterase type 5 in human clitoral corpus caver- diabetic female: a comparative study. J Sex Marital Ther 2002;
nousum smooth muscle. Biochem Biophys Res Commun 1998; 28(Suppl 1): 55–62.
249: 612–17. 48. Min K, O’Connell L, Munarriz R, et al. Experimental model for the
27. Traish A, Moreland RB, Huang YH, et al. Development of human investigation of female sexual function and dysfunction. Int J Impot
and rabbit vaginal smooth muscle cell cultures: effects of vasoactive Res 2001; 13: 151–6.
448 Textbook of Erectile Dysfunction

49. Caruso S, Rugolo S, Mirabella D, et al. Changes in clitoral 51. Perelman MA. The impact of the new sexual pharmaceuticals on
blood flow in premenopausal women affected by type 1 diabetes sex therapy. Curr Psychiatry Rep 2001; 3: 195–201.
after a single 100 mg administration of sildenafil. Urology 2006; 52. Basson R. The complexities of female sexual arousal disorder:
68: 161–5. potential role of pharmacotherapy. World J Urol 2002; 20:
50. Caruso S, Rugolo S, Agnello C, et al. Sildenafil improves sexual 119–26.
functioning in premenopausal women with type 1 diabetes who 53. Mayer M, Stief CG, Truss MC, Uckert S. Phosphodiesterase
are affected by sexual arousal disorder: a double-blind, crossover, inhibitors in female sexual dysfunction. World J Urol 2005; 23:
placebo-controlled pilot study. Fertil Steril 2006; 85: 1496–501. 393–7.
59 Erectile dysfunction and diabetes
Suks Minhas, Ian Eardley, and Michael G Kirby

Introduction Historically, it was considered that diabetes led to gonadal

dysfunction with associated endocrine abnormalities, and that
Diabetes mellitus is the single most common cause of erectile this contributed to the pathophysiology of the condition.
dysfunction (ED) seen in clinical practice, with up to 28% of Murray showed that testosterone levels were lower in men
men attending an ED clinic presenting with diabetes.1 The with diabetes and he also showed that testosterone therapy
association between diabetes and ED was first documented by improved the ED, but only in those men who did not have
Rollo in 1798 and, although some of the mechanisms by which severe vascular disease.8 The Rancho Bernado Study followed
diabetes leads to ED remain unclear, a number of factors up 985 men and reported on 110 of the men who also had
appear to be involved, of which vascular and neuronal factors diabetes. The incidence of hypogonadism in these men
are probably the most important. with diabetes was 21%, whereas the incidence in the general
population was 13%.9 A further study reported a prevalence of
secondary hypogonadism of 33%, in a cohort of men with
Epidemiology type 2 diabetes.10
Currently, attention is increasingly being focused on the
Around 50% of men with diabetes have ED.2–4 In most, the role of the vascular endothelium and the control of smooth
problem develops during the course of the disease but, in a muscle tone within the penis. There is increasing evidence
small proportion, it may be the presenting feature. Indeed, in that diabetes leads to abnormal endothelial and smooth mus-
one study of 497 men who had been referred for assessment cle function throughout the body and that, in the penis, this
of their ED, 11.1% were found to suffer from undiagnosed can lead to ED.
diabetes mellitus while a further 4.2% had impaired glucose
tolerance.1 Performing a fasting glucose is the most reliable
way to detect asymptomatic diabetes. Animal models of erectile dysfunction and diabetes
Although there is some evidence that patients with diet-
There are a number of models of diabetic ED,11,12 but only
controlled diabetes are less likely to develop ED,4 most reports
four have been used to any extent in the study of diabetic ED.
suggest that there is no difference in incidence between those
First, diabetes may be induced by the intravenous or intra-
who are treated with oral hypoglycemics and those who
peritoneal injection of streptozotocin so that diabetes develops
require insulin. In those men who do develop ED, the onset is
within 8–14 weeks. In studying diabetic impotence, the strep-
associated with increasing age,4–7 the duration of the diabetes,4,6
tozotocin has usually been administered to rats, with indica-
and the development of other complications, of which
tors such as weight loss, glycosuria, and an increase in the
microangiopathy and neuropathy are the most important.5–7
serum blood sugar confirming the developement of diabetes.
The most usual clinical indicator of microangiopathy used in
Similarly, diabetes may also be induced (usually in rabbits) by
these studies was retinopathy, while symptomatic autonomic
the intravenous injection of alloxan. Two rat models in which
neuropathy was found to be more closely associated with the
the rat is genetically predisposed to develop diabetes (the BB
development of ED than was peripheral sensory neuropathy.
rat, which is insulin-dependent, and the BBZ rat, which
It has also been suggested that the likelihood of developing
is insulin-independent) have also been used to study ED in
ED is directly related to the degree of glycemic control;6,7 for
diabetes.
instance, one study demonstrated a definite association
Although animal models are an imperfect means of under-
between ED and the level of the glycosylated hemoglobin.7
standing any human disease, for the purpose of studying the
Other factors that appear to increase the risk of ED in diabetic
physiology and pharmacology of erection and the pathophys-
subjects include alcohol intake7 and the use of antihyperten-
iology of a condition such as diabetic impotence, they are
sive medication.6
invaluable. Corporal tissue from both potent men and from
diabetic men (both potent and impotent) is often difficult to
obtain and the models outlined above at least provide tissue
Pathophysiology for study in the laboratory. However, there are a number of
problems: for instance, some of the animals have uncontrolled
The roles of neuropathy and vasculopathy in the etiology and untreated hyperglycemia, which does not directly relate
of diabetic ED are well recognized and are discussed below. to the human situation, in which treatment with insulin or

449
450 Textbook of Erectile Dysfunction

with oral hypoglycemic agents is usual. Secondly, clinical dia- In clinical studies, a number of groups have investigated
betes is a chronic condition and the animal models are largely neurophysiological changes in patients with diabetes. The
acute diabetic models. It is unclear exactly what effect the most usual measure has been the latency of the bulbocaverno-
duration of the hyperglycemia has on the results obtained in sus reflex (BCR), whereby a response is measured electrically
experimental studies. Finally, the animal models described in a muscle of the pelvic floor such as the striated urethral
above are all different, and it is not clear what their relation- sphincter or the bulbocavernosus muscle itself, following elec-
ship is with each other, let alone what their relationship is trical stimulation of the dorsum of the penis or occasionally of
with human physiology and pathophysiology. the bladder neck. The reflex is known to be polysynaptic, with
Despite these disadvantages, animal models continue to be both somatic afferents (when the dorsal nerve of the penis is
integral to the investigation of diabetic ED, and in the future stimulated) and efferents (the pudendal nerve). Using this
it will be vital that both the similarities and the differences technique, abnormal BCR latencies have been demonstrated
between the different animal models are identified, together in up to 50% of patients.24–28 However, when taken as a group,
with the relevance of the animal models to the human some studies have shown no difference from control values29
situation. and most have concluded that the BCR has little role in the
diagnosis of neuropathic ED in men with diabetes.26,29
The fundamental problem with the BCR (and other tests of
Neurogenic factors the sacral reflex latency) is that it measures conduction in
There is considerable evidence to suggest that the develop- large myelinated fibers, whereas the autonomic neuropathy of
ment of neuropathy in men with diabetes might have a role diabetes primarily affects the small unmyelinated nerves and
in the subsequent development of ED. The neuropathy seen affects the larger fibers only relatively late in the disease.
in diabetes initially affects small unmyelinated fibers, and Accordingly, there will always be a proportion of men with
this, in turn, can lead to functional abnormalities in a number diabetic autonomic neuropathy who will have normal BCR
of organ systems: for instance, there may be postural hypo- latencies. This means that the BCR has little diagnostic accu-
tension and disorders of the gastrointestinal tract, while racy in this respect and, indeed, is a marker only of relatively
peripherally there may be disordered thermal sensation and severe neuropathy.
abnormalities of sweating. In the later stages of the disease, A number of approaches have been tried to resolve this
larger myelinated fibers are also affected, with the longest fibers problem. One variation of the BCR is to stimulate the vesico-
usually being affected first. This produces the classical ‘glove- urethral junction with a catheter-mounted stimulating elec-
and-stocking’ distribution of the peripheral neuropathy. trode. This approach stimulates small unmyelinated afferent
Morphological evidence from both human tissue and from nerves, and an electrical response can be recorded in the pelvic
diabetic animal models has usually demonstrated changes in floor. Using this technique it was found that 66% of men with
innervation. In diabetic rats, a reduction in the size of the diabetes and ED exhibited abnormal responses and, as a
myelinated nerve fibers, together with accumulation of glyco- group, there was a significant difference from control values.30
gen in axons and lipid droplets in Schwann cells, has been Other groups have tested for thermal threshold (which assesses
demonstrated in the dorsal nerve, although no changes were small unmyelinated cutaneous nerve fibers) either on penile
noted within the cavernous nerve.13 Human studies have pro- skin31 or on the sole of the foot,24 and both have been claimed
vided conflicting evidence: whereas both light microscopy to be a much more sensitive indicator of neuropathic ED in
and electron microscopy have demonstrated changes in the men with diabetes. Finally, the use of corpus cavernosum
nerves of the corpus cavernosum in some groups,14–16 these electromyography, if it really does record cavernosal smooth
changes have not been demonstrated in other groups.17 muscle activity, may also provide evidence about neuropathy
At a cellular level, the bulk of the evidence, both in humans and diabetic ED.27,32
and in animal models, seems to suggest depletion of neu-
rotransmitters. Early qualitative studies in both humans and
rats demonstrated both reduced vasoactive intestinal poly- Vascular factors
peptide (VIP) and reduced acetylcholinesterase immuno- The penis is a vascular organ. Increased arterial inflow and
reactivity.18,19 Later studies have usually demonstrated reduced relaxation of the smooth muscle lining the sinusoidal spaces is
VIP and nitric oxide synthase (NOS) immunoreactivity, both fundamental to the process of penile erection. Factors that
in experimental animals and in humans,20,21 although two impede blood flow into the penile helicine vessels and sinusoi-
reports in the streptozotocin rat have appeared to contradict dal spaces will lead to ED. Diabetes mellitus is associated both
these findings.22,23 These differences may simply reflect the dif- with atherosclerosis in large arteries (which appears more fre-
ferent tissues being used and, in particular, the duration of the quently and at an earlier age than in non-diabetics) and with
diabetes. However, it is interesting that, although the levels of a microangiopathy, characterized by increased thickening of
VIP were increased in the penis and major pelvic ganglia of the capillary basement membrane.
the diabetic rat, intracavernous injection of VIP induced erec- Arteriography has demonstrated that stenosis of the inter-
tions in control rats but not in diabetic rats, suggesting an nal pudendal artery is more common in impotent than in
abnormality at the receptor level.22 A reduction in norepi- potent diabetics,33 and duplex ultrasound scanning of the
nephrine levels in both animal and human erectile tissue has penile arteries has shown that, in impotent men, diabetes is
also been demonstrated,17,18 suggesting that any neuropathy associated with a smaller penile artery diameter and lower
may affect sympathetic as well as the parasympathetic nerve peak flow velocities following injection of an intracorporal
fibers. vasoactive agent.31,34,35 Morphological studies of diabetic tissue
 Erectile dysfunction and diabetes 451

have demonstrated ultrastructural changes within small penile have demonstrated an augmentation of the contractile
vessels, including endothelial proliferation, subintimal fibro- response to adrenergic agonists and a reduced relaxation
sis, and endarteritis obliterans.36,37 Recently, endothelial injury, response to nitric oxide upon exposure to hyperglycemia.53,54
as well as morphological changes in the smooth muscle cells, Initial studies in rabbit corporal tissue have provided similar
have been documented in diabetic rabbits,38 while, in the same findings, and it may be that some of these effects are due to an
animal model, a direct correlation between smooth muscle increased production of constrictor prostanoids.55
fibrosis and the degree of hyperglycemia has been demon- Oxygen free radicals (such as the superoxide anion) have a
strated.39 The fibrosis was thought to be consistent with a role in producing impaired cavernosal relaxation. It is known
vascular lesion. that free radicals are able to inactivate nitric oxide and regu-
Clinical studies have clearly demonstrated a close correla- late smooth muscle tone in some tissues56 and it has been pro-
tion between diabetic ED and other manifestations of diabetic posed that, in diabetes, increased auto-oxidation of glucose
vascular disease – namely, retinopathy, intermittent claudica- results in overproduction of free radical species, which in turn
tion, and the risk of amputation.4,6,7 leads to smooth muscle dysfunction.57,58
Diabetes is also associated with other conditions that can Interestingly, the impaired endothelium-dependent relax-
cause vascular problems. For instance, there is an increased ation seen in diabetic vascular tissues is reversed by the addi-
risk of both hypercholesterolemia and hypercoagulability.40,41 tion of superoxide dismutase, which is able to inactivate the
Hypercholesterolemia is a risk factor for impotence in its own superoxide anion.58 The polyol pathway is also involved in the
right and also leads to an increased risk of atherosclerosis.42 At pathogenesis of hyperglycemia-induced changes of vascular
a cellular level it can lead to increased contractility and endothelial and smooth muscle function.54,59,60 In hyperglyce-
impaired endothelium-dependent relaxation of the cavern- mia, induction of the enzyme aldose reductase leads to an
osal smooth muscle, both of which have been demonstrated increased production of sorbitol, which in turn causes an
in animal models of hypercholesterolemia.43,44 The hyperco- increased consumption of NAD(P)H, which is an essential
agulability associated with diabetes is secondary to an increase cofactor in the production of nitric oxide. Although it has
in coagulation factors such as factor IX (von Willebrand been proved that this is important in the diabetic rat aorta, as
factor) and tissue plasminogen activator, which in turn can yet it has not been confirmed in penile erectile tissue from
lead to subsequent vessel thrombosis and reduced vascular either experimental animals or humans.
inflow. Advanced glycosylation end-products (AGEs) have an
The recognition of ED as a warning sign of silent vascular important pathophysiological role in the complications of
disease has led to the concept that a man with ED and no diabetes mellitus. AGEs are compounds that are formed as a
cardiac symptoms is a cardiac (or vascular) patient until result of non-enzymatic reaction between glucose and the
proven otherwise.45 amino groups of long-lived tissue proteins such as collagen.59,61
They are found to occur in increasing amounts not only in
association with diabetes but also with aging. Amongst their
Endothelial and smooth muscle factors various pathological effects has been demonstrated an ability
The endothelium lining the lacunar spaces is important in to bind (or ‘quench’) nitric oxide, at least in animal models
controlling corporal smooth muscle tone. Nitric oxide, con- including corpus cavernosum.62,63 AGEs have now been dem-
strictor prostanoids, and endothelins are all produced by the onstrated in both human corpus cavernosum and tunica
endothelium46–48 and act directly on the smooth muscle cell. albuginea and, as noted above, have been found to increase
In diabetes, impaired neurogenic and endothelium-dependent with age.64
smooth muscle relaxation in response to acetylcholine has However, a simple reduction in mediators of smooth mus-
been demonstrated in both animal and human studies of cle relaxation, as would be produced by any of the above
penile erection.49,50 In one diabetic rat model there was reduced explanations, may provide only part of the story. Certainly,
soluble nitric oxide synthase (NOS) activity in the penis one group of investigators65 has demonstrated an increase in
together with reduced neuronal NOS.20 endothelin-1 binding in the diabetic rabbit penis and has sug-
In another human study there was reduced NOS immuno- gested that this may represent a possible pathophysiological
reactivity within the nerves of the penis affected by diabetes.21 mechanism of the ED seen in diabetes. Others have demon-
However, increased NOS activity has been demonstrated in strated an increased sensitivity of human diabetic smooth
the corpus cavernosum of another diabetic rat model,23 muscle cells to alpha-adrenergic agonists,66,67 and it may be
whereas increased numbers of NOS-binding sites have been that, in diabetes, there is heightened contractility as well as
demonstrated in this rat model.51 With evidence that NOS is decreased relaxation of the corporal smooth muscle. It also
impaired in the penis of the diabetic rabbit,52 the situation is seems clear that the vascular and sinusoidal endothelium has
most confused. a central role in the modulation of this process.
It seems that diabetes may lead to depletion of the neuronal An extensive review of the literature has shown that ele-
NOS with other effects upon the endothelial NOS, but why is vated blood sugar may cause regional hemodynamic changes,
both neuronal and endothelial-dependent relaxation of the particularly endothelial-dependent relaxation.68 Protein kinase
cavernosal smooth muscle impaired? There are a number of C becomes activated and nitric oxide is inactivated by the gen-
possible explanations for this and, as is often the case, several eration of oxygen radicals, which cause injury to the endothe-
of them may ultimately prove to be important. It has been lial cells. This has been studied in patients with poorly
suggested that a simple rise in the blood sugar may mediate controlled diabetes, and those patients whose glycosylated
these changes. Certainly, in vitro experiments in other tissues hemoglobin levels decreased from 10.2% to 8.2% noted a
452 Textbook of Erectile Dysfunction

non-significant improvement over the short term in endothe- their ED.75–77 In the majority of cases these were secondary
lial activation and fibrinolysis.69 to the organic problems but in a significant proportion the
Free radicals can be produced when endothelial function is psychogenic factors were the most important.76
abnormal and it has been shown that hypoglycemia induces
significant levels of free oxygen radicals.70 Poor control of dia-
betes leads to glycosylated hemoglobin-generated superoxide Summary
anions, which decrease the production and bioavailability of In most patients with diabetic ED there will be a number of
endothelial and neuronal nitric oxide.71 pathophysiological mechanisms at work and the relative
importance of these factors will vary between patients. Whereas
neuropathy, endocrinopathy, and atherosclerosis are undoubt-
Endocrine factors edly important in a proportion, it is becoming increasingly
Both erectile function and sexual physiology are reliant upon evident that endothelial and smooth muscle function is disor-
a normal endocrine milieu that is provided by a normally dered in diabetes and that this may be the most important
functioning pituitary, hypothalamus, adrenal gland and testis. factor for the majority of men.
An early study suggested both that hypogonadism was com-
mon in diabetes and that treatment with testosterone was
effective.72 A number of studies have demonstrated that dia-
betes may be associated with diminished levels of serum Management of erectile dysfunction
testosterone as well as impairment in testicular function. For in patients with diabetes
instance, it was shown that there were decreased serum free
testosterone levels in men with diabetes and primary organic Clinical features
ED compared with both normal men and diabetic men with The clinical assessment of men with diabetes ED is similar
primary psychogenic ED.67 This study also demonstrated to the assessment of other men with ED. Although ED is
increased urinary excretion of luteinizing hormone (LH), occasionally the presenting symptom of undiagnosed diabetes,1
although the serum LH level was similar in all groups. Those in the majority the diabetes has already been diagnosed. It is
authors also reported improved sexual function, both subjec- important not to miss other potentially important etiological
tively and as assessed by nocturnal penile tumescence (NPT) factors, some of which may be associated with diabetes.
studies following therapy with parenteral testosterone. Finally, For instance, if the patient is also hypertensive it is possible
studies in diabetic rats demonstrated both a reduced serum that the antihypertensive medication may be contributing to
testosterone20,72 and a reduction in size of androgen-sensitive the ED.
accessory reproductive organs.72 Clinical experience confirms that certain antihypertensive
Treatment of the low levels of testosterone that are often drugs not only affect the blood pressure but also the compli-
discovered in patients with diabetes may correct many of the ance of the erectile tissue, resulting in a functional venous
symptoms of androgen deficiency and may improve ED. This, leak. This may impair erectile function as much as the arterio-
however, will depend on how many other comorbidities are sclerotic changes of the vascular system secondary to hyper-
present, especially in terms of vascular disease. A study involv- tension.78 Fogari et al. compared the effect of antihypertensive
ing the treatment of hypogonadism in men with diabetes treatment with valsartan versus carvedilol on sexual activity in
using testosterone undecanoate 120mg daily for 3 months 120 hypertensive men in a randomized, crossover study.79
showed that androgen replacement had a positive effect on Erectile dysfunction was spontaneously complained of by
visceral obesity, body weight, waist–hip ratio, and body fat. In 15 patients in the carvedilol group and only 1 patient in the
addition to this, there was improved metabolic control and a valsartan group.
fall in glycosylated hemoglobin from 10.4% to 8.6%, and there The angiotensin receptor blocking drugs are the drug of
was a reversal in the symptoms of androgen deficiency, includ- choice in hypertensive patients suffering from ED. In 1998 the
ing an improvement in erectile function.73 advent of the phosphodiesterase (PDE) type 5 inhibitors revo-
Sildenafil has been found to be more effective in diabetic lutionized the treatment of ED, especially in men suffering
men when the diabetes is well controlled. In a study of men from diabetes. The PDE-5 inhibitors reduced the breakdown
with diabetes there was a 64% success rate when their levels of of cGMP to GMP, which prolongs vasodilatation. cGMP is
glycosylated hemoglobin were less than 9% and a 44% success produced from nitric oxide, which in turn is produced from
rate when the levels were greater than 9%. Additionally, neu- the endothelium and also from the non-A–non-C nerve fibers.
ropathy in men with diabetes but with good glucose control In patients with diabetes, the production of nitric oxide by the
also reduced the success rate to 50%.74 non-A–non-C fibers will be decreased, because they have dia-
betic neuropathy. No head-to-head studies of PDE-5 inhibi-
tors have been done in a diabetic population.80
Psychogenic factors Although the physical examination often contributes very
Although the majority of men with diabetes will probably little to patient management, it does provide an opportunity
have primarily an organic component to their ED, a number to identify other diabetic complications and to form an opin-
may have additional psychological factors. In fact, in a number ion about whether there are prominent vascular or neurologi-
of studies, some of which have used NPT to identify organic cal components to the development of ED. For instance,
ED, up to 30% of diabetic men with ED have been found to diabetic retinopathy appears to correlate directly with the pres-
have significant psychogenic problems that contributed to ence of ED,4,6,7 while evidence of peripheral vascular disease
 Erectile dysfunction and diabetes 453

with loss of peripheral pulses and intermittent claudication a small proportion of men there is no response, even at
suggests significant large-vessel disease. The neurological maximal doses.
examination may identify a peripheral sensory neuropathy, It can be argued that patients with diabetes are likely to
which typically has a glove-and-stocking distribution and comply better with injection therapy than many other patient
which initially affects the small unmyelinated fibers that medi- groups: first, they are often young men who are well moti-
ate vibration. Finally, there may be postural hypotension, vated; second, a significant proportion will already be self-
indicative of an autonomic neuropathy. injecting with insulin. However, it also seems that patients
The quality of diabetic control should be assessed, by with diabetes are less likely to respond to injection therapy.
performing a random blood sugar and a glycosylated hemo- In one study, using PGE-1 as monotherapy, only 52% of
globin test, particularly since the quality of the diabetic control diabetic men responded successfully to injection therapy,85
seems to be a significant risk factor in the development of dia- and in another study, using papaverine monotherapy, only
betic ED.6,7 Blood lipids and blood pressure should also be 61% of men responded.76 Finally, in a third study, using a
reviewed. Given the possible increased risk of hypogonadism, papaverine–phentolamine combination, 21 of 33 diabetic
serum testosterone should be checked, together with thyroid patients with ED failed to get a satisfactory response.86 Interest-
function. ingly, there was no difference in neurological, vascular, or
drug-related risk factors between those patients who responded
and those who did not. There was, however, a correlation with
Treatment the age of the patient, in that younger men tended to respond
The PDE-5 inhibitors are first-line therapy and more effica- better to injection therapy.
cious when diabetic control is good.74 Vardenafil has been Complications of injection therapy in diabetic patients are
studied in patients with diabetes, including those with neu- similar to those seen in the general ED population. However,
ropathy (sildenafil failures were excluded). Sixty-four percent there is potentially an increased risk of infection and occa-
of the men were able to penetrate their partners and 54% to sional rare cases of sepsis have been reported in patients with
complete intercourse, versus 36% and 23%, respectively, for diabetes following injection therapy.87 In addition, it has
the placebo group.81 recently been reported that pain at the site of injection may be
Tadalfil has also been studied in men with diabetes and ED. more problematic in these patients and particularly in those
Patients had mainly moderate to severe ED, but did include who use high doses of PGE-1.88
men with neuropathy and retinopathy.82 The drug was less For patients who have pain with PGE-1 injection, a combi-
efficacious than in non-diabetic patients. There was a percent- nation of vasoactive intestinal peptide and phentolamine can
age improvement over baseline, with the ability to penetrate be tried.89 An alprostadil preparation using transurethral
increasing – 22.6% vs 4% for placebo. The results for tadalafil application with a small single-use applicator was introduced
in patients with diabetes have been pooled, giving a total of in 1994 and marketed as MUSE (Medicated Urethral System
637 men with diabetes. The results were compared with those for Erection).90 This product is preferred by some patients
of 1681 men without diabetes.83 The baseline from the Inter- to the injection therapy, but the typical side-effects limit its
national Index of Erectile Function (IIEF) scores in the erectile usefulness. These include urethral pain in 25–43% of patients
function domain confirmed that men with diabetes had and occasionally urethral bleeding (in 5%).91
more severe ED (12.6 vs 15); however, the diabetic men who
received tadalafil had a mean improvement in the IIEF score
of 7.4 compared with 0.9 for those men in the placebo group. Vacuum erection devices
The baseline IIEF scores correlated inversely with the control Vacuum erection devices are the other main form of treat-
of diabetes as measured by glycosylated hemoglobin. There ment for diabetic men with ED, and a number of studies have
have also been good results with sildenafil versus placebo confirmed their efficacy in such men. Prior to the use of oral
in men with diabetes. As with all PDE-5 inhibitors, the agents, one study reported that, when given the choice, 44 of
results are not quite as good as in the pivotal trials in a general 54 men chose vacuum therapy over injection therapy and that
population.84 75% of them were able to achieve a satisfactory erection after
Because this is a difficult group to treat, other therapies for 2 months.92 Another group suggested that vacuum erection
ED may be required, including intraurethral alprostadil, devices might provide an effective alternative in the significant
penile self-injection therapy, vacuum constriction devices, proportion of diabetic men who fail to respond to intracorpo-
and, as a last resort, penile prosthesis. ral injections.93

Intracorporal injection therapy Other treatments

Many diabetic men will respond to intracorporal injection Androgen deficiency has a role in the pathogenesis of ED in
therapy. The standard primary agent is prostaglandin E-1 patients with diabetes, and while some studies have shown
(PGE-1), although papaverine is also effective in many men. moderate efficacy for testosterone in the treatment of these
In men with prominent neuropathy, relatively small doses of patients,67,72 others have not.94 However, it is obviously impor-
both agents are effective, whereas in men with severe vascular tant to diagnose and to treat any remediable endocrinological
disease large doses may be needed and, indeed, combination causes for the ED, particularly in the young diabetic patient.
therapy may be required. PGE-1 can usefully be combined In a number of patients, psychological factors will be impor-
with either papaverine or phentolamine, or both, although in tant. One group reported the value of initial psychosexual
454 Textbook of Erectile Dysfunction

assessment: in 52% of their patients, significant psychosexual adherence to a meticulous preoperative, intra-operative
factors were identified and, of 24 men with diabetes who and postoperative regime. When they used this protocol on
then went on to receive psychosexual therapy, 60% were a group of 62 patients, there was only one infected prosthesis,
successfully treated.76 and in the 13 diabetic patients there were no infections
at all.99
A much larger series has reviewed the results of 1337
Vascular surgery implants and has reported no increased risk of prosthesis
infection in diabetic patients compared with the general pop-
Patients with diabetes often have co-existing arteriosclerotic ulation.100 Prosthesis revision surgery was reported, although
disease and, in some cases, this may be the primary factor in this did not reach statistical significance. The difference
the pathogenesis of the ED. In a few cases, either aorto–iliac between the older results and the more recent reports may
reconstruction or angioplasty may theoretically improve simply reflect more meticulous preoperative preparation, bet-
the penile circulation; however, this is rarely indicated or ter antibiotic prophylaxis, and improved surgical technique.
effective. Similarly, reconstructive microvascular surgery is However, when infections do occur in patients with diabe-
also often unsuccessful, even in the hands of enthusiasts. The tes the consequences can be severe. An early report described
current consensus is that, in patients with arteriosclerotic three cases of gangrene of the penis following implantation of
disease, arterial–arterial anastomosis is not indicated. Dorsal a prosthesis in patients with insulin-dependent diabetes; in
vein arterialization has been shown to be effective in a propor- two of the patients, penile amputation was required.101 As to
tion.95 The obvious problem with patients with diabetes is the reasons behind this apparent increased risk of peripros-
that, even if any reconstructive procedure is technically thetic infection, there is controversy as to whether poor con-
successful, effective erections may not be possible because of trol of the diabetes is important. Data suggest that preoperative
co-existing neuropathy or endothelial dysfunction. glycosylated hemoglobin levels in excess of 11.5% predispose
to periprosthetic infections,102 whereas another prospective
study showed no correlation between the glycosylated hemo-
Penile prostheses globin and the risk of prosthesis infection: indeed, there were
If all other treatments have failed or have proved unaccept- no infected prostheses in the group of patients with poorly
able, the final therapeutic option remaining is a penile pros- controlled diabetes.103
thesis. The different types of implant, the selection criteria for
surgical implantation and the techniques of surgery have all
been outlined elsewhere in this volume and apply equally Conclusion
to patients with diabetes. However, where the use of implants
in these patients does differ from that in other patient groups The etiology of ED in diabetes mellitus is multifactorial, with
is in the septic complications of surgery. Most importantly, neurovascular and endothelial factors playing a prominent
it appears that diabetic patients are probably more prone than role. There has been much research into the underlying
the general population to infection of the prosthesis. Certainly, pathophysiology and there is still much to learn. Patients with
a number of early studies all suggested an increased risk of diabetes will continue to present with ED in increasing num-
infection in diabetic patients.96–98 A British group confirmed bers owing to the rising prevalence of obesity in our commu-
this increased infective risk in a group of patients operated nities. Therefore, we need clear strategies to deal with the
upon between 1985 and 1990. Interestingly, however, they were problem and reduce the stress and anxiety that accompanies
able to reduce the risk of prosthesis infection significantly by the disease.

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75. Bancroft J, Malone N. The clinical assessment of erectile 97. Wilson SK, Wahman GE, Lange JL. Eleven years experience with
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60 Chronic renal failure and
sexual dysfunction
Culley C Carson III and Aaron C Lentz

Introduction frequency of intercourse correlated with NPT findings in this

group of patients. Interestingly, the incidence of depression
Erectile dysfunction (ED) is defined as the persistent inability common in uremic patients did not correlate with NPT find-
to attain or maintain penile erection sufficient for sexual ings or frequency of intercourse. Thus, this study strongly
intercourse. In men with chronic renal failure (CRF), quality suggests an organic or physiological cause for ED in uremic
of life is significantly impacted by ED.1,2 The etiology is often patients on hemodialysis.
multifactorial. Uremia, medications, associated comorbid con-
ditions, physiologic changes with dialysis, and the causative
pathophysiology leading to the patient’s CRF should all be Chronic renal failure and causes
considered prior to initiating treatment (Table 60.1). Regardless
of the primary cause, ED can have a negative impact on self- of erectile dysfunction
esteem, quality of life, and interpersonal relationships.
As a result of the multisystem disease processes present in many
uremic men, it is apparent that the pathogenesis of impotence
is most probably multifaceted. Uremic men complain of loss
Incidence of erectile dysfunction in of libido, loss of potency, inadequate or lost ejaculation, and
chronic renal failure decreased penile sensation. Alterations in venous and arterial
flow patterns, altered smooth muscle tone, hormonal aber-
Abnormalities in male sexual function and reproductive rations, neurogenic abnormalities, and structural damage sec-
function have been widely reported in patients with CRF. ondary to infection, trauma, or associated diseases should all
Studies in which patients and spouses were inteviewed or be considered in the initial evaluation of physiologic causes of
evaluated by questionnaire have demonstrated impotence in ED. In addition, chronic fatigue, depression, and psychosocial
20–60% of patients surveyed.3–8 Masters and Johnson reported stress may result from chronic, indolent illnesses that can con-
that the incidence of ED in normal men under the age of tribute as psychological components of ED (Figure 60.2).14
50 years was less than 5%.9 The Massachusetts Male Aging
Study reported that 5% of men at age 40 years have complete
ED; and this rises to 50% among men aged 70.10 Rodger et al.
reported on 100 uremic men with a significantly higher preva- Erectile dysfunction and
lence.3 In a more recent study, Rosas et al. found that 82% of physiologic changes
patients on hemodialysis had ED.11 ED was much more preva-
lent in the dialysis patients older than 50 years (63% in those The physiologic processes that contribute to erectile problems
younger than 50 compared with 90% in those older than 50). in patients with CRF include vascular insufficiency and venous
Using nocturnal penile tumescence (NPT) monitors, Karacan imcompetence, neurologic compromise, endocrine abnor-
et al. observed that rapid eye movement (REM) sleep was malities, diminished oxygen delivery, pharmacologic manipu-
associated with penile tumescence.12 These studies proved that lations, psychological disturbances, and associated chronic
organic disturbances or pharmacological alteration of phy- diseases (such as hypertension, diabetes mellitus, anemia, and
siology correlated with altered NPT and impotence. If psycho- electrolyte abnormalities). Often, multiple physiologic abnor-
logical factors predominate, the NPT results should not be malities contribute to the patient’s ED.
affected. Karacan et al. reported that 50% of patients on
hemodialysis had abnormal NPT. Thus, it appears the
increased incidence of ED in CRF is not due simply to psycho- Vascular insufficiency
genic causes. Procci et al. combined questionnaires and NPT Nitric oxide is released by sexual stimulation. The role of
monitoring to evaluate further the incidence of ED in uremic nitric oxide in erectile function has been well defined, and
males (Figure 60.1).13 Procci et al.’s results demonstrated it works to relax smooth muscle and dilate the arterioles, thus
a significant abnormality in NPT recordings in 50% of increasing blood flow. Blood trapped in the expanding sinusoids
uremic patients on hemodialysis. Questionnaires quantifying compresses the venous system, increasing the pressure within

457
458 Textbook of Erectile Dysfunction

Table 60.1 Causes of erectile dysfunction in men

with chronic renal failure 200

Anatomic
Trauma
Pelvic surgery

NPT (> 13 mm change in circumference), min

Renal transplant
Vasculitits 150
Penile surgery
Arteriovenous malformations
Vascular
Arterial compromise
Veno-occlusive dysfunction
100
Neurologic
Autonomic innervation
Somatic innervation
Physiological
Endocrine
Abnormal testosterone metabolism and excretion 50
Stimulation of pituitary function
Elevated prolactin
Elevated parathyroid hormone
Diabetes mellitus
Neurogenic
Autonomic dysfunction 0
Supratentorial lesions (tumor, Alzheimer’s disease, Normal Chronic Uremia
Parkinson’s disease, trauma) illness dialysis
Infratentorial lesions (suprasacral or sacral)
Peripheral somatic nervous system deterioration Figure 60.1 Nocturnal penile tumescence (NPT) in normal
Vascular subjects, patients with chronic illness and normal renal function,
Arterial blood flow obstruction those with advanced renal failure, and dialysis patients. The
Venous occlusive incompetence vertical bars represent the mean +/− SEM. Reproduced with
permission from Kidney Int 1981; 19: 317–23.13
Other
Pharmacologic causes
Hypoxia
Comorbid disease states (hypertension, diabetes,
smoking, anemia, Paget’s disease, Dupuytren’s
contracture, liver failure) 100
Pelvic radiation
Peyronie’s disease 90
Psychosocial concerns
80

70

the cavernosal bodies to approximately 100mmHg. Contrac-

Frequency (%)

60
tion of the ischiocavernosus muscle further raises pressure in
the penis, leading to a rigid erection. 50
It is well known that patients with uremia or on chronic
40
hemodialysis have accelerated atherosclerosis associated with
both large-vessel and small-vessel occlusive disease. Vasculo- 30
genic ED from occlusion of large vessels and their arterial
tributaries is a result of the acceleration of atherosclerosis. 20
Therefore, vasculogenic ED occurs even in younger men with 10
CRF. Kaufman et al. reported that 78% of impotent CRF
patients had significant occlusive disease of the cavernosal 0
–7.5 –4.5 –1.5 +1.5 +4.5 +7.5
artery.15 The multifactorial nature of vascular insufficiency
Time from start of dialysis (months)
in uremic patients makes specific treatment difficult. Diabetes
mellitus, smoking, hypertension, hyperlipidemia, and multi- Figure 60.2 Quality of sexual performance (very good, good,
ple medications are all factors producing arterial insufficiency poor, very poor) relative to the start of dialysis in 26 uremic
in these patients. Since many dialysis patients require continu- patients during an 18-month follow-up. Reproduced with
ous antihypertensive therapy, hypertension and its treatment permission from Contrib Nephrol 1990; 77: 34–44.2
 Chronic renal failure and sexual dysfunction 459

medications can be strongly suspected as contributing to hemodialysis, have a significant incidence of psychiatric and
arterial ED. Since as many as 15% of uremic patients are depressive illness compared with the normal population.7
diabetic, diabetic vascular changes also can be expected to These psychological abnormalities will certainly add to the
contribute to ED. already significant physiological abnormalities in these
Additionally, those patients who have undergone renal patients. The psychological conditions identified include low
transplantation may have vascular compromise to their lower self-esteem; lack of a sense of wellbeing; a significant increase
extremities and genitalia. These vascular changes can be docu- in stress from chronic illness, job loss, and financial concerns;
mented using Doppler sonography and are well reported.16 and a documented increase in depression and marital discord.
Techniques to identify venous outflow abnormalities in ED Dunante et al. clearly demonstrated the association between
include dynamic infusion studies, pharmacocavernosometry, depression, its severity and ED in the Massachusetts Male
and pharmacocavernosography.17 These studies, combined Aging Study.21 Procci et al. have identified a higher incidence
with color Doppler evaluation of arterial inflow, are necessary of depressive episodes in patients on hemodialysis in compa-
to identify specific vascular abnormalities producing ED. In a rision with a normal population.13 Glass et al. studied the
series by Kaufman et al., 90% of CRF patients had venous psychological impact of CRF, dialysis, and renal transplanta-
occlusive incompetence.15 Veno-occlusive dysfunction as a tion and found that dialysis patients were more likely to be
cause of erectile problems probably results from a combina- depressed than transplant patients, whereas transplant patients
tion of venous vascular abnormalities associated with peri- showed a greater level of anxiety.8 Marital discord rates were
pheral smooth muscle function of the corpora cavernosa. higher in all patients with CRF, and they were especially
marked in those patients on hemodialysis. The findings of
Glass et al., which demonstrated impotence in many patients
Neurogenic alterations in whom physiological erectile function could be measured,
Autonomic control of erectile smooth muscle tissue is critical suggested that psychological stresses and abnormalities were a
in the maintenance of erectile function. Sympathetic neural significant part of uremic sexual dysfunction.8
activity predominates in the flaccid state and during detume-
scence of the erectile bodies. Norepinephrine activates post-
synaptic alpha-1a, alpha-1b, and alpha-1c receptors, and its Abnormalities in the endocrine system
activity is modulated by presynaptic alpha-2 receptors.18 The The kidney plays an integral role in endocrine function.
parasympathetic system mediates erections via acetylcholine. Hormonal effects of the kidney are well known, and the kidney
Activation of muscarinic receptors liberates nitric oxide, provides significant hormonal metabolism. CRF, therefore,
which relaxes smooth muscle and causes erection. There are can be expected to produce profound changes in endocrine
also non-adrenergic, non-cholinergic (NANC) neurons that function and hormone balance that affect many bodily func-
release nitric oxide. Nitric oxide increases cGMP production, tions, including male sexual activity.
which relaxes cavernous smooth muscle.19 The hypothalamic–pituitary–gonadal axis is negatively affec-
Campese et al. studied the autonomic nervous system in ted by CRF; this has been well documented (Figure 60.3).22–25
uremic patients by monitoring the heart rate response to the Decreased testosterone levels are common, and this correlates
Valsalva maneuver.20 This technique can, to some extent, with inferior semen quality.22 These abnormalities are sup-
measure the integrity of the afferent parasympathetic and ported by testicular histological abnormalities on biopsy,
efferent sympathetic pathways. In studies of 12 CRF patients including abnormalities in both spermatogenesis and inter-
with ED, an abnormal Valsalva maneuver correlated with stitial cell morphology.26
abnormal NPT and diminished ability to achieve erections Most male patients with CRF on dialysis have low serum
suitable for intercourse. These data suggest that autonomic testosterone levels, although many may be at the low end of
nervous system dysfunction is an etiological factor in impo- the normal range.26 Low testosterone levels are most probably
tence associated with uremia. caused by decreased testosterone production, but there is
Peripheral neuropathy in CRF is frequent. Peripheral neuro- evidence for elevated metabolic clearance of testosterone in
pathy that occurs most commonly in patients with diabetes addition to decreased production.22,24,26 As a result of normal
mellitus also can be seen in patients with non-diabetic uremia. testicular binding capacity, free testosterone and salivary tes-
Athough there are few satisfactory neurophysiological tests to tosterone levels are low.22,25,27,28 These abnormalities have been
identify patients with neurogenic impotence, clincal neuro- identified in patients despite differing methods of dialysis
physiology can be useful in assessing patients with defects including hemodialysis and peritoneal dialysis (continuous
in somatic nervous system pathways to the sacral segments ambulatory peritoneal dialysis, CAPD).29,30 Some dialysis
affected by uremia, diabetes, or other metabolic disease patients have elevated levels of testosterone-binding globulin,
processes. Practitioners must rely on clinical judgement when and some patients have normal testosterone and free testos-
evaluating patients with suspected neurogenic causes for terone levels.31–33 The levels of free and total testosterone
impotence.20 remain low despite attempted stimulation with administra-
tion of exogenous human chorionic gonadotropin.34 Thus
patients with CRF are likely to have a deficiency in hormone
Psychological factors production and secretion as the primary mechanism for their
The psycological impact of uremia and its treatment and hypogonadism, as well as an element of end-organ failure.
management have a significant role in sexual dysfunction in Investigation of patients immediately after initiation of
patients with CRF. Patients with uremia, especially those on dialysis in early uremia demonstrates an initial elevation
460 Textbook of Erectile Dysfunction

production is quite normal.33,35,39,40 The rise in serum LH and

Testosterone
5

(ng/ml)
FSH correlates well with the pituitary response to hypotha-
lamic stimulation by GnRH, which is preserved in the CRF
2 patient. Thus, if the LH response to low testosterone levels is
** inadequate, a pituitary abnormality may be present.
50 ** Sexual dysfunction may be due to the frequently elevated
**
* prolactin levels in men with CRF. Sexual dysfunction is com-
(ng/ml)

40 monly experienced by patients with normal renal function

PRL

and hyperprolactinemia caused by pituitary neoplasms or

30 pharmacological abnormalities. Although the mechanism of
sexual dysfunction caused by hyperprolactinemia remains
controversial, loss of libido, decreased erectile function, and
30
*
infertility have been widely associated with elevations in
* *
prolactin.41 The cause of sexual dysfunction in those patients
(mlU)
LH

20
with elevated prolactin may be a disordered hypothalamic–
pituitary axis or a direct peripheral gonadal effect of prolactin.
10
Hyperprolactinemia without renal failure usually results in
20 increased levels of LH and hypogonadism. This response dif-
(mlU)
FSH

fers from the usual low testosterone and low LH associated

10 with the hyperprolactinemia of CRF. Hyperprolactinemia
can be induced by several medications, including methyldopa,
6 * *
* digoxin, cimetidine, and metoclopramide. Patients with hyper-
(ng/ml)

prolactinemia often have ED. Once the hyperprolactinemia is

PTH

4
treated, erectile function improves, as does fertility.42
Other endocrinologic abnormalities can strongly contribute
2
B 3 6 9 12 15 18 to ED in patients with CRF on dialysis treatment. Most com-
Time from start of dialysis (months) mon among these is diabetes mellitus, which is one of the
most common causes of ED. Vascular changes in long-term
Figure 60.3 Behavior of serum hormone in males during the insulin-dependent diabetic patients are well known and cause
18-month follow-up. *p < 0.05; **p < 0.001 vs basal. Reproduced corporal arterial insufficiency and veno-occlusive dysfunc-
with permission from Contrib Nephrol 1990; 77: 34–44. tion. The autonomic and sensory neuropathic dysfunctions
resulting in ED are not amenable to medical therapy. This is
in testosterone levels, suggesting that circulating toxins may especially difficult for the young patient who has adequate
be important in uremic testicular failure.24 Unfortunately, vascular and venous function but insufficient neurologic ability
however, testicular function is only temporarily restored, and to produce a sufficient erectile response.36
men with CRF on hemodialysis or CAPD fail to experience Other hormonal abnormalities that contribute to ED in
restoration of hormone production satisfactory to restore uremic men include abnormalities in parathyroid hormone
fertility or potency. Although the exact level of testosterone (PTH). Secondary hyperparathyroidism is a common mani-
synthesis deficiency remains controversial, recent evidence festation of CRF. Massry et al. suggested in 1977 that the
points to abnormalities in the production of dehydroiso- excess blood levels of PTH in uremic patients might contri-
androsterone (DHA) from 17-hydroxypregnenolone via the bute, at least partly, to the disturbance in hormones of the
enzyme-catalyzed reaction with desmolase C17,20. Giving hypothalamic–pituitary–gonadal axis and in the genesis of
exogenous testosterone to CRF patients with diminished the impotence of uremia.43 They reported on two impotent
levels of circulating testosterone has not been shown to dialysis patients in whom sexual function was restored fol-
improve erectile function or fertility.35 lowing parathyroidectomy without other changes in CRF
Men with CRF have abnormal secretion of luteinizing management.
hormone (LH), follicle stimulating hormone (FS), and pro-
lactin. LH levels are generally increased in response to low
testosterone levels and because of a decrease in the metabolic Anemia and diminished oxygen delivery
clearance of LH.35–37 It has been estimated that LH levels Hypoxia associated with CRF has been implicated as a poten-
exceed 20% of normal in many of these patients, probably as tial cause of ED.44,45 Two sources of hypoxia in CRF have
a result of decreased testosterone levels caused by hypogonad- been identified – pulmonary-associated hypoxia and anemia-
ism. FSH is also elevated in those men with suboptimal sper- associated hypoxia. Pulmonary-associated hypoxia is due to
matogenesis.35 Holdsworth et al. have suggested that the FSH hypoventilation and pulmonary microembolization, whereas
levels in patients with uremia can be used as prognostic indi- anemia-associated hypoxia is due to diminished erythropoietin
cators for the return of fertility following renal transplanta- production.44,46 Hypoxia can lead to ED by affecting nitric oxide
tion.35 Occasionally, pituitary abnormalities can be suggested synthesis in the corpora cavernosa. Cavernosal nitric oxide
by low LH levels despite low testosterone concentration;38,39 synthesis is impaired by low partial pressures of oxygen.
more commonly, however, pituitary response to gonadotropin- The decreased nitric oxide synthesis subsequently leads to
releasing hormone (GnRH) with increased FSH and LH worsened erectile function in patients with CRF. Kim et al.
 Chronic renal failure and sexual dysfunction 461

found decreased nitric oxide synthesis and elevated smooth On the other hand, beta-blockers, sympatholytics, and
muscle tone in patients with low oxygen tension at the cor- vasodilators are strongly associated with local effects that
pora cavernosa.19 Luscher et al. found increased endothelium- overcome the normal physiological response of the smooth
derived contracting factors, which could further increase muscles of the corpora cavernosa and (locally as well as
smooth muscle tone and inhibit erection.47 Finally, metabo- centrally) inhibit erectile function.52 These drugs, if causing
lites that inhibit nitric oxide synthase accumulation in CRF ED, may be changed to alpha-adrenergic blocking agents
patients may possibly contribute to the ED. such as terazosin, prazosin, or doxazosin, or ACE inhibitors
and calcium-channel blockers. Many dialysis patients are
treated with sympatholytic medications such as methyldopa
Pharmacological factors and clonidine, beta-blockers such as propranolol, and vasodi-
Because of the underlying conditions that have produced ED lators such as hydralazine. Patients treated with these agents
in patients with CRF, close attention must be paid to erectile can be expected to exhibit physiological ED as a result of
abnormalities asssociated with medications. Pharmacological the local cavernosal effects of these agents.50 Alpha-2 adrener-
treatment of conditions associated with CRF may produce gic antagonists, such as clonidine, may produce central caver-
side-effects causing or increasing impotence and diminished nosal artery constriction or limit its dilatation potential,
libido. Table 60.2 lists the medications frequently associated decreasing cavernosal perfusion and diminishing erectile
with ED. Such agents may produce abnormalities in central, function.53
neuroendocrine regulation or in the neurovascular control of
erectile function, either in the copora cavernosa or at a central
level.48 Centrally acting agents like clonidine and reserpine, as Evaluation of erectile dysfunction in
well as drugs that increase prolactin levels, frequently result in
decreased libido. men with CRF
ED has been associated with virtually all antihypertensive
It is clear from the foregoing discussion that the causes of ED
agents.49–51 These antihypertensive medications, added to the
and infertility in uremic men can be multifactorial. ED in men
associated physiological arterial changes noted to occur with
with CRF should proceed systematically (Table 60.3) and
atherosclerosis, magnify the problem of ED in these patients.
Calcium-channel blockers, angiotensin converting enzyme
(ACE) inhibitors, angiotensin receptor blockers, and alpha-
Table 60.3 Evaluation of erectile dysfunction in men
adrenergic antagonists are least likely to cause iatrogenic ED.
with chronic renal failure

History
Table 60.2 Pharmalogical agents frequently used Physical examination
in chronic renal failure and associated with sexual General examination
dysfunction Genitourinary examination: testicles, scrotum, phallus,
meatus, prepuce, and glans
Antihypertensive agents Digital rectal examination
Sympatholytics Neurological examination: S2–S4 sensation,
Methyldopa bulbocavernosus reflex, anal wink, anal tone, and
Clonidine penoscrotal sensation
Reserpine Laboratory evaluation to assess general and specific causes
Guanethidine of erectile dysfunction
Beta-adrenergic antagonists Serum testosterone
Propranolol Luteinizing hormone
Pindolol Follicle stimulating hormone
Atenolol Prolactin
Metoprolol Complete blood count
Labetalol Serum glucose or glycosylated hemoglobin and baseline
Vasodilators electrolytes
Hydralazine Lipid profile
White men >50 years and black men >40 years should
Diuretics have a prostate-specific antigen test
Thiazides
Spironolactone Further referral to a urologist if considering certain studies
Doppler screening studies
Antidepressants Color Doppler ultrasound for flow
Tricyclics Pharmacocavernosography
Serotonin reuptake inhibitors Pharmacocavernosometry
Other agents Dynamic infusion studies
Cimetidine Nocturnal penile tumescence studies
Digoxin Biothesiometry
Clofibrate Injection therapy
Metoclopramide Surgical therapy
462 Textbook of Erectile Dysfunction

always begin with a thorough history and physical examina- Medical management
tion. A careful history to identify psychological factors, such Hormone regulation
as significant depression, must be carried out by a qualified
Patients who have low testosterone levels may respond to
mental healthcare professional. A careful physical examina-
replacement therapy, which normally improves libido with-
tion, including studies for the identification of peripheral
out a significant impact on potency or fertility. Data on the
neuropathy and vascular abnormalities, is also helpful. The
effects of testosterone replacement in end-stage renal disease
use of NPT monitors can identify patients with a true organic
are scant. There have been several small studies suggesting
cause for their ED in whom vascular problems are suspected.
that testosterone therapy does not improve erectile function
In patients in whom veno-occlusive incompetence or arterial
in the majority of hemodialysis patients for whom it was
abnormalities are suspected by Doppler screening studies,
prescribed.54–56 Effective replacements include injectable
pharmacocavernosometry, pharmacocavernosography, and
preparations, transdermal delivery systems, or sustained-
dynamic infusion studies, together with color Doppler arterial
release products. However, testosterone 100–200mg weekly
response studies, may be helpful, especially if a surgical inter-
by injection produces only small and variable responses in
vention is planned.
erectile function.57
Finally, hormonal studies, including testosterone, LH, FSH,
Clomiphene citrate, which is a partial agonist of the estro-
and prolactin, should be obtained. These may be supple-
gen receptor, increases secretion of gonadotropins and
mented by serum glucose, glycosylated hemoglobin, lipid pro-
increases plasma testosterone in CRF. One study used clomi-
file, and thyroid function studies. Communication with the
phene citrate to increase testosterone levels from the hypo-
nephrologist and transplant surgeon is essential, since trans-
gonadal range to the high end of the normal range in five
plantation may reverse many of the previously mentioned
uremic men. The five men subsequently reported uniform
abnormalities of uremia, and initiation of specific impotence
increases in libido and sexual function.58
treatment modalities may be delayed until after transplanta-
If hyperprolactinemia is found, chromophobic tumors
tion is carried out in some patients.
of the anterior pituitary must be excluded, since these may
present with ED or decreased libido. Pharmacological methods
for decreasing hyperprolactinemia also appear to be effective
Treatment options in some men with uremia-associated sexual dysfunction.
Methyldopa and reserpine interfere with dopamine secretion
Treatment options for ED are reviewed in Table 60.4. and therefore lead to hyperprolactinemia. If these causes
are excluded, dopaminergic agonists may be of benefit.28,59
Bromocriptine (1.25–5mg daily) and lisuride hydrogen maleate
(0.05–0.2mg daily) decrease prolactin and elevate testosterone.
Table 60.4 Treatment options in men with chronic Bromocriptine can induce hypotension, nausea, vertigo, and
renal failure and impotence dizziness – side-effects that are intolerable to many patients.
These side-effects are less prominent with lisuride hydrogen
Medical maleate. Subsequent rises in plasma testosterone, with expected
Medications improvement in sexual function, result from these medications.
Hormone replacement therapy For patients with symptomatic secondary hyperparathy-
Oral medications to improve arterial flow
roidism, it was recently found that sexual function of male
Intracavernosal injection therapy
Transurethral therapy
patients can be improved by parathyroidectomy and auto-
Dopaminergic agonists transplantation. The report also demonstrated a decrease in
Erythropoietin the levels of prolactin in association with decreasing levels of
Devices calcium, phosphorus, and immunoreactive PTH.60
Vacuum constriction device CRF and uremia are frequently associated with profound
Constriction bands anemia, which may result in psychological ED caused by
Surgical weakness, fatigue, and anxiety. The physiological effects of
Revascularization techniques anemia and hypoxia on erectile function have been described
Penile prosthetic devices previously in this chapter. Treatment of anemia with recombi-
nant human erythropoietin in male uremic patients has been
Psychiatric
reported to improve sexual performance and fertility and to
Post-transplantation
increase serum testosterone and FSH levels. Although the
Other issues studies on recombinant human erythropoietin are preliminary,
Adjust medications where appropriate there appears to be some salutary effect of this method of
Control comorbid disease states treatment in some uremic patients.61,62
Evaluate for psychosocial stresses
Discuss expectations with patient
Routinely evaluate efficacy of therapy and patient
satisfaction Phosphodiesterase type 5 inhibitors
Realize the changing patterns of erectile dysfunction and Since 1998 the Food and Drug Administration in the USA
need to change therapy or modality has approved three selective phosphodiesterase (PDE) type 5
Consider early referral to a urologist
inhibitors: sildenafil, tadalafil, and vardenafil. Each of the
 Chronic renal failure and sexual dysfunction 463

registration programs of the PDE-5 inhibitors involved more erectile function domain score of the International Index of
than 2000 patients. In the USA, sildenafil was approved in Erectile Function, successful penetration attempts and success-
1998 and both vardenafil and tadalafil were approved in ful intercourse attempts, and overall satisfaction compared
2003. with placebo have reported with an on-demand schedule
Erectile function depends on the neuronal pathways (NANC of the drug.77–79 Tadalafil has a terminal half-life of 17.5 hours,
neurons) and release of nitric oxide.63,64 PDE-5 inhibitors which is consistent with a broad window of clinical respon-
inhibit the breakdown of cGMP, thereby allowing continued siveness.79,80 Tadalafil enhances erectile function in men with
relaxation of smooth muscle in the corpus cavernosum.65 All ED for up to 36 hours. Thus, tadalafil may be associated with
three drugs in this class have similar pharmacokinetic and less planning or pressure to have sexual intercourse after
pharmacodynamic profiles, and each is effective for patients dosing. Unlike sildenafil and vardenafil, meal intake has no
with ED in all ages and of all severities and etiologies. effect on the absorption of tadalafil.
In patients with CRF, sildenafil has the longest patient The cytochrome P450 system is the chief metabolic path-
experience and the most robust data confirming its activity, way for sildenafil, vardenafil, and tadalafil. All three agents
safety, and tolerability. The best results in the initial human are P3A4 substrates, and concomitant administration with
trials were obtained with sildenafil 100mg; however, up to P34A inhibitors such as ritonavir, indinavir, ketoconazole,
24% of men responded effectively on the 50mg dosage and erythromycin can increase plasma levels of the PDE-5
schedule. Also significant was the increase in frequency of inhibitors.81–83 Because PDE-5 inhibitors potentiate the vaso-
intercourse, with those receiving sildenafil making on average dilator and hypotensive effects of nitric oxide, treatment with
5.9 successful attempts per month compared with 1.5 among any PDE-5 inhibitor is contraindicated in patients taking
those receiving placebo.66 Sildenafil studies in patients on organic nitrates.81–83 According to USA prescribing informa-
dialysis show a good response rate (66.7–80%). The majority tion, co-administration of alpha-blockers with sildenafil,
of sildenafil responders had success with the 50mg tablets.67,68 vardenafil, and tadalafil is listed as a precaution.81–83 None of
Sildenafil has been shown to be effective in patients with the three agents is dangerously associated with prolongation
difficult-to-treat ED, and the Sildenafil Diabetes Study Group of the corrected QT interval.
showed that 56% of men with ED and diabetes who received The recent advent of vardenafil, which has the highest
sildenafil (25–100mg) for 12 weeks reported improved erec- in vitro potency of all available PDE-5 inhibitors, and of tada-
tions, in contrast to 10% of patients receiving placebo lafil, which has a prolonged half-life that may enable couples
(p < 0.001).69 to have sexual activity with less planning, represent further
Sildenafil given to transplant patients does not affect levels advances. However, while there are clear pharmacokinetic dif-
of anti-rejection medications and has a 60% satisfactory ferences amongst these agents, the data from preference trials,
response rate.70 Most commonly reported side-effects are head-to-head clinical trials, and selection trials are few.84
headache (16%), flushing (10%), and dyspepsia (7%).71 Con-
comitant nitrate administration can lead to hypotensive side-
effects in some patients. It is unclear how long the patient Intracavernosal injection therapy
must wait until nitrates can be safely administered. Sildenafil Alprostadil, an exogenous form of prostaglandin E (PGE)-1, is
decreases systolic and diastolic blood pressure by 10mmHg and administered by intracavernosal injection. Alprostadil causes
7mmHg, respectively. Nitrate use leads to a synergistic increase smooth muscle relaxation, vasodilatation, and inhibition of
in cGMP levels, which can cause excessive hypotension and platelet aggregation. Some 96% of alprostadil is locally meta-
occasionally ischemic cardiac events or strokes.72 Sildenafil bolized within 60 minutes. No change in peripheral blood
can be safely administered in CRF if there is no serious cardiac levels occurs, because of extensive pulmonary metabolism.85
disease. Sildenafil is primarily metabolized in the liver but there Linet and Neff concluded that alprostadil produced full erec-
is some renal excretion; lower doses (25mg) are recommended tions in 70–80% of patients.86 Side-effects include pain (17%),
initially in CRF patients. hematoma or echymosis (1.5%), and priapism or prolonged
In vitro studies have shown that the potency of vardenafil in erection (1.3%).86
inhibiting PDE-5 purified from the human corpus caverno- Other agents used alone or in combination with PGE-1
sum tissue was approximately 25 times greater than that of include papaverine and phentolamine mesylate. Papaverine
sildenafil and 48 times greater than that of tadalafil.73 In a inhibits PDE, leading to increases in cAMP, elevated nitric
study by Hellstrom et al., many patients returned to normal oxide, and eventual relaxation of cavernosal smooth muscle
erectile function after treatment with vardenfil.74 For example, and arterial dilatation. Kapoor et al. reported on the use of
89% of patients with mild ED at baseline returned to normal papaverine in men with spinal cord injuries, of whom 98%
function after treatment with vardenafil 10mg. Forty percent obtained satisfactory erections capable of successful penetra-
of patients with severe ED at baseline returned to normal tion.87 Papaverine, however, causes priapism and fibrosis in
function after treatment with vardenafil 20mg, compared with up to 35% and 33% of men, respectively, with increased
only 4% who received placebo. There is limited evidence that a incidence in young and neurogenic ED patients.88
small percentage of sildenafil non-responders can be salvaged Phentolamine mesylate is a competitive non-selective alpha-
with vardenafil.75 A starting dose of 5mg of vardenafil should adrenergic receptor antagonist. It has been used in combina-
be used in men with severe renal impairment.76 tion with papaverine to increase blood flow. Side-effects include
Recent double-blind, placebo-controlled, multicenter trials hypotension, reflex tachycardia, and nasal congestion.
have assessed the efficacy and safety of tadalafil in the treat- These agents can be used successfully in CRF patients with
ment of ED. Significant improvements from baseline in the vascular compromise, diabetic microangiopathy, moderate
464 Textbook of Erectile Dysfunction

atherosclerosis, and partial arterial dysphasia, although higher had undergone pelvic organ transplant prior to placement of
doses may be necessary. Patients with veno-occlusive disease a penile prosthesis.94 The risk of infection after insertion of
may also benefit from increased engorgement of the corpora, penile prostheses in patients with pelvic organ transplantation
leading to increased compression of the tunica albuginea and, was similar to that in non-transplant patients.
therefore, occlusion of the emissary veins. It is interesting to
note that patients with neurogenic and hormonal causes of
ED also do well with this therapy (as do older patients), with- Renal transplantation
out increased side-effects. Long-term use of these injection
therapies is effective, with few complications in transplant As a result of normalization of metabolic and hormonal
patients.89 No major complications on transplanted kidneys function in patients after successful renal transplantation,
have been noted. Contraindications to therapy include sickle many patients report improved erectile function and libido
cell anemia, severe psychiatric disorders, severe venous incom- following heterotopic renal transplantation. Testosterone levels
petence, and severe systemic disease. return to normal within 2–3 months, as do LH, FSH, and
prolactin levels. Sperm counts normalize in 9–16 months.38
Patients who receive human chorionic gonadotropin stimula-
Transurethral suppositories tion show improved responses, with higher testosterone levels.
The transurethral delivery system marketed as the Medicated Salvatierra et al. found pre-transplant potency to be 22%
Urethral System for Erection (MUSE), allows for delivery of while on dialysis; however, after renal transplant, 84% of men
alprostadril to the corpora by direct venous communication.90 resumed levels of potency comparable to a time before the
The mechanism of action of alprostadil has been discussed onset of uremia.95 Post-transplant psychological disturbances,
earlier. Although the system has not been tested in patients except for anxiety, appear to diminish.
with CRF, it has been effective in the treatment of ED arising Although data are limited, studies evaluating commonly
from most other causes. used immunosuppressive agents such as cyclosporine, azathio-
prine, tacrolimus, and prednisone suggest that these agents
do not have significant effects on the sex hormone profiles of
Devices renal transplant patients.96–99 Sirolimus, a new immunosup-
Vacuum constriction devices work by engorging the penis pressive, has been found to lower total testosterone and
with blood by negative pressure. A constriction band is placed increase LH and FSH in renal transplant patients; however, this
at the base of the penis, through for no longer than 30 minutes has not proven to result in a change in sexual function.100
in order to avoid injury. These devices have local side-effects It is important to remember that a significant proportion
such as pain from the constriction band, entrapment of ejacu- of post-transplant men will continue to have ED despite
lation by the constriction band, a cold and dusky penis, numb- normalization of hormone values and improved physiology.101
ness of the penis, and local irritation. Many men use these Causes of post-transplant impotence include failure to resolve
devices. Using the device can be difficult for men with a short hormonal abnormalities, underlying diease processes that
penis or an extensive suprapubic fat pad. In those who need have resulted in continued ED, and the effects of the tranplant
pharmacological manipulation for an adequate erection but itself. Many of these patients suffer from vasculogenic ED.
who have evidence of venous incompetence, a constriction Reports of marked increase in ED following bilateral renal
band alone may be used to sustain rigidity of the penis that is transplantation may be a result of changes in pelvic hemody-
suitable for intercourse. namics resulting in decreased penile blood flow, although
reports of patients who are potent following interruption of
bilateral hypogastric arteries are common. Impotence follow-
Surgical treatment ing sequential bilateral renal transplantation, however, appears
to be increased as a result of decreased blood flow associated
Vascular procedures for erectile dysfunction
with the ligation of both internal iliac arteries. These patients
As most patients with renal failure have small-vessel disease, should be evaluated in a way similar to pre-transplant patients,
the use of revascularization techniques and veno-occlusive and treatment plans should be generated for their specific
surgery is not commonly employed. In selected patients, how- needs.
ever, balloon dilatation of pelvic arteries may be helpful, with
low morbidity expected.91
Conclusion
Penile prostheses Sexual dysfunction is common in patients with CRF. Sexual
Implantation of a penile prosthesis is safe and usually success- dysfunction in these patients should be thought of as a multi-
ful, with low morbidity. Renal transplant patients commonly factorial problem that is affected by a variety of physiological
benefit from the device.92 Such procedures should be performed and psychological factors, as well as by comorbid conditions.
after renal transplantation, if possible, because many men ED includes a vast array of organic, anatomic, and psychoso-
have improved sexual function, fertility, and potency after the cial elements, which make evaluation and treatment complex.
operation. In immunocompromised patients, the risks of However, a practitioner who takes a good history and per-
implanting an artificial device include prosthetic infection.93 forms a good physical examination and laboratory evaluation
Cuellar et al. examined their own cohort of 46 patients who can provide a great service to the quality of life of the patient
 Chronic renal failure and sexual dysfunction 465

with CRF. The physician must address the topic and make the comorbid conditions. Psychological, medical, and surgical
patient feel comfortable with his changing physiology and therapies can be highly effective in correctly evaluated patients.
anatomy. Renal transplantation has the potential to normalize A multidisciplinary approach to care should be employed,
hormone profiles and subdue some of the physiologic changes, involving the primary care physician, a nephrologist, a urologist,
although it may not solve the problem because of associated a psychiatrist, and a psychologist.

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61 Evaluation of ejaculatory disorders
Jason M Greenfield and Craig F Donatucci

Introduction spinal cord (S2–S4) via the pudendal nerve, which innervates
the bulbospongiosus and bulbocavernosus muscles.5
Ejaculatory dysfunction, especially premature ejaculation (PE), Ejaculation is a reflex involving sensory receptors of the
is one of the most common sexual complaints of adult men. glans penis, afferent pathways (dorsal nerve of the penis),
The National Health and Social Life Survey (NHSLS), con- cerebral sensory and motor centers, spinal motor centers, and
ducted in the USA in 1992, examined sexual complaints in a efferent pathways. Although the exact process is not com-
cohort of over 1200 men. The results of this survey revealed pletely understood, copulatory behavior is regulated by fore-
an incidence of PE of approximately 30%, while 7–9% experi- brain structures, including the medial preoptic area as well as
enced anorgasmia.1 Ejaculatory disorders as a whole are quite the paraventricular nucleus of the hypothalamus.5 Studies of
prevalent in patients with benign prostatic hyperplasia (BPH) the male rat have demonstrated that the neurotransmitters
and lower urinary tract symptoms (LUTS). Clinical studies dopamine and serotonin play a major role in ejaculation.
have estimated the incidence of these disorders to be approxi- While dopamine has been shown to play an excitatory role,
mately 30–80% and that they increase as men age.2,3 serotonin is inhibitory.6,7 Increasing understanding of the role
Although once thought to be purely psychological condi- of these neurotransmitters has led to developments in the
tions, ejaculatory disorders are also influenced by organic treatment of ejaculatory disorders over the past few years.
factors and have recently begun to receive greater interest.
Certainly, this may be partially attributed to the greater over-
all attention paid to sexual dysfunction in men that has
accompanied advances in treatment options for men with
Premature ejaculation
erectile dysfunction (ED). Although the guidelines of diagno- Definition
sis and management of ED are still in evolution, a standard-
Premature ejaculation is by far the most common ejaculatory
ized approach to the patient with a disorder of ejaculation is
disorder, with rates among US men believed to be as high as
even further behind.
30%, or even greater.1,8 Despite the prevalence of this disor-
This chapter serves to outline and distinguish the various
der, PE remains undiagnosed or misdiagnosed in many cases.
ejaculatory disorders as well as provide information regarding
There are several potential reasons for this. Patients may have
the approach to their diagnosis and initial management. The
embarrassment over their condition, believe the problem is
bulk of this chapter focuses on premature ejaculation, owing
only temporary, or be unaware that PE is a medical problem
to a recent surge in research and development of knowledge
for which available treatments exist.9 Many physicians also fail
about this particular disorder.
to inquire about PE and other sexual disorders. Reasons for
this may include lack of time, concern for other medical con-
Overview of ejaculation ditions felt to be more important, embarrassment over asking
a patient about sexual dysfunction, or a lack of knowledge or
Ejaculation is composed of two separate events, emission and training in sexual disorders.10
ejaculation. Before this process is initiated, the bladder neck One of the initial barriers to the diagnosis of PE has been
closes. During the emission phase, sperm and seminal fluid lack of a consensus on how to define the condition. According
are deposited into the prostatic urethra. The ejaculation phase to the American Urological Association (AUA) Guidelines, PE
specifically consists of the muscular contractions and subse- is defined as ‘ejaculation that occurs sooner than desired,
quent expulsion of contents from the urethra, normally out either before or shortly after penetration, causing distress to
the urethral meatus.4 Although orgasm is commonly associ- either or both partners’.11 It should be noted that in this par-
ated with ejaculation, it is actually a distinct, separate event ticular definition there is no mention of a specific time frame
that occurs centrally. in which ejaculation must occur.
Emission is mediated by sympathetic fibers (T10–L2) that The panel for these guidelines also constructed several
travel to the pelvic plexus via the hypogastric nerves. Stimula- recommendations for the diagnosis and management of PE.
tion causes closure of the bladder neck and sequential con- In terms of diagnosis, the panel concluded that the diagnosis
traction of the epididymis, vas deferens, seminal vesicles, and of PE is based on sexual history alone, and a detailed sexual
prostate, which result in the deposition of sperm and seminal history should be obtained from all patients with ejaculatory
fluid. Ejaculation is mediated by somatic fibers from the sacral complaints.11

468
 Evaluation of ejaculatory disorders 469

In 2003 the second International Consultation on Sexual ejaculation, and level of distress for him and his partner.13
Dysfunctions (ICSD) convened. The definition used by the Similarly, the AUA guideline proposed information that
ICSD for PE is ‘ejaculation with minimal stimulation and should be gathered during the history. Clinicians should
earlier than desired, before or soon after penetration, which determine the onset, frequency, and duration of PE, including
causes bother or distress and over which the sufferer has little the proportion of sexual attempts that are affected by PE.
or no voluntary control’.12 This panel of experts further Again, an emphasis is placed on determining whether the PE
proposed that PE is based on three essential criteria:12 was lifelong or acquired, situational or global. The frequency
and nature of the patient’s sexual practices (masturbation,
1. Brief ejaculatory latency foreplay, intercourse, etc.) may provide insight. The effect of
2. Loss of control over ejaculation PE on relationships, sexual activity, and quality of life for both
3. Psychological distress to the patient and/or partner. partners should also be a focus of the patient interview.11
An emphasis has been placed on the relationship between
Further definitions have been proposed citing specific ejacula- PE and ED. In fact, these two disorders have been found to
tory latency times, number of penile thrusts, or responsive- occur together in as high as 30% of patients.12 Confusion
ness of the partner, but these have been proven to be unreliable between these two disorders may arise because PE may be
and difficult to support.13 misdiagnosed as ED. Generally, men with ED lose their erec-
tion before ejaculation, although the patient or clinician may
confuse the actual circumstances. In addition, it is believed
Etiology
that men with ED may actually condition themselves to ejacu-
There is no consensus on the exact etiology of PE and, in fact, late rapidly so that they may complete the act before losing an
it is likely a multifactorial disorder. Many theories have been erection.15 This is believed to be PE secondary to ED rather
proposed ranging from psychogenic (e.g. anxiety, frequency of than primary PE. Thus, the AUA guideline currently recom-
intercourse, evolutionary) to biological (e.g. penile hypersensi- mends that patients with both disorders be treated for the ED
tivity, hyper-excitable ejaculatory reflex, endocrinopathy, sero- before PE.11 Finally, some men believe the loss of erection
tonin receptor dysfunction).13,14 PE has been sub-categorized following ejaculation to be related to PE although this process
as either lifelong or acquired. The disorder may also present is normal. Given these opportunities for misdiagnosis, it is
as situational (occurring only with certain partners or under imperative for the clinician to determine whether or not
certain conditions) or global (always occurs during sexual the patient actually ejaculates during intercourse and whether
intercourse). It is generally believed that acquired or situa- or not ejaculation precedes detumescence.10 This gives further
tional PE is more likely to be due to a psychogenic cause evidence to the value of an accurate, detailed sexual history.
and may be best treated with behavioral therapy whereas life- A general medical history and physical examination may be
long or global PE suggests a biological cause and may be best necessary, although it is usually less contributory than the
approached with pharmacologic treatment.13 sexual history. It may help to rule out any other medical con-
dition or surgical injury that could have an effect on sexual
functioning.10 During the medical history, attention should be
History
paid toward use of prescription and recreational drugs. With-
A detailed history and physical examination are essential com- drawal from trifluoperazine, opiates, and ephedrine has been
ponents of the evaluation of the patient with PE (Table 61.1). associated with PE or rapid ejaculation.5
The clinician should attempt to determine whether the com-
plaint is lifelong or acquired, global or situational.12 The ICSD
has recommended that the medical history should include Further evaluation
assessment of potential comorbid factors including anxiety, Lack of standardized objective criteria for assessing PE has led
interpersonal relationship factors, and other sexual dysfunc- to difficulty in defining PE and assessing efficacy of treatment.
tions (especially ED).13 Based on the panel’s definition of PE, Several criteria have been proposed, including intravaginal
the clinician should also verify the patient’s own subjective ejaculatory latency time (IELT) and number of penile thrusts.16
assessment of ejaculatory latency, sense of control over Generally, IELT has been the favored criterion. IELT is defined
as the time from the start of vaginal intromission to the time
of intravaginal ejaculation. Generally, men with PE have a
Table 61.1 Key components of the sexual history in
shortened IELT, which may range from a few seconds to a
the evaluation of ejaculatory disorders
few minutes. Alternatively, men with PE may actually ejacu-
Clarification of exact sexual dysfunction(s) late before intromission and therefore have no measurable
IELT.
Global versus situational
As previously mentioned, no standardized ‘cut-off’ for
Lifelong versus acquired IELT exists for defining PE. In a recent international study,
Comorbidities (anxiety, effect on interpersonal relationships) men who did not report having symptoms of PE were found
Other concomitant sexual dysfunction to have an IELT ranging from 7 minutes to over 13 minutes.17
Level of distress for patient and partner Another international study reported a median IELT of 5.4
minutes and a mean IELT of 8.1 minutes.18 Patients and their
Frequency and nature of sexual practices (e.g. masturbation,
respective partners have been found to have disparaging
foreplay, intercourse)
opinions on what was the patient’s estimated IELT and
470 Textbook of Erectile Dysfunction

what should be considered ‘normal’.19 Studies concerning PE inhibited ejaculation to account for 3–8% of patients who
using IELT as an instrument of evaluation have measured present to a physician with a sexual complaint.8,22 Although
latency time both as a subjective estimation as well as with a relatively rare, it can be quite distressing to patient and part-
stopwatch. ner. While causing distress to the patient it may also cause the
Owing to the wide variability in reported methodology and patient’s partner to feel less attractive, undesirable, and sexu-
findings of ‘normal’ and ‘abnormal’ IELT across studies, the ally inadequate. This may lead to a lack of desire for sexual
data have been difficult to assess. An observational study con- interaction and stress on the relationship.
ducted in the USA found a mean IELT of less than 3 minutes Delayed or inhibited ejaculation is defined by the Diagnos-
for men with PE and over 9 minutes for ‘normal’ men. How- tic and Statistical Manual of Mental Disorders (DSM-IV) as
ever, there was considerable overlap between each group.19 the persistent or recurring difficulty, delay in, or absence of
Clearly, IELT itself cannot be utilized as a single criterion for attaining orgasm following sufficient sexual stimulation which
the diagnosis of PE. In a recent study, Vanden Broucke et al. causes personal distress.23 However, the symptom of DE
sought to determine the normal range and repeatability of IELT should be differentiated from inhibited orgasm or anorgas-
in a laboratory compared with at home (masturbation and mia. Although ejaculation and orgasm commonly occur con-
intercourse), the threshold and repeatability of penile sensitiv- comitantly, they are two separate processes and confusion
ity on six penile surface areas, and finally whether penile sensi- over the diagnosis can result from a lack of a proper patient
tivity correlates with ejaculatory latency time.20 In a study of 58 history.
healthy men, ejaculatory latency time was found to be highest As with the patient complaining of PE, a detailed sexual and
during intercourse (median 8.25 minutes), lower in the labo- medical history is essential in the evaluation of DE. Again, the
ratory (7.22 minutes), and lowest for masturbation (4.89 min- clinician should assess whether the patient’s symptoms are
utes). There was high variability between subjects but scores lifelong or acquired, global or situational. It may be beneficial
were reliably reproducible by individual subjects. Reproduc- to enquire about the patient’s personal and religious views
ible penile sensitivity thresholds were also achieved using two regarding sexual behavior, since this may play a role in DE. As
vibrostimulation devices. Interestingly, no correlation was would be expected, the status and quality of the patient’s
found between penile sensitivity and ejaculatory latency.20 interpersonal relationship (or relationships) may also have an
More investigation is needed to determine the exact role of influence. Men presenting with DE may commonly also admit
measurements of IELT and whether it will become a useful to relationship stress, fear of inadequate performance, or poor
clinical tool in the diagnosis and management of PE. Cur- partner arousal.22
rently, measurement of IELT is generally reserved for clinical Other factors to consider include frequency of intercourse
trials and research, and it is not recommended for the routine and masturbation. Certain habits in masturbation practices
evaluation of the patient with complaints of PE. have also been proposed to play a role.24 For example, a man
In attempting to define parameters to help to distinguish who aggressively masturbates may ‘train’ himself so that he no
men with and without PE, an observational study by Patrick longer responds to the stimulation experienced with sexual
et al. identified three measures.19 These patient-reported out- intercourse. Results of the Massachusetts Male Aging Study
comes (PRO) were control over ejaculation, satisfaction with (MMAS) demonstrated that the incidence of DE increases as
intercourse, and distress. Not surprisingly, IELT was found to men age.25 Beginning in the third decade of life, progressive
correlate most reliably with control over ejaculation.19 Com- loss of peripheral sensory axons occurs. As men age, dermal
bining IELT and these three core PROs is a potential tool for atrophy, myelin collagen infiltration, and Pacinian corpuscle
diagnosing PE and evaluating treatment efficacy. Develop- degeneration occur, and this may lead to progressive penile
ment of a validated questionnaire to screen for PE has been hypoesthesia.13
recently proposed.21 This may eventually help to combat the Several pharmacologic agents have been associated with
lack of an effective screening tool for PE, a major barrier to the DE, including serotonin reuptake inhibitors (SSRIs), tricyclic
diagnosis of this condition. antidepressants, methyldopa, monoamine oxidase inhibitors,
and certain antipsychotics.5,13 Alcohol use or abuse has also
Summary been linked to DE.13
Identifying the factors that may be causing DE in the indi-
Premature ejaculation is a common condition in men that
vidual patient is critical. In order to identify the most effective
often goes undiagnosed or misdiagnosed. A thorough sexual
manner of treating the patient affected by DE, the clinician
and medical history is essential to the evaluation. While PE
must elucidate the psychological, physical, and pharmaco-
often occurs with ED or may confound the diagnosis, a
logical factors (Table 61.2) that can contribute to this condi-
properly completed sexual history aids in the diagnosis.
tion. Unfortunately, a lack of effective therapies is a significant
Measurement of IELT aids in the evaluation of PE but is not
barrier to treatment of DE.
reliable as a sole criterion for diagnosis. The diagnosis of PE
is based on a brief ejaculatory latency, loss of control over
ejaculation, and psychological distress to patient or partner
(or both). Anejaculation and aspermia
Anejaculation may, for certain patients, be an extreme form of
Delayed or inhibited ejaculation delayed ejaculation, or it may be a different problem entirely.
This difference can usually be ascertained from the sexual his-
Delayed ejaculation (DE) is considerably rarer that PE. In a tory, especially if the patient notes orgasm without ejaculation
review of the medical literature, Spector and Casey found (‘dry orgasm’). The key is to differentiate anejaculation from
 Evaluation of ejaculatory disorders 471

Table 61.2 Pharamacologic agents with potential Acquired anejaculation may be due to a surgical procedure
effect on ejaculatory function that also disrupts the normal anatomy of the male reproduc-
tive tract. Transurethral resection of the prostate (TURP) and
Pharmacologic agent Related disorder incision of the bladder neck are two surgical procedures that
Serotonin modifying Delayed ejaculation, possible may be implemented in men with LUTS and that can lead
agents (SSRIs, retrograde ejaculation to anejaculation. Of course, any surgical injury to the nerve
clomipramine) supply involved in ejaculation may also lead to acquired
Tricyclic antidepressants Delayed ejaculation, possible
anejaculation. Examples of this would include aortic or para-
retrograde ejaculation aortic surgery (abdominal aortic aneurysm, retroperitoneal
lymphadenectomy), proctocolectomy, radical prostatectomy,
Methyldopa Delayed ejaculation, possible
bilateral sympathectomy, or spinal cord injury.13 The effect of
retrograde ejaculation
spinal cord injury on ejaculation has been well established,
Monoamine oxidase Delayed ejaculation, possible with an incidence of about 90%. The level and completeness
inhibitors retrograde ejaculation
of the injury are factors in the ability of the patient to ejacu-
Antipsychotics Delayed ejaculation, possible late, with lower injuries having a greater chance of preserving
(e.g. haloperidol) retrograde ejaculation function.27 Other medical diseases affecting the nervous
Antiandrogens Anejaculation, possible system may also adversely affect ejaculation, including diabe-
low-volume ejaculate tes mellitus or multiple sclerosis. Hypogonadism and hypo-
Ethanol Delayed ejaculation thyroidism have been linked to anejaculation as well.13
Alpha-receptor Retrograde ejaculation One final point of the patient interview is to determine
antagonists if fertility is an issue for the patient. If the patient has solitary
anejaculation without other sexual dysfunction, the only
SSRI, selective serotonin reuptake inhibitor indication for intervention is to retrieve sperm for fertility
purposes (e.g. by electroejaculation or sperm aspiration).

anorgasmia or retrograde ejaculation. If orgasm is occurring

and retrograde ejaculation has been ruled out (see below) Anorgasmia
then the patient has true anejaculation (aspermia).
Usually the clinician will be able to determine if anejacula- Orgasm is a centrally mediated, subjective perception of plea-
tion is accompanied by anorgasmia by the patient interview sure that normally occurs at the time of ejaculation in men.
and sexual history. Certainly, the factors mentioned in the Anorgasmia, however, may occur with or without ejaculation
section on DE, above, can also impair the patient’s ability to and should be distinguished from DE, retrograde ejaculation,
reach ejaculation and orgasm altogether. If the patient is anejaculation, and aspermia. It is important for the clinician
reaching orgasm (a process that occurs centrally) but ejacula- to understand, as well as communicate to the patient, that
tion does not occur then organic factors are likely involved. orgasm and ejaculation are separate processes. It is common
Any medical disease, surgery, or pharmacologic intervention for patients and even treating physicians to confuse the two
that interferes with central control of ejaculation or the entities.
afferent or efferent nerve supply to the vas deferens, bladder As described above, several behavioral, religious and cul-
neck, pelvic floor, or penis may result in inhibited ejaculation, tural, and psychological factors may play a role in inhibiting
anejaculation, or anorgasmia.13 orgasm (and ejaculation). These may be identified in the
The clinician should attempt to determine whether the ane- patient’s sexual history. Again, assessing whether the symp-
jaculation is lifelong or acquired, situational or global. This tom is situational or global, acquired or lifelong is helpful, as
may provide insight as to whether the patient is experiencing is determining whether ejaculation is occurring. It is relatively
anejaculation due to psychological factors or physiological easy to distinguish between primary and secondary anorgas-
factors (or possibly both). The patient’s medication list should mia through taking a proper sexual and medical history.
be reviewed for medications that can inhibit ejaculation or Primary anorgasmia or ‘congenital anorgasmia’ occurs
cause retrograde ejaculation. Medications that inhibit con- when a patient has never experienced an orgasm at any point
traction of the ejaculatory apparatus, which is mediated by in his life. It is believed to be an extremely rare condition,
alpha-adrenergic input, can actually cause anejaculation with occurring in less than 1% of the population.28 Although
complete blockade rather than simply retrograde ejaculation. the exact etiology is unknown, it is believed to generally be
A complete medical history and directed physical exam is psychogenic, and nocturnal emissions will still occur. This
important to determine potential causes of anejaculation. may be important to verify in the event that sperm retrieval is
Lifelong anejaculation may be due to a congenital anatomic desired for assisted reproduction.29
abnormality. Examples of congenital causes of anejaculation Secondary anorgasmia occurs when a patient who at one
include Müllerian duct cysts, Wolffian duct abnormalities, time did achieve orgasm is currently unable to do so. Unlike
and prune belly syndrome. Transrectal ultrasound may be primary anorgasmia, which is believed to be usually psycho-
necessary to confirm the diagnosis of a Müllerian duct cyst genic, secondary anorgasmia may have an organic etiology.
(prostatic utricle).26 Congenital absence of the vas deferens As with anejaculation, neurologic injury or disease may
may occur in patients with cystic fibrosis or in isolation. contribute to anorgasmia, as can drugs such as SSRIs.30 Mul-
However, these patients normally have low-volume ejaculate tiple sclerosis and spinal cord injury are common causes of
rather than aspermia, owing to secretions from the prostate. secondary anorgasmia.31
472 Textbook of Erectile Dysfunction

It is worthwhile to note that some patients do relate a prevalence of sexual dysfunction. A 25-item questionnaire has
decrease in intensity of orgasm with a decrease in ejaculatory been developed and validated for this purpose and a short form
volume. It is known that androgen levels influence seminal is currently under development.34
fluid formation. Advancing age or any iatrogenic cause Any surgical procedure that compromises closure of the
of hypogonadism may lead to decreased ejaculatory volume bladder neck may potentially lead to RE. Examples of this
(or even aspermia) and subsequently a reduced perception of would include surgery to the bladder neck itself, such as TURP
sexual pleasure. Thus, some clinicians recommend determin- or bladder neck incision. Rates of RE after these procedures are
ing a testosterone level for patients with anorgasmia who may relatively high but vary; they are estimated to be 25–80%.35,36
potentially be hypogonadal. As with patients who are apparently anejaculatory from major
abdominopelvic or retroperitoneal surgery, RE may be occur-
ring instead.
Since there is extensive overlap in potential causes of
Retrograde ejaculation anejaculation and RE, the diagnosis of RE may be confirmed
or excluded by a PEU. The term ‘post-ejaculatory urinalysis’
Retrograde ejaculation (RE) presents as anejaculation but is
is actually somewhat misleading. Generally it is not known if
diagnosed conclusively by the finding of sperm in the urine on
the patient is truly ejaculating or not (the reason for the test).
a post-ejaculatory urinalysis (PEU). Unlike delayed or inhib-
The majority of patients will experience orgasm so the test is
ited ejaculation or anorgasmia, retrograde ejaculation occurs conducted after masturbation or other stimulation to the
from an organic etiology. As with aspermia without anorgas-
point of orgasm. The patient then voids and the urine sample
mia, treatment is rarely necessary unless fertility is an issue.
is examined for spermatozoa. The presence of sperm confirms
Although a sexual history is still obtained, the patient’s
the diagnosis of RE, although the minimum number of sperm
medical and surgical history usually provides insight into the needed to be seen on PEU has not been defined. In addition,
diagnosis. As with anejaculation, systemic or neuropathic
transrectal ultrasound may be performed, which classically
disease may lead to RE. Autonomic neuropathy from diabetes
would demonstrate an open bladder neck at rest.5
mellitus or multiple sclerosis has been associated with RE, as
has spinal cord injury. The incidence of RE in men with an
extensive history of diabetes is high, with one particular study Summary
reporting an incidence of 32%.32
Congenital abnormalities such as bladder extrophy may Ejaculatory disorders are a common disorder, increasing as
result in incompetence of the bladder neck thus yielding retro- men age. Despite their prevalence they often go untreated or
grade ejaculation. RE is more commonly iatrogenic from surgi- misdiagnosed by clinicians. Patients may fail to bring up ejac-
cal or pharmacologic therapy. The clinician should pay special ulatory complaints because of embarrassment or a belief that
attention to the patient’s list of medications. As with other dis- no treatments are available. In turn, clinicians may be reluc-
orders of ejaculation, RE may be caused by many commonly tant to inquire about these conditions, or be unaware how to
prescribed drugs such as antidepressants (SSRIs, haloperidol, diagnose or treat. Once thought to be purely psychological
monoamine oxidase inhibitors, tricyclics) and agents that block conditions, recent investigation has demonstrated an organic
alpha-adrenergic function. Urologists and primary care physi- basis for several ejaculatory disorders, with PE receiving exten-
cians who prescribe alpha-blocker therapy for LUTS commonly sive attention in recent years. A complete sexual and medical
see this association. This side-effect of alpha-receptor blocking history and a directed physical examination are often essential
therapy is seen most commonly with tamsulosin, at a rate of to diagnose these disorders and categorize them appropri-
approximately 30%.33 It should be emphasized that ejaculatory ately. Once the treating clinician has determined the diagnosis
disorders are common in men with BPH and LUTS, even those and possible etiology, the appropriate therapy may be initi-
not treated with tamsulosin.2,3 Although questionnaires are in ated. As awareness and knowledge of the organic basis for
common use for evaluating LUTS in BPH-prone patients, no these disorders increases, innovative therapies will arise
questionnaire for the evaluation of ejaculatory disorders has that, when combined with behavioral therapy, can result in
been commonly implemented in these patients despite the effective treatment for these distressing conditions.

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2. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms 7-OH-DPAT on male rat ejaculatory behavior. Pharmacol Bio-
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9. Symonds T, Roblin D, Hart K, Althof S. How does premature ejac- 24. Perelman MA. Retarded ejaculation. Curr Sex Health Rep 2004; 1:
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11. Montague DK, Jarow J, Broderick GA, et al. AUA Erectile Dysfunc- Male Aging Study. J Urol 1994; 151: 54–61.
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14. Donatucci CF. Etiology of ejaculation and pathophysiology of pre- 28. Geboes K, Steeno O, De Moor P. Primary anejaculation: diagnosis
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15. Sharlip I. Diagnosis and treatment of premature ejaculation: the 29. Hovav Y, Dan-Goor M, Yaffe H, et al. Nocturnal sperm emission
physician’s perspective. J Sex Med 2005; 2: 103–9. in men with psychogenic anejaculation. Fertil Steril 1999; 72:
16. Rowland DL, Cooper SE, Schneider M. Defining premature ejacu- 364–5.
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18. Waldinger MD, Zwinderman AH, Olivier B, et al. Proposal for a retarding properties of paroxetine in patients with primary prema-
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23. American Psychiatry Association. Diagnostic and Statistical plus bladder neck incision versus standard transurethral prostatec-
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62 Medical treatment of
ejaculatory dysfunction
Chris G McMahon

Introduction behavior by several forebrain structures, including the medial

preoptic area (MPOA) and the nucleus paragigantocellularis
Ejaculatory dysfunction (EjD) is one of the most common (nPGi) (Figure 62.1).3,4 Descending serotonergic pathways
male sexual disorders. The spectrum of EjD extends from pre- from the nPGI to the lumbosacral motor nuclei tonically
mature ejaculation (PE), through delayed ejaculation, to a inhibit ejaculation.4 Disinhibition of the nPGI by the MPOA
complete inability to ejaculate (anejaculation), and includes facilitates ejaculation. A population of lumbar spinothalamic
retrograde ejaculation and painful ejaculation. The sexual (LSt) neurons has been identified in male rats, which consti-
response cycle comprises four interactive, non-linear stages: tute an integral part of the generation of ejaculation. LSt cells
desire, arousal, orgasm, and resolution. In males, the fourth send projections to the autonomic nuclei and motor neurons
stage of orgasm is usually coincident with ejaculation, but involved in the emission and expulsion phase, and they receive
represents a distinct cognitive and emotional cortical event. sensory projections from the pelvis.5 Several brain areas are
EjD is a disruption of the fourth stage of orgasm. activated after ejaculation by ascending fibers from the spinal
cord and may have a possible role in satiety and the post-
ejaculatory refractory time.
Animal and human sexual psychopharmacological studies
Physiology of ejaculation have attributed a serotonergic basis and possible genetic
Ejaculation is a reflex comprising sensory receptors and areas, etiology to PE.6–9 Male rat studies demonstrate that serotonin
afferent pathways, cerebral sensory areas, cerebral motor cen- (5-hydroxytryptamine, 5-HT) and 5-HT receptors are involved
ters, spinal motor centers, and efferent pathways. There are in the ejaculatory process. The speed of ejaculation appears
three basic mechanisms involved in normal antegrade ejacula- to be determined by 5-HT-2C and 5-HT-1A receptors. Stimu-
tion – emission, ejection and orgasm.1 Emission is the result lation of 5-HT-2C receptors with non-selective 5-HT-2C ago-
of a sympathetic spinal cord reflex initiated by genital or cere- nists delays ejaculation in male rats whereas stimulation of
bral erotic stimuli (or both) and involves the sequential con- postsynaptic 5-HT-1A receptors results in shorter ejaculation
traction of accessory sexual organs. Considerable initial latency.10 Administration of selective serotonin reuptake
voluntary control of emission progressively decreases until the inhibitors (SSRIs) results in active blockade of presynaptic
point of ejaculatory inevitability.2 Ejection also involves a membrane 5-HT transporters, and the resultant higher synap-
sympathetic spinal cord reflex over which there is little or no tic cleft levels of 5-HT activate postsynaptic 5-HT-2C and
voluntary control. Ejection involves bladder neck closure; 5-HT-1A receptors and delay ejaculation.7,11
rhythmic contractions of bulbocavernous, bulbospongiosus
and other pelvic floor muscles; and relaxation of the external
urinary sphincter.2 Orgasm is the result of cerebral processing Premature ejaculation
of pudendal nerve sensory stimuli resulting from increased
pressure in the posterior urethra, sensory stimuli arising from The American Psychiatric Association’s Diagnostic and
the veramontanum, and contraction of the urethral bulb and Statistical Manual, 4th edition, text revision (DSM-IV-TR)
accessory sexual organs. defines PE as ‘… persistent or recurrent ejaculation with min-
The ejaculatory reflex is predominantly controlled by a imal stimulation before, on, or shortly after penetration, and
complex interplay between central serotonergic and dop- before the person wishes it’. DSM-IV-TR goes on: ‘The clini-
aminergic neurons with secondary involvement of oxytocin- cian must take into account factors that affect duration of the
ergic, cholinergic, adrenergic, nitrergic, galanergic, and excitement phase (such as age, novelty of the sexual partner or
GABAergic neurons. The cerebral events that occur during situation, and recent frequency of sexual activity); whether the
ejaculation and the abnormalities present in men with PE disturbance causes marked distress or interpersonal difficulty;
have not been clearly defined with positron emission tomog- and whether the PE is not due exclusively to the direct effects
raphy (PET) and functional magnetic resonance imaging of a substance (e.g., withdrawal from opioids).’12
(fMRI) brain imaging techniques. Seminal emission and ejec- This multivariate definition is manifestly inadequate, with
tion are integrated into the complex pattern of copulatory a low predictive value for PE,13 but it does encompass the

474
 Medical treatment of ejaculatory dysfunction 475

Sensory
cortex MEApd BNSTpm

Hypothalamus Thalamus
MPOA SPFps

Somatosensory
tactile input
Brainstem
nPGi Efferent output Post-ejaculation
afferent input

Lumbosacral spinal cord

Pudendal nerves Sympathetic nerves

Tactile stimulation Penis Ejaculation

Figure 62.1 Central nervous system areas involved before, during, and after ejaculation. Somatosensory tactile input from the
genitals ascend to the cerebral cortex. Efferent pathways project from the hypothalamus to the sacral spinal cord and genitals. After
ejaculation, information is returned from the genitals to several brain areas. MEApd, posterodorsal medial amygdala; BNSTpm,
posteromedial bed nucleus of stria terminalis; MPOA, medial preoptic area; nPGi, nucleus paragigantocellularis; SPFps, medial
parvicellular subparafasicular nucleus of the thalamus. From J Urol 2002; 168: 2359–67.69

main dimensions of PE – ejaculatory latency, control, sexual 253 men (25.6%).23 Men with PE appear younger than those
satisfaction, and distress. without, and after adjusting for concomitant erectile dysfunc-
tion (ED) the risk of PE significantly decreased with aging.24
Epidemiology of premature ejaculation Higher levels of education, divorce, and the presence of social
phobia appear to increase the risk of PE.24,25 A decreased risk
PE is often reported, perhaps erroneously, as one of the most of PE has been reported in men with treated diabetes, and no
common male sexual disorders, and has been estimated to
association was found with hypertension, cardiac disease,
occur in 4–39% of men in the general community. However,
hypercholesterolemia, and peripheral or central neuropathy.
it remains poorly defined and inadequately characterized.14–20 Men with self-reported PE have a lower frequency of sexual
As a result, there is a substantial disparity between the reported intercourse and higher levels of intercourse-related anxiety,
incidence of PE in many epidemiological studies19 (which rely
and they note greater impairment in intercourse satisfaction
heavily on self-reported PE) and the incidence suggested by
and sexual relationship satisfaction compared with men with-
community-based normative stopwatch intravaginal ejacula-
out PE.26 However, they do not report a reduced quality of
tory latency time (IELT) studies.21
life, reduced sexual desire, or a reduced ability to become sex-
Most community-based epidemiological studies are limited
ually aroused.26,27
by their reliance on either patient self-report of PE or incon-
There are few published data on impact of birth country,
sistent and poorly validated definitions of PE. A recent multi-
religion, or culture on the prevalence of PE. An increased
national, community-based, age-ranging study of an unselected susceptibility to PE in men from the Indian subcontinent
‘normal’ population of 500 heterosexual couples, which
has been reported.28,29 Kinsey’s observation that Asian men
involved stopwatch timing of the IELT during sexual inter-
have shorter times to ejaculation than Caucasian men, who in
course, has provided previously lacking normative data.21 This
turn have shorter times to ejaculation than Afro-Caribbean
study demonstrated that the distribution of the IELT was pos-
men, has been interpreted to suggest that some races are
itively skewed, with a median IELT of 5.4 minutes (range,
more ‘sexually restrained’ than others.30,31 A recent study
0.55–44.1 minutes) (Figure 62.2). The median IELT decreased
reported a preponderance of men from Middle Eastern and
with age and varied between countries. The authors regarded
Asian backgrounds presenting for treatment of PE which
the 0.5 and 2.5 percentiles as acceptable standards of disease exceeded the representation of these ethnic groups in the local
definition in this type of skewed distribution, and proposed population.32,33
that men with an IELT of less than 1 minute (belonging to the
0.5 percentile) have ‘definite’ PE, while men with IELTs
between 1 and 1.5 minutes (between 0.5 and 2.5 percentile)
have ‘probable’ PE.22 Classification of premature ejaculation
In a study of 1326 consecutive men with PE, lifelong PE was The premise that PE is a psychosomatic disturbance and due to
present in 736 men (74.4%), and acquired PE was present in a psychologically overanxious personality was first suggested
476 Textbook of Erectile Dysfunction

100

80

Number of subjects (%) 60

40

20

0
0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800
Mean IELT (seconds)

Figure 62.2 Distribution of intravaginal ejaculatory latency times (IELT) in a random cohort of 491 men.21

Table 62.1 The four premature ejaculation (PE) syndromes

Variable Lifelong premature Acquired premature Natural variable Premature-like

ejaculation ejaculation premature ejaculation ejaculatory dysfunction
IELT Very short IELT (<1–1.5 (Very) short IELT (<1.5–2 Normal IELT (3–8 Normal or long IELT
minutes) minutes) minutes) (3–30 minutes)
Frequency Consistent (In)consistent Inconsistent (In)consistent
Etiology Neurobiological and Medical and/or Normal variation of Psychological
genetic psychological ejaculatory performance
Treatment Medication with or Medication and/or Psychoeducation, Psychotherapy
without counseling psychotherapy reassurance
Prevalence Low (?) Low (?) High (?) High (?)
IELT, intravaginal ejaculation latency time. From Drugs 2007; 67: 547–63.

by Schapiro in 1943. He classified PE as either primary (life- This type of PE should not be regarded as a normal variation
long) or secondary (acquired).34 The behavioristic view that in sexual performance and is characterized by inconsistent
chronic PE was the result of performance anxiety related to and irregular early ejaculation, often with reduced ejaculatory
a disturbing initial episode of PE was first proposed by control.41
Masters and Johnson.35 Most of the behavioral treatments Men with premature-like ejaculatory dysfunction complain
currently used are based on this premise. Waldinger has of PE but have a normal ejaculatory latency of 3–6 minutes. It
extended Schapiro’s classification to include lifelong PE, is characterized by a preoccupation with a subjective percep-
acquired PE, natural variable PE, and premature-like ejacula- tion of rapid ejaculation, with an IELT within the normal
tory dysfunction (EjD) (Table 62.1).36 range, but often with reduced ejaculatory control.
Lifelong PE is a syndrome characterized by a cluster of
core symptoms including early ejaculation at nearly every
intercourse, within 30–60 seconds in the majority of cases Defining premature ejaculation
(80%) or between 1–2 minutes (in 20%), with every or nearly Medical literature contains several univariate and multivariate
every sexual partner and from the first sexual encounters operational definitions of PE.12,42,43 The definitions of PE in
onwards. DSM-IV-TR and the International Classification of Diseases
Acquired PE differs in that sufferers develop early ejaculation (ICD)-10 of the World Health Organization differ substan-
at some point in their life having previously had normal ejacu- tially and are authority-based and not evidence-based, having
lation experiences; it may be due to psychological or relation- no support from controlled clinical trials or epidemiological
ship problems,37 ED,38 prostatitis39 or thyroid dysfunction.40 studies. This lack of agreement as to what constitutes PE has
In natural variable PE, the ejaculation time is never consis- hampered basic and clinical research into the etiology and
tently rapid but merely coincidentally and situationally rapid. management of this condition. Quantitative measures of
 Medical treatment of ejaculatory dysfunction 477

intercourse, such as the IELT, and subjective measures such as IELT upon satisfaction and distress appears to be mediated via
voluntary control over ejaculation or self-efficacy, the extent of its direct effect upon control.60 Clearly, the patient’s percep-
patient sexual satisfaction and the level of bother or distress, tion of control over ejaculation is central to understanding
have been employed as patient reported outcomes (PROs) in how PE is associated with satisfaction with sexual intercourse
PE clinical trials. Each of the three criteria above has been and ejaculation-related distress.
operationalized, although not always with consistency.44

Sexual satisfaction
Intravaginal ejaculatory latency time Men with PE report lower levels of sexual satisfaction than
Operationalization of PE using the length of time between men with normal ejaculatory latency. Patrick et al. reported
penetration and ejaculation, the IELT, forms the basis of most ratings of ‘very poor’ or ‘poor’ for sexual satisfaction in 31%
current clinical studies on PE. There is considerable variance of men with PE compared to 1% in a group of normal con-
of the latencies used to identify men with PE, with IELTs trols.58 The inability to control and defer ejaculation until the
ranging from 1 to 7 minutes, and none of the definitions is female partner was sexually satisfied on at least 50% of inter-
based on normative data or offers any supportive rationale for course attempts was proposed as a definition of PE by Masters
their proposed cut-off time.45–48 An average duration of inter- and Johnson.61 An inherent problem exists here in defining a
course of 4–7 minutes was reported by Gebhard, suggesting man as dysfunctional based on the sexual responsiveness of
that ejaculation before 4 minutes after intromission should be his partner. This definition implies that any male whose
considered premature.49 female partner has difficulty in reaching orgasm should be
IELT is measured by a stopwatch operated by the partner. labeled as a premature ejaculator. This definition is at odds
Treating physicians must interpret patient self-report of PE with the report that only 30% of women achieve orgasm
and self-estimation of IELT with some caution, since the during sexual intercourse regardless of the extent of their
estimation of ejaculatory latency by men and women may partner’s ejaculatory control and latency. Rowland reported
correlate poorly with stopwatch-recorded IELT. However, that over 89.4% of men with self-reported PE regarded
several authors have reported that patient self-estimation of fulfilling their partner’s sexual needs as very or extremely
IELT correlates reasonably well with subsequent stopwatch important.62
IELT.50–52 However, caution should be exercised in attributing
Waldinger et al. reported IELTs of less than 30 seconds and improved satisfaction solely to the effect of drug treatment,
less than 60 seconds in 77% and 90% of 110 men with PE, and contributions from other difficult-to-quantify issues such
respectively.53 McMahon et al. reported similar results in as intimacy, friendship, sexual attraction, and communication
1346 consecutive men with PE and a mean IELT of 43.4 sec- should not be ignored. Furthermore, men with PE are easily
onds.23 Predominant anteportal ejaculation (during foreplay) pleased and report improved satisfaction with minimal
occurred in 5.6% of men. Recent normative data parallel improvements in IELT. There is an inherent problem in
these findings in demonstrating a median IELT of 5.4 minutes using sexual satisfaction as a measure of treatment efficacy.
and suggests that men with an IELT of less than 1 minute It is at best a surrogate for treatment efficacy and must be
have ‘definite’ PE, while men with IELTs between 1 and regarded as a ‘soft’ study end-point compared to objective
1.5 minutes have ‘probable’ PE.22 end-points.

Voluntary control Distress

Kaplan and other authors have suggested that an inability to Existing definitions of PE include distress as an important
defer ejaculation voluntarily defines PE.54–57 Patrick et al. dimension of PE.12,43,63 However, the word ‘distress’ has nega-
reported ratings of ‘very poor’ or ‘poor’ for control over ejac- tive social implications and its existence is denied by most
ulation in 72% of men with PE compared with 5% in a group men with PE. This dimension of PE is better captured by the
of normal controls.58 However, control is a subjective measure word ‘bother’. One study reported that 64% of men with
that is difficult to translate into quantifiable terms, and it is PE rated their extent of personal distress as ‘quite a bit’ or
the most inconsistent dimension of PE. Control has yet to be ‘extreme’ compared to 4% in a group of normal controls.58
adequately operationalized to allow comparison across sub- The extent of psychological impact on patients, partners, and
jects or across studies. Grenier and Byers failed to demonstrate the overall relationship are perhaps the most important
a strong correlation between ejaculatory latency and subjec- aspects of treatment-seeking behavior and best define the
tive ejaculatory control.18 Several authors report that dimin- severity of PE.
ished control is not exclusive to men with PE and that some Although partner distress is a significant contributor to
men with a brief IELT report adequate ejaculatory control and treatment-seeking behavior, there is limited information
vice versa, suggesting that the dimensions of ejaculatory con- regarding the effect of PE on the partner. Several studies have
trol and latency are distinct concepts.18,58 Furthermore, there reported that the effects of PE on the female partner are inte-
is a higher variability in changes in control compared with gral to understanding the impact of PE on the male and on the
IELT in men treated with SSRIs.59 sexual relationship as a whole.64–66 Patrick et al. reported that
However, Rosen et al. report that control over ejaculation, 44% of partners of men with PE rated their extent of personal
personal distress, and partner distress was more influential in distress as ‘quite a bit’ or ‘extreme’ compared to 3% in a group
determining PE status than IELT.5 In addition, the effect of of partners of normal controls.58 Patrick et al. also reported
478 Textbook of Erectile Dysfunction

that partner PRO measures differentiated men with PE from Anxiety has been reported as a cause of PE by multiple
men without PE and correlated moderately with measures of authors and is entrenched in the folklore of sexual medicine
IELT and subject PRO measures. However, partner percep- as the most likely cause of PE despite scant empirical research
tions of PE generally indicated less dysfunction than those of evidence to support any causal role.34,54,70 Several authors have
subjects.58 Although PE adversely affects partner sexual satis- suggested that anxiety activates the sympathetic nervous sys-
faction, it appears to have minimal impact upon relationship tem and reduces the ejaculatory threshold as a result of an
satisfaction.65 Furthermore, partners of men with PE report earlier emission phase of ejaculation.54,70 The possibility that
relatively high levels of female sexual dysfunction.67,68 The high levels of anxiety and excessive and controlling concerns
observation that PE often pre-dates the time of onset of the about sexual performance and potential sexual failure might
women’s sexual symptoms suggests that PE may be a risk distract a man from monitoring his level of arousal and recog-
factor for female sexual dysfunction.67 nizing the prodromal sensations that precede ejaculatory
The design of all future studies on any aspect of PE inevitability has been suggested as a possible cause of PE by
should include a uniform operationalized multivariate defini- several authors.56,57,71–74 The causal link between anxiety and
tion of PE in which the dimensions of latency, control, satis- PE is speculative, is not supported by any empirical evidence,
faction, and distress or bother are defined, measured, and and is in fact contrary to empirical evidence, from some
analyzed as continuous variables without arbitrary cut-off researchers.75
values. Recent data demonstrate that almost half of men with ED
also experience PE.38 Men with early ED may intentionally
‘rush’ sexual intercourse to prevent premature loss of their
The etiology of premature ejaculation erection and ejaculate with a brief latency. This may be com-
Historically, attempts to explain the etiology of PE have pounded by the presence of high levels of performance anxi-
included a diverse range of biological and psychological theo- ety related to their ED, which serves only to worsen the
ries. Most of these proposed etiologies are not evidence-based prematurity. In the absence of a thorough sexual history, these
and are speculative at best. Psychological theories include the men may be incorrectly diagnosed as suffering from PE and
effect of early experience and sexual conditioning, anxiety, not the underlying ED.
sexual technique, the frequency of sexual activity, and psy-
chodynamic explanations. Biological explanations include
evolutionary theories, penile hypersensitivity, central neuro- Premature ejaculation drug trial design
transmitter levels and receptor sensitivity, degree of arousabil- The results of PE clinical drug trials are only reliable, interpre-
ity, the speed of the ejaculatory reflex, and the level of sex table, and capable of being generalized to patients with the
hormones. disorder studied when conducted in well-defined and consis-
There is little empirical evidence to suggest a causal link tent populations, using a double-blind placebo-controlled
between PE and any of the factors thought to cause PE. There study design, and consistent objective physiological measures
is, however, limited correlational evidence to suggest that life- or sensitive, validated outcome assessment instruments as
long PE is a genetically determined biological variable related study end-points.27 Subjects with lifelong and acquired PE
to the inherited sensitivity of central 5-HT receptors and that should be treated as separate PE subgroups, and subjects with
acquired PE is due to high levels of sexual anxiety, ED, or ED or other co-morbid sexual disorders should be either
lower urinary tract infection. excluded or treated as a separate subgroup.
Ejaculatory latency time is probably a biological variable, In PE studies, the study population should be well charac-
which is genetically determined and may differ between pop- terized, representative of the overall patient population, and
ulations and cultures, ranging from extremely rapid through defined using a multivariate definition of PE. As the popula-
average to slow ejaculation. Hyposensitivity of the 5-HT-2C tion of men with PE is not homogeneous, lifelong and acquired
or hypersensitivity of the 5-HT-1A receptors (or both) have PE should be treated as demographically and etiologically
been suggested as possible explanations of lifelong PE.11,69 distinct disorders and analyzed as separate PE subgroups.23
Men with low 5-HT neurotransmission and probable 5-HT-2C Subjects should be involved in a stable, monogamous, hetero-
receptor hyposensitivity may have their ejaculatory threshold sexual relationship, prepared to attempt intercourse on a
genetically ‘set’ at a lower point and ejaculate quickly and with regular basis and to provide written informed consent. The
minimal stimulation, whereas men with a higher set-point presence of comorbid ED should be evaluated using a vali-
can sustain more prolonged and higher levels of sexual stimu- dated instrument such as the International Index of Erectile
lation and can exert more control over ejaculation. Men with Function (IIEF) and patients with any degree of ED should be
a very high set-point may experience delayed or absent ejacu- either excluded from the study or treated as a separate sub-
lation despite achieving a full erection and prolonged sexual group. Patients with hypoactive sexual desire or other sexual
stimulation. Treatment with an SSRI activates the 5-HT-2C disorders, urogenital infection, major psychiatric disorders, a
receptor, elevates the ejaculatory threshold set-point, and history of drug and alcohol abuse, or contraindications to the
delays ejaculation. The extent of ejaculatory delay may vary study drug should be excluded from the study.
widely in different men according to the dosage and frequency Measurement of the IELT by stopwatch is the best method
of administration of the SSRI and the genetically determined to diagnose PE and the response to treatment, and should be
ejaculatory threshold set-point. Cessation of treatment results used as a primary efficacy end-point and reported as the fold
in re-establishment of the previous set-point within 5–7 days increase of median IELT over pre-treatment IELT. It is well
in men with lifelong PE. recognized that IELT in both the general population and in
 Medical treatment of ejaculatory dysfunction 479

men with PE is distributed in a positively skewed pattern.21,23 and in the screening phase of drug trials, and can measure
Waldinger’s assertion that reporting arithmetic means overes- response to treatment.
timates both baseline and end-point IELTs and his suggestion Clinical drug trial design in sexual medicine has largely
that either the median or geometric mean IELT values are relied on retrospective reporting of adverse effects after an
more representative of treatment response are well-founded.76,77 interval of up to 4 weeks, with the consequence that patient
The arithmetic mean IELT may exceed median values by as recall of the details, frequency, severity, duration, and tempo-
much as 45%.23 Furthermore, because a typical study popula- ral relationship of adverse events to dosing may be unreliable.
tion has a broad range of baseline IELT values (0–90 seconds), It has been suggested that adverse events be reported prospec-
reporting mean raw study-end IELT is confusing since it tively in a patient diary within 24 hours using a validated
incorrectly suggests that all men respond to that extent. The questionnaire, such as the UKU side-effect rating scale, and
study-end fold increase in median or geometric mean IELT is this would represent a significant advance in basic clinical trial
more representative of true treatment outcome and must be design.77,90
regarded as the contemporary universal standard.
Laboratory studies of EjD may be simplified by the use of
the Sexual Assessment Monitor (SAM), an electronic data col- Treatment of premature ejaculation
lector that comprises a vibrator to induce ejaculation and a
sensor to measure time to erection and IELT by the detection Over the past 15 years, an increasing number of publications
of ejaculatory pulses, but the role of such devices in large at- have reported the pharmacological treatment of PE with a
home phase 3 clinical trials is limited.78 Recent normative variety of different medications, which act centrally or locally
IELT data support earlier suggestions by several authors that to retard the psychoneurological control of ejaculation and
IELTs of less than 1 minute or less than 2 minutes be regarded subsequent orgasm.63 It is well established that major tran-
as cut-off points for inclusion in a clinical trial.21,44,76 quilizers and SSRIs retard ejaculation significantly and will, in
Subjective PROs of ejaculatory control, sexual satisfaction, a small percentage of men, result in anejaculation.91–93 The
and bother or distress are important additional efficacy end- efficacy of SSRIs in delaying ejaculation combined with the
points and can be evaluated using validated PRO instru- low side-effect profile make them first-line agents for PE,
ments.58,79–89 Symonds et al. report the development and administered either on a daily or an on-demand basis.76,94
validation of a brief self-administered five-item questionnaire,
the Premature Ejaculation Diagnostic Tool (PEDT), to diag-
nose PE in clinical trials.82 A pilot development tool of nine Psychosexual counseling
questions was derived from qualitative research involving In many relationships, PE causes few if any problems. In oth-
focus-group and individual interviews of men with either ers, the couple may reach an accommodation of the problem
physician-diagnosed or self-reported PE; this research was through various strategies – young men with a short refrac-
psychometrically analyzed and distilled into a five-item, tory period may often experience a second and more con-
0–25 score, unidimensional measure that captures the essence trolled ejaculation during a subsequent episode of lovemaking.
of DSM-IV-TR and the dimensions of control, satisfaction, Frequently however, PE eventually leads to significant rela-
personal distress, and interpersonal distress. The PEDT has tionship problems, with the partner regarding the man as self-
good convergent validity and re-test reliability, and sensitivity– ish and developing a pattern of sexual avoidance. This only
specificity analysis suggests that a score ≥11 indicates PE.83 worsens the severity of the prematurity on the occasions when
The PEDT is limited in several respects, but represents a sig- intercourse does occur.
nificant development towards simplifying the methodology The cornerstones of behavioral treatment are the Seman’s
of PE drug studies. Future development of this diagnostic ‘stop–start’ maneuver and its modification proposed by
tool would be incomplete without further validation of this Masters and Johnson, the squeeze technique. Both are based
tool to determine the potential relationship between score, on the theory that PE occurs because the man fails to pay
severity of PE, and response to treatment. sufficient attention to pre-orgasmic levels of sexual tension.61,95
The reliability of stopwatch IELT alone in assigning PE As most men with PE are aware of their anxiety and the
status, the use of PROs to replace stopwatch IELT, or the pre- sources of that anxiety tend to be relatively superficial, treat-
dictive value of single-item PRO measures compared with ment success with these behavioral approaches is relatively
multiple-item measures are incompletely understood issues. good in the short term but convincing long-term treatment
PRO measures, while providing important information, are at outcome data are lacking.55,96–98
best subjective and relate to highly interpretable and impre-
cise dimensions of ejaculation, and their significance is
weighted differently for different patients. On the other hand, Pharmacological treatment
IELT may not adequately categorize patients since some Pharmacological modulation of ejaculatory threshold repre-
patients with a brief IELT report little or no bother and are sents a novel and refreshing approach to the treatment of PE
therefore asymptomatic and so not ‘suffering’ from PE. and a radical departure from the psychosexual model of treat-
Clearly, none of the dimensions of PE can universally distin- ment, previously regarded as the cornerstone of treatment.
guish men with PE from non-PE men. The current consensus The introduction of the SSRIs has revolutionized the approach
is that a combination of stopwatch IELT and a validated PRO to and treatment of PE. SSRIs encompass five compounds:
of control, satisfaction, personal distress, and interpersonal citalopram, fluoxetine, fluvoxamine, paroxetine, and sertra-
distress can adequately identify PE status in prevalence studies line, all with a similar pharmacological mechanism of action.
480 Textbook of Erectile Dysfunction

Although the methodology of the initial drug treatment stud- reported that alfuzosin (6 mg/day) and terazosin (5 mg/day)
ies was rather poor, later double-blind and placebo-controlled were effective in delaying ejaculation in approximately 50% of
studies replicated the genuine effect of clomipramine and the cases.100 Similarly, Basar reported that terazosin was effec-
SSRIs to delay ejaculation. In spite of a development towards tive in 67% of men.101 However, both studies were limited by
more evidence-based drug treatment research, the majority of the use of subjective study end-points of patient impression of
studies still lack adequate design and methodology.99 A recent change and sexual satisfaction, and neither evaluated objec-
meta-analysis of all drug treatment studies demonstrated that tive end-points such as IELT.
only 14.4% had been performed according to the established However, in the rat model, systemic injection of tamsulosin
criteria of evidence-based medicine, and that open-design impaired bulbospongiosus muscle contractile capacity and
studies and studies using subjective reporting or question- bladder neck and seminal vesicle pressures, whereas alfuzosin
naires showed a higher variability in ejaculation delay than did not.102,103 Consistent with this, Hellstrom et al. reported
double-blind studies in which the ejaculation delay was decreased ejaculate volume in almost 90% of subjects and
prospectively assessed with a stopwatch.99 anejaculation in approximately 35% of participants with tam-
sulosin, but he failed to observe anejaculation with alfuzosin.104
Contrary to these results, a comparison of tamsulosin with
Daily treatment with selective serotonin alfuzosin in men symptomatic BPH and normal ejaculatory
reuptake inhibitors latency demonstrated minimal ejaculatory dysfunction.105,106
Daily treatment can be performed with paroxetine 20–40mg, Additional controlled studies are required to determine the
clomipramine 10–50mg, sertraline 50–100mg, or fluoxetine role of alpha-1-blockers in the treatment of PE.
20–40mg (Figure 62.3). Paroxetine appears to exert the stron-
gest ejaculation delay, increasing IELT approximately 8.8-fold
over baseline.99 Ejaculation delay usually occurs within 5–10 On-demand treatment with selective serotonin
days but may occur earlier. Adverse effects are usually minor, reuptake inhibitors
start in the first week of treatment, and gradually disappear Administration of clomipramine, paroxetine, sertraline, or
within 2–3 weeks; they include fatigue, yawning, mild nausea, fluoxetine 4–6 hours before intercourse is efficacious and well
loose stools, and perspiration. Diminished libido or mild ED tolerated but is associated with less ejaculatory delay than
is infrequently reported. Significant agitation is reported by a daily treatment. Daily administration of an SSRI is associated
small number of patients and treatment with SSRIs should be with superior increases in IELT compared with on-demand
avoided in men with a history of bipolar depression. administration, owing to the greatly enhanced 5-HT neuro-
transmission resulting from several adaptive processes, which
may include presynaptic 5-HT-1A and 5-HT-1B or 5-HT-1D
Daily treatment with alpha-1-adrenoceptor antagonists receptor desensitization (Figure 62.4).11 On-demand treat-
Ejaculation is a sympathetic spinal cord reflex that could theo- ment may be combined with either an initial trial of daily
retically be delayed by alpha-1-adrenoceptor blockers. Several treatment or concomitant low-dose daily treatment.94,107,108
authors have reported their experience with the selective The assertion that on-demand drug treatment of PE is
alpha-1-blockers alfuzosin and terazosin in the treatment of preferable to daily dosing parallels the rationale for the treat-
PE. In a double-blind, placebo-controlled study, Cavallini ment of ED but is contrary to personal experience and the

140
Placebo
Fluvoxamine 100mg
120
Paroxetine 20mg

100 Fluoxetine 20mg

Sertraline 50mg
Mean IELT
(seconds)

80

60

40

20

0
0 1 2 3 4 5 6
Weeks

Figure 62.3 Selective serotonin reuptake inhibitors produce ejaculatory delay within 5–10 days. IELT, intravaginal ejaculatory
latency time. From J Clin Psychopharmacol 1998; 18: 274–81.76
 Medical treatment of ejaculatory dysfunction 481

5-HT release 5-HT release 5-HT release

↑ Synaptic ↑ Synaptic ↑ Synaptic

5-HT 5-HT 5-HT

Activates 5-HT Blocks 5-HT Acute Blocks 5-HT Chronic

transporters transporters SSRIs transporters SSRIs

↓ Synaptic Desensitizes
↑↑ Synaptic ↑↑↑ Synaptic
5-HT 5-HT-1A
5-HT 5-HT
receptors

Activates Minimal Maximal

5-HT-1A 5-HT-2C 5-HT-2C
receptors activation activation

(a) (b) (c)

Figure 62.4 Synaptic cleft serotonin (5-hydroxytryptamine, 5-HT) and 5-HT neurotransmission are regulated by somatodendritic
5-HT-1A autoreceptors, presynaptic 5-HT-1B–1D autoreceptors and a 5-HT transporters reuptake system. As 5-HT is released into
the synaptic cleft from presynaptic axonal vesicles, 5-HT transporters reuptake and remove 5-HT from the synaptic cleft, preventing
over-stimulation of the postsynaptic receptors. (b) After blockage of 5-HT transporters by acute administration of selective serotonin
reuptake inhibitors (SSRIs), synaptic cleft 5-HT increases but is counteracted by activation of 5-HT-1A autoreceptors, which inhibit
further 5-HT release. (c) Chronic administration of SSRIs results in greatly enhanced 5-HT neurotransmission, owing to several
adaptive processes, which may include presynaptic 5-HT-1A and 5-HT-1B–1D receptor desensitization. From Int Clin Psychopharmacol
1998; 13 (Supp16): S9–14.7

results of the only PE drug preference study.109 Whilst many of PE. The pharmacokinetics of both single doses and multiple
men suffering from PE who infrequently engage in sexual doses over 6–9 days (30mg, 60mg, 100mg, 140mg, or 160mg)
intercourse may prefer on-demand treatment, the majority of have been evaluated. Dapoxetine has a time to maximum
men in established relationships prefer the convenience of concentration of 1.4–2.0 hours, and it rapidly achieves peak
daily medication. plasma concentration following oral administration.114 Both
plasma concentration and area under the curve (AUC) are
dose-dependent up to 100mg. The mean half-life of dapox-
On-demand treatment with dapoxetine etine after a single dose is 0.5–0.8 hours and plasma concentra-
A number of rapid-acting, short half-life SSRIs are under tions rapidly decline to about 5% of peak plasma concentration
investigation as on-demand treatments for PE. Dapoxetine is at 24 hours. The pharmacokinetics of dapoxetine and its meta-
an SSRI and was originally developed as a short half-life drug bolites were not affected by repeated daily dosing, and state
for the treatment of depression.110 In December 2004, a plasma concentrations were reached within 4 days, with only
new drug application was submitted to the Food and Drug modest accumulation of dapoxetine (approximately 1.5-fold).115
Administration in the USA for dapoxetine hydrochloride Food does not have a clinically significant effect on dapox-
as a drug to treat PE. Dapoxetine is a potent SSRI (binding etine pharmacokinetics.116
affinity, pKi = 8 nM), structurally similar to fluoxetine.111 Equi- No drug–drug interactions associated with dapoxetine have
librium radioligand binding studies using human cells dem- been reported. Co-administration of dapoxetine with ethanol
onstrate that dapoxetine binds to 5-HT, norepinephrine and did not produce significant changes in the pharmacokinetics
dopamine reuptake transporters and inhibits uptake in the of dapoxetine and its metabolites.117 Drug interaction studies
following rank order of potency: 5-HT> norepinephrine >> demonstrate that tadalafil, a phosphodiesterase (PDE) type 5
dopamine.112 Brain PET studies have demonstrated significant inhibitor used in the treatment of ED, did not affect the phar-
displaceable binding of radiolabeled dapoxetine in the cere- macokinetics of dapoxetine, whereas sildenafil increased the
bral cortex and subcortical gray matter.113 dapoxetine AUC by 22%.118 However, this was not regarded as
Dapoxetine undergoes rapid absorption and elimination, clinically important. Dapoxetine did not appear to affect the
resulting in minimal accumulation, and it has dose- pharmacokinetics of tadalafil or sildenafil.
proportional pharmacokinetics, which are unaffected by Preliminary data suggest that dapoxetine administered
multiple dosing. The pharmacokinetic profile of dapoxetine 1–2 hours prior to planned intercourse is modestly effective
suggests that it is a candidate for on-demand treatment and well tolerated, superior to placebo, and increases IELT
482 Textbook of Erectile Dysfunction

two- to three-fold over baseline in a dose-dependent fashion or very good increased from 2.8% at baseline to 51.8% and
(Figure 62.5).119 In randomized, double-blind, placebo- 58.4% at study end with dapoxetine 30mg and 60mg, respec-
controlled, multicenter, phase 3 12-week clinical trials involv- tively. Treatment-related side effects were uncommon and
ing 2614 men with a mean baseline IELT ≤2 minutes, dose-dependent; they included nausea, diarrhea, headache,
dapoxetine 30mg or 60mg was more effective than placebo for and dizziness, and they were responsible for study discontinu-
all study end-points.120 Mean IELT increased from 0.91 min- ation in 4% (30mg) and 10% (60mg) of subjects.
utes at baseline to 2.78 minutes (3.0-fold) and 3.32 minutes However, Waldinger et al. have suggested that dapoxetine-
(3.6-fold) at study end with dapoxetine 30mg and 60mg, induced ejaculation delay is marginal and has been systemati-
respectively, compared with a 1.9-fold increase with placebo. cally overestimated by the misleading use of arithmetic mean
Mean patient rating of control over ejaculation as fair, good, IELTs as opposed to geometric mean IELTs or median IELTs

4
*P=0.0006 3.32**
**P<0.001
3 2.78*
(minutes)
IELT

Baseline
2 1.75
Week 12

0.9 0.92 0.91

1

0
(a) Placebo Dapoxetine 30mg Dapoxetine 60mg

100

80
Subjects (%)

58.4
60
51.8 Baseline
Week 12
40
26.4
20
3.5 2.5 3.3
0
(b) Placebo Dapoxetine 30mg Dapoxetine 60mg

100

79.2
80
70.9

55.2
Subjects (%)

60 56.7
51.8 52.4
Baseline
Week 12
40

20

0
(c) Placebo Dapoxetine 30mg Dapoxetine 60mg

Figure 62.5 (a) Dapoxetine increased intravaginal ejaculatory latency time (IELT) from 0.91 minutes at baseline to 2.78 and
3.32 minutes at study end with dapoxetine 30mg and 60mg, respectively. (b) Percentage of subjects rating control over ejaculation
as fair, good, or very good increased from 3.1% at baseline to 51.8% and 58.4% at study end with dapoxetine 30mg and 60mg,
respectively. (c) Percentage of subjects rating sexual satisfaction as fair, good, or very good increased from 53.6% at baseline to
70.9% and 79.2 % with dapoxetine 30mg and 60mg, respectively. (Rating scale 0–5 scale, where 0 is very poor and 5 is very good.)
From Lancet 2006; 368: 929–37.120
 Medical treatment of ejaculatory dysfunction 483

at study end.77 They assert that the use of median IELTs at men treated with a combination of papaverine and phen-
study end would result in a substantially lower study end IELT tolamine administered by intracavernous auto-injection in
fold increase of 1.2, 1.9 and 2.3 for placebo, dapoxetine 30mg, which the treatment success was defined as prolongation of
and dapoxetine 60mg, respectively. This is of marginal clinical erection after ejaculation and not by any measure of ejacula-
significance, is only slightly higher than the 1.4-fold increase tory latency. Three of eight men stated that they were cured
of placebo and is substantially less than the 8.8-fold increase and suspended treatment while the other five men continued
seen with daily dosing of paroxetine.121 Waldinger et al. also using the medication. In the absence of well-controlled stud-
assert that the dapoxetine phase 3 study lacks an adequate ies, treatment of PE by intracavernous auto-injection cannot
methodology of assessment of dapoxetine-related adverse be recommended.
effects, since adverse effects were retrospectively assessed with
a non-validated questionnaire at each monthly visit to the
clinic.77 They cite the disparity between the incidence of Phosphodiesterase type 5 inhibitors
dapoxetine adverse effects in volunteer control pharmacoki- Medications that inhibit PDE-5 isoenzyme – sildenafil, tada-
netic studies and the dapoxetine phase 3 study as consistent lafil, and vardenafil – are effective treatments for ED. Several
with this aspect of inadequate study design and the risk of authors have reported their experience with PDE-5 inhibitors
underestimating the incidence of adverse effects like dizziness, alone or in combination with SSRIs as a treatment for PE.133–146
headache, and diarrhea.115,120,122 The putative role of PDE-5 inhibitors as a treatment for
It is likely that dapoxetine, despite its modest effect upon PE is based upon the role of the nitric oxide (NO)–cGMP
ejaculatory latency, has a place in the management of PE, transduction system as a central and peripheral mediator
which will eventually be determined by market forces once the of inhibitory non-adrenergic, non-cholinergic nitrergic neu-
challenge of regulatory approval has been met. rotransmission in the urogenital system.147 Several studies
suggest that elevation of extracellular NO in the MPOA
accelerates dopamine release and facilitates male copulatory
On-demand treatment with tramadol behavior of rats, whereas a decrease of NO reduces their cop-
The efficacy of on-demand tramadol in the treatment of PE ulatory behavior.148–150 Hull et al. demonstrated that microin-
was recently reported.123,124 Tramadol is a centrally acting syn- jection of the NO synthase (NOS) inhibitor, N-nitro-L-arginine
thetic opioid analgesic with an unclear mode of action that is methyl ester (NAME) decreased the number of erections, but
thought to include binding of parent and M1 metabolite to also increased the number of seminal emissions and decreased
micro-opioid receptors and weak inhibition of reuptake of the latency to the first seminal emission.151 The results indicate
norepinephrine and 5-HT.125 Serotonin syndrome has been that not only does NO promote erection in intact male rats,
reported as an adverse effect of tramadol alone or in combina- but it may also inhibit seminal emission.
tion with SSRIs.126,127 In a double-blind, placebo-controlled NOS isoenzymes are present in human seminal vesicle
study, the on-demand use of tramadol 50mg, taken 2 hours smooth muscle.152 Several authors have reported the effects of
prior to intercourse, exerted a clinically relevant ejaculation NO donor drugs on electrically induced contractions and on
delay in men with PE with a 12.7-fold increase in IELT.123 In a tissue levels of cGMP and cAMP in isolated human seminal
single-blind, placebo-controlled study, the on-demand use vesicle smooth muscle preparations and have concluded that
of tramadol 25mg, taken 1–2 hours prior to intercourse, was NO might be involved in the control of secretory activity and
associated with a 6.3-fold increase in IELT.124 Additional flex- smooth muscle function of human seminal vesicles.153–155
ible dose studies and long-term follow-up studies to evaluate Consistent with this, Kriegsfeld reported that mice homozy-
the risk of opioid addiction are required. gous for endothelial NOS (eNOS) gene deletion have striking
ejaculatory anomalies.156 A significantly higher percentage of
eNOS gene deletion mice than normal controls ejaculated
Anesthetic topical ointments during the testing period, requiring less stimulation and fewer
The use of topical local anesthetics such as lidocaine and mounts and intromissions.
prilocaine as a cream, gel, or spray is well established and is A recent systematic review of 14 studies published in peer-
moderately effective in retarding ejaculation. A recent study reviewed journals or the proceedings of major international
reported that a metered-dose aerosol spray containing a eutec- and regional scientific meetings on the PDE-5 inhibitor treat-
tic mixture of lidocaine and prilocaine produced a 2.4-fold ment for PE examined the role of NO as a neurotransmitter
increase in baseline IELT and significant improvements in involved in the central and peripheral control of ejaculation,
ejaculatory control and in both patient and partner sexual the methodology of PDE-5 inhibitor treatment studies, the
quality of life.128 They may be associated with significant penile adherence of methodology to the contemporary consensus of
hypoesthesia and possible transvaginal absorption, resulting ideal PE drug trial design, the impact of methodology on
in vaginal numbness and resultant female anorgasmia unless treatment outcomes, and the role of PDE-5 inhibitors in the
a condom is used.129–131 treatment of PE.157 These studies cover a total of 1102 subjects
suffering from PE and treated with sildenafil,133,137–140,146
tadalafil,142 or vardenafil,141 either as monotherapy or in com-
Intracavernous injection of vasoactive drugs bination with SSRIs,133,134,143,133–135,140–143,145,158 clomipramine,133
Intracavernous self-injection treatment of PE has been or topical anesthetics.143,146
reported but is without any evidence-based support for the Most of these studies support a role for PDE-5 inhibitors
efficacy of this strategy.132 Fein reported an open study of eight in the treatment of PE and speculate multiple mechanisms,
484 Textbook of Erectile Dysfunction

including a central effect involving increased NO and reduced with vardenafil reported by Sommer et al.141 indicates that
sympathetic tone, smooth muscle dilatation of the vas defer- reduced PE severity related to PDE-5 inhibitor use is due to
ens and seminal vesicles, which may oppose sympathetic improved erectile function. The IELT fold increase observed
vasoconstriction and delay ejaculation, reduced performance by Sommer et al. with on-demand sertraline (4.4) is less than
anxiety as a result of better erections, and down-regulation that reported in reviewed studies on men with normal erectile
of the erectile threshold to a lower level of arousal so function (mean 5.57, range 3.0–8.5),133,135,140,145 suggesting that
that increased levels of arousal are required to achieve the men with PE and comorbid ED are less responsive to on-
ejaculation threshold. demand SSRIs and are best managed with a PDE-5 inhibitor
The small number of publications and the lack of sufficient alone or in combination with an SSRI. Furthermore, the
data preclude any meta-analysis of results. However, exami- report of Chia that the addition of sertraline to sildenafil in
nation of the methodology of these studies, the adherence of the treatment of men with ED with comorbid PE was associ-
methodology to the contemporary consensus of ideal clinical ated with a lesser IELT fold increase (3.3) and lower levels of
trial design,159 and the impact of study methodology on treat- treatment satisfaction than that seen in men with lifelong PE
ment outcomes fails to provide any robust empirical evidence and normal erectile function treated with on-demand sertra-
to support a role of PDE-5 inhibitors in the treatment of PE, line, suggests that this group of men are less responsive to
with the exception of men with PE and comorbid ED. Of the pharmacotherapy.145
14 studies reviewed, only one fulfilled these criteria and this The proposed mechanism of action of PDE-5 inhibitors as
study failed to confirm any significant treatment effect on monotherapy or in combination with a SSRI in the treatment
IELT.138 of acquired PE in men with comorbid ED includes the ability
Caution should be exercised in interpreting data from inad- to maintain an erection following ejaculation, reduction of
equately designed studies of PDE-5 inhibitors and on-demand the erectile refractory period,138,160,161 and reliance upon a sec-
SSRI treatment, and their results must be regarded as unreli- ond and more controlled ejaculation during a subsequent epi-
able. The extremely broad range of IELT fold increases reported sode of intercourse, and a reduction in performance anxiety
with sildenafil (2.7–15.0, mean 6.6), combined sildenafil and due to better erections or down-regulation of the erectile
on-demand sertraline (3.3–10.0, mean 6.9), and combined threshold to a lower level of arousal so that increased levels of
sildenafil and on-demand paroxetine (6.6–14.9, mean 10.7) in arousal are required to achieve the ejaculation threshold.
this systematic review is testament to the unreliability of inad-
equate study design. In contrast to these findings, the range of
placebo IELT fold-increases was relatively narrow (IELT-range The future of drug development
1.2–1.6, mean 1.4) and was identical to the mean 1.4 IELT Several in vitro and animal studies have demonstrated that the
fold-increase reported in a meta-analysis of other PE drug desensitization of 5-HT-1A receptors, increased activation of
studies.59 postsynaptic 5-HT-2C receptors, and the resultant higher
increase in synaptic 5-HT neurotransmission seen with daily
dosing of SSRIs can be acutely achieved by blockade of these
Treatment of premature ejaculation and comorbid receptors by administration of an on-demand SSRI and a
erectile dysfunction 5-HT-1A receptor antagonist.162–164
There is evidence to suggest that PDE-5 inhibitors alone or in An increasing number of studies report the involvement of
combination with an SSRI may have a role in the management central oxytocinergic neurotransmission in the ejaculatory
of acquired PE in men with comorbid ED. This systematic process. In human males, plasma oxytocin levels are elevated
review includes three studies139,141,145 of patients with PE with during penile erection and at the time of orgasm.165,166 Electri-
comorbid ED treated with a PDE-5 inhibitor alone or in com- cal stimulation of the dorsal penile nerve produced excitation
bination with sertraline. In 45 men with PE and comorbid ED in about half of the oxytocin cells in the paraventricular
treated with flexible doses of sildenafil (50–100mg) for peri- nucleus and supraoptic nucleus of rats.167,168 In a rat model,
ods of 1–3 months, Li et al. reported improved erectile func- systematic administration of oxytocin facilitated ejaculation
tion in 40 (89%) and reduced severity of PE in 27 (60%).139 by reducing the number of intromissions required for ejacula-
Improved erectile function was reported by all of the 27 men tion, ejaculation latencies, and post-ejaculation intervals.169,170
with reduced severity of PE, of whom 81.5% described them- The use of oxytocin receptor antagonists may also have a
selves as satisfied or very satisfied. Contrary to these findings, role but there have been no reports of their efficacy in the
only 1 of the 18 men (5.6%) who did not obtain improvement treatment of PE.
of PE reported treatment satisfaction. Drug combinations of on-demand rapid-acting SSRIs
In a group of 37 men with primary or acquired PE and a and 5-HT-1A receptor antagonists or oxytocin receptor
baseline score from the erectile function domain of the Inter- antagonists, or single agents that target multiple receptors,
national Index of Erectile Function (IIEF) of 20.9 (consistent may form the foundation of more effective future on-demand
with mild ED), Sommer et al. reported a 9.7-fold IELT increase medication.
and normalization of erectile function (score of 26.9) with
vardenafil treatment as opposed to a 4.4-fold IELT increase
with on-demand sertraline.141 Surgery
The high level of correlation between improved erectile Several authors have reported the use of surgically induced
function with sildenafil and reduced severity of PE reported penile hypoesthesia via selective dorsal nerve neurotomy or
by Li et al.139 and the superior IELT fold-increase observed augmentation of the glans penis with hyaluronic acid gel in
 Medical treatment of ejaculatory dysfunction 485

the treatment of lifelong PE that is refractory to behavioral Men with natural variable PE and PE-like ejaculatory dys-
and pharmacological treatment.171 The role of surgery in the function should be managed with psychoeducation, reassur-
management of PE remains unclear until the results of further ance, or psychotherapy and should not, in general, be treated
studies have been reported. with pharmacotherapy.

Office management of premature ejaculation

Summary
Men with PE should be evaluated with a detailed medical and
sexual history, a physical examination, and appropriate inves- Recent epidemiological and observational research has
tigations to establish the true presenting complaint and to provided new insights into PE and the associated negative
identify obvious biological causes such as genital or lower uri- psychosocial effects of this dysfunction. Recent normative
nary tract infection (Figure 62.5). data suggest that men with an IELT of less than 1 minute
Men with PE secondary to ED, other sexual dysfunction, or have ‘definite’ PE, while men with IELTs between 1 and
genitourinary infection should receive appropriate etiology- 1.5 minutes have ‘probable’ PE. Although there is insufficient
specific treatment. Men with lifelong PE should be initially empirical evidence to identify the etiology of PE, there is
managed with pharmacotherapy. Men with significant con- limited correlational evidence to suggest that men with PE
tributing psychogenic or relationship factors may benefit from have high levels of sexual anxiety and altered sensitivity of
concomitant behavioral therapy. Men with PE secondary to central 5-HT receptors.
ED can be treated with either ED-specific pharmacotherapy The off-label use of SSRIs and clomipramine, along with
(e.g. PDE-5 inhibitors as monotherapy) or combination the development of new on-demand drugs for the treatment
therapy with PE-specific pharmacotherapy (e.g. daily or on- of PE, has drawn new attention to this common and often
demand SSRIs). Recurrence of PE is highly likely to occur ignored sexual problem. Daily administration of an SSRI is
following withdrawal of treatment. Men with acquired PE can associated with superior fold increases in IELT compared with
be treated with pharmacotherapy or behavioral therapy (or on-demand administration of SSRIs, including dapoxetine,
both) according to patient and partner preference. Restora- owing to greatly enhanced 5-HT neurotransmission resulting
tion of ejaculatory control in men with acquired PE is likely to from several adaptive processes, which may include presyn-
occur following completion of treatment but is the exception aptic 5-HT-1A and 5-HT-1B or -1D receptor desensitization.
in men with lifelong PE. Behavioral therapy may augment However, until the neurobiological, physiological, and
pharmacotherapy to enhance relapse prevention. psychological mechanisms responsible for PE are better

Premature ejaculation-like
ejaculation dysfunction Treatment:
Reassurance
Patient and partner history No Education
Natural variable Behavioral therapy
Yes premature ejaculation

Premature ejaculation

Yes

Manage
Premature ejaculation secondary to erectile
primary Yes
dysfunction or other sexual dysfunction
cause

No

Acquired premature ejaculation Lifelong premature ejaculation

Treatment: Treatment:
Behavioral therapy Patient SSRI pharmacotherapy
SSRI pharmacotherapy preference Behavioral therapy
Combination treatment Combination treatment

Attempt graduated withdrawal of

drug therapy after 6–8 weeks

Figure 62.6 Algorithm for the office management of premature ejaculation. SSRI, selective serotonin reuptake inhibitor.
486 Textbook of Erectile Dysfunction

understood, ideal treatment outcomes may remain elusive. be distinguished by examination of a post-masturbatory spec-
Drug treatment fails to address directly the causal psychologi- imen of urine for the presence of spermatozoa and fructose.
cal or relationship factors, and data are either lacking or scarce The finding of >5–10 sperm per high-power field in a post
on the efficacy of combined psychosexual counseling and ejaculation urine specimen confirms the presence of retrograde
pharmacological treatment, and on the maintenance of ejaculation. In patients with low-volume ejaculate, the finding
improved ejaculatory control after drug withdrawal. Drug of more sperm in the urine than in the antegrade ejaculate
combinations or single agents that target multiple 5-HT recep- indicates a significant component of retrograde ejaculation.172
tors may represent the next stage of PE drug development.

Treatment
Dry ejaculation Retrograde ejaculation can be surgically treated with bladder
neck reconstruction but results remain consistently poor.1,173
Dry ejaculation is a relatively common complaint in older Drug treatment is the most promising approach. As men-
men. It can be due to either retrograde ejaculation or true tioned earlier, alpha-adrenergic sympathetic nerves mediate
failure of emission. both bladder neck closure and emission. Several sympathomi-
metic agents have been described as useful, with mixed results.174
These drugs include pseudoephedrine and ephedrine, and
Retrograde ejaculation phenylpropanolamine. These agents work by stimulating the
Retrograde ejaculation is due to incompetence of the bladder release of norepinephrine from the nerve axon terminals but
neck mechanism most often following transurethral resection may also directly stimulate both alpha- and beta-adrenergic
of the prostate or open prostatectomy (Table 62.2). These men receptors. The most useful is pseudoephedrine, which is
may have some antegrade ejaculation and usually experience administered at a dose of 120mg 2–2.5 hours before inter-
orgasmic sensation. This may, however, be reduced as part course. The tricyclic antidepressant imipramine, which blocks
of the changes that occur in the male sexual response as a the reuptake of norepinephrine by the axon from the synaptic
man ages. Retrograde ejaculation and failure of emission can cleft, is also occasionally useful.175 The usual dose is 25mg
twice daily. Current feeling is that long-term treatment with
imipramine is likely to be more effective.
Table 62.2 Causes of retrograde ejaculation, delayed Whilst medical treatment may not always produce normal
ejaculation, anejaculation, and anorgasmia ejaculation it may result in some prograde ejaculation. In
patients who do not achieve antegrade ejaculation with either
Psychogenic Inhibited ejaculation surgery or medication, sperm retrieval and artificial insemina-
causes tion is an alternative approach. The basic method of sperm
Congenital causes Müllerian duct cyst retrieval involves recovery of urine by either catheter or void-
Wolffian duct abnormality ing after masturbation, and then centrifugation and isolation
Prune belly syndrome of the sperm.
Urethral valves
Anatomic causes Transurethral resection of prostate
Failure of emission
Bladder neck incision
Urethral stricture Any medical disease or surgical procedure that interferes with
Neurogenic Diabetic autonomic neuropathy the sympathetic nerve supply to the vas and bladder neck, the
causes Multiple sclerosis somatic efferent nerve supply to the pelvic floor, or the somatic
Spinal cord injury afferent nerve supply to the penis can result in failed emission
Radical cystectomy or prostatectomy or retarded ejaculation. Causes include spinal trauma, espe-
Proctocolectomy cially above the level of T10; the functional sympathectomy
Bilateral sympathectomy that can result from diabetic autonomic neuropathy and sur-
Abdominal aortic aneurysmectomy gical sympathectomies following a colectomy, proctectomy,
Para-aortic lymphadenectomy bilateral sympathectomy, abdominal aortic aneurysmectomy
Infective causes Urethritis and other vascular surgical procedures; open prostatectomy;
Genitourinary tuberculosis and retroperitoneal lymph node dissections for testicular
Schistosomiasis tumors (see Table 62.2). Ejaculatory dysfunction following
Endocrine causes Hypogonadism retroperitoneal lymph node dissections is a major concern
Hypothyroidism since it is a procedure usually performed on young men in the
Medication- and Alpha-methyl dopa prime of their reproductive years. Fossa et al., however, sug-
drug-related Ganglion blockers (guanethidine) gest that the use of a modified unilateral node dissection in
Alpha-1-adrenoceptor antagonists patients with Stage A tumors lowers the incidence of postop-
Thiazide diuretics erative ejaculatory disturbance without interfering with the
Tricyclics and selective serotonin excellent survival rates associated with standard treatment.176
reuptake inhibitors The progressive loss of the fast conducting peripheral
Antipsychotics (phenothiazines)
sensory axons, which begins to be apparent in the third decade
Alcohol abuse
of life, and the dermal atrophy, myelin collagen infiltration,
 Medical treatment of ejaculatory dysfunction 487

and pacinian corpuscle degeneration observed in older men, oedipal fears of retaliation, and fears of soiling or of defiling
may result in a degree of age-related degenerative penile hypo- the partner with semen.
esthesia and difficulty in achieving the ejaculatory threshold.177
This is anecdotally exaggerated in men with ED treated with
intracavernous pharmacotherapy and is often compounded Treatment
by the loss of pelvic floor muscle tone seen in the similarly As a rule, treatment of inhibited ejaculation with behavioral
aged, postmenopausal, and often multiparous sexual partners sex therapy tends to be less successful for orgasm inhibition
of these men. Certain medications can result in a type of than for other sexual disorders. The basic treatment strategy
‘chemical sympathectomy’; included in this category are requires that the man move by the method of successive
methyldopa and thiazide diuretics. approximation from extravaginal ejaculation to ejaculation in
Whilst retrograde ejaculation can be surgically treated with the vagina. A treatment sequence might involve a progression
bladder neck reconstruction, no surgical procedure exists for from solitary masturbation to masturbation with his wife in
the treatment of failed emission. As is the case with retrograde the next room, to masturbation in her presence but with her
ejaculation, drug treatment is the most promising approach. back turned, to masturbation with her looking on, to wife-
Whilst medical treatment may not always produce normal assisted masturbation to orgasm. Once he has traversed these
ejaculation, it may convert a patient with lack of emission into steps with successful ejaculatory outcome, the patient is asked
one with retrograde ejaculation and may result in small to insert his penis into the lubricated vagina just at the point
amounts of viable sperm, both of which can be combined of ejaculatory inevitability. After several repetitions of this
with standard artificial insemination techniques to produce a maneuver, which is designed to desensitize the man to the
pregnancy. anxiety associated with intravaginal orgasm, he is asked to
insert at plateau, but before ejaculatory inevitability. If he can
proceed to ejaculation he is given permission to insert yet ear-
Inhibited ejaculation lier in the sexual response cycle. The couple is encouraged to
Inhibited ejaculation is the psychogenic variant of retarded do everything possible to enhance the erotic aspects of the
ejaculation, also called ejaculatory incompetence by Masters sexual experience and the wife is taught how to cup her hus-
and Johnson.177 It may be defined as ‘recurrent and persistent band’s testicles for an extra sensation when he is at high levels
inhibition of the ejaculation’ as manifested by delay in or of erotic tension. Liberal use of fantasy is encouraged, as is the
absence of ejaculation following an adequate phase of sexual use of commercially available erotica. It is particularly impor-
excitement. It may range in severity from very severe, in which tant that the man not attempt insertion until he has reached
a man has never been able to experience waking climax even high levels of erotic tension during sex play.
with masturbation, to milder forms, in which intravaginal cli-
max occurs but only after prolonged thrusting. Clinically it is
the least common sexual disorder and it most often presents Drug treatment of delayed ejaculation
as a primary disorder. In most cases, however, the problem is and anejaculation
situational. Orgasm occurs readily with masturbation but not There are multiple reports in the literature of the use of a
during intercourse. variety of drugs in the treatment of delayed ejaculation or
Usually only the rare global case of retarded ejaculation anejaculation. The drugs facilitate ejaculation by either a
presents any difficulty with differential diagnosis. Secondary central dopaminergic or anti-serotoninergic mechanism of
retarded ejaculation, when it is situational, strongly suggests a action. There are no published placebo-controlled studies
problematic relationship. Global secondary retarded ejacula- and most reports are anecdotal case reports or series that deal
tion suggests the development of some psychophysiologic with the treatment of SSRI-induced ejaculatory dysfunction.
or pharmacologic cause, such as sedative hypnotic abuse, nar-
cotic abuse, or alcohol abuse. In very rare instances neurologic
disease or neurologic trauma may account for this disorder. Serotonin receptor antagonists
The prevailing wisdom holds that inhibited ejaculation is Several authors have reported that the cerebral serotoninergic
analogous to female anorgasmia. According to this theory, system exerts an inhibitory role on ejaculation and male sex-
psychogenically mediated reflex inhibition occurs despite high ual activity in the rat model and that the dopaminergic sys-
levels of sexual tension. Apfelbaum has proposed, however, tem, particularly in the anterior hypothalamus, has a
that the disorder is best understood as the surface manifesta- facilitatory role.180,181 The ejaculatory dysfunction commonly
tion of an underlying disorder of sexual desire.178 He has theo- associated with the antihypertensive alpha-methyldopa, which
rized that these patients, though they have erections, never reduces cerebral monoamine levels by suppressing the cere-
pass from initial penile engorgement to the plateau level with bral dopaminergic system, is consistent with these reports.182
high levels of sexual tension. There are patients who typify The occurrence of paradoxical hypersexuality (e.g. spontane-
both of the above perspectives but Martin believes that the ous orgasm) with clomipramine and fluoxetine, however,
majority of patients do reach plateau at some point during suggests that this balance is more complex and that different
thrusting only to experience reflex inhibition and subse- 5-HT receptor subtypes may have opposing effects on sexual
quently subside back to pre-plateau levels of tension.179 A wide function.183,184
variety of psychologic factors may be responsible for the inhi- The antihistamine cyproheptadine, which increases cere-
bition, including fear of impregnating the partner, religion, bral 5-HT levels, has been shown to increase male sexual
guilt, depressed or repressed hostility towards the partner, activity in the rat.180 The literature contains several anecdotal
488 Textbook of Erectile Dysfunction

case reports and other small case series of the use of cyprohep- dopamine ‘auto-receptors’, which decrease dopamine acti-
tadine to reverse the anorgasmia induced by the SSRI antide- vity and respond to lower doses than do the stimulatory
pressants but contains no controlled studies.185–190 These studies dopamine-2 receptors. In theoretical clinical use, lowering the
suggest an effective dose range of 2–16mg and administration dose to avoid excess excitement may result in worse sexual
on a chronic or on-demand basis. McCormick reported the dysfunction than existed before treatment. Human double-
use of cyproheptadine to reverse the anorgasmia induced by blind, placebo-controlled clinical studies of quinelorane were
the SSRI fluoxetine in two patients.185 Ashton et al. also reported commenced in the late 1980s. They took place at multiple sites
improvement in 12 of 25 men with SSRI-induced sexual dys- and involved more than 500 men and women with ED,
function with a mean dose of 8.6mg, with efficacy limited by reduced sexual desire, and reduced arousal. The US Food and
sedation and potential reversal of antidepressant effect.186 My Drug Administration review of the trial data was inconclusive
experience suggests a role for cyproheptadine in the treatment and concern was expressed over the >50% incidence of nausea
of both retarded ejaculation and anejaculation, which is and hypotension and the indirect negative sexual adverse
limited to a degree by its sedative effect. effects. Clinical studies were terminated and the results remain
confidential and unpublished.

Dopamine agonists
Central dopamine activity can be increased by a variety of Yohimbine
mechanisms, ranging from the provision of dopamine synthe- Several authors have reported their experience with yohim-
sis precursors (e.g. L-dopa) to the use of substitute neurotrans- bine, a derivative of the bark of the yocon tree, in the manage-
mitters to stimulate central dopamine receptors directly. ment of SSRI-induced sexual dysfunction.204–206 Yohimbine
Amantadine, an indirect stimulant of dopaminergic nerves is an alpha-2 antagonist, an alpha-1-adrenoceptor agonist,
both centrally and peripherally, which is used in the treatment and a calcium-channel blocker. It inhibits platelet aggrega-
of Parkinson’s disease and has a limited role as an antiviral tion. Price and Grunhaus reported reversal of clomipramine-
agent, has been reported to stimulate sexual behavior, ejacu- induced anorgasmia with a dose of 10mg administered
lation, and other sexual reflexes in rats.191,192 Several authors 90 minutes prior to coitus.204 In a placebo-controlled study
have reported a place for amantadine in the reversal of SSRI- of 15 patients with fluoxetine-induced anorgasmia, Jacobsen
induced anorgasmia.186,193–197 Ashton et al. reported improve- reported a 73% response rate to yohimbine.205 Hollander
ment in SSRI-induced sexual dysfunction in 8 of 19 men reported yohimbine reversal of anejaculation in five of
with a mean dose of 200 mg.186 Balon reported some efficacy six men with intercourse or masturbation (or both).206
with on-demand amantadine 100 mg administered 5–6 hours The response to yohimbine is typically delayed, taking up to
before coitus in a similar group of patients.193 8 weeks, and is often associated with adverse effects includ-
Several authors have reported induction of ‘PE’ in rats ing nausea, headache, dizziness, and anxiety. Careful dose
following administration of apomorphine, a central and titration is important since the extremes of dose have less
peripheral dopamine-2 receptor agonist, at a dose of 50 µg/kg. pro-sexual effect.
Dopamine receptor antagonists block this effect.198,199 A poten-
tial role for apomorphine in the management of ED was first
highlighted by Segraves et al.,200 and more recently Heaton 5-hydroxytryptamine-1A receptor agonists
et al.201 have reported an efficacy in excess of 50% with apo- Buspirone is a benzodiazepine class anxiolytic that possesses
morphine in patients with psychogenic ED when it is admin- 5-HT-1A receptor agonist activity.207 Othmer et al. reported
istered sublingually. Adverse effects of nausea, vomiting, normalization of sexual function in 8 of 10 men with a gener-
and dizziness are minimized with this sublingual route of alized anxiety disorder and associated sexual dysfunction
administration. using a dose range of 15–60mg daily.208 Bupropion is a novel
Quinelorane is a highly selective, potent dopamine-2 ago- antidepressant that prolongs the action of dopamine by redu-
nist that was extensively studied in animals in the early part of cing its uptake from the synaptic cleft.209 Ashton and Rosen
this decade. Foreman and Hall observed increased mounting, described reversal of SSRI-induced anorgasmia in 66% of
intromission, and ejaculation in both sexually inactive and patients studied. An improvement in sexual function was
sluggish rats following administration of quinelorane.202 Prior noted by Rowland in 14 non-depressed diabetic men with ED
administration of a dopamine antagonist eliminated these with on-demand doses of 75–150mg.210
stimulatory effects confirming that these sexual effects were
due to stimulation of dopamine receptors. They reported that
many rats failed to ejaculate at the extremes of doses, with low Mianserin
doses causing sedation and high doses causing hyperactive Aizenberg et al. examined the effect of the 5-HT-2a–2c and
behavior such as chewing or sniffing. Animals appear to alpha-2-receptor antagonist mianserin in the treatment of
become more sensitive to dopamine agonists with increased patients with sexual dysfunction induced by SSRIs.211 Nine of
use, suggesting that abuse may eliminate any sexual benefits. the 15 subjects reported a marked improvement in their sex-
Eaton et al. injected quinelorane directly into the rat paraven- ual functioning in the areas of orgasm and satisfaction, usually
tricular nucleus and MPOA and reported different response within the first and second week of mianserin treatment. The
with different doses.203 At extremes, quinelorane could cause authors suggested that co-administration of low-dose mian-
paradoxical PE, reduced sexual desire, and ED. The reduced serin might be an additional option in the treatment of sexual
sexual response observed at low doses is due to stimulation of dysfunction induced by SSRIs.
 Medical treatment of ejaculatory dysfunction 489

Table 62.3 Correlation of erection, ejaculation, and intercourse with level and severity of spinal cord injury213

Cord lesion Reflexogenic Psychogenic Successful Ejaculation (%)

erections (%) erections (%) coitus (%)

Upper motor neuron Complete 92 9 66 1

Incomplete 93 48 86 22
Lower motor neuron Complete 0 24 33 15
Incomplete 0 1 100 100
214
From Urol Int 1970; 25: 134–68.

Sperm retrieval reported that sperm density and motility were higher in those
In patients who do not achieve antegrade ejaculation with with incomplete lesions.217
either surgery or medication, sperm retrieval and artificial Vibratory stimulation is successful in obtaining semen in
insemination is an alternative approach if a pregnancy is up to 70% of men with SCI.218 This technique induces a reflex-
required. ogenic ejaculation via the sacral roots and the ejaculatory
co-ordination center in the upper thoracolumbar spinal cord.
It is, however, associated with a significantly higher risk of
autonomic dysreflexia than electro-ejaculation. Pre-treatment
Ejaculatory dysfunction in spinal with a fast-acting vasodilator such as nifedipine will minimize
cord injury the risk of severe hypertension should autonomic dysreflexia
occur with either form of treatment.219 Percutaneous aspira-
The ability to ejaculate is severely impaired by spinal cord tion of semen from the vas deferens has also been reported as
injury (SCI). Bors and Comarr highlighted the impact of the a means of harvesting semen for use with artificial reproduc-
level and completeness of SCI on the post-injury erectile and tive techniques.220
ejaculatory capacity (Table 62.3).212,213 Unlike erectile capacity, Semen collected from men with SCI is often initially senes-
the ability to ejaculate increases with descending levels of spi- cent and of poor quality, with a low sperm count and reduced
nal injury. Less than 5% of patients with complete upper sperm motility, but it may improve with subsequent ejacula-
motor neuron lesions retain the ability to ejaculate. Ejacula- tions. This poor semen quality may be due to chronic urinary
tion rates are higher (15%) in patients with both a lower tract infection, sperm contamination with urine, chronic use
motor neuron lesion and an intact thoracolumbar sympa- of various medications, elevated scrotal temperature caused
thetic outflow. Approximately 22% of patients with an incom- by prolonged sitting, and stasis of prostatic fluid. Testicular
plete upper motor neuron lesion and almost all men with biopsies in men with SCI demonstrate a wide range of testicu-
incomplete lower motor neuron lesions will retain the ability lar dysfunction, including hypospermatogenesis, maturation
to ejaculate. In those patients who are capable of successful arrest, atrophy of seminiferous tubules, germinal cell hypo-
ejaculation, the sensation of orgasm may be absent and retro- plasia, interstitial fibrosis, and Leydig cell hyperplasia. In
grade ejaculation often occurs. addition, prostatitis secondary to prolonged catheterization,
Several techniques for obtaining semen from SCI men with epididymitis, and epididymo-orchitis can precipitate obstruc-
ejaculatory dysfunction have been reported. The intrathecal tive ductal lesions and testicular damage.
administration of the anticholinesterase inhibitor neostigmine
and the subcutaneous administration of physostigmine to
induce ejaculation is more of historical interest and is no Painful ejaculation
longer used, owing to a 60% risk of autonomic dysreflexia,
especially in men with injuries above the T5 level.214,215 The use Painful ejaculation can be caused by any acute genitourinary
of electro-ejaculation to obtain semen by electrical stimula- infection, particularly acute prostatitis or seminal vesiculitis. It
tion of efferent sympathetic fibers of the hypogastric plexus is may also have a psychogenic basis. The former can be treated
an effective and safe method of obtaining semen. Brindley with antibiotics, non-steroidal anti-inflammatory agents, pro-
reported that 71% of men with spinal cord injury who under- static decongestants such as bromhexine, and, if indicated,
went electro-ejaculation achieved ejaculation.216 Ohl et al. prostate massage. The latter can be treated by sex therapy.

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inhibitors. J Urol 2005; 174: 201. tion: a comparative vardenafil and SSRI crossover study. J Urol
119. Hellstrom WJ, Gittelman M, Althof S. Dapoxetine HCl for the treat- 2005; 173: 202.
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121. Waldinger MD. Towards evidence-based drug treatment research 144. Linn R, Ginesin Y, Hardak S, Mertyk S. Treatment of sildenfil as
on premature ejaculation: a critical evaluation of methodology. part of the treatment in premature ejaculation. Int J Imp Res 2002;
Int J Impot Res 2003; 15: 309–13. 14: S39.
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145. Chia S. Management of premature ejaculation – a comparison of 167. Honda K, Yanagimoto M, Negoro H, et al. Excitation of oxytocin
treatment outcome in patients with and without erectile cells in the hypothalamic supraoptic nucleus by electrical stimu-
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146. Atan A, Basar MM, Tuncel A, et al. Comparison of efficacy of penis in the rat. Brain Res Bull 1999; 48: 309–13.
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EMLA-cream-only in treatment of premature ejaculation. Urology ing from the dorsal penile nerve excite oxytocin cells in the hypo-
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87–9. penis augmentation using hyaluronic acid gel for premature
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152. Machtens S, Uckert S, Stanarius A. Identification of NADPH- 174. Kedia K, Markland C. The effect of pharmacological agents on
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163. Williamson IJ, Turner L, Woods K, Wayman CP, van der Graaf 187. Feder R. Reversal of antidepressant activity of fluoxetine by
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164. de Jong TR, Pattij T, Veening JG, et al. Citalopram combined with gasmia by cyproheptadine. Acta Psychiatr Scand 1996; 93:
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166. Uckert S, Becker AJ, Ness BO, et al. Oxytocin plasma levels Clin Neuropharmacol. 1995; 18: 320–4.
in the systemic and cavernous blood of healthy males during 191. Ferraz MR, Santos R. Amantadine stimulates sexual behavior in
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192. Yells DP, Prendergast MA, Hendricks SE, Miller ME. Monoamin- 207. Witkin JM PL. Comparison of effects of buspirone and gepirone
ergic influences on temporal patterning of sexual behavior in with benzodiazepines and antagonists of dopamine and sero-
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193. Balon R. Intermittent amantadine for fluoxetine-induced anorgas- 1989; 3: 247–54.
mia. J Sex Marital Ther 1996; 22: 290–2. 208. Othmer E OS. Effect of buspirone on sexual dysfunction in
194. Shrivastava RK SS, Overweg N, Schmitt M. Amantadine in the patients with generalized anxiety disorder. J Clin Psychiatry 1987;
treatment of sexual dysfunction associated with selective sero- 48: 201–3.
tonin reuptake inhibitors. J Clin Psychopharmacol 1995; 15: 209. Cooper BR HT, Maxwell RA. Behavioral and biochemical effects
83–4. of the antidepressant bupropion (Wellbutrin): evidence for selec-
195. Balogh S HS, Kang J. Treatment of fluoxetine-induced anorgasmia tive blockade of dopamine uptake in vivo. J Pharmacol Exp Ther
with amantadine. J Clin Psychiatry 1992; 53: 212–13. 1980; 215: 127–34.
196. Valevski A MI, Zbarski E, Zemishlany Z, Weizman A. Effect of 210. Ashton AK RR. Bupropion as an antidote for serotonin reuptake
amantadine on sexual dysfunction in neuroleptic-treated male inhibitor-induced sexual dysfunction. J Clin Psychiatry 1998; 59:
schizophrenic patients. Clin Neuropharmacol 1998; 21: 355–7. 112–15.
197. MJ. G. Treatment of sexual side effects with dopaminergic agents. 211. Aizenberg D GS, Zemishlany Z, Granek M, Jeczmien P,
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198. Napoli-Farris L, Fratta W, Gessa GL. Stimulation of dopamine the treatment of sexual dysfunction induced by serotonin reuptake
autoreceptors elicits ‘premature ejaculation’ in rats. Pharmacol inhibitors. Clin Neuropharmacol 1997; 20: 210–14.
Biochem Behav 1984; 20: 69–72. 212. Bors E, Comarr AE. Neurological disturbances of sexual function
199. Kaplan JM, Hao JX, Sodersten P. Apomorphine induces ejacula- with special reference to 529 patients with spinal cord injury.
tion in chronic decerebrate rats. Neurosci Lett 1991; 129: 205–8. Urol Surv 1960; 10: 191.
200. Segraves RT BM, Segraves K, Spirnak P. Effect of apomorphine on 213. Comarr AE. Sexual function among patients with spinal cord
penile tumescence in men with psychogenic impotence. J Urol injury. Urol Int 1970; 25: 134–68.
1991; 145: 1174–5. 214. Spira R. Artifical insemination after intrathecal injection of
201. Heaton JP MA, Adams MA, Johnston B, el-Rashidy R. Recovery neostigmine in a paraplegic. Lancet 1956; 1: 670–1.
of erectile function by the oral administration of apomorphine. 215. Guttmann L, Walsh JJ. Prostigmin assessment test of fertility in
Urology 1995; 45: 200–6. spinal man. Paraplegia 1971; 9: 39–51.
202. Foreman MM, Hall JL. Effects of D2-dopaminergic receptor stim- 216. Brindley GS. Sexual and reproductive problems of paraplegic
ulation on male rat sexual behavior. J Neural Transm 1987; 68: men. Oxf Rev Reprod Biol 1986; 8: 214–22.
153–70. 217. Ohl DA, Bennett CJ, McCabe M, Menge AC, McGuire EJ. Predic-
203. Eaton RC, Markowski VP, Lumley LA, et al. D2 receptors in the tors of success in electroejaculation of spinal cord injured men.
paraventricular nucleus regulate genital responses and copula- J Urol 1989; 142: 1483–6.
tion in male rats. Pharmacol Biochem Behav 1991; 39: 177–81. 218. Brindley GS. The fertility of men with spinal injuries. Paraplegia
204. Price J GL. Treatment of clomipramine-induced anorgasmia with 1984; 22: 337–48.
yohimbine: a case report. J Clin Psychiatry 1990; 51: 32–3. 219. Steinberger RE, Ohl DA, Bennett CJ, McCabe M, Wang SC.
205. Jacobsen FM. Fluoxetine-induced sexual dysfunction and an Nifedipine pretreatment for autonomic dysreflexia during electro-
open trial of yohimbine. J Clin Psychiatry 1992; 53: 119–22. ejaculation. Urology 1990; 36: 228–31.
206. Hollander E MA. Yohimbine treatment of sexual side effects 220. Hovatta O, von Smitten K. Sperm aspiration from vas deferens
induced by serotonin reuptake blockers. J Clin Psychiatry 53: and in-vitro fertilization in cases of non-treatable anejaculation.
207–9. Hum Reprod 1993; 8: 1689–91.
63 Topical agents for the treatment of
premature ejaculation
Michael G Wyllie

Introduction Considering that the frequency of sexual intercourse is

highly variable, and spontaneity in sexual intercourse is usually
Premature ejaculation (PE) or rapid or early ejaculation is an important factor, the ideal treatment for PE would have
generally regarded as one of the most common male sexual the following characteristics; it would:13
problems, with an incidence of 20–30%.1–4 Some have sug-
gested a prevalence as high as 75%,5 although the actual • be discreet;
incidence of PE depends on how PE is defined. • be an ‘on-demand’ therapy;
Numerous definitions of PE exist, but one of the most • have rapid action;
commonly accepted is that from the Diagnostic and Statistical • be effective from the first dose;
Manual of Mental Disorders, 4th edition (DSM-IV),6 which • have high efficacy on IELT and patient-reported outcomes;
defines PE as ‘the persistent or recurrent onset of orgasm and • have a low incidence of side-effects; and
ejaculation with minimal sexual stimulation before, on, or • have no unwanted effect on the partner.
shortly after penetration and before the person wishes it’. This It has also been suggested that medication could be used to
definition is a subjective one and does not seek to quantify restore confidence together with behavioral treatment, where
ejaculatory latency. In practice the intravaginal ejaculatory available, to help men to learn to overcome PE on their
latency time (IELT), measured with a stopwatch, is commonly own.14,15 PE is of course not a life-threatening condition;
used as a way of quantifying PE and treatment success, and therefore safety should be a primary consideration when
also as a standardized way of comparing treatments in clinical deciding on a course of treatment.16
research. Considerable variation exists as to where the thresh-
old IELT should be set to define PE, although the consensus
of opinion seems to be that men with PE tend to have an IELT Current approaches to treatment
of 1–2 minutes or less.7–9
However, the impact that PE has on quality of life is There are a range of treatment options for men with PE,
significant,3 with a similar qualitative impact on the sufferer as directed at different components of the complex mechanism
erectile dysfunction.10 Consequently, there is now general of the ejaculatory process. These include behavioral therapy,
agreement that although IELT comparisons are valuable, the systemic treatments, and topical therapies. However, there are
evaluation of treatments in well-designed clinical trials should currently no pharmacological agents approved for use in PE,
include measures of sexual satisfaction (by the man and his and all drugs have to be administered off-label.
partner), and perception of control over ejaculation, in addi- Current recommendations from the American Urological
tion to IELT.8,11 Association (AUA)16 and the second International Consulta-
PE is a self-diagnosed condition and most men with the tion on Sexual Dysfunctions (ICSD)8 recognize that PE is a
condition do not seek treatment, for reasons of embarrass- self-reported diagnosis and emphasize the importance of
ment, shame, or the belief that no effective treatment exists, obtaining a comprehensive sexual history when making a
but they may try self-help techniques or self-medication: In a diagnosis; no laboratory or physiological tests are usually
large multi-country survey of more than 11,500 men in the required. It is recommended that clinicians also determine if
USA, Italy, and Germany, fewer than 12% of men who self- there is concomitant ED and, if present, it should be treated
reported PE had sought treatment.12 In a small survey involving first.8,16 The management algorithm for PE produced by the
in-depth interviews with 28 men with self-diagnosed PE, 89% ICSD recommends pharmacotherapy with a selective sero-
had tried some form of treatment (including behavioral ther- tonin reuptake inhibitor (SSRI) or topical anesthetics as the
apies, pharmaceutical agents, over-the-counter remedies, first-line treatment in patients with lifelong PE and as second-
herbal remedies, creams, and condoms), regardless of whether line treatment in patients with acquired PE.8 In reality, phar-
or not they had consulted a healthcare professional.10 Such a macotherapy is likely to be used first-line in both cases, owing
high figure indicates that men experiencing PE are highly to the limited availability of skilled sex therapists and relation-
motivated to seek a solution or treatment. ship counselors.

495
496 Textbook of Erectile Dysfunction

Patient complaining of premature ejaculation

Patient and partner history

Establish presenting complaint Onset and duration of premature ejaculation

Intravaginal Ejaculatory Latency Time (IELT) Degree of patient or partner distress
Perceived degree of ejaculatory control Psychosocial history
Medical history Physical examination

Manage Premature ejaculation secondary to

primary erectile dysfunction or other sexual
Yes
cause dysfunction?

No

Acquired premature Lifelong premature

ejaculation ejaculation

Pharmacotherapy
Selective serotonin reuptake
inhibitors
Topical agents

Attempt graduated withdrawal of pharmacotherapy

after 6–8 weeks

Behavioral therapy Combined therapy

Stop–start technique Pharmacotherapy and
Squeeze technique behavioral therapy/or
Sensate focus relationship counseling
Relationship counseling

Attempt graduated withdrawal of pharmacotherapy

after 6–8 weeks

Figure 63.1 Management algorithm for premature ejaculation. Modified from Lue TF, Basson R, Rosen R, et al. Sexual Medicine:
Sexual Dysfunctions in Men and Women. Paris: Edition 21, 2004: 411–68.8

The choice between oral therapy with SSRIs (daily or such therapies can be useful for some couples, they are rarely
as-needed), or the use of a topical agent is a decision to be successful in the long term since most post-therapy benefits
made jointly by the patient or couple and the physician after are lost within 3 years of treatment without regular follow-up
the physician has ascertained their desires and expectations. therapies.17,18 In addition, the high cost and limited availability
If acceptable to the patient or couple, a trial of a topical agent of sex therapists means that this approach is not always prac-
could be a prudent first step, owing to the favorable risk– tical and indeed is not suitable for men without a steady and
benefit ratio of these products. This is reflected in the treat- supportive sexual partner.
ment algorithm in Figure 63.1, which is modified from the
ICSD recommendations.8
Systemic therapy
The AUA currently recommends three drug treatment strate-
Behavioral therapy gies to treat PE:16
Behavioral therapies for PE (such as the ‘stop–start’ and 1. Daily treatment with serotonergic antidepressants
‘squeeze’ techniques) require a high level of commitment 2. As-needed treatment with serotonergic antidepressants
and the involvement of the man’s sexual partner. Although 3. Anesthetic topical treatment.
 Topical agents for the treatment of premature ejaculation 497

Delayed ejaculation is a common side-effect of many over-the-counter remedies and the ‘off-label’ use of local
psychotropic or antidepressant drugs, in particular of the anesthetics. However, there are also novel desensitizing
serotonergic tricyclic antidepressant clompiramine and the agents specifically designed to treat PE in development.
SSRIs fluoxetine, paroxetine, and sertraline.13,19,20 These drugs, Compared with orally delivered treatments for PE, topical
which are primarily indicated for the treatment of depression, treatments are appealing in that they can be applied on an as-
can increase the level of serotonin in the brain, inhibiting needed basis and because systemic side-effects are likely to be
the ejaculatory reflex center, and they can prolong IELT for minimal. However, the application of a desensitizing agent to
several minutes. the penis does have the potential for some degree of penile
Dosing levels of SSRIs are generally lower for PE than for hypoesthesia and theoretically, transvaginal contamination
depression, and various dosing regimens have been tested and female genital hypoesthesia as side-effects.
(including continuous, daily, or situational). Despite this the An important consideration for physician and patient,
adverse-event profile appears to be similar; adverse events in this era of evidence-based medicine, is whether there is
include dry mouth, drowsiness, nausea, and reduced libido.21 adequate supportive clinical data for the use of these off-label
There is also the potential for development of a serious drug and novel topical agents. The efficacy and adverse-events
interaction that can lead to serotoninergic syndrome, which profiles for topical treatments, where available, are discussed
manifests itself as headache, nausea, sweating, and dizziness in in the following sections, and comparative data are presented
mild cases and as hyperthermia, rigidity, and delirium in in Table 63.1.
severe cases.21 Many physicians may consider the side-effects
hard to justify for the treatment of PE, in which the primary
outcome is patient satisfaction, although the AUA has sug- Over-the-counter topical treatments
gested that the level of adverse events is acceptable for the
benefit derived by the patient with PE, and the type and rate Lidocaine spray
of occurrence of side-effects also appears to be acceptable to Lidocaine 9.6% spray, marketed as ‘Studd 100’ or ‘Premjact’,
most patients.16 has been available over the counter for over 25 years in some
Dapoxetine, a novel SSRI, is the first oral agent specifically countries and, as their names suggest, these are marketed as
developed for the management of PE and it has been shown products for delaying ejaculation. However the absence of
to be effective, well tolerated, and suitable for on-demand reliable data from clinical trials means that the validity of the
use.22 Further research with this drug continues despite the US claims by the manufacturers cannot be assessed.
Food and Drug Administration’s non-approval of dapoxetine
for the treatment of PE in 2005.23
Severance secret-cream
Severance secret-cream (SS-cream; Cheil Jedan Corporation,
Seoul, Korea), developed at the Yong-Dong Severance Hospital
Rationale for the use of in Korea is made with extracts from nine natural products.
topical treatment Some of these products have local anesthetic as well as vasoac-
tive properties. Several studies using SS-cream on men with
There are a variety of theories concerning the etiology of PE.8 PE have been carried out in Korea, but the cream is not
Historically, PE was considered a learned behavior and, as approved for use in Europe or the USA and is not legally
a result, behavioral therapy was the standard treatment. available outside Korea.
However, it is now generally accepted that both biological and SS-cream is applied to the glans penis 1 hour before inter-
psychological factors are important in the etiology of PE. Men course and washed off immediately prior to coitus. Both the
with PE appear to have a heightened sensory response to latency and amplitude of somatosensory evoked potentials
penile stimulation, with a vibration threshold significantly measured at the glans penis were increased over baseline after
lower than that of normal men.24,25 They also generally exhibit the application of SS-cream,28 which has also been shown to
other abnormal autonomic reflex pathways for the ejaculatory increase the penile vibratory threshold at the glans penis in a
process, including shorter bulbocavernous latency time, and dose-dependent fashion.29 Xin et al. reported significantly
higher bulbocavernous evoked potentials.25–27 Considering prolonged ejaculatory latency in 89.2% of patients treated
these sensory differences in men with PE, agents that selec- with SS-cream.30 Adverse effects were noted in 5.9% of
tively produce some degree of penile desensitization or act patients; these included mild local irritation (local burning or
within the afferent–efferent reflex should be effective therapy pain) and delayed ejaculation.
for PE. Thus, reducing the sensitivity of the glans penis with The prologation of IELT has been shown to be dose-
topical desensitizing agents (such as local anesthetics) should dependent,31 with an optimal dose of 0.2g cream. In a multi-
delay ejaculatory latency without adversely affecting the center, double-blind study involving 106 patients, the use of
sensation of ejaculation. 0.2g of SS-cream was reported to increase the mean stop-
watch-measured IELT from a baseline of 1.37 minutes to
10.92 minutes, compared with 2.45 minutes with placebo
Current status of topical treatments (p<0.001) and was 27 times more effective than placebo in
increasing sexual satisfaction (p<0.001). However, almost 19%
As described above there is currently no approved pharma- of episodes of use were associated with mild localized irrita-
cological therapy for PE and this has led to the use of tion, including pain and burning, and 12 patients reported
 Table 63.1 Comparative efficacy and adverse event data for clinical trials of topical treatments for PE

Reference Treatment Summary methods N completing study Baseline IELT, Follow-up IELT Satisfaction (man) AE, incidence – for
(mean age or range, mean (SD), min mean (SD), min active treatment
years)

EMLA cream

Berkovitch et al. 2.5 g (pilot study) Applied to glans penis 11a (36) ND ND 5/11 excellent 1/11
199534 and penile shaft 30 min 4/11 better
before intercourse; 2 no changeb
covered with condom
498 Textbook of Erectile Dysfunction

Atikeler et al. 2.5 g, (placebo- 4 groups × 10 men: 3 40c (29.4) <1 min Placebo 1.0 ND 16/40 = erection loss
200235 controlled, applying 2.5 g, covered 20 min group 6.71 (numbness)
dose-finding study) with condoms and (2.54) (6/10 in 30 min
waiting 20, 30 or 45 30 min group 8.7 group 10/10 in 45
min, + placebo group (1.70) min group)
45 min group loss
of erection in all
Busato & Double-blind, A ‘thin layer’ applied to 29d (completing Placebo Placebo 1.95 (0.12) EMLA 11/16 great/ Men, all, 17% (5/29)
Galindo 200436 placebo-controlled the glan penis and up study) 1.67 (0.7) EMLA 8.45 (0.9) excellente Women partners
to 2 cm of penile shaft; Placebo (32.3) EMLA 1.49 (0.9) p < 0.001 1/29
covered with a condom EMLA (33.4) (placebo vs EMLA)
for 10–12 min
TEMPE spray

Henry & 30–50mg 3–5 sprays (30–50 mg) 11c (42) 1.4 (1.1) 11.35 (10:72) 8/11 better/much Men 3/11
Morales 200337 (proof of concept) to glans penis; in situ p = 0.008 vs betterb Women 2/11
for 15 min; wipe of baseline 7/11 partners
before contact with better/much
partner betterb
Dinsmore et al. 30–50mg 3–5 sprays (30–5mg) to 54c TEMPE 1.0 (1:2) TEMPE 4.9 (4.9) Mean change in Men 4/26
200638 (double-blind, glans penis; in situ for TEMPE (38.5) Placebo 0.9 (0.7) Placebo 1.6 (1.6) SQoL points Female 1/26
placebo-controlled) 15 min; wipe off before Placebo (39.3) p < 0.01 vs baseline baseline to end of
contact with partner treatmentf
Men: TEMP 7.0
Placebo 5.5
(p = 0.48)
Women
TEMP 3.3
Placebo 1.8
(p = 0.56)
Dyclonine/alprostadil cream

Gittelman et al. Comparison of Cream administered ‘to 30g (28–62) Not stated Placebo 2.34 (0.34) %answering ‘yes’ Placebo 5%
200532 cream formulation; tip of the penis at the Dyclonine 3.21 to patient Dyclonine 17.5%
dyclonine 1%, meatus’ 5–10 min (0.31) satisfaction Alprostadil 20%
alprostadil 0.4%, before coitus Alprostadil 3.75 question in diary Dyclonine/
dyclonine 0.5%/ (0.34) Placebo 66.7 Alprostadil 17.5%
alprostadil Dclonine/alprostadil Dyclonine 73.3 All AEs were local
(placebo 4.08 (0.3) Alprostadil 83.3 and mild to moderate
controlled) p < 0.05 vs placebo Dyclonine/ in nature
Alprostadil 86.7
SS-cream

Xin et al. 199727 0.1g Applied 1 hour before 186h (42.3) 1.50 (0.58) 10.89 (5.60) % Satisfied with Overall 5.9% (11/86)
sexual contact and p < 0.001 vs baseline treatmenti 7/186 mild local
washed off before Not satisfied irritation
intercourse (10.8) 4/186 delayed
Satisfied (89.2%) ejaculation
Choi et al. 0.05g Applied 1 hour before 50c (37) 1.35 (0.07) Placebo 2.27 (0.32) Sexual satisfaction All test trials:
199928 0.10g sexual contact and SS-cream: ratioj 14.8% (37/250) mild
0.15g washed off before 0.05g 4.47 (0.81) Placebo 26% local burning
0.20g intercourse 0.10g 5.34 (0.79) SS-cream: sensation
(placebo 0.15g 6.22 (0.87) 0.05g 60% 0.04 (1/250) mild
controlled) 0.20g 11.06 (1.17) 0.10g 70% penile pain
0.15g 78% Reports of mild local
0.20g 90% burning sensations
increased in a
dose-dependent
fashion
Choi et al. 0.2g (double- Applied 1 hour before 106c (38.7) 1.37 (0.12) Placebo 2.45 (0.29) Sexual satisfaction All test trials:
200029 blind, placebo- sexual contact and SS-cream 10.92 rationk 14.72% (78/530)
controlled) washed off before (0.95) placebo 19.81% mild burning 3.77%
intercourse p<0.001 (between SS-cream 82.19% (20/530) mild pain
treatments) Mem
3/106 erectile
dysfunction
4/106 delayed
ejaculation 5/106
no ejaculation

ND=not done; aPatients with self-diagnosed PE. History of primary or secondary PE not stated; bSatisfaction assessed on a scale of −1 for worse, 0 for no change, 1 for better than usual, 2 for excellent; cSelf-
diagnosed primary PE; dPatients with self-diagnosed primary and secondary PE; eLevel of satisfaction defined using a linear scale pf 1–10, as bad (1–4), regular (5,6), good, (7),great (8,9) or excellent (10);
f
Study-specific male and female sexual quality of life questionnaires, each containing 10 statements; gEntry criteria not stated; h132 with primary PE and 54 with secondary PE and including 64 patients with
PE combined with mild ED; iPatients were asked to estimate the degree of satisfaction for both their partners and themselves; jmethod of determining sexual satisfaction not stated; kSexual satisfaction rations
determined by adding the percentage of patients who reported being satisfied (effective) and very satisfied (excellent).
Topical agents for the treatment of premature ejaculation 499
500 Textbook of Erectile Dysfunction

negative sexual side-effects such as delayed ejaculation, Loss of penile sensation, retarded ejaculation, and penile
anejaculation, and erectile dysfunction.32 irritation were a problem for 5 men, and 1 female partner
Despite these promising results, SS-cream has an unpleas- reported decreased vaginal sensitivity.
ant smell and color, which makes it unacceptable to many It can be concluded that lidocaine–prilocaine cream has
patients. A reformulation has resulted in ‘renewed SS-cream’ some degree of efficacy in the treatment of PE but is inconve-
(RSSC) which is a new topical agent composed of the two nient, messy, and slow-acting, and it is not approved for this
main components of the original SS-Cream; Korean ginseng indication. It also has problems associated with hypoesthesia.
and Bufonis venenum in a hydrobase and enhancer without
smell or color.33 So far, only the results of animal studies
have been published. The authors claim that RSSC delays
the latencies of the spinal somatosensory evoked potentials Novel topical agents in development
in rabbits more effectively than the original SS-cream. How-
ever, the ingredient Bufonis venenum, has been shown to Dyclonine–alprostadil cream
produce contact dermatitis34 and the likelihood of this cream Dyclonine, a local anesthetic used most commonly in dentistry,
gaining regulatory approval outside of Korea appears to be has been combined in a cream formulation with alprostadil
remote. (prostaglandin E-1), a vasodilator used in erectile dysfunction
(ED), and the combination is under development (NexMed,
USA) as a topical treatment for PE. So far only one pilot study
Off-label topical treatments has been published (in abstract form) in which creams con-
taining dyclonine alone, alprostadil alone, or a dyclonine–
Lidocaine–prilocaine cream alprostadil combination with two different drug concentrations
Separately, lidocaine and prilocaine are crystalline solids. were compared in a double-blind, crossover trial.38 This pilot
When mixed together in equal quantities by weight, however, study involved 30 patients who applied the cream 5–20 minutes
they form a liquid eutectic mixture that can be formulated before intercourse. A significant synergistic effect was observed
into preparations without the use of a non-aqueous solvent. with the cream containing 0.5% dyclonine and 0.4% alpros-
This allows higher concentrations of anesthetic to be formu- tadil in comparison with the treatment with creams contain-
lated into the preparation and maintained during application. ing 1% dyclonine alone or 0.4% alprostadil alone (p<0.05)
EMLA® (Eutectic Mixture of Local Anaesthetic; AstraZeneca) (see Table 63.1). Baseline IELTs are unfortunately not
is a local anesthetic cream containing 2.5% each of lidocaine reported, but the mean IELT post-dosing were 2.34 minutes
and prilocaine for topical application. Developed to anesthe- and 4.08 minutes in the placebo and dyclonine–alprostadil
tize intact skin, it is available as an over-the-counter product combination groups, respectively (p<0.05). Adverse events
in some countries. were experienced by 17.5% of men and are described as local
The first pilot study evaluating lidocaine–prilocaine cream and mild to moderate in nature, with an average duration of
for the treatment of PE included 11 subjects.35 The cream 18.2 minutes. Details of the adverse events and also whether
(2.5g) was applied to the whole glans and shaft of the penis or not any of the patients’ partners experienced adverse events
30 minutes prior to intercourse and covered with a condom, are also not provided. The most frequently reported adverse
which could be removed prior to intercourse (and the cream events in patients using alprostadil cream to treat erectile dys-
wiped off) if desired. Nine of the 11 patients rated their function are application site-related, such as penile burning,
performance as ‘excellent’ or ‘better’ and all 11 partners were genital pain, and genital erythema, mostly resolving within
satisfied with the treatment results.35 2 hours.39 The results of further studies using this cream are
In order to determine the optimal time that the anesthetic awaited with interest.
cream should be on the penis prior to intercourse, Atikeler et al.
carried out a placebo-controlled trial with 10 patients in
each treatment group, varying the application time from Prilocaine–lidocaine spray
20–45 minutes, with a condom. In the 20- and 30-minute TEMPE (Topical Eutectic Mixture for Premature Ejaculation,
application groups the IELT increased compared with placebo, Plethora Solutions Ltd.) is a proprietary formulation of lido-
but all men in the 45-minute group suffered from penile numb- caine and prilocaine in a metered dose aerosol delivery system
ness and loss of erection. The optimal application time was specifically designed for use in PE; the system delivers 7.5mg
considered to be 20 minutes.36 lidocaine base plus 2.5mg prilocaine base per actuation. The
The largest double-blind, placebo-controlled clinical trial of mixture is alcohol-free so there is little risk of stinging on
lidocaine–prilocaine cream to date involved 42 patients; 21 in application, and although it is oil-free, the mixture forms a
each group.37 Patients were asked to apply a thin layer of cream clear, slightly oily, odorless solution that remains adherent to
to the glans penis, extending the coverage for up to 2cm on the application site. It can easily be wiped off if necessary with
the penile shaft. They were then asked to cover the cream with a damp cloth, so no condom is required.40
a condom for 10–20 minutes before intercourse and to use The metered dose spray delivery system allows the desensi-
this treatment each time they had intercourse over 30–60 days. tizing agents to be deposited in a dose-controlled, concen-
The treatment resulted in a 5.6-fold increase in IELT. How- trated film on the glans penis, and they can then penetrate the
ever, only 29 of the initial 42 participants completed the study. glans within 5–10 minutes.40 The eutectic mixture is slower to
Of the patients completing the study, 11 out of the 16 who penetrate intact keratinized skin and as such is not likely to
responded reported ‘great’ or ‘excellent’ sexual satisfaction. anesthetize the shaft of the penis or the hands.41
 Topical agents for the treatment of premature ejaculation 501

In the first open-label pilot study, 11 patients recorded effect and need either to be used with a condom or be washed
stopwatch-timed IELTs at baseline and on five subsequent or wiped off before intercourse, which will have an effect on
encounters when using the spray 15 minutes before inter- spontaneity and may decrease arousal. The cream formulations
course. The average IELT increased from 1 minute 24 seconds (lidocaine–prilocaine, dyclonine–alprostadil, and EMLA®)
to 11 minutes 21 seconds (p = 0.008), representing an average require a 5–20-minute application and the potential use of a
eight-fold increase. In addition, 8 out of 11 patients and 7 out condom, whereas the spray formulation (lidocine–prilocaine)
of 11 partners rated their sexual satisfaction as ‘better’ or has 5–15-minute application time and is easy to administer,
‘much better’. remaining adherent to the glans penis after application and
In a recently published phase 2, placebo-controlled trial, being less likely to penetrate intact keratinized skin causing
54 patients using the prilocaine–lidocaine spray were able anesthesia of the shaft of the penis.41
to prolong their IELT from a baseline of 1.0 minute to However, the evaluation and comparison of the outcomes
4.9 minutes. The treatment was also well tolerated, with only of clinical trials for PE agents remains difficult whilst consi-
three patients (12%) experiencing hypoesthesia (numbness derable debate over the definition of PE continues. A critical
of the penis) and a fourth patient experiencing loss of review of the methodology of studies in PE has revealed the
erection; none of the adverse events resulted in treatment dis- scale of the differences and the resultant difficulties in com-
continuation. The spray was also well tolerated by the female paring results from these studies.42 It is therefore important to
partners, with only one partner experiencing a mild burning exercise a degree of caution when comparing headline results.
sensation during intercourse each time her partner used the Recommendations for standards for clinical trials in PE8,11,42
spray; again, this did not result in discontinuation. include the use of a precise definition of premature ejacula-
tion (e.g. ejaculation that occurs within 1 minute after vaginal
penetration in more than 90% of intercourses); a randomized,
Discussion double-blind, prospective design; the use of validated out-
come measures (such as IELT); and the use of a stopwatch at
Compared with systemic treatments for PE, topical treatments each coitus, both during baseline and during drug treatment.
do offer certain advantages: they can be applied when needed, Use of such stringent parameters in all future trials would
and systemic side effects are unlikely. However, they do have enable meaningful meta-analyses to be carried out.
a number of potential drawbacks: they can be messy, they can In conclusion, the treatments options for men with PE
interfere with spontaneity, and they can cause numbness in are limited until a safe, efficacious, practical and preferably
the man or his partner. Dependent on formulation, they also as-needed agent with a suitable risk–benefit profile is
require a period of time between application and maximum approved.

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64 Potency-preserving surgery: radical
prostatectomy and other pelvic
surgery
Paolo Gontero and Roger S Kirby

Introduction small caliber and lie encased within fibrofatty tissue, they are
difficult to dissect in the adult cadaver. Walsh and Donker
Sexual dysfunction, especially erectile dysfunction (ED), is a therefore initially traced their course by dissections in male
well-recognized complication of abdominal and pelvic fetuses and stillborn infants.3 Their findings were later
surgery. Radical procedures for pelvic malignancy, vascular confirmed in adult cadavers.4 The pelvic plexus is formed by
operations, and transurethral prostatic surgery can all lead parasympathetic visceral efferent preganglionic fibers (the
to erectile and ejaculatory dysfunction. As most of these nervi erigentes) arising from sacral segments S2, S3, and S4
procedures are performed in middle-aged to elderly patients, and from postganglionic sympathetic fibers arising from the
there has, in the past, been a tendency to disregard the thoracolumbar region (T11–L2) and traveling to the plexus
importance of loss of potency. However, some men now have via the hypogastric nerve. The parasympathetic fibers control
expectations of unimpaired sexual function well into their erectile function, while the sympathetic fibers play an impor-
seventh or even eighth decades; impotence can, therefore, tant role in ejaculation.
have a profound effect on their quality of life. The plexus is situated retroperitoneally in the sagittal plane
Over the past 20 years, major advances in understanding on the lateral wall of the rectum, 5–11 cm from the anal verge
of the mechanisms leading to erectile dysfunction after sur- (Figure 64.1). It lies lateral and posterior to the seminal vesi-
gery have fostered the development of surgical approaches cle. Because the plexus is surrounded by thick fascia, the sem-
that allow preservation of sexual function. Together with inal vesicle is a useful intra-operative landmark as its tip is
improvements in the treatment of postoperative ED, potency- opposite the midpoint of the plexus. The cavernous branches
preserving techniques have significantly improved the outlook travel from the plexus towards the posterolateral aspect of the
for patients undergoing abdominal and pelvic surgery. base of the prostate in association with the capsular arteries
and veins of the prostate. As they gradually coalesce towards
the gland, the fibers are running in the lateral pelvic fascia
Radical prostatectomy outside the prostatic capsule and outside Denonvillier’s fascia.
This arrangement underlies two important anatomical prin-
As prostatic carcinoma continues to undergo a real increase in ciples: first, the location of the cavernous nerves outside the
incidence1 and diagnosis tends to be made at earlier stages prostatic capsule and Denonvillier’s fascia means that, if can-
than in the past,2 an increasing number of men are being cers are located entirely within the capsule, preservation of
offered treatment by radical prostatectomy, usually via the ret- potency should be possible without compromising excision of
ropubic route and lately by laparoscopic means, with or with- organ-confined tumors; and secondly, the cavernous nerves
out robotic assistance. Traditionally, impotence was almost are not themselves visible with the naked eye, and their asso-
inevitable after this procedure; in the early 1980s, however, ciation with the capsular vessels of the prostate to constitute
Patrick Walsh and his colleagues demonstrated that ED after the neurovascular bundle therefore provides a macroscopic
radical prostatectomy was secondary to injury to the branches landmark for these microscopic nerves. From the apex of the
of the pelvic plexus that innervate the corpora cavernosa.3 prostate, the nerves run posterolateral to the urethra to pen-
On the basis of their discovery, they proposed alterations in etrate the urogenital diaphragm. The fibers then pass behind
surgical technique to avoid this complication. the dorsal penile artery and nerve before diverging laterally to
enter the corpora cavernosa.3–5
Recently, a slightly different view of the anatomical location
Anatomy of the neurovascular bundles at the prostate level has been
Although the importance of the pelvic plexus in erectile pro- proposed. By studying the development of cavernosal nerve
cesses was well recognized, the branches of the plexus supply- fibers in fetuses of different gestational age, Lunaceket et al.6
ing the corpora cavernosa had not been accurately located found that the neurovascular bundles run dorsolateral to the
prior to Walsh’s work. Because the cavernous nerves are of future prostate only in the early gestational phase (up to the

503
504 Textbook of Erectile Dysfunction

Pelvic plexus

Bladder

Rectum
Prostate

Figure 64.1 Anatomical details of the pelvic plexus as shown in a classic anatomical textbook drawing and in a cadaveric
picture.

10th week). Thereafter, as the prostate begins to develop, the et al.9 The nerve-sparing technique involves initial control
nerve fibers are displaced more anteriorly, along the convex of bleeding from the dorsal complex followed by transection
surface of the prostatic capsule, assuming the shape of a ‘con- of the urethra.
cave curtain’ covering both prostatic lobes. With the develop- This is the first critical point where the bundles may be
ment of benign prostatic hyperplasia (BPH) in the adult, the damaged. Because the neurovascular bundle when approach-
nerves are increasingly displaced laterally and anteriorly. ing the prostatic apex is located underneath the sphincter and
Another finding of the study was that at the membranous ure- can be fixated into a medial position by an apical vessel, care
thra the nerve fibers are present all around the urethra between is used to transect only the lateral edges of the sphincter at the
the 3 o’clock and the 9 o’clock positions and not only lateral urethral level, refraining from any dissection underneath the
to the urethra. These new anatomical insights have led to prostatic apex.10 Subsequently, the dissection of the bundle is
recent refinements in the surgical technique of nerve-sparing carried out starting at the bladder neck and proceeding down
radical prostatectomy. to the apex until a groove appears on the posterolateral edge
of the prostate that serves as a landmark for the neurovascular
bundle, which is located just laterally to it. Following the
Surgical technique
groove down to the apex will enable the identification of
Open radical retropubic prostatectomy the bundles at the level of the transected urethra: only at this
nerve-sparing techniques point can the dissection be completed at the apex and carried
Traditional methods of open radical prostatectomy have out posterior to develop the prostatic–rectal plane without
often relied on blind or blunt dissection. Since the importance damaging the nerves.
of the neurovascular bundle in erectile function was not The last critical point for a successful nerve-sparing tech-
appreciated, no attempts were made to preserve it. Examina- nique is represented by the dissection of the seminal vesicles.
tion of pathological specimens from non-nerve-sparing pros- Because the midportion of the pelvic plexus is anatomically
tatectomies reveals no evidence that the bundles were actually located at the tip of the seminal vesicles, the dissection of these
resected;7 instead, it appears that they were inadvertently small organs must be carried out very carefully, particularly
damaged. The cavernous nerves are particularly vulnerable in the lateral aspect, where small arterial branches are
at several points during the procedure, including apical often encountered and need to be clipped close to the seminal
dissection and transection of the urethra, separation of vesicles.
the prostate from the rectum, and division of the lateral If unilateral neurovascular bundle excision is necessary, it
pedicle.3,5,7,8 may be possible to preserve the contralateral bundle. When
On the basis of his anatomical studies, Walsh described a this technique is used, all structures can be visualized and a
new method of radical prostatectomy designed to avoid dam- deliberate decision made as to whether they can be preserved
age to the cavernous nerves in these areas. His single most or must be sacrificed for disease control.5
important innovation was the application of the neural anat- Based on the anatomical findings of a ‘curtain-shaped’ dis-
omy described above to facilitate accurate intra-operative position of the neurovascular bundles on the anterolateral
identification of the neurovascular bundles. This in turn is surface of the prostatic lobes, other authors6,11 now prefer to
critically dependent on a second maneuver – namely, control start the dissection of the prostatic fasciae more anterior (i.e.
of blood loss from the dorsal venous complex and Santorini’s at the 1 o’clock and 11 o’clock positions) to preserve all the
plexus, the anatomy of which was also clarified by Walsh nerve fibers that are spread concavely in the ‘curtain’.
 Potency-preserving surgery 505

Endoscopic techniques of nerve-sparing whole-mount specimens from standard blunt dissection radi-
radical prostatectomy cal retropubic and perineal prostatectomies have therefore
Techniques for nerve preservation during the laparoscopic been compared with nerve-sparing prostatectomy specimens
and the robotic radical prostatectomy are currently available, to determine the effect of the nerve-sparing modification on
with preliminary functional outcomes at least as good as those histology of the surgical margins.
achieved with open surgery. Although perineal prostatectomy tends to remove less
For the laparoscopic approach, both retrograde and ante- periprostatic tissue and skeletal muscle than either of the ret-
grade techniques of nerve preservation have been described. ropubic techniques, it appears that all of the approaches allow
In the former,12 the periprostatic fascia is initially incised at adequate removal of limited prostatic cancer.7 In one series of
the apex of the prostate and the neurovascular bundle dis- 100 nerve-sparing radical prostatectomies, capsular penetra-
sected off. The latter consists of making a ‘lateral’ incision in tion was present in 41% of cases but only seven patients had
the periprostatic fascia after dividing the prostatic pedicles positive surgical margins, all of whom had extensive extrapro-
and then carrying out the bundles dissection from these lat- static disease.19 In no case was the margin positive only at the
eral incisions.13,14 In a recent modified technique – intrafascial site of the nerve-sparing modification.
nerve-sparing endoscopic extraperitoneal radical prostatec- Further studies have also indicated that patients with posi-
tomy – the dissection starts at the bladder neck without tive surgical margins tend to have extensive extracapsular dis-
incision of the endopelvic fascia. A bilateral sharp incision of ease, often with seminal vesicle or lymph node involvement.20,21
the periprostatic fascia is then conducted from the bladder It is unlikely that surgery of any type will eradicate these tumors
neck down to the apex, and the plane between the prostate completely.8,20 In one series of 459 patients, three patients were
and the fascia developed. Only at this point is the endopelvic identified with positive margins only at the site of the nerve-
fascia reflection over the prostate incised. sparing modification.22 Although margin positivity might have
The main goal of this approach is to develop the right plane been avoided by excision of the neurovascular bundle, the
and detach the prostate from its ‘envelopment’, leaving intact number of affected patients is small. Furthermore, the long-
all lateral enveloping periprostatic fascia (including the term significance of these involved margins remains unclear.
endopelvic fascia) and puboprostatic ligaments as a continu- Current wisdom therefore is that the nerve-sparing tech-
ous structure.15 nique rarely compromises cancer control. Precise identifica-
Similar techniques have been reported for the robotic radi- tion of the neurovascular bundle with wide excision when
cal prostatectomy.16,17 Above all, the Vattikuti Institute pros- necessary may even allow more extensive resection than blunt
tatectomy claims promising functional results by sparing the dissection in selected cases.5 Several major centers have
whole periprostatic fascia (named the veil of Aphrodite in view reported the results of large series of open nerve-sparing radi-
of the peculiar distribution of the cavernosal nerve fibers).18 cal retropubic prostatectomies since the introduction of the
technique.
The supporters of the endoscopic techniques of radical
Results of nerve-sparing radical prostatectomy
prostatectomy advocate the achievement of better preserva-
Tumor excision tion of neurovascular bundles as a result of improved magni-
It is clearly important that preservation of potency is fication. Indeed, excellent potency rates have been reported
not achieved at the expense of cancer control. Findings on particularly with the robotic ‘veil of Aphrodite’ technique.18

Table 64.1 Comparative potency rates and surgical margins with open retropubic and endoscopic radical
prostatectomy contemporary series

Series Technique n Mean follow-up Positive SM (%) Intercourse rate Patients with
(months) at 1 year (%) normal IIEF (%)

Rabbani F et al.24 RRP 225 12 NA 42 8

Schover L et al.67 RRP 240 52 NA NA 33
Chuang et al.68 RRP 56 5.5 NA 66 NA
69
Guillonneau et al. Laparoscopic 550 36 16.7 66 NA
Stolzenburg et al.70 Laparoscopic 70 12 21 33 NA
71
Ahlering et al. Robotic 60 9 17 33 NA
Bentas et al.72 Robotic 40 15 30 22 NA
73
Menon et al. Robotic 200 7.9 6 68 NA
Tewari et al.74 Robotic 530 12 9 78 NA
Kaul et al.18 Robotic 154 12 6.4 96 71
Chien et al.75 Robotic 56 Minimum 10.7 NA 66
3 months
SM, surgical margin; NA, not available; IIEF, International Index of Erectile Function. Modified from BJU Int 2006; 97: 467–72.
506 Textbook of Erectile Dysfunction

Table 64.1 shows comparative potency rates and surgical higher incidence of sexual activity in younger men.22 In the
margins from open retropubic and endoscopic radical study by Raina et al.,36 a preoperative erectile function domain
prostatectomy series. score of the International Index of Erectile Function (IIEF)
For the open approach, the best results are reported by the below 16 was associated with a reduced probability of postop-
originator of the technique and his associates, with overall erative recovery of potency.27
potency rates of 68% among men potent preoperatively.23 The Although impotence after radical prostatectomy is primarily
robotic approach seems to guarantee even better functional neurogenic in most cases, the existence of patients who do not
results with no additional or even less cost in terms of surgical respond to intracavernosal papaverine postoperatively suggests
margins, but data are not yet mature. On the whole, other that vascular injury can also contribute to ED.28 This impres-
groups have found potency rates to be somewhat lower. sion is confirmed by penile Doppler ultrasound studies that
Therefore, although rates of recovery of erectile function are reveal evidence of arterial insufficiency in 40% of men after
better than with non-nerve-sparing techniques, the morbidity radical prostatectomy.29 The main blood supply to the corpora
in terms of sexual function is still considerable. Various fac- cavernosa is from the internal pudendal artery, which is not
tors affect the likelihood of impotence following open radical usually ligated during radical prostatectomy. However, it is
prostatectomy. likely that there are also collateral sources, and it is thought that
loss of these collaterals may lead to vasculogenic impotence.
Number of neurovascular bundles spared Older patients with atherosclerosis of the internal pudendal
vessels may be at particular risk. Likely sources of collateral
The single most important factor in determining preservation
of potency is the number of neurovascular bundles injured. blood supply to the penis include the arterial branches running
beneath the anterior capsule of the prostate, which are visible
Potency rates are reported as 31.9–76% for bilateral nerve-
sparing procedures, 13.3–60% for unilateral nerve-sparing following division of the dorsal complex. These vessels are not
amenable to preservation during radical prostatectomy.30
procedures, and 0–1.1% for non-nerve-sparing procedures.22,33
On the whole, a 25% reduction in the success of a nerve- There has also been a great deal of interest in the effect of
damage to accessory branches to the internal pudendal artery,
sparing procedure has to be expected if only one neurovascu-
which can arise from the obturator and inferior and superior
lar bundle is spared at the time of surgery.24
vesical arteries (Figure 64.2). One cadaveric study has sug-
gested that accessory arteries are present in 70% of patients.31
Stage and tumor volume At radical prostatectomy, however, it appears that accessory
Stage and tumor size also influence postoperative arteries amenable to preservation are present in only 4% of
potency.22,23,26,27 In one series, a tumor volume of less than patients and that preservation has no effect on potency rates.30
3cm3 and the absence of lymph node or seminal vesicle It is also important to recognize that, although most impo-
involvement were associated with preservation of potency.22 tence after radical prostatectomy has an organic basis, anxiety
However, stage determines the extent of surgery required for is common in men receiving treatment for prostate cancer
tumor excision and therefore the number of neurovascular and psychogenic factors may contribute to ED.32
bundles that can be spared; it is not, therefore, an indepen- Most patients who regain potency after radical prostatec-
dent predictor of outcome. For example, in one report, only tomy recover within 6–12 months,22 although improvement
9% of patients in whom a bilateral nerve-sparing procedure can continue for up to 2 years postoperatively. Patients who
was possible presented with clinical stage B2 or C disease have undergone excision of one neurovascular bundle lag
compared with 51% of those in whom unilateral excision of behind those who have a bilateral nerve-sparing operation.23
the neurovascular bundle was required.23 Although potency rates from several large series are impres-
sive, these data should be interpreted with caution. In the
Age literature, potency is generally defined as the ability to achieve
an erection sufficient for vaginal penetration and orgasm.
Younger patients tend to fare better in terms of postoperative Although patients may fit this description, many notice a def-
potency than their older counterparts.22,23,25,26 Men less than
inite change in the quality of their erections after surgery,
50 years of age tolerate unilateral neurovascular bundle exci-
which can be associated with reduced sexual satisfaction.22,25
sion with potency rates similar to those of bilateral nerve-
Koeman et al. found that fewer than half of their patients
sparing procedures (90% potency). In older men, however,
defined as potent on the basis of erections sufficient for vagi-
excision of one neurovascular bundle significantly reduces the
nal penetration were satisfied with their erections or achieved
likelihood that potency will be retained.23 The relatively young
intercourse at least once a month.33
average age of patients in Walsh’s series may partly explain the Furthermore, potency is only a single aspect of sexual func-
excellent overall results achieved in this center.33
tion. Radical prostatectomy may also alter orgasmic sensation,
Response to sildenafil treatment, a known indicator of a although few studies address this problem. Geary et al. noted
successful nerve preservation following radical prostatectomy,
that only 10% of patients (regardless of potency) reported
is significantly enhanced in patients less than 65 years com- decreased orgasmic sensation.22 This is important, in that
pared with those over 65 (63% versus 43%).27
these patients are likely to respond well to intracavernosal
injection therapy, vacuum devices, or penile prostheses. In a
Preoperative sexual activity study from the Netherlands, however, that was based on a
Patients who are sexually active before surgery are more likely semi-structured interview and a self-administered question-
to recover their potency postoperatively, even allowing for the naire, 80% of men experienced weakened orgasmic sensation
 Potency-preserving surgery 507

Pubis bone

Right accessory
pudendal artery

External iliac vein

Umbilical artery

Figure 64.2 (a) Accessory pudendal artery arising from the right umbilical artery. (b) A similar accessory pudendal branch is shown
in a drawing.

after surgery. Moreover, 64% suffered involuntary loss of Radical cystectomy and urethrectomy
urine at orgasm, although all but one were completely conti-
nent at other times; this caused half of these men to avoid In males
sexual contact. Diminished libido was also common.33 ED is a common complication of radical cystoprostatectomy
The pathophysiology of these changes in orgasmic sensa- for bladder carcinoma, and the nerve-sparing approach des-
tion is poorly understood but may relate to the unavoidable cribed above can also be applied to this procedure.36 Initially,
excision of small nerve fibers surrounding the prostate and proponents of the technique have reported potency rates sim-
seminal vesicles. These statistics illustrate two important prin- ilar to those achieved following radical prostatectomy (71%).37
ciples: first, preservation of erections adequate for penetration In a recent series, the five-item version of the IIEF (IIEF-5)
does not in itself guarantee satisfactory sexual performance was administered to 49 preoperatively potent subjects who
in all patients; and secondly, it is becoming clear that, when had undergone cystoprostatectomy at a median follow-up of
patients are asked in person about their sexual function, 47 months.38 The mean postoperative scores were significantly
satisfaction rates tend to be lower than those reported by reduced compared with the preoperative values, with 86% of
clinicians.22,34 Allowing for these factors, it is probably unreal- patients unable to achieve vaginal penetration after surgery.
istic to offer the average prostate cancer patient a greater than Of note, only 6 out of 16 (37%) patients who had undergone
50% chance of retaining preoperative levels of sexual function a nerve-sparing procedure had erections sufficient for vaginal
after radical prostatectomy; however, a proactive approach penetration.
with an emphasis on penile rehabilitation with phospho- Understanding of the pelvic neuroanatomy has also been
diesterase (PDE) type 5 inhibitors and other techniques can applied to urethrectomy. As described above, the cavernous
definitely improve outcomes. nerves lie posterolateral to the membranous urethra as
they traverse the urogenital diaphragm. Distal to the membra-
Transurethral prostatic surgery nous urethra they diverge laterally into the corpora cavernosa.
The nerves are, therefore, most vulnerable during dissection
ED is less common following transurethral prostatic surgery of the membranous urethra. Brendler et al. recommend
but nevertheless affects up to 14% of men undergoing trans- removing only urethral mucosa and smooth muscle during
urethral resection of the prostate (TURP).35 The etiology of separation of the urethra from the urogenital diaphragm,
post-TURP impotence is not absolutely clear; it is, however, preserving as much striated muscle as possible; the neurovas-
likely that the cavernous nerves and arteries are damaged by cular bundles can then be gently pushed away from the poste-
perforation of the prostatic capsule, extravasation of irrigant, rolateral aspect of the urethra.39 This technique has allowed
or injudicious electrocautery of the capsule, particularly at the preservation of potency in the small number of cases
apices. These events should therefore be avoided if possible. It reported.
is also essential to discuss the risk of postoperative impotence For accurate nerve preservation during radical cystectomy,
with the patient when obtaining informed consent for the Kessler et al. advise neurovascular bundle preservation dorso-
procedure. Other techniques, such as Greenlight laser vapor- lateral to the prostate as well as more cranially in the angle
ization of the prostate, are claimed to have a lesser impact on between the prostate, bladder and seminal vesicle by ligation
erectile function but there are little published comparative and division of the dorsomedial pedicle close to the seminal
data to corroborate that claim. vesicle.40
508 Textbook of Erectile Dysfunction

With the aim of preserving erectile and ejaculatory function, more extensive resection required when dealing with malig-
a modified cystectomy that successfully preserves seminal ves- nancy: wide excision of perirectal tissues carries a greater risk
icles and the prostatic capsule after transurethral resection41 or of neural damage and consequent impotence than techniques
that leaves the prostate intact42 has been reported. Despite the such as close rectal dissection and mucosal proctectomy,
concerns for the oncological control of the disease, excellent which can be exploited in benign disease.52,53
results in terms of potency preservation and successful inter- As in prostatectomy and cystectomy, accurate knowledge of
course have been reported with the nerve- and seminal- the pelvic neuroanatomy is the key to preservation of potency.
sparing cystectomy.43–45 The pelvic parasympathetic nerves may be damaged at a num-
ber of points during rectal surgery. Excessive traction on the
rectum during posterior mobilization can result in neuropraxia
In females or avulsion of roots S2, S3, and S4.5 The pelvic plexus itself is
Female sexual function relies on the integrity of the female most at risk during ligation of the middle hemorrhoidal ves-
external genitalia (which comprise the labia, the clitoris, and sels, to which it is intimately related.52,53 Neural injury may also
the vestibular bulbs) and the internal genitalia (the vagina, fal- occur during perineal dissection of the rectum. After division
lopian tubes, uterus, and ovaries). The clitoris is an erectile of the rectourethralis muscle, the neurovascular bundles are
organ formed by two erectile bodies fused in the midline, visible in association with the lateral prostatic fascia and are
similar to the penile cavernosal bodies. During sexual stimula- vulnerable to trauma by excessive dissection or diathermy
tion, increased blood flow causes clitoris engorgement and anterolateral to the rectum.5 As stated, ED following colorectal
subsequent lubrication. The same occurs for the vagina, which surgery is usually neurogenic in origin. However, ligation of
becomes engorged during sexual stimulation and forms a the anterior division or distal branches of the internal iliac
plasma trasudate that is critical during the sexual arousal artery is sometimes necessary. As a result, patients occasionally
phase.46,47 The autonomic innervation of the proximal two- develop vasculogenic impotence, particularly if both internal
thirds of the vagina and clitoris (the equivalent of the male pudendal arteries are ligated.5
neurovascular bundles) leaves the pelvic plexus and travels
within the uterosacral and cardinal ligaments, along with
the vessels.48 Vascular surgery
Surgical factors that can affect female sexuality in regard to
ED complicates between 30% and 80% of aortoiliac opera-
cystectomy are the preservation of the nerves (located on the
tions.54–56 Since pre-existing erectile problems due to athero-
lateral walls of the vagina), the preservation of a stump of
sclerotic arterial disease or diabetes are also common in this
distal urethra (in order not to devascularize the clitoris), and
population, sexual dysfunction is a major concern for some
the technique of vaginal reconstruction. Horenblas et al. con-
patients.57 The pelvic plexus and cavernous nerves are not at
ducted a prospective trial of modified cystectomy for normal
risk during dissection around the bifurcation of the aorta and
sexual function and anatomic urinary tract reconstruction
iliac vessels. The internal iliac artery, however, is commonly
without oncological concessions.49 They managed to preserve
occluded during these procedures, leading to a reduction in
clitoral vasculature with the transection of the urethra at the
pelvic visceral blood flow and consequent vasculogenic ED.58,59
level of the bladder neck and retrograde dissection of the blad-
Although restoration of adequate blood flow to the lower
der from the anterior vaginal wall. The dissection close to the
limbs or safe resection of aneurysmal disease are the primary
vaginal wall allows the preservation of both the clitoris and the
aims in aortoiliac surgery, careful technique can allow preser-
neurovascular bundle.
vation of potency in men with normal preoperative sexual
Reconstruction of the vagina is achieved by retubulariza-
function. Internal iliac ligation or embolization of atheroscle-
tion in a vertical fashion, creating a narrower cylinder or by
rotic debris and thrombus into this vessel during flushing
dissecting the posterior vaginal wall off the rectum to create a
maneuvers should be avoided, if possible. It is also worth
flap that is turned downwards to form an adequate vaginal
remembering that a number of patients with pre-existing
caliber but one of decreased depth. A case series reported
vasculogenic impotence do regain erectile function following
by Schover et al. found a higher rate of sensation of vaginal
aortoiliac reconstruction.57,59,60 In one series, for example,
tightness following radical cystectomy for vertical than for
sexual function was regained in 30% of patients with pre-
longitudinal retubularization.50 Of course the extent of disease
operative impotence and no normal patients were rendered
influences the amount of upper vaginal wall that has to be
impotent.60
removed, with possible significant limitations in size after
reconstruction with both techniques.
Treatment
Colorectal surgery Current treatment options for male ED are:61

ED is a well-recognized complication of colorectal surgery • the oral PDE-5 inhibitors sildenafil, vardenafil, and tadalafil;
and is usually a result of injury to pelvic autonomic nerves.51 • intracavernous injections of vasoactive agents [such as
The incidence after abdominoperineal excision or anterior prostaglandin (PGE)-1];
resection for carcinoma is between 15% and 100%, whereas • the vacuum pump; and
only 4.7% of men undergoing coloproctectomy for inflamma- • different models of penile prosthesis that can be surgically
tory bowel disease are affected. This difference reflects the implanted.
 Potency-preserving surgery 509

All these erectile aids are usually adopted after radical pelvic compared with sildenafil alone started at the fourth postopera-
surgery with variable degrees of success depending on the tive month. At the 6 months’ follow-up, 82% of patients in the
patient’s motivation to resume sexual activity, treatment com- combination arm responded to subsequent sildenafil com-
pliance, and the type of surgery (nerve-sparing versus non- pared with only 52% in the sildenafil-only arm.65 Intracavern-
nerve-sparing). As an example, the PDE-5 inhibitors, usually osal therapy has been found to produce a good erectile response
considered as the first-line treatment option, are thought to in non-nerve-sparing patients and therefore it may be the
be highly ineffective after a non-nerve-sparing procedure treatment of choice in the early postoperative period following
since no amplification of the nitric oxide (NO) cascade occurs a nerve-sparing procedure. Similarly, the use of a vacuum con-
after the administration of a PDE-5 inhibitor in the absence of strictor device may facilitate early sexual intercourse and the
NO release from intact cavernosal nerve fibers. By contrast, potentially early return of natural erections, although no con-
the same drugs can produce a significant response rate when trolled study has been carried out to test this hypothesis.
the nerves have been carefully preserved. Based on the few data available, either intracavernosal
The same drugs have also been employed with a ‘prophy- injections or a vacuum device should be offered as a first-line
lactic intent’ in order to optimize the recovery of spontaneous option for the first few months after the procedure, since their
erectile function after a nerve-sparing procedure. Nocturnal mechanism of action does not require intact neural tissue for
penile tumescence is still severely impaired 8 months after erection. Thereafter sildenafil, or an equivalent PDE-5, may
a nerve-sparing radical prostatectomy as a consequence of be a reasonable choice for those patients who can achieve at
neuropraxia of the cavernosal nerves.62 Early intake of a PDE-5 least a partial erection.
inhibitor at bedtime has been recommended with the aim of
making nocturnal erections more potent. In the preliminary
study by Padma-Nathan et al., patients who were potent pre- Conclusion
operatively were randomized after nerve-sparing radical pros-
tatectomy to sildenafil or a placebo for 36 weeks.63 Those who Recent advances in the understanding of pelvic autonomic
regained sexual function after 9 months of treatment (27%) neuroanatomy have led directly to the development of potency-
also had better nocturnal erections recorded a year after the preserving surgical techniques. These new approaches have
operation. had a major impact on surgical practice, particularly in urol-
It is possible that sildenafil as well as the other currently ogy. New approaches such as robotically assisted radical pros-
available PDE-5 inhibitors may not be so effective in the early tatectomy may result in improved potency outcomes as a
phase of nerve healing, as documented by the clinical ineffi- result of improved visualization of the neurovascular bundles
cacy of sildenafil in the first 9 months after a nerve-sparing and a more proactive approach towards penile rehabilita-
radical prostatectomy.64 Three-monthly intracavernous tion.66 As a result, it is now possible to preserve potency in
injections with PGE-1, starting the first postoperative month, many patients who undergo abdominal and pelvic surgery,
significantly enhanced subsequent response to sildenafil without compromising cancer control.

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36. Schlegel PN, Walsh PC. Neuroanatomical approach to radical of Urology. Guidelines on erectile dysfunction. Eur Urol 2002;
cystectomy with preservation of sexual function. J Urol 1987; 41: 1–5.
138: 1402–6. 62. Fraiman MC, Lepor H, McCullough AR. Nocturnal penile tumescence
37. Marshall FF, Mostwin JL, Radebaugh LC, et al. Ileocolic neoblad- activity in 81 patients presenting with erectile dysfunction (ED) after
der post-cystectomy: continence and potency. J Urol 1991; 145: nerve sparing radical prostatectomy. J Urol 1999; 161 Suppl 4: 179.
502–4. 63. Padma-Nathan H, McCullough AR, Giuliano F, et al. Postoperative
38. Zippe CD, Raina R, Shah AD, et al. Female sexual dysfunction nightly administration of sildenafil citrate significantly improves
after radical cystectomy: a new outcome measure. Urology 2004; the return of normal spontaneous erectile function after bilateral
63: 1153–7. nerve-sparing radical prostatectomy. J Urol 2003; 169 Suppl: 1402.
39. Brendler CB, Schlegel PN, Walsh PC. Urethrectomy with preserva- 64. Zagaja GP, Mhoon DA, Aikens JE, Brendler CB. Sildenafil in the
tion of potency. J Urol 1990; 144: 270–3. treatment of erectile dysfunction after radical prostatectomy. Urol-
40. Kessler TM, Burkhard FC, Perimenis P, et al. Attempted nerve spar- ogy 2000; 56: 631–4.
ing surgery and age have a significant effect on urinary continence 65. Montorsi F, Salonia A, Barbieri L, et al. The subsequent use of
and erectile function after radical cystoprostatectomy and ileal I.C. alprostadil and oral sildenafil is more efficacious than sil-
orthotopic bladder substitution. J Urol 2004; 172: 1323–7. denafil alone in nerve sparing radical prostatectomy. J Urol 2002;
41. Colombo R, Bertini R, Salonia A, et al. Nerve and seminal sparing 167 Suppl 4: 279.
radical cystectomy with orthotopic urinary diversion for select 66. Menon M, Kaul S, Bhandari A, et al. Potency following robotic
patients with superficial bladder cancer: an innovative surgical prostatectomy: a questionnaire based analysis of outcomes after
approach. J Urol 2001; 165: 51–5. conventional nerve sparing and prostatic fascia sparing techniques.
42. Horenblas S, Meinhardt W, Ijzerman W, Moonen LF. Sexuality J Urol 2005; 174: 2291–6.
preserving cystectomy and neobladder: initial results. J Urol 2001; 67. Schover LR, Fouladi RT, Warneke CL, et al. The use of treatments
166: 837–40. for erectile dysfunction among survivors of prostate carcinoma.
43. Vallancien G, Abou El Fettouh H, Cathelineau X, et al. Cystectomy Cancer 2002; 95: 2397–407.
with prostate sparing for bladder cancer in 100 patients: 10-year 68. Chuang MS, O’Connor RC, Laven BA, Orvieto MA, Brendler CB.
experience. J Urol 2002; 168: 2413–17. Early release of the neurovascular bundles and optical loupe
 Potency-preserving surgery 511

magnification lead to improved and earlier return of potency fol- Frankfurt experience with robotic radical prostatectomy and one
lowing radical retropubic prostatectomy. J Urol 2005; 173: 537–9. year follow-up. Eur Urol 2003; 44: 175–81.
69. Guillonneau B, Cathelineau X, Doublet JD, Baumert H, Vallancien 73. Menon M, Tewari A, Baize B, Guillonneau B, Vallancien G.
G. Laparoscopic radical prostatectomy: assessment after 550 pro- Prospective comparison of radical retropubic prostatectomy and
cedures. Crit Rev Oncol Hematol 2002; 43: 123–33. robot-assisted anatomic prostatectomy: the Vattikuti Urology Insti-
70. Stolzenburg JU, Do M, Rabenalt R, et al. Endoscopic extraperito- tute experience. Urology 2002; 60: 864–8.
neal radical prostatectomy: initial experience after 70 procedures. 74. Tewari A, Kaul S, Menon M. Robotic radical prostatectomy: a
J Urol 2003; 169: 2066–71. minimally invasive therapy for prostate cancer. Curr Urol Rep
71. Ahlering TE, Woo D, Eichel L, et al. Robot-assisted versus open 2005; 6: 45–8.
radical prostatectomy: a comparison of one surgeon’s outcomes. 75. Chien GW, Mikhail AA, Orvieto MA, et al. Modified clipless ante-
Urology 2004; 63: 819–22. grade nerve preservation in robotic-assisted laparoscopic radical
72. Bentas W, Wolfram M, Jones J, et al. Robotic technology and the prostatectomy with validated sexual function evaluation. Urology
translation of open radical prostatectomy to laparoscopy: the early 2005; 66: 419–23.
65 Rehabilitation of sexual function
following prostatectomy
Francesco Montorsi and Alberto Briganti

Introduction prostate-specific antigen (PSA) levels and the biopsy Gleason

sum, it has been suggested that a nerve-sparing approach may
Radical prostatectomy is an increasingly used therapeutic be considered in patients with PSA <10ng/ml and a Gleason
option for patients with clinically localized prostate cancer sum ≤7.14
and a life expectancy of at least 10 years.1 The pioneering work Patients being considered for a nerve-sparing radical pros-
by Walsh and Donker2 significantly contributed to the under- tatectomy should be potent prior to the procedure. This is
standing of the surgical anatomy of the prostate and posed the of major importance since patients who report some degree of
bases for the subsequent development of the anatomic radical ED or patients who use phosphodiesterase (PDE) type 5
prostatectomy technique (i.e. a surgical approach aimed at inhibitors prior to the procedure are more likely to develop
completely excising the prostate and providing optimal cancer severe ED after the procedure itself.15 The use of validated
control while maintaining the integrity of the anatomical questionnaires such as the IIEF may facilitate the diagnosis of
structures devoted to the functions of urinary continence and preoperative ED during the initial patient assessment. This
sexual potency.3–5 Since the initial reports on this technique an questionnaire assesses various domains of male sexuality,
increasing number of studies have reported very satisfactory including erectile and ejaculatory function, orgasm, desire,
postoperative rates of urinary continence, while the preserva- and intercourse satisfaction, and the results of this patient
tion of erectile function after surgery is clearly shown to be a self-assessment always yield useful baseline information. The
major challenge for most urologists.6–8 This finding contrib- morphology of the corpora cavernosa deteriorates with age
uted to the development of an increasing interest in the eluci- and this may be correlated with the high prevalence of ED
dation of the pathophysiology of postoperative erectile seen in aging men.16 Rates of recovery of erectile function after
dysfunction (ED) and on its potential prophylaxis and a nerve-sparing radical prostatectomy are inversely correlated
treatment.9,10 Furthermore, ED after radical prostatectomy with the patient’s age (i.e. the best postoperative potency rates
shows a profound effect on quality of life (QOL). Indeed it has are obtained in the younger patient population), and it seems
been shown that more than 70% of patients who had under- reasonable to consider patients ≤65 years of age as candidates
gone radical retropubic prostatectomy had a moderately or for a nerve-sparing procedure.3,17 Patient age also seems to be
severely affected QOL because of their postoperative ED.11 one of the most important factors for the recovery of sexual
Moreover, although the International Index of Erectile Func- potency after unilateral nerve-sparing surgery. Indeed, in a
tion (IIEF)12 has been widely accepted as a validated instru- group of 46 patients who received unilateral nerve-sparing
ment to assess ED, it has been demonstrated that different radical retropubic prostatectomy, 14 (30.4%) regained full
definitions of potency after surgery yield different results potency after surgery and, in the vast majority of them, recov-
when applied to the same patients in the same time. This ery occurred within a period of 18 months. Of these patients,
underlines the observation that sexual function entails more those aged <60 years reported the highest rate of recovery of
than penile erection (firm enough for intercourse) as the potency sufficient for vaginal penetration after a mean of
classic definition of potency.13 13 months after surgery.18 Comorbid conditions also seem to
affect the recovery of spontaneous erections postoperatively
since they may have an impact on the baseline penile hemody-
Patient selection namics. A concomitant diagnosis of diabetes mellitus, hyper-
tension, ischemic heart disease, or hypercholesterolemia or a
The anatomical nerve-sparing approach to the prostate is history of cigarette smoking identified at the time of the preop-
considered for patients with clinically localized prostate erative patient assessment should be taken into account as a
cancer. A detailed description of the most widely used criteria potential negative predictive factor for recovery of potency after
to select patients eligible for a nerve sparing procedure surgery.15 Although a higher prostate volume could be associ-
are detailed in Chapter 64. However, clinical stages T1 and ated with greater intraoperative bleeding, it does not seem to
T2 patients, as defined following digital rectal examination influence the postoperative potency rate.19,20 Nevertheless, body
or transrectal ultrasonography of the prostate, are the weight does not seem to be related to the feasibility of a
best indicators. As clinical stage is often correlated to both nerve-sparing approach in patients who are clinically obese.20

512
 Rehabilitation of sexual function following prostatectomy 513

Surgical technique might be performed by using a small Allis clamp to grasp the
two medial borders of the incised levator fascia.27 This maneu-
In suitable candidates, radical excision of the prostate should ver is used to pull together only the superficial components of
be performed with the objective of achieving total cancer con- Santorini’s plexus; then, a 3–0 monocryl suture on a UR-6
trol (i.e. of removing all cancer present in the prostatic tissue) needle is passed distal to the Allis clamp. It is important to
while maintaining the integrity of the anatomical structures note that this suture is not used to control all branches of
on which urinary continence and erectile function are based. Santorini’s plexus, since it is passed quite superficially to avoid
The corpora cavernosa receive the innervation responsible for any damage to the urethral sphincter. Indeed it allows the
erections through the cavernosal nerves, which branch out external urethral sphincter to be approached under direct
from the pelvic plexus. This latter structure is located adjacent vision, thus limiting the possible damage during its dissection.
to the tip of the seminal vesicles on the anterolateral wall of This passage is repeated twice and the suture is tied while leav-
the rectum and may be damaged during radical prostatec- ing the Allis clamp in place. This maneuver allows the branches
tomy. The cavernous nerves lie adjacent to small vessels of Santorini’s plexus to be pulled together and facilitates its
forming the so-called neurovascular bundle along the postero- subsequent division. Santorini’s plexus is then sharply divided.
lateral margin of the prostate bilaterally, and they are located A running suture with a 3–0 monocryl on a UR-6 needle
between the visceral layer of the endopelvic fascia and the is used to control bleeding from the deeper portion of the
prostatic fascia. The neurovascular bundle is located at the distal trunk of Santorini’s plexus. This suture must take only
5 o’clock and the 7 o’clock positions at the level of the mem- Santorini’s plexus; neither the urethral sphincter nor the most
branous urethra and, after piercing the urogenital diaphragm, distal fibers of the levator ani (also named the levator urethrae)
it enters the corpora cavernosa, where it innervates the smooth should be included in this suture, thus leaving the external
muscle cells of the penile vessel walls and sinusoids.21 It has sphincter and levator ani muscles completely intact. Once
been suggested that while the main trunk of the cavernous these bleeders are controlled, a running suture controlling
nerves runs posterolateral to the prostate from the level of the the proximal (prostatic) trunk of Santorini’s plexus is used,
seminal vesicles to the prostatic apex,22 a significant number following the technique described by Walsh.2,3
of nerves branch off the pelvic plexus to course along the After Santorini’s plexus has been controlled and divided
anterolateral surface of the prostate.23 These nerves run the visceral layer of the endopelvic fascia should be bluntly
between the prostatic fascia and the levator fascia.21,23–25 incised on the lateral side of the prostate to allow for the gen-
Distally, fibers of the cavernous nerves join together at the tle lateral displacement of the neurovascular bundles, which is
level of the urethral sphincter and are mainly located from the obtained with the use of small sponge sticks. If this maneuver
4 o’clock to the 5 o’clock position and from the 7 o’clock to is performed correctly, the neurovascular bundles become
the 8 o’clock position. Based on the better understanding of clearly visible in most patients along their entire course from
the surgical anatomy of the prostate, Walsh and Garcia have the membranous urethra and the seminal vesicles.
clearly described the technique of anatomic radical prostatec- Other investigators have subsequently proposed different
tomy in a step-by-step fashion.24 techniques aimed at achieving the best possible rates of
The use of frontal xenon light and of magnifying loupes postoperative normal urinary continence and potency, namely
significantly improves vision during the procedure, and the the importance of removing the prostate while leaving in place
authors of this chapter feel that this armamentarium should a large portion of the levator and prostatic fasciae that cover
be always used when performing nerve-sparing radical pros- the gland has been recently proposed, by using both open
tatectomies. Indeed it has been recently demonstrated that the and robotic techniques.23,28 A novel nerve-sparing surgical
use of 2.5× optical loupe magnification during neurovascular approach has been recently proposed, consisting of a high
bundle preservation was associated with a better recovery of anterior incision of the levator and prostatic fascia aimed
erectile function after surgery, with a follow-up of more than at efficiently preserving the urethral sphincter and neurovas-
1 year.26 cular bundles during open radical retropubic prostatectomy.
Some crucial surgical steps deserve particular attention. Indeed, starting from the bladder neck, using dissecting
Following pelvic lymphadenectomy, the endopelvic fascia is scissors the levator and prostatic fasciae are perforated and
incised to allow the dissection of the prostatic apex. Care the development of the plane running between the prostatic
should be taken to ligate small branches of pudendal vessels capsule and the prostatic fascia is initiated. This plane is devel-
located just underneath the endopelvic fascia in the area of the oped in a step-by-step fashion, from the region of the bladder
prostatic apex; cautery should not be used to secure these ves- neck to the urethral sphincter. The correct plane is easily
sels in order to avoid damage to pudendal nerve branches also identified because the reflection of the prostatic fascia is
located there. Ligation of the Santorini’s plexus is a funda- smooth and veins can be seen clearly, as through a transparent
mental step in the procedure as it must guarantee perfect sheet. This maneuver must be performed very gently. In this
hemostasis in order to obtain the best visualization of the sur- way, the prostatic fascia is detached from the prostatic capsule
gical field during the excision of the prostate. Walsh has sug- and from the urethral sphincter. This maneuver allows for
gested ligating the Santorini’s plexus distally first and preservation of all vessels and nerves included between the
subsequently dividing it with scissors; control of the proximal prostatic and levator fasciae. The space created on both sides
stump of the venous plexus is then achieved with a V-shaped between the lateral border of the urethral sphincter, the pros-
suture, which avoids a central retraction of the neurovascular tatic apex, and the reflected prostatic fascia is usually remark-
bundles, thus facilitating the nerve-sparing procedure. It has able in size. The dissection of the anterolateral surface of
recently been suggested that control of Santorini’s plexus the prostate is extended as laterally as possible. When this
514 Textbook of Erectile Dysfunction

dissection is completed on both sides of the prostate, the ure- Absence of early postoperative erections is associated with poor
thral sphincter and the prostatic apex are clearly visible. By corporeal oxygenation, which may facilitate the development
performing an incision of the levator fascia at the 1 o’clock of corporeal fibrosis, ultimately leading to veno-occlusive
and 11 o’clock positions to start the dissection of the neuro- dysfunction.33
vascular bundle, the largest possible fraction of the pelvic Recently, the role of apoptosis has been considered in
plexus branches, including cavernous nerve fibers, may be the pathophysiology of post-prostatectomy ED. Apoptosis, or
preserved. programmed cell death, is essential for the normal develop-
Early release of neurovascular bundles laterally, starting ment of a multicellular organism as well as for physiological
from the apex of the prostate just after the division of the cell turnover. Morphologically this phenomenon is character-
anterior urethra, has also been proposed and is associated ized by chromatin condensation, membrane blabbing, and
with a greater percentage of patients reporting preserved cell volume loss. In the penis, chronic hypoxia and denerva-
erectile function after surgery than after a standard release of tion have been shown to stimulate apoptosis: it is possible that
neurovascular bundles technique.26 cellular apoptosis leads to increased deposition of connective
It is mandatory to avoid the use of the cautery during tissue that may finally lead to a decrease in penile distensi-
every step of the prostatic excision. Recently, the Hopkins bility.34–37 Recently, User et al. have elegantly elucidated the
group has also suggested that any type of energy used during role of apoptosis in the pathophysiology of post-prostatectomy
the dissection of the prostate will inevitably damage the neu- ED in a rat model.38 Post-pubertal rats were randomized to
rovascular bundles: ultrafine clips and suture ligatures are bilateral or unilateral cavernous nerve transection versus a
thus recommended to guarantee adequate hemostasis during sham operation. At different time intervals following the pro-
a nerve-sparing radical prostatectomy.29 As the pelvic plexus is cedure, penile wet weight, DNA content, and protein content
located adjacent to the posterolateral tips of the seminal vesi- were measured. Tissue sections of the penis were stained for
cles, particular care should be taken while excising them. The apoptosis and the apoptotic index was calculated. Finally,
possible advantage of partial excision of the seminal vesicles staining for endothelial and smooth muscle cells was done to
to reduce the risk of damaging the pelvic plexus and thus pres- identify the apoptotic cell line. Wet weight of the denervated
ervation of postoperative urinary continence and erectile penises was significantly decreased after bilateral cavernous
function has been reported.30 When pelvic hematomas occur neurotomy whilst unilateral cavernous neurotomy allowed
it is advisable to drain them surgically since the fibrosis much greater preservation of penile weight. DNA content was
occurring after the slow spontaneous resolution of any blood also significantly reduced in bilaterally denervated penises
collection significantly lengthens the duration of cavernosal whilst no difference was found between unilaterally dener-
neuropraxia. vated penises and controls. Bilateral cavernous neurotomy
Although the number of cases performed per unit of time induced significant apoptosis, which peaked on postoperative
(surgeon’s volume) is a recognized predicting factor for success day 2. In addition, it was found that most apoptotic cells were
or failure in maintaining potency following a nerve-sparing located just beneath the tunica albuginea of the corpus caver-
radical prostatectomy, it has now been suggested that the nosum (i.e. the anatomical area where the subtunical venular
surgeon himself probably plays the most fundamental role in plexus is located). Finally, these authors found that apoptotic
determining the postoperative outcome: in other words, a cells were smooth muscle cells and not endothelial cells.
large-volume surgeon may potentially keep doing things The subsequent hypothesis suggested by the authors was
wrong if his surgical technique is not adequate.31 Therefore, that the bilateral injury to the cavernous nerves may induce
an important take-home message is the need to compare one’s significant apoptosis of smooth muscle cells, particularly in
own surgical technique with that used by recognized experts the subtunical area, thus causing an abnormality of the veno-
in this field. Reviewing the videotapes of one’s own nerve- occlusive mechanism of the corpus cavernosum. Apoptosis
sparing radical prostatectomies and comparing the surgical also seems to play a role in the genesis of ED seen in the aging
technique and results seen in terms of margin status, urinary population (which is clearly of crucial importance in the rad-
continence, and erectile function may be of significant impor- ical prostatectomy patient group), since it has been shown
tance because it allows identification of the parts of the that anti-apoptotic genes and proteins are expressed in young
operation that are at higher risks for surgical errors from a rats but not in aging rats.34
particular surgeon.32 These findings on apoptosis following radical prostatec-
tomy confirm the fact that most patients reporting postopera-
tive ED do develop massive corporeal venous leaks in the
long term.39 However, a reduction of the arterial inflow to the
Pathophysiology of erectile corpora cavernosa in patients with post-prostatectomy ED
dysfunction following nerve-sparing has been reported by several authors as a significant etiologi-
radical prostatectomy cal cofactor.40,41 Postoperative penile hypoxia seems to play an
important role in inducing histological and thus functional
Patients undergoing nerve-sparing radical prostatectomy often changes in the corpora cavernosa after surgery. Indeed, a
experience impairment of erections in the early postoperative recent clinical trial performed by Iacono et al. has clearly
period. This has been related to the development of neuro- demonstrated that, in a selected preoperatively potent popu-
praxia, which is believed to be caused by the damage to the lation of 19 non-diabetic patients undergoing radical pros-
cavernosal nerves that inevitably occurs during the excision of tatectomy and penile biopsies before surgery and at 2 months
the prostate, even in the hands of most experienced surgeons. and 12 months after surgery, a progressive increase in penile
 Rehabilitation of sexual function following prostatectomy 515

organized collagen content and a decrease in interstitial elastic radical prostatectomy when the return of spontaneous erec-
fibers and smooth muscle cells was evident after surgery.42 tions is slow, a dysfunctional sexual dynamic may develop in
The more relevant structural penile changes were reported at couples. The patient withdraws sexually as he is increasingly
the 12-month follow-up biopsy evaluation. Interestingly, discouraged with his lack of erectile function, which is a
none of the preoperatively potent patients experienced return constant reminder of his cancer. The female partner is
of spontaneous erections or responded to prophylactic post- relieved that the patient has survived the surgery, and may be
operative sildenafil administration (100 mg, once weekly for 3 satisfied with his companionship and is anxious not to upset
weeks starting 2 months after surgery), thus strongly suggest- him by making sexual overtures that may frustrate him.
ing that a non-nerve-sparing procedure had been performed Successful intracorporeal injection therapy early after radical
in the same patients. prostatectomy may contribute to breaking this negative
In conclusion, the postoperative combination of reduced cycle.15
penile arterial inflow and excessive venous outflow due to the Prophylactic administration of a vacuum constriction device
apoptosis-induced damage of the veno-occlusive mechanism has also been recently proposed as an early penile rehabili-
leads to reduced oxygen transport and increased production tation approach aimed at promoting adequate cavernosal
of transforming growth factor-beta. This subsequently causes oxygenation and therefore preventing penile fibrosis after
significant tissue damage (i.e. increased corporeal fibrosis, surgery.47
which not only is at the root of the known penile hemody- The advent of PDE-5 inhibitors in the treatment of ED has
namic abnormality but also is probably the cause of the post- clearly revolutionized the management of this medical condi-
operative decrease of penile length recently reported in an tion. This class of agents acts within the smooth muscle cell by
interesting study by Savoie et al.43 inhibiting the enzyme PDE-5, which naturally degrades
cGMP, an intracellular nucleotide that acts as a second mes-
senger in the process of smooth muscle cell relaxation. The
Pharmacological prophylaxis and cascade of intracellular events that leads to the relaxation of
the smooth muscle cell is initiated by the release of nitric
treatment of postoperative oxide, which follows sexual stimulation. Both intracorporeal
erectile dysfunction cavernous nerve terminals and endothelium release nitric
oxide, which as a gas diffuses into the smooth muscle cells and
Prophylaxis activates the enzyme guanylate cyclase, which ultimately
The better understanding of the pathophysiology of post- catalyzes the reaction from guanosintriphosphate to cGMP.
prostatectomy ED, including the concept of tissue damage Increased levels of cGMP lead to the activation of cGMP-
induced by poor corporeal oxygenation, paved the way for specific protein kinases, which activate further intracellular
the application of pharmacological regimens aimed at improv- events leading to the final reduction of intracellular calcium,
ing early postoperative corporeal blood filling. Montorsi et al. this being associated with smooth muscle cell relaxation. At
showed that, by using intracorporeal injections of alprostadil present, sildenafil, tadalafil, and vardenafil are approved for
early after a bilateral nerve-sparing radical prostatectomy, the clinical use in the European Union and the USA and have
rate of recovery of spontaneous erections was significantly been utilized also to treat post-prostatectomy ED.
higher than that in untreated patients.44 In the authors’ The rationale for the use of these drugs as prophylaxis is not
experience, alprostadil injection therapy should be started as yet completely understood. However, recent studies have elu-
soon as possible after the procedure, usually at the end of the cidated some potential mechanisms.48–52 The basic concept
first postoperative month. The initial dose is alprostadil 5 µg. would be to administer a PDE-5 inhibitor at bedtime in order
Patients should be instructed to use injections two or three to facilitate the occurrence of nocturnal erections, which are
times per week in order to obtain penile tumescence; injec- believed to have a natural protective role on the baseline func-
tions are not necessarily associated with sexual intercourse but tion of the corpora cavernosa. Montorsi et al. showed that when
it is clear that if the patient desires, he may be able to resume sildenafil 100 mg is administered at bedtime in patients with ED
satisfactory sexual intercourse with penetration as soon as he of various etiologies, the overall quality of nocturnal erections
is able to identify the correct dosing of the drug. Brock et al. as recorded with the RigiScan device is significantly better than
have also shown that the continuous use of intracavernous those obtained after the administration of placebo.48 Further-
alprostadil injection therapy was able to bring about signifi- more, experimental data regarding the potential mechanisms
cant improvement in penile hemodynamics and a return of involved in chronic administration of sildenafil have been
spontaneous erections (either partial or total) in patients with very recently published.49 Indeed, the effect of an 8-week treat-
arteriogenic ED, thus confirming a potential curative role of ment with sildenafil (60 mg/kg per day subcutaneously) in
this therapeutic modality in selected patients.45 These data male rats was evaluated on electrically induced erectile
have also been recently confirmed by Mulhall et al., who response in vivo before and after an acute injection of sildena-
showed that the prophylactic use of intracorporeal injections fil (0.3 mg/kg intravenously). Furthermore, endothelial-
of alprostadil in patients not responding to oral sildenafil dependent and -independent relaxations of strips of corpus
resulted in higher rates of spontaneous functional erections cavernosum were examined in vitro and compared with cav-
and erectogenic drug response 18 months after nerve-sparing ernosal strips from untreated rats. Interestingly, the authors
radical retropubic prostatectomy.46 The early postoperative found that endothelial relaxation induced by acetylcholine
use of intracavernosal injection therapy may also exert a sig- was significantly enhanced in rats treated chronically with
nificant psychological role. Commonly, after a nerve-sparing sildenafil compared with untreated rats. This could imply
516 Textbook of Erectile Dysfunction

that either muscarinic receptors or the transduction mecha- removal.52 Patients underwent percutaneous penile biopsy
nisms leading to the activation of endothelial nitric oxide both preoperatively (under general anesthesia prior to
synthase are up-regulated by chronic sildenafil treatment. surgical incision) and at 6 months after surgery (using local
Moreover, functional in vivo evaluations showed that chronic anesthesia). Interestingly, in group 1 there was no statistically
administration of sildenafil significantly enhanced frequency- significant change in the mean intracavernosal smooth
dependent erectile response and was associated with a greater muscle content between the preoperative and postoperative
response to an acute injection of sildenafil in treated rats com- measurements (51.1% and 52.6%, respectively), but in group
pared with controls. This study represents the first experi- 2 a statistically significant increase in mean smooth muscle
mental support for chronic consumption of sildenafil, which content after surgery (42.8% vs 56.8%, p < 0.05) was found.
could be associated with a higher rate of erectile function Thus, although it remains unclear how the chronic adminis-
recovery after radical prostatectomy. tration of sildenafil could increase the intracavernosal smooth
In this context, Padma Nathan et al. recently reported on muscle content after surgery, daily administration of high-
the prospective administration of sildenafil 50 mg and 100 mg dose PDE-5 inhibitors may be a key factor in cavernosal
versus placebo, daily at bedtime, in patients undergoing bilat- smooth muscle preservation, thus reinforcing the idea of the
eral nerve-sparing radical prostatectomy who were potent clinical application of sexual pharmacological prophylaxis
preoperatively.50 Four weeks after surgery patients were ran- after surgery.
domized to sildenafil or placebo for 36 weeks. Eight weeks However, despite the enthusiasm associated with these
after discontinuation of treatment erectile function was studies, the benefit induced by a rehabilitative PDE-5 inhibi-
assessed with the question, ‘Over the past 4 weeks, have your tor approach compared with an on-demand PDE-5 inhibitors
erections been good enough for satisfactory sexual activity?’ schedule has not been confirmed. We recently prospectively
and by IIEF and nocturnal penile tumescence assessments. studied a cohort of 80 patients submitted to bilateral nerve-
Responders were defined as those having a combined score of sparing radical retropubic prostatectomy with adequate
≥8 for IIEF questions 3 and 4 and a positive response to the postoperative erectile function data 12 months after surgery.53
above question. Twenty-seven percent of the patients receiv- Patients were assigned to four different groups after surgery:
ing sildenafil were responders (i.e. demonstrated return of no erectile therapy, on-demand intracavernosal injection of
spontaneous normal erectile function) compared with 4% in prostaglandin E-1 (PGE-1), on-demand PDE-5 inhibitors,
the placebo group (p = 0.0156). Postoperative nocturnal penile and rehabilitative PDE-5 inhibitor therapy (either every day
tumescence assessments were supportive. We believe that in or every other day for 3 months). Interestingly, we did not
the hands of experienced surgeons a 27% overall rate of return record any significant difference 12 months after surgery in
to normal erectile function after a bilateral nerve-sparing pro- the mean IIEF erectile function domain score between patients
cedure is far from being impressive, but the important mes- who received PDE-5 inhibitors on demand and those treated
sage from this study is that daily bedtime administration of with a rehabilitative intent. However, further large random-
sildenafil 50 mg or 100 mg after this procedure should be able ized trials are needed to confirm the validity of these prelimi-
to improve every surgeon’s baseline results. Although similar nary data. Therefore, an open debate regarding the efficacy
data are not available yet for tadalafil and vardenafil, we of an oral rehabilitation after radical prostatectomy is still
believe there is no reason not to expect similar findings with ongoing.
these drugs. Recently, a prophylactic regimen with methylprednisolone
Moreover, the rationale for PDE-5 inhibitor administration has been used in an interesting trial involving 70 young
at bedtime in patients undergoing nerve-sparing radical ret- patients (40–60 years) undergoing bilateral nerve-sparing
ropubic prostatectomy has recently been evaluated by radical retropubic prostatectomy who were randomized
Bannowsky et al.51 In fact, in a cohort of 27 patients submitted to receive either 6 days of placebo or escalating doses of
to nerve-sparing radical retropubic prostatectomy, nocturnal methylprednisolone starting from postoperative day 1.54 The
penile tumescence recording during the acute phase after sur- rationale of corticosteroid use early after surgery was based on
gery showed residual erectile function as early as the first night the potential use of this treatment in reducing the surgical
after catheter removal. Conversely, in a small control group of neural inflammation and local edema that might contribute
four patients treated with non-nerve-sparing radical retro- to postoperative dysfunction in neurovascular bundles.
pubic prostatectomy, no nocturnal erections were recorded Nevertheless no clinical benefit has been reported in patients
early after catheter removal. Based on these results, the authors receiving corticosteroids compared with placebo in terms of
concluded that in cases of early nocturnal tumescence, erectile function recovery based on IIEF evaluation at the
administration of a PDE-5 inhibitor can support successful 3-month, 6-month, and 12-month evaluations (p = 0.08, p = 0.50,
organ rehabilitation. However, further studies are needed to p = 0.71, respectively). Even in presence of disappointing results,
confirm the rationale of this approach. many important factors such as timing of administration
Furthermore, early use of high-dose sildenafil after radical of the drug, doses used, and duration of therapy might be
prostatectomy seems to be associated with preservation of considered as potential explanation of lack of corticosteroid-
smooth muscle content within human corpora cavernosa. induced benefits.
Indeed, Schwartz et al. enrolled 40 potent patients affected by In practical terms, we feel that the need for postoperative
localized prostate cancer who underwent radical retropubic prophylactic therapy should be discussed with the patient
prostatectomy at a single institution and were subsequently when counseling him about radical prostatectomy as one of
treated either with daily sildenafil 50 mg (group 1) or 100 mg the treatment options for prostate cancer. Patients must also
(group 2) for 6 months, starting from the day of catheter have the chance to guide their choice by being informed of the
 Rehabilitation of sexual function following prostatectomy 517

pharmacological approaches needed to recover normal post- to the type of nerve-sparing procedure they had undergone:
operative erectile function. bilateral nerve-sparing (53 patients), unilateral nerve-sparing
(12 patients) and non-nerve-sparing (26 patients). All patients,
at least 3 months after surgery, were prescribed sildenafil with
Treatment
the starting dose of 50 mg, which was tritated up to 100 mg in
Phosphodiesterase type 5 inhibitors the case of non-satisfactory response. At the 12-month assess-
PDE-5 inhibitors have acquired an established role in the ment performed by means of SHIM and Erectile Dysfunction
treatment of post-prostatectomy ED. As the mechanism of Inventory for Treatment Satisfaction (EDITS) questionnaires,
action of this class of drugs implies the presence of nitric oxide 48 of the 91 patients enrolled (52.7%) reported successful
within the corporeal smooth muscle cells, only patients under- vaginal intercourse. This percentage increased up to 71.7%
going a nerve-sparing procedure should be expected to (38 of 53) if only those who had a bilateral nerve-sparing
respond to these agents. Sildenafil is the drug that has been approach were considered. Moreover, at the 3-year follow-up
studied most extensively in this patient subgroup because it assessment, 31 of 43 (72%) patients who returned the ques-
has been on the market worldwide since 1998. In general tionnaires were still using sildenafil for sexual intercourse,
terms, it is now known that the best results with sildenafil are with a variable degree of partial erections. Interestingly, when
in young patients, those under 60 years of age being the best the responses were stratified according to the neurovascular
responders among patients treated having a bilateral nerve- bundle status, the magnitude of improvement in SHIM score
sparing procedure. Sildenafil is usually administered at the over time was greater in the bilateral nerve-sparing group
largest available dose although it is common to have post than in the unilateral nerve-sparing and non-nerve-sparing
prostatectomy patients responding also to the 25 mg and 50 mg groups. Significant erectile improvement was also reported
doses. Typically the response to sildenafil has been shown to by combining sildenafil 100 mg (taken 1 to 2 hours prior to
improve with time after the procedure: best results are seen intercourse) with vacuum tumescence device use in men
from 12–24 months postoperatively.5,55–62 Unfortunately, no affected by ED after radical prostatectomy who were dissatis-
data from multicenter, randomized, placebo-controlled trials fied with the results of the vacuum tumescence device alone.65
assessing sildenafil in patients undergoing nerve-sparing Indeed, this combination regimen allowed for significant
radical prostatectomy are available to date. It has been sug- erectile improvement and sexual satisfaction in 77% of the
gested that the early postoperative prophylactic administra- patients (24 of 31); furthermore, the addition of sildenafil was
tion of alprostadil injections allows a better response rate to associated with a significant increase in penile axial rigidity as
subsequent sildenafil, with lower doses of the drug being reported by both patients and their partners. Moreover, 30%
necessary.63 (7 of 24) of the patients responding to this combination treat-
Several studies have been published regarding the post- ment reported a return of natural erections at the 18-month
operative benefit of sildenafil as treatment of ED after a nerve- follow-up.
sparing procedure.55–59 The response rate to sildenafil treatment Vardenafil has been tested in patients with ED following a
for ED after radical prostatectomy ranged from 35% to 75% unilateral or bilateral nerve-sparing prostatectomy in a multi-
amongst those who underwent nerve-sparing surgery and from center, prospective, placebo-controlled, randomized study
0% to 15% amongst those who underwent non-nerve-sparing undertaken in the USA and Canada. This was a 12-week par-
surgery. A recent report has identified many factors signifi- allel arm study comparing placebo to vardenafil 10 mg and
cantly associated with a successful outcome of sildenafil treat- 20 mg.66 In this study patients in whom sildenafil had failed
ment after surgery in terms of erectile response, including the were excluded. Sixty percent and 71% of patients treated with
presence of at least one neurovascular bundle, a preoperative a bilateral nerve-sparing procedure reported an improvement
good erectile function [Sexual Health Inventory of Men of erectile function following the administration of vardenafil
(SHIM) score ≥15], age ≤65 years, and the interval from 10 mg and 20 mg, respectively. A positive answer to SEP ques-
radical prostatectomy to drug use (more than 6 months).61 tion 2 (‘Were you able to insert your penis into your partner’s
Zagaja et al. found an inverse relationship between age and vagina?’) was seen in 47% and 48% of patients using vardena-
response to sildenafil therapy for ED after radical retropubic fil 10 mg and 20 mg, respectively. A positive answer to the more
prostatectomy. Among men who underwent bilateral nerve- challenging SEP question 3 (‘Did your erections last enough
sparing surgery, response rates decreased from 80% in those to have successful intercourse?’) was seen in 37% and 34% of
<55 years to 45% in those aged 56–65 years and 33% in those patients using vardenafil 10 mg and 20 mg, respectively.66
>66 years.58 Zippe et al. stratified response rate by three time Recently an extended analysis focusing on the other domains
intervals post-surgery and by sildenafil dosage. The response of the IIEF in the same patients undergoing nerve-sparing
rate increased with time during the first year: 3–6 months radical retropubic prostatectomy has underlined how vard-
(44%), 6–12 months (55%), and <12 months (53%), and enafil was significantly superior to placebo with respect to
more responders required the 100 mg dose of sildenafil (71%) intercourse satisfaction, hardness of erection, orgasmic func-
than the 50 mg dose (29%). Thus, the data suggest that the tion, and overall satisfaction with sexual experience (p < 0.0009
early initiation of treatment is recommended, but realistic vs placebo for each of the variables studied), both at 10 mg and
improvement in response should not be expected until 1 year 20 mg doses.67
after surgery.56 Tadalafil was also evaluated in a large multi-center trial
Raina et al. recently reported the long-term results of conducted in Europe and the USA involving patients with
sildenafil use in patients affected by ED after radical prostat- ED following a bilateral nerve-sparing procedure. Seventy-one
ectomy.64 This study enrolled 91 patients stratified according percent of patients treated with tadalafil 20 mg reported
518 Textbook of Erectile Dysfunction

improvement in their erectile function compared with 24% of This off-label use requires the approval of the Ethics Com-
those treated with placebo (p < 0.001). The erectile function mittee of the hospital and a signed informed consent from
domain score of the IIEF was significantly higher after treat- the patient. In a retrospective study conducted by Raina et al.,
ment with tadalafil 20 mg compared with placebo (21.0 vs 102 patients using intracorporeal injections for ED following
15.2; p < 0.001), and this difference was clinically significant.12 radical prostatectomy were assessed by means of preoperative
Tadalafil 20 mg allowed men to achieve a 52% rate of success- and postoperative SHIM questionnaire, a mean of 4.0 ± 2.2 years
ful intercourse attempts, which was significantly higher than after surgery.74 Of these 102 patients, 40 had a bilateral nerve-
the 26% obtained with a placebo (p < 0.001).68 sparing procedure, 19 had a unilateral nerve-sparing proce-
The adverse event profile of the three PDE-5 inhibitors has dure, and 43 had a non-nerve-sparing procedure. Injection
been very similar also in this patient population and the therapy, based on the use of PGE-1 alone (10 µg/ml or 20 µg/ml
authors of this review feel that discontinuation from treat- in normal saline) (61% of patients), high-dose triple therapy
ment with one of the PDE-5 inhibitors is usually caused by (PGE-1 20 µg/ml plus phentolamine 1 µg/ml plus papaverine
lack of efficacy and that tolerability is overall more than 30 µg/ml) (19% of patients), or low-dose triple therapy (PGE-1
satisfactory. 5.88 µg/ml plus phentolamine 0.59 µg/ml plus papaverine
17.65 µg/ml) (20% of patients), was started a mean of 9 months
Other medical treatments (range 6–12) after the surgical procedure. Overall, 68% (69
of 102) of the patients achieved and maintained an erection
Patients either not responding to or who cannot use PDE-5
sufficient for sexual intercourse and 48% (49 of 102) of the
inhibitors are typical candidates for second-line pharmaco-
patients continued on long-term therapy. This excellent long-
logical treatment, which currently includes the intraurethral
term efficacy, whatever the type of the intracavernosal com-
and the intracorporeal administration of alprostadil. The most
pound used, has also been associated with a high compliance
recent information on the use of intraurethral alprostadil use
rate (< 70% of the patients). Although no statistically signifi-
suggests that its combination with oral sildenafil may salvage
cant differences have been reported among the three-drug
a significant proportion of sildenafil failures.69,70 Long-term
formulation, no mention has been made by these authors
efficacy and compliance data regarding intraurethral alpros-
regarding eventual differences in local or systemic side
tadil as a treatment for post-prostetctomy ED showed that
effects.
this therapy was effective in 55% of treated patients, with a
The same authors recently published an extended long-
drug compliance rate of 63% at mean follow-up of 2.3 ± 1.2
term analysis aimed at assessing the potential use of open-
years after surgery. Furthermore intraurethral alprostadil was
label sildenafil in men affected by post-prostatectomy ED,
associated with a significant increase in mean score on the
who had been treated for a mean of 3.7 ± 1.9 years with intra-
SHIM compared with the preoperative period for all men
cavernosal agents, either PGE-1 alone or triple therapy (PGE-1
enrolled and treated either with a nerve-sparing or non-nerve-
plus phentolamine plus papaverine). Overall, 41% of the
sparing procedure. Better results in terms of treatment-
patients enrolled (15 of 36%) successfully switched to silde-
induced erections were reported in patients with partially
nafil 50 mg (27%) or 100 mg (73%), with a higher switch rate
maintained erectile function after surgery (SHIM score ≥16).71
obtained in previous PGE-1 users compared with patients
Intracorporeal injection therapy with alprostadil is effec-
using triple therapy, with a higher preoperative and post-
tive in the majority of post-prostatectomy patients, regardless
intracavernosal injection SHIM score.75
of the status of their cavernosal nerves. Recently, Gontero
et al. have shown that the best clinical and hemodynamic
responses with alprostadil injection therapy are seen 1 month
after the procedure but that the attrition rate for this approach Summary
is higher when it is started at least 3 months after surgery.
They proposed that in order to optimize long-term success Radical prostatectomy is an increasingly performed procedure
with intracavernous injections of alprostadil, this treatment in patients with prostate cancer. As the mean age of this
should be started 3 months after surgery, as a reasonable patient group is progressively declining owing to the advent of
compromise between effectiveness and patient compliance.72 prostate cancer screening programs, the demand for optimal
In the experience of the authors of this review, the use of postoperative QOL is becoming more important. Erectile
alprostadil monotherapy should be matched against the use of function can be preserved in patients undergoing a nerve-
the combination of alprostadil, papaverine, and phentolamine. sparing radical prostatectomy provided that patients are rig-
Patients treated with the three-drug combination obtain very orously selected prior to surgery and that an anatomic radical
high response rates and only rarely report penile pain, the prostatectomy following the most modern techniques is care-
typical adverse event related to alprostadil.73 The major dis- fully performed. Pharmacological prophylaxis, either with
advantage of using the three-drug combination is its non- oral or intracavernosal drugs, may potentially have a signifi-
availability on the market, which obliges the urologist to cantly important role in future strategies aimed at preserving
prepare the solution and then distribute it to the patient. postoperative erectile function.
 Rehabilitation of sexual function following prostatectomy 519

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66 Sexual dysfunction and prostate
cancer therapy
John M Fitzpatrick, Roger S Kirby, Robert J Krane, Jan Adolfsson,
Don WW Newling, and Irwin Goldstein

Introduction which in turn leads to veno-occlusive dysfunction. The fibrosis

is probably due to increased local deposition and activation
The management of prostate cancer focuses on effective of transforming growth factor beta-1, resulting from the
methods of cure and palliation. The complications associated ischemia.
with radical surgery for localized disease, such as urinary
incontinence and erectile dysfunction (ED), have been greatly
reduced with the development of the nerve-sparing radical Androgen withdrawal
prostatectomy technique.1 In advanced disease, palliation of Patients with advanced prostate cancer who are receiving
pain and prevention of additional complications of prostate androgen withdrawal therapy may be unable to develop
cancer are the main treatment objectives. With the diagnosis erections and, in addition, may experience a loss of libido.
of prostate cancer shifting to younger patients than was the Tiredness, reduced levels of concentration, and hot flushes are
case 10 years ago, and with the availability of effective treat- also serious side-effects, which may result in withdrawal from
ment of localized disease, attention has shifted to issues of working life and an inability to enjoy hobbies. Androgen
quality of life. Factors affecting patients’ lifestyles are being withdrawal can also produce a change in body image, with the
considered, sexuality in particular. Physicians should consider development of a more female form; some men may fear the
how a patient will feel when given treatment options that development of osteoporosis.
might deprive him of his sexual function. For all patients,
seemingly irrespective of age, sexual dysfunction is still an
important element in their perceived quality of life and must Radiation therapy
be discussed fully when planning any therapeutic strategy. Radiation therapy (external beam), conformal beam radio-
therapy, and brachytherapy can cause ED in 50%, 35%, and
25% of cases, respectively. Goldstein et al. evaluated radiation-
induced alterations to penile hemodynamics using history,
Causes of erectile dysfunction in physical examination, and dynamic infusion pharmacocaver-
prostate cancer nosometry and cavernosography.3 The cause of ED was found
to be arterial insufficiency, which has a higher incidence in
ED in prostate cancer patients has a number of causes smokers, older patients, and those with pre-existing vascular
(Table 66.1). Psychologically, some patients fear that sexual conditions, such as hypertension and diabetes.
activity may cause pain, may stimulate the cancer, or, indeed, Both proximal corporal veno-occlusive dysfunction and
may cause the cancer to spread to their partner. Depression cavernosal arterial insufficiency were present in all patients.
itself is an important cause of ED and loss of libido. Patients Cavernosography indicated that, in the majority of cases,
may also put up a psychological barrier to sexual activity site-specific venous leakage was crucial; proximal spongiosal,
because they feel less attractive to their partner. These issues cavernosal, and dorsal venous leaks were far less frequent.
must be taken into consideration when discussing sexual
potency with prostate cancer patients. Pain from metastatic
disease and lack of muscle strength are two important physical Surgery
problems that can lead to ED. Painful gynecomastia may also Non-nerve-sparing radical prostatectomy can result in impo-
limit sexual activity in some patients. tence rates as high as 98%. If preservation of the neurovascu-
Treatment for prostate cancer can, in itself, cause a consid- lar bundles is achieved, the rate drops to between 30% and
erable degree of dysfunction (Table 66.2).2 Tissue fibrosis 75%, depending on whether the bundles are preserved bilater-
resulting in veno-occlusive ED can be caused in a variety of ally or unilaterally and on the patient’s age. ED following
ways (Table 66.3). Absence of erections can lead to decreased nerve-sparing prostatectomy may be due to removal of an
blood flow to the corpora cavernosa. The concomitant reduc- accessory pudendal artery that had been acting as the main
tion in oxygen supply to the tissues produces tissue fibrosis, cavernosal artery.4 The prevalence of this phenomenon is

521
522 Textbook of Erectile Dysfunction

Patients should be made fully aware of the risk of dys-

Table 66.1 The main causes of erectile dysfunction
function in order to avoid subsequent frustration, which
(ED) in prostate cancer patients
in itself can lead to decreased potency. It is interesting to
• Neurological observe that, statistically, of the approximately 17 million
men with ED of various etiologies in the USA, only 10% will
• Psychological
seek treatment and even fewer will adjust to the subsequent
• Arterial therapy.5
• Hormonal It is important to maintain sexual desire when treating
• Veno-occlusive dysfunction patients with prostate cancer as, in most patients with an
• Geometric
intact vascular system, loss of potency can be treated by injec-
tion therapy, vacuum pump devices, or a penile prosthesis.
Loss of libido cannot be treated unless patients are given
androgen replacement, and this is a separate but important
Table 66.2 Mean percentage of patients developing issue. Injection therapy, if selected, should be started at an
ED following a particular treatment2 early stage, owing to the risk of tissue anoxia and corporal
fibrosis associated with lack of erections. Injection therapy
Treatment ED (%) and vacuum devices appear to be acceptable therapeutic
Medical/surgical castration 100 options from the patient’s perspective, although neither is
Radical prostatectomy 98 without drawbacks. A penile prosthesis is another option that
is sometimes requested at the same time as surgery for the
Nerve-sparing radical prostatectomy 30–75
cancer itself. Caution should be exercised in these circum-
Radiation therapy 50 stances, since it is not clear which patients will actually become
Brachytherapy 25 impotent. The possibility of penile shortening following
Watchful waiting 0 radical prostatectomy is a serious concern to patients. An
assessment of penile length pre- and postoperatively in the
erect state should be carried out to judge the effects of surgery
accurately. The patient’s anger and frustration over this pro-
Table 66.3 Causes of veno-occlusive ED
blem may be avoided with the use of a penile prosthesis at
• Arterial injury; prolonged tissue ischemia; tissue fibrosis;
the time of radical prostatectomy.
veno-occlusive dysfunction
• Radiation injury to tissues; tissue fibrosis;
veno-occlusive dysfunction Quality of life
• Nerve injury; loss of nocturnal erections; tissue fibrosis;
Treatment choices for prostate cancer are frequently based
veno-occlusive dysfunction
on the evaluation of possible benefits balanced against side-
effects of treatment. Owing to a lack of information, little
regard is paid to quality-of-life issues.
thought to be approximately 35%, with the origin of the artery Previous assessments of quality of life are unsatisfactory,
occurring from the left side in 50% of cases and from the right because they measured sexual function and not how the
side or bilaterally in 25% of cases each. In the majority of patient felt about potency or lack of it. These assessments
cases, the accessory pudendal artery arises from the internal dealt only with figures, functions, and scales. Understandably,
pudendal or the obturator artery. it may mean very little to the patient that he has a score of
10.7 on a ‘health and quality of life’ scale. Physicians should
be aware that this assessment does not truly reflect the
Management of erectile dysfunction patient’s quality of life. For example, there are major differ-
ences between the patient’s and the physician’s appreciation
Normal sexual activity for a patient’s own age-group is an of quality-of-life issues in endocrine treatment of prostate
important consideration for urologists treating patients with cancer.
prostate cancer. Older patients may be satisfied with less Physicians tend to overestimate patients’ quality of life with
sexual activity and tolerate more complications than younger respect to sexual activity and hot flushes, and underestimate
patients. Consequently, it is important to establish baseline their psychological distress.6 A validated instrument is essen-
values for sexual activity. tial in order for the physician to know what should be, and
Patient expectations of treatment depend on a number of what is being, measured.
factors, such as age and disease stage. For instance, the expec-
tations of a 40-year-old patient with localized disease who had
full sexual function before therapy and is now left with no Quality-of-life instruments
erectile function will certainly differ from those of a 75-year- A psychometric scale is the most commonly used method for
old patient with metastatic cancer. Patient counseling is evaluating quality of life. Each symptom experienced by the
essential in order to clarify the likelihood of developing ED patient is given a value and the total score is analyzed statisti-
following treatment. cally. Such symptom-based assessment can be carried out in a
 Sexual dysfunction and prostate cancer therapy 523

Table 66.4 Proportion of men reporting decrease in sexual function compared with then youth; prostate cancer
therapy indicated

Aspects Men without Men with Endocrine Radical External Mixed group Other cases
assessed prostate prostate treatment/ prostatectomy radiation (n = 35) (n = 139)
cancer cancer castration (n = 22) (n = 37)
(n = 314) (n = 342) (n = 109)

Sexual 156/305 240/321 82/99 (83%) 16/22 (73%) 27/37 24/33 (73%) 91/130
desire/ (51%) (75%) (73%) (70%)
thoughts
Erection 235/304 286/318 93/97 (96%) 19/22 (86%) 35/37 34/37 (100%) 105/128
capacity (77%) (90%) (95%) (82%)
Organsm 209/305 252/302 81/93 (87%) 14/20 (70%) 32/37 23/31 (84%) 99/121
pleasure (69%) (83%) (86%) (82%)
Ejaculate 232/298 256/287 78/89 (87%) 18/21 (86%) 31%33 25/28 (89%) 104/116
volume (78%) (89%) (94%) (90%)

∗ Variations in denominators of ‘n’ are caused by different response rates for individual questions.

number of ways: pain, fatigue, and general symptoms can be Prostatectomy Radiation
evaluated in a health-related quality-of-life questionnaire; Orchiectomy No surgery
alternatively, symptoms prevalent in a selected group of Hormone therapy Unknown
patients can be identified (e.g. characterization of symptoms
related to localized or advanced prostate cancer) in order to
evaluate sexual dysfunction. 10.5%
Physicians need to devise methods of evaluating their 44.7%
patients’ symptoms in the absence of a validated questionnaire.
The actual development of a formal questionnaire is a long and
laborious process. Initially, in-depth interviews with a number
of patients are conducted, followed by re-testing of the ques-
tions on a similar patient group. Validation should ideally be
carried out against a ‘gold standard’ instrument of assessment,
which unfortunately is not available in the area of sexual func-
tion. Test–re-test reliability is measured by asking the same 23.7%
question of the same group of patients after a specific time
3.5%
interval. It should be noted that the resulting questionnaire is
specific only for the condition for which it was designed. 8.8%
A questionnaire for assessing sexual function in patients 8.8%
with prostate cancer has been developed in Sweden by
Helgason.7 A three-level approach was involved, with patients Figure 66.1 Patient profile by treatment status.
first being asked how frequently a particular dysfunction
occurred; verbal categories of numbers (1–7) were used to
represent the answers. The next question asked was: ‘If you the RigiScan device, compared with evidence of nocturnal
were to live with this problem for the rest of your life, how tumescence in the 80% who said that they were potent.
much distress would you get from it?’ Four categories of The questionnaire was tested in men with and without
answer were provided: none; a little; a moderate amount; and prostate cancer, including 342 patients diagnosed in 1992 in
a lot. The third question, to which an answer on a scale of 1–7 Stockholm.9 An equivalent sample of healthy men from the
was requested, was: ‘How would this affect your overall well- general population was investigated. The assessment looked at
being, either psychological or physical?’ In this way, the ques- the prevalence of decreased sexual function by comparing
tionnaire assessed three aspects of quality of life: function, current function with that experienced in a patient’s youth.
inconvenience, and overall wellbeing, resulting in a scale This also provided a ‘maximum’ function reference for each
specific to prostate cancer patients. Elements of the question- of the men studied.
naire were validated against objective measurements and One interesting observation was that there was a high
found to have a very high reliability (90%).8 For example, prevalence of decreased desire and erections among the group
three different aspects of erection were assessed with regard to of healthy men: 77% reported decreased function compared
nocturnal tumescence. The observation was made that all with that experienced in their youth (Table 66.4).10 The
patients who said that they were impotent had no erections on study indicated that the relative risk of experiencing ED and
524 Textbook of Erectile Dysfunction

General practitioner

Hospital doctor

Sex therapist

USA
Nurse UK
Germany
Italy
Other professionals

0% 20% 40% 60%

Figure 66.2 Patients given advice by different medical professionals according to country.

8 All countries were interviewed within 5 years of being diagnosed. Radical

USA prostatectomy had been performed in 44.7% of patients,
7 UK while 8.8% had received hormone therapy, and 3.5% had
Germany undergone bilateral orchiectomy (Figure 66.1). Patients were
6
Italy asked whether they were given sexual advice or help after diag-
nosis or treatment. Overall, of the five categories of healthcare
5
professional about which enquiry was made, hospital doctors
were cited as giving advice by 46% of patients, general practi-
tioners by 21%, sex therapists by 9%, other professionals by
4
7%, and nurses by 3%. On a country basis, the hospital doctor
was more likely to give advice in the USA, Germany, and Italy,
3
whereas in the UK this advice was more likely to have been
given by a sex therapist (Figure 66.2). With regard to patients
2 who would find sex counseling helpful to themselves or their
partner, 46% of all patients said that they would.
Before 3 months after In the last Preferred
diagnosis diagnosis month level A comparison was made of patients’ sexual activity before
diagnosis, 3 months after diagnosis, and in the previous
Figure 66.3 Comparison of patients’ preferred level of sexual month, and what the patient would prefer the activity to be
activity with levels before and after diagnosis and current (Figure 66.3). Clearly, patients in each of the countries studied
levels. would prefer their sexual activity to be the same as it was
before diagnosis, or even greater. Patients’ preferences for the
mode and frequency of delivery of hormonal treatment were
a decreased sexual desire in prostate cancer patients in general studied, and interesting differences according to country were
was almost double that in the controls. observed. In the UK, patients preferred to take one to three
tablets daily, whereas in Italy, patients were more willing to
have monthly injections (Figure 66.4). From a pyschological
Patient preference survey viewpoint, seeing a patient on a monthly basis makes a
significant difference.
A survey was conducted in 400 patients with prostate cancer The survey also showed a tendency for patients to discon-
in four countries – the USA, Germany, Italy, and the UK. tinue certain hobbies and activities – an important aspect in
The objectives of the study were to investigate the patients’ terms of diminished quality of life. Almost one-third of
understanding of the treatment options they received, to patients gave up sporting activities, which (although this was
explore the importance of patient–doctor communication not determined) could be because of pain or weakness caused
in the treatment of prostate cancer, and to determine the by hormonal therapy.
effect of treatment on patients’ sexual function. Concomitant In conclusion, this survey raised a number of important
conditions such as hypertension, heart disease, and psycho- issues. Sexual dysfunction following therapy for prostate
logical illness, therapy for which may have influenced erectile cancer should be assessed. Large multicenter, prospective,
function, were not recorded. The majority of the patients controlled studies into the incidence of ED after radical
 Sexual dysfunction and prostate cancer therapy 525

1 tab 2–3 x/day

1 tab/day
Injection/month
Injection/3 month

1st 2nd 1st 2nd 1st 2nd 1st 2nd

USA UK Germany Italy

Figure 66.4 Patients’ preferences for mode and frequency of delivery of hormonal therapy by country.

prostatectomy are needed. With regard to hormonal therapy, should be evaluated. Studies are also needed on what is con-
the effect on sexuality should be assessed prospectively through sidered to be the normal level of sexual activity in different age
questionnaires and objective methods. The problem must be groups. In general, a universally accepted method of quantifi-
quantified, with definition of the number of patients suffering cation of sexual dysfunction is urgently required, since this is
from sexual dysfunction and the ways in which they are an area that will be increasingly important to urologists
affected, and the effects on patient–partner relationships involved in the management of prostate cancer.

REFERENCES

1. Walsh PC, Lepor H, Eggleston JC. Radical prostatectomy with 6. Fossa SD, Woehre H, Kurth KH, et al. Influence of urological mor-
preservation of sexual function: anatomical and pathological bidity on quality of life in patients with prostate cancer. Eur Urol
considerations. Prostate 1983; 4: 473–85. 1997; 31: 3–80.
2. Meuleman EJ, Diemont WL. Investigation of erectile dysfunction. 7. Helgason AR. Prostate cancer treatment and quality of life: a three
Diagnostic testing for vascular factors in erectile dysfunction. Urol level epidemiological approach. Thesis: University of Stockholm,
Clin North Am 1995; 22: 803–19. 1997.
3. Goldstein I, Feldman M, Deckers PJ, Krane RJ. Radiation associ- 8. Helgason AR, Aldolfsson J, Dickman P, et al. Factors associated
ated impotence: a clinical study of its mechanism. JAMA 1984; with waning sexual function among elderly men and prostate
1251: 9031. cancer patients. J Urol 1997; 158: 155–9.
4. Nehra A, Ramakumar S, McKusick MA, et al. Pharmacoangio- 9. Helgason AR, Aldolfsson J, Dickman P, et al. Waning sexual
graphic prevalence of accessory pudendal arteries: role of main- function: the most important disease-specific distress for patients
taining sexual function following radical retropubic prostectomy. J with prostate cancer. Br J Cancer 1996; 72: 1417–21.
Urol 1997; 157: 357. 10. Helgason AR, Adolfsson J, Dickman P, et al. Sexual desire, erec-
5. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its tion, orgasm and ejaculatory functions and their importance to
medical and psychosocial correlates: results of the Massachusetts elderly Swedish men: a population-based study. Age Ageing 1996;
Male Aging Study. J Urol 1994; 151: 54–7. 25: 285–91.
67 Gender reassignment surgery
Michael Sohn and Klaus Exner

Introduction and history They provide minimum requirements for diagnostic and
therapeutic procedures, consisting of:
Trans-sexualism is defined as ‘a strong and persistent
cross-gender identification with persistent discomfort for the • diagnostic assessment;
patient with his or her sex in the sense of inappropriateness in • real-life experience and psychotherapy;
the gender role of that sex’.1 Until the late 1980s the prevailing • hormonal therapy; and
assumption was that trans-sexualism was a well-defined • surgical therapy.
identity with sharply marked boundaries. In the meantime it
became evident that not all patients fit into these strict crite-
ria. This may be the reason, that in the fourth edition of the Preconditions for surgical treatment
Diagnostic and Statistical Manual (DSM-IV), published in in trans-sexual patients
1994, the term ‘trans-sexualism’ is replaced by ‘gender iden-
tity disorder’. There are no specific laboratory or psychomet- If a patient has achieved 12 months of real-life experience
ric tests to confirm that a patient has an irreversible gender (ideally combined with psychotherapy), received at least
identity disorder. 6 months of continuous hormonal treatment, and has reached
The concept of medicalized sex change did not depend on a reasonable understanding of the costs, length, likely compli-
the later invention of synthetic hormones or the development cations and post-surgical rehabilitation requirements of the
of elaborate surgical techniques. Ablative surgical procedures various surgical procedures, then readiness criteria for surgi-
such as orchiectomy or hysterectomy have long been per- cal treatment have to be approved and reconfirmed by two
formed for sex change purposes before the term ‘trans-sexual’ letters of recommendations from mental health professionals.2
was introduced into the scientific literature in 1923. It was in The mental health professionals, the surgeon, and the patient
1931 that a complete staged genital reassignment procedure in share responsibility for the decision to make irreversible
a male-to-female trans-sexual (MF-TS) was reported in a changes to the body. The two independent letters of recom-
medical journal.2 In 1966 the influential book by Harry mendation by mental health professionals should be structured
Benjamin, The Transsexual Phenomenon, brought genital sex and clearly indicate surgical therapy.
reassignment surgery to a scientific level and made the medi- The surgeon performing genital reconstruction should
cal societies aware of potential benefits of this type of surgery. be a urologist, gynecologist, plastic surgeon, or general
It took another 14 years before the first standards of care were surgeon and be board-certified by a nationally known and
published in 1997, under the auspices of the Harry Benjamin reputable association. He or she should also have specialist
International Gender Dysphoria Association (HBIGDA). competence in genital reconstructive techniques attained
These standards have been continuously updated, and the by documented supervised training, and be knowledgeable
sixth version was published in 2001.3 Recently, the HBIGDA about more than one of the surgical techniques for genital
changed its name to the World Professional Association for reconstruction.
Transgender Health (WPATH), and the latest standards of Genital surgery for the MF-TS patient can include orchiec-
care for trans-sexual patients were published in 2001.3 tomy, penectomy, vaginoplasty, clitoroplasty, and labioplasty.
These standards should be seen as an international interdis- Techniques include penile skin inversion and pedicled recto-
ciplinary recommendation, which must be brought into con- sigmoid transplant of free skin graft to line up the neovagina.
text with national forensic and medical recommendations for Genital surgery for the female-to-male trans-sexual (FM-TS)
the individual patient. Prevalence data for gender identity dis- patient can include hysterectomy, salpingo-oophorectomy,
orders vary with the survey methods used in various countries vaginectomy, metoidoioplasty, scrotalplasty, urethralplasty,
and have been reported as 1 in 2900 in Singapore and 1 in placement of testicular prosthesis, and phalloplasty. There are
36,000 in Germany. Gender identity disorders seem to affect various current operative techniques for phalloplasty. Even
more biological males than females with a sex ratio in various metoidoioplasty, which in theory is a one-stage procedure
reports being about three males to every female. for construction of a microphallus, often requires more
The standards of care of WPATH reflect a professional than one operation. The plethora of techniques for penis
consensus about the psychiatric, psychological, medical, and reconstruction indicates that further technical development is
surgical management of patient with gender identity disorders. necessary.3

526
 Gender reassignment surgery 527

While the WPATH recommendations for diagnostic evalu- Table 67.1 Steps of genital sex reassignment surgery
ation and indications for treatment fulfill the prerequisites for in male-to-female trans-sexual patients
international guidelines, operative details of genital sex reas-
signment surgery remain open to debate. Several medical 1. Bilateral ablation of the testes
societies and journals have repeatedly published standards of 2. Amputation of the penis
care and continuing medical education (CME) reports on 3. Creation of a neovaginal cavity with a sensitive lining
subtopics of this field but these have not been able to elimi- 4. Creation of a female urethral meatus
nate the lack of consensus on surgical details, especially in 5. Construction of labia and clitoris
FM-TS genital reassignment. Adapted from A Plast Surg 1996; 37: 669–75,6 and Plast Reconstr Surg
2005; 116: 135e–45e.7

Surgical reassignment in sensation, and lack of any lubrication have withdrawn atten-
male-to-female trans-sexuals tion from these techniques as first-line procedures. Penile skin
grafts were popularized in the early period of genital reassign-
Non-genital surgery ment and represented some advantages over non-genital skin,
Even after several years of estrogen therapy, breast formation but consensus developed in the past few decades that conver-
is often insufficient and requires operative breast augmenta- sion of a possible skin flap into a graft does not seem to be
tion. Despite some sexual differences in mammary anatomy, justified.4–7 Non-genital skin flaps, such as medial thigh flaps
and chest wall anatomy, the implantation of mammary pros- or inguinopudendal flaps, have been reported but have never
theses is not essentially different from a breast augmentation gained widespread popularity owing to the resulting donor
in biologically female patients. Further operative procedures site morbidity and the bulky flap characteristics, which may
such as cricothyropexy for voice augmentation or resection of reduce neovaginal volume. These techniques may be more
the thyroid prominence as well as rhinoplasty to provide the appropriate for genital reconstruction in biologically female
patient with a more feminine nose profile may be indicated.4 patients after cancer surgery.
Timing of all these procedures in relationship to surgical gen- Pedicled intestinal transplants have been used in trans-
ital reassignment is optional. It may be prudent to postpone sexual patients since 1974. A similar appearance to normal
breast augmentation for several months after genital reassign- vaginas and lubrication may be possible advantages; neverthe-
ment in order to await the potential effect of castration on less, this approach demands additional transabdominal sur-
breast tissue. If breast surgery is performed together with gen- gery with all its possible inherent complications. Retention
ital surgery, it should be the first step of the procedure since it of mucus, introital stenosis, persistent odor, and colitis are
represents the most aseptic part of the intervention. further possible complications, which make these techniques
less attractive as a primary procedure.8 Rectosigmoid trans-
plants remain a viable option for secondary vaginoplasties
Genital reassignment surgery after failed penoscrotal flap procedures or in non-trans-sexual
The goals of genital gender reassignment surgery in MF-TS women with vaginal atresia.6
patients summarized by Karim et al. in 1996:5 ‘The surgical Penoscrotal skin flaps today are favored by most authors
aim of genital reassignment in MF-TS is to create a perineo- in the field of trans-sexual surgery. The inverted penile skin is
genital complex as feminine in appearance and function as used as a tube, augmented by a triangular perineal–scrotal flap
possible. The perineogenital area should be free of poorly for construction of the posterior introitus (Figure 67.1).
healed areas, scars and neuromas. The neovagina should ide- Several modifications have recently been published – for
ally be lined with moist, elastic and hairless epithelium. Its example, the inclusion of a pedicled and opened urethral
depth should be at least 10cm and its diameter should be segment into the tube for diameter enlargement and better
30mm’ (Table 67.1). lubrication.9 In patients with a short penis or a radical cir-
cumcision, the length of the inverted penile skin may be too
short to reach the neovaginal vault. In these cases elongation
Vaginoplasty of the penile skin tube may be facilitated by split skin grafts or
Methods for the lining of the neovaginal cavity between both full scrotal skin grafts after thinning and depilation.10
sheets of Denauvielle’s fascia can be classified into five Daily postoperative dilatation of the neovagina is of utmost
options:6 importance for preservation of neovaginal length and width.
Several obturators have been recommended for this purpose.
1. Non-genital skin grafts A pneumatic soft silicone device with a valve for individual
2. Penile skin graft filling may be an attractive dilator for the first 6–8 weeks after
3. Penile scrotal skin flaps surgery. This should be replaced by a more solid device after
4. Non-genital skin flap wound healing in order to prevent contractile scar formation.
5. Pedicled intestinal transplants. Patients must be informed that vaginoplasty with skin lining
demands lifelong regular self-dilatation, which only rarely can
While non-genital skin grafts were used in the first reports on be replaced by sexual intercourse. Shrinkage of the neovaginal
genital reassignments,2 disadvantages such as donor area scars, cavity with need for secondary procedures occurs in less
frequent circular scar formation at the introitus, suboptimal than 10% of cases in large-volume centers that specialize in
528 Textbook of Erectile Dysfunction

(a) (b)

Figure 67.1 (a) Postoperative result after male-to-female trans-sexual genital reassignment. Vaginal dilator in place. (b) Genital
aspect 6 months after male-to-female trans-sexual genital reassignment.

sex-reassignment surgery.6,10,11 If the penile skin tube is not suf- Strong tension on the abdominal pedicle of the penile skin
ficiently long to reach the neovaginal wall, extensive infra- and flap used for invertion vaginoplasty results in the ventral
suprapubic mobilization of the penile island flap is demanded. aspect of the labia majora remaining too far apart. In order to
There is no supporting evidence in the literature to recom- correct this anterior dehiscence of the labia majora simultane-
mend whether the neovaginal lining should be fixated to the ous infrapubic double Z-plasties have been recommended.14
sacrospinous ligament or to the rectus muscle. These additional incisions may endanger penile skin blood
supply and result in hypertrophic scar formation, owing to
high tension on the suture lines.10,13 Consequently, it appears
Clitoral–labioplasty wise to delay these procedures until complete wound healing
The creation of a sensitive, well-vascularized neoclitoris has occurred. Recently, much effort has been invested by sev-
during MF-TS genital reassignment has been accepted as a eral surgical teams in sophisticated techniques for reconstruc-
very important surgical step. Up to 1995 it was not an integral tion of the clitoral–vestibular–labial complex during primary
part of surgical standards in reassignment surgery.12 Since then genital reassignment procedures. It remains open to debate
nearly all reports on MF-TS genital reassignment include clito- whether such detailed procedures might be better performed
roplasty in the standard surgical procedure: part of the glans as planned secondary procedures after complete wound
penis, with the neurovascular dorsal bundle in continuity, is healing.6,10,15–17
dissected from the corpora cavernosa for this purpose.
Torsion- and pressure-free positioning of the bundle is essen-
tial in order to avoid postoperative necrosis of the neoclitoris. Postoperative follow-up studies
More than 80% of operated MF-TS patients report erogenous A comprehensive compilation of follow-up studies after
sensation of the neoclitoris after this procedure.13 Complete gender reassignment surgery was published by Pfäfflin et al.
resection of both corpora cavernosa and partial resection of in 1992.18 An actual analysis of this and other compilation
the corpus spongiosum are further important steps to refine reports by Hartmann et al. identified a negative postoperative
the vestibulum and introitus area in order to avoid obstruc- outcome in about 15% of all operated patients.19 Good surgical
tion during intercourse caused by arousal-induced swelling of results have been identified as a significant indicator for over-
erectile tissue.6,10 all positive outcome. Advanced age at first presentation and
The creation of esthetically acceptable labia majora from personal as well as social instability have been identified as
scrotal skin normally does not represent a problem for sur- negative predictors. Considering the progress of surgical tech-
geons experienced in gender reassignment surgery. In the niques achieved in the past 15 years, it may be wise to search
majority of cases, sufficient well-vascularized scrotal skin is for follow-up studies comparing older and newer operative
available for labia formation. Creation of an esthetically strategies. Van Eldt et al. examined 93 MF-TS patients after
appealing posterior commissure is facilitated by a small surgery and were able to compare results before and after
posterior base of the inverted Y-incision, advocated by Karim 1996.20 Hospital stay and the number of re-admissions and
et al. in 1995.13 re-operations significantly dropped after changing to newer
 Gender reassignment surgery 529

operative strategies. Stenoses of the neovagina were common vaginal flap can be included in the urethroplasty, the rest
after split skin graft lining, but 32 of 42 patients were content of the vagina is completely excised, and the labia majora
with vaginal volume after the introduction of the use of peno- reconstructed into a neoscrotum.24 Recently Hage and Van
scrotal skin for neovaginal lining. Over 80% stated satisfaction Turnhout analyzed the long-term results of such a procedure
with their status after surgery. From other reports it becomes in 70 patients.25 An average of 2.6 surgical procedures per
obvious that satisfaction with vaginal volume can be observed patient was needed to complete genital reassignment and
in around 74% of all operated patients. A 10–20% stenosis manage such postoperative complications as urinary fistulae
rate has to be expected after vaginoplasty.10–13 If the neurovas- and stenoses. In 17 of the 70 patients, additional phalloplasty
cular bundle is preserved, an 80–87% clitoral orgasm rate can with free flaps was performed after metoidoioplasty. Metoidoio-
be achieved.10,13 A re-operation rate of more than 20% has to plasty may be the method of choice in FM-TS patients who
be expected, mostly because of a need for corrective surgery to are in doubt about their need for phalloplasty, but patients
the introitus and the clitoral labial complex.21 should be informed that complication rates and the need for
re-operations are considerable. Owing to the recent advances
in free-flap phalloplasty these procedures will become less
Surgical reassignment in attractive for FM-TS patients in the future.
female-to-male trans-sexual patients
Breast reduction Phalloplasty and
Obtaining a male chest configuration is of utmost importance scrotal reconstruction
for FM-TS patients. A subcutaneous mastectomy in patients
The first series of successful phalloplasties, using a tubed
with larger breasts is a significantly more difficult operation
abdominal flap, was reported by Bogoras in 1936.26 During
than simple breast augmentations in MF-TS patients. It should
the following decades the search for the best method encom-
precede other operative procedures, and it greatly facilitates the
passed numerous variations of abdominal flaps, scrotal skin
real-life test and the adjustment to a male lifestyle. In the case
flaps, tubed thigh flaps, gracilis musculocutaneous flaps, groin
of small breasts and elastic skin, a simple semi-areolar incision
flaps, and iliac crest flaps. In 1984 the first neophallus derived
can be used for subcutaneous mastectomy. In patients with
from microsurgically transplanted free radial forearm flaps
larger breasts, skin reduction is required and usually performed
initiated a plethora of free-flap designs and techniques. The
by circular periareolar excision and de-epithelialization.4
availability of microsurgical neurovascular anastomoses
enabled reconstructive surgeons to look for other less exposed
Hysterectomy and oophorectomy donor areas for free-flap retrieval, such as upper medial
Hysterectomy and oophorectomy may be performed as a pre- arm, upper lateral arm, and saphenous, deltoid, and fibular
liminary procedure to reconstructive genital reassignment in osteocutaneous flaps.27 The variety of more than 20 different
FM-TS patients, or it may be an integrated part of the proce- free and pedicled flaps that are used for phalloplasty suggests
dure. ‘All-in-one’ procedures may be more cost- and time- that one single ideal technique that fulfills all the demands of
effective, but they expose the patient to extended trauma, neophallus formation does not exist (Table 67.2).28
blood loss, and anesthesia time. The actual standards of care The most promising techniques are described below, with
available do not permit a conclusion to be drawn as to which an emphasis on recent reports by interdisciplinary teams from
of the options may be recommended.3,4,15,22 If hysterectomy and peer-reviewed journals. To date, no detailed standards of care
oophorectomy are performed as a separate first step of gender concerning operative techniques exist.
reassignment, vaginal length should be reduced as much as
possible during the hysterectomy in order to facilitate later Regional flaps for phalloplasty
colpocleisis. The gynecologists performing these procedures Before microsurgically transplanted free flaps were introduced,
should take care to prevent damage to abdominal wall blood regional flaps represented the only possibility of adequate
vessels during the hysterectomy, which may be important as
future recipient vessels during free-flap transposition for penile
reconstruction (the inferior epigastric artery and vein).
Table 67.2 Goals of modern phalloplasty
Metoidoioplasty A one-stage procedure that can be predictably reproduced
The first description of surgical enlargement procedures using Creation of a competent neourethra to allow for voiding in
the clitoris, date back to 1973. The techniques have been sub- the standing position
sequently refined and have come to be called ‘metoidoioplasty’ Return of tactile and erogenous sensibility
or ‘metaidoioplasty’.23 Long-term androgen treatment in
Enough bulk to tolerate the insertion of a prosthetic device
FM-TS patients stimulates the growth of the clitoris, in some
patients to a degree where this organ can serve as a penis. A result that is esthetically acceptable to the patient
Actual techniques include release of the ventral clitoral chorda Minimal scarring or disfigurement
and ligaments with consequent strengthening and lengthening No functional loss in the donor area
of the clitoris. A urethroplasty to the tip of the clitoris is per-
From Semin Urol 1987; 5: 262–69.28
formed using vestibulum and labia minora. An anterior-based
530 Textbook of Erectile Dysfunction

tissue transfer for neophallus reconstruction. They still remain donor site morbidity with the need for wearing a lower
a viable option in many centers specializing in reconstructive leg splint for at least 6 weeks and the potential for long-term
surgery. Bettochi et al. compiled long-term follow-up data donor site problems with decreased power, suboptimal gait
from 85 FM-TS patients after pedicled pubic phalloplasty, co-ordination, and ankle instability. A recent report on the use
including urethroplasty to the tip of the neophallus.29 The of a septocutaneous fibula free flap without fibula bone may
stricture and fistula rate was 94%, so that after 1993 the team help to modify the technique and to decrease morbidity.35
switched to a two-stage procedure in order to reduce urethral In experienced hands, the free forearm flap has gained
complications. However, more than 50% of these patients increasing acceptance over the 23 years since its first descrip-
developed urethral complications.29 If prosthesis implantation tion. It has also been used as an osteocutaneous flap, but sig-
was desired, malleable devices tended to erode distally (50%) nificant donor forearm morbidity in half of the patients made
which could be overcome by implantation of hydraulic devices this modification less attractive.36 In specialized centers, where
within a Dacron® sleeve as a tunica albuginea substitute. In urologists and plastic reconstructive surgeons work together,
the authors’ institution, a bilateral groin flap technique, the free forearm flap without urethral pre-lamination and
including a unilateral rectus muscle flap, has been in use since without inclusion of osseous segments has become the first
1988.30 The bulk of rectus muscle permits simultaneous choice for penile reconstruction.4,11,15,37,38 Functionally and
implantation of a malleable or hydraulic prosthetic device cosmetically, microsurgical free forearm flaps lead to the best
without significant risk of erosion. The proximal urethra is results.39 Furthermore the operation may be done as a one-
reconstructed from vestibulum and labia minora up to the session procedure by an interdisciplinary team (Table 67.3,
clitoral tip. The clitoris remains in place due to the low Figures 67.2 and 67.3).
sensitivity of pedicled regional flaps. A second operation is Details of the operation may differ between leading centers
generally necessary for scrotal reconstruction by VY-plasty of in this field. Some authors prefer to select branches of the
the labia majora and for thinning of the bulky neophallus. ileoinguinalis or ileohypogastricus nerves, others prefer clito-
An analysis of 136 cases of phalloplasties using various ral nerves for coaptation of the forearm nerves. The clitoris is
methods of local flaps and distant free flaps compared favor- usually denuded and buried underneath the neophallus.5
ably for local flaps with regard to postoperative shrinkage and Owing to the complexity of the operation, complications
necrotic complications as well as the size of donor site defects.31 are numerous and should be explained in detail to the patient.
It must be noted that procedures using distant free flaps were These include:4,11,40
accompanied by an unacceptably high complication rate in
this series.32 • partial or total flap loss, occurring in less than 5% of
cases;
• nerve compression or compartment syndrome, owing to
Free flaps for phalloplasty the prolonged lithotomy position, occurring in less than
Recent publications on the use of free flaps for phalloplasty 2% of cases; and
concentrate on the fibula and forearm as preferred donor • urethral complications, such as fistula formation or
sites. In 1993, Sadove et al. popularized fibula flaps for penile stenoses, the leading causes of re-intervention, occurring
reconstruction as so-called free sensate osteocutaneous fibula in around 50–60% of cases.
flaps.33 Part of the fibula was included as a substitute for penile
stiffening. The urethra reconstruction was first accomplished Penile prosthesis implantation after phalloplasty
by full-thickness skin graft and later by ‘pre-fabrication’ several
Implantation of testicle and penile prostheses can be under-
months before flap transfer. Split skin or full-thickness skin
taken 6–12 months after complete urethral healing and after
was rolled over a 22–30F catheter and inserted at the desired
length into a subcutaneous tunnel of the flap area.34 The
operation included coaptation of lateral sural nerves to ade- Table 67.3 Steps in one-session genital reassignment
quate cutaneous nerves deriving from the ileoinguinalis nerves in female-to-male trans-sexual patients using the free
or ileohypogastricus nerves. The use of dorsal clitoral nerves forearm flap
for coaptation to flap nerves was successfully attempted.35
1. Hysterectomy, oophorectomy, vaginectomy
Preferred recipient vessels were the femoral artery and (gynecologist)
branches of the long saphenous vein. Flap size depended 2. Proximal urethroplasty, colpocleisis (urologist)
on anatomical preconditions and was about 20cm in length 3. Preparation of recipient nerves and vessels (urologist)
and 12cm in width. 4. Scrotoplasty (urologist)
During the past 5 years it has become obvious that phallo- 5. Retrieval of a full skin graft from the groin (urologist)
plasty from fibula free flaps is best accomplished as staged 6. Free forearm flap, including distal neourethra by
procedures. Proximal urethroplasty to the tip of the clitoris is tube-in-a-tube formation (plastic surgeon)
combined ideally with vaginectomy and should precede fibula 7. Free flap transfer and microsurgical nerve and vessel
flap transfer by several months.35 Fibula bone inclusion in the coaptation (plastic surgeon)
8. Urethral anastomosis (urologist)
flap is still a point of debate and many plastic and reconstruc-
9. Full skin graft coverage of forearm defect and primary
tive surgeons prefer vascularized bone segments to synthetic
closure of the harvesting site in the groin (plastic
prosthetic material. Nevertheless, a permanently rigid struc- surgeon)
ture in the neophallus has to be considered as an imperfect
solution. The most important shortcoming may be the resulting From World J Urol 1987; 5: 9–13.43
 Gender reassignment surgery 531

(a) (b)

Figure 67.2 (a) Penile and urethral reconstruction from free radial forearm flap before transposition to the genital area. (b) Elongation
of the female urethra to the tip of the clitoris. Preparation of the dorsal clitoral nerves for coaptation.

(a) (b)

Figure 67.3 (a) Final result after penile reconstruction in a female-to-male trans-sexual patient. (b) Neophallus in a female-to-male
trans-sexual patient after prosthesis implantation (with the three-component device fully inflated).

return of tactile sensitivity to the neopenis.4,11 The best func- In a comprehensive follow-up report by Eldn et al. in 1997,
tional and esthetic results are obtained by using hydraulic more than 80% of patients stated an overall satisfaction with
multicomponent devices, including a covering of the cylin- their new postoperative situation after regional flap phallo-
ders with Dacron® in order to prevent migration and erosion plasty.20 Hoebeke et al. reported a successful prosthetic
of the device. The Dacron® sock should be fixed to the lower implantation in 32 of 35 FM-TS patients after complete fore-
arch of the pubic bone with non-resorbable sutures. In the arm flap penile reconstruction; of these, 29 were sexually
authors’ experience, prosthesis implantation should be done active with a partner and reported patient satisfaction.41
in two sessions: during the first session one hydraulic cylinder In the authors’ institution, 140 FM-TS patients had a com-
is implanted with a Dacron® sock and left in half-inflation. plete penile reconstruction by forearm flaps between 1990 and
During the same session two testicular prostheses are 2007. Preliminary data from 29 patients who recently under-
implanted into the neoscrotum formed from the labia majora. went subjective and objective follow-up showed that 70%
After 3 months a reservoir is positioned beside the bladder were able to have sexual intercourse, 72% were able to reach
and one testicular prosthesis is replaced by the prosthetic orgasm by neophallus stimulation, 90% were able to void in a
pump mechanism. Pre-formation of the scrotal cavity lined standing position, and 90% would undergo the procedure
by a fibrous capsule caused by the temporary implantation again if necessary.42 Measurement of pudendus sensory evoked
of a testicular prosthesis enables subsequent easy handling potentials showed normal or slightly prolonged latency times
of the pump mechanism by the patient.11 Nevertheless, in 27 patients. In all these patients at least one clitoral nerve
complications are expected to be more frequent than after had been coapted to the forearm flap nerves under microsur-
penile prosthesis implantation in biologically male patients gical conditions, which may prove the possible efficiency of
(10–20%) and should be explained in detail to the patient (see this technique to give erotic sensitivity to a neophallus.
Figure 67.3).4,11,41 Conclusive long-term follow-up data on the wide variety of
newer surgical techniques for neophallus reconstruction is
still lacking. However, microsurgically transferred free fore-
Postoperative follow-up studies arm flap, followed by later implantation of a hydraulic three-
Follow-up studies published before 1991 are not helpful owing component prosthetic device, seems to be the most promising
to the lack of modern phalloplasty techniques at that time. approach.4
532 Textbook of Erectile Dysfunction

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19. Hartmann U, Becker H eds. Störungen der Geschlechtsidentität. after penile reconstruction; sensory-evoked potentials (SEP) in
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Index
Note: Page references in italic refer to tables or figures in the text.

ABT-670 92 AMS Ambicor prosthesis 329, 340, 340

accessory arteries 33, 113, 506, 507, 521–3 anandamide 99
acetazolamide 135 Androgen Deficiency in Aging Males (ADAM) questionnaire 272
acetylcholine 87, 97 androgen receptors 65, 434–5
actin filameznts 37 androgens 94–5
ADAM, see Androgen Deficiency in Aging Males effects on penile tissues 64–5, 99–100, 384, 435
adenosine 87 and PDE-5 expression 435, 436
adipocytes, corpus cavernosum 65, 384, 385 role in ED 134, 137, 138
adolescent and sexual desire 65–6, 66
assessment of sexual function 372 withdrawal therapy 521
impotetence 375 see also testosterone
adolescents, varicocele 378–9 anejaculation 487–9
adrenocorticotropic hormone (ACTH) 93 anemia, chronic renal failure 460–1, 462
advanced glycosylation end-products (AGE) 77, 451 anesthesia
aetiology of dysfunction 17–18 penile prosthesis implantion 343
age see also local anesthetics
and ejaculatory dysfunction 470 angiopoietin-1 gene transfer 310
and hypogonadism 271 angiotensin-converting enzyme (ACE) inhibitors 461
and LUTS 142 angiotensin II 78, 84
pathophysiology of associated ED 76 angiotensin II receptor antagonists 123
and potency after prostatectomy 506, 512 animal models
and prevalence of ED 19–20, 19, 22, 176 cavernous nerve damage 514
and sexual function 142 central control of sexual function 42–3
and testosterone levels 18 ED in diabetes 449–50
agouti 276 environmental chemical exposure 110
agouti-related protein 276 treatment of ejaculation failure 488
alcohol use 2, 123, 233, 267 anisotropine 136
alfuzosin 143, 144, 480 anorgasmia, male 471–2
Allis clamp 513 anti-androgens 154, 155, 425
ALLOW algorithm 204, 205 antibiotics, peri-operative 325, 331, 343, 344
Alpha-1 Tital (Mentor) prosthesis 329, 330 anticholinergic drugs 136, 140
alpha-adrenoceptor agonists 135, 139, 140, 424 anticholinesterase inhibitors, intrathecal 489
alpha-adrenoceptor antagonists (alpha-blockers) 2, 22, 135, 138–9, 140, antidepressants 241, 461, 461
141, 143, 144–5, 154 causing hyperprolactinemia 68
and ejaculation 56, 480 effects on sexual function 124, 136–7, 139, 140
use with PDE-5 inhibitor therapy 84, 226, 265–6 antihistamines 487–8
alpha-adrenoceptors 56, 83–4, 84, 96, 144, 144 antihypertensive drugs
5-alpha-reductase inhibitors 21–2 associated with sexual dysfunction 22, 141, 154–5, 154–5, 461, 461
impact on sexual function 143–4 diabetes mellitus 452
alprazolam 136 and PDE-5 inhibitors 265
alprostadil (PGE-1) 116 anti-parkinsonian drugs 135–6, 138, 140
intracavernosal injection 116, 156, 268, 281–4 antipsychotics 68, 136, 138, 141
adverse effects 282 antisense oligonucleotides, gene transfer 309
after prostatectomy 509, 515 anxiety 18, 476, 478, 487
chronic renal failure 463 anxiolytics 136, 154
intraurethral injection 116, 268, 284, 464, 518 aortoiliac surgery 508
Ambicor prosthesis 329, 340, 340 apes, testicular grafts 4, 5
ambiguous genitalia 377–8 aphrodisiacs, history 1–2
American Medical Systems 323, 324, 329, 330, 338 apomorphine 2, 91, 92, 93, 135, 138, 145, 208, 277
American Psychiatric Association 474 adverse effects/cardiovascular safety 277–8
American Urological Association 468, 495, 496 affinity for dopamine receptor subtypes 277
amiloride 135 ED treatment 277
2(s)-amino-6-boronohexanoic acid 307 ejaculation failure 488
amino acids, excitatory 93 apoptosis 76, 177, 384, 384, 514
amitryptyline 136, 241 Arabic Index of Premature Ejaculation (AIPE) 356
amoxapine 136 arachnodactyly 180
amphetamine 2, 138, 138, 140 area under the curve (AUC) 348
AMS 600M implant 324, 324 arginase inhibitors 307
AMS 650 implant 324, 327 L-arginine 73, 85, 87, 408, 431
AMS 700 CX InhbiZone prosthesis 338, 339 Arizona sexual experience scale (ASEX) 349–50
AMS 700 Ultrex Plus prosthesis 338, 339 arterial stiffness, effects of PDE-5 inhibitors 223, 226

533
534 Index

arterial wave reflections 223 penile 176–7, 514–15

arteries, penile 26, 27 testicular 489
accessory 33, 113, 506, 507, 521–3 biopsychosocial model of ED 184, 298, 304
atherosclerosis 33, 77 and assessment of patient 184–8
revascularization 383, 454 Biopty gun 176–7
Asian men 475 biothesiometer 156
aspermia 470–1 biothesiometry 156, 157, 169–70
aspirin 267 clinical value 170
assessment, premature ejaculation 479 normal findings 170, 170
assessment of ED Peyronie’s disease 156
biopsychosocial model basis 184–8 procedure 169–70
chronic renal failure patient 461–2, 461 bladder, blood flow 144
clinician synthesis 188 bladder cancer, surgery 507–8
detection of cardiovascular disease 153–4 bladder exstrophy 472
discussions with patient 347–8 bladder neck, closure 43, 57, 472
erection hardness score 153 bladder outlet obstruction 99
lifestyle factors 187 blood count, hypogonadism 180
medical history 154–5, 154, 155, 187, 206–7 blood gas analysis, priapism 423
physical examination 179–80 blood pressure
primary care setting 206–7, 207 concomitant alpha-blocker/PDE-5 inhibitors 226, 265–6
sexual history 148–54, 203–4, 203, 206 and PDE-5 inhibitor therapy 222–3, 222, 226, 253, 260
special investigations 156–7 sexual activity 258
see also questionnaires body mass index (BMI) 120–1, 126, 127
assessment scales 188 body weight 120–2, 121, 127, 130
atenolol 135 bone-marrow-derived (BMD) cells 315
atherosclerosis Boston Area Community Health survey 108–9
chronic renal failure 458 BPH, see benign prostatic hypertrophy
penile vasculature 33, 77 brachial artery flow-mediated dilatation 223, 225, 320
risk factors 127 brachytherapy, prostate 113–14
atorvastatin 123 brain areas, in sexual function control
atrial septal defects 227 brainstem 46–8
atropine sulfate 384 changes in aging 76
Augusta Medical Systems 291, 293 ejaculation control 55, 55, 468, 474, 475
autonomic dysreflexia 489 erection control 134, 276–7
autonomic nervous system forebrain 43–6, 44, 45, 50, 134, 276, 474, 475
control of sexual function 48 brain-derived neurotrophic factor (BDNF) 76, 309
dysfunction in CRF 459 breast augmentation 527
neurophysiological tests 172–3 breast reduction 529
awards, International Society for Sexual Medicine 14–15, 15 brief male sexual function inventory (BSFI) 350
Ayurvedic medicine 2 British Regional Heart Study (BRHS) 122
azapirone 136 Brodman areas 65
bromocriptine 135, 138, 462
Babcock clamp 342 Brooks corporal dilators 342, 342
Babinski response 168 Buck’s fascia 25, 26, 30
bacitracin 344 compromise in penile fracture 393
back pain, PDE-5 inhibitor therapy 244, 263, 263 incisions 415, 415, 416, 417
baclofen 138 bulbar vein 27
balanitis xerotica obliterans (BXO) 373, 373, 374 bulbocavernosus reflex 168, 450
barbiturates 138 in diabetic men 450
Barrington’s nucleus (pontine micturition center) 46, 48 testing 172
basic fibroblast growth factor (bFGF) 74, 77 bulbospongiosus muscles 25, 43, 56
Beach, Frank 42 bulbourethral artery 26, 27, 33
Beck Depression Inventory 188 bulbourethral vein 27
bed nucleus of the stria terminalis (BNST) 45 bupivacaine 325
behavioral therapy 479, 496 bupropion 137, 138, 488
see also sex therapy buspirone 136, 139, 488
bendroflumethiazide 135 butaperazine 136
benign prostatic hypertrophy (BPH) 142–3, 156, 202, 503
drug therapies 21–2, 143–5 calcitonin gene-related peptide (CGRP) 87, 310
combined PDE-5 inhibitors/testosterone 439–40 calcitonin receptor-like receptor (CRLR) 87
impact on sexual function 143–5, 143 calcium, intracellular fluxes 37, 74, 85, 87, 88
PDE-5 inhibitors 145–6 calcium-channel blockers 68, 138, 407, 408, 409, 461
ejaculatory disorders 472 calcium sensitization 74, 87–8, 89, 99
Benjamin, Harry 526 calmodulin 37, 39–40
benperidol 136 cAMP-responsive element binding proteins (CREBs) 85
benzodiazepines 136, 446 cAMP signaling pathway 85–7
beta-blockers 135, 154, 461, 461 cannabinoids 94, 98–9
bethanidine 135, 141 canola oil 129
Bible 2–3 carbachol 97
biliary cirrhosis 98–9 carbon disulfide 108
Bioflex material 339 cardiac history 257
biopsy cardiac index 227
 Index 535

cardiac repolarization 222 chlordiazdepoxide 136

cardioprotection, preconditioning 221, 222 chlorpromazine 136
cardiovascular disease (CVD) 151, 153, 225–6 chlorprothixene 136
association with ED 202–3, 257, 319–20 chlorthalidone 135
early identification 153–4, 157, 202–3 cholesterol 21, 77, 127, 153, 202
endothelial dysfunction 151, 439 cholinergic mechanisms 87, 97
progression and ED severity 151, 153 chordee 371–3, 372
risk evaluation 207 chronic renal failure
risk factors 120–4, 121, 127–8, 202, 319–20 causes of ED 457–61, 458
cardiovascular safety evaluation of ED 461–2, 461
apomorphine 278 incidence of ED 457
PDE-5 inhibitors 264–6 renal transplantation 464
sildenafil 225, 233–4, 264 treatment of ED 462–4, 462
tadalafil 242, 264–5 Church, medieval ‘non-consummation’ trials 1, 2
vardenafil 265 cigarette smoke, exposure 108–9
carnitine 406–8, 407 cigarette smoking 20, 22, 122, 155, 206
carotid-femoral pulse wave velocity 223 cimetidine 138, 267
carvedilol 123, 452 ciprofloxacin 344
castration circumflex artery 27
effects on penile tissues 64–5, 100, 384, 384 circumflex vein 27
historical 3 cirrhosis 98–9, 267
hot flushes 138 L-citrulline 85, 87
medical 155 claudication 206
and sexual desire 65–6, 66, 94–5 clidinium 136
cauda equina lesions 155, 172 clinical trials
caudal raphe 47–8 data analysis and interpretation 365–6, 365
cautery, in prostatectomy 514 gene therapies 311–12
caveolae 36 outcome assessments 364
caverMAP device 117 PDE-5 inhibitors 234, 242
cavernosal artery 26, 27, 32 premature ejaculation 478–9
duplex Doppler scanning 159, 160 rationale and design 360–2
flow rates, normative age-related 162 safety assessments 364–5
injury 160 standards 360
cavernosography 382 study population selection 362–4
penile fracture 394 clitoral blood flow 444, 446
testosterone therapy 387 clitoral-labioplasty 528
cavernosometry 165–6, 166, 382 cloacal exstrophy 370
complications 166 clofibrate 138
interpretation 166, 166 clomiphene citrate 462
technique 165–6 clomipramine 137, 485, 497
cavernous nerves 29, 31–2, 48, 503, 507 clonidine 49, 135, 139, 154, 461
grafting 100, 117 cocaine 2, 138, 140
in radical prostatectomy 31, 112–13, 504 coelenteral fusion model 4, 7
cavernous sinusoids 29, 30, 176 colchicine 406, 407, 410
cefazolin 331 collagen 28, 29, 29, 177, 515
cell-based therapies collagenase therapy 409
comparison with gene and pharmacotherapy 315, 316 Colles’ fascia 25, 393
genetically-modified cells 311 Cologne Male Survey 284
mesenchymal stem cells 316–18 Coloplast Alpha-1 prosthesis 339
neurogenic erectile dysfunction 318–19 Coloplast Corporation 324, 338, 339
potential drawbacks 319 colorectal surgery 508
principles 314–15 combination treatments 116, 268, 295, 300–2, 436–40, 518
vasculogenic erectile dysfunction 315–18 Committee for Proprietary Medicinal Products 287
Center for Epidemiological Studies Depression Scale (CES-D) 124, 188 communication
central nervous system (CNS) clinician-patient 203–4, 203, 209, 347–8
control of sexual function 42, 43 couple 192–4, 194, 198
brainstem 46–8 comorbidities 202, 363
c-fos studies 45 female partner 190–1, 191
ejaculation 474, 475 premature ejaculation 484
erection 276–7 testosterone therapy 384–6, 386
forebrain 43–6, 44–6, 134, 276, 474, 475 see also cardiovascular disease; diabetes mellitus; hypertension;
neuromediation 49–50, 91–5 metabolic syndrome
PRV tracing studies 45–6, 47–8, 47 congenital anomalies
spinal pathways 42, 43, 48–9, 55–6, 56 causing ED 153
drugs acting on 177, 277–8 obstructive/developmental 374–5
neurophysiological tests 173, 174 pelvic innervation 375–7
cerebral blood flow 224 perception 375
cetrorelix 144 reasons for sexual dysfunctioning in 367
c-fos studies 45 and retrograde ejaculation 472, 486
change in sexual function questionnaire (CSFQ) 349 sexual development 377–8
Child–Pugh score 267 congenital heart disease 227
Chinese Index of Premature Ejaculation (CIPE) 355–6, 356 connective tissue diseases 227–8
536 Index

connexin 40 (Cx40) 36 depression

connexin 43 (Cx43) 32, 36 association with ED 124, 202, 241
corpoplastic augmentation surgery 400 in chronic renal failure 459
corpora cavernosa 25, 35 effects of tadalafil therapy 241
biopsy 176–7 evaluation 188
changes after radical prostatectomy 112–13 screening 207
changes in diabetes 31, 384, 385 derisoquine 141
dilatation 332, 333, 342, 342 Derogatis interview for sexual functioning (DISF-SR) 349
disruption in penile fracture 167, 167 Derogatis sexual functioning inventory (DSFI) 350
electromyography (EMG) 169, 173, 450 desipramine 137
female 444 detrusor, blood flow 144
fibrosis 177, 282, 289 detumescence, control 32, 33–4, 83–5, 84
smooth muscle structure 29–30, 30, 31, 32, 314 dexamethasone, intralesional injection 409
effects of androgens 64–5, 384, 435 diabetes mellitus 182
surgical approach 332 animal models of ED 449–50
corpora spongiosa 25, 26, 30, 425 cardiovascular disease risk 123–4
corporotomy 327, 341–2 corpus cavernosum changes 31, 384, 385
corticosteroids 516 epidemiology/risk of ED 20–1, 20, 123–4, 182, 240, 449
intralesional in Peyronie’s disease 408–9 female sexual arousal disorder 446
cosmetic surgery, see penile augmentation glycemic control 453
couple 301–2 hypogonadism 449, 452
benefits of ED treatment 194–6, 196, 197 management of ED 452–4
communication about ED 192–4, 194, 198 intracorporeal injection therapy 453
impact of ED 190–1, 191 PDE-5 inhibitors 234, 240, 452, 453
impact of premature ejaculation 477–8, 479, 485 penile prostheses 454
impact of radical prostatectomy 515 vacuum erection devices 453
inclusive approach to ED management 196–8 vascular surgery 454
sexual scripts 302 neurophysiological tests 171, 172, 174
craniopharyngioma 156 pathophysiology of ED 76–7, 449–52
C-reactive protein (CRP) 121, 126, 127, 128, 224 penile prosthesis implantation 344
CRF, see chronic renal failure retiniopathy 452–3
cross-bridge cycle 37 testosterone therapy 182, 384–6, 386–8, 440, 453–4
CRP, see C-reactive protein 4,4’-diaminostilbene-2-2’-disulfonic acid (DAS) 108
cryotherapy, prostate cancer 114 diarrhea, PDE-5 inhibitor therapy 214, 232
Curling, Thomas 5 diary, patient 364
CVD, see cardiovascular disease diazepam 136
cyclic GMP (cGMP) p,p-dichlorodiphenyldichloroethylene (p, p-DDE) 110
interaction with PDE-5 catalytic site 215–16, 216, 248–9, 251 dichlorphenamide 135
molecular structure 215, 250 dicyclomine 136
in priapism 424, 430–1 diet
role in smooth muscle function 64, 213, 214, 248, 249, 314, 315, Mediterranean-style 123, 128–31, 129
429–30, 429 modification 130–1, 130, 208, 209
cyproheptadine 487–8 and risk of ED 127–8
cyproterone acetate 137, 155 dietary patterns 127–8
cystectomy diethylstilbesterol 425
female patient 508 digital rectal examination 156
radical 507–8 digoxin 138
cystoprostatectomy, radical 507–8 dihydrotestosterone (DHT) 61, 62, 143, 434
cytochrome P450 system 232, 237, 252, 267, 463 3,4-dihydroxy-phenylacetic acid (DOPAC) 91
inhibitors 233 dilatation
cytokines 74, 76, 126, 127 neovagina 527–8
penile 342, 342
Dacomed Corporation 323 disopyramide 138
Dacron® grafts 416 disorders of sexual development (DSD) 377–8
Dacron® sock 531 disulfiram 138
daily activities, metabolic equivalents 260 diuretics 135, 154
Danish Prostate Symptom Score questionnaire 353 dizziness 263, 264
dapoxetine 145, 481–3, 482 l-dopa 136, 138, 140
Dartos fascia 25 dopamine 49, 57–8, 92–3, 98
data anlysis 365–6 dopamine agonists 2, 91, 92, 135, 138, 145
DDE, see p,p-dichlorodiphenyldichloroethylene ejaculation failure 488
debrisoquine 135 see also apomorphine
deep dorsal vein 26, 27 dopamine antagonists 137, 138
arterialization 454 dopamine receptors
embolization 383 central 91–2, 277, 277
ligation 6, 382–3 peripheral 98
rupture 394 dorsal artery 26, 27, 33
deformities, see congenital anomalies; penile deformities dorsal gray commissure (DGC) 49, 49
delequamine 135 dorsal nerve 26, 32
Denonvillier’s fascia 503 conduction studies 170–1
dense bodies 37 neurectomy 484–5
deprenyl 135, 138 dorsal vein, superficial 26
 Index 537

double-Z plasty 399, 399 endocrine abnormalities

doxazosin 22, 135, 143, 144, 154, 266 chronic renal failure patient 459–60, 460
drug history 154–5, 154, 155 thyroid hormones 68–9, 69, 181–2
drug interactions see also hyperprolactinemia; hypogonadism
PDE-5 inhibitors 233, 266–7, 267, 481 ‘endocrine disrupters’ 107
SSRIs 481 Endocrine Society 437–8
drugs endocrinopathy 134, 138
associated with ED 21–2, 135–8, 139–40, 461, 461 endothelial dysfunction 202, 223
causing hyperprolactinemia 68, 181, 460 cardiovascular disease 151, 439
and ejaculatory control 140–1 and combined testosterone-PDE-5 inhibitor therapy 438–9
increasing libido 138 in diabetes mellitus 451–2
recreational 2, 154, 155, 253 indices of 126, 127
duplex Doppler scanning and PDE-5 inhibitors 223, 225
clinical uses 159, 163 endothelial progenitor cells (EPCs)
diagnosis of penile conditions 162, 162 and androgen levels 384–5
penile fracture 161, 162 as biomarkers for ED 319–20
Peyronie’s disease 159–60, 161, 413–14 definition 315
priapism 160, 161, 423 and PDE-5 inhibitors 223
protocols 162, 162 endothelins (ET) 84–5, 96
Dura II prosthesis 323–4, 326 endothelin-1 96–7, 451
patient satisfaction 327 endothelium-derived hyperpolarizing factor 73–4
Duraphase implant 323 Enlightenment 2–3
dutasteride 143 environmental exposure risk
dyclonine-alprostadil cream 499, 500 biological basis 106–7
Dynaflex prosthesis 329, 330 epidemiological evidence 107–10
dynamic infusion cavernosography and cavernosometry (DICC) 113 experimental studies 110
dyspepsia, PDE-5 inhibitor therapy 232, 244, 262, 263, 264 population-based studies 110
EPCs, see endothelial progenitor cells
Ebbehoj procedure 425 ephedrine 135, 486
education, medical 201 epidemiology
educational interventions 207–8 definition 18
Eisenmenger’s syndrome 227 descriptive 19–20
ejaculation 474 of ED 106, 176, 314, 360
assessment 186 and aging 19–20, 19, 22, 176
drug affecting 135–8, 140–1 determination of dysfunction frequency 18
in hypospadias 373 in diabetes 20–1, 20, 182, 449, 452
phases 54, 56 future projections 347
physiology research priorities 22
afferent (sensory) stimuli 54–5 hypogonadism 271
efferent pathways 56–7 premature ejaculation 475
neurotransmitters 57–9 priapism 420, 428
spinal reflexes 43, 44, 55–6 epinephrine 2, 424
UG reflex 43, 44 epispadias 367–70
and thyroid hormones 69, 69 ErecAid System® 9, 291, 292
triggers 57 Erectile Dysfunction Inventory for Treatment Satisfaction (EDITS) 235,
voluntary control 477 240, 242, 517
ejaculatory dysfunction 353 erection, see penile erection
anejaculation 470–1 erection hardness score 153
assessment instruments 357 erythromycin 267
definition 357 erythropoiesis 180–1, 462
delay/inhibition 470, 487–9 erythropoietin, human recombinant 462
dry 486 Escherichia coli 344
emission failure 486–9 escutcheon, female/trangular 179
incidence 468 essential fatty acids 129, 131
painful 489 estradiol 61, 436
retrograde 141, 472, 486, 486 estrogen 137, 444
in spinal cord injury 489 ethinyl estradiol 137
see also premature ejaculation ethnicity 475
ejaculatory reflex 474 ethosuximide 138
electro-ejaculation 489 etiology of ED 17–18
electromyography (EMG) 169, 173, 450 after prostatectomy 31, 112–13
electroshock wave therapy, penile 407, 408, 409–10 in chronic renal failure 457–61, 458
El-Ghourab procedure 425 in diabetes mellitus 76–7, 449–52
embryonic stem cells 316, 318–19 maintaining factors 184
emissary veins 26, 27, 28, 29 neurogenic 31, 74–6
emission organic 153
control 56 precipitating factors 184
failure of 486–9 predisposing factors 184
EMLA cream 498, 500 psychogenic 4, 18, 22, 375
emotional responses 194, 195 psychogenic-organic paradigm 184
emotional withdrawal 187 psychosocial-cultural factors 298–9, 299
endocannabinoids 98–9 vasculogenic 72–4, 382
538 Index

eunuchs 3 gap junctions 32, 36

European Scheduled Use versus on-demand Regimen Evaluation Geddings Osbon Foundation, Impotence Resource Center 295
(SURE) 241 gender reassignment surgery
excitatory amino acids 93 female-to-male 529–31, 529–31
exclusion criteria 363, 363 follow-up studies 528–9
ex copula reflexes 42–3, 47 history of 526
exercise 120–2, 122, 208 male-to-female 527–9, 527
exercise testing 234, 258, 260 preconditions for 526–7
exstrophy 367–70 general practitioner 524
cloacal 370 see also primary care physicians (PCPs)
external genitalia, examination 155–6 Genesis penile implant 324–5, 324
external urethral sphincter 513 gene therapy 306
extracellular matrix (ECM) 40, 177 cAMP pathway modulation 310
cell-based 311
farm animals 17 comparison with cell-based and pharmacotherapy 315, 316
fascia, penile 25 human clinical trials 311–12
fat, autologous injection for penis augmentation 400, 401 neurotrophic factors 309
fatty acids 129, 131 NO–cGMP pathway modulation 97, 306–8
female partners 190, 301–2 potassium channels 311
benefits of ED treatment 194–6, 196, 197 RhoA 310–11
comorbidity in ED 190–1, 191 risks 315
co-operation with ED treatment 301–2 superoxide dismutase 308–9
integration into ED treatment 196–8 vascular endothelial-derived growth factor 309–10
non-sexual relationship 187 Genital Perception Score (GPS) 371, 371, 372
perspectives on ED 185 gentamicin 331
and premature ejaculation 477–8, 479, 485 glans penis
responses to ED 186–7, 515 blood supply 33, 33
satisfaction with ED treatment sensory innervation 32
tadalafil therapy 242, 243 sensory receptors 54
vacuum erection devices 295–6 structure 30
talking to PCP 203–4 glial-cell-line-derived neurotrophic factor (GDNF) 309
female sexual function Global Assessment Question (GAQ) 114, 115
after bladder surgery 508 Global Study of Sexual Attitudes and Behaviour (GSSAB) 122
and development of ED 191 glucose, blood levels 127
past and current concepts 443–4 glutamate receptor agonists 279
urethrogenital reflex 43 glycopyrrolate 136
female sexual function inventory (FSFI) 190, 195 cGMP, see cyclic GMP
fenfluramine 138 gonadotropin-releasing hormone (GnRH) 61, 62, 460
fertility agonists 143, 144, 425
hypospadias 374 analogs 155
myelomeningocele 376–7 Gore-Tex grafts 416
fibrates 123 goserelin 155
fibroblast growth factor (FGF) 76 G-protein receptors 74, 84
fibrosis, cavernosal 177, 282, 289 G proteins 58
finasteride 21–2, 143, 143 GPS, see Genital Perception Score
Finland, depression and ED 124 grapefruit juice 233, 267
Finney Flexirod device 323, 325 Grayhack shunt 425
flaccidity, see penile flaccidity Greece, diet 129
Flexiflate device 323 Greenlight laser vaporization 507
fluoxetine 137, 480 grooming responses 93
fluphenazine 136 growth factors 40–1, 74, 76, 77
flurazepam 136 guanadrel 135, 141
flushing guanethidine 135, 141
PDE-5 inhibitor therapy 232, 244, 253, 262, 263 gynecomastia 179–80
VIP/Invicorp therapy 287, 289
flu syndrome 232 habituation, and ED 17
fluvoxamine 480 Hagar dilators 342
follicle stimulating hormone (FSH) 61, 180, 460 hair
follow-up body 179
ED treatment 209–10, 302 pubic 369
gender reassignment surgery 528–9 haloperidol 136
forearm flap, penile reconstruction 530, 531 Hammond, TE 4
fracture of penis, see penile fracture Hauri’s arterial-venous shunt 383
free forearm flap 530, 531 HDL, see high-density-lipoprotein (HDL) cholesterol
Freud, Sigmund 4 headache, PDE-5 inhibitor therapy 232, 244, 253, 262, 263, 264
fruit and vegetable intake 127, 128 health care delivery, trends in 201, 298–9
fundiform ligament 25 health care professionals, patient advice 524, 524
Health Hazard Evaluation (NIOSH) 108
galanin 49 Health Professionals Follow-Up Study (HPFS) 121, 126
gamma-aminobutyric acid (GABA) 94 heart disease, congenital 227
gangrene, penis 454 heart failure 226, 226, 439
 Index 539

heart rate benign prostatic hypertrophy 439

and PDE-5 inhibitor therapy 223, 253 circulating EPCs 384–5
sexual activity 258 clinical signs and symptoms 62, 155, 271, 272
heat shock protein 90 (Hsp90) 73 defined 179, 434
Heineke-Mikulicz principle 415 in diabetes 449
helicine arteries 26, 29, 32 diagnosis 180–1, 271–2
hemodialysis patient epidemiology 271
NPT abnormalities 457, 458 and erectile dysfunction 62, 64–5
testosterone levels 459–60, 460 etiology of 62, 63–4, 153, 155–6, 181, 271
see also chronic renal failure health associations 179
heparin 138 primary 62
hepatic cirrhosis 267 secondary 62
herbal supplements 209 testosterone therapy 272–4, 384–5, 387, 435–6
herbicides 107 combined with PDE-5 inhibitors 436–40
heroin addiction 139–40 hypospadias 370–4, 371
herpes simplex virus (HSV) gene vector 309 chordee correction 371–2, 372
hexarelin analogs 279 new adult patient 374
hexocyclium 136 psychological aspects 373–4
high-density-lipoprotein (HDL) cholesterol 21, 123, 127, 439 sexual function 372–3
Hijaras 3 hypotension, drug therapy of ED 260, 265–6, 463
Hippocrates 3 hypothalamic-pituitary stalk damage 67
history hypothalamus-pituitary-testis axis 61–2
cardiac 257 hypothyroidism 69
in hypogonadism 179 hypoxia 460–1, 514
medical 154–5, 154, 155, 187, 206–7 hysterectomy, gender reassignment 529
mental health 187–8
in Peyronie’s disease 405 imipramine 137, 486
in premature ejaculation 469 immunosuppressive agents 464
in priapism 420 impotence, definition of 17
sexual 148–54, 185, 203–4, 203, 206, 298–9, 469, 469 implants, see penile prostheses
history of erectile dysfunction 1, 2, 17 inclusion criteria 363
HIV protease inhibitors 233 Index of Premature Ejaculation (IPE) 355, 356
hMaxi-K 311–12 indinavir 267
homatropine 136 Indo-Mediterranean diet 129–30
hormonal therapy, prostate cancer 524, 525 industrial chemicals, exposure to 107–11
hot flushes 138, 179 infections, penile implant placement 325, 343–4, 454
hSlo 311 inferior epigastric artery 383
Huhner, Max 5 inositol phosphate 85
Hunter, John 54, 57 insecticides 110
hyaluronic acid gel 484–5 insulin 127
hydralazine 138 insulin-like growth factor 1 (IGF-1) 76, 77
hydrocortisone, intralesional injection 409 insulin resistance 440
Hydroflex implant 323 intention-to-treat (ITT) 366
hydroxyprogesterone 137 intercellular adhesion molecule (ICAM) 128, 224
5-hydroxytryptamine (5-HT), see serotonin interferons 407, 409
hypercholesterolemia 21, 77, 127, 153, 451 interleukin 6 (IL-6) 126, 127, 224
hypercoagulability 451 interleukin 8 (IL-8) 126, 127
hyperglycemia 76–7, 202 interleukin 18 (IL-18) 126, 127
pathophysiological effects 450–2 internal iliac artery 508
hyperlipidemia 123 internal pudendal vein, embolization 383
hyperparathyroidism 460, 462 International Consultation on Sexual Dysfunctions (ICSD) 469, 495
hyperprolactinemia 94, 156, 156, 181, 181 International Index of Erectile Dysfunction (IIEF) 18, 150–1,
in CRF 460, 462 188, 364
etiology 67, 67–8 correlation with indices of endothelial dysfunction 126, 127
drugs inducing 68, 181, 460 domains 349
prevalence 67–8 erectile function (IIEF-6) 349
and sexual activity 67, 94 and gene therapy 312
hypertension 20, 77, 123, 202, 226, 363 and lifestyle interventions 121, 131
chronic renal failure patient 458 and LUTS 142
pathophysiology of ED in 77–8 prostate cancer treatment 113, 114
pulmonary 226–7, 227 tadalafil therapy 239–40, 241, 242
and testosterone therapy of ED 384–5, 386, 388 and testosterone therapy 386, 388
hyperthyroidism 68–9, 69, 181–2 International Prostatic Symptom Score (IPSS) 146
hypnotics 155 International Society for Sexual Medicine
hypoactive sexual desire disorder (HSDD) 444, 445 biennial meetings 11–13
hypoesthesia, penile 484–5 founding 11
hypogastric nerve 48–9, 54–5 officers 12
hypogastric plexus 26 publications and communications 13–14
superior 32, 56 scientific awards and research 14–15
hypogonadism 179–81 interneurons 49, 55
age of onset 62, 65 intestinal transplants, pedicled 527
540 Index

intracavernosal injection therapy 281 topical in premature ejaculation 497, 498, 500–1
adverse effects 282, 289 Life Satisfaction checklist 444
after prostatectomy 116, 509, 515, 518 lifestyle factors
chronic renal failure 463–4 assessment 187
clinical efficacy 282 modification 121, 123, 206, 208
patient satisfaction 283, 283 and risk of ED 21, 120, 121–2, 126–7
combined agents 282, 384, 518 lignocaine, topical 497
contraindications 282 lipid-lowering therapy 123
diabetes mellitus 453 lipid profiles 21, 123, 202, 439
indications 282 Lissauer’s tract 48
in non-responders to PDE-5 inhibitor therapy 283–4 lisuride 136
papaverine 165, 282, 283, 283, 463, 483 lisuride hydrogen maleate 462
phentolamine 282, 463, 483 lithium 137
premature ejaculation 483 local anesthetics
prostaglandin E-1 (alprostadil) 116, 156, 281–2, 463, 509, 515, 518 penile implant placement 325
techniques of adminstration 282 premature ejaculation treatment 483, 497, 498, 500–1
veno-occlusive ED 384 lorazepam 136
intracavernous pressure 33, 43 low-density lipoprotein (LDL) cholesterol 77, 123
intraurethral drug delivery 116, 268, 284, 464, 518 lower urinary tract symptoms (LUTS)
intravaginal ejaculatory latency time (IELT) 354, 469–70, 475, 477 drug therapies
distribution in random sample 476 PDE-5 inhibitors 145–6, 439–40
measurement 477, 478–9 and sexual function 143–5, 143
and premature ejaculation classification 476, 476 ejaculatory disorders 472
response to treatment 478–9, 482, 482 relationship to sexual function 142–3, 146
topical agents 497, 498–9, 500, 501 Lower, WE 4, 7
investigations 156–7 lumbar medial gray matter 49
Invicorp 186 lumbar spinothalamic (LSt) neurons 49, 55–6, 56, 474
clinical outcomes 288–9, 288 luteinizing hormone (LH) 61, 180, 460
dosing 288 LUTS, see lower urinary tract symptoms
rationale for development 286–8 lymphatics, penile 26
safety and adverse events 289 Lyon Diet Heart Study 129
iontophoresis 410
iproniazid 137 magnetic resonance imaging (MRI)
ischiocavernosal muscles 25, 43, 56 penile 166–7, 367, 394
plication 6–7, 8 pituitary in hypogonadism 181
isocarboxazid 137 magnetic stimulation 169
itraconazole 267 male sexual health questionnaire (MSHQ) 350, 357
ejaculation domain 356, 357
Jonas device 323 short form 357–8
junctional plaques 36 maprotoline 137
marijuana 2
marriage, non-consummation 1, 2
kainic acid (KA) lesions 47, 48 Massachusetts Male Ageing Study (MMAS) 19, 20–1, 106, 314, 457
kanamycin 344 comorbidity in ED 363
ketoconazole 155, 267 delayed ejaculation 470
17-ketosteroid (17-KS) levels 109 ED severity 363
King, John 291 lifestyle interventions 130
Kinsey Report 8 risk factors for ED 121, 124, 126
Klinefelter’s syndrome 62 masturbation
as cause of impotence 4, 5–6, 7
labetalol 135 damaging practices 393, 470
labia majora, creation of 528 mCPP, see meta-chlorophenyl piperazine (trazadone)
laboratory investigations mebanazine 137
ED 156, 207 medial preoptic area (MPOA) 44–5, 44, 45, 50, 134, 276, 474, 475
priapism 423 ejaculation control 55
lacZ 319 neurotransmitters 57, 92
laparoscopy, radical prostatectomy 504–5 medical disorders, associated with ED 73
laser surgery, prostate 507 medical history 154–5, 154, 155, 187
latch state 38–9 medicalization of health care 298–9
LDL, see low-density lipoprotein (LDL) cholesterol medical schools, sexual health teaching 201
lead, exposure to 108, 109–10 Medicated Urethral System for Erection (MUSE) 284, 464
Lederer, Dr Otto 291 Mediterranean diet 123, 128–31, 129
Leonardo da Vinci 3 medrogestone 137
lesion studies 42, 47, 48 medroxyprogesterone 137
leuprolide 155 Meisner’s corpuscles 54
levator ani muscles 56 melanocortin 49, 276
levator fascia 513 melanocortin receptors 93, 276, 277
Leydig cell, hyperplasia 3–4 agonists 278
LGX Inhibi-Zone prosthesis 338, 339 melanotan II 93, 278
libido, see sexual desire mental health, history of 187–8
lidocaine Mentor Accuform implant 327
penile block 325 Mentor prosthesis 329, 330
 Index 541

mepenzolate 136 neural embryonic stem cells (NESC) 318

Merkel cell corpuslces 54 neural tube defects (NTD) 375–7
mesenchymal stem cells 316–18, 316 neurectomy, dorsal nerve 484–5
mesoridazine 136 neuroanatomy 31–2
metabolic disorders neurogenic ED 31
causing ED 153 chronic renal failure 459
see also diabetes mellitus pathophysiology 74–6
metabolic equivalents (METs) neurological disorders 18
daily activities 260 causing ED 151, 153
sexual activity 258, 260 recovery and PDE-5 inhibitors 222, 224
metabolic syndrome 78, 123, 202 neurological examination 168–9, 169
dietary interventions 130–1, 130 neuromediation
lifestyle interventions 123 central 91–5
risk factors 126–7 peripheral 95–100
and testosterone therapy of ED 384–6, 386, 387–8 neurophysiological tests
meta-chlorophenyl piperazine (mCPP/trazadone) 139, 140, 279 autonomic nervous system 172–3
methadone 137, 139–40 characteristics and anatomical neural pathways 173, 174
methandrostenenolone 137 motor system 169
methantheline 136 reflexes 172
methazolamide 135 sensory system 169–71
methyl bromide 107 neurotoxins 107
methyldopa 135, 138, 141, 460, 461, 462 neurotransmission, nitrergic 75–6
methylene blue 424 neurotransmitters 49, 76
methylprednisolone 516 central 92–4
metoclopramide 138 corpus cavernosum 83–7
metoidoioplasty 529 ejaculation control 57–9, 468
metoprenol 135 peripheral 95–8
mianserin 488–9 see also named neurotransmitters
microangiopathy 449, 450–1 neurotrophic factors 76, 309
micropenis 370, 371 neurotrophin-3 (NT3) 309
Middle Eastern races 475 neurovascular bundles 503, 513
misconceptions of ED 209, 209 in prostatectomy 21, 504, 506, 513
molidone 136 nicorandil 260
Mondor’s disease, ruptured 394 nifedipine 138, 489
monoamine oxidase inhibitors 137 nitrates 225, 253, 260, 463
morpine 94 nitric oxide (NO) 58–9, 314, 457–8
moxifloxacin 234 CNS 93
MPOA, see medial preoptic area nitric-oxide (NO)–cGMP pathway 64, 72, 73, 85, 87, 97, 213, 214, 248, 249,
MSA, see multiple system atrophy 314, 429, 429, 439
Müllerian duct cyst 486 gene therapy targeting 97, 306–8
multidisciplinary team 300, 302–4 nitric oxide (NO) donors 225, 233, 253, 260, 483
in-house 302–3 nitric oxide synthase (NOS) 32, 85, 451
virtual 303 endothelial (eNOS) 59, 73, 73, 76, 97
Multinational Survey of the Ageing Male (MSAM-7) 142 phosphorylation 76, 77
multiple sclerosis 151 gene therapy 306–8
multiple system atrophy (MSA) 151, 153 inducible (iNOS) 408
MUSE therapy 284, 464 inhibitors 59, 91, 93
myalgia 232, 242, 244, 263, 263 isoforms 306–7
myelomeningocele 375–7 neuronal (nNOS) 72, 75–6, 83, 85, 97
myocardial infarction (MI) N-methyl-D-aspartate (NMDA) 93
incidence in sildenafil trials 234 N-methyl-D-aspartate receptor (NMDAR) 76
risk and PDE-5 inhibitor therapy 225, 264 N-nitro-L-arginine methyl ester (NAME) 483
risk of in sexual activity 258, 260 nocturnal penile tumescence (NPT)
myocardium, effects of PDE-5 inhibitors 222, 226, 227, 265 chronic renal failure 457, 458
myosin 37, 37 environmental toxin exposure 109
myosin light chain kinase (MLCK) 37, 39, 39, 40, 74 monitoring 109
myosin light chain phosphatase (MLCP) 37–8, 39, 39, 40, 88, 99, 429–30, 430 and testosterone levels 95
nomifensine 137, 138
NAION, see non-arteritic ischemic optic neuropathy (NAION) non-adrenergic non-cholinergic (NANC) systems 145, 145
naloxone 137 non-arteritic ischemic optic neuropathy (NAION) 234, 253, 266
naltrexone 137, 140 noradrenergic mechanisms 49, 94
naproxen 138 norepinephrine 83, 94, 96, 450
nasal congestion 244, 263 uptake inhibitors 137
nasopharyngitis 232, 244, 263 norethandrolone 137
National Health and Nutrition Examination Survey (NHANES) 121 nortriptyline 137
National Institute for Occupational Safety and Health (NIOSH) 108 nucleolin 41
neostigmine 489 nucleus paragigantocellularis (nPGi) 47, 47, 48, 50, 55, 55, 276, 474
neovagina 527–8 nurse, patient advice 524
nerve conduction studies 170–1 Nurses’ Health Study 128
nerve grafting, cavernous 117 nutrition
nerve growth factor 76 and ED risk 123, 127–8
Nesbit procedure 415–16 Mediterranean diet 128–31, 129
542 Index

obesity 120–2 complications 400, 400

and ED risk 121 correction 402–3, 402
lifestyle/dietary interventions 130, 130 girth enhancement 399–400, 402
obturators, vaginal reconstruction 527–8 lengthening 377–8, 398–9, 399, 402
occupation, patient 187 results 400–2
olive oil consumption 129, 131 risks of 400
Olmsted County Study of Urinary Symptoms and Health Status Among penile block 325, 415
Men 20 penile deformities
omega-3 fatty acids 131 exstrophy 367–70
Omniphase implant 323 hypospadias 370–4
Onuf’s nucleus 32, 48, 56, 56, 153 and PDE-5 inhibitor therapy 267–8
oophorectomy, gender reassignment 529 Peyronie’s disease 413, 415
opioids 68, 94, 483 penile erection
agonists 137 drugs affecting 135–8, 139–40
antagonists 137, 140 evaluation, pateint questioning 186
optical loupe magnification 513 microscopic changes 29–30, 30
optic neuropathy, non-arteritic ischemic (NAION) 234, 253, 266 physiology 18, 28–9, 35, 213, 214, 248, 249, 286, 382, 429–50
organochlorines 109 molecular mechanisms 85–7, 86
organophosphates 107 penile flaccidity
orgasm 56, 474 control 83–5, 84
after prostatectomy 506–7 maintenance 87–8
Osbon, Geddings D Sr 291 penile fracture 161, 162, 167, 167
osteopenia 180 clinical presenttion 393
outcome assessment 364 differential diagnosis 394
oxidative stress 73, 75, 76, 222, 223–4, 406 etiology 392–3
oxybutynin 136 incidence 392
oxygen free radicals 74, 406, 451–2 investigations 167, 394
oxygen tension, penis 177, 460–1 late presentation 393
oxyprenolol 135 pathogenesis 392
oxytocin 49, 58, 91–2, 278–9 recurrent 393
treatment 395–6
Pacinian corpuscles 54 penile hypoesthesia, surgical 484–5
pain penile innervation 26, 31–2
after intracavernosal injection thearpy 282 penile length
after Invicorp injection 289 after prostate cancer treatment 522
ejaculation 489 surgical increase 377–8, 398–9, 399, 402
Peyronie’s disease 405 penile prostheses
priapism 428 after phalloplasty 530–1
see also myalgia chronic renal failure patient 464
papaverine 9, 116, 140, 231 diabetes mellitus 454
intracavernosal injection 165 early development 7–9, 323, 338
adverse effects 282 history of 7–9, 7, 9
in CRF patient 463 ‘ideal’ 329
efficacy and patient satisfaction 282, 283, 283 indications 383
premature ejaculation 483 inflatable 329, 338
parasympathetic innervation 31 complications 343–5, 418
parasympathetic nerves 503 currently available 338–40, 339
parathyroid hormone (PTH) 460 patient selection 340–1
paraventricular nucleus (PVN) 44–5, 55, 55, 91, 92, 93, 276 postoperative care 336
pargyline 137 reliability 116
paroxetine 137, 480 self-contained 329, 330
partners, see female partners surgical placement 330–2, 331, 333–4, 341–3, 341, 343
patient compliance 118 three-component 329–30, 331
intracavernosal injection therapy 116 two-component 329, 330, 331, 340, 340
intraurethral alprostadil 116 use after prostate cancer treatment 116
PDE-5 inhibitors 298 malleable 324–5, 324
see also discontinuation rates mechanical 323–4
patient-reported outcomes (PROs) 353, 364 complications 327, 345
premature ejaculation 354–7, 355, 356, 470, 479 patient satisfaction 327
single-item 355–6 reliability 326
patient satisfaction surgical placement 325–6, 325, 326
PDE-5 inhibitor therapy, tadalafil 242, 243 Peyronie’s disease 332, 335–6, 341, 417–18
sildenafil treatment 235 semi-rigid 325, 345
vacuum erection devices 295–6 spinal cord injury 327
PCP, see primary care physician penile reconstruction, see phalloplasty
PD-168077 91, 92 penile scaffold 7
Pearman penile prosthesis 338, 339 penile skin 25
pelvic nerve 48–9, 54–5 penile straddle injury 160
pelvic plexus 26, 56, 503, 504, 508, 513, 514 penile traction 408, 410
penile arteries 26, 27 penile trauma 160, 161, 162, 167, 167
revascularization 383, 454 duplex Doppler scanning 160, 161, 162
penile augmentation MRI 167, 167, 394
 Index 543

straddle injury 160 and antihypertensive drugs 265

see also penile fracture in BPH/LUTS 145–6
penis cardiovascular effects 221–7, 222, 260
congenital absence 377–8 cardiovascular safety 225, 233–4, 264–6
congenital small size 370, 371 chronic renal failure patient 462–3
scrotalization 398, 400, 400 and circulating EPCs 320
correction 402–3, 402 combination therapies
surgical creation 377, 378 intracavernosal injections 116, 268, 284, 518
surgical enlargement 377–8 testosterone 434, 436–40
penoscrotal skin flaps 527 vacuum devices 295
pentoxifylline 407, 408 comparative trials 242
performance anxiety 476, 478 concomitant nitrates 225, 253, 260, 463
pergolide 136, 138, 140 contraindications 115, 253, 266
periaqueductal gray (PAG) 44, 46, 50 couple benefits 194–6, 196, 197
perineal muscles 6–7, 8, 25, 43, 56 discontinuation rates 262, 263, 264, 264, 298
perineal trauma 423 discovery of 159
peripheral blood mononuclear cells (PMBCs) 315 effects on peripheral vasculature 223, 225
peripheral neuropathy female sexual arousal disorder 443–6, 445
chronic renal failure 459 limitations 284
diabetes 77, 450 long-term use, veno-occlusive ED 383–4
peripheral vascular disease 21, 449, 450–1 mechanism of action 216–17, 217, 248–9, 249
perphenazine 136 metabolism 232, 237, 252, 267, 463
pesticides 107, 108, 109 molecular structures 215, 232
Peyronie’s disease 28, 413 patient preferences 284
biothesiometry 156 precautions and interactions 233, 266–8, 267, 481
definition 405 premature ejaculation treatment 483–4
evaluation of patient 405 priapism treatment 425, 431–2
duplex Doppler penile scanning 159–60 prior to duplex Doppler scanning 162, 162
management 160 in pulmonary hypertension 226–7, 227, 235
non-surgical treatment 405–6, 413 selectivity for PDE isoenzymes 214–15, 231, 232, 238–9
combination therapy 408, 410 systemic effects 223–4
external energy therapies 407, 409–10 treatment failure 209, 209, 283–4, 518
intralesional 407, 408–9 treatment optimization 209
oral 406–8, 407 see also named agents
penile traction 408, 410 phosphodiesterase-6 (PDE-6) 214
topical 407, 408 inhibition 234, 253, 262
pathogenesis 159–60, 161 phosphodiesterase-11 (PDE-11) 214–15, 238–9
surgery 413 phospholipase C (PLC) 40, 74
patient evaluation 413–14 phospholipase D 40
penile prostheses 332, 335–6, 336, 341, 417–18 physical activity 120–2, 122
tunica lengthening 416–17 physical examination 155–6, 179–80
tunica shortening 415–16 cardiovascular risk 257
vacuum erection devices 295, 296, 417 hypogonadism 155, 272
Peyronie’s plaques 155 neurological 168–9, 169
and penile fracture 393 primary care setting 207
phalloplasty 529–31, 529, 531 PhysioMed ® device 410
phenelzine 137 physostigmine 489
phenoxybenzamine 135, 139, 154 pimozide 136
phentolamine 9, 84, 116, 135, 287 pindolol 135
combined with VIP (Invicorp) 286–9, 288 pituitary
intracavernosal injection 282, 384, 463, 483 disorders/lesions 67, 156, 156, 462
phenylephrine 424 imaging 181
phenylpropanolamine 135, 486 PKC, see protein kinase C
phenytoin 138 PKG, see protein kinase, cGMP-dependent
phimosis 325 plasticizers 107
phosphodiesterase-5 (PDE-5) 429, 435 platelet-derived growth factor (PDGF) 177
antisense oligonucleotide therapy 309 platelets 222, 224
deficiency 425 polyneuropathy, neurophysiological tests 172, 173, 174
dysregulation in priapism 430–1, 430 polyol pathway 451
expression pontine micturition center (Barrington’s nucleus) 46, 48
in non-penile tissues 221, 223 post-ejaculatory urinalysis (PEU) 472
regulation 435, 436, 436 posterior urethral valves 374–5, 486
isoenzymes 215 postsurgical causes of ED 153
molecular characteristics 215–16, 216, 249, 251, 253–4, 254 see also radical prostatectomy
pulmonary vascular smooth muscle 223 postural hypotension 151
phosphodiesterase-5 (PDE-5) inhibitors 9, 260 Pos-T-Vac Therapy System 294
adverse effects 232, 233, 253, 262–4, 263, 264, 266 potassium aminobenzoate 406, 407
after penile prosthesis placement 345 potassium channels 40, 74, 85
after Peyronie’s disease treatment 415, 417 gene therapy 311
after radical prostatectomy 115–17, 506, 509, 517–18 povidone-iodine 344
as prophylaxis 114, 515–17 prazosin 96, 135, 139, 154
and alpha-blockers 84, 226, 265–6 precipitating factors 184
544 Index

predisposing factors 184 prostanoid receptors 86–7, 98

premature ejaculation prostanoids 84, 86–7, 98
association with ED 469 see also alprostadil; prostaglandin E-1
classification 475–6, 476 prostate
clinical trial design 478–9 dilation 374, 374
comorbid erectile dysfunction 484 in exstrophy 367–8
definitions 353–4, 354, 468–9, 474–5, 495 hypertrophy, see benign prostatic hypertrophy
diagnostic problems 468, 495 size 180
epidemiology 475 prostate cancer
etiology 69, 69, 469, 478, 497 causes of ED 112–13, 521–3
evaluation 469–70 prevalence of ED 113–14
history and examination 469 risk and testosterone therapy 439
lifelong 476, 485 treatment 112, 521–2
management algorithm 485, 485, 495, 496 androgen withdrawal 521
patient-reported outcomes (PROs) 354–7, 355, 356 management of ED after 522
and sexual satisfaction 477 patient preference survey 524–5, 524, 525
treatment radiotherapy 521
AUS recommendations 496 see also radical prostatectomy
behavioral 479, 496 Prostate Cancer Awareness Week 19–20
‘ideal’ 495 Prostate Cancer Prevention Trial (PCPT) 106, 202
pharmacological 58, 145, 474, 479–83, 480, 496–7 prostatectomy, see radical prostatectomy; transurethral resection of
psychosexual counseling 479 prostate (TURP)
surgery 484–5 ‘prostate shrinkers’, see 5-alpha-reductase inhibitors
topical agents 483, 497–501, 498–9 prostatic fascia 513
Premature Ejaculation Diagnostic Tool (PEDT) 355–6, 356, 479 prostheses, see penile prostheses
Premature Ejaculation Profile (PEP) 357 protein inhibitor of nNOS 76
premature-like ejaculatory dysfunction 476, 476 protein kinase, cGMP-dependent (PKG) 40, 85, 88, 97, 213, 248, 307, 429
prepuce 25 protein kinase C (PKC) 41, 77, 85, 97
examination 155 protriptyline 137
prevalence, see epidemiology of ED prozosin 144
priapism prune belly syndrome 375, 486
after intracavernosal injection therapy 282, 289 P-selectin 224
after PDE-5 inhibitor therapy 268 pseudoephedrine 135, 486
definition 428 pseudo-hyperprolactinemia 67
diagnosis and evaluation 160, 161, 423 Pseudomonas spp. 344
drugs causing 140 pseudorabies virus (PRV) tracing studies 45–6, 47–8, 47
duplex Doppler scanning 160, 161 psychiatric symptoms 179
epidemiology 420, 428 psychoanalysis 4
high-flow 423, 423, 425, 428 psychogenic erectile dysfunction 4, 18, 22
history 420 in adolescents 375
low-flow (ischemic) 420–5, 423, 428 vacuum erection devices 295
pain associated with 428 in women 446
pathogenesis 430–1, 430 psychological factors
recurrent 425 after radical prostatectomy 515
treatment 423–6, 431–2 anxiety 18, 476, 478, 487
prilocaine 483 chronic renal failure 459
prilocaine-lidocaine spray (TEMPE) 498, 500–1 diabetes mellitus 452, 453–4
primadone 138 habituation 17
primary care physician (PCP) 201, 298–9, 524 inhibited ejaculation 487
follow-up of ED treatment 209 premature ejaculation 478, 485
patient evaluation 206–7 psychosocial-cultural factors (PSCFs) 298
response to ED identification 104, 206 etiology of ED 298–9, 299
sex counseling 204–5 severity and treatment format 300, 300
specialist referrals 210 PT-141 278
talking to patients/partners 203–4, 203 pubic hair, distribution 369
treatment of ED 207–9, 208 pudendal artery
trends in sexual health involvement 201 accessory branches 33, 113, 506, 507, 521–2
value of ED enquiry and mangement 201–3, 202 internal 26, 27, 33
Princeton Guidelines 207, 257, 258–60, 258 stenosis 450–1
prizes and awards, International Society for Sexual Medicine 14–15, 15 pudendal nerve 26, 32, 48–9
progesterone 137 pudendal vein, internal, embolization 383
progestins 137 pulmonary hypertension 223, 224, 226, 227, 228, 235
prolactin 66–8, 94, 156, 181 pulmonary vasculature, effects of PDE-5 inhibitors 222, 223, 224
in chronic renal failure 460, 462 PVN, see paraventricular nucleus
and sexual activity/desire 67, 94
see also hyperprolactinemia qolenj shekestan 393
propanolol 135 QOL-MED questionnaire 149, 151
propantheline 136 QT interval 222, 234, 265
prophylaxis of ED, after prostate cancer treatment 114, 515–17 Quakles shunt 425
prostacyclin 74 quality of life (sexual) 495
prostaglandin E1 (PGE-1) 86–7 after prostate cancer treatment 512, 522–4, 523
see also alprostadil assessment questionnaires 149, 151, 522–4
 Index 545

and patient compliance 118 renal insufficiency

and PDE-5 inhibitor therapy 195 PDE-5 inhibitor therapy 266–7
couple benefits 195–6, 197, 198 see also chronic renal failure (CRF)
questionnaires 18, 347, 353 renal transplantation 463, 464
Arizona sexual experience scale (ASEX) 349–50 renin-angiotensin system 84
brief male sexual function inventory (BSFI) 350 reserpine 68, 135, 138, 141, 154, 462
change in sexual function (CSFQ) 349 Resist implant coating 339
Derogatis interview for sexual functioning 349 retinopathy, diabetes 452–3
Derogatis sexual functioning inventory (DSFI) 350 retrograde ejaculation 141, 472, 486, 486
EDITS 240, 242, 517 retroperitoneal lymph node dissection 486
essential criteria 348, 523 rhinitis, with PDE-5 inhibitor therapy 232, 253, 264
evaluation of ED 148, 149–50, 188, 347 RhoA-Rho-kinase pathway 74, 74, 87–8, 88, 99, 310, 429–30, 430
evaluation of ejaculatory disorders 353–7, 355–6 in diabetes 99
hypogonadism diagnosis 271–2 gene therapy targeting 310–11
male sexual health (MSHQ) 350, 356, 357–8 rifampin 267
quality of life (sexual) 149, 151, 522–4 Rigiscan device 364
quality-of-life 364 risk behaviors, assessment 187
self-esteem and relationship (SEAR) 350 risk factors for ED 106
sexual encounter profile 350 lifestyle 126–7
sexual experience (Sex-Q) 148, 152 shared with CAD 120–4, 121, 126–7, 127, 202, 319–20
Sexual Health Inventory for Men (SHIM) 188, 350 shared with metabolic syndrome 123, 126–7
test-retest reliability 348, 523 ritonavir 252, 267
‘validated’ 348–9 ROS, see reactive oxygen species
see also International Index of Erectile Dysfunction (IIEF); Ruffini corpuscles 54
patient-reported outcomes (PROs) Ruskin, John 1
questions
open-ended 203 sacral reflexes, examination 168
permission-giving 204 Safe-T-ring 291
quinelorane 138, 488 Santorini’s plexus 504, 513
saquinavir 267
radical prostatectomy 21, 503–7 satisfaction, see patient satisfaction; sexual satisfaction
anatomy 503–4 Satyricon (Petronicus) 1
etiology of ED following 31, 112–13 Scott retractor 343
intraoperative nerve function evaluation 117 sedentary life style 121–2
laparoscopic 504–5 selective norepinephrine reuptake inhibitors (SNRIs) 138
nerve-sparing 112, 113, 512 selective serotonin reuptake inhibitors (SSRIs) 137, 139, 145, 241
pathophysiology of ED following 514–15 dapoxetine 481–3, 482
patient selection 512 female sexual disorder 446
prophylaxis of ED 114, 515–17 interactions 481
results 505–7, 505 premature ejaculation 58, 474, 478, 479–83, 480, 484
surgical technique 504–5, 513–14 self-esteem and relationship (SEAR) questionnaire 350
orgasmic sensation after 506–7 Seman’s ‘stop-start’ maneuver 479
penile biopsy after 177, 514–15 semen collecion, SCI patient 489
postoperative penile rehabilitation 114 seminal vesicles
prevalence of ED following 113–14 alpha-adrenoreceptors 56
robotic 505 dissection during prostatectomy 504, 514
treatment of ED after 115–17, 508–9, 517–18 sensory system 26, 31, 32, 48–9
PDE-5 inhibitors 234–5, 506 clinical tests 168, 169–71
vacuum erection devices 296 biothesiometry 156, 157, 169–70, 170
radiotherapy, prostate cancer 113–14, 116, 521 thermal testing 170, 171
Rancho Bernado Study 126, 449 ejaculation control 54–5
raphe magnus 47–8 serotonin (5-HT) 49, 58, 93–4, 98
raphe pallidus 47–8 serotonin (5-HT) receptors
Raynaud’s phenomenon 228 5-HT-2C 94
reactive oxygen species (ROS) 73, 74, 75, 76, 78, 406, 451–2 agonists 49, 58, 93–4, 98, 139, 279, 488–9
receiver operating characteristics (ROC) curves 348 antagonists 94, 487–8
recreational drugs 2, 154, 155, 253 central 93–4
rectal surgery 508 and ejaculation 58, 357, 474, 478, 481, 484, 485
red wine 233 peripheral 98
referrals, primary care 210 serotonin syndrome 483
reflexes sertraline 137, 480, 484
bulbocavernosus 168, 450 Severance secret-cream (SS-cream) 497, 499, 500
clinical examination 168 reformulation 500
ex copula 42–3, 47 sex change surgery, see gender reassignment surgery
neurophysiological tests 172 sex counseling
spinal 42, 43, 55–6, 56 in combination treatment 300–2
urethrogenital 43, 43, 44, 45 premature ejaculation 479
relapse prevention 302 primary care physician 204–5, 205
relationships 191 tips for physicians 300–1
benefits of good 203 sex hormone binding globulin (SHBG) 61, 62, 180, 180, 436, 440
see also couple; female partners Sex-Q questionnaire 152
Renaissance 3 sex status examination 301
546 Index

sex therapist 210, 303–4, 524 in pulmonary hypertension 226–7, 227

sex therapy Sildenafil Diabetes Study Group 234, 463
inhibited ejaculation 487 sinusitis, PDE-5 inhibitor therapy 232
integrated 303, 304 sinusoids, cavernous 29, 30, 176
see also sex counseling sirolimus 464
sexual activity skin, penile 25
cardiac risk 258, 260 skin flaps, vaginal reconstruction 527
cardiovascular response 257–8 Small–Carrion implant 323, 325, 338
decline, impact on female partner 190–2, 191 smoking 20, 22, 108–9, 122, 155, 206
energy expenditure/metabolic equivalents 258, 260 society and impotence 1, 2
patient expectations 207–8 soluble guanylyl cyclase (sGC) 73, 85
and testosterone production 66 somatosensory evoked potential (SEP) studies 171
sexual arousal 17 Spanish fly 2
Sexual Assessment Monitor (SAM) 479 sperm
sexual desire lack of (aspermia) 471–2
after prostate cancer treatment 522, 523–4, 523 motility and tadalafil therapy 263
assessment 186 presence in urine 472
drugs increasing 138 quality in SCI patient 489
female partner 190–1, 191 spina bifida 375–7
and prolactin levels 67, 94 spinal cord injury (SCI)
and testosterone levels 65–6, 66, 94–5 correlation of erection, ejaculation, intercourse with lesion 489, 489
sexual development disorders 377–8 ejaculation, spinal generator 55–6, 56
Sexual encounter profile 350 penile prosthesis placement 327, 344
Sexual Encounter Profile (SEP) diary 115, 239, 239 vacuum erection devices 295
sexual experience, assessment of current 185 spinal ejaculatory generator 55–6, 56
Sexual Function Index 18 spinal interneurons 49
Sexual Health Inventory for Men (SHIM) 188, 203, 209, 350, 517, 518 spinal pathways 42, 43, 49, 55–6, 56
sexual history 148–54, 301 spironolactone 135
onset of ED 185 squeeze technique 479
and premature ejaculation 469, 469 SR141716 94
primary care evaluation 206, 298–9 SS-cream, see Severance secret-cream
sexual intimacy 187 Stanley, Dr Leo 4
sexuality, and acknowledgement of ED 18 Staphylococcus epidermidis 344
sexual problem clinics 19 statins 123
sexual satisfaction Steinach, Professor 4
assessment 186 stem cells 314
and premature ejaculation 477 allogenic versus autologous 319, 319
sexual scripts 302 definition 315
Sexual Tipping Point 299, 299 embryonic 316, 318–19
SHIM, see Sexual Health Inventory for Men mesenchymal 316–18, 316
shunt muscle-derived 316, 319
corpora cavernosa–corpora spongiosa 425 stem cell therapy
Hauri’s arterial-venous 383 genetically-modified cells 311, 318
Shy–Drager syndrome, see multiple system atrophy (MSA) neurogenic ED 318–19
sickle cell disease potential drawbacks 319
laboratory tests 423 vasculogenic ED 315–18
PDE-5 inhibitors in 228 steroids, anabolic 4
priapism 425, 428–9 ‘stop-start’ maneuver 479
signal transduction stress 187
gene therapy modulating 310 stretching responses 93
smooth muscle contraction 39–40, 39, 314, 315 stroke, recovery 214, 224
smooth muscle relaxation 40, 72, 73, 85–7, 86, 97, 213, 214 subparafasicular thalamic nucleus (SPFp) 45
sildenafil 9, 213 subspecialists, referrals 210
adverse effects 232, 233, 262, 266 sulpiride 136
after radical prostatectomy 114, 115, 506, 509, 515–16, 517–18 superior hypogastric plexus 32, 56
and alpha-blockers 265–6 superoxide anion 74, 75, 308–9
and antihypertensive drugs 265 superoxide dismutase (SOD) 78
in BPH/LUTS 145–6, 439–40 gene transfer 308–9, 308
cardiovascular safety 225, 233–4, 264 surgery
chronic renal failure 463 causing ED 153
clinical effectiveness vascular 382–3, 454, 508
long-term use 234 see also gender reassigment surgery; radical prostatectomy
treatment failure 177, 235, 283–4 SurgiSIS Biograft 416
combined with intracavernosal/intraurethral injection 116, 284, 518 Surgitek Corporation 323
combined with vacuum devices 295 surveys
difficult-to-treat patients 234–5 impotence 19
discontinuation 262, 298 see also questionnaires
female sexual disorder 443–6, 445 suspensory ligament, penile 25
interactions 233 division 398–9, 402, 403
molecular structure 215, 232, 253–5 Susrata Samitha 2
pharmacokinetics 231–3, 232 sympathetic skin response 172
premature ejaculation 483–4 sympatholytic agents 135
priapism 432 sympathomemetic agents 141
 Index 547

sypathetic innervation 26 premature ejaculation 483, 497–501, 498–9

systemic lupus erythematosus 228 tramadol 483
systemic sclerosis 228 tranquillizers 154, 155
transcypromine 137
tachyphylaxis 439 transductosomes 36
tadalafil transforming growth factor-β (TGF- β) 74, 77, 177, 406, 408
adverse effects 232, 242, 244, 266 trans-sexualism
and alpha-blockers 265–6 defined 526
and antihypertensive drugs 265 standards of care 526
in BPH/LUTS 440 see also gender reassignment surgery
cardiovascular safety 242, 264–5 The Transsexual Phenomenon (Benjamin) 526
chronic renal failure patient 463 transurethral drug delivery, alprostadil 116, 268, 284, 464, 518
clinical efficacy transurethral resection of the prostate (TURP) 21, 507
daily administration 241–2 trauma, see penile trauma, perineal trauma
on demand use 239–41 trazadone (mCPP) 139, 140, 279
in diabetes 240 treatment, failure/non-response 209, 209, 283–4, 518
discontinuation 244 treatment of ED
molecular structure 215 avoidance 185, 201
patient/partner satisfaction/preference 242, 243 combination 116, 268, 295, 300–2, 436–40, 518
pharmacokinetics 237–8, 238 previous 185
premature ejaculation 483–4 primary care 207–9, 208
selectivity for PDE isoenzymes 214–15, 232, 238–9 relapse prevention 302
use after radical prostatectomy 115, 517–18 see also individual treatment modalities
tamoxifen 406, 407 Treatment of ED (TED) trial 242
tamsulosin 56, 135, 141, 143, 144–5, 154, 266, 472 Treatment of Mild Hypertension Study (TOMS) 154
taqaandan 393 triamcinolone 409
TEMPE (prilocaine-lidocaine) spray 498, 500–1 tricyclic antidepressants 136, 486, 497
terazosin 143, 144, 154, 266, 480 tridihexithyl 136
terbutaline 424 trifluoperazine 136
testes triglycerides 127, 439
influence on sexual behaviour 3 trimix 165
volume 180, 378 tunica albuginea
testicular biopsy, SCI patient 489 disruption 161, 162, 167, 167
testicular grafts 4, 5 fibrosis 393
testicular transplantation 4, 5, 6 function 28
testosterone 61–6, 94–5 gross anatomy 25, 26
aromatization 61, 181 lengthening 414, 416–17
effects on penile tissues 64–5, 99–100, 384–5, 384, 385, 435 microscopic anatomy 28–9, 29
formation and activity 61–2, 62 pathophysiological changes 28, 160, 161
role in erectile physiology 62, 64–5, 134, 138, 384–5, 384, 385, plication 416, 416
434–5 rupture, see penile fracture
testosterone levels 156 shortening 414, 415–16
and aging 18 TURP, see transurethral resection of the prostate (TURP)
chronic renal failure 459–60, 460
udenafil 213, 215
in diabetes mellitus 449, 452
ultrasonography
in hypogonadism 179, 180, 434
penile fracture 394
laboratory assays 272
see also duplex Doppler scanning
normal values 180, 272, 434
upper:lower body ratio 180
and sexual activity 66
urethral injuries 395, 396
testosterone therapy 208, 272–4, 384–8, 384–8, 435–6
urethral sphincter, external 513
adverse effects 274
urethral valves 374–5, 486
buccal patches 273, 273
urethrectomy 507–8
chronic renal failure 462
urethrogenital (UG) reflex 43, 43, 44, 45, 46–7, 49
and circulating EPCs 384–5
urethrography 394
combined with PDE-5 inhibitors 436–40
urethroscopy 394
diabetes mellitus 182, 384–6, 386–8, 440, 452, 453–4
urologists 210
gels 235, 273, 273, 436–7
intramuscular injections 273, 273 vaculogenic ED, diagnosis 382
monitoring 273–4 vacuum erection devices 9, 386–7
oral 273, 273 after Peyronie’s disease surgery 417
suggested regimens 272–3 after prostatectomy 116, 296, 509
transdermal patches 273, 273, 436 chronic renal failure patient 464
thermal testing 170, 171 current manufacturers 292
thiothixene 136 in diabetes mellitus 453
thromboxane A2 84, 98 erection characteristics 293–4
thyroid hormones 68–9, 69, 181–2 history of development 291
thyrotropin-releasing hormone (TRH) 66 mechanisms and principles 291–4
Timm Medical Technologies 292, 293 patient selection and contraindications 294–5
timolol 135 in penile curvature 296
tissue expanders 410 results of use 295, 387
Titan prosthesis 338, 339 side-effects 296
topical therapies tension rings 292–3, 293
Peyronie’s disease 407, 408 time to erection 293
548 Index

vagina, reconstruction 508 PDE-5 inhibitor treatment 383–4

vaginoplasty 527 surgical management 382–3
vaji karana 2 testosterone therapy 384–6, 384–8
Valsalva maneuver 459 vacuum devices 386–7
valsartan 123, 452 vas deferens, ligation 3–4
vardenafil 213 vasoactive intestinal polypeptide (VIP) 97–8, 310
adverse effects 253, 263–4, 264, 266 endogenous 86, 97–8, 286, 450
and alpha-adrenergic antagonists 265–6 exogenous therapy 86, 286–7, 450
and antihypertensive drugs 265 gene transfer 310
cardiovascular safety 265 vasoconstriction 74, 77
chronic renal failure patient 463 venlafaxine 241
and circulating EPCs 320 veno-occlusion, in penile erection 28–9, 35, 72, 286
contraindications 253 venous drainage, penile 26, 27, 32, 33
discontinuation rates 264 venous embolization 383
mechanism of action 248–9, 249, 251, 253–5, 254 venous leaks, corporeal 514
molecular structure 215, 248, 249, 253–5, 254 imaging 165–6, 166
comparison with sildenafil 253–5 surgical management 382–3
pharmacokinetics 250–3, 252 venous ligation 382–3
post-marketing surveillance 264 ventral tegmental area (VTA) 45
potency 249–50, 253 ventromedial nucleus of the hypothalamus (VMN) 45
premature ejaculation 483–4 venules 26, 32, 33
use after radical prostatectomy 115, 506, 517–18 verapamil 138, 407, 408, 409
varicocele, adolescent 378–9 verumonanum, electrical desensitization 6, 7
vascular anatomy 26, 26, 27 vesicular acetylcholine transporter (VAChT) 98
vascular cell adhesion molecule (VCAM) 128, 224 viloxazine 137, 138
vascular disease, peripheral 21, 449, 450–1 Virilis implant 325
vascular diseases 21, 153 viscose rayon workers 108, 109
vascular endothelial-derived growth factor (VEGF) 73, 74, 77 visual problems
gene transfer 309–10 non-arteritic ischemic optic neuropathy (NAION) 234, 253, 266
vascular endothelium 35–6 PDE-5 inhibitors 232, 253, 262, 263–4, 263–4, 266
dysfunction, see endothelial dysfunction vitamin E therapy 406, 407, 410
vascular risk factors 18, 20, 120–2 v-myc oncogene 318
vascular smooth muscle 31 vocational life, patient 187
contraction 74, 83–5, 84, 99, 314, 315 Voronoff, S. 4, 5
latch state 38–9 VY plasty 398–9, 399, 400
mechanism 37–9, 38 reversal 402–3
molecular pathways 39–40, 39, 314, 315
multiple functions 36 waist-hip ratio (WHR) 127
relaxation 72 walking, metabolic equivalents 260
age-related changes 76 war victims 7–8
molecular pathways 40, 72, 73, 85–7, 86, 97, 213, 214 weight 120–2, 121, 127
structure 29–30, 30, 31, 32, 314 weight loss 121, 130
effects of androgens 64–5, 384, 385 Western dietary pattern 128
vascular smooth muscle cells (VSMC) 36–7 West of Scotland Coronary Prevention Study (WOSCOPS) 123
apoptosis 177, 514 Wolffian duct abnormality 486
co-ordinated regulation 36–7 women, see couple; female partners; female sexual arousal disorder (FSAD);
non-contractile responses 40–1 female sexual function
vascular surgery 383, 454, 508 World Professional Association for Transgender Health (WPATH) 526
vasculogenic ED 72–4, 382
chronic renal failure 457–9 yawning responses 91–2, 93
oxidative-nitrosative stress 74, 75 yohimbine 2, 135, 139, 488
pathophysiology 72–4 Youth Equivalent Device 291, 292