CUA GUIDELINE

2015 CUA Practice guidelines for erectile dysfunction

Anthony J. Bella, MD, FRCSC;* Jay C. Lee, MD, FRCSC;† Serge Carrier, MD, FRCSC;§
Francois Bénard, MD, FRCSC;¥ Gerald B. Brock, MD, FRCSC±
*
Greta and John Hansen Chair in Men’s Health Research, Assistant Professor of Urology, Department of Surgery, University of Ottawa, Ottawa, ON; †Clinical Assistant Professor, University of Calgary, Calgary,
AB; §Associate Professor, Department of Surgery, Urology Division, McGill University, Montreal, QC; ¥Chair, Division of Urology, Department of Surgery, Université de Montréal, Montreal, QC; ±Professor of
Surgery, Western University, London, ON

See related article on page 30.

Cite as: Can Urol Assoc J 2015;9(1-2):23-9. http://dx.doi.org/10.5489/cuaj.2699

Published online February 5, 2015.

Summary of recommendations play a contributory role. Addressing these issues may

enhance treatment efficacy.
• Underlying risk factors associated with ED are common to
• Erectile dysfunction (ED) is the preferred clinical term
cardiovascular disease in general, and should be identi-
describing the persistent or recurrent inability to achieve
fied during evaluation as they may represent the initial
and maintain a penile erection of sufficient rigidity to
clinical sign of generalized endothelial disease (vascular
permit satisfactory sexual activity for at least 3 months.
insufficiency). Evaluation of family history, nicotine use,
• The initial diagnosis and treatment of ED is most com-
blood pressure, lipid profile, and glucose is required or
monly performed in Canada by primary care physicians
should be documented if previously performed. Active
(PCPs).
management of identified cardiac risk factors should be
• PCPs, urologists, internists, psychiatrists, and other treat-
instituted (i.e., smoking cessation, blood pressure treat-
ing healthcare professionals should be encouraged to ini-
ment).
tiate an open dialogue of sexual issues to identify men
• Once reversible causes of ED are ruled out, a trial of oral
with ED who may not otherwise volunteer their sexual
medication is recommended as first-line therapy, based
concerns.
on treatment efficacy, side effect profile, and minimal
• Frequently a careful history, physical exam, serum glu-
invasiveness. Specialized testing and referral are generally
cose or hemoglobin A1C, lipid profile and optional hor-
reserved for cases where oral first-line treatments fail or
monal testing facilitate the diagnosis of ED and effective
are not appropriate, of if greater insight into the etiology
therapy. Patient history can differentiate ED from other
is desired by the patient/physician.
male sexual dysfunctions, including ejaculatory disorders
• Second-line therapies, although more invasive than oral
(premature ejaculation and other abnormalities), hypo-
agents, are generally well-tolerated and effective.
gonadism, disorders of orgasm, and Peyronie’s disease.
• Surgery remains an important option for men refractory
• Organic (physical) causes of ED are present in most men,
to medical management, offering effective and durable
but situational or psychosocial contributing factors often
ED treatment outcomes.

Background highly effective, minimally invasive therapeutic agents – most

commonly oral therapies using phosphodiesterase type 5-
Erectile dysfunction (ED) is a highly prevalent condition, (PDE5) inhibitors. Second-line self-injection with vasoactive
which affects the physical and psychosocial well-being agents, vacuum erection devices, and surgical approaches
and quality of life (QoL) for thousands of Canadian men, with inflatable penile prostheses offer ED management with
their partners, and families. The Canadian Study of Erectile high potential for patient and partner treatment satisfaction.
Dysfunction identified 49.4% of men over 40 with ED, with Most cases of ED in Canada are identified and effectively
other studies showing that 5% to 20% of men have moder- treated by primary care physicians (PCPs).4 Evidence-based
ate to severe ED.1-3 Contemporary treatment options include diagnostic and therapeutic approaches, including effective

CUAJ • January-February 2015 • Volume 9, Issues 1-2 23

© 2015 Canadian Urological Association
Bella et al.

oral agents like the PDE5-inhibitors, has allowed for a shift America, and evolving research on new approaches to ED
of ED management from a historical surgical approach to management.4,6-7
contemporary medical management. Family physicians,
urologists, internists, endocrinologists, cardiologists, and Global management objectives
other medical specialists are approached by couples with
ED requesting treatment more frequently. In many cases 1. To help the patient and partner establish their objec-
longstanding relationships exist between the couple and tives of treatment.
their treating physician, fostering an important therapeu- 2. To select diagnostic tests based on presenting com-
tic alliance which may translate into improved clinical plaints and goals of therapy.
response to the selected treatment approach. A shared- 3. To use diagnostic tests in a cost-effective and mean-
care model for the treatment of ED is a valid concept and ingful manner which would affect choice of treat-
also may reflect optimal utilization of healthcare resources ment as well as help to identify and disqualify certain
in the Canadian healthcare environment.4,5 This shared- contributory health problems.
care model is one in which PCPs initially identify and treat 4. To provide a diagnosis and understanding of the
patients with ED and refer primarily those individuals who likely etiology of the ED to the patient and partner.
have incomplete responses or require more invasive or 5. To identify ED etiologies which may affect patient
specialized testing and treatment. The combined experi- morbidity and mortality (if not previously identified),
ence and knowledge of PCPs coupled with the diverse ED including screening for vascular risk, and facilitate
knowledge of the specialist can ideally result in optimal access to the most appropriate healthcare providers
care for the patient. for definitive management.
In the contemporary model of ED care delivery, urologists 6. To offer treatment choices with comprehensive infor-
remain an essential resource for several important reasons: mation on cost, likelihood of success and common
1. Referral requested for the difficult-to-treat, oral- side effects.
refractory cases. 7. To initiate therapy with the least invasive option
2. Second-line intracavernous and intraurethral vasoac- which would satisfy the patient and partner goals
tive therapy may be outside of the practice pattern of treatment.
of some PCPs and therefore require urologic care. 8. To provide patients with information and ongoing
3. In some cases anatomical penile deformity support to maximize treatment success.
(Peyronie’s disease or post-trauma) may play an 9. To re-establish the couples’ ability to achieve and
important role in the ED and more frequently require maintain sexual intimacy in the most natural man-
operative correction. ner possible.
4. In a small but definable population (often men with 10. To choose approaches which are reversible when-
severe vascular disease or poorly controlled diabe- ever possible.
tes), a trial of nonsurgical approaches may not suc-
ceed, requiring surgical options in the difficult-to- Management approach: Diagnosis
treat group.
5. Patients with congenital venous leak as the cause
of their ED require urologic care. These patients are Overview
usually young and do not respond to PDE5-inhibitors.
6. Specific tests performed by urologists may be indi- The CUA supports the view that the general framework for
cated at the request of the patient or his partner or the evaluation of patients with any type of sexual dysfunc-
for medico-legal issues. tion should follow the same basic principles.3,4,6 The sexual
7. Ongoing research into the basic and clinical conse- history should ascertain the severity, onset, and duration
quences of ED is performed in urologic laboratories of the problem, concomitant medical or psychosocial fac-
and clinical practices tors, and bother to the patient and partner (if applicable).
As presented in this document, the Canadian Urological In-person interview is often supplemented with question-
Association (CUA) Guidelines Committee has updated the naires or potential web-based methods. The manner of
CUA Erectile Dysfunction Guidelines using a Canadian per- sexual inquiry is important and should reflect a high level
spective. Suggestions were based on peer-reviewed literature of sensitivity and regard for each individual’s unique ethnic,
through 2015, and the ED recommendations from the World cultural, and personal background.
Health Organization (WHO)-endorsed 2010 International 1. Determine that the problem is ED versus other
Consultation on Sexual Medicine, the International Society aspects of the sexual response cycle (desire, ejacu-
for Sexual Medicine, the Sexual Medicine Society of North lation, orgasm) or from other causes (Peyronie’s dis-

24 CUAJ • January-February 2015 • Volume 9, Issues 1-2

 CUA Guidelines on ED

ease, lifestyle factors including illicit drug use, quality • Nocturnal penile tumescence testing (NPTR)
of partners relationship). (Rigiscan)
2. Determine the timing of onset, nature of the prob- • Dynamic infusion cavernosography and caver-
lem, and significance to the partner (if applicable). nosometry (DICC)
The patient (with or without their partner) will guide • Penile and pelvic angiogram
whether treatment is desired.
3. Identify whether a potentially reversible cause to the Diagnosis history
ED exists (medications), stress, depression, hormonal
abnormalities including androgen, thyroid and pitu- Obtaining a diagnostic history is the cornerstone of the eval-
itary, tobacco, excessive alcohol use, drug abuse, and uation of sexual dysfunction and ED. The history will provide
partner-specific issues). Testosterone profile is appro- the likely diagnosis in most cases.4,6,8 A supportive healthcare
priate at the ED diagnosis if hypogonadism suspected, professional allows the couple to relate their concerns and
but screening is not recommended for all ED patients. express their goals of treatment in an unhurried manner.
4. Establish a likely underlying etiology based on his- A monogamous, heterosexual relationship should not be
tory, physical exam, and lab testing. Obtaining or assumed. Potential etiologies for sexual dysfunction include
confirming recent blood pressure measurements, a wide range of organic and medical factors, but multiple
lipid profile, and glucose/HgBA1C are highly rec- psychological or interpersonal factors (i.e., anxiety, depres-
ommended. sion, relationship distress) can be causal or contributory.
A commonly used schema is:
• Vascular General domains of the history
• Endocrine
• Neurological • Determine specifics related to ED (onset, severity, sig-
• Situational nificance and situations) and desire, arousal, orgasm,
• End organ (penile deformity – Peyronie’s disease or and ejaculation.
trauma) • Sexual desire, relationship issues, stressors at home and
• Mixed (Most cases have an underlying organic cause work.
or causes; similarly most men will subsequently • Genital pain or altered shape.
report anxiety, stress, and depression as a conse- • Lifestyle factors: smoking, substance use/abuse, seden-
quence of ED.) tary lifestyle.
• Comorbid conditions: hypertension, peripheral vascular
Methodology disease, diabetes, obesity, and renal disease.
• Pelvic surgery, radiation or trauma.
1. History and clinical questioning (most important • Medications.
component of the ED evaluation). • Psychiatric illness or conditions.
2. Focused physical examination (directed at anatomic,
vascular and neural systems essential for erections). Questionnaires
3. Use of formalized questionnaire instruments (e.g.,
Sexual Health Inventory for Men [SHIM], Appendix- Use of validated questionnaires may be beneficial. These
http://journals.sfu.ca/cuaj/index.php/journal/article/ tools can be patient self-administered and provide much
view/2699/2022) is recommended but not manda- of the above information in an efficient non-threatening
tory, as the questionnaires are useful in establishing manner, while being time-saving and cost-effective.6 There
baseline function, ED severity, evaluate treatment are validated instruments designed to evaluate sexual and
response, and in most cases questionnaire results do erectile function. The greatest utility of these questionnaires
not add significantly to duration of the doctor-patient may be in establishing a response to therapy and determin-
encounter. ing overall satisfaction with drug use over a specified length
4. Laboratory investigations: serum glucose, lipid pro- of time (i.e., 4 weeks). The most common questionnaire is
file, and in select cases hormonal screening (total the SHIM (Appendix-http://journals.sfu.ca/cuaj/index.php/
testosterone/bioavailable testosterone). journal/article/view/2699/2022).9
5. Consultation with subspecialists (endocrinology, psy-
chology, cardiology). Physical exam
6. Specialized tests:
• Combined injection and stimulation test (CIS) The aim of a focused physical examination in men with ED is
• Duplex ultrasound with vasoactive penile injection to examine genital anatomy and identify any related abnor-

CUAJ • January-February 2015 • Volume 9, Issues 1-2 25

Bella et al.

malities (e.g., Peyronie’s plaques), endocrine signs, and pos- Optional testing such as thyroid-stimulating hormone
sible comorbidities (neurological, vascular, and possible (TSH), luteinizing hormone (LH) and follicle-stimulating
life-threatening conditions).10 An association exists between hormone (FSH), prolactin, complete blood count (CBC), and
erectile dysfunction and peripheral vascular disease, as well urinalysis are considered complementary and not felt to be
as ED and the potential development of coronary artery dis- mandatory in the evaluation of ED in most cases, but are
ease.11 Assessment should include body habitus (secondary added when dictated by clinical context.3,6,10
sexual characteristics), peripheral circulation (ED is a predic-
tor of cardiovascular morbidity and mortality, findings con- Specialized testing
sistent when controlled for confounders), neurological and
genitourinary systems.10 Testicular examination is important
to ensure testes/testis presence and to examine consistency 1. Psychological/psychiatric assessment
of the testicle (i.e., atrophy, hypogonadism). The identifica-
tion of penile deformities may be best achieved in the erect These assessments often provide important complementary
state, but is most commonly examined by stretching the insight into relationships and situational causes to ED. The
penis to make the Peyronie’s plaque(s) more pronounced. lack of widespread availability and cost limit their use in most
The physical examination can also be a source of embarrass- cases of ED treatment. The primary goals of psychotherapy are
ment or discomfort for some patients; therefore, every effort to reduce or eliminate performance anxiety, to understand the
should be made to ensure privacy and personal comfort. context in which men or a couple function sexually, to imple-
ment psycho-education in order to modify sexual scripts, and
Laboratory testing to reduce premature discontinuation of pharmacotherapy.3,6,14

2. NPTR
Overview
NPTR is a minimally invasive means to measure and record
The recommendations by the International Society for Sexual nighttime erectile events (nocturnal penile tumescence),
Medicine’s International Consultation on Sexual Medicine but has limited availability in Canada and costs are not
suggest that laboratory tests for men with sexual problems covered by most provinces. Nocturnal penile tumescence
may include fasting glucose, lipid profile and, in select cases, and rigidity testing using Rigiscan should take place for
a hormone profile. Hormone profiles are used to identify or at least 2 nights, measuring 2 to 5 overnight erections. A
confirm specific etiologies (e.g., hypogonadism) or to assess functional erectile mechanism is indicated by an erectile
the role of potential medical comorbidities or concomitant event of 60% rigidity recorded on the tip of the penis lasting
illnesses.6,12 for 10 minutes. NPTR’s greatest utility is in medico-legal
Assessment for occult diabetes may be performed with a cases and in investigative pharmacological studies to assess
fasting glucose or HbA1c. Although recommended by the treatment impact.15
WHO consensus panel, the lipid screen is considered an
optional component of the Canadian ED assessment but is 3. Vascular testing
suggested as a valuable addition to the evaluation and good
general practice.2 A variety of vascular tests exist. Penile duplex cavernous
Hormonal profile screening remains a controversial aspect artery flow determination after corporal injection of vaso-
of the routine evaluation of ED. There is a general guideline active agents is commonly performed.16 Use of ultrasound
agreement that in a man with ED and hypoactive desire, to localize and measure the size and flow through the cav-
incomplete response to PDE5-inhibitor treatment, and in all ernous vessels, pre- and post-vasoactive injection allow a
men with known diabetes (as suggested by 2013 Canadian more refined assessment of penile circulation. This test is
Diabetes Association guidelines)2 testing and potential treat- performed less frequently in Canada since the advent of
ment for low levels of testosterone is appropriate. In men effective oral medications. In cases where indicated, fur-
with normal desire and ED the need for global testing is ther vascular investigation is unnecessary if duplex ultra-
controversial and currently undetermined. In the appropri- sound is normal, as indicated by a peak systolic blood flow
ate patient, once treatment with exogenous testosterone is >30 cm/sec and a resistance index >0.8. If the ultrasound
initiated, ongoing follow-up is mandatory according to pub- is abnormal, however, arteriography and dynamic infusion
lished guidelines.12,13 cavernosometry and cavernosography should be performed
For men with diabetes, the 2013 Canadian Diabetes only in patients who are potential candidates for vascular
Association guidelines also support annual review of sexual reconstructive surgery – these tests though are rarely used
function and determination of testosterone levels. in current Canadian ED treatment.

26 CUAJ • January-February 2015 • Volume 9, Issues 1-2

 CUA Guidelines on ED

DICC aims to define how well the penile blood-trapping Treatment options
mechanism (the veno-occlusive mechanism) works.17 In
brief, dye and fluid are delivered into the penis to induce
an erection. Measurement of the rise and fall of intra-penile Overview
pressure with radiologic visualization of the veins draining
the penis determine whether a competent or incompetent Management of ED most often will occur concurrently with
veno-occlusive mechanism exists. lifestyle modification and treatment of organic or psycho-
The most invasive diagnostic test is an arteriography. It is sexual dysfunctions. Patients and partners are made aware of
reserved generally for cases of high-flow priapism or planned efficacy, risks and benefits of appropriate treatments, taking
vascular bypass. A penile angiogram allows visualization into consideration preferences and expectations. Oral ther-
of the penile circulation and directs embolization for the apy failure may often be salvaged by patient re-education
unusual case of penile injury induced high-flow priapism. on PDE5-inhibitor use and optimization of dosing. Stepwise
progression from oral agents through second- and third-line
4. Endocrinological tests therapies occurs as needed (Fig. 1).
1. Oral therapy (on-demand or daily dosing). Given
There is still controversy on the ideal endocrine workup the differences between oral agents, the choice of
for men with ED.3,6 A morning
total testosterone or bioavailable
testosterone is logical in men ASSESSMENT FOR SEXUAL DYSFUNCTION

with: decreased sexual interest,

delayed ejaculation, reductions Other sexual dysfunction
History ED Ejaculatory problem Treatment/
in ejaculate volume, failure of Physical and Labs Desire disorder possible referral
(Glucose, Lipids*,
PDE5-inhibitor treatment, and Testosterone*,
Anorgasmia

men with ED and diabetes. 13 Profactin*)

Complete exam Penile deformity –‰

Free testosterone measurements Peyronie’s disease†
have significant intra-assay vari-
ability which limits their clini- Replace and correct
cal utility in Canada and is not Normal exam Laboratory abnormality possible endocrinology referral,
e.g., prolactinoma, thyroid
recommended. Bioavailable tes- abnormality
Trial first-line
tosterone is clinically useful and oral therapy
recommended, but is not avail-
able in all areas of Canada; as Poor result,
Patient on NTG
well, patients may incur a cost for Success, assess how
or unable to
continue drugs taken,
a bioavailable testosterone assay. oral meds take PDE-5 inhibitor
optimize timing,
Calculated bioavailable testoster- situation and
one (which requires a morning hormone testing
Trial
total testosterone, albumin and Trial ICI Trial VED
intraurethral Tx
sex-hormone binding globulin) Success, Poor efficacy,
is an acceptable substitute for continue Not tolerated
oral meds If unsuccessful
measured bioavailable testoster-
one if it is not available or cost- Trial second-line,
injection therapy,
prohibitive. urethral therapy,
VED*
5. Neuro-physiological testing
Success, Unsuccessful
This form of testing generally continue consider third-line
treatment therapy
allows us to measure the sacral
reflex arc, an indirect measure of
the perineal neural integrity, and Penile implant
surgery
has limited clinical availability
and utility.18
Fig. 1. Management of erectile dysfunction. †Consider first-line ED treatment for men with ED and Peyronie’s
disease. *Optional testing.
ICI: intracavernosal injections; VED: vacuum erection device; NTG: nitrates/nitroglycerine; ED: erectile dysfunction.

CUAJ • January-February 2015 • Volume 9, Issues 1-2 27

Bella et al.

which initiating PDE5-inhibitor you should use may Conclusions

be influenced by several factors, including timing or
frequency of intercourse, and interactions with food 1. A careful history and physical exam are the essential
or alcohol (Table 1).3,6,19-21 elements of the ED workup in most cases.
2. Testosterone replacement therapy in men with doc- 2. Basic screening tests include the identification of car-
umented hypogonadism is an option. Testosterone diac risk factors and blood tests. The following tests
may be used alone for hypogonadism, or in combi- are recommended: serum fasting glucose, lipids and
nation with oral PDE5-inhibitor therapy when ED is testosterone (if indicated).
present.20-21 3. A stepwise treatment approach using the least inva-
3. Sexual counselling (this may represent a spectrum of sive option is suggested.
approaches from a simple open discussion with the 4. In some cases where greater detailed information
PCP to psychologist, sexual therapists and/or psy- is desired or failure of the initial oral medication
chiatrists).3,6 is encountered, trials of more invasive second-line
4. Local therapy (intracavernous or intraurethral treatment or investigations may be appropriate.
agents).2,3,6,22 5. Surgery should be reserved for men in whom less
5. Vacuum erection device therapy.23 invasive reversible treatment has not succeeded or
6. Surgery.3,6,23 is contraindicated.
a. Penile implant. 6. Treatment should be individualized and patient fol-
b. Peyronie’s surgical repair. low-up should be arranged to assess the efficacy of
c. Vascular bypass procedure (generally reserved treatment.
for young men after traumatic arterial penile vas-
cular injury). Competing interests: Dr. Bella is a member of the advisory boards for Lilly, Actavis, American
Medical Systems, and Coloplast. He is also a member of the Speakers’ Bureau for Lilly and CUA
(accredited CME speaker) and a co-principal investigator and cofounder of the PROPPER (Prospective
Registry of Outcomes with Penile Prosthesis for Erectile Restoration) registry. Dr. Lee is a member of

Table 1. Comparison of the properties of PDE5-inhibitors

Property Sildenafil Tadalafil Vardenafil
30–120 minutes 30–360 minutes 30–120 minutes
>TMAX
(median 60 minutes) (median 120 minutes) (median 60 minutes)
T½ 4 hours 17.5 hours 4 hours
Fatty meals cause a mean delay in Fatty meals cause a reduction in
Absorption Not affected by food
TMAX of 60 minutes CMAX
2.5 mg, 5 mg daily 10 mg oral dissolvable tablet
Available Doses 25 mg, 50 mg, 100 mg PRN
5 mg, 10 mg, 20 mg PRN 2.5 mg, 5 mg, 10 mg, 20 mg PRN
Maximum Dose 100 mg daily 20 mg daily 20 mg daily
Efficacy Each of the PDE5 inhibitors offers similar efficacy.
• Patients >65 years old • Patients >65 years old • Patients >65 years old
• Hepatic impairment • Hepatic impairment • Hepatic impairment
• Renal impairment • Renal impairment • Renal impairment
Dose adjustments may be
• Concomitant use of potent • Concomitant use of potent • Concomitant use of potent
needed
cytochrome P450 3A4 inhibitors, cytochrome P450 3A4 cytochrome P450 3A4
such as ritonavir and erythromycin inhibitors, such as ritonavir inhibitors, such as ritonavir
• Concomitant use of cimetidine and erythromycin and erythromycin
• Any patient using organic • Any patient using organic
• Any patient using organic nitrates
nitrates either regularly or nitrates either regularly or
either regularly or intermittently
Contraindications intermittently intermittently
• Known hypersensitivity to any
• Known hypersensitivity to • Known hypersensitivity to any
component of the tablet
any component of the tablet component of the tablet
Concomitant use of selective alpha blockers does not present a risk for significant hypotension. There is a
Use with alpha blockers
potential risk of significant hypotension when using non-selective alpha blockers.
Side effects (5 most common Headache, dyspepsia,
Headache, flushing, dyspepsia, nasal Headache, flushing, rhinitis,
in order of frequency when backpain, myalgia, nasal
congestion, alteration in colour vision dyspepsia, sinusitis
compared to placebo) congestion
Please consult the individual product monographs for additional information.

28 CUAJ • January-February 2015 • Volume 9, Issues 1-2

 CUA Guidelines on ED

the advisory boards for Abbott and Lilly. He has also received grants from Abbott, Lilly and Actavis 10. Ghanem HM, Salonia A, Martin-Morales A. SOP: Physical examination and laboratory testing for
and is participating in a clinical trial with Lilly. Dr. Carrier is a member of the advisory boards for men with erectile dysfunction. J Sex Med 2013;10:108-10. http://dx.doi.org/10.1111/j.1743-
Astellas, Eli Lilly Canada, Pfizer Canada, Abbott, Novartis, and Actavis. He is also a member of the 6109.2012.02734.x
Speakers’ bureau for Eli Lilly Canada, Pfizer Canada, Abbott, Merck, and Actavis. He is participating 11. Jackson G, Nehra A, Miner M, et al. The assessment of vascular risk with erectile dysfunction: the role of
the cardiologist and general physician. Int J Clin Prac 2013;67:1163-72. http://dx.doi.org/10.1111/
in clinical trials with Astellas and Eli Lilly Canada. Dr. Bénard is a member of the advisory boards
ijcp.12200
and part of the Speakers’ Bureau for Abbott, Astellas, Pfizer, Lilly, Paladin, and Actavis. He has 12. Meuleman EJ, Hatzichristou D, Rosen RC, et al. Diagnostic tests for male erectile dysfunction revis-
received payment for talks from Abbott, Astellas, Pfizer, Lilly, Paladin, and Actavis. He also has ited. Committee Consensus Report of the International Consultation in Sexual Medicine. J Sex Med
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Correspondence: Dr. Anthony Bella, Room A345, B3 Urology Civic Campus, 1053 Carling Ave.,
http://dx.doi.org/10.5489/cuaj.2311 Ottawa ON K1Y 4E9; abella@ohri.ca
9. Ramanathan R, Mulhall J, Rao S, et al. Predictive correlation between the International Index of Erectile
Function (IIEF) and Sexual Health Inventory for Men (SHIM): Implications for calculating a derived SHIM
for clinical use. J Sex Med 2007;4:1336-44. http://dx.doi.org/10.1111/j.1743-6109.2007.00576.x

CUAJ • January-February 2015 • Volume 9, Issues 1-2 29

4/20/2015 Erectile Dysfunction Treatment & Management

Erectile Dysfunction Treatment & Management
Author: Edward David Kim, MD, FACS; Chief Editor: Edward David Kim, MD, FACS   more...

Updated: Aug 21, 2014

Approach Considerations
After all the information regarding the patient’s status has been gathered, the various options for management of
erectile dysfunction (ED) can be discussed. It is best to include the patient’s partner in this discussion. [67] The task
of the physician is to help the patient seek the best solution. Finding a trained and understanding physician who is
willing to take the time to understand the patient’s problem is the first step in identifying which therapeutic option
will ultimately be most appropriate and successful.

Enough options are available that every man who wants to be sexually active can be, regardless of the etiology of
the problem. These include sexual counseling if no organic causes can be found for the dysfunction, oral
medications, external vacuum devices, or some type of invasive therapy. One of the most difficult aspects of
treatment is teaching men that sex entails more than simply achieving an erection.

Treatment in men with cardiovascular disease

Many patients with ED also have cardiovascular disease—not surprisingly, given that the two disorders have a
common etiology. Treatment of ED in these patients must take cardiovascular risks into account.

Sexual activity, in and of itself, increases the chances of ischemic events and myocardial infarction (MI) because of
the exertion and sympathetic activation that may accompany it. The absolute risk of MI during sexual activity and for
2 hours afterward is only 20 chances per million per hour in post­MI patients and is even lower in men without a
history of MI. [1]

The Princeton Consensus Panel has produced guidelines for managing ED in patients with cardiovascular disease.
[68, 7] The panel advises that a man with ED and no cardiac symptoms should be considered to have cardiac or
vascular disease until proven otherwise. ED patients should be assessed and categorized as high­, intermediate­, or
low­risk. This stratification can guide management.

Risk­factor modification, including lifestyle interventions (eg, exercise and weight loss) is strongly encouraged for ED
patients with cardiovascular disease. A study by Gupta et al supports the view that for men with cardiovascular risk
factors, modifications in lifestyle along with pharmacotherapy are helpful in improving sexual function. [69]

Patients who have serious cardiac disease or exertional angina or are taking multiple antihypertensive medications
should seek the advice of a cardiologist before beginning therapy with a phosphodiesterase type 5 (PDE5) inhibitor.
Nevertheless, several studies examining the cardiac effects of sildenafil and tadalafil have demonstrated that there
is no increased risk of cardiovascular events in comparison with placebo. [70, 71] No significant differences in the
incidence of MI, myocardial ischemia, or postural hypotension has been reported.

Pharmacologic Therapy
An increasing array of medications is available to assist in the management of ED. New agents are still undergoing
clinical testing, and more are in the early phases of development. For any medication to be effective, the
physiologic components involved in the erectile process must be functional. Serious impairments render the
medication either completely or partially ineffective.

Phosphodiesterase­5 inhibitors

In current practice, PDE5 inhibitors are the most commonly used treatment for ED. [72] This drug class consists of
sildenafil, vardenafil, tadalafil, and avanafil. Sildenafil was the first in this series of PDE inhibitors; avanafil is the
newest, having been approved by the US Food and Drug Administration (FDA) in April 2012. In a study of 390 men
with diabetes and erectile dysfunction, avanafil was found to be a safe and effective treatment as early as 15
minutes and more than 6 hours after dosing. [73]

Guidelines from the American Urological Association (AUA) recommend offering PDE5 inhibitors as first­line
therapy for ED unless the patient has contraindications to their use. [1]

Guidelines from the American College of Physicians (ACP) on hormonal testing and pharmacologic treatment of
erectile dysfunction, issued in 2009, strongly urge physicians to initiate therapy with a PDE5 inhibitor in men seeking
treatment for ED who have no contraindications to the use of these agents (eg, concurrent nitrate therapy). [74]

The ACP guidelines recommend choosing a specific PDE5 inhibitor for patients with ED on the basis of individual
patient preference, ease of use, cost of medication, and adverse effects. [74] They stress that PDE5 inhibitors are
relatively well tolerated by patients and that adverse effects are usually mild or moderate.

In patients with ED that is refractory to therapy with oral PDE5 inhibitors, one of these agents can be combined with
an injection of prostaglandin E1 (PGE1; alprostadil). [2] Gutierrez et al demonstrated that this combination was more
effective than either one alone. [75] The combination of a PDE5 inhibitor with intraurethral PGE1 has also proved
successful.

Androgens

Men who present with diminished libido and ED may be found to have low serum testosterone levels

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(hypogonadism). Hormone replacement may benefit men with severe hypogonadism and may be useful as
adjunctive therapy when other treatments are unsuccessful by themselves. Libido and an overall sense of well­being
are likely to improve when serum testosterone levels are restored to the reference range. [76, 77, 78, 79, 80, 81]

According to the 2009 ACP guidelines, the evidence for the efficacy of hormonal treatment of ED in men with low
testosterone levels is inconclusive. The ACP is neither in favor of or opposed to routine hormonal blood tests or
hormonal treatment in patients with ED, though it states that measurement of hormone levels may be appropriate
in certain patients. [74]

The ACP guidelines recommend that clinicians assess the presence or absence of symptoms of hormonal
dysfunction when deciding whether to measure hormone levels in men with ED. Symptoms of hormone dysfunction
include decreased libido, premature ejaculation, fatigue, and physical findings such as testicular or muscle atrophy.
[74]

Replacement androgens are available in the following four forms:

Oral
Injectable
Gel
Transdermal

Oral therapy is rarely used; of the available approaches, it is the least effective and the most likely to be associated
with hepatotoxicity, even though the risk is relatively small.

Parenteral therapy is the approach most likely to restore androgen levels to the reference range, but it requires
periodic injections (usually every 2 weeks) to sustain an effective level. Measurement of peak and trough levels can
help avoid symptomatic troughs and supernormal peak levels, though such measurement is rarely done in clinical
practice. Typically, a level is obtained 1 week after an injection. Weekly injections using lower doses can be used to
minimize the wide swings in blood levels noted with less frequent dosing.

Skin patches deliver a sustained dose and are generally accepted by patients. Testosterone gels are available for
daily topical use to treat male hypogonadism and have the advantage of minimizing the peaks and troughs
associated with the use of injectable agents. However, these gels require daily application and are relatively
expensive.

Implantation of longer­acting testosterone pellets has become increasingly popular. The pellet is placed during an
office visit. The advantage of this approach is the infrequency of pellet placement (only every 3­6 months).

The use of exogenous androgens suppresses natural androgen production. Elevation of serum androgen levels has
the potential to stimulate prostate growth and may increase the risk of activating a latent cancer. Periodic prostate
examinations, including digital rectal examinations, prostate­specific antigen (PSA) determinations, and blood
counts (ie, complete blood count [CBC]), are recommended in all patients receiving supplemental androgens.
Obtaining a testosterone level during therapy is necessary for optimizing the dosage.

Intracavernosal injection of vasodilators

The modern age of pharmacotherapy for ED began in 1993, when papaverine, an alpha­receptor blocker that
produces vasodilatation, was shown to produce erections when injected directly into the corpora cavernosa. Soon
afterward, other vasodilators, such as alprostadil (ie, synthetic PGE1) and phentolamine, [39] were demonstrated to
be effective either as single agents or in combination. [82, 83]

Alprostadil is the single agent most commonly used for intracavernosal injections. In a study of 683 men, 94%
reported having erections suitable for penetration after alprostadil injections. [84] Self­injection of this and similar
agents has been of enormous benefit because they represent an effective way to achieve adequately rigid erections
for a wide variety of men who otherwise would be unable to do so.

If the vasculature within the corpora cavernosa is healthy, intracavernosal injection therapy is almost always
effective. However, careful instruction in how to perform the injections is essential. The dosage is adjusted so as to
achieve an erection with adequate rigidity for no more than 90 minutes. Alprostadil doses as high as 40 µg can be
used. An abnormal finding after biothesiometry testing has been suggested as an indicator of possible heightened
sensitivity to intracavernosal injections, but this suggestion remains unproven.

The main adverse effects of intracavernosal injection are as follows[84, 85, 86] :

Painful erection
Priapism
Development of scarring at the injection site

Intraurethral prostaglandin E1 pellets

Another option for ED is the Medicated Urethral System for Erections (MUSE). MUSE involves the formulation of
alprostadil (PGE1) into a small intraurethral suppository that can be inserted into the urethra (see the image below).
In one study, the agent was effective in 65% of a selected group of men. [87] Widespread application of MUSE has
been limited by the system’s cost and its inability to provide rigid erections consistently.

The Medicated Urethral System for Erections (MUSE) is a small suppository placed into the urethra with this device.

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MUSE may be effective in men who have vascular disease or diabetes or have undergone prostate surgery.
Intraurethral alprostadil is a useful agent for men who do not want to use self­injections or for men in whom oral
medications have failed. It has been successfully used together with sildenafil in cases in which each agent alone
failed.

Few adverse effects occur. The most common is a painful erection and urethral burning, which occurs in fewer than
10% of patients.

A topical gel formulation of alprostadil for treatment of ED has been developed. [88] However, it has not been
approved for use by the FDA.

Vascular endothelial growth factor

One area of research has involved the use of vascular endothelial growth factor (VEGF), an angiogenic growth
factor and endothelial cell mitogen. VEGF is produced by vascular smooth muscle, endothelial, and inflammatory
cells. It increases production of nitric oxide (NO), which results in improves endothelial function and blood flow in
chronic ischemic disorders. [89, 90]

Direct intracavernosal injection of recombinant VEGF protein or adenoviral VEGF that contains plasmids has shown
dramatic results on cavernosography in animal models with arteriogenic, venogenic, and neural forms of ED.
Burchardt et al identified VEGF 165 as the predominant isoform in the corpora cavernosa, as well as a novel splice
variant. [71]

Although VEGF is a potent and important vascular regulator, it probably acts in conjunction with other vascular
factors. Although a single­agent VEGF is unlikely to ever be used as monotherapy for ED, the research done into its
actions represents an important step in understanding the normal and abnormal vascular physiology associated with
ED.

Other oral agents

Before the advent of oral PDE5 inhibitors, various other oral medications were investigated for treatment of ED,
including the following[72] :

Adrenergic receptor antagonists (eg, phentolamine, yohimbine, and delequamine)
Dopamine receptor antagonists (eg, apomorphine and bromocriptine)
Serotoninergic receptor activators (eg, trazodone)
Xanthine derivatives (eg, pentoxifylline)
Oxytocinergic receptor stimulators (eg, oxytocin)

Although the AUA does not recommend the use of any of these agents, [1] several are worth reviewing briefly.

Yohimbine

Yohimbine, a bark extract, has been available for many years. It has both a central and a peripheral effect. Even in
properly conducted, well­controlled studies, it is only slightly more effective than placebo. Even though yohimbine is
not recommended by AUA guidelines, there has been a renewed interest in this agent, particularly when it is
combined with an oral PDE5 inhibitor. [91] Yohimbine is a safe agent with few known adverse effects. It is
administered in a dosage of 5.4 mg (1 tablet) 3 times daily

Apomorphine

A sublingual formulation of apomorphine has demonstrated some benefit in ED. Apomorphine is not approved by
the FDA for this indication.

Phentolamine

Phentolamine is an alpha­receptor blocker that has not been approved by the FDA for the treatment of ED but has
undergone limited clinical testing. Two placebo­controlled trials reported effectiveness in 42% and 32% of patients
taking 50 mg, compared with 9% and 13% of control subjects, respectively. The erections occurred in 20­30
minutes. The drug was well tolerated, with mild­to­moderate adverse effects (usually headaches or light­
headedness) occurring in less than 10% of patients.

External Erection­Facilitating Devices
Constriction devices

Men who have a vascular (venous) leak phenomenon may need a constriction device placed at the base of the penis
to maintain their erection (see the image below). Such a device may be effective by itself or in combination with a
PDE5 inhibitor. In selected cases, combination therapy with one of the PDE5 inhibitors plus an intraurethral or
intracavernosal agent may be tried.

This is one of many types of constricting devices placed at the base of the penis to diminish venous outflow and improve the quality
and duration of the erection. This is particularly useful in men who have a venous leak and are only able to obtain partial erections
that they are unable to maintain. These constricting devices may be used in conjunction with oral agents, injection therapy, and
vacuum devices.

Vacuum devices

Vacuum devices for drawing blood into the penis are a relatively inexpensive method for producing an erection that

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has been used for many years. These devices are plastic cylinders that are placed over the penis. Air is pumped
out, causing a partial vacuum. Releasing the vacuum after a few minutes and then reapplying the vacuum
sometimes gives a better result. After an erection is obtained, a constricting band is placed at the base of the penis
(see the images below). [92]

This image depicts a vacuum device used to produce an erection (also see next image). In this image, the elements are shown. They
include the cylinder, a pump to create a vacuum, and a constriction ring to be placed at the base of the penis after an erection has
been obtained in order to maintain the erection.

This image demonstrates the vacuum device in place (see previous image). Note the presence of the constricting ring at the base of
the penis.

This technique is effective in 60­90% of patients and maintains the erection for up to 30 minutes. (In fact, the
erection would last until the constricting band is released, but keeping the band in place for longer than 30 minutes
is not recommended.) The devices are very reliable and seem to work better with increased use and practice. They
can be operated and used quickly with experience but still tend to be less “romantic” than other therapeutic options.

Although vacuum devices are generally safe, hematomas, petechia, and ecchymosis have been reported. Other
adverse effects include pain, lower penile temperature, numbness, absent or painful ejaculation, and pulling of
scrotal tissue into the cylinder, where it becomes trapped under the ring. Many of these problems can be alleviated
by proper selection of the tension rings and cylinders.

Drawbacks to the use of external vacuum devices include the need to assemble the equipment and the difficulty of
transporting it. Many patients lose interest in using the device because of the preparations that are necessary, the
lack of easy transportability, the inability to hide the tension ring, and the relative lack of spontaneity. Approximately
half the men who use a vacuum device obtain very good erections, but only half of these men consistently use the
device for a prolonged period.

Surgical Intervention

Selected patients with ED are candidates for surgical treatment.

Surgical revascularization

A small number of healthy young men have developed ED as a result of trauma to the pelvic arteries.
Revascularization procedures such as rotating the epigastric artery (or even smaller vessels) into the corpora have
been attempted. Long­term results have been marginal. AUA guidelines recommend arterial reconstructive surgery
as a treatment option only in healthy patients who have recently acquired ED as the result of a focal arterial
occlusion and who have no evidence of generalized vascular disease. [1]

Surgical elimination of venous outflow

On occasion, men who have difficulty maintaining erections as a result of venous leaks may benefit from undergoing
a surgical procedure designed to eliminate much of the venous outflow. Although there was considerable initial
enthusiasm for this and other surgical approaches was significant, this type of surgery has become rare because of
a lack of long­term efficacy. AUA guidelines recommend against the use of such procedures. [1]

Placement of penile implant

In the past, the placement of prosthetic devices within the corpora was the only effective therapy for men with
organic ED. At present, however, it is the last option considered, even though more than 90% of men with an
implant would recommend the procedure to their friends and relatives. Before selecting this form of management,
the patient and his sexual partner should be counseled regarding the benefits and risks of this procedure (see Table
2 below). [93, 94]

Table 2. Advantages and Disadvantages of Different Types of Penile Implants for Erectile Dysfunction (Open Table
in a new window)

Treatment Advantages Disadvantages

Semirigid or malleable rod Simple surgery Constant erection at all times
implants

Relatively few complications May be difficult to conceal

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No moving parts Does not increase width of penis

Least expensive implant Risk of infection

Success rate of 70­80% Permanently alters or may injure
erection bodies

Highly effective
Most likely implant to cause pain or
erode through skin

If unsuccessful, interferes with other
treatments

Fully inflatable implants Mimics natural process of rigidity­flaccidity Relatively high rate of mechanical

failure

Patient controls state of erection
Risk of infection

Natural appearance
Most expensive implant

No concealment problems
Permanently alters or may injure
erection bodies

Increases width of penis when activated

If unsuccessful, interferes with other
treatments
Success rate of 70­80%

Highly effective

Self­contained inflatable Mimics natural process of rigidity­flaccidity Sometimes difficult to activate the

unitary implants inflatable device

Patient controls state of erection
Does not increase width of penis

Natural appearance
Mechanical breakdowns possible

No concealment problems
Long­term results not available

Simpler surgical procedure than that required for
fully inflatable prosthesis Risk of infection

Success rate of 70­80% Relatively expensive

Highly effective Permanently alters or may injure
erection bodies

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If unsuccessful, interferes with other
treatments

Implants are usually used for men who have not experienced success with other therapies or who require penile
reconstructions. Men who have undergone a radical prostatectomy for prostate cancer and in whom a nerve­sparing
procedure was not performed or was not successful often do not respond to oral PDE5 inhibitors, and these men
are good candidates for a penile implant. The same is true for men treated with radiation therapy, though more of
these men tend to respond to oral agents.

There is some evidence to suggest that an additional benefit may be gained by some men who have an implant but
also take an oral PDE5 inhibitor. Sexual stimulation and sensation are enhanced.

Penile prostheses can be divided into 2 broad categories as follows:

Semirigid
Inflatable

With the semirigid prosthesis, 2 matching cylinders are implanted into the corpora cavernosa (see the image below).
These devices provide enough rigidity for penetration and rarely break. The major drawbacks are the cosmetic
appearance of the penis (which remains semierect at all times), the need for surgery, and the destruction of the
natural erectile mechanism when the prosthesis is implanted.

Two rigid cylinders have been placed into the corpora cavernosa. This type of implant has no inflation mechanism but provides
adequate rigidity to the penis to allow penetration.

The inflatable devices consist of 2 Silastic or Bioflex cylinders inserted into the corpora cavernosa, a pump placed in
the scrotum to inflate the cylinders, and a reservoir that is contained either within the cylinders or in a separate
reservoir placed beneath the fascia of the lower abdomen (see the images below). The inflatable prosthesis
generally remains functional for 7­10 years before a replacement may be necessary. Improvements in these devices
have resulted in a failure rate lower than 10%.

This inflatable penile prosthesis has 3 major components. The 2 cylinders are placed within the corpora cavernosa, a reservoir is
placed beneath the rectus muscle, and the pump is placed in the scrotum. When the pump is squeezed, fluid from the reservoir is
transferred into the 2 cylinders, producing a firm erection. The deflation mechanism is also located on the pump and differs by
manufacturer.

Patient acceptance of these devices is very high, with nearly 100% of recipients expressing satisfaction. Part of this
enthusiasm is related to the failure of other therapies and the highly motivated patient population.

Rajpurkar and Dhabuwala reported significantly better erectile function and satisfaction with a penile implant than
with sildenafil or intracavernosal alprostadil (PGE1). [95] This was a nonrandomized study in which all 138 subjects
were initially offered sildenafil. The mean follow­up was 19.54 months, and questionnaires were used to obtain the
data.

Complications include infections (occurring in 2% of patients), erosion of the device through the urethra or skin (2%),
and painful erections (1%). The development of an antibiotic­coated device has further reduced the infection rate.
Patients should also be counseled that the penis does not lengthen as much as with normal erections.

Counseling and Psychological Care
Sexual counseling is the most important part of treatment for patients with sexual problems. Many professional
sexual counselors are skilled in working with patients, but the primary care physician, the urologist, and the
gynecologist also serve in this capacity to some degree. These are usually the first professionals to learn about the
problem, and they often have to extract the information about the sexual problem from the patient.

Men are frequently reluctant to discuss their sexual problems and must be specifically asked. Opening a dialogue
allows the clinician to begin the investigation or to refer the patient to a consultant. Regardless of any subsequent
therapy, the emotional aspects of the disorder must be addressed. Ideally, the patient’s partner should be involved
in counseling, but even if this is not possible, the time spent may help resolve or at least clarify the problem and
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certainly helps determine which of the other options would be most beneficial and appropriate.

Regardless of the etiology of ED, a psychological component is frequently associated with the disorder. The ability
to achieve erection is intimately connected to a man’s self­esteem and sense of worth. Pure psychogenic ED is
generally evident when a man reports that he has normal erections some of the time but is unable to achieve or to
maintain a full erection at other times. Once the man has doubt regarding sexual performance, he loses confidence;
thus, future attempts to have sexual relations provoke anxiety.

In many instances, the couple must work together to resolve the problem, although in some cases, the relationship
itself may be responsible for the problem. Referral to a sex therapist may be helpful.

A study of 31 newly diagnosed men with ED (aged 20­55 years) who were treated with either tadalafil (n = 12) or
tadalafil plus 8 weeks of stress management (n = 19) found that both groups showed significant improvement in
perceived stress and erectile function scores but that the reduction in perceived stress was greater in the latter
group. [96] This result suggests that stress reduction may be a useful component of ED treatment. Further research,
involving randomized, controlled trials with larger samples and longer follow­up time, is needed.

Men with organic ED can be treated with one or more of the various available therapies (see above). However, if
they have lost confidence in their ability to obtain and maintain an erection suitable for penetration, a few words of
encouragement from their physician can be of great help.

Prevention
The AUA observes that because diabetes, heart disease, and hypertension increase the risk of developing ED,
optimal management of these diseases may prevent the development of ED. [1] Similarly, because attaining and
maintaining a firm erection requires good vascular function, it is reasonable to assume that lifestyle modifications to
improve vascular function (eg, smoking cessation, maintenance of ideal body weight, and regular exercise) may
prevent or reverse ED. At present, however, only minimal data support these suppositions. [1]

Contributor Information and Disclosures
Author
Edward David Kim, MD, FACS  Professor of Surgery, Division of Urology, University of Tennessee Graduate
School of Medicine; Consulting Staff, University of Tennessee Medical Center 

Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons,
American Society for Reproductive Medicine, American Society of Andrology, American Urological Association,
Sexual Medicine Society of North America, and Tennessee Medical Association

Disclosure: Lilly Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Actavis Honoraria
Speaking and teaching; Auxilium Honoraria Speaking and teaching

Coauthor(s)
Stanley A Brosman, MD  Clinical Professor, Department of Urology, University of California, Los Angeles, David
Geffen School of Medicine 

Stanley A Brosman, MD is a member of the following medical societies: Alpha Omega Alpha, American
Academy of Pediatrics, American Association for Cancer Research, American Association for the Advancement
of Science, American College of Surgeons, American Medical Association, American Society of Clinical
Oncology, American Urological Association, Association of Clinical Research Professionals, International Society
of Urological Pathology, Société Internationale d'Urologie (International Society of Urology), Society for Basic
Urologic Research, Society of Surgical Oncology, Society of Urologic Oncology, and Western Section American
Urological Association

Disclosure: Nothing to disclose.

Chief Editor
Edward David Kim, MD, FACS  Professor of Surgery, Division of Urology, University of Tennessee Graduate
School of Medicine; Consulting Staff, University of Tennessee Medical Center 

Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons,
American Society for Reproductive Medicine, American Society of Andrology, American Urological Association,
Sexual Medicine Society of North America, and Tennessee Medical Association

Disclosure: Lilly Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Actavis Honoraria
Speaking and teaching; Auxilium Honoraria Speaking and teaching

Additional Contributors
Mark Jeffrey Noble, MD Consulting Staff, Urologic Institute, Cleveland Clinic Foundation

Mark Jeffrey Noble, MD is a member of the following medical societies: American College of Surgeons,
American Medical Association, American Urological Association, Kansas Medical Society, Sigma Xi, Society of
University Urologists, and Southwest Oncology Group

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College
of Pharmacy; Editor­in­Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Martha K Terris, MD, FACS Professor, Department of Surgery, Section of Urology, Director, Urology Residency
Training Program, Medical College of Georgia; Professor, Department of Physician Assistants, Medical College
of Georgia School of Allied Health; Chief, Section of Urology, Augusta Veterans Affairs Medical Center

Martha K Terris, MD, FACS is a member of the following medical societies: American Cancer Society, American
College of Surgeons, American Institute of Ultrasound in Medicine, American Society of Clinical Oncology,
American Urological Association, Association of Women Surgeons, New York Academy of Sciences, Society of

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Government Service Urologists, Society of University Urologists, Society of Urology Chairpersons and Program
Directors, and Society of Women in Urology

Disclosure: Nothing to disclose.

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 Clinical Guidelines

Hormonal Testing and Pharmacologic Treatment of Erectile

Dysfunction: A Clinical Practice Guideline From the American
College of Physicians
Amir Qaseem, MD, PhD, MHA; Vincenza Snow, MD; Thomas D. Denberg, MD, PhD; Donald E. Casey, Jr., MD, MPH, MBA;
Mary Ann Forciea, MD; Douglas K. Owens, MD, MS; and Paul Shekelle, MD, PhD, for the Clinical Efficacy Assessment Subcommittee
of the American College of Physicians*

Description: The American College of Physicians developed this who seek treatment for erectile dysfunction and who do not have
guideline to present the available evidence on hormonal testing in a contraindication to PDE-5 inhibitor use (Grade: strong recommen-
and pharmacologic management of erectile dysfunction. Current dation; high-quality evidence).
pharmacologic therapies include phosphodiesterase-5 (PDE-5) in-
Recommendation 2: The American College of Physicians recom-
hibitors, such as sildenafil, vardenafil, tadalafil, mirodenafil, and
mends that clinicians base the choice of a specific PDE-5 inhibitor
udenafil, and hormonal treatment.
on the individual preferences of men with erectile dysfunction,
Methods: Published literature on this topic was identified by using including ease of use, cost of medication, and adverse effects
MEDLINE (1966 to May 2007), EMBASE (1980 to week 22 of profile (Grade: weak recommendation; low-quality evidence).
2007), Cochrane Central Register of Controlled Trials (second quar-
Recommendation 3: The American College of Physicians does not
ter of 2007), PsycINFO (1985 to June 2007), AMED (1985 to June
recommend for or against routine use of hormonal blood tests or
2007), and SCOPUS (2006). The literature search was updated by
hormonal treatment in the management of patients with erectile
searching for articles in MEDLINE and EMBASE published between
dysfunction (Grade: insufficient evidence to determine net benefits
May 2007 and April 2009. Searches were limited to English- and harms).
language publications. This guideline grades the evidence and rec-
ommendations by using the American College of Physicians’ clinical
practice guidelines grading system.
Ann Intern Med. 2009;151:639-649. www.annals.org
Recommendation 1: The American College of Physicians recom- For author affiliations, see end of text.
mends that clinicians initiate therapy with a PDE-5 inhibitor in men This article was published at www.annals.org on 20 October 2009.

E rectile dysfunction (ED) is defined as the persistent in-

ability to achieve or maintain penile erection sufficient
for satisfactory sexual performance (1). Erectile dysfunc-
ment of ED in the United States could reach $15 billion if
all affected men sought care (7).
The purpose of this guideline is to present the avail-
tion lasting for 3 months is considered a reasonable length able evidence on the hormonal testing and pharmacologic
of time to warrant evaluation and consideration of treat- management of ED. The target audience for this guideline
ment. Erectile dysfunction is a common disorder of male is all clinicians, and the target population is all men with
sexual function and affects all age groups, especially people ED. Recommendations are based on the systematic evi-
with advanced age, diabetes, vascular diseases, psychiatric dence review by Tsertsvadze and colleagues (8) and the
disorders, and possibly hypogonadism (1– 4). With the ag-
ing general population and increased life expectancy, com- See also:
bined with the high prevalence of diabetes and cardiovas-
cular disease, the health care burden and quality-of-life Print
issues associated with ED are projected to be substantial Related article. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
(5). In 1995, more than 152 million men worldwide were Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-44
estimated to have experienced ED. The prevalence of ED Web-Only
is predicted to be approximately 322 million worldwide by CME quiz
2025 (6). Estimates from the National Health and Nutri- Conversion of graphics into slides
tion Examination Survey suggested that the cost of treat-

* This paper, written by Amir Qaseem, MD, PhD, MHA; Vincenza Snow, MD; Thomas D. Denberg, MD, PhD; Donald E. Casey Jr., MD, MPH, MBA; Mary Ann Forciea, MD;
Douglas K. Owens, MD, MS; and Paul Shekelle, MD, PhD, was developed for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians (ACP): Paul
Shekelle, MD, PhD (Chair); Roger Chou, MD; Paul Dallas, MD; Thomas D. Denberg, MD, PhD; Mary Ann Forciea, MD; Robert H. Hopkins Jr., MD; Linda Humprey, MD, MPH;
David B. Nash, MD, MBA; Douglas K. Owens, MD, MS; and Donna Sweet, MD. Approved by the ACP Board of Regents on 11 July 2009.

© 2009 American College of Physicians 639

Downloaded From: http://annals.org/ on 04/20/2015

 Clinical Guidelines Hormonal Testing and Pharmacologic Treatment of Erectile Dysfunction

evidence report by the Agency for Healthcare Research and

Table. The American College of Physicians’ Guideline
Quality–sponsored University of Ottawa Evidence-based
Grading System*
Practice Center (5). Erectile dysfunction may be caused by
chronic diseases, such as obesity, hypertension, dyslipide-
Quality of Strength of Recommendation
mia, and cardiovascular disease, or smoking; medications; Evidence
psychosocial factors; and hormonal abnormalities. This Benefits Clearly Outweigh Benefits Finely Balanced
Risks and Burden OR With Risks and Burden
guideline addresses only the utility of hormonal testing and Risks and Burden Clearly
treatment of ED. Such treatments as vacuum constriction Outweigh Benefits
devices, intraurethral suppositories, intracavernosal injec- High Strong Weak
tions, and psychotherapy were not included in the evidence Moderate Strong Weak
Low Strong Weak
review and are not addressed in this guideline.
Insufficient evidence to determine net benefits or risks

* Adopted from the classification developed by the Grading of Recommendations,

METHODS Assessment, Development, and Evaluation (GRADE) workgroup.
The databases used for the literature search included
MEDLINE (1966 to May 2007), EMBASE (1980 to week
22 of 2007), Cochrane Central Register of Controlled Tri- The objective of this guideline is to synthesize the ev-
als (second quarter of 2007), PsycINFO (1985 to June idence for the following key questions:
2007), AMED (1985 to June 2007), and SCOPUS Key question 1: What is the clinical utility of routine
(2006). The literature search was limited to studies pub- hormonal blood tests—testosterone and prolactin—in
lished in English. Reference lists of retrieved publications identifying and affecting therapeutic outcomes for treatable
were scanned. The literature search was updated by search- causes of ED?
ing for articles on MEDLINE and EMBASE published Key question 2: What are the benefits of pharmaceu-
between May 2007 and April 2009. tical treatments for patients with ED?
Two persons independently reviewed abstracts and Key question 3: What are the harms of the pharma-
relevant full-text articles regarding study, study popula- ceutical treatments for patients with ED?
tion, and treatment characteristics. Disagreements were
discussed and resolved by consensus. The reviewers ex-
cluded reviews, pooled analysis, editorials, commentaries,
and letters. To assess the relative benefits and harms of CLINICAL UTILITY OF ROUTINE HORMONAL
pharmacologic treatments for ED, eligible studies included DIAGNOSTIC TESTS
randomized, controlled trials (RCTs) of pharmacologic ED Evidence was gathered from 29 studies, of which 28
treatments in men aged 18 years or older with ED. To reported measurement of testosterone (9 –37) and 10 re-
assess the clinical value of routine hormonal blood tests in ported measurement of prolactin (9, 10, 12, 14, 15, 20,
men with ED, eligible studies were those reporting preva- 22, 27, 28, 38). Mean age of participants ranged from 47
lence of hypogonadism, hyperprolactinemia, or both in to 60 years. The overall quality of evidence was rated as
men with ED and RCTs comparing hormone treatment low because of between-study variability in study popula-
alone or in combination versus control in men with ED.
tions, varying hormone measurement methods, and preva-
For adverse events, data abstracted included the number of
lence rates of hormonal abnormalities.
patients with any adverse event, specific adverse events,
The prevalence of low total testosterone levels (12, 23,
withdrawals due to adverse events, serious adverse events,
34, 35), low free testosterone levels (21, 29), and hyper-
and serious cardiovascular adverse events. To assess the
risks for nonarteritic anterior ischemic optic neuropathy prolactinemia (14, 27, 28) in men with ED varied widely
(NAION) in men receiving phosphodiesterase-5 (PDE-5) across studies. The prevalence of low testosterone levels
inhibitors, eligible studies included RCTs; nonrandom- (defined in the studies as ⬍288 ng/dL [⬍9.9 nmol/L] or
ized, controlled trials; and observational studies. Treat- ⬍9.0 pg/mL [⬍31.2 pmol/L]) in men with ED varied
ments not generally prescribed by primary care physicians, from 12.5% to 35% (20, 21, 31). This variability may be
such as vacuum constriction devices, intraurethral suppos- due to between-study differences in study population char-
itories, intracavernosal injections, or psychotherapy, were acteristics, hormonal measurement methods, diagnostic
considered beyond the scope of this guideline. criteria for ED or hormonal abnormalities, or a combina-
This guideline rates the evidence and recommenda- tion of these factors. Because evidence was insufficient to
tions by using the American College of Physicians’ guide- determine whether men with ED had a higher preva-
line grading system, which is a slightly modified version of lence of hypogonadism or hyperprolactinemia than men
the Grading of Recommendations, Assessment, Develop- without ED (31, 32), the value of routine hormonal
ment, and Evaluation (GRADE) system (Table). testing for the evaluation of ED is unclear.
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 Hormonal Testing and Pharmacologic Treatment of Erectile Dysfunction Clinical Guidelines

BENEFITS OF PHARMACOLOGIC TREATMENT PDE-5 Inhibitor Versus Non–PDE-5 Inhibitor

Oral PDE-5 Inhibitors Sildenafil was more effective than non–PDE-5 in-
Evidence was gathered from 130 RCTs that evaluated hibitor treatments, such as sublingual apomorphine,
oral PDE-5 inhibitors, alone or combination (72 RCTs of psychotherapy, continuous positive airway pressure,
sildenafil [39 –107], 27 RCTs of vardenafil [13, 108 –133], phentolamine, and alfuzosin, in improving erectile func-
28 RCTs of tadalafil [134 –161], 2 RCTs of mirodenafil tion (170 –174), frequency of penile penetration or erec-
[156, 157], and 1 RCT of udenafil [162]), and 4 RCTs tion maintenance, and percentage of successful inter-
with head-to-head comparisons of PDE-5 inhibitors (163– course attempts (175–179).
166). Treatment duration for most trials was 12 months,
and 85% of the trials did not report treatment allocation PDE-5 Inhibitor Plus Non–PDE-5 Inhibitor Versus
concealment. PDE-5 Inhibitor
Sildenafil combined with other ED therapies (such as
psychotherapy, dihydroergotamine, cabergoline, atorvasta-
PDE-5 Inhibitor Versus Placebo tin, quinapril, and alfuzosin) resulted in greater improve-
Successful Sexual Intercourse. High-quality evidence ments in erectile function and frequency of penile penetra-
from RCTs showed that PDE-5 inhibitors improved suc- tion or maintenance of erection than did sildenafil alone
cessful sexual intercourse. The weighted mean percentage (169, 175, 179 –185).
of successful sexual intercourse attempts was 69% (range,
52% to 85%) for sildenafil versus 35.5% (range, 19% to PDE-5 Inhibitor Versus PDE-5 Inhibitor
68%) for placebo (41, 43, 44, 47, 48, 57, 66, 69, 78, 83, Successful Sexual Intercourse. Low-quality studies com-
84, 90, 93, 100, 102, 103), 68% (range, 50% to 88%) for paring tadalafil and sildenafil provided insufficient evi-
vardenafil versus 35% (range, 20% to 40%) for placebo dence to determine whether 1 treatment was more effective
(13, 108, 110, 112, 115, 116, 121, 123, 124, 126, 127, than the other (163).
130, 132), and 69% (range, 50% to 85%) for tadalafil Improvement in Erections. Evidence from 2 low-quality
versus 33% (range, 23% to 52%) for placebo (136, 137, RCTs comparing tadalafil and sildenafil was insufficient to
139 –141, 143, 144, 147, 149, 153–157, 159). In trials determine the effectiveness of 1 drug over the other (163,
enrolling men with a wide spectrum of diseases, corre- 166).
sponding values were 69% versus 36% (41, 43, 44, 47, 48,
Hormonal Treatments
57, 66, 69, 78, 83, 84, 90, 93, 100, 102, 103, 108), 68%
Evidence was gathered from 15 RCTs that evaluated
versus 35% (13, 110, 112, 115, 116, 121, 123, 124, 126,
the efficacy of hormonal therapy (oral, intramuscular, gel,
127, 130 –132), and 69% versus 33% (136, 137, 139 – cream, or patch testosterone) on ED outcomes in hypogo-
141, 143, 144, 147, 149, 153–157, 159). nadal men (186 –200).
Improvement in Erections. High-quality evidence indi-
cated that all 5 agents (sildenafil, vardenafil, tadalafil, mi-
rodenafil, and udenafil) improved erections (range, 73% to Hormonal Therapy Versus Placebo
88%) compared with placebo (range, 26% to 32%) (13, Successful Sexual Intercourse. Low-quality evidence was
40 – 43, 47– 49, 51, 54 –58, 60, 62, 64, 66, 69 –71, 74, insufficient to show whether testosterone was more effec-
77– 80, 82– 84, 91, 95, 99, 100, 106, 109 –113, 115, 116, tive than placebo (193, 200). In 1 low-quality trial, gel
118, 120, 122–124, 130, 132, 136 –144, 146, 147, 149, testosterone (50 to 100 mg) but not patch testosterone
153–157, 161, 162, 167, 168). Men assigned to PDE-5 modestly improved the frequency of successful sexual in-
inhibitors experienced improved erections compared with tercourse compared with placebo (187).
placebo recipients in trials limited to patients with specific Improvement in Erections. Low-quality evidence was
medical conditions, such as diabetes (42, 53, 54, 58, 60, insufficient to determine whether testosterone was more
104, 107, 109, 126, 127, 146, 161), depression (40, 52, effective than placebo (186, 189, 191, 193, 195, 197).
66, 91, 122), cardiovascular disease (45, 61, 64, 74, 80, 82,
95, 120, 133), prostate cancer (73, 96, 101, 111, 131, 142, Hormonal Therapy Plus PDE-5 Inhibitor Versus PDE-5 Inhibitor
158, 169), multiple sclerosis (62, 106), colorectal cancer Successful Sexual Intercourse. Low-quality evidence was
(71), schizophrenia (92), liver failure (63), and renal failure insufficient to determine whether testosterone plus a
(89, 128). PDE-5 inhibitor (sildenafil) was more effective than a
Dose. Improvement in erectile function was related to PDE-5 inhibitor (sildenafil) and placebo in improving fre-
higher dose for sildenafil (50 mg vs. 25 mg but not 100 mg quency or percentage of successful sexual intercourse at-
vs. 50 mg) and vardenafil (20 mg vs. 10 mg vs. 5 mg) but tempts (188, 190).
not tadalafil (20 mg vs. 10 mg vs. 5 mg) (53, 57, 74, 77, Improvement in Erections. Low-quality evidence was
109, 113, 114, 116, 118, 127, 161, 162, 167, 168). insufficient to determine whether testosterone plus a
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 Clinical Guidelines Hormonal Testing and Pharmacologic Treatment of Erectile Dysfunction

PDE-5 inhibitor (sildenafil) was more effective than a nitrate) is a contraindication for oral PDE-5 inhibitor
PDE-5 inhibitor (sildenafil) and placebo (188, 190, 194). therapy.
Hormonal Treatments
HARMS OF PHARMACOLOGIC TREATMENT Hormonal Therapy Versus Placebo
Oral PDE-5 Inhibitors Very-low-quality evidence showed that adverse events
PDE-5 Inhibitor Versus Placebo did not differ between oral or gel testosterone and placebo
High-quality evidence showed that men receiving (187, 193, 200). Prostate-specific antigen levels were sim-
PDE-5 inhibitors are more likely to have at least 1 adverse ilar in testosterone and placebo groups in 3 trials reporting
event compared with placebo recipients. However, the in- these data (189, 198, 199).
cidence for more serious adverse events was less than 2%,
with no difference between PDE-5 inhibitors and placebo.
Hormonal Therapy Plus PDE-5 Inhibitor Versus PDE-5 Inhibitor
The most common adverse effects were headache, flushing,
rhinitis, and dyspepsia. Less common adverse effects were Low-quality evidence showed that the incidence of ad-
visual disturbances, myalgia, nausea, diarrhea, vomiting, verse events was low and did not differ between sildenafil
dizziness, and chest pain. alone versus sildenafil plus patch, gel, or oral testosterone
(188, 190, 194). Prostate-specific antigen levels were not
significantly higher in the sildenafil plus testosterone
PDE-5 Inhibitor Versus Non–PDE-5 Inhibitor groups than the sildenafil groups in 2 trials reporting these
Sildenafil was associated with fewer adverse events data (190, 194).
than non–PDE-5 inhibitors (170 –179).

PDE-5 Inhibitor Plus Non–PDE-5 Inhibitor Versus

SUMMARY
PDE-5 Inhibitor The evidence regarding the utility of hormonal blood
Sildenafil was associated with fewer adverse events tests in identifying and affecting therapeutic outcomes for
than PDE-5 inhibitors combined with non–PDE-5 inhib- treatable causes of ED was inconclusive. The evidence
itors (169, 175, 179, 181–185). demonstrated clinical benefit associated with the use of
PDE-5 inhibitors regardless of the cause (such as diabetes,
depression, or prostate cancer) or baseline severity of ED.
PDE-5 Inhibitor Versus PDE-5 Inhibitor The magnitude of benefit increased with severity of ED.
Very-low-quality evidence showed that adverse events Higher doses of sildenafil and vardenafil were associated
did not statistically significantly differ among men receiv- with a modestly greater magnitude of benefit with respect
ing sildenafil, tadalafil, and vardenafil (163–166). to erectile function; however, this was not true for tadalafil.
NAION Overall, PDE-5 inhibitors were relatively well tolerated
Nonarteritic anterior ischemic optic neuropathy is de- and were associated with mild or moderate adverse events.
fined as ischemic optic neuropathy in the absence of tem- The incidence of adverse events did not significantly differ
poral arteritis and polymyalgia rheumatica, and “possible” among the various PDE-5 inhibitors. Evidence was insuf-
NAION is defined as papillitis, optic neuritis, or both in ficient to determine whether PDE-5 inhibitors are associ-
the absence of temporal arteritis, polymyalgia rheumatica, ated with an increased risk for NAION.
and previous optic neuropathies. Very-low-quality evi-
dence evaluating the association of NAION with the use of
PDE-5 inhibitors showed that among 4 million veterans FUTURE RESEARCH
aged 50 years or older, PDE-5 inhibitors were not associ- The quality of reporting primary studies should be
ated with an increased risk for NAION (absolute risk, 4.6 improved. Authors reporting trials in journals that publish
cases per 10 000 men per year; relative risk, 1.02 [95% CI, ED-related research should consider using the CONSORT
0.92 to 1.12]); however, PDE-5 inhibitors were associated (Consolidated Standards of Reporting Trials) Statement
with an increased risk for possible NAION (absolute risk, as a reporting guide. Some studies evaluated the dose–
2.4 cases per 10 000 men per year; relative risk, 1.34 [CI, response effect of PDE-5 inhibitors with respect to efficacy
1.17 to 1.55]) (201). and harms; however, more high-quality studies are needed.
The evidence regarding the incidence of adverse events was
Priapism
limited and inconclusive, and more high-quality head-to-
Trials evaluated for this guideline did not report pria- head trials are needed to explore differences in adverse
pism. Prolonged erection and priapism were reported in- events, especially severe adverse events. The evidence
frequently during postmarketing surveillance (202). regarding the utility of routine hormonal blood tests
Contraindications was inconclusive, given the limited number of studies
Concurrent use, regularly or intermittently, of nitrates and various methodological issues, and needs to be fur-
in any form (for example, nitroglycerin and isosorbide di- ther developed.
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 Hormonal Testing and Pharmacologic Treatment of Erectile Dysfunction Clinical Guidelines

Figure. The American College of Physicians guideline on hormonal testing and pharmacologic treatment of erectile dysfunction.

PDE-5 ⫽ phosphodiesterase-5.

RECOMMENDATIONS available. Therefore, individual preferences, ease of use,

Recommendation 1: The American College of Physi- and cost of medication are reasonable criteria to help select
cians recommends that clinicians initiate therapy with a a treatment.
PDE-5 inhibitor in men who seek treatment for erectile Recommendation 3: The American College of Physicians
dysfunction and who do not have a contraindication to does not recommend for or against routine use of hormonal
PDE-5 inhibitor use (Grade: strong recommendation; blood tests or hormonal treatment in the management of pa-
high-quality evidence). tients with erectile dysfunction (Grade: insufficient evidence to
Treatment with an oral PDE-5 inhibitor demonstrated determine net benefits and harms).
statistically significant and clinically relevant improvements
The prevalence of low testosterone varies from
in sexual intercourse and erectile function in patients with
12.5% to 36% in studies of men with ED. However,
ED. Improvement in erectile function was related to
the evidence is inconclusive about the effectiveness of
higher doses for sildenafil and vardenafil. However, higher
doses were associated with a greater risk for an adverse hormonal treatment in the management of patients with
effect. Nitrate therapy is a contraindication for treatment ED, even in patients with low testosterone levels. Trials
with oral PDE-5 inhibitors. comparing testosterone (in oral, injection, gel, patch,
Recommendation 2: The American College of Physicians and cream forms) with placebo in hypogonadal men
recommends that clinicians base the choice of a specific PDE-5 with ED were small, were of low quality, or reported
inhibitor on the individual preferences of men with erectile inconsistent effects on erectile function. Clinicians
dysfunction, including ease of use, cost of medication, and should individualize decisions to measure hormone lev-
adverse effects profile (Grade: weak recommendation; low- els on the basis of the clinical presentation (for exam-
quality evidence). ple, decreased libido, premature ejaculation, and fa-
The evidence is insufficient to compare the efficacy tigue) and physical findings (for example, testicular
and adverse effects of different PDE-5 inhibitors for the atrophy and muscle atrophy) that suggest hormonal
treatment of ED because only few head-to-head trials are abnormality.
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 Clinical Guidelines Hormonal Testing and Pharmacologic Treatment of Erectile Dysfunction

SUMMARY OF RECOMMENDATIONS AND EVIDENCE 177:1675-81. [PMID: 17437781]

8. Tsertsvadze A, Fink HA, Yazdi F, MacDonald R, Bella AJ, Ansari MT, et al.
See the Figure for a summary of the recommendations Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dys-
and clinical considerations. The Table describes the Amer- function: a systematic review and meta-analysis. Ann Intern Med. 2009;151:650-
ican College of Physicians’ guideline grading system. 61.
9. Johnson AR 3rd, Jarow JP. Is routine endocrine testing of impotent men
From the American College of Physicians and University of Pennsylva- necessary? J Urol. 1992;147:1542-3; discussion 1543-4. [PMID: 1593685]
10. Buvat J, Lemaire A. Endocrine screening in 1,022 men with erectile dysfunc-
nia, Philadelphia, Pennsylvania; University of Colorado, Aurora, Colo-
tion: clinical significance and cost-effective strategy. J Urol. 1997;158:1764-7.
rado; Atlantic Health, Morristown, New Jersey; Veterans Affairs Palo
[PMID: 9334596]
Alto Health Care System and Stanford University, Stanford, California; 11. Citron JT, Ettinger B, Rubinoff H, Ettinger VM, Minkoff J, Hom F, et al.
and Veterans Affairs Greater Los Angeles Healthcare System, Los Ange- Prevalence of hypothalamic-pituitary imaging abnormalities in impotent men
les, California. with secondary hypogonadism. J Urol. 1996;155:529-33. [PMID: 8558653]
12. Hatzichristou D, Hatzimouratidis K, Bekas M, Apostolidis A, Tzortzis V,
Note: Clinical practice guidelines are “guides” only and may not apply to Yannakoyorgos K. Diagnostic steps in the evaluation of patients with erectile
all patients and all clinical situations. Thus, they are not intended to dysfunction. J Urol. 2002;168:615-20. [PMID: 12131320]
override clinicians’ judgment. All ACP clinical practice guidelines are 13. Martin-Morales A, Meijide F, Garcı́a N, Artes M, Muñoz A. Efficacy of
considered automatically withdrawn or invalid 5 years after publication, vardenafil and influence on self-esteem and self-confidence in patients with severe
erectile dysfunction. J Sex Med. 2007;4:440-7. [PMID: 17367439]
or once an update has been issued.
14. Acar D, Cayan S, Bozlu M, Akbay E. Is routine hormonal measurement
necessary in initial evaluation of men with erectile dysfunction? Arch Androl.
Disclaimer: The authors of this article are responsible for its contents, 2004;50:247-53. [PMID: 15277002]
including any clinical or treatment recommendations. No statement in 15. Earle CM, Stuckey BG. Biochemical screening in the assessment of erectile
this article should be construed as an official position of the Agency for dysfunction: what tests decide future therapy? Urology. 2003;62:727-31. [PMID:
Healthcare Research and Quality or the U.S. Department of Health and 14550452]
Human Services. 16. Rhoden EL, Telöken C, Mafessoni R, Souto CA. Is there any relation
between serum levels of total testosterone and the severity of erectile dysfunction?
Grant Support: Financial support for the development of this guideline Int J Impot Res. 2002;14:167-71. [PMID: 12058243]
comes exclusively from the American College of Physicians’ operating 17. Rhoden EL, Telöken C, Sogari PR, Souto CA. The relationship of serum
testosterone to erectile function in normal aging men. J Urol. 2002;167:1745-8.
budget.
[PMID: 11912401]
18. Bunch TJ, Abraham D, Wang S, Meikle AW. Pituitary radiographic abnor-
Potential Conflicts of Interest: Grants received: V. Snow (Bristol-Myers malities and clinical correlates of hypogonadism in elderly males presenting with
Squibb, Centers for Disease Control and Prevention, Novo Nordisk, erectile dysfunction. Aging Male. 2002;5:38-46. [PMID: 12040974]
Merck Vaccines, Boehringer Ingelheim, Wyeth, Sanofi Pasteur), P. Shek- 19. Fahmy AK, Mitra S, Blacklock AR, Desai KM. Is the measurement of serum
elle (Pfizer). Royalties: P. Shekelle (Up-to-Date). Any financial and non- testosterone routinely indicated in men with erectile dysfunction? BJU Int. 1999;
financial conflict of interest of the group members were declared, dis- 84:482-4. [PMID: 10468766]
cussed, and resolved. 20. Akpunonu BE, Mutgi AB, Federman DJ, York J, Woldenberg LS. Routine
prolactin measurement is not necessary in the initial evaluation of male impo-
tence. J Gen Intern Med. 1994;9:336-8. [PMID: 8077999]
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, Amer-
21. Drinka PJ, Voeks S, Bauwens S, Binkley N. Sensitivity and positive predic-
ican College of Physicians, 190 N. Independence Mall West, Philadel-
tive value of clinical signs of hypogonadism in elderly men. South Med J. 1993;
phia, PA 19106; e-mail, aqaseem@acponline.org. 86:1264-5. [PMID: 8235781]
22. El-Sakka AI, Hassoba HM, Sayed HM, Tayeb KA. Pattern of endocrinal
Current author addresses and author contributions are available at www changes in patients with sexual dysfunction. J Sex Med. 2005;2:551-8. [PMID:
.annals.org. 16422853]
23. Tsujimura A, Matsumiya K, Miyagawa Y, Takao T, Fujita K, Takada S,
et al. Comparative study on evaluation methods for serum testosterone level for
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testosterone levels are significantly correlated to improvements in sexual function- Transdermal testosterone gel increases serum testosterone levels in hypogonadal
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 Annals of Internal Medicine
Current Author Addresses: Drs. Qaseem and Snow: American College Analysis and interpretation of the data: A. Qaseem, D.E. Casey Jr., M.A.
of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106. Forciea, D.K. Owens.
Dr. Denberg: 12631 East 17th Avenue, B180, Academic Office 1, Au- Drafting of the article: A. Qaseem, V. Snow, T.D. Denberg, D.E. Casey
rora, CO 80045. Jr., M.A. Forciea, D.K. Owens.
Dr. Casey: 475 South Street, PO Box 1905, Morristown, NJ 07962. Critical revision of the article for important intellectual content: A. Qas-
Dr. Forciea: 3615 Chestnut Street, Philadelphia, PA 19104. eem, V. Snow, T.D. Denberg, D.E. Casey Jr., M.A. Forciea, D.K.
Dr. Owens: 117 Encina Commons, Stanford, CA 94305. Owens, P. Shekelle.
Dr. Shekelle: 1776 Main Street, Santa Monica, CA 90401. Final approval of the article: A. Qaseem, V. Snow, T.D. Denberg, D.E.
Casey Jr., M.A. Forciea, D.K. Owens, P. Shekelle.
Statistical expertise: A. Qaseem.
Author Contributions: Conception and design: A. Qaseem, V. Snow, Administrative, technical, or logistic support: A. Qaseem.
D.E. Casey Jr., D.K. Owens. Collection and assembly of data: A. Qaseem.

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MUA / MEDACT CLINICAL PRACTICE
GUIDELINE COMMITTEE :
1. Dato' Dr. Tan Hui Meng (Chairman)
2. Dr. Yap Piang Kian (Secretary)
3. Dato' Dr. Khairullah Abdullah
4. Prof. Dr. Ramli Hassan
5. Dr. Mohd Ismail Mohd Tambi
6. Dr. Steven Chow Kim Weng
7. Dr. David Quek Kwang Leng
8. Dr. Loh Chit Sin
9. Dr. Sahabudin Raja Mohamed
10. Dato' Dr. Siti Zaliha Zainal

i
 CLINICAL PRACTICE GUIDELINES ON
ERECTILE DYSFUNCTION (ED):

Contents

SUMMARY OF GUIDELINES 2-7

(A) The key to The Diagnosis of
Erectile Dysfunction (ED)
(B) The Key to The Treatment of
Erectile Dysfunction (ED)

INTRODUCTION 10 - 14
Definition of Erectile Dysfunction (ED)
Impact of ED
Prevalence and Association with Age
Misconception of ED and
the Importance of Communication

PHYSIOLOGY OF ERECTION 16 - 17

ERECTILE DYSFUNCTION 20 - 21
Causes and Risk Factors

EVALUATION AND ASSESSMENT 24 - 36

Standard Questionnaires
Comprehensive Sexual, Medical &
Psychosocial History
Physical Examination
Laboratory Studies
Cardiac Status Evaluation

ii
PREVENTION 38

TREATMENT FOR 40 - 49
ERECTILE DYSFUNCTION (ED)
General Considerations
Altering Modifiable Risk Factors or Causes
Direct Treatment Interventions
• Sexual Counseling and Education
• Oral Agents
• Local Therapy
• Surgical Therapy

REASSESSMENT AND FOLLOW-UP 52

SHARED CARE CONCEPT 54 - 55

REFERENCES 58 - 59

iii
 SUMMARY OF GUIDELINES
SUMMARY OF GUIDELINES

(A) The key to The Diagnosis of

Erectile Dysfunction

(B) The Key to The Treatment of

Erectile Dysfunction
 SUMMARY OF GUIDELINES
Definition: "Erectile Dysfunction" is defined as the
consistent or recurrent inability of a male to attain and/or
maintain a penile erection sufficient for sexual performance.
Erectile dysfunction is a symptom based on the patient's
complaints. Objective testing (or partner reports) may be
used to support the diagnosis of erectile dysfunction.
Cultural factors and patient-physician communication will
be important determinants in defining and diagnosing the
disorder.
It is noteworthy that erectile dysfunction might not be the
primary complaint (and / or) be associated with other
sexual problems.
The rational selection of therapy for patients is only
possible following appropriate education, including
information about sexuality and all treatments for erectile
dysfunction.
In contrast to most other medical conditions, the various
treatments for ED have to be considered in the context of
traditions, ethnicity and socio-economic conditions and also
the patient and partner's preference, expectations and
psychological status. However, due to the huge diversity of
the Malaysian culture, this consensus does not attempt to
cover the details of the ethical sensitivities involved when
dealing with ED patients.

2
(A) The key to The Diagnosis of
Erectile Dysfunction
The cornerstone of clinical assessment of all men with ED is an
initial diagnostic work-up and evaluation. This evaluation
should be performed by a physician knowledgeable in male
sexual function and dysfunction with sensitivity toward
cultural, ethnic and religious factors.
The diagnostic tests utilized in the assessment of the
patient with ED may be stratified as:
• Routine and necessary: an assessment necessary in all
patients
- a comprehensive sexual, medical and psycho-social
history are the most important elements in the
evaluation of ED.
- a focused physical examination should be performed
on every patient with ED.
- Symptom intensity and impact scales could be used for
several purposes: (i) to aid clinicians in recognizing and
diagnosing the disorder, (ii) to permit patients to
acknowledge the problem in routine office settings,
and (iii) to assist researchers in the collection of
epidemiological and clinical trial data.
• Recommended: tests of proven value in the
evaluation of most patients. Their use is strongly
encouraged during initial evaluation. These would
include the fasting blood glucose and lipid profile and
an evaluation of the hypothalamic-pituitary-gonadal
axis with a testosterone assay
• Optional: tests of proven value in the evaluation of
specific patient profiles, at the discretion of the
attending physician.
• Specialized: tests of value in select patient profiles in
specialized settings.

3
 (B) The Key to The Treatment of
Erectile Dysfunction
The first step in the management of the patient with ED
is to facilitate the patient's and partner's (if available)
understanding of the condition, the results of the diagnostic
assessment and to identify patient's and partner's needs,
expectations, priorities and preferences. The identification
and recognition of ED's associated medical and psychological
factors in the individual patient must be emphasized.
Prior to direct intervention, good medical practice
recognizes the value of altering modifiable risk factors
which may benefit selected patients to various degrees.

(1) Alter Modifiable Risk Factors or Causes

These potentially modifiable risk factors and causes
include the following:
• Lifestyle and psychosocial factors
• Prescription or non- prescription drug use
• Hormone replacement therapy for hormonal
abnormalities
(2) Direct Treatment Interventions for ED
The vast majority of patients will need to consider direct
treatment options for ED. It is reasonable to discuss the
benefits, risks, and costs of the available treatment strategies
with the patient and have the patient actively participating
in the choice of therapy (shared decision making)
The treatment selected by a patient will be influenced not
only by issues such as efficacy and safety but also by the
patient's cultural, religious and economic background.
Additionally, such factors as (1) ease of administration, (2)
invasiveness, (3) reversibility, (4) cost, (5) the mechanism of
action (peripheral vs central, inducer vs enhancer) and (6)
legal regulatory approval and availability; may all critically
influence the individual patient's selection of therapy.
4
An important issue prior to the institution of any
therapy and the subsequent resumption of sexual
activity is the overall cardiovascular condition of the
patient. Is this patient able to resume the exercise of
sexual activity? If not, priority cardiovascular assessment
and intervention may be appropriate.

Sexual counseling and education

Sexual counseling and education (sex therapy,
psychosexual therapy or marital therapy) for individuals
or couples addresses specific psychological or
interpersonal factors such as relationship distress, sexual
performance concerns, dysfunctional communication
patterns and comorbid sexual conditions that are likely
to impact sexual functioning.

Oral Agents
When indicated oral therapies will probably become the
first line treatment for the majority of patients because
of potential benefits and lack of invasiveness.
Historically, prior to the advent of sildenafil, oral
medications such as yohimbine have been utilized
empirically without the support of rigorous clinical trial
data on efficacy and safety.
Sildenafil citrate, a selective inhibitor of
phosphodiesterase V (PDE V), has been approved in
many countries for the treatment of ED. In clinical trials,
sildenafil has shown broad spectrum efficacy in a
majority of patients regardless of the underlying
etiology of the ED, the baseline severity of the ED or the
age of the patient. In general, sildenafil when
prescribed appropriately, has demonstrated broad
efficacy and an acceptable safety profile.

5
 Apomorphine, a dopaminergic agonist acting at the
central nervous system level and phentolamine, an
alpha-adrenergic blocking agent with both central and
peripheral activity, are under review at the time of this
writing.
Other drugs under investigation include IC 351, a PDE V
inhibitor, melanotan II, an alpha-MSH analogue and the
combination of L-arginine and yohimbine.

Local Therapy
They include intracavernosal injection therapy,
intraurethral therapy and the use of vacuum devices.
Patients who fail oral drug therapy, who have
contraindications to specific oral drugs or who
experience adverse events from oral drugs might
consider these local therapies. Additionally, individual
preferences may direct a patient to consider local
therapies prior to or as an alternative to oral drug
therapy.
Intracavernosal injection therapy is a well established
medical therapy for ED. Injection therapy with
alprostadil or a combination of drugs is effective in a
large majority of patients, although discontinuation
rates are usually high.
The intraurethral application of alprostadil is an
alternative to injection therapy. Intraurethral therapy is
associated with significantly less efficacy than direct
injection of alprostadil.
The advantages of Vacuum Device Therapy (VCD)
include its nonpharmacologic nature, on demand use,
lack of contraindications and cost. The disadvantages of
VCD therapy include their cumbersome utilization and
minor local side-effects.

6
Surgical Therapy
Microvascular arterial bypass and venous ligation
surgery may achieve the goal of increasing arterial
inflow and decreasing venous outflow. Certain young
patients with vascular insufficiency may be candidates
for surgical cure or at least significant improvement of
their ED.
The final treatment option for ED is the surgical
implantation of a malleable or inflatable penile
prosthesis. This option is highly invasive and irreversible
and should therefore be reserved for select cases failing
other treatment modalities. When properly selected,
penile prosthesis may be associated with high rates of
patient satisfaction.

Reassessment and Follow-Up

Reassessment and follow-up should be conducted at
regular intervals with every patient receiving treatment
for ED.

7
 Page 9

INTRODUCTION
INTRODUCTION

Definition of Erectile Dysfunction (ED)

Impact of ED
Prevalence and Association with Age
Misconception of ED and
the Importance of Communication
 INTRODUCTION
Definiton of Erectile Dysfunction (ED)
Erectile dysfunction is defined as the persistent or recurrent
inability, for at least 3 months duration, to achieve and/or
maintain an erection sufficient for satisfactory sexual
performance (1,2).
Erectile Dysfunction is currently the preferred term instead
of 'impotence' as the latter term lack specificity and has
negative connotations (1).
ED does not refer to penile curvatures, spontaneous or
drug-induced prolonged erections and painful erections.
ED must also be distinguished from other sexual disorders
such as premature ejaculation, anorgasmia and lack of
desire, although ED may occur concurrently with these
other sexual disorders.
Erectile Dysfunction is a symptom based on the patient's
complaints. Objective testing (or partner reports) may be
used to support the diagnosis of erectile dysfunction, but
these measures cannot substitute for the patient's self-
report in defining the disorder or establishing the
diagnosis. The necessary reliance on patient reports implies
that cultural factors and patient-physician communication
will be important determinants in defining and diagnosing
the disorder. Consistency is a part of the definition of
erectile dysfunction. Erectile difficulties must be reported
to occur on a consistent or recurrent basis in order to
qualify for the diagnosis of erectile dysfunction. At present,
a minimum duration of three months is generally accepted
for establishment of the diagnosis.

10
Erectile dysfunction may occur regardless of the post-
pubertal age and there are many underlying aetiological
factors. It is noteworthy that erectile dysfunction might not
be the primary complaint and/or be associated with other
sexual problems.
Sexuality, including erection, is a complex biopsychosocial
process. The physician and collaborating specialists should
possess broad knowledge about human sexuality. In the
case of erectile dysfunction, problems may be lifelong or
acquired, global or situational. Adequate attention to
these details during the history will educate the often
uninformed patient regarding the complex nature of
sexuality, and prepare him for understanding treatment
and outcome realities. Patient and partner expectations,
needs and priorities will be significantly influenced by
cultural, social, ethnic, religious and national/regional
perspectives. The rational selection of therapy by patients is
only possible following appropriate education, including
information about sexuality and all treatments for erectile
dysfunction. Although not always possible on the first visit,
every effort should be made to involve the patient's
primary sexual partner early in the therapeutic process.
In contrast to most other medical conditions, the various
treatments for ED have to be considered in the context of
traditions, ethnicity and socio-economic conditions and also
the patient and partner's preference, expectations and
psychological status.

11
 Impact of Erectile Dysfunction (ED)
Erectile Dysfunction is a significant and common medical
problem affecting many men worldwide.
Cause-specific assessment and treatment of male sexual
dysfunction will require recognition by the public and the
medical community that erectile dysfunction is a part of
overall male sexual dysfunction. Erectile dysfunction is a very
common medical condition leading to fear, loss of image
and self-confidence and depression. The multifactorial
nature of erectile dysfunction, comprising both organic and
psychologic aspects, may often require a multidisciplinary
approach to its assessment and treatment. This consensus
report addresses these issues, not only as isolated health
problems but also in the context of social and individual
perceptions and expectations.
Erectile dysfunction is often assumed to be a natural
concomitant of the aging process, to be tolerated along
with other conditions associated with aging. This assumption
may not be entirely correct. For the elderly and for others,
erectile dysfunction usually occurs as a consequence of
specific illnesses or of medical treatment for certain illnesses.
Physicians, health educators, and patients and their families
are sometimes unaware of this potential complication.
Whatever the causal factors, the embarrassment among
patients and health care providers in discussing sexual
issues becomes a barrier to pursuing treatment.

12
Erectile dysfunction can be effectively treated with a
variety of methods. Many patients and health care providers
are unaware of these treatments, and the dysfunction thus
often remains untreated, compounded by its psychological
impact. Concurrent with the increase in the availability of
effective treatment methods has been increased availability
of new diagnostic procedures that may help in the
selection of an effective, cause-specific treatment. This
guideline was designed to address these issues and to
define the state of the art.

Prevalence and Association with Age

There is an estimated 100 million men having ED worldwide(3).
In the USA, the Massachusetts Male Aging Study, reported
in 1994, provide data on the prevalence of erectile
dysfunction in a general population of men who were 40
to 70 years of age(4).
The combined prevalence of all degrees of erectile
dysfunction was 52%. The category with the highest
prevalence was moderate erectile dysfunction with a rate
of 25%, followed by minimal erectile dysfunction at 17%
and complete erectile dysfunction at 10%(4).
The Cross National Prevalence Study on ED, was jointly
carried out by the National Population and Family
Development Board of Malaysia and the New England
Research Institute from the USA in 1998. Based on this
survey, ED was defined as mild (occasional), moderate
(most of the time) and complete ED (all the time)(5). The
prevalence of moderate to complete erectile dysfunction in
Malaysian men aged 40 and above is 16%. Based on these
statistics, the number of men with moderate and complete
ED is 448,000. If we include the mild ED cases, the
prevalence is raised to 60% in this survey, which is 1.68
million men aged 40 and above (5).

13
 Misconception of ED and the Importance of
Communication
A number of survey on attitudes to ED have been reported.
One recent important survey was conducted by the Market
and Opinion Research Institute (MORI) of London in 1998,
involving 10 countries, of which 4 were Asian countries(6).
The MORI findings showed from Europe, Asia to Latin
America, men share many similar views and misconceptions
about ED. Not one of the main organic risk factors is
included in the top four perceived causes of ED - even
among those who reported having the condition. Half of
men aged 40 and above, the highest proportion, consider
ED to be 'a natural part of aging'. In contrast, far fewer
(around one in five) are aware that diabetes and
hypertension - both significant risk factors - are causes of
ED. ED is not solely a psychological condition, nor an
inevitable result of aging, and communication is needed
about the underlying medical conditions that can result in
ED. The survey also highlighted the low likelihood of men
being asked by their doctors about sexual functioning.
Eighty-three percent of men aged 40 and above said their
doctors had never asked them about their sexual
functioning and 84% said they had never initiated a
discussion with their doctors about these topics. And 40%
of men aged 40 and above identified ED as the health issue
that men their age would be least likely to approach health
professionals for help with. ED came highest on the list of
12. However, two in three men agree that talking about ED
would help lift the stigma associated with the condition
and result in more men with ED being helped.

14
 15

PHYSIOLOGY OF ERECTION
PHYSIOLOGY OF ERECTION
 PHYSIOLOGY OF ERECTION
A normal erectile mechanism entails an intact nervous
system and adequate blood supply to the penis and a
competent veno-occlusive mechanism of the penis.
Penile erection and detumescence are haemodynamic
events that are regulated by corporal smooth muscle
relaxation and contraction respectively.
In the flaccid state, a dominant sympathetic influence
prevails, and the arteries and corporal smooth muscle are
tonically contracted. There is a constant but minimal blood
flow into the lacuna spaces (sponge-like penile tissue).
After sexual stimulation, parasympathetic activity increases
resulting in vasodilatory effects. This decreases the
peripheral resistance bringing about tremendous increase
in blood flow through the cavernous and helicine arteries.
Relaxation of corporal smooth muscle increases compliance
and the expansion of the lacuna spaces compresses the
outflow veins (subtunical veins) resulting in maintenance of
erection.
Detumescence occurs when sympathetic activity (following
orgasm) increases the tone of the helicine arteries and the
corporal smooth muscle.
Normal erectile process begins with sexual stimulation in
the brain (perception, desire, etc) from where impulses are
transmitted via the spinal cord and the pelvic nerve to the
penile corpus cavernosum (corporal smooth muscle).

16
In the corpus cavernosum, a gaseous neurotransmitter, nitric
oxide (NO) acts as a physiological mediator, activating the
enzyme, guanylate cyclase through the cell membrane of
the corporal smooth muscle cells. This enzyme guanylate
cyclase is responsible for converting guanosine triphosphate
(GTP) into cyclic guanosine monophosphate (cGMP). Cyclic
GMP then induces calcium to leave the corporal smooth
muscle cells. These cells relax syncitially and penile erection
results. Penile erection is maintained by continuous central
and local stimuli. The local stimuli act through the sacral
cord reflex pathway. When sexual stimulation is terminated,
the NO stimulus is removed or ceased, cGMP is no longer
produced and the erection subsides with cGMP being
degraded by the enzyme phosphodiesterase type V (PDE V).

17
 page 19

ERECTILE DYSFUNCTION
ERECTILE DYSFUNCTION

Causes And Risk Factors

 ERECTILE DYSFUNCTION
Erectile dysfunction can occur as a result of a neurological
disorder affecting the central nervous system or anywhere
in the erection pathway, an arterial disorder, as in
generalised arteriopathy or localised as seen after pelvic
surgery or radiotherapy, or a defective veno-occlusive
mechanism, either congenital or acquired. Less commonly,
ED can result from endocrinological factors (abnormal
hormonal milieu) and penile or cavernosal factors (e.g.
fibrosis, curvatures).
Psychological processes such as depression, anxiety, and
relationship problems can impair erectile functioning by
reducing erotic focus or otherwise reducing awareness of
sensory experience. This may lead to inability in initiating
or maintaining an erection. Aetiologic factors for erectile
disorders may be categorized as neurogenic, vasculogenic,
psychogenic, endocrinologic or cavernosal, but most
commonly, they appear to derive from various
combinations of these factors.

Causes and Risk Factors

Psychogenic
Performance anxiety
Loss of attraction
Relationship difficulties
Stress
Psychiatric
Anxiety disorders
Depression

20
Neurogenic
Trauma
Myelodysplasia (spinal bifida)
Intervertebral disc lesions
Diabetes mellitus
Alcohol abuse
Pelvic surgery
Endocrine
Hyperprolactinaemia
Hypo- and hyperthyroidism
Hypogonadism leading to testosterone deficiency
Arteriogenic
Hypertension
Smoking
Diabetes mellitus
Hyperlipedaemia
Peripheral vascular disease
Penile disorders
Peyronie's disease
Drugs and substance abuse
Narcotics
Antihypertensives (thiazides, beta blockers, methyldopa,
spironolactone)
Antidepressants and tranquilisers
NSAID's
H2 antagonists (cimetidine)
Miscellaneous drugs (ketoconazole, hyoscine,
anti-cancer agents)

21
 page 23

EVALUATION AND ASSESSMENT

EVALUATION AND
ASSESSMENT

Standard Questionnaires
Comprehensive Sexual, Medical &
Psychosocial History
Physical Examination
Laboratory Studies
Cardiac Status Evaluation
 EVALUATION AND ASSESSMENT
Patients usually do not volunteer their problem with ED.
Screening should be employed if the doctor suspects that
his patient has ED. Screening is advised for males around 40
years of age, especially if they have risk factors viz.:
a. Diabetes b. Hypertension
c. Hyperlipidaemia d. Heavy smoking
e. Cardiac disease f . Depression

Standard Questionnaires
An acceptable screening tool using a 5 question
questionnaire is as follows (see Table I) (7,8)
Table I (7,8)

1. How often were you able to get an erection during

sexual activity?

Almost A few times Sometimes Most times Almost

never or (much less (about half (much more always or
never than half the time) than half always
the time) the time)

1 2 3 4 5

2. When you had erections with sexual stimulation,

how often were your erections hard enough for
penetration (entering your partner)?

Almost A few times Sometimes Most times Almost

never or (much less (about half (much more always or
never than half the time) than half always
the time) the time)

1 2 3 4 5

24
 3. When you attempted intercourse, how often were
you able to penetrate (enter) your partner?

Almost A few times Sometimes Most times Almost

never or (much less (about half (much more always or
never than half the time) than half always
the time) the time)

1 2 3 4 5

4. During sexual intercourse, how often were you

able to maintain your erection after you had
penetrated (entered) your partner?

Almost A few times Sometimes Most times Almost

never or (much less (about half (much more always or
never than half the time) than half always
the time) the time)

1 2 3 4 5

5. During sexual intercourse, how difficult was it to

maintain your erection to completion of
intercourse?

Extremely Very Difficult Slightly Not difficult

difficult difficult difficult

1 2 3 4 5
* All questions are preceeded by the phrase ' Over the past 4 weeks.'

Instructions for Scoring: Add the scores for each item 1-5 (total possible score =25). ED Severity Classification :
Total score 5-10 (severe); 11-15 (moderate); 16-20 (mild); 21-25 (normal).

Note: The following questions should only be completed by individuals who have been sexually active and have
attempted sexual Intercourse in the past 3 months. For sexually inactive individuals, the questionnaire may be
answered for the last period of time (3 months or longer) during which the individual was sexually active.

25
 Should the patient be found to have ED from the above
questionnaire (i.e. total score 20 or less, a subjective
bothersome questionnaire (Table II) may be useful:
Table II (9)

Very Rather Mixed, Rather Very

dissatisfied dissatisfied about satisfied satisfied
equally
satisfied

If you were
to spend
the rest of
your life
with your
erectile 1 2 3 4 5
condition,
the way it
is now,
how would
you feel
about that?

For patients suspected to be suffering from depression, a

two-question screening tool (as shown in Table III) may be
useful:

Table III (10)

• During the past month, have you often been

bothered by feeling down, depressed or hopeless?

• During the past month, have you often been

bothered by little interest or pleasure doing things?

Although normal aging can result in a decline in sexual

performance, persistent erectile dysfunction should be
investigated. The appropriate evaluation of all men with
erectile dysfunction should include a comprehensive sexual,
medical and psychosocial history, physical examination and
focused laboratory studies.

26
Comprehensive Sexual, Medical &
Psychosocial History
A sexual history is needed to accurately define the patient's
specific complaint and to distinguish between true erectile
dysfunction, changes in sexual desire, and orgasmic or
ejaculatory disturbances.
The patient should be asked specifically about perceptions of
his erectile dysfunction, including the nature of onset,
frequency, quality, and duration of erections; the presence of
nocturnal or early morning erections; and his ability to
achieve sexual satisfaction. Psychosocial factors related to
erectile dysfunction should be probed, including specific
situational circumstances, performance anxiety, the nature of
sexual relationships, details of current sexual techniques,
expectations, motivation for treatment, and the presence of
specific discord in the patient's relationship with his sexual
partner. The sexual partner's own expectations and
perceptions should also be sought since they may have an
important bearing on diagnosis and treatment
recommendations.
Other essential components of history taking should cover
the following :
• Altered sexual desire
• Ejaculation
• Orgasm
• Sexual related genital pain
• Lifestyle factors
• Smoking

27
 • Chronic medical illness :
- hypertension
- diabetes mellitus
- atherosclerosis and cardiovascular risk factors
including hyperlipidaemia
- renal and hepatic dysfunction
• Pelvic / perineal / penile trauma :
- bicycling injury
- motor vehicle accident etc.
• Medications / recreational drug use :
- antihypertensives
- antidepressants
- alcohol
- cocaine
• Past surgery :
- radical prostatectomy
- laminectomy
- vascular bypass surgery
• Neurological illnesses :
- spinal cord injury
- multiple sclerosis
- lumbosacral disc injury
• Endocrinological illnesses :
- hypogonadism
- hyperprolactinaemia
- thyroid disease
• Sexually transmitted diseases :
- gonorrhoea
• Psychiatric illnesses :
- depression
- anxiety

28
Psychosocial history should cover symptoms of depression
(Table III), altered self esteem, past and present partner
relationships, past and present sexual practices, history of
sexual trauma / abuse, job and social position satisfaction,
economic position and educational attainment.

Sample Psychosocial Assessment Questions

• "Do you suffer from depression or other mood

problems?"

• "How are your relationships with family members and

other important people in your life?"

• "Do you have any difficulties in your work situation?"

(if applicable)

• "How is your current relationship with your partner?

How was it in the past?"

• "Were you ever the victim of sexual abuse (forced to

have sex)? If yes, what effect did this have on you
then or now?"

29
 Sample Sexual History Questions

• "Many men of your age start to experience sexual

difficulties, if you have such a problem, I would be
happy to discuss this further":

• "Could you describe your sexual problem?"

• "When did your erection problems begin?" "Please

describe the circumstances."

• "How was your sexual functioning prior to this time?"

• "How are your erections that you achieve with

masturbation or those that occur with sleep or upon
awakening early in the morning?" (The discussion of
masturbation is a sensitive issue that is often
influenced by cultural and religious perspectives).

• "How strong is your desire for sex, now and in the

past?"

• "Do you have difficulties in ejaculating, either too fast

or slow, either now or in the past?"

• "Is your partner able to become aroused and reach

climax when you have sex together?"

• "What has been your partner's reaction to your

current sexual difficulties?"

• "What has been the effect of your sexual difficulties

on your partner relationship?"

• "What has been the effect of your sexual difficulties

on your overall lifestyle?"

30
Physical Examination include the following:
• General Appearance
Secondary sexual characteristics
• Cardiovascular System
Blood pressure
Peripheral pulses
• Neurological system
Reflexes, bulbocavernosus reflex
Penile sensation
• Genito-urinary system
Penile examination : circumcision, deformity, plaques,
phimosis, hypoaesthesia
Testes examination : size and consistency
Rectal examination : sphincter tone and prostate examination

Laboratory Studies
The physician must tailor the laboratory work up based
on patient complaints and risk factors outlined by the
history and physical examination. One should also take into
consideration the cost and availability of testing resources.
Recommended Tests
• Urine analysis
• Fasting blood glucose
• Testosterone
If indicated - full blood count, lipid profile, renal profile,
serum prolactin, LH, TSH, free T4, liver profile, PSA.
Further Specialised Tests include :
• Office Intracavernosal Injection Tests
• Nocturnal Penile Tumescence (NPT) Tests
• Penile Doppler Ultrasonography
• Dynamic Infusion Cavernosometry, Cavernosography
• Angiography

31
 Cardiac Status Evaluation (11)
• Sexual activity is no more stressful to the heart than
when compared with a number of other natural daily
activities e.g. walking one mile on the level in 20
minutes.

• The cardiac risk of sexual activity, in patients

diagnosed with cardiovascular disease, is minimal in
properly assessed and advised patients.

• Erectile dysfunction (ED) is common, affecting 10% of

men aged 40-70 years and increases in frequency with
age.

• ED and cardiovascular disease share many of the same

risk factors and often coexist.

• ED in patient with cardiovascular disease, should be

identified by routine questioning in general practice.
Modern therapies can restore a sexual relationship in
the majority of patients with ED and can lead to a
substantial improvement in quality of life.

• The majority of patients assessed to be at low or

intermediate cardiac risk, as defined in Table V, can be
effectively managed in primary care. Primary care
treatment for ED in patients defined as high risk can
be initiated following a specialist opinion and/or
confirmation that the patient's cardiovascular
condition is stable.

• There is no evidence that currently licensed

treatments for ED add to the overall cardiovascular
risk in patients with or without cardiovascular disease.

32
Table IV: METs Equivalents (12)

Daily Activity METs Score Rating

Sexual intercourse with

long-standing partner
- lower range ('normal') 2-3
- upper range (vigorous activity) 5-6

Lifting and carrying objects

(9-20kg)
4-5

Walking one mile in 20 minutes

3-4
on the level

Golf 4-5
Gardening (digging) 3-5
DIY, wallpapering, etc 4-5
Light housework
e.g. ironing, polishing
2-4

Heavy housework
e.g. making beds, 3-6
scrubbing floors

33
 Table V: Management Algorithm according to
Graded Risk (11)

Grading of Cardiovascular ED Management

Risk Status upon Recommendations
Presentation for the Primary
Care Physician

Low Risk • Controlled hypertension • Manage within the

• Asymptomatic ≤ 3 risk primary care setting
factors for CAD -
excluding age & gender • Review treatment
• Mild valvular disease options with patient
• Mild stable angina and their partner
• Post successful (where possible)
revascularisation

Intermediate • History of recent MI or • Specialised evaluation

Risk CVA (less than 6 weeks) recommended (e.g.
• ≥ 3 risk factors for CAD - exercise test for angina,
excluding age and echocardiogram for a
gender murmur)
• LVD/CHF (I, II) • Patient to be placed in
• Murmur of unknown high or low risk category
origin depending upon
• Moderate stable angina outcome of testing

High Risk • Unstable or refractory • Refer for specialised

angina cardiac evaluation and
• Uncontrolled management
hypertension
(SBP > 180mmHg) • Treatment for ED to be
• CHF (III, IV) deferred until cardiac
• Recent MI*, CVA condition stabilised
• High risk arrhythmias and/or specialist
• Hypertrophic evaluation completed
cardiomyopathy
• Moderate/severe valve
disease

* Recent MI = within last

14 days

34
Glossary of Terms: New York Heart
Association
Classification of CHF

- Coronary Artery Disease, CAD Class I Patients with cardiac

disease but with no
- Myocardial Infarction, MI limitation during
- Cerebral Vascular Accident, CVA ordinary physical
activity
- Congestive Heart Failure, CHF
Class II Slight limitations
- Left VentricularDysfunction, LVD caused by cardiac
disease. Activity such
- Systolic Blood Pressure, SBP
as walking causes
- Erectile Dysfunction, ED dyspnoea.
Class III Marked limitation.
Symptoms are
provoked easily,
e.g. by walking on
the flat
Class IV Breathlessness at rest

35
 Management algorithm of ED in the patient with
diagnosed cardiovascular disease (11)

ASSESSMENT
• Consider level of normal daily activities compared with the level of
exertion associated with resuming sexual activity (Table IV)
• Conduct routine ED investigations
• Grade as low, intermediate or high risk using simple criteria in Table V

IS IT SAFE FOR THE PATIENT TO RESUME SEXUAL ACTIVITY?

YES NO

ED TREATMENT OPTIONS ACTION

- Oral sildenafil • Optimise management of the
- Injectable alprostadil cardiovascular disease
- Intraurethral alprostadil
- Vacuum constriction devices
• Discuss with the patients, and if
- Psychosexual/couple therapy possible the parther, the reasons
for management decision
• KEY CONSIDERATIONS • Consider psychosexual/couple
1. Informed patient choice therapy
- discuss advantages and disadvantages
of all available options with patient • Re-assess cardiovascular status
and partner (where possible) and reconsider treatment of
2. Patients taking warfarin the ED.
- consider increased risk of bruising with
injectable alprostadil and bleeding
with intraurethral alprostadil
- consider increased risk of haematoma
with vacuum constriction devices
3. Patients taking nitrates
- if patient is on nitrate therapy, stop
his nitrate before sildenafil is
initiated.

FOLLOW-UP
• Arrange initial follow-up to assess efficacy of therapy and tolerability of patient to
resuming sexual activity
• After initial follow-up ED assessments can be conducted as routine checks for
cardiovascular symptoms - discuss compliance and any recurrence of spontaneous
erections.
36
 page 37

PREVENTION
PREVENTION
 PREVENTION
ED is not an inevitable consequence of aging. Modifying
any known risk factors can help reduce the risk of ED. This
includes regular review of the use of any drug that may
cause ED. Lack of sexual knowledge and anxiety about
sexual performance are common contributing factors to
erectile dysfunction. Education and reassurance may be
helpful in preventing the cascade into serious erectile
failure in individuals who experience minor erectile
difficulty due to medication or common changes in erectile
functioning associated with chronic illnesses or with aging.
Contrary to popular belief, an active sex life does not
contribute to ED.

38
page 39

TREATMENT FOR ERECTILE DYSFUNCTION (ED)

TREATMENT FOR ERECTILE
DYSFUNCTION (ED)

General Considerations
Altering Modifiable Risk Factors or Causes
Direct Treatment Interventions
• Sexual Counseling and Education
• Oral Agents
• Local Therapy
• Surgical Therapy
 TREATMENT FOR ERECTILE
DYSFUNCTION (ED)
General Considerations
The first step in the management of the patient with ED is
to facilitate the patient's and partner's (if available)
understanding of the condition, the results of the
diagnostic assessment and to identify patient's and
partner's needs, expectations, priorities and preferences.
The identification and recognition of associated medical
and psychological factors in the individual patient must be
emphasized.
Clearly, the selection of therapy is strongly influenced by
personal, cultural, ethnic, religious and economic
(affordability) factors. The presentation and stratification
of therapies may therefore vary from individual to
individual, culture to culture, religious persuasion to
religious persuasion and from one economic tier to
another. Sensitivity to these factors is important in
determining the long-term success of any selected
therapeutic course. Prior to direct intervention, good
medical practice recognizes the value of altering
modifiable risk factors, and this step alone may be of some
value in selected patients.

40
Altering Modifiable Risk Factors or Causes
Potentially modifiable risk factors and causes include the
following:
1. Lifestyle and psychosocial factors (e.g. partner conflict,
cigarette smoking, substance abuse or depression, sexual
misinformation)
2. Prescription or non-prescription drug use (e.g. most
commonly antihypertensives, psychotropic drugs
including antidepressants and anti-psychotics, as well as
anti-arrhythmics, anti-androgens and steroids)
3. Appropriate therapy for hormonal abnormalities (e.g.
hypogonadism, hyperprolactinemia)
Although the quantitative benefits of altering modifiable
risk factors or causes, particularly when associated with the
need to modify behaviour, are not documented, good
clinical practice mandates attention to these issues either
prior to or along with direct therapies as a key to treating
ED. Alterations in drug dosages or classes may be of
significant benefit in select patients but this should be
coordinated with the primary physician managing, for
example, the patient's hypertension or depression.
Lifestyle factors such as relationship issues or substance
abuse may require priority management specific to the
particular issue.

41
 Appropriate therapy for hormonal abnormalities
Appropriate therapy in the presence of a documented
deficiency (e.g. androgen deficiency and hypogonadism),
may not necessarily improve ED and thus one may need to
consider direct intervention therapy even in this patient
population. The issue of androgen replacement therapy is
complicated. There is a statistical decline of testosterone
levels, particularly free testosterone, in aging men. While
this fall is only moderate, aging men show clinical signs of
hypogonadism (loss of muscle mass / strength, reduction in
bone mass and an increase in visceral fat).
Testosterone replacement or supplement therapy may
improve bone mass, muscle mass, strength and frequently
nocturnal erections as well in this age group. However, the
effects on sexual function, mood and cognition are less
clear but may be meaningful in certain men. The
identification of that segment of the aging male
population that might possibly benefit from androgen
supplementation remains difficult. Questions still remain
regarding the magnitude and longevity of these potential
beneficial effects. More importantly, the long-term risks of
androgen therapy in this age group really are now known,
especially in the areas of cardiovascular and prostate
diseases(13). Despite increasing evidence that patients with
subnormal or borderline normal levels of testosterone
could be considered as candidates for testosterone
treatment, until more information is available, testosterone
and androgens in general should not be recommended as
supplemental therapy.

42
Direct Treatment Interventions
The patient and his partner (if available) should be
informed of all of the available and acceptable treatment
options applicable to his clinical condition and the related
benefits, risks, and costs of each modality. The development
of ED can significantly affect the quality of life, but it is not
a life-threatening disease. Consequently, it is reasonable to
discuss the benefits, risks, and costs of the available
treatment strategies with the patient and have the patient
actively participate in the choice of therapy (shared decision
making). An important issue prior to the institution of any
therapy and the subsequent resumption of sexual activity is
the overall cardiovascular condition of the patient. Is this
patient able to resume the exercise of sexual activity? If
not, priority cardiovascular assessment and intervention
may be appropriate. The partner's sexual function if
possible should be considered prior to initiating therapy.
The vast majority of patients will need to consider direct
treatment options for ED. Only those pharmacological
treatments that have been thoroughly tested in
randomized clinical trials, with subsequent publication of
results in peer-reviewed literature, should be considered
for general use. Long-term follow-up of all treatment
options must be performed to demonstrate durability and
continued efficacy and safety as well as patient and partner
acceptability. Additionally, new treatment options that
enter the arena will need to meet not only the above
efficacy and safety criteria but also should be compared to
available therapies for cost-effectiveness.

43
 The treatment selected by a patient, will be influenced not
only by issues such as efficacy and safety, but also by the
patient's cultural, religious and economic background.
Additionally, such factors as (1) ease of administration,
(2) invasiveness, (3) reversibility, (4) cost and (5) the
mechanism of action (peripheral vs. central, inducer vs.
enhancer) and (6) availability, may critically influence the
individual patient's selection of therapy. As previously
mentioned, affordability is a prime factor in influencing
patient acceptance and utilization of a specific therapy
for ED.
The use of the internet to prescribe therapies for erectile
dysfunction should be strongly discouraged since it fails to
meet the need for direct physician-patient contact in the
assessment of all patients presenting with this complain.

• Sexual Counseling and Education

Sexual counseling and education (sex therapy, psychosexual
therapy or marital therapy) for individuals or couples
addresses specific psychological or interpersonal factors
such as relationship distress, sexual performance concerns,
dysfunctional communication patterns and comorbid sexual
conditions that are likely to impact sexual functioning.
Modified sex therapy may serve as an adjunct to the other
direct therapies for ED to address psychological reactions to
these medical or surgical therapies which may be perceived
as temporary, unnatural or unacceptable by the patient
and / or partner. The advantages of psychosexual therapy
include its noninvasive nature and broad applicability. The
disadvantages of psychosexual therapy include its variable
efficacy in the treatment of ED, cost and acceptability by
the patient or the couple.

44
• Oral Agents
When indicated oral therapy will probably become the
first line treatment for the majority of patients because of
potential benefits and lack of invasiveness. Historically,
prior to the advent of sildenafil, oral medications such as
yohimbine have been utilized empirically without the
support of rigorous clinical trial data on efficacy and
safety. Oral agents may act centrally as dopaminergic
agonists; some may act both centrally and peripherally,
like the alpha adrenergic blockers; and yet others like the
phosphodiesterase type V (PDE V) inhibitors or nitric oxide
(NO) precursors, act only peripherally. Sildenafil citrate, a
selective inhibitor of PDE V(14), has been approved in many
countries for the treatment of ED. Phosphodiesterases are
the enzymes responsible for the breakdown of the
intracellular second messenger of nitric oxide i.e. cyclic
guanosine monophosphate (cGMP)(15,16) and PDE V is the
predominant isoform of phosphodiesterase found in the
corporal smooth muscle(15,17). In clinical trials, sildenafil has
shown broad spectrum efficacy in a majority of patients
regardless of the underlying aetiology of the ED, the
baseline severity of the ED or the age of the patient(18).
Recently, studies on patients with specific disorders such as
diabetes mellitus, hypertension, spinal cord injury, multiple
sclerosis and depression have also shown sildenafil to be
effective(3,19,20,21,22). Side effects include transient headache,
flushing, dyspepsia, nasal stuffiness and transient altered
color vision (due to PDE VI inhibition)(18). A relatively small
number of deaths have been reported in association with
sildenafil usage but the specific relationship to the drug is
uncertain(3). This underscores the need for cardiovascular
assessment prior to the treatment of ED and regular
follow up. A small percentage of these deaths occurred
with concomitant use of nitrates and are presumed to be
due to severe hypotension that may ensue following this
combination(11). In addition, patients with possible or

45
 active coronary heart disease or other significant
cardiovascular diseases such as aortic stenosis should
undergo cardiac evaluation and management prior to
considering sildenafil usage(11). To date, there is no
physiological reason to indicate sildenafil exerts a direct
effect on the myocardium(3). In general, sildenafil when
prescribed appropriately has demonstrated broad
efficacy and an acceptable safety profile.
Apomorphine is a dopaminergic agonist acting at the
central nervous system level. It was initially administered
subcutaneously. However intolerable adverse events
prompted the development of a sublingual pill.
Apomorphine has shown efficacy in placebo-controlled
fixed and dose escalation studies(23). In responders,
erection usually begins within 20 minutes. Its principal
adverse effect is nausea which is usually minimal at lower
dosages (2mg and 4 mg). Other adverse effects are
dizziness, sweating, somnolence and yawning as well as
rarely, syncope.
Phentolamine is an alpha adrenergic blocking agent with
both central and peripheral activity. In placebo controlled
studies, it has been found to have modest efficacy in
patients with mild to moderate ED. Adverse reactions
include dizziness, nasal stuffiness and tachycardia. These
events are minimal at the usual dose of 40mg(24,25).
Other drugs under investigation include IC 351 a more
selective and longer acting PDE V inhibitor; melanotan II,
an alpha-MSH analogue and the combination of
L-arginine and yohimbine.
In the future, combination oral therapy may be employed
for potentially additive or synergistic actions (e.g.
sildenafil and apomorphine). However, clinical trials are
required to evaluate not only efficacy but also safety.

46
 The advantages of oral drug therapy include broad
patient acceptance, ease of administration and
relative efficacy. The disadvantages include specific
contraindications such as the concomitant use of nitrates
with respect to sildenafil and the relative cost.

• Local Therapy
Local therapy include intracavernosal injection therapy,
intraurethral therapy and vacuum device therapy.
Patients who fail oral drug therapy, who have
contraindications to specific oral drugs or who experience
adverse events from oral drugs might consider these.
Additionally, individual preferences may direct a patient
to consider local therapy prior to or as an alternative to
an oral drug therapy.
Intracavernosal Injection Therapy
Intracavernosal injection therapy is a well-established
medical therapy for ED. The delivery, by penile injection,
of agents that directly relax corporal smooth muscle such
as papaverine, phentolamine or more recently alprostadil
(prostaglandin E1) is associated with broad efficacy and
relative safety. Alprostadil is widely approved worldwide
as alprostadil sterile powder or alfadex. Combinations of
agents have established efficacy and safety based upon
common usage. Injection therapy with alprostadil or a
combination of drugs is effective in a large majority of
patients, although discontinuation rates are usually
high(26). The side effects associated with injection therapy
are primarily local and include pain, priapism and
scar tissue formation over time. This therapy is
contraindicated in patients with sickle cell anemia and
with other conditions that predispose them to priapism.
The advantages of penile injection therapy include broad
efficacy, relative safety and the rapidity of onset of
action. The disadvantages include invasive local
administration and relative cost.

47
 Intraurethral Therapy
The intraurethral application of alprostadil is an
alternative to injection therapy. Intraurethral therapy is
associated with significantly less efficacy than direct
injection of alprostadil. The efficacy may be increased by
using an elastic band placed at the base of the penis. The
associated side effects include pain as well as systemic
hypotension. The advantages of intraurethral therapy
include its less invasive nature. The disadvantages include
local as well as systemic side-effects, relative cost and
partner related vaginal irritation.
Transdermal penile delivery of vasoactive drugs is
currently under investigation at the time of writing.

Vacuum Constriction Devices

Vacuum constriction devices (VCD) are widely available
and may be sold over-the-counter (without prescription)
in some countries. They are of appeal to a group of men
that are not interested in pharmacological therapy or
have specific contraindications to these therapies. VCD's
apply a negative pressure to the pendulous penis, thus
drawing blood into the penis, which is then retained by
the application of an elastic band at the base of the
penis. The side effects associated with VCD therapy
include penile pain, penile numbness, bruising and
retarded ejaculation. The advantages of VCD therapy
include its nonpharmacologic nature, on demand use,
lack of contraindications and cost. The disadvantages of
VCD therapy include their cumbersome utilization and
minor local side effects (27).

48
• Surgical Therapy
Vascular Surgery
Microvascular arterial bypass and venous ligation surgery
may achieve the goal of increasing arterial inflow and
decreasing venous outflow. Certain young patients with
vascular insufficiency may be candidates for surgical cure
or improvement of ED. These patients must be evaluated
by specialized testing and should be treated by an
experienced surgeon, usually in research centres.

Penile implants
The final treatment option for ED is the surgical
implantation of a malleable or inflatable penile
prosthesis. This option is highly invasive and irreversible
and should therefore be reserved for select cases failing
other treatment modalities. However, under unique and
uncommon circumstances a penile implant could be
selected as a primary option. When properly selected,
penile prostheses may be associated with high rates
of patient satisfaction(28). Penile implant surgery is
uncommonly associated with prosthesis infection but
such cases usually require explanation and may result in
severe scarring and penile deformity. The advantages of
penile prosthesis implantation include relative efficacy
and a 'long term solution'. The disadvantages of penile
prostheses include irreversibility, invasiveness, surgical
complications and mechanical failure.

49
 Page 51

REASSESSMENT AND FOLLOW-UP

REASSESSMENT AND
FOLLOW-UP
 REASSESSMENT AND FOLLOW-UP
Reassessment and follow-up should be conducted at
regular intervals (the recommendation is six-monthly) for
every patient receiving treatment for ED. The goals of
follow-up include:
1. The need for dose titration or substitution of
another treatment intervention may be considered
when necessary. Patients may change treatment
preferences, seek new information, or wish to
reevaluate their current treatment choices.

2. Patient communication. Patients may have concerns

regarding treatment administration, other sexual
dysfunction problems (e.g. premature ejaculation),
partner issues (e.g. anorgasmia) or lifestyle factors
(e.g. emotional stress) and these should be
addressed.

3. Patients may change medication regimens, either

for ED or a concomitant medical disorder. The
possibility of adverse drug reactions or drug
interaction effects with oral medications for ED
should be carefully monitored.

4. General medical and psychosocial reassessment

should occur at regular intervals, depending upon
the patient's health, physical and psychosocial
needs. Follow up also provides an additional
opportunity for patient education.

52
Page 53

SHARED CARE CONCEPT

SHARED CARE CONCEPT (29)
 SHARED CARE CONCEPT(29)
Currently only about 10% of the ED sufferers seek
treatment. This low figure is expected to change radically
in the near future because of the increasing population of
the aging men, who are better educated, more affluent
and have higher expectations of maintaining good quality
of life.
A high percentage of this graying population has
concomitant disease leading to ED. With widespread
awareness that ED is a disease and is currently easily
treatable with effective oral medication and many other
easy-to-administer therapies, a huge population of
sufferers will be expected to come forward to seek
treatment. The primary care physicians who are the
frontline health care providers will be exposed to most of
the ED patients. These primary care physician who
understand the background of their patients will be the
ideal persons to raise the subject of ED and proceed on to a
comprehensive work-up which entails a full medical and
sexual history, relevant physical examination and order
focussed laboratory tests.
Most of today's easy-to-administer treatment options, can
be handled by the primary care physicians. The urologist
and other related specialists will play a supportive role in
handling ED patients who have failed simple therapies and
are keen to try more invasive forms of treatments. The
urologists or other related specialists will also provide
backup for any treatment complications, handle any
abnormal clinical or laboratory results needing further
evaluation and also carry out a full diagnostic work-up on
the patient's request or for medico-legal purposes (See
Table ).

54
A share care approach to the management of ED
patients will be most productive and beneficial to
the patient, health care provider and health care
financier.

Shared Care Management in ED

Indications for referral to specialists :-

• Contraindication to oral medication
• First line treatment failure
• Unexpected clinical and laboratory results
• Complicated psychiatric or psychosexual disorder
• Complicated endocrinopathy
• Significant penile curvature
• Pelvic / perineal trauma
• Cases requiring vascular or neurosurgical
intervention
• Primary ED
• Request for specialized evaluation
• Medico legal issues

55
 Page 57

REFERENCES
REFERENCES
 REFERENCES
1. NIH Consensus Development Panel on Impotence. Impotence. JAMA. 1993;
270(1):83-90.
2. Montague DK, Barada JH, Belker AM, et al. Clinical guidelines panel on erectile
dysfunction: summary report on the treatment of erectile dysfunction. J Urol.
1996; 156:2007-2011.
3. Pfizer. Data on file.
4. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and
psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol.
1994; 151:54-61.
5. Tambi I. Epidemiology of ED in Malaysia. Highlights of Symposium at 5th Asian
Congress on Sexology. Nov 1998; Seoul Korea.
6. Corrado M. Man and Erectile Dysfunction: A Survey of Attitudes in 10
Countries. Survey by Market & Opinion Research International. Presented at
The 8th World Meeting on Impotence Research, August 1998; Amsterdam, The
Netherlands
7. Rosen RC, Riley A, Wagner G, et al. The International Index of Erectile Function
(IIEF): A Multidimensional Scale for Assessment of Erectile Dysfunction. Urology
1997; 49:822-830.
8. Cappelleri JC, Rosen RC, Smith MD, et al. Diagnostic Evaluation of the Erectile
Function Domain of the International Index of Erectile Function. Urology 1999;
54:346-351.
9. Wagner G, et al. Committee on 'Symptom Scores and Quality-of-Life'.
Presented at 1st International Consultation on Erectile Dysfunction, July 1999;
Paris.
10. Whooley MA, Avins AL, Miranda J, et al. Case-finding Instruments for
Depression. Two questions are as good as many. J. Gen. Intern. Med.
1997;12:439-445.
11. Jackson G, et al. A Systematic Approach to Erectile Dysfunction in the
Cardiovascular Patient - A Consensus Statement. Int. Jrnl. of Clin. Pract. 1999;
53(6):445-451.
12. Eds Wilson PK, Farday PS, Froelicher V. Cardiac Rehabilitation - Adult Fitness
and Exercise Testing. Formulating the exercise prescription. Chapter 14.
Philadelphia: Lee & Fabiger 1981:333-353. National Heart Association of
Malaysia - Consensus Statement on Use of Sildenafil in Patients with
Cardiovascular Disease November 1999
13. Lei CCM, Kim YC. Hormonal Therapy for Erectile Dysfunction. APSIR Book on
Erectile Dysfunction. Chapter 9. APSIR 1999:113-117.

58
14. Boolell M, Allen MJ, Ballard SA, et al. Sildenafil: an orally active type 5 cyclic
GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile
dysfunction. Int. J. Impotence Res. 1996; 8(2);47-52
15. Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of
multiple isoforms. Physio. Rev. 1995; 75:725-748.
16. McDonald LJ, Murad F. Nitric oxide and cyclic GMP signaling. Proc. Soc. Exp.
Biol. Med. 1996; 211:1-6.
17. Andersson KE, Wagner G. Physiology in penile erection. Physiol. Rev. 1995;
75:191-236.
18. Morales A, Gingell, Collins M, et al. Clinical safety of Oral Sildenafil Citrate
(ViagraTM) in the treatment of Erectile Dysfunction. Int. J. Impotence Res.
1998; 10:69-74.
19. Guiliano F, Hultling C, El Masry WS, et al. Randomised trial of Sildenafil for the
treatment of Erectile Dysfunction in Spinal Cord Injury. Ann Neurol. 1999;
46:15-21
20. Rendell MS, Rajfer J, Wicker PA, Smith MD for the Sildenafil Diabetes Study
Group. Sildenafil for the treatment of Erectile Dysfunction in Men with
Diabetes. JAMA. 1999;281: 421-426
21. Feldman R. Sildenafil in the treatment of Erectile Dysfunction: efficacy in
patients taking concomitant antihypertensive therapy (abstract). Am. J.
Hypertens. 1998; 11:10A
22. Hargreave T. Efficacy of Sildenafil in the treatment of Erectile Dysfunction in
patients with Depression. Paper presented at: Annual Congress of the
Collegium Internationale Neuro-Psychopharmacologicum; 1998; Glasgow, UK.
23. Padma-Nathan H, et al. Efficacy and safety of apomorphine sl vs. placebo for
male erectile dysfunction. J. Urol. 1998; 159:A920.
24. Becker AJ, Stief CG, Machtens S, et al. Oral phentolamine as treatment for
erectile dysfunction. J.Urol. 1998; 159:1214-1216.
25. Goldstein I, et al. Efficacy and safety of oral phentolamine (Vasomax) for the
treatment of minimal erectile dysfunction. J. Urol. 1998; 159:A919.
26. Ng PEP, Tan HM. The Use of Intracorporeal Self Injection of Prostaglandin E1 in
Malaysian Men. Int. J. Impotence Res. 1994; 6:D105.
27. Mah PKK, Yap HW. Vacuum Erection Devices for Erectile Dysfunction. APSIR
Book on Erectile Dysfunction. Chapter 11. APSIR 1999:126-133.
28. Tan HM, Ng PEP. The Malaysian Experience with Penile Implants. Int. J.
Impotence Res. 1994; 6:D133.
29. Tan HM. Shared Care Concept in the Management of Erectile Dysfunction. 1st
ASEAN Conference on Primary Healthcare, March 1999; Ipoh, Malaysia.

59
Notes - last page

Notes
Sponsored by
 Guidelines on
Male Sexual
Dysfunction:
Erectile dysfunction and
premature ejaculation
K. Hatzimouratidis (chair), I. Eardley, F. Giuliano,
D. Hatzichristou, I. Moncada, A. Salonia, Y. Vardi, E. Wespes

© European Association of Urology 2014

TABLE OF CONTENTS PAGE
1. BACKGROUND 4
1.1 Introduction 4
1.2 Methodology 4
1.3 Level of evidence and grade of recommendation 4
1.4 Publication History 5
1.5 Potential conflict of interest statement 5
1.6 References 5

2. ERECTILE DYSFUNCTION 6
2.1 Epidemiology and risk factors 6
2.1.1 Epidemiology 6
2.1.2 Risk factors 6
2.1.3 Post-radical prostatectomy ED, post-radiotherapy ED & post-brachytherapy ED 7
2.1.4 Managing ED: implications for everyday clinical practice 7
2.1.5 Conclusions on the epidemiology of ED 7
2.1.6 References 7
2.2 Diagnostic evaluation 10
2.2.1 Basic work-up 10
2.2.1.1 Sexual history 11
2.2.1.2 Physical examination 11
2.2.1.3 Laboratory testing 11
2.2.2 Cardiovascular system and sexual activity: the patient at risk 12
2.2.2.1 Low-risk category 14
2.2.2.2 Intermediate- or indeterminate-risk category 14
2.2.2.3 High-risk category 14
2.2.3 Specialised diagnostic tests 14
2.2.3.1 Nocturnal penile tumescence and rigidity test 14
2.2.3.2 Intracavernous injection test 14
2.2.3.3 Duplex ultrasound of the penis 14
2.2.3.4 Arteriography and dynamic infusion cavernosometry or
cavernosography 14
2.2.3.5 Psychiatric assessment 14
2.2.3.6 Penile abnormalities 14
2.2.4 Patient education - consultation and referrals 14
2.2.5 Guidelines for the diagnostic evaluation of ED 15
2.2.6 References 15

3. TREATMENT OF ERECTILE DYSFUNCTION 17

3.1 Treatment options 17
3.2 Lifestyle management in ED with concomitant risk factors 17
3.3 Erectile dysfunction after radical prostatectomy 17
3.4 Causes of ED that can be potentially treated with a curative intent 19
3.4.1 Hormonal causes 19
3.4.2 Post-traumatic arteriogenic ED in young patients 19
3.4.3 Psychosexual counselling and therapy 19
3.5 First-line therapy 19
3.5.1 Oral pharmacotherapy 19
3.5.1.1 Sildenafil 20
3.5.1.2 Tadalafil 20
3.5.1.3 Vardenafil 20
3.5.1.4 Choice or preference between the different PDE5 inhibitors 21
3.5.1.5 On-demand or chronic use of PDE5 inhibitors 21
3.5.1.6 Safety issues for PDE5 inhibitors 22
3.5.1.6.1 Cardiovascular safety 22
3.5.1.6.2 Nitrates are contraindicated with PDE5 inhibitors 22
3.5.1.6.3 Antihypertensive drugs 22
3.5.1.6.4 α-Blocker interactions 23
3.5.1.6.5 Dosage adjustment 23

2 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

 3.5.1.7 Management of non-responders to PDE5 inhibitors 23
3.5.1.7.1 Check that the patient has been using a licensed medication 23
3.6.1.7.2 Check that the medication has been properly prescribed and
correctly used 23
3.5.1.7.3 Possible manoeuvres in patients correctly using a PDE5
inhibitor 24
3.5.2 Vacuum erection devices 24
3.5.3 Shockwave therapy 24
3.6 Second-line therapy 25
3.6.1 Intracavernous injections 25
3.6.1.1 Alprostadil 25
3.6.1.2 Combination therapy 25
3.6.1.3 Intraurethral alprostadil 26
3.7 Third-line therapy (penile prostheses) 26
3.7.1 Efficacy and satisfaction rates 26
3.7.2 Complications 27
3.7.3 Conclusions 27
3.8 Guidelines for the treatment of ED 27
3.9 References 27

4. PREMATURE EJACULATION (PE) 36

4.1 Introduction 36
4.2 Definition of PE 36
4.2.1 Overview 36
4.2.2 Classifications 36
4.3 Epidemiology of PE 37
4.3.1 Prevalence 37
4.3.2 Pathophysiology and risk factors 37
4.4 Impact of PE on QoL 38
4.5 Diagnosis of PE 38
4.5.1 Intravaginal ejaculatory latency time (IELT) 38
4.5.2 PE assessment questionnaires 39
4.5.3 Physical examination and investigations 39
4.6 Recommendations 39
4.7 References 39
4.8 Treatment 43
4.8.1 Psychological/behavioural strategies 43
4.8.1.1 Guideline recommendation 44
4.8.2 Dapoxetine 44
4.8.2.1 Guideline recommendation 44
4.8.3 Off-label use of antidepressants: SSRIs and clomipramine 44
4.8.3.1 Guideline recommendation 45
4.8.4 Topical anaesthetic agents 45
4.8.4.1 Lidocaine-prilocaine cream 45
4.8.4.2 Guideline recommendation 46
4.8.5 Tramadol 46
4.8.5.1 Guideline recommendation 46
4.8.6 Other drugs 46
4.8.6.1 Phosphodiesterase type 5 inhibitors 46
4.8.6.2 Guideline recommendation 47
4.8.7 Guidelines on treatment of PE 47
4.9 References 48

5. CONCLUSION 51

6. ABBREVIATIONS USED IN THE TEXT 52

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 3

1. BACKGROUND
1.1 Introduction
Erectile dysfunction (ED) and premature ejaculation (PE) are the two main complaints in male sexual medicine
(1,2). New oral therapies have completely changed the diagnostic and therapeutic approach to ED and the
Guidelines Office of the European Association of Urology (EAU) has appointed an Expert Panel to update
previously published EAU guidelines for ED or impotence.

1.2 Methodology
For Chapters 2 and 3 (Erectile Dysfunction and Treatment of Erectile Dysfunction) a systemic literature search
performed by the panel members. The MedLine database was searched using the major Medical Subject
Headings (MeSH) terms “erectile dysfunction”, “sexual dysfunction” “ejaculation”. All articles published
between January 2009 (previous update) and January 2013 were considered for review. For Chapter 4
(Premature Ejaculation) the MedLine search was supplemented by the term “premature ejaculation” in all
search fields, for this 2014 print, covering a time frame up to August 2013. The Expert Panel has also identified
critical problems and knowledge gaps, setting priorities for future clinical research.

1.3 Level of evidence and grade of recommendation

References in the text have been assessed according to their level of scientific evidence (LE), and guideline
recommendations have been graded follow the listings in Tables 1 and 2, based on the Oxford Centre for
Evidence-based Medicine Levels of Evidence (3). Grading aims to provide transparency between the underlying
evidence and the recommendation given.

Table 1: Level of evidence*

Level Type of evidence

1a Evidence obtained from meta-analysis of randomised trials.
1b Evidence obtained from at least one randomised trial.
2a Evidence obtained from one well-designed controlled study without randomisation.
2b Evidence obtained from at least one other type of well-designed quasi-experimental study.
3 Evidence obtained from well-designed non-experimental studies, such as comparative studies,
correlation studies and case reports.
4 Evidence obtained from expert committee reports or opinions or clinical experience of respected
authorities.
*Modified from (3).

It should be noted that when recommendations are graded, the link between the LE and grade of
recommendation (GR) is not directly linear. Availability of RCTs may not necessarily translate into a grade A
recommendation where there are methodological limitations or disparity in published results.
Alternatively, absence of high level of evidence does not necessarily preclude a grade A
recommendation, if there is overwhelming clinical experience and consensus. There may be exceptional
situations where corroborating studies cannot be performed, perhaps for ethical or other reasons and in this
case unequivocal recommendations are considered helpful. Whenever this occurs, it is indicated in the text
as “upgraded based on panel consensus”. The quality of the underlying scientific evidence - although a very
important factor - has to be balanced against benefits and burdens, values and preferences, and costs when a
grade is assigned (4-6).
The EAU Guidelines Office does not perform structured cost assessments, nor can they address local/national
preferences in a systematic fashion. But whenever these data are available, the expert panel will include the
information.

Table 2: Grade of recommendation*

Grade Nature of recommendations

A Based on clinical studies of good quality and consistency that addressed the specific
recommendations, including at least one randomised trial.
B Based on well-conducted clinical studies, but without randomised clinical trials.
C Made despite the absence of directly applicable clinical studies of good quality.
*Modified from (3).

4 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

1.4 Publication History
The first European Association of Urology (EAU) Guidelines on Erectile Dysfunction were published in
2000 (6) with subsequent updates in 2001, 2002, 2004, 2005, 2009, 2013 and 2014. In particular the 2009
document presented a significant update of the previous publication with the inclusion of the topic “Premature
Ejaculation” and the text was renamed to “EAU Guidelines on Male Sexual Dysfunction" (7). In 2011 the expert
panel decided to develop separate guidelines addressing Penile Curvature, which resulted in a separate
publication in 2012 (8). Recently a guideline on Priapism was completed (9).

Several scientific summaries have been published in the EAU scientific journal, European Urology (10-14).
Quick reference documents (pocket guidelines) are available presenting the main findings of both the Male
Sexual Dysfunction Guidelines and the Penile Curvature Guidelines. These documents follow the updating
cycle of the underlying large texts. All material can be viewed and downloaded for personal use at the EAU
website. The EAU website also includes a selection of translations and republications produced by national
urological associations: http://www.uroweb.org/guidelines/online-guidelines/.

1.5 Potential conflict of interest statement

The expert panel have submitted potential conflict of interest statements which can be viewed on the EAU
website: http://www.uroweb.org/guidelines/online-guidelines/.

1.6 References
1. Lindau ST, Schumm LP, Laumann EO, et al. N Engl J Med. 2007 Aug 23;357(8):762-74.
http://www.ncbi.nlm.nih.gov/pubmed/17715410
2. Rosenberg MT, Sadovsky R. Identification and diagnosis of premature ejaculation. Int J Clin Pract
2007 Jun;61(6):903-8.
http://www.ncbi.nlm.nih.gov/pubmed/17504352
3. Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob
Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since
November 1998.
http://www.cebm.net/index.aspx?o=1025 [Access date February 2014].
4. Atkins D, Best D, Briss PA, et al; GRADE Working Group. Grading quality of evidence and strength of
recommendations. BMJ 2004 Jun 19;328(7454):1490.
http://www.ncbi.nlm.nih.gov/pubmed/15205295
5. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence
and strength of recommendations. BMJ 2008;336(7650):924-6.
http://www.ncbi.nlm.nih.gov/pubmed/18436948
6. Guyatt GH, Oxman AD, Kunz R, et al; GRADE Working Group. Going from evidence to
recommendations. BMJ 2008 May 10;336(7652):1049-51.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376019/?tool=pubmed
http://www.gradeworkinggroup.org/publications/Grading_evidence_and_recommendations_BMJ.pdf
7. Wespes E, Amar E, Eardley I, et al; EAU Guidelines Panel on Male Sexual Dysfunction. EAU Guidelines
on Male Sexual Dysfunction (Erectile Dysfunction and premature ejaculation). Edn. presented at the
EAU Annual Congress Stockholm, 2009. ISBN 978-90-79754-09-0.
8. Hatzimouratidis K, Eardley I, Giuliano F, et al; EAU Guidelines Panel on Male Sexual Dysfunction.
EAU guidelines on Penile Curvature. Edn. presented at the EAU Annual Congress Paris, 2012. ISBN
978-90-79754-83-0. Arnhem, The Netherlands.
9. Salonia A, Eardley I, Giuliano F, et al; EAU Guidelines Panel on Male Sexual Dysfunction. European
Association of Urology guidelines on priapism. Edn. presented at the EAU Annual Congress
Stockholm 2014. ISBN 978-90-79754-65-6. Arnhem, The Netherlands.
10. Wespes E, Amar E, Hatzichristou DG, et al. European Association of Urology Guidelines on erectile
dysfunction. Eur Urol 2002 Jan;41(1):1-5.
http://www.ncbi.nlm.nih.gov/pubmed/11999460
11. Wespes E, Amar E, Hatzichristou D, et al; EAU. EAU Guidelines on erectile dysfunction: an update.
Eur Urol 2006 May;49(5):806-15.
http://www.ncbi.nlm.nih.gov/pubmed/16530932
12. Hatzimouratidis K, Amar E, Eardley I, et al; European Association of Urology. Guidelines on male
sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010 May;57(5):804-14.
http://www.ncbi.nlm.nih.gov/pubmed/20189712
13. Hatzimouratidis K, Eardley I, Giuliano F, et al; European Association of Urology. EAU guidelines on
penile curvature. Eur Urol 2012 Sep;62(3):543-52.
http://www.ncbi.nlm.nih.gov/pubmed/22658761

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 5

14. Salonia A, Eardley I, Giuliano F, et al. European association of urology guidelines on priapism.
Eur Urol 2014 Feb;65(2):480-9.
http://www.ncbi.nlm.nih.gov/pubmed/24314827

2. ERECTILE DYSFUNCTION
2.1 Epidemiology and risk factors
Erection is a neuro-vasculo-tissular phenomenon under hormonal control. It includes arterial dilatation,
trabecular smooth muscle relaxation, and activation of the corporeal veno-occlusive mechanism (1,2).
Erectile dysfunction is defined as the persistent inability to attain and maintain an erection sufficient
to permit satisfactory sexual performance. Although ED is a benign disorder, it may affect physical and
psychosocial health and may have a significant impact on the quality of life (QoL) of sufferers and their partners
(3). There is increasing evidence that ED can be an early manifestation of coronary artery and peripheral
vascular disease; thus, ED should not be regarded only as a QoL issue but also as a potential warning sign of
cardiovascular disease (4-8).

2.1.1 Epidemiology
Epidemiological data have shown a high prevalence and incidence of ED worldwide. The first large, community-
based study of ED was the Massachusetts Male Aging Study (MMAS) (3). The study reported an overall
prevalence of 52% ED in non-institutionalised men aged 40-70 years in the Boston area; specific prevalence
for minimal, moderate, and complete ED was 17.2%, 25.2%, and 9.6%, respectively. In the Cologne study
of men aged 30-80 years, the prevalence of ED was 19.2%, with a steep age-related increase from 2.3% to
53.4% (9). In the National Health and Social Life Survey (NHSLS), the prevalence of sexual dysfunction in males
(not specific ED) was 31% (10). The incidence rate of ED (new cases per 1,000 men annually) was 26 in the
MMAS study (11), 65.6 (mean follow-up of 2 years) in a Brazilian study (12), and 19.2 (mean follow-up of 4.2
years) in a Dutch study (13). In Taiwan, the prevalence of ED was 27% among all patients investigated and 29%
among those aged > 40 years (14). In Ghana, the overall prevalence of ED was 59.6% and there were positive
correlations between ED, dissatisfaction, age and other sexual dysfunctions (15). Differences between these
studies can be explained by differences in methodology and in the ages, socioeconomic and cultural status of
the populations studied.
Data from epidemiological studies have demonstrated consistent and compelling evidence for an
association between lower urinary tract symptoms (LUTS)/benign prostatic hypertrophy (BPH) and sexual
dysfunction in aging men that is independent of the effects of age, other comorbidities, and various lifestyle
factors (16). The Massachusetts Male Aging (MSAM-7) study systematically investigated the relationship
between LUTS and sexual dysfunction in > 12,000 men aged 50-80 years. It was performed in the US and
six European countries (France, Germany, Italy, Netherlands, Spain, and UK). Eighty-three percent of men
considered themselves sexually active, and 71% reported at least one episode of sexual activity in the past
4 weeks. The overall prevalence of LUTS was 90%. Only 19% of men had sought medical help for LUTS
and only 11% were medically treated. The overall prevalence of ED was 49%, and 10% of patients reported
complete absence of erection. The overall prevalence of ejaculation disorders was 46% and 5% reported
anejaculation (17).

2.1.2 Risk factors

Erectile dysfunction shares common risk factors with cardiovascular disease (e.g., lack of exercise, obesity,
smoking, hypercholesterolaemia, and metabolic syndrome); some of which can be modified. Moreover, men
with mild ED have similar risk factors to those of a general ED clinical trial population. Thus, mild ED is an
important indicator of risk for associated underlying disease. Men complaining of mild ED should be evaluated
adequately (for underlying cardiovascular risk) (18).
In the MMAS, men who began exercising in midlife had a 70% reduced risk for ED compared to
sedentary men and a significantly lower incidence over an 8-year follow-up period of regular exercise (19).
A multicentre, randomised, open-label study in obese men with moderate ED compared 2 years of intensive
exercise and weight loss with a control group given general information about healthy food choices and
exercise (20). Significant improvements in body mass index (BMI) and physical activity scores, as well as
erectile function, were observed in the lifestyle intervention group. These changes were highly correlated with
both weight loss and activity levels.
Some studies have shown some evidence that lifestyle modification and pharmacotherapy for
cardiovascular risk factors are effective in improving sexual function in men with ED. However, it should be

6 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

emphasized that more controlled prospective studies are necessary to determine the effects of exercise or
other lifestyle changes in prevention or treatment of ED (6).

2.1.3 Post-radical prostatectomy ED, post-radiotherapy ED & post-brachytherapy ED

Radical prostatectomy (RP) in any form (open, laparoscopic, or robotic) is a widely performed procedure for
patients with clinically localised prostate cancer and a life expectancy of at least 10 years. This procedure
may lead to treatment-specific sequelae affecting health-related QoL. This outcome has become increasingly
important with the more frequent diagnosis of prostate cancer in younger patients (21-22). Research has
shown that 25-75% of men experience postoperative ED (23). A systematic review has shown that incidence of
potency recovery after robotic prostatectomy is influenced by numerous factors. It reported, for the first time,
a significant advantage in favor of robotic laparoscopic radical prostatectomy in comparison with retropubic
radical prostatectomy in terms of 12-month potency rates (24). However, there was no significant difference
between laparoscopic RP and robot-assisted laparoscopic RP. Currently, we do not have enough evidence-
based data to confirm that robot-assisted laparoscopic RP has any advantageous effect on functional
outcome. Experience of the surgeon seems to be the main factor besides preservation of neurovascular
bundles and patient age.
Post-RP ED is multifactorial. Cavernosal nerve injury induces proapoptotic (loss of smooth muscle)
and profibrotic (increase in collagen) factors within the corpora cavernosa. These changes may also be caused
by poor oxygenation due to changes in the blood supply to the cavernosa because of possible arterial damage
during the surgical procedure.
Preoperative potency is a major factor associated with the recovery of erectile function after surgery,
therefore, patients being considered for nerve-sparing radical prostatectomy (NSRP) should ideally be potent
preoperatively (24-29). It is also clear that cavernosal nerves must be preserved to ensure erectile function
recovers after RP. In addition, the role of vascular insufficiency is of increasing interest in postoperative ED
(30,31).
ED is also a common sequela after external beam radiotherapy and brachytherapy for prostate cancer.
The mechanisms contributing to ED after prostate irradiation involve injury to the neurovascular bundles, penile
vasculature, and cavernosal structural tissue (32,33). Alternative treatments for prostate cancer including
cryotherapy and high-intensity focused ultrasound are associated with equivalent or worsened rates of ED
compared to surgery or radiation therapy (34,35).

2.1.4 Managing ED: implications for everyday clinical practice

Advances in basic and clinical research in ED during the past 15 years have led to the development of a variety
of new treatment options, including pharmacological agents for intracavernous, intraurethral, and oral use
(36-38). Reconstructive vascular surgery is reserved for select cases of arterial insufficiency, with no current
indications for venous ligation procedures, given the poor overall outcomes (39,40).
An increasing number of men are currently seeking help for ED due to the growing public awareness
of the condition and the availability of effective, safe and user-friendly oral drug therapy. However, not all
physicians evaluating and treating ED have appropriate background knowledge and clinical experience in
sexual medicine. Thus, men with ED may receive little or no evaluation before treatment and will therefore
not receive treatment for any underlying disease that may be causing their ED. Other men without ED may be
requesting treatment simply to enhance their sexual performance.

2.1.5 Conclusions on the epidemiology of ED

LE
Erection is a neuro-vasculo-tissular phenomenon under hormonal control. 2b
ED is common worldwide. 2b
ED shares risk factors with cardiovascular disease. 2b
Lifestyle modification (intensive exercise and decrease in BMI) can improve erectile function. 1b
ED is a symptom, not a disease. Some patients may not be properly evaluated or receive treatment for 4
an underlying disease or condition that may be causing ED.
ED is common after radical prostatectomy, irrespective of the surgical technique used. 2b
ED is common after external radiotherapy and brachytherapy. 2b

2.1.6 References
1. Lue TF, Tanagho EA. Physiology of erection and pharmacological management of impotence.
J Urol 1987 May;137(5):829-36.
http://www.ncbi.nlm.nih.gov/pubmed/3553617

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 7

2. Gratzke C, Angulo J, Chitaley K, et al. Anatomy, physiology, and pathophysiology of erectile
dysfunction. J Sex Med 2010 Jan;7(1 Pt 2):445-75.
http://www.ncbi.nlm.nih.gov/pubmed/20092448
3. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial
correlates: results of the Massachusetts Male Aging Study. J Urol 1994 Jan;151(1):54-61.
http://www.ncbi.nlm.nih.gov/pubmed/8254833
4. Jackson G, Boon N, Eardley I, et al. Erectile dysfunction and coronary artery disease prediction:
evidence-based guidance and consensus. Int J Clin Pract 2010 Jun;64(7):848-57.
http://www.ncbi.nlm.nih.gov/pubmed/20584218
5. Dong JY, Zhang YH, Qin LQ. Erectile dysfunction and risk of cardiovascular disease: Meta-analysis of
prospective cohort studies. J Am Coll Cardiol 2011 Sep;58(13):1378-85.
http://www.ncbi.nlm.nih.gov/pubmed/21920268
6. Gupta BP, Murad MH, Clifton MM, et al. The effect of lifestyle modification and cardiovascular risk
factor reduction on erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 2011
Nov;171(20):1797-803.
http://www.ncbi.nlm.nih.gov/pubmed/21911624
7. Guo W, Liao C, Zou Y, et al. Erectile dysfunction and risk of clinical cardiovascular events: A meta-
analysis of seven cohort studies. J Sex Med 2010 Aug;7(8):2805-16.
http://www.ncbi.nlm.nih.gov/pubmed/20367771
8. Batty GD, Li Q, Czernichow S, et al. Erectile dysfunction and later cardiovascular disease in men with
type 2 diabetes: Prospective cohort study based on the ADVANCE (Action in Diabetes and Vascular
Disease: Preterax and Diamicron Modified-Release Controlled Evaluation) trial. J Am Coll Cardiol 2010
Nov;56(23):1908-13.
http://www.ncbi.nlm.nih.gov/pubmed/21109113
9. Braun M, Wassmer G, Klotz T, et al. Epidemiology of erectile dysfunction: results of the ‘Cologne Male
Survey’. Int J Impot Res 2000 Dec;12(6):305-11.
http://www.ncbi.nlm.nih.gov/pubmed/11416833
10. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors.
JAMA 1999 Feb;281(6):537-44.
http://www.ncbi.nlm.nih.gov/pubmed/10022110
11. Johannes CB, Araujo AB, Feldman HA, et al. Incidence of erectile dysfunction in men 40 to 69 years
old: longitudinal results from the Massachusetts Male Aging Study. J Urol 2000 Feb;163(2):460-3.
http://www.ncbi.nlm.nih.gov/pubmed/10647654
12. Moreira ED Jr, Lbo CF, Diament A, et al. Incidence of erectile dysfunction in men 40 to 69 years old:
results from a population-based cohort study in Brazil. Urology 2003 Feb;61(2):431-6.
http://www.ncbi.nlm.nih.gov/pubmed/12597962
13. Schouten BW, Bosch JL, Bernsen RM, et al. Incidence rates of erectile dysfunction in the Dutch
general population. Effects of definition, clinical relevance and duration of follow-up in the Krimpen
Study. Int J Impot Res 2005 Jan-Feb;17(1):58-62.
http://www.ncbi.nlm.nih.gov/pubmed/15510192
14. Hwang TI, Tsai TF, Lin YC, et al. A survey of erectile dysfunction in Taiwan: use of the erection
hardness score and quality of erection questionnaire. J Sex Med 2010 Aug;7(8):2817-24.
http://www.ncbi.nlm.nih.gov/pubmed/20456624
15. Amidu N, Owiredu WK, Woode E, et al. Prevalence of male sexual dysfunction among Ghanaian
populace: myth or reality? Int J Impot Res 2010 Nov-Dec;22(6):337-42.
http://www.ncbi.nlm.nih.gov/pubmed/20927122
16. Seftel AD, de la Rosette J, Birt J, et al. Coexisting lower urinary tract symptoms and erectile
dysfunction: a systematic review of epidemiological data. Int J Clin Pract 2013 Jan;67(1):32-45.
http://www.ncbi.nlm.nih.gov/pubmed/23082930
17. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the
multinational survey of the aging male (MSAM-7). Eur Urol 2003 Dec;44(6):637-49.
http://www.ncbi.nlm.nih.gov/pubmed/14644114
18. Lee JC, Bénard F, Carrier S, et al. Do men with mild erectile dysfunction have the same risk factors as
the general erectile dysfunction clinical trial population? BJU Int 2011 Mar;107(6):956-60.
http://www.ncbi.nlm.nih.gov/pubmed/20950304
19. Derby CA, Mohr BA, Goldstein I, et al. Modifiable risk factors and erectile dysfunction: can lifestyle
changes modify risk? Urology 2000 Aug;56(2):302-6.
http://www.ncbi.nlm.nih.gov/pubmed/10925098

8 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

20. Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obese
men: a randomized controlled trial. JAMA 2004 Jun;291(24):2978-84.
http://www.ncbi.nlm.nih.gov/pubmed/15213209
21. Salonia A, Burnett AL, Graefen M, et al. Prevention and management of postprostatectomy sexual
dysfunctions. Part 1: choosing the right patient at the right time for the right surgery. Eur Urol 2012
Aug;62(2):261-72.
http://www.ncbi.nlm.nih.gov/pubmed/22575909
22. Salonia A, Burnett AL, Graefen M, et al. Prevention and management of postprostatectomy sexual
dysfunctions part 2: recovery and preservation of erectile function, sexual desire, and orgasmic
function. Eur Urol 2012 Aug;62(2):273-86.
http://www.ncbi.nlm.nih.gov/pubmed/22575910
23. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among
prostatecancer survivors. N Engl J Med 2008 Mar;358(12):1250-61.
http://www.ncbi.nlm.nih.gov/pubmed/18354103
24. Ficarra V, Novara G, Ahlering TE, et al. Systematic review and meta-analysis of studies reporting
potency rates after robot-assisted radical prostatectomy. Eur Urol 2012 Sep;62(3):418-30.
http://www.ncbi.nlm.nih.gov/pubmed/22749850
25. Hatzimouratidis K, Burnett AL, Hatzichristou D, et al. Phosphodiesterase type 5 inhibitors in
postprostatectomy erectile dysfunction: a critical analysis of the basic science rationale and clinical
application. Eur Urol 2009 Feb; 55:334-347.
http://www.ncbi.nlm.nih.gov/pubmed/18986755
26. Magheli A, Burnett AL. Erectile dysfunction following prostatectomy: prevention and treatment. Nat
Rev Urol 2009 Aug;6(8):415-27.
http://www.ncbi.nlm.nih.gov/pubmed/19657376
27. Ferronha F, Barros F, Vaz Santos V, et al. Is there any evidence of superiority between retropubic,
laparoscopic or robot-assisted radical prostatectomy? International Braz J Urol 2011 March-
April;37(2):146-60.
http://www.ncbi.nlm.nih.gov/pubmed/21557832
28. Barry MJ, Gallagher PM, Skinner JS, et al. Adverse effects of robotic-assisted laparoscopic versus
open retropubic radical prostatectomy among a nationwide random sample of medicare-age men.
J Clin Oncol 2012 Feb;30(5):513-8.
http://www.ncbi.nlm.nih.gov/pubmed/22215756
29. Vickers A, Savage C, Bianco F, et al. Cancer control and functional outcomes after radical
prostatectomy as markers of surgical quality: analysis of heterogeneity between surgeons at a single
cancer center. Eur Urol 2011 Mar;59(3):317-22.
http://www.ncbi.nlm.nih.gov/pubmed/21095055
30. Mulhall JP, Slovick R, Hotaling J, et al. Erectile dysfunction after radical prostatectomy: hemodynamic
profiles and their correlation with the recovery of erectile function. J Urol 2002 Mar;167(3):1371-5.
http://www.ncbi.nlm.nih.gov/pubmed/11832735
31. Secin FP, Touijer K, Mulhall J, et al. Anatomy and preservation of accessory pudendal arteries in
laparoscopic radical prostatectomy. Eur Urol 2007 May;51(5):1229-35.
http://www.ncbi.nlm.nih.gov/pubmed/16989942
32. van der Wielen GJ, Mulhall JP, Incrocci L. Erectile dysfunction after radiotherapy for prostate cancer
and radiation dose to the penile structures: a critical review. Radiother Oncol 2007 Aug;84(2):107-13.
http://www.ncbi.nlm.nih.gov/pubmed/17707936
33. Stember DS, Mulhall JP. The concept of erectile function preservation (penile rehabilitation) in the
patient after brachytherapy for prostate cancer. Brachytherapy 2012 Mar-Apr;11(2):87-96.
http://www.ncbi.nlm.nih.gov/pubmed/22330103
34. Cordeiro ER, Cathelineau X, Thuroff S, et al. High-intensity focused ultrasound (HIFU) for definitive
treatment of prostate cancer. BJU Int 2012 Nov;110(9):1228-42.
http://www.ncbi.nlm.nih.gov/pubmed/22672199
35. Williams SB, Lei Y, Nguyen PL, et al. Comparative effectiveness of cryotherapy vs brachytherapy for
localised prostate cancer. BJU Int. 2012 Jul;110(2 Pt 2):E92-8.
http://www.ncbi.nlm.nih.gov/pubmed/22192688
36. Goldstein I, Lue TF, Padma-Nathan H, et al; Sildenafil Study Group. Oral sildenafil in the treatment of
erectile dysfunction. 1998. J Urol 2002 Feb;167(2 Pt 2):1197-203.
http://www.ncbi.nlm.nih.gov/pubmed/11905901

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 9

37. Hellstrom WJ, Gittelman M, Karlin G, et al; Vardenafil Study Group. Sustained efficacy and tolerability
of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile
dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial. Urology
2003 Apr;61(4 Suppl 1):8-14.
http://www.ncbi.nlm.nih.gov/pubmed/12657355
38. Brock GB, McMahon CG, Chen KK, et al. Efficacy and safety of tadalafil for the treatment of erectile
dysfunction: results of integrated analyses. J Urol 2002 Oct;168(4 Pt 1):1332-6.
http://www.ncbi.nlm.nih.gov/pubmed/12352386
39. Wespes E, Schulman C. Venous impotence: pathophysiology, diagnosis and treatment. J Urol 1993
May;149(5 Pt 2):1238-45.
http://www.ncbi.nlm.nih.gov/pubmed/8479008
40. Rao DS, Donatucci CF. Vasculogenic impotence. Arterial and venous surgery. Urol Clin North Am 2001
May;28(2):309-19.
http://www.ncbi.nlm.nih.gov/pubmed/11402583

2.2 Diagnostic evaluation

2.2.1 Basic work-up
The first step in evaluating ED is always a detailed medical and sexological history of patients and partners
when available (1,2). Often it is not possible to include the partner on the patient’s first visit, but an effort
should be made to include the partner at the second visit. The pathophysiology of ED may be vasculogenic,
neurogenic, anatomical, hormonal, drug-induced and/or psychogenic (Table 3) (3). Taking a comprehensive
medical history may reveal one of the many common disorders associated with ED.
It is important to establish a relaxed atmosphere during history-taking. This will make it easier to ask
questions about erectile function and other aspects of sexual history. A relaxed atmosphere will also make it
easier to explain the diagnosis and therapeutic approach to the patient and his partner.

Table 3: Pathophysiology of ED

Vasculogenic
- Cardiovascular disease
- Hypertension
- Diabetes mellitus
- Hyperlipidaemia
- Smoking
- Major surgery (RP) or radiotherapy (pelvis or retroperitoneum)
Neurogenic
Central causes
- Degenerative disorders (multiple sclerosis, Parkinson’s disease, multiple atrophy etc.)
- Spinal cord trauma or diseases
- Stroke
- Central nervous system tumours
Peripheral causes
- Type 1 and 2 diabetes mellitus
- Chronic renal failure
- Polyneuropathy
- Surgery (pelvis or retroperitoneum, radical prostatectomy, colorectal surgery, etc.)
Anatomical or structural
- Hypospadias, epispedias
- Micropenis
- Congenital curvature of the penis
- La Peyronie’s disease
Hormonal
- Hypogonadism
- Hyperprolactinemia
- Hyper- and hypothyroidism
- Hyper- and hypocortisolism (Cushing’s disease etc.)

10 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

Drug-induced
- Antihypertensives (diuretics are the most common medication causing ED)
- Antidepressants (selective serotonin reuptake inhibitors, tricyclics)
- Antipsychotics (incl. neuroleptics)
- Antiandrogens; GnRH analogues and antagonists
- Recreational drugs (alcohol, heroin, cocaine, marijuana, methadone)
Psychogenic
- Generalised type (e.g., lack of arousability and disorders of sexual intimacy)
- Situational type (e.g., partner-related, performance-related issues or due to distress)
Trauma
- Penile fracture

2.2.1.1 Sexual history

The sexual history must include (when available) information about previous and current sexual relationships,
current emotional status, onset and duration of the erectile problem, and previous consultations and
treatments. The sexual health status of the partner(s) (when available) can also be useful. A detailed description
should be made of the rigidity and duration of both sexually stimulated and morning erections and of problems
with arousal, ejaculation, and orgasm. Validated psychometric questionnaires, such as the International
Index for Erectile Function (IIEF) (4), help to assess the different sexual function domains (i.e., sexual desire,
erectile function, orgasmic function, ejaculation, intercourse, and overall satisfaction), as well as the impact
of a specific treatment modality. Psychometric analysis also supports the use of erectile hardness score as
a simple, reliable and valid tool for the assessment of penile rigidity in practice and in clinical trials research
(5). In cases of clinical depression, the use of a 2-question scale for depression is recommended: “During the
past month have you often been bothered by feeling down, depressed or hopeless? During the past month
have you often been bothered by little interest or pleasure, doing things?” (6). Patients should be screened for
symptoms of possible hypogonadism, including decreased energy, libido, fatigue, and cognitive impairment, as
well as for symptomatic lower urinary tract symptoms. Where indicated, screening questionnaires, such as the
International Prostate Symptom Score may be utilised.

2.2.1.2 Physical examination

Every patient must be given a physical examination focused on the genitourinary, endocrine, vascular, and
neurological systems (1). A physical examination may reveal unsuspected diagnoses, such as La Peyronie’s
disease, prostatic enlargement or irregularity/nodularity, or signs and symptoms suggesting hypogonadism
(small testes, alterations in secondary sexual characteristics etc.) (2). A rectal examination should be performed
in every patient older than 40 years. Blood pressure and heart rate should be measured if they have not been
assessed in the previous 3-6 months. Particular attention must be given to patients with cardiovascular disease
(Section 2.2.2).

2.2.1.3 Laboratory testing

Laboratory testing must be tailored to the patient’s complaints and risk factors. Patients may need a fasting
glucose or HbA1c and lipid profile if not recently assessed. Hormonal tests include a morning sample of total
testosterone. If indicated bioavailable or calculated-free testosterone may be needed to corroborate total
testosterone measurements. However, the threshold of testosterone to maintain ED is low and ED is usually a
symptom of more severe cases of hypogonadism (7). For levels > 8 nmol/l the relationship between circulating
testosterone and sexual function is very low (7,8).
Additional laboratory tests may be considered in selected patients, for example, prostate-specific
antigen (PSA) for detection, or suspicion, of prostate cancer (9). Additional hormonal tests, for example,
prolactin, and luteinizing hormone, are performed when low testosterone levels are detected. If any abnormality
is observed, referral to an endocrinologist may be indicated (10,11).
Although physical examination and laboratory evaluation of most men with ED may not reveal the
exact diagnosis, these opportunities to identify critical comorbid conditions should not be missed (12).

Figure 1 gives the minimal diagnostic evaluation (basic work-up) in patients with ED.

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 11

Figure 1: Minimal diagnostic evaluation (basic work-up) in patients with ED

Patient with ED (self-reported)

Medical and psychosexual history (use of validated instruments, e.g. IIEF)

Identify other than Identify common Identify reversible Assess psychosocial

ED sexual problems causes of ED risk factors for ED status

Focused physical examination

Penile Prostatic Signs of Cardiovascular and

deformities disease hypogonadism neurological status

Laboratory tests

Glucose-lipid profile
Total testosterone (morning sample)
(if not assessed in
If indicated, bio-available or free testosterone
the last 12 months)

ED = erectile dysfunction; IIEF = International Index of Erectile Function.

2.2.2 Cardiovascular system and sexual activity: the patient at risk

Patients who seek treatment for sexual dysfunction have a high prevalence of cardiovascular disease. The
cardiac risks associated with sexual activity are well established. Epidemiological surveys have emphasised
the association between cardiovascular and metabolic risk factors and sexual dysfunction in men and women
(13). ED can improve the sensitivity of screening for asymptomatic cardiovascular disease in men with diabetes
(14,15). ED significantly increases the risk of cardiovascular disease, coronary heart disease, stroke, and all-
cause mortality, and the increase is probably independent of conventional cardiovascular risk factors (16).
There has been an extensive investigation of the pharmacological properties of phosphodiesterase
5 inhibitors (PDE5Is), including their effects on cardiac smooth muscle activity and overall cardiovascular safety.
The EAU Guidelines for treating men with ED have been adapted from previously published recommendations
from the Princeton Consensus conferences on sexual dysfunction and cardiac risk (17-19). The Princeton
Consensus (Expert Panel) Conference is dedicated to optimizing sexual function and preserving cardiovascular
health. A total of three consensus papers have been published (17-19). The Third Princeton Consensus had
two primary objectives. The first focused on evaluation and management of cardiovascular risk in men with
ED and no known cardiovascular disease, with particular emphasis on identification of men with ED who may
require additional cardiological work-up. The second objective focused on re-evaluation and modification of
previous recommendations for evaluation of cardiac risk associated with sexual activity in men with known
cardiovascular disease. The recommendations built on those developed during the first and second Princeton
Consensus Conferences; first, emphasising the use of exercise ability and stress testing to ensure that each
man’s cardiovascular health is consistent with the physical demands of sexual activity before prescribing
treatment for ED; and second, highlighting the link between ED and cardiovascular disease, which may be
asymptomatic and benefit from cardiovascular risk reduction (19). Patients with ED can be stratified into three
cardiovascular risk categories (Table 4), which can be used as the basis for a treatment algorithm for initiating
or resuming sexual activity (Figure 2). It is also possible for the clinician to estimate the risk of sexual activity in
most patients from their level of exercise tolerance, which can be determined when taking the patient’s history.

12 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

Table 4: Cardiac risk stratification (based on 2nd Princeton Consensus) (18)

Low-risk category Intermediate-risk category High-risk category

Asymptomatic, < 3 risk factors for > 3 risk factors for CAD (excluding High-risk arrhythmias
CAD (excluding sex) sex)
Mild, stable angina Moderate, stable angina Unstable or refractory angina
(evaluated and/or being treated)
Uncomplicated previous MI Recent MI (> 2, < 6 weeks) Recent MI (< 2 weeks)
LVD/CHF (NYHA class I) LVD/CHF (NYHA class II) LVD/CHF (NYHA class III/IV)
Post-successful coronary Non-cardiac sequelae of Hypertrophic obstructive and other
revascularisation atherosclerotic disease (e.g., cardiomyopathies
stroke, peripheral vascular disease)
Controlled hypertension Uncontrolled hypertension
Mild valvular disease Moderate-to-severe valvular
disease
CAD = coronary artery disease; CHF = congestive heart failure; LVD = left ventricular dysfunction;
MI = myocardial infarction; NYHA = New York Heart Association.

Figure 2: T
 reatment algorithm for determining level of sexual activity according to cardiac risk in ED
(based on 3rd Princeton Consensus) (19)

Sexual inquiry of all men

ED confirmed

Exercise abilitya

Low risk Intermediate risk High risk

Stress testb

Pass Fail

Low risk High risk

Advice, treat ED Cardiologist

Sexual activity is equivalent to walking 1 mile on the flat in 20 min or briskly climbing two flights of stairs in 10 s.
a

Sexual activity is equivalent to 4 min of the Bruce treadmill protocol.

b

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 13

2.2.2.1 Low-risk category
The low-risk category includes patients who do not have any significant cardiac risk associated with sexual
activity. Low risk is typically implied by the ability to perform exercise of modest intensity, which is defined as
> 6 “metabolic equivalents of energy expenditure in the resting state” (METs) without symptoms. According to
current knowledge of the exercise demand or emotional stress associated with sexual activity, low-risk patients
do not need cardiac testing or evaluation before the initiation or resumption of sexual activity or therapy for
sexual dysfunction.

2.2.2.2 Intermediate- or indeterminate-risk category

The intermediate- or indeterminate-risk category consists of patients with an uncertain cardiac condition
or patients whose risk profile requires testing or evaluation before the resumption of sexual activity. Based
upon the results of testing, these patients may be moved to either the high- or low-risk group. A cardiology
consultation may be needed in some patients to help the primary physician determine the safety of sexual
activity.

2.2.2.3 High-risk category

High-risk patients have a cardiac condition that is sufficiently severe and/or unstable for sexual activity to
carry a significant risk. Most high-risk patients have moderate-to-severe symptomatic heart disease. High-risk
individuals should be referred for cardiac assessment and treatment. Sexual activity should be stopped until
the patient’s cardiac condition has been stabilised by treatment, or a decision made by the cardiologist and/or
internist that it is safe to resume sexual activity.

2.2.3 Specialised diagnostic tests

Most patients with ED can be managed within the sexual care setting, conversely, some patients may need
specific diagnostic tests (Tables 5 and 6).

2.2.3.1 Nocturnal penile tumescence and rigidity test

The nocturnal penile tumescence and rigidity (NPTR) assessment should be done on at least two nights. A
functional erectile mechanism is indicated by an erectile event of at least 60% rigidity recorded on the tip of the
penis that lasts for > 10 min (20).

2.2.3.2 Intracavernous injection test

The intracavernous injection test gives limited information about vascular status. A positive test is a rigid
erectile response (unable to bend the penis) that appears within 10 min after the intracavernous injection
and lasts for 30 min (21). This response indicates a functional, but not necessarily normal, erection, and the
erection may coexist with arterial insufficiency and/or veno-occlusive dysfunction (22). A positive test shows
that a patient will respond to the intracavernous injection programme. The test is inconclusive as a diagnostic
procedure and duplex Doppler study of the penis should be requested, if clinically warranted.

2.2.3.3 Duplex ultrasound of the penis

A peak systolic blood flow > 30 cm/s, an end-diastolic velocity of < 3 cm/s and a resistance index > 0.8 are
generally considered normal (21). Further vascular investigation is unnecessary when a Duplex examination is
normal.

2.2.3.4 Arteriography and dynamic infusion cavernosometry or cavernosography

Arteriography and dynamic infusion cavernosometry or cavernosography (DICC) should be performed only in
patients who are being considered for vascular reconstructive surgery (23).

2.2.3.5 Psychiatric assessment

Patients with psychiatric disorders must be referred to a psychiatrist who is particularly interested in ED. In
younger patients (< 40 years) with long-term primary ED, psychiatric assessment may be helpful before any
organic assessment is carried out.

2.2.3.6 Penile abnormalities

Surgical correction may be needed for patients with ED due to penile abnormalities, e.g. hypospadias,
congenital curvature, or Peyronie’s disease with preserved rigidity.

2.2.4 Patient education - consultation and referrals

Consultation with the patient should include a discussion of the expectations and needs of both the patient
and his stable sexual partner, if available. It should also review both the patient’s and partner’s understanding

14 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

of ED, the results of diagnostic tests, and provide a rational selection of treatment options. Patient and partner
education is an essential part of ED management (24,25).

Table 5: Indications for specific diagnostic tests

Primary ED (not caused by organic disease or psychogenic disorder).

Young patients with a history of pelvic or perineal trauma who could benefit from potentially curative vascular
surgery.
Patients with penile deformities that might require surgical correction, e.g., Peyronie’s disease, congenital
curvature.
Patients with complex psychiatric or psychosexual disorders.
Patients with complex endocrine disorders.
Specific tests may be indicated at the request of the patient or his partner.
Medicolegal reasons, e.g., implantation of penile prosthesis, sexual abuse.

Table 6: Specific diagnostic tests

NTPR using Rigiscan

Vascular studies
- Intracavernous vasoactive drug injection
- Duplex Doppler study of the penis
- Dynamic Infusion Cavernosometry and Cavernosography (DICC)
- Internal pudendal arteriography
Neurological studies, e.g., bulbocavernosus reflex latency, nerve conduction studies
Endocrinological studies
Specialised psychodiagnostic evaluation

2.2.5 Guidelines for the diagnostic evaluation of ED

LE GR
Clinical use of validated questionnaire related to ED may help to assess all sexual function 3 B
domains and the effect of a specific treatment modality.
Physical examination is needed in the initial assessment of men with ED to identify underlying 4 B
medical conditions that may be associated with ED.
Routine laboratory tests, including glucose-lipid profile and total testosterone, are required to 4 B
identify and treat any reversible risk factors and lifestyle factors that can be modified.
Specific diagnostic tests are indicated by only a few conditions. 4 B

2.2.6 References
1. Davis-Joseph B, Tiefer L, Melman A. Accuracy of the initial history and physical examination to
establish the etiology of erectile dysfunction. Urology 1995 Mar;45(3):498-502.
http://www.ncbi.nlm.nih.gov/pubmed/7879338
2. Hatzichristou D, Hatzimouratidis K, Bekas M, et al. Diagnostic steps in the evaluation of patients with
erectile dysfunction. J Urol 2002 Aug;168(2):615-20.
http://www.ncbi.nlm.nih.gov/pubmed/12131320
3. Lewis RW. Epidemiology of erectile dysfunction. Urol Clin North Am 2001 May;28(2):209-16, vii.
http://www.ncbi.nlm.nih.gov/pubmed/11402575
4. Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): a
multidimensional scale for assessment of erectile dysfunction. Urology 1997 Jun;49(6):822-30.
http://www.ncbi.nlm.nih.gov/pubmed/9187685
5. Mulhall JP, Goldstein I, Bushmakin AG, et al. Validation of the erection hardness score. J Sex Med
2007 Nov;4(6):1626-34.
http://www.ncbi.nlm.nih.gov/pubmed/17888069
6. Whooley MA, Avins AL, Miranda J, et al. Case-finding instruments for depression. Two questions are
as good as many. J Gen Intern Med 1997 Jul;12(7):439-45.
http://www.ncbi.nlm.nih.gov/pubmed/9229283

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 15

7. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum
testosterone in older men. J Clin Endocrinol Metab 2006 Nov;91(11):4335-43.
http://www.ncbi.nlm.nih.gov/pubmed/16926258
8. O'Connor Db, Lee DM, Corona G, et al. The relationship between sex hormones and sexual function in
middle-age and older European men. J Clin Endocrinol Metab 2011 Oct;96(10):E1577-87.
http://www.ncbi.nlm.nih.gov/pubmed/21849522
9. Heidenreich A, Bellmunt J, Bolla M, et al. European Association of Urology. EAU guidelines on
prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol
2011 Jan;59(1):61-71.
http://www.ncbi.nlm.nih.gov/pubmed/21056534
10. Morales A, Heaton JP. Hormonal erectile dysfunction. Evaluation and management. Urol Clin North Am
2001 May;28(2):279-88.
http://www.ncbi.nlm.nih.gov/pubmed/11402581
11. Lue TF, Giuliano F, Montorsi F, et al. Summary of the recommendations on sexual dysfunctions in men.
J Sex Med 2004 Jul;1(1):6-23.
http://www.ncbi.nlm.nih.gov/pubmed/16422979
12. Ghanem HM, Salonia A, Martin-Morales A. SOP: Physical Examination and Laboratory Testing for Men
with Erectile Dysfunction. J Sex Med 2013 Jan;10(1):108-110. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22524416
13. Laumann EO, Paik A, Rosen RC. The epidemiology of erectile dysfunction: results from the National
Health and Social Life Survey. Int J Impot Res 1999 Sep;11(Suppl 1):S60-4.
http://www.ncbi.nlm.nih.gov/pubmed/10554933
14. Gazzaruso C, Coppola A, Montalcini T, et al. Erectile dysfunction can improve the effectiveness of the
current guidelines for the screening for asymptomatic coronary artery disease in diabetes. Endocrine
2011 Oct;40(2):273-9.
http://www.ncbi.nlm.nih.gov/pubmed/21861245
15. Batty GD, Li Q, Czernichow S, et al. Erectile dysfunction and later cardiovascular disease in men with
type 2 diabetes: prospective cohort study based on the ADVANCE (Action in Diabetes and Vascular
Disease: Preterax and Diamicron Modified-Release Controlled Evaluation) trial. J Am Coll Cardiol 2010
Nov;56(23):1908-13.
http://www.ncbi.nlm.nih.gov/pubmed/21109113
16. Dong JY, Zhang YH, Qin LQ. Erectile dysfunction and risk of cardiovascular disease: meta-analysis of
prospective cohort studies. J Am Coll Cardiol 2011 Sep;58(13):1378-85.
http://www.ncbi.nlm.nih.gov/pubmed/21920268
17. DeBusk R, Drory Y, Goldstein I, et al. Management of sexual dysfunction in patients with
cardiovascular disease: recommendations of the Princeton Consensus Panel. Am J Cardiol 2000
Jul;86(2):175-81.
http://www.ncbi.nlm.nih.gov/pubmed/10913479
18. Kostis J, Jackson G, Rosen R, et al. Sexual dysfunction and cardiac risk (the Second Princeton
Consensus Conference). Am J Cardiol 2005 Jul;96(2):313-21.
http://www.ncbi.nlm.nih.gov/pubmed/16018863
19. Nehra A, Jackson G, Miner M, et al. The Princeton III Consensus recommendations for the
management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc 2012 Aug;87(8):
766-78.
http://www.ncbi.nlm.nih.gov/pubmed/22862865
20. Hatzichristou DG, Hatzimouratidis K, Ioannides E, et al. Nocturnal penile tumescence and rigidity
monitoring in young potent volunteers: reproducibility, evaluation criteria and the effect of sexual
intercourse. J Urol 1998 Jun;159(6):1921-6.
http://www.ncbi.nlm.nih.gov/pubmed/9598488
21. Meuleman EJ, Diemont WL. Investigation of erectile dysfunction. Diagnostic testing for vascular
factors in erectile dysfunction. Urol Clin North Am 1995 Nov;22(4):803-19.
http://www.ncbi.nlm.nih.gov/pubmed/7483130
22. Hatzichristou DG, Hatzimouratidis K, Apostolidis A, et al. Hemodynamic characterization of a
functional erection. Arterial and corporeal veno-occlusive function in patients with a positive
intracavernosal injection test. Eur Urol 1999;36(1):60-7.
http://www.ncbi.nlm.nih.gov/pubmed/10364657
23. Wespes E, Schulman C. Venous impotence: pathophysiology, diagnosis and treatment. J Urol 1993
May;149(5 Pt 2):1238-45.
http://www.ncbi.nlm.nih.gov/pubmed/8479008

16 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

24. Rosen RC, Leiblum SR, Spector IP. Psychologically based treatment for male erectile disorder: a
cognitive-interpersonal model. J Sex Marital Ther 1994 Summer;20(2):67-85.
http://www.ncbi.nlm.nih.gov/pubmed/8035472
25. Hatzichristou D, Rosen RC, Broderick G, et al. Clinical evaluation and management strategy for sexual
dysfunction in men and women. J Sex Med 2004 Jul;1(1):49-57.
http://www.ncbi.nlm.nih.gov/pubmed/16422983

3. TREATMENT OF ERECTILE DYSFUNCTION

3.1 Treatment options
The primary goal in the management strategy of a patient with ED is to determine its etiology and treat it when
possible, and not to treat the symptom alone. ED may be associated with modifiable or reversible risk factors,
including lifestyle or drug-related factors. These factors may be modified either before, or at the same time as,
specific therapies are used.
As a rule, ED can be treated successfully with current treatment options, but cannot be cured. The
only exceptions are psychogenic ED, post-traumatic arteriogenic ED in young patients, and hormonal causes
(e.g., hypogonadism and hyperprolactinaemia), which potentially can be cured with specific treatment.
Most men with ED will be treated with therapeutic options that are not cause specific. This results
in a structured treatment strategy that depends on efficacy, safety, invasiveness and cost, as well as patient
preference (1). To properly counsel patients with ED, physicians must be fully informed of all available treatment
options. In this context, physician-patient (partner) dialogue is essential throughout the management of ED.
The assessment of treatment options must consider patient and partner satisfaction and other QoL
factors as well as efficacy and safety. A treatment algorithm for ED is given in Figure 3.

3.2 Lifestyle management in ED with concomitant risk factors

The basic work-up of the patient must identify reversible risk factors for ED. Lifestyle changes and risk factor
modification must precede or accompany any pharmacological treatment.
The potential benefits of lifestyle changes may be particularly important in individuals with ED and
specific comorbid cardiovascular or metabolic disorders, such as diabetes or hypertension (2-4). Besides
improving erectile function, aggressive lifestyle changes may also benefit overall cardiovascular and metabolic
health, with recent studies supporting the potential of lifestyle intervention to benefit both ED and overall health
(5,6).
Although further studies are needed to clarify the role of lifestyle changes in management of ED
and related cardiovascular disease, lifestyle changes can be recommended alone or combined with PDE5
therapy. Some studies have suggested that the therapeutic effects of PDE5Is may be enhanced when other
comorbidities or risk factors are aggressively managed (7). A significant improvement can be expected as soon
as 3 months after initiating lifestyle changes (8).
However, these results have yet to be confirmed in well-controlled, long-term studies. As a result of
the success of pharmacological therapy for ED, clinicians need to provide specific evidence for the benefits of
lifestyle change, and hopefully, future research will show this.

3.3 Erectile dysfunction after radical prostatectomy

Use of proerectile drugs following RP is important in achieving postoperative erectile function. Several trials
have shown higher rates of erectile function recovery after RP in patients receiving any drug (therapeutic or
prophylactic) for ED. Early compared with delayed erectile rehabilitation brings forward the natural healing time
of potency (9).
Historically, the treatment options for postoperative ED have included intracavernous injections
(10), urethral microsuppository (11), vacuum device therapy (12), and penile implants (13). Intracavernous
injections and penile implants are still suggested as second- and third-line treatments, respectively, when oral
compounds are not adequately effective or contraindicated for postoperative patients (Sections 3.6 and 3.7).
The management of post-RP ED has been revolutionised by the advent of PDE5Is, with their
demonstrated efficacy, ease of use, good tolerability, excellent safety, and positive impact on QoL. Overall,
it must be emphasized that post-RP ED patients are poor responders to PDE5Is. However, PDE5Is are the
first-line choice of oral pharmacotherapy for post-RP ED in patients who have undergone nerve-sparing (NS)
surgery. The choice of PDE5Is as first-line treatment is controversial because the experience (surgical volume)
of the surgeon is a key factor in preserving postoperative erectile function, in addition to patient age and NS
technique (14-16). In fact, PDE5Is are most effective in patients who have undergone a rigorous NS procedure,

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 17

Figure 3: Treatment algorithm for ED

Treatment of ED

Identify and treat Lifestyle changes Provide education

‘curable’ causes of and risk factor and counselling to
ED modification patients and partners

Identify patient needs and expectations

Shared decision-making
Offer conjoint psychosocial and medical treatment

Intracavernous injections
PDE5 Vacuum devices
inhibitors Intraurethral alprostadil

Assess therapeutic outcome:

• Erectile response
• Side-effects
• Treatment satisfaction

Inadequate treatment outcome

Assess adequate use of treatment options

Provide new instructions and counselling
Re-trial
Consider alternative or combination therapy

Inadequate treatment outcome

Consider penile prosthesis implantation

18 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

which is more commonly performed by large-volume surgeons (14,15).
Early use of high-dose sildenafil after RP has been suggested to be associated with preservation of
smooth muscle within the corpora cavernosa (17). Daily sildenafil also results in a greater return of spontaneous
normal erectile function after RP compared to placebo following bilateral NSRP in patients who were fully
potent before surgery (18,19). The response rate to sildenafil treatment for ED after RP in different trials
has ranged from 35% to 75% among those who underwent NSRP and from 0% to 15% among those who
underwent non-NSRP (18-21).
Effectiveness of tadalafil and vardenafil as on-demand treatment has been evaluated in post-RP ED.
• A large multicentre trial in Europe and USA has studied tadalafil in patients with ED following bilateral
NS surgery. Erectile function was improved in 71% of patients treated with 20 mg tadalafil versus 24%
of those treated with placebo, while the rate of successful intercourse attempts was 52% with 20 mg
tadalafil versus 26% with placebo (22).
• Similarly, vardenafil has been tested in patients with ED following either unilateral or bilateral NS
surgery in a randomised, multicentre, prospective, placebo-controlled study in North America (23).
Following bilateral NSRP, erectile function improved by 71% and 60% with 10 and 20 mg vardenafil,
respectively. An extended analysis of the same patients undergoing NSRP has underlined the benefit
of vardenafil compared to placebo regarding intercourse satisfaction, hardness of erection, orgasmic
function, and overall satisfaction with sexual experience (24).

A randomised, double-blind, double-dummy, multicentre, parallel-group study in 87 centres across Europe,

Canada, South Africa and the USA, compared on-demand and nightly dosing of vardenafil in men with ED
following bilateral NSRP. In patients whose IIEF erectile function domain (IIEF-EF) score was > 26 before
surgery, vardenafil was efficacious when used on demand, supporting a paradigm shift towards on-demand
dosing with PDE5Is in post-RP ED (25). A prospective, randomised, open label, multicentre American study in
men with normal erection who underwent bilateral NSRP showed that oral and intraurethral treatment has the
same benefit for penile recovery within the first year after surgery (26).
Patients who do not respond to oral PDE5Is after NSRP may be treated with prophylactic
intracorporeal alprostadil (27,28). Penile prosthesis remains a satisfactory approach for patients who do not
respond to either oral or intracavernous pharmacotherapy or to a vacuum device (29).

3.4 Causes of ED that can be potentially treated with a curative intent

3.4.1 Hormonal causes
The advice of an endocrinologist may be beneficial for managing patients with hormonal abnormalities.
Testosterone deficiency is either a result of primary testicular failure or secondary to pituitary/hypothalamic
causes, including a functional pituitary tumour resulting in hyperprolactinaemia.
Testosterone replacement therapy (intramuscular, oral, or transdermal) is effective, but should only
be used after other endocrinological causes for testicular failure have been excluded (30). Testosterone
replacement is controversial in men with a history of prostate carcinoma (LE: 4) (31). There is limited evidence
suggesting that such treatment may not pose an undue risk of prostate cancer recurrence or progression
(32). Before initiating testosterone replacement, digital rectal examination, serum PSA test, haematorcrit, liver
function tests and lipid profile should be performed (33). Patients given androgen therapy should be monitored
for clinical response, elevated haematorcrit and development of hepatic or prostatic disease. Testosterone
therapy is contraindicated in patients with untreated prostate cancer or unstable cardiac disease.

3.4.2 Post-traumatic arteriogenic ED in young patients

In young patients with pelvic or perineal trauma, surgical penile revascularisation has a 60-70% long-term
success rate (34). The lesion must be demonstrated by duplex Doppler study of the penis and confirmed by
penile pharmacoarteriography. Corporeal veno-occlusive dysfunction is a contraindication to revascularisation
and must be excluded by DICC. Vascular surgery for veno-occlusive dysfunction is no longer recommended
because of poor long-term results (35).

3.4.3 Psychosexual counselling and therapy

For patients with a significant psychological problem, psychosexual therapy may be given either alone or with
another therapeutic approach. Psychosexual therapy requires ongoing follow-up and has had variable results
(36).

3.5 First-line therapy

3.5.1 Oral pharmacotherapy
PDE5 hydrolyses cGMP in the cavernosum tissue. Inhibition of PDE5 results in smooth muscle relaxation with
increased arterial blood flow, leading to compression of the subtunical venous plexus and penile erection (37).

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 19

 Three potent selective PDE5Is have been approved by the European Medicines Agency (EMA) for the
treatment of ED. They are not initiators of erection and require sexual stimulation to facilitate an erection.

3.5.1.1 Sildenafil
Sildenafil was launched in 1998 and was the first PDE5I available on the market. Efficacy is defined as an
erection with rigidity sufficient for vaginal penetration. Sildenafil is effective from 30-60 min after administration.
Its efficacy is reduced after a heavy, fatty meal due to prolonged absorption. It is administered in doses of 25,
50 and 100 mg. The recommended starting dose is 50 mg and should be adapted according to the patient’s
response and side effects. Efficacy may be maintained for up to 12 h (38). The pharmacokinetic data of
sildenafil are presented in Table 7. Adverse events (Table 8) are generally mild in nature and self-limited by
continuous use. The drop-out rate due to adverse events is similar to that with placebo (39).
After 24 weeks in a dose-response study, improved erections were reported by 56%, 77% and 84%
of a general ED population taking 25, 50 and 100 mg sildenafil, respectively, compared to 25% of men taking
placebo (40). Sildenafil significantly improves patient scores in IIEF, sexual encounter profile (SEP)2, SEP3, and
general assessment question (GAQ) and treatment satisfaction.
The efficacy of sildenafil in almost every subgroup of patients with ED has been successfully
established. In patients with diabetes, 66.6% reported improved erections (GAQ) and 63% successful
intercourse attempts compared to 28.6% and 33% of men taking placebo, respectively (41).

3.5.1.2 Tadalafil
Tadalafil was licenced for treatment of ED in February 2003 and is effective from 30 min after administration,
with peak efficacy after about 2 h. Efficacy is maintained for up to 36 h (42) and is not affected by food. Ten and
20 mg doses have been approved for on-demand treatment of ED. The recommended starting dose is 10 mg
and should be adapted according to the patient’s response and side effects. Pharmacokinetic data of tadalafil
are presented in Table 7. Adverse events (Table 8) are generally mild in nature and self-limited by continuous
use. The drop-out rate due to adverse events is similar to that with placebo (43).
In premarketing studies, after 12 weeks of treatment and in a dose-response study, improved
erections were reported by 67% and 81% of a general ED population taking 10 and 20 mg tadalafil,
respectively, compared to 35% of men in the control placebo group (43). Tadalafil significantly improves
patient scores in IIEF, SEP2, SEP3, and GAQ and treatment satisfaction. These results have been confirmed in
postmarketing studies (44).
Tadalafil also improves erections in difficult-to-treat subgroups. In patients with diabetes, 64%
reported improved erections (i.e., improved GAQ) versus 25% of patients in the control group, and the change
in the final score for IIEF-EF was 7.3 compared to 0.1 for placebo (45). Nevertheless diabetic patients remain
poor responders to tadalafil on demand, with a successful intercourse rates increasing from 21.8% with
placebo to 45.4 and 49.9% with 10 and 20 mg of tadalafil on demand respectively (46).

3.5.1.3 Vardenafil
Vardenafil became commercially available in March 2003 and is effective from 30 min after administration.
Its effect is reduced by a heavy, fatty meal (> 57% fat). Five, 10 and 20 mg doses have been approved for
on-demand treatment of ED. The recommended starting dose is 10 mg and should be adapted according to
the patient’s response and side effects. In vitro, it is 10-fold more potent than sildenafil, although this does not
necessarily mean greater clinical efficacy (47). Pharmacokinetic data of vardenafil are presented in Table 7.
Adverse events (Table 8) are generally mild in nature and self-limited by continuous use, with a drop-out rate
similar to that with placebo (48).
After 12 weeks in a dose-response study, improved erections were reported by 66%, 76% and 80%
of a general ED population taking 5, 10 and 20 mg vardenafil, respectively, compared with 30% of men taking
placebo (49). Vardenafil significantly improved patient scores for IIEF, SEP2, SEP3, and GAQ and treatment
satisfaction. Efficacy has been confirmed in postmarketing studies (50).
Vardenafil improves erections in difficult-to-treat subgroups. In patients with diabetes, the final IIEF-EF
score was 19 compared to 12.6 for placebo (51). Nevertheless, again, diabetic patients remain poor responders
to vardenafil on-demand with a successful intercourse rates increasing from 23% with placebo to 49% and
54% with 10 and 20 mg of vardenafil on-demand, respectively (51).
Recently, a new formulation of vardenafil has been released, in the form of an orodispersable tablet
(ODT). Orodispersable tablet formulations offer improved convenience over film-coated formulations and may
be preferred by patients. Absorption is unrelated to food intake and they exhibit better bioavailability compared
to film-coated tablets (52). The efficacy of vardenafil ODT has been demonstrated in several randomised
controlled trials and did not seem to differ from the regular formulation (53-56).

20 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

3.5.1.4 Choice or preference between the different PDE5 inhibitors
To date, no data are available from double- or triple-blind multicentre studies comparing the efficacy and/or
patient preference for sildenafil, tadalafil, and vardenafil. Choice of drug will depend on the frequency of
intercourse (occasional use or regular therapy, 3-4 times weekly) and the patient’s personal experience.
Patients need to know whether a drug is short- or long-acting, its possible disadvantages, and how to use it.

3.5.1.5 On-demand or chronic use of PDE5 inhibitors

Animal studies have shown that chronic use of PDE5Is improves or prevents significantly the intracavernous
structure alterations due to age, diabetes, or surgical damage (57-62). No data exists for a human population.
In humans, a randomised study (n = 145) has shown that daily tadalafil led to a significantly higher
IIEF-EF score and higher completion of successful intercourse attempts compared to on-demand tadalafil (63).
Two major randomised double-blind studies, using 5 and 10 mg/day tadalafil for 12 weeks (n = 268) (64) and
2.5 and 5 mg/day tadalafil for 24 weeks (n = 286) (65), have shown that daily dosing was well tolerated and
significantly improved erectile function. However, these studies lacked a comparative on-demand treatment
arm. An open-label extension was carried out for both studies in 234 patients for 1 year and 238 patients for 2
years. Tadalafil, 5 mg once daily, was shown to be well tolerated and effective (66). Tadalafil, 5 mg once daily,
therefore provides an alternative to on-demand dosing of tadalafil for couples who prefer spontaneous rather
than scheduled sexual activities or who anticipate frequent sexual activity, with the advantage that dosing and
sexual activity no longer need to be temporally linked. Nevertheless, in the 1-year open-label 5 mg tadalafil
extension study followed by 4 weeks wash-out, erectile function was not maintained after discontinuation of
therapy in most patients (about 75%).
In 2007, tadalafil 2.5 and 5 mg have been approved by the European Medicines Agency (EMA) for
daily treatment of ED. According to EMA, patients who anticipate a frequent use of tadalafil (i.e., at least twice
weekly) a once daily regimen with tadalafil 2.5 mg or 5 mg might be considered suitable, based on patient
choice and the physician's judgement. In these patients, the recommended dose is 5 mg taken once a day at
approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual
tolerability. The appropriateness of the continuous use of a daily regimen should be reassessed periodically

A double-blind, placebo-controlled, multicentre, parallel-group study was conducted in 236 men with
mild-to-moderate ED randomised to receive 10 mg vardenafil once daily plus on-demand placebo for 12 or 24
weeks, or once-daily placebo plus on-demand 10 mg vardenafil for 24 weeks, followed by 4 weeks wash-out
(67). Despite preclinical evidence, the results suggested that once-daily dosing of 10 mg vardenafil does not
offer any sustainable effect after cessation of treatment compared to on-demand administration in patients with
mild-to-moderate ED.
Other studies (open-label, randomised, crossover studies with limited patient numbers) have shown
that chronic, but not on-demand, tadalafil treatment improves endothelial function with a sustained effect after
its discontinuation (68,69). This has been confirmed in another study of chronic sildenafil in men with type 2
diabetes (70).
Recently, in a double-blind, placebo-controlled study of 298 men with diabetes and ED, 2.5 and 5 mg
tadalafil once daily for 12 weeks was efficacious and well tolerated. This regimen provides an alternative to
on-demand treatment for some men with diabetes (71).

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 21

Table 7: Summary of the key pharmacokinetic data for the three PDE5 inhibitors used to treat ED*

Parameter Sildenafil, 100 mg Tadalafil, 20 mg Vardenafil, 20 mg

Cmax 560 μg/L 378 μg/L 18.7 μg/L
Tmax 0.8-1 h 2h 0.9 h
T1/2 2.6-3.7 h 17.5 h 3.9 h
AUC 1685 μg.h/L 8066 μg.h/L 56.8 μg.h/L
Protein binding 96% 94% 94%
Bioavailability 41% NA 15%
Cmax: maximal concentration, Tmax: time-to-maximum plasma concentration; T1/2: plasma elimination halftime;
AUC: area under curve or serum concentration time curve.

* Fasted state, higher recommended dose. Data adapted from EMA statements on product characteristics.

Table 8: Common adverse events of the three PDE5 inhibitors used to treat ED*

Adverse event Sildenafil Tadalafil Vardenafil

Headache 12.8% 14.5% 16%
Flushing 10.4% 4.1% 12%
Dyspepsia 4.6% 12.3% 4%
Nasal congestion 1.1% 4.3% 10%
Dizziness 1.2% 2.3% 2%
Abnormal vision 1.9% < 2%
Back pain 6.5%
Myalgia 5.7%
* Adapted from EMA statements on product characteristics.

Sildenafil: http://www.emea.europa.eu/humandocs/Humans/EPAR/viagra/viagra.htm
Tadalafil: http://www.emea.europa.eu/humandocs/Humans/EPAR/cialis/cialis.htm
Vardenafil: http://www.emea.europa.eu/humandocs/Humans/EPAR/levitra/levitra.htm

3.5.1.6 Safety issues for PDE5 inhibitors

3.5.1.6.1 Cardiovascular safety
Clinical trial results and post-marketing data of sildenafil, tadalafil, and vardenafil have demonstrated no
increase in myocardial infarction rates in patients receiving PDE5Is, as part of either double-blind, placebo-
controlled trials or open-label studies, or compared to expected rates in age-matched male populations.
None of the PDE5Is had an adverse effect on total exercise time or time-to-ischaemia during exercise
testing in men with stable angina (72,73). In fact, they may even improve exercise tests. Sildenafil does not
alter cardiac contractility, cardiac output or myocardial oxygen consumption according to available evidence.
Chronic or on-demand use is well tolerated with a similar safety profile.

3.5.1.6.2 Nitrates are contraindicated with PDE5 inhibitors

Organic nitrates (e.g., nitroglycerine, isosorbide mononitrate, and isosorbide dinitrate) and other nitrate
preparations used to treat angina, as well as amyl nitrite or amyl nitrate (“poppers” used for recreation), are
absolute contraindications for the use of PDE5Is. They result in cGMP accumulation and unpredictable falls in
blood pressure and symptoms of hypotension. The duration of interaction between organic nitrates and PDE5Is
depends upon the PDE5I and nitrate used.
If a PDE5I is taken and the patient develops chest pain, nitroglycerine must be withheld for at least 24
h if sildenafil (and probably also vardenafil) is used (half-life, 4 h), and for at least 48 h if tadalafil is used (half-
life, 17.5 h).
If a patient develops angina while taking a PDE5I, other agents may be given instead of nitroglycerine
until the appropriate time has passed. If nitroglycerine must be reintroduced following administration of a PDEI,
the patient should receive it only after an appropriate interval has elapsed, as described above, and under
close medical observation.

3.5.1.6.3 Antihypertensive drugs

Co-administration of PDE5Is with antihypertensive agents (angiotensin-converting enzyme inhibitors,
angiotensin-receptor blockers, calcium blockers, β-blockers, and diuretics) may result in small additive

22 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

decreases in blood pressure, which are usually minor. In general, the adverse event profile of a PDE5I is
not made worse by a background of antihypertensive medication, even when the patient is taking several
antihypertensive agents.

3.5.1.6.4 α-Blocker interactions

All PDE5Is show some interaction with α-blockers, which under some conditions may result in orthostatic
hypotension.
• Sildenafil labelling currently advises that 50 or 100 mg sildenafil should be used with caution in
patients taking an α-blocker (especially doxazosin). Hypotension is more likely to occur within 4 h
following treatment with an α-blocker. A starting dose of 25 mg is recommended.
• Concomitant treatment with vardenafil should only be initiated if the patient has been stabilised on his
alpha-blocker therapy.
• Co-administration of vardenafil with tamsulosin is not associated with clinically significant hypotension
(74).
• Tadalafil is not recommended in patients taking doxazosin but this is not the case for tamsulosin,
0.4 mg (75).

These interactions are more pronounced when PDE5Is are given to healthy volunteers not previously taking
α-blockers. Therefore, patients should be stable on α-blocker therapy prior to initiating combined treatment,
and that the lowest dose should be started initially of PDE5Is. Further research is needed into the interaction
between other PDE5Is and other α-blockers (e.g., alfuzosin, once-daily), or mixed α/β-blockers (e.g., carvedilol
and labetalol).

3.5.1.6.5 Dosage adjustment

Drugs that inhibit the CYP34A pathway will inhibit the metabolic breakdown of PDE5Is. They include
ketoconazole, itraconazole, erythromycin, clarithromycin, and HIV protease inhibitors (ritonavir and saquinavir).
Such agents may increase blood levels of PDE5Is, so that lower doses of PDE5Is are necessary.
However, other agents, such as rifampin, phenobarbital, phenytoin and carbamazepine, may induce
CYP3A4 and enhance the breakdown of PDE5Is, so that higher doses of PDE5Is are required.
Severe kidney or hepatic dysfunction may require dose adjustments or warnings.

3.5.1.7 Management of non-responders to PDE5 inhibitors

The two main reasons why patients fail to respond to a PDE5I are either incorrect drug use or lack of efficacy of
the drug. The management of non-responders depends upon identifying the underlying cause.

3.5.1.7.1 Check that the patient has been using a licensed medication
There is a large black market in PDE5Is. The amount of active drug in these medications varies enormously and
it is important to check how and from which source the patient has obtained his medication.

3.6.1.7.2 Check that the medication has been properly prescribed and correctly used
The main reason why patients fail to use their medication correctly is inadequate counselling from their
physician. The main ways in which a drug may be incorrectly used are:
• failure to use adequate sexual stimulation;
• failure to use an adequate dose;
• failure to wait an adequate amount of time between taking the medication and attempting sexual
intercourse.

Lack of adequate sexual stimulation: PDE5I action is dependent on the release of NO by the parasympathetic
nerve endings in the erectile tissue of the penis. The usual stimulus for NO release is sexual stimulation, and
without adequate sexual stimulation (and NO release), the drugs cannot work.
Oral PDE5Is take different times to reach maximal plasma concentrations (76,77). Although
pharmacological activity is achieved at plasma levels well below the maximal plasma concentration, there will
be a period of time following oral ingestion of the medication during which the drug is ineffective. Even though
all three drugs have an onset of action in some patients within 30 min of oral ingestion, most patients require
a longer delay between taking the medication, with at least 60 min being required for men using sildenafil and
vardenafil, and up to 2 h being required for men using tadalafil (78-80).
Absorption of sildenafil can be delayed by a meal, and absorption of vardenafil can be delayed by a
fatty meal (81). Absorption of tadalafil is less affected provided there is enough delay between oral ingestion
and an attempt at sexual intercourse (77).
It is possible to wait too long after taking medication before attempting sexual intercourse. The half-life

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 23

of sildenafil and vardenafil is about 4 h, suggesting that the normal window of efficacy is 6-8 h following drug
ingestion, although responses following this time period are well recognised. Tadalafil has a longer half-life of
~17.5 h, so the window of efficacy is much longer at ~36 h.
For financial reasons, some physicians may prescribe only lower doses of a drug. It is important to
check that the patient has had an adequate trial of the maximal dose of the drug. Data suggest an adequate
trial involves at least six attempts with a particular drug (82).
Data from uncontrolled studies suggests patient education can help salvage an apparent non-
responder to a PDE5I. After emphasising the importance of dose, timing, and sexual stimulation to the patient,
erectile function can be effectively restored following re-administration of the relevant PDE5I (83-85).
One study (84) went further, and in those patients who still did not respond to the PDE5I, a second-line
adjustment was instituted. Patients taking tadalafil were advised to wait at least 2 h between oral ingestion and
attempting intercourse. Patients taking vardenafil were advised to use the drug only after a fast. In both patient
groups, further apparent non-responders were salvaged. No patients using sildenafil were included in this
study.

3.5.1.7.3 Possible manoeuvres in patients correctly using a PDE5 inhibitor

When the patient is using an adequate dose of the drug properly and the response is still inadequate, there
are several changes that may improve drug efficacy, although the evidence supporting these interventions is
limited.
Erectile dysfunction is typically a symptom of an underlying condition, such as diabetes, hypertension,
or dyslipidaemia. There is evidence suggesting that, in patients with hypogonadism, normalisation of serum
testosterone might improve response to a PDE5I (86). Modification of other risk factors may be also be
beneficial as discussed in section 3.2.
A randomised trial has suggested that vardenafil benefits non-responders to sildenafil (87), but
because of poor study design, the results are considered to overstate the benefits of switching PDE5Is.
However, a randomised, open-label, crossover trial comparing sildenafil and tadalafil has indicated that some
patients might respond better to one PDE5I than to another (88). According to the IIEF-EF score, 17% of
patients had a better response (> 5 points) to tadalafil than to sildenafil, while 14% had a better response to
sildenafil than tadalafil.
Although these differences might be explained by variation in drug pharmacokinetics, they do raise the
possibility that, despite an identical mode of action, switching to a different PDE5I might be helpful.
Two non-randomized trials have suggested that daily dosing with a PDE5I might salvage some
non-responders to intermittent dosing. In one trial (89), some men benefited from regular dosing with either
vardenafil or tadalafil, while in the other trial (84) daily dosing with tadalafil salvaged some men who had failed
to respond to intermittent dosing with a PDE5I.
Currently, there are no randomised trials to support this intervention. Although tadalafil is licensed for
daily dosing at 2.5 and 5 mg, neither sildenafil nor vardenafil are licensed for use in this way.
If drug treatment fails, then patients should be offered an alternative therapy such as intracavernosal
injection therapy or use of a vacuum erection device.

3.5.2 Vacuum erection devices

Vacuum erection devices (VEDs) provide passive engorgement of the corpora cavernosa, together with a
constrictor ring placed at the base of the penis to retain blood within the corpora. Thus, erections with these
devices are not normal because they do not use physiological erection pathways. Efficacy, in terms of erections
satisfactory for intercourse, is as high as 90%, regardless of the cause of ED and satisfaction rates range
between 27% and 94% (90). Men with a motivated, interested, and understanding partner report the highest
satisfaction rates. Long-term use of VEDs decreases to 50-64% after 2 years (91). Most men who discontinue
use of VEDs do so within 3 months.
The commonest adverse events include pain, inability to ejaculate, petechiae, bruising, and
numbness, which occur in < 30% of patients (92). Serious adverse events (skin necrosis) can be avoided
if patients remove the constriction ring within 30 min. VEDs are contraindicated in patients with bleeding
disorders or on anticoagulant therapy.
VEDs may be the treatment of choice in well-informed older patients with infrequent sexual intercourse
and comorbidity requiring non-invasive, drug-free management of ED (90).

3.5.3 Shockwave therapy

Recently, the use of low-intensity extracorporeal shock wave therapy was proposed as a novel treatment for
ED (93). In the first randomised, double-blind, sham-controlled study, it was demonstrated that low-intensity
extracorporeal shock wave therapy had a positive short-term clinical and physiological effect on the erectile
function of men who respond to oral PDE5Is (94). Moreover, there are preliminary data showing improvement

24 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

in penile haemodynamics and endothelial function, as well as IIEF-EF domain score in severe ED patients who
are poor responders to PDE5Is (95).The feasibility and tolerability of this treatment, coupled with its potential
rehabilitative characteristics, make it an attractive new therapeutic option for men with ED. However, current
data are limited and clear recommendations cannot be given. Data regarding the mechanism of action of this
procedure are still lacking. In a diabetic rat model, low-intensity extracorporeal shock wave therapy ameliorated
diabetes mellitus associated ED by promoting regeneration of nNOS-positive nerves, endothelium, and
smooth muscle in the penis. These beneficial effects appear to be mediated by recruitment of endogenous
mesechymal stem cells (MSCs) (96).

3.6 Second-line therapy

Patients not responding to oral drugs may be offered intracavernous injections. Success rate is high (85%)
(97,98). Intracavernous administration of vasoactive drugs was the first medical treatment for ED more than 20
years ago (99).

3.6.1 Intracavernous injections

3.6.1.1 Alprostadil
Alprostadil (CaverjectTM, Edex/ViridalTM) was the first and only drug approved for intracavernous treatment of
ED (99). Intracavernous alprostadil is most efficacious as monotherapy at a dose of 5-40 μg; although the 40
μg dose is not registered in every European country. The erection appears after 5-15 min and lasts according to
the dose injected. An office-training programme (one or two visits) is required for the patient to learn the correct
injection process. In cases of limited manual dexterity, the technique may be taught to their partners. The use
of an automatic special pen that avoids a view of the needle can resolve fear of penile puncture and simplifies
the technique.
Efficacy rates for intracavernous alprostadil of > 70% have been found in general ED populations, as
well as in patient subgroups (e.g., diabetes or cardiovascular disease), with reported sexual activity after 94%
of the injections and satisfaction rates of 87-93.5% in patients and 86-90.3% in partners (100-102).
Complications of intracavernous alprostadil include penile pain (50% of patients reported pain
but pain reported only after 11% of total injections), prolonged erections (5%), priapism (1%), and fibrosis
(2%) (103). Pain is usually self-limited after prolonged use. It can be alleviated with the addition of sodium
bicarbonate or local anaesthesia (104,105). Cavernosal fibrosis (from a small hematoma) usually clears within a
few months after temporary discontinuation of the injection program. However, tunical fibrosis suggests early
onset of La Peyronie’s disease and may indicate stopping intracavernosal injections indefinitely. Systemic side
effects are uncommon. The most common is mild hypotension, especially when using higher doses.
Contraindications include men with a history of hypersensitivity to alprostadil, men at risk of priapism,
and men with bleeding disorders.
Despite these favourable data, intracavernous pharmacotherapy is associated with high drop-out
rates and limited compliance. Drop-out rates of 41-68% have been described (106-108), with most drop-
outs occurring within the first 2-3 months. In a comparative study, alprostadil monotherapy had the lowest
discontinuation rate (27.5%) compared to overall drug combinations (37.6%), with an attrition rate after the first
few months of therapy of 10% per year. Reasons for discontinuation included desire for a permanent modality
of therapy (29%), lack of a suitable partner (26%), poor response (23%) (especially among early drop-out
patients), fear of needles (23%), fear of complications (22%), and lack of spontaneity (21%). Careful counselling
of patients during the office-training phase as well as close follow-up is important in addressing patient
withdrawal from an intracavernous injection programme (109).
Today, intracavernous pharmacotherapy is considered a second-line treatment. Patients not
responding to oral drugs may be offered intracavernous injections with a high success rate of 85%. Most long-
term injection users can switch to sildenafil despite underlying pathophysiology (110-112). However, almost
one-third of long-term intracavernous injection users who subsequently also responded to sildenafil preferred
to continue with an intracavernous injection programme (112,113).

3.6.1.2 Combination therapy

Combination therapy enables a patient to take advantage of the different modes of action of the drugs being
used, as well as alleviating side effects by using lower doses of each drug.
• Papaverine (20-80 mg) was the first oral drug used for intracavernous injections. It is most commonly
used in combination therapy today due to its high incidence of side effects as monotherapy.
• Phentolamine has been used in combination therapy to increase efficacy. As monotherapy, it produces
a poor erectile response.
• Sparse data in the literature support the use of other drugs, such as vasoactive intestinal peptide
(VIP), NO donors (linsidomine), forskolin, potassium channel openers, moxisylyte or calcitonin gene-
related peptide (CGRP), usually combined with the main drugs (114,115). Most combinations are not

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 25

 standardised and some drugs have limited availability worldwide.
• Papaverine (7.5-45 mg) plus phentolamine (0.25-1.5 mg), and papaverine (8-16 mg) plus phentolamine
(0.2-0.4 mg) plus alprostadil (10-20 μg), have been widely used with improved efficacy rates, although
they have never been licensed for ED (116-118). The triple combination regimen of papaverine,
phentolamine and alprostadil has the highest efficacy rates, reaching 92%; this combination has
similar side effects as alprostadil monotherapy, but a lower incidence of penile pain due to lower
doses of alprostadil. However, fibrosis is more common (5-10%) when papaverine is used (depending
on total dose). In addition, mild hepatotoxicity has been reported with papaverine (119).

Despite high efficacy rates, 5-10% of patients do not respond to combination intracavernous injections. The
combination of sildenafil with intracavernous injection of the triple combination regimen may salvage as many
as 31% of patients who do not respond to the triple combination alone (120). However, combination therapy is
associated with an incidence of adverse effects in 33% of patients, including dizziness in 20% of patients. This
strategy can be considered in carefully selected patients before proceeding to a penile implant.

3.6.1.3 Intraurethral alprostadil

A specific formulation of alprostadil (125-1000 μg) in a medicated pellet (MUSETM) has been approved for use in
ED (121). A vascular interaction between the urethra and the corpora cavernosa enables drug transfer between
these structures (121). Erections sufficient for intercourse are achieved in 30-65.9% of patients. In clinical
practice, only the higher doses (500 and 1000 μg) have been used with low consistency response rates (121-
123). The application of a constriction ring at the root of the penis (ACTISTM) may improve efficacy (123,124).
The most common adverse events are local pain (29-41%) and dizziness with possible hypotension
(1.9-14%). Penile fibrosis and priapism are very rare (< 1%). Urethral bleeding (5%) and urinary tract infections
(0.2%) are adverse events related to the mode of administration.
Efficacy rates are significantly lower than intracavernous pharmacotherapy (125). Intraurethral
pharmacotherapy is a second-line therapy and provides an alternative to intracavernous injections in patients
who prefer a less-invasive, although less-efficacious treatment.

3.7 Third-line therapy (penile prostheses)

The surgical implantation of a penile prosthesis may be considered in patients who do not respond to
pharmacotherapy or who prefer a permanent solution to their problem. The two currently available classes of
penile implants include inflatable (2- and 3-piece) and malleable devices (126-129).
Most patients prefer the three-piece inflatable devices due to the more “natural” erections obtained.
The three-piece inflatable penile include a separate reservoir placed in the abdominal cavity. Three-piece
devices provide the best rigidity and the best flaccidity because they will fill every part of the corporal bodies.
However, the two-piece inflatable prosthesis can be a viable option among patients who are deemed high risk
of complications with reservoir placements. Malleable prostheses result in a firm penis, which may be manually
placed in an erect or flaccid state (126-129).
There are two main surgical approaches for penile prosthesis implantation: peno-scrotal and
infrapubic (126-129). The penoscrotal approach provides an excellent exposure, it affords proximal crural
exposure if necessary, avoids dorsal nerve injury and permits direct visualisation of pump placement. However,
with this approach the reservoir is blindly placed into the retropubic space, which can be a problem in patients
with a history of major pelvic surgery (mainly radical cystectomy). The infrapubic approach has the advantage
of reservoir placement under direct vision but the implantation of the pump may be more challenging, and
patients are at a slightly increased risk of dorsal nerve injury. Revision surgery is associated with decreased
outcomes and may be more challenging.

3.7.1 Efficacy and satisfaction rates

Prosthesis implantation has one of the highest satisfaction rates (92-100% in patients and 91-95% in partners)
among the treatment options for ED based on appropriate consultation (130-137). Mulhall and colleagues
have used the IIEF and the Erectile Dysfunction Index for Treatment Satisfaction (EDITS) at 3-month intervals
following implantation of inflatable penile prostheses. There was a continued improvement in scores for
the IIEF and EDITS stabilised 9-12 months following surgery. All variables, including erection, ejaculation,
orgasm, and overall sexual satisfaction, improved above baseline values at 1 year after surgery. However, at
3 months following surgery, the results were less satisfactory, suggesting that postoperative counselling and
encouragement of patients is important to obtain ultimate satisfaction and positive outcomes at 9-12 months
(134).
In a long-term multicentre study of the AMS 700CX three-piece inflatable prosthesis, with a median
follow-up of 48 months, 79% of patients were using their device at least twice monthly and 88% would
recommend the prosthesis to a friend or relative (135). In another multicentre study with 59 months follow-up,

26 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

at almost 5 years after surgery, 92.5% of patients were using their prosthesis an average of 1.7 times weekly
and excellent or satisfactory results were reported by patients and their partners (132).
Increasingly, in patients with favourable prognosis after RP for prostate cancer, the presence of
urinary incontinence and sexual dysfunction (primarily ED and orgasmic dysfunction) is leading doctors to the
need for global management of both conditions. Based on appropriate clinical and diagnostic assessments of
severity of adverse outcomes depending on patient preference, combination surgery for treatment of ED, with
the implant of a penile prosthesis, and stress urinary incontinence (male sling or artificial urinary sphincter) is
effective and durable and has an established, definitive role to address this problem (138).

3.7.2 Complications
The two main complications of penile prosthesis implantation are mechanical failure and infection. Several
technical modifications of the most commonly used three-piece prosthesis (AMS 700CX/CXRTM and Coloplast
Alpha ITM) resulted in mechanical failure rates of < 5% after 5 years follow-up (135,139). Careful surgical
technique with proper antibiotic prophylaxis against Gram-positive and Gram-negative bacteria reduces
infection rates to 2-3% with primary implantation in low-risk patients. The infection rate may be further
reduced to 1-2% by implanting an antibiotic-impregnated prosthesis (AMS InhibizoneTM) or hydrophilic-coated
prosthesis (Coloplast itanTM) (140-143).
Higher risk populations include patients undergoing revision surgery, those with impaired host
defenses (immunosuppression, diabetes mellitus, spinal cord injury) or those with penile corporal fibrosis (126-
129). Although diabetes is considered to be one of the main risk factors for infection, this is not supported by
current data (126-129). Infections, as well as erosions, are significantly higher (9%) in patients with spinal cord
injuries (9%) (126-129). Infection requires removal of the prosthesis and antibiotic administration. Alternatively,
removal of the infected device with immediate replacement with a new prosthesis has been described using
a washout protocol with successful salvages achieved in > 80% of cases (144,145). The majority of revisions
are secondary to mechanical failure and combined erosion or infection. Overall, 93% of cases are successfully
revised, providing functioning penile prosthesis.

3.7.3 Conclusions
Penile implants are an attractive solution for patients who do not respond to more conservative therapies.
There is enough evidence to recommend this approach in patients not responding to less-invasive treatments
due to its high efficacy, safety and satisfaction rates.

3.8 Guidelines for the treatment of ED

LE GR
Lifestyle changes and risk factor modification must precede or accompany ED treatment. 1a A
Pro-erectile treatments have to be given at the earliest opportunity after RP. 1b A
When a curable cause of ED is found, it must be treated first. 1b B
PDE5Is are first-line therapy. 1a A
Inadequate/incorrect prescription and poor patient education are the main causes of a lack of 3 B
response to PDE5Is.
A VED can be used in patients with a stable relationship. 4 C
Intracavernous injection is second-line therapy. 1b B
Penile implant is third-line therapy. 4 C

3.9 References
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116. Bechara A, Casabé A, Chéliz G, et al. Comparative study of papaverine plus phentolamine versus
prostaglandin E1 in erectile dysfunction. J Urol 1997 Jun;157(6):2132-4.
http://www.ncbi.nlm.nih.gov/pubmed/9146599
117. Bennett AH, Carpenter AJ, Barada JH. An improved vasoactive drug combination for a
pharmacological erection program. J Urol 1991 Dec;146(6):1564-5.
http://www.ncbi.nlm.nih.gov/pubmed/1719248
118. McMahon CG. A comparison of the response to the intracavernosal injection of papaverine and
phentolamine, prostaglandin E1 and a combination of all three agents in the management of
impotence. Int J Impot Res 1991;3:113-21.
119. Levine SB, Althof SE, Turner LA, et al. Side effects of self administration of intracavernous papaverine
and phentolamine for the treatment of impotence. J Urol 1989 Jan;141(1):54-7.
http://www.ncbi.nlm.nih.gov/pubmed/2908954
120. McMahon CG, Samali R, Johnson H. Treatment of intracorporeal injection nonresponse with sildenafil
alone or in combination with triple agent intracorporeal injection therapy. J Urol 1999 Dec;162(6):
1992-7;discussion 1997-8.
http://www.ncbi.nlm.nih.gov/pubmed/10569554
121. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al. Treatment of men with erectile dysfunction with
transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med
1997 Jan;336(1):1-7.
http://www.ncbi.nlm.nih.gov/pubmed/8970933
122. Fulgham PF, Cochran JS, Denman JL, et al. Disappointing initial results with transurethral alprostadil
for erectile dysfunction in a urology practice setting. J Urol 1998 Dec;160(6 Pt 1):2041-6.
http://www.ncbi.nlm.nih.gov/pubmed/9817319
123. Mulhall JP, Jahoda AE, Ahmed A, et al. Analysis of the consistency of intraurethral prostaglandin E(1)
(MUSE) during at-home use. Urology 2001 Aug;58(2):262-6.
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124. Costa P, Potempa AJ. Intraurethral alprostadil for erectile dysfunction: a review of the literature. Drugs
2012 Dec;72(17):2243-54.
http://www.ncbi.nlm.nih.gov/pubmed/23170913
125. Shabsigh R, Padma-Nathan H, Gittleman M, et al. Intracavernous alprostadil alfadex is more
efficacious, better tolerated, and preferred over intraurethral alprostadil plus optional actis: a
comparative, randomized, crossover, multicentre study. Urology 2000 Jan;55(4):109-13.
http://www.ncbi.nlm.nih.gov/pubmed/10654905
126. Mulcahy JJ, Austoni E, Barada JH, et al. The penile implant for erectile dysfunction. J Sex Med 2004,
Jul;1(1):98-109.
http://www.ncbi.nlm.nih.gov/pubmed/16422990
127. Montague DK, Angermeier KW. Penile prosthesis implantation. Urol Clin North Am 2001 May;28(2):
355-61, x.
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128. Montague DK. Penile prosthesis implantation in the era of medical treatment for erectile dysfunction.
Urol Clin North Am 2011 May;38(2):217-2.
http://www.ncbi.nlm.nih.gov/pubmed/21621088
129. Martinez-Salamanca JI, Mueller A, Moncada I, et al. Penile prosthesis surgery in patients with corporal
fibrosis: a state of the art review. J Sex Med 2011 Jul;8(7):1880-9.
http://www.ncbi.nlm.nih.gov/pubmed/21492405
130. Holloway FB, Farah RN. Intermediate term assessment of the reliability, function and patient
satisfaction with the AMS700 Ultrex penile prosthesis. J Urol 1997 May;157(5):1687-91.
http://www.ncbi.nlm.nih.gov/pubmed/9112506
131. Tefilli MV, Dubocq F, Rajpurkar A, et al. Assessment of psychosexual adjustment after insertion of
inflatable penile prosthesis. Urology 1998 Dec;52(6):1106-12.
http://www.ncbi.nlm.nih.gov/pubmed/9836564
132. Montorsi F, Rigatti P, Carmignani G, et al. AMS three-piece inflatable implants for erectile dysfunction:
a long-term multi- institutional study in 200 consecutive patients. Eur Urol 2000 Jan;37(1):50-5.
http://www.ncbi.nlm.nih.gov/pubmed/10671785
133. Lux M, Reyes-Vallejo L, Morgentaler A, et al. Outcomes and satisfaction rates for the redesigned
2-piece penile prosthesis. J Urol 2007 Jan;177(1):262-6.
http://www.ncbi.nlm.nih.gov/pubmed/17162061
134. Mulhall JP, Ahmed A, Branch J, et al. Serial assessment of efficacy and satisfaction profiles following
penile prosthesis surgery. J Urol 2003 Apr;169(4):1429-33.
http://www.ncbi.nlm.nih.gov/pubmed/12629377
135. Carson CC, Mulcahy JJ, Govier FE. Efficacy, safety and patient satisfaction outcomes of the AMS
700CX inflatable penile prosthesis: results of a long-term multicenter study. AMS 700CX Study Group.
J Urol 2000 Aug;164(2):376-80.
http://www.ncbi.nlm.nih.gov/pubmed/10893589
136. Natali A, Olianas R, Fisch M. Penile implantation in Europe: successes and complications with 253
implants in Italy and Germany. J Sex Med 2008 Jun;5(6):1503-12.
http://www.ncbi.nlm.nih.gov/pubmed/18410306
137. Bernal RM, Henry GD. Contemporary patient satisfaction rates for three-piece inflatable penile
prostheses. Adv Urol 2012;2012:707321.
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138. Lee D, Westney OL, Wang R. Combination surgery for erectile dysfunction and male incontinence.
Curr Urol Rep 2011 Dec;12(6):461-9.
http://www.ncbi.nlm.nih.gov/pubmed/21956147
139. Wilson SK, Cleves MA, Delk JR 2nd. Comparison of mechanical reliability of original and enhanced
Mentor Alpha I penile prosthesis. J Urol 1999 Sep;162(3 Pt 1):715-8.
http://www.ncbi.nlm.nih.gov/pubmed/10458350
140. Carson CC 3rd. Efficacy of antibiotic impregnation of inflatable penile prostheses in decreasing
infection in original implants. J Urol 2004 Apr;171(4):1611-4.
http://www.ncbi.nlm.nih.gov/pubmed/15017233
141. Wolter CE, Hellstrom WJ. The hydrophilic-coated inflatable penile prosthesis: 1-year experience.
J Sex Med 2004 Sep;1(2):221-4.
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142. Carson CC 3rd, Mulcahy JJ, Harsch MR. Long-term infection outcomes after original antibiotic
impregnated inflatable penile prosthesis implants: up to 7.7 years of follow-up. J Urol 2011
Feb;185(2):614-8.
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143. Serefoglu EC, Mandava SH, Gokce A, et al. Long-Term Revision Rate due to Infection in Hydrophilic-
Coated Inflatable Penile Prostheses: 11-Year Follow-up. J Sex Med 2012 Aug;9(8):2182-6.
http://www.ncbi.nlm.nih.gov/pubmed/22759917
144. Mulcahy JJ. Long-term experience with salvage of infected penile implants. J Urol 2000 Feb;
163(2):481-2.
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145. Henry GD, Donatucci CF, Conners W, et al. An outcomes analysis of over 200 revision surgeries for
penile prosthesis implantation: a multicenter study. J Sex Med 2012 Jan;9(1):309-15.
http://www.ncbi.nlm.nih.gov/pubmed/22082149

4. PREMATURE EJACULATION (PE)

4.1 Introduction
Although PE is a very common male sexual dysfunction, it is poorly understood. Patients are often unwilling to
discuss their symptoms and many physicians do not know about effective treatments. As a result, patients may
be misdiagnosed or mistreated (1).

These guidelines provide an evidence-based analysis (2) of published data on definition, clinical evaluation and
treatment. It provides recommendations to help clinicians with the diagnosis and treatment of PE.

4.2 Definition of PE
4.2.1 Overview
There have previously been two official definitions of PE, neither of which have been universally accepted:
• In the Diagnostic and Statistical Manual of Mental Disorders IV-Text Revision (DSM-IV-TR), PE is
defined as a ‘persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly
after penetration and before the person wishes it. The clinician must take into account factors that
affect duration of the excitement phase, such as age, novelty of the sexual partner or situation, and
recent frequency of sexual activity’ (3).
• In the World Health Organization’s International Classification of Diseases-10 (ICD-10), PE is defined
as ‘the inability to delay ejaculation sufficiently to enjoy lovemaking, which is manifested by either
an occurrence of ejaculation before or very soon after the beginning of intercourse (if a time limit is
required: before or within 15 seconds of the beginning of intercourse) or ejaculation occurs in the
absence of sufficient erection to make intercourse possible. The problem is not the result of prolonged
absence from sexual activity’ (4).

More recently, two more definitions have been proposed:

• The Second International Consultation on Sexual and Erectile Dysfunction defined PE as ‘ejaculation
with minimal stimulation and earlier than desired, before or soon after penetration, which causes
bother or distress, and over which the sufferer has little or no voluntary control’ (5).
• The International Society for Sexual Medicine (ISSM) has adopted a completely new definition of
PE which is the first evidence-based definition, ‘Premature ejaculation is a male sexual dysfunction
characterized by ejaculation which always or nearly always occurs prior to or within about one minute
of vaginal penetration; and inability to delay ejaculation on all or nearly all vaginal penetrations; and
negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual
intimacy’. It must be noted that this definition is limited to men with lifelong PE who engage in vaginal
intercourse since there are insufficient objective data to propose an evidence-based definition for
acquired PE (6).

All four definitions have taken into account the time to ejaculation, the inability to control or delay ejaculation,
and negative consequences (bother/distress) from PE. However, the major point of debate is quantifying the
time to ejaculation, which is usually described by intravaginal ejaculatory latency time (IELT). Several proposals
for updating the definition of PE in the forthcoming DSM-V and ICD-11 have been presented (7-11).

4.2.2 Classifications
Premature ejaculation is classified as ‘lifelong’ (primary) or ‘acquired’ (secondary) (12).
• Lifelong PE is characterized by onset from the first sexual experience, remains so during life and
ejaculation occurs too fast (before vaginal penetration or < 1-2 min after).

36 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

• Acquired PE is characterized by a gradual or sudden onset following normal ejaculation experiences
before onset and time to ejaculation is short (usually not as short as in lifelong PE).

Recently, two more PE syndromes have been proposed (11):

• ‘Natural variable PE’ is characterized by inconsistent and irregular early ejaculations, representing a
normal variation in sexual performance.
• ‘Premature-like ejaculatory dysfunction’ is characterized by subjective perception of consistent or
inconsistent rapid ejaculation during intercourse, while ejaculation latency time is in the normal range
or can even last longer. It should not be regarded as a symptom or manifestation of true medical
pathology.
The addition of these new types may aid patient stratification, diagnosis and treatment, but their exact role
remains to be defined (13).

4.3 Epidemiology of PE
4.3.1 Prevalence
The major problem in assessing the prevalence of PE is the lack of an accurate (validated) definition at the time
the surveys were conducted (14). However, epidemiological research has consistently shown that PE, at least
according to the DSM-IV definition, is the most common male sexual dysfunction, with prevalence rates of
20-30% (15-17).
The highest prevalence rate of 31% (men aged 18-59 years) was found by the National Health and
Social Life Survey (NHSLS) study in USA (16). Prevalence rates were 30% (18-29 years), 32% (30-39 years),
28% (40-49 years) and 55% (50-59 years). These high prevalence rates may be a result of the dichotomous
scale (yes/ no) in a single question asking if ejaculation occurred too early, as the prevalence rates in European
studies have been significantly lower. A British self-completed mailed questionnaire survey estimated that the
prevalence rate of PE was between 14% (3 months) and 31% (life-time) (18). A French telephone survey of
men aged 40 to 80 years estimated the prevalence of premature ejaculation at 16% (19). A Swedish interview
reported an overall prevalence rate of 9% in men aged 18 to 74 years (20), with prevalence by age being 4%
(18-24 years), 7% (25-34 years), 8% (35-49 years), 8% (50-65 years) and 14% (66-74 years). A Danish study
about sexual problems using a questionnaire (12 questions) and an interview (23 questions) reported the
prevalence rate for PE to be 14% in men aged 51 years (21) while in another Danish random population survey
using a structured personal interview the prevalence rates of PE were 7% in men aged 16-95 years (22). An
Italian questionnaire-based survey in andrological centres recorded a prevalence rate of 21% (23). In a self-
administered questionnaire-based survey in the Netherlands, the prevalence rate was 13% in men aged 50-78
years (24).
The prevalence of PE in the Premature Ejaculation Prevalence and Attitudes (PEPA) survey (a
multinational, internet-based survey) was 22.7% (24.0% in the USA, 20.3% in Germany, and 20.0% in Italy)
(17). The Global Study of Sexual Attitudes and Behaviors (GSSAB) survey was conducted in men between 40
and 80 years old in 29 different countries using personal and telephone interviews and self-completed mailed
questionnaires; it confirmed that the worldwide prevalence of PE was almost 30%. Except for a low reported
rate of PE in Middle Eastern countries (10-15%), prevalence was relatively similar throughout the rest of the
world (15). The prevalence rate of PE was 18% in a five-country European Observational study using the IELT
and the Premature Ejaculation Profile (PEP) (25), comparable to those obtained in a similarly designed US
observational study (26).
Two studies reported on PE prevalence rates based on the Premature Ejaculation Diagnostic Tool
(PEDT) (27,28). A computer-assisted interviewing, online, or in-person survey in nine countries in the Asia-
Pacific region reported prevalence rates of 16% (premature ejaculation), 15% (probable PE) and 13% (self-
reported PE) (27). Another study at a primary care clinic in Malaysia reported prevalence rates of 20.3% for PE
and 20.3% for probable PE (28).
Finally, the only study reporting prevalence of all four proposed classifications of PE was a non-
interventional, observational, cross-sectional field survey conducted in Turkey (29). Overall, the prevalence rate
of PE was 20%. The prevalence rates were 2.3% (lifelong), 3.9% (acquired PE), 8.5% (natural variable PE) and
5.1% (premature-like ejaculatory dysfunction).
Further research is needed on the prevalence of lifelong and acquired PE. Limited data suggests that
the prevalence of lifelong PE, defined as IELT < 1-2 min, is about 2-5% (20,26). These results are supported by
the moderate genetic influence on PE (30) and low prevalence rates of IELT < 1 minute (31).

4.3.2 Pathophysiology and risk factors

The aetiology of PE is unknown, with little data to support suggested biological and psychological hypotheses,
including anxiety, penile hypersensitivity, and 5-HT receptor dysfunction (5). In addition, the pathophysiology of
PE is largely unknown. In contrast to ED, there is no impairment of the physiological events leading up to the

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 37

forceful expulsion of sperm at the urethral meatus.
A significant proportion of men with ED also experience PE (15). High levels of performance anxiety
related to ED may worsen PE, with a risk of misdiagnosing PE instead of the underlying ED.
According to the NHLS, the prevalence of PE is not affected by age (16,17), unlike ED, which
increases with age. Premature ejaculation is not affected by marital or income status (16). However, PE is more
common in blacks, Hispanic men and men from Islamic backgrounds (32,33) and may be higher in men with a
lower educational level (15,16). Other risk factors may include a genetic predisposition (34), poor overall health
status and obesity (16), prostate inflammation (35,36), thyroid hormone disorders (37), emotional problems and
stress (16,38), and traumatic sexual experiences (15,16).
In the only published study on risk modification/prevention strategies (39), successful eradication of
causative organisms in patients with chronic prostatitis and PE produced marked improvements in IELT and
ejaculatory control compared to untreated patients.

4.4 Impact of PE on QoL

Men with PE are more likely to report low satisfaction with their sexual relationship, low satisfaction with sexual
intercourse, difficulty relaxing during intercourse, and less frequent intercourse (40,41). However, the negative
impact of PE extends beyond sexual dysfunction. PE can have a detrimental effect on self-confidence and
the relationship with the partner, and may sometimes cause mental distress, anxiety, embarrassment and
depression (40,42). Sex drive and overall interest in sex does not appear to be affected by PE (43). However,
the partner’s satisfaction with the sexual relationship decreased with increasing severity of the man’s condition
(44).
Despite the possible serious psychological and QoL consequences of PE, few men seek treatment. In
the GSSAB survey, 78% of men who self-reported a sexual dysfunction sought no professional help or advice
for their sexual problems (15), with men more likely to seek treatment for ED than for PE (15). In the PEPA
survey, only 9% of men with self-reported PE consulted a doctor (17).
The main reasons for not discussing PE with their physician are patient embarrassment and a belief
that there is no treatment. Physicians are often uncomfortable discussing sexuality with their patients usually
because of embarrassment and a lack of training or expertise in treating PE (45,46). Physicians need to
encourage their patients to talk about PE.

4.5 Diagnosis of PE
Diagnosis of PE is based on the patient’s medical and sexual history (47,48). History should classify PE as
lifelong or acquired and determine whether PE is situational (under specific circumstances or with a specific
partner) or consistent. Special attention should be given to the duration time of ejaculation, degree of sexual
stimulus, impact on sexual activity and QoL, and drug use or abuse. It is also important to distinguish PE from
ED.
Many patients with ED develop secondary PE caused by the anxiety associated with difficulty in
attaining and maintaining an erection (49). Furthermore, some patients are not aware that loss of erection after
ejaculation is normal and may erroneously complain of ED, while the actual problem is PE (50).
There are several overlapping definitions of PE (see 4.2.1), with four shared factors (Table 7), resulting
in a multidimensional diagnosis (51).

Table 7: Common factors in different definitions of ED

• Time to ejaculation assessed by IELT

• Perceived control
• Distress
• Interpersonal difficulty related to the ejaculatory dysfunction

4.5.1 Intravaginal ejaculatory latency time (IELT)

The use of IELT alone is not sufficient to define PE, as there is significant overlap between men with and
without PE (25, 26). Moreover, IELT has a significant direct effect on perceived control over ejaculation, but not
a significant direct effect on ejaculation-related personal distress or satisfaction with sexual intercourse (52). In
addition, perceived control over ejaculation has a significant direct effect on both ejaculation-related personal
distress and satisfaction with sexual intercourse (each showing direct effects on interpersonal difficulty related
to ejaculation).
In everyday clinical practice, self-estimated IELT is sufficient (53). Self-estimated and stopwatch-
measured IELT are interchangeable and correctly assign PE status with 80% sensitivity and 80% specificity
(54). Specificity can be improved further to 96% by combining IELT with a single-item patient-reported outcome
(PRO) on control over ejaculation and satisfaction with sexual intercourse (scale ranging from 0 = very poor to

38 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

4 = very good) and on personal distress and interpersonal difficulty (0 = not at all to 4 = extremely). However,
stopwatch-measured IELT is necessary in clinical trials. While IELT is an objective tool for PE assessment, a
recent study reported that sexual satisfaction and distress correlated more strongly with the feeling of control
than with the self-reported latency time (55).

4.5.2 PE assessment questionnaires

The need to assess PE objectively has led to the development of several questionnaires based on the use of
PROs (51). Only two questionnaires can discriminate between patients who have PE and those who do not:
• Premature Ejaculation Diagnostic Tool (PEDT): five-item questionnaire based on focus groups and
interviews from the USA, Germany and Spain. Assesses control, frequency, minimal stimulation,
distress and interpersonal difficulty (56,57). A total score > 11 suggests a diagnosis of PE, a score of 9
or 10 suggests a probable diagnosis of PE while a score of < 8 indicates a low likelihood of PE.
• Arabic Index of Premature Ejaculation (AIPE): seven-item questionnaire developed in Saudi Arabia
assesses sexual desire, hard erections for sufficient intercourse, time to ejaculation, control,
satisfaction for the patient and partner, anxiety or depression (58). A cutoff score of 30 (range of
scores 7-35) discriminated best PE diagnosis. Severity of PE was classified as severe (score: 7-13),
moderate (score: 14-19), mild to moderate (score: 20-25) and mild (score: 26-30).

The most widely used tool is the PEDT. However, there is a low correlation between a diagnosis provided by
PEDT and a self-reported diagnosis. A recent study reported that only 40% of men with PEDT-diagnosed PE
and 19% of men with probable PE self-reported the condition (27). A sexual health survey conducted by the
Turkish Society of Andrology reported that, although the sensitivity values of PEDT and AIPE were 89.3% and
89.5%, respectively, the specificity values were only 50.5% and 39.1%, respectively (59). Moreover, there were
statistically significant differences in detection rates of PEDT and AIPE among the four PE syndromes, being
higher in acquired and lifelong PE and lower in natural variable PE and premature-like ejaculatory dysfunction.
These tools are a significant step in simplifying the methodology of PE drug studies, although further
cross-cultural validation is needed (60).
Other questionnaires used to characterize PE and determine treatment effects include the PEP
(26), Index of Premature Ejaculation (IPE) (61) and Male Sexual Health Questionnaire Ejaculatory Dysfunction
(MSHQ-EjD) (62). Currently, their role is optional in everyday clinical practice.

4.5.3 Physical examination and investigations

Physical examination may be part of the initial assessment of men with PE. It may include a brief examination
of the endocrine and neurological systems to identify underlying medical conditions associated with PE or
other sexual dysfunctions, such as endocrinopathy, Peyronie’s disease, urethritis or prostatitis. Laboratory or
physiological testing should be directed by specific findings from history or physical examination and is not
routinely recommended (48).

4.6 Recommendations

Recommendations LE GR
Diagnosis and classification of PE is based on medical and sexual history. It should be 1a A
multidimensional and assess IELT, perceived control, distress and interpersonal difficulty due
to the ejaculatory dysfunction.
Clinical use of self-estimated IELT is adequate. Stopwatch-measured IELT is necessary in 2a B
clinical trials.
Patient-reported outcomes (PROs) have the potential to identify men with PE. Further research 3 C
is needed before PROs can be recommended for clinical use.
Physical examination may be necessary in initial assessment of PE to identify underlying 3 C
medical conditions that may be associated with PE or other sexual dysfunctions, particularly
ED.
Routine laboratory or neurophysiological tests are not recommended. They should only be 3 C
directed by specific findings from history or physical examination.

4.7 References
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2007 Jun;61(6):903-8.
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men attending the andrology prevention week 2001-a study of the Italian Society of Andrology (SIA).
J Sex Med 2005 May;2(3):376-82.
http://www.ncbi.nlm.nih.gov/pubmed/16422869
24. Blanker MH, Bosch JL, Groeneveld FP, et al. Erectile and ejaculatory dysfunction in a community-
based sample of men 50 to 78 years old: prevalence, concern, and relation to sexual activity. Urology
2001 Apr;57(4):763-8.
http://www.ncbi.nlm.nih.gov/pubmed/11306400
25. Giuliano F, Patrick DL, Porst H, et al; 3004 Study Group. Premature ejaculation: results from a five
country European observational study. Eur Urol 2008 May;53(5):1048-57.
http://www.ncbi.nlm.nih.gov/pubmed/17950985
26. Patrick DL, Althof SE, Pryor JL, et al. Premature ejaculation: an observational study of men and their
partners. J Sex Med 2005 May;2(3):358-67.
http://www.ncbi.nlm.nih.gov/pubmed/16422867
27. McMahon CG, Lee G, Park JK, et al. Premature ejaculation and erectile dysfunction prevalence and
attitudes in the Asia-Pacific region. J Sex Med 2012 Feb;9(2):454-65.
http://www.ncbi.nlm.nih.gov/pubmed/22023395
28. Tang WS, Khoo EM. Prevalence and correlates of premature ejaculation in a primary care setting: a
preliminary cross-sectional study. J Sex Med 2011 Jul;8(7):2071-8.
http://www.ncbi.nlm.nih.gov/pubmed/21492404
29. Serefoglu EC, Yaman O, Cayan S, et al. Prevalence of the complaint of ejaculating prematurely and
the four premature ejaculation syndromes: results from the Turkish Society of Andrology Sexual Health
Survey. J Sex Med 2011 Feb;8(2):540-8.
http://www.ncbi.nlm.nih.gov/pubmed/21054799
30. Jern P, Santtila P, Witting K, et al. Premature and delayed ejaculation: genetic and environmental
effects in a population-based sample of Finnish twins. J Sex Med 2007 Nov;4(6):1739-49.
http://www.ncbi.nlm.nih.gov/pubmed/17888070
31. Waldinger MD, Quinn P, Dilleen M, et al. A multinational population survey of intravaginal ejaculation
latency time. J Sex Med 2005 Jul;2(4):492-7.
http://www.ncbi.nlm.nih.gov/pubmed/16422843
32. Richardson D, Goldmeier D. Premature ejaculation-does country of origin tell us anything about
etiology? J Sex Med 2005 Jul;2(4):508-12.
http://www.ncbi.nlm.nih.gov/pubmed/16422845
33. Carson C, Gunn K. Premature ejaculation: definition and prevalence. Int J Impot Res 2006 Sep-
Oct;18(Suppl 1):S5-13.
http://www.ncbi.nlm.nih.gov/pubmed/16953247
34. Waldinger MD, Rietschel M, Nöthen MM, et al. Familial occurrence of primary premature ejaculation.
Psychiatr Genet 1998 Spring;8(1):37-40.
http://www.ncbi.nlm.nih.gov/pubmed/9564687
35. Screponi E, Carosa E, Di Stasi SM, et al. Prevalence of chronic prostatitis in men with premature
ejaculation. Urology 2001 Aug;58(2):198-202.
http://www.ncbi.nlm.nih.gov/pubmed/11489699
36. Shamloul R, el-Nashaar A. Chronic prostatitis in premature ejaculation: a cohort study in 153 men.
J Sex Med 2006 Jan;3(1):150-4.
http://www.ncbi.nlm.nih.gov/pubmed/16409229
37. Carani C, Isidori AM, Granata A, et al. Multicenter study on the prevalence of sexual symptoms in male
hypo- and hyperthyroid patients. J Clin Endocrinol Metab 2005 Dec;90(12):6472-9.
http://www.ncbi.nlm.nih.gov/pubmed/16204360
38. Dunn KM, Croft PR, Hackett GI. Association of sexual problems with social, psychological, and
physical problems in men and women: a cross sectional population survey. J Epidemiol Community
Health 1999 Mar;53(3):144-8.
http://www.ncbi.nlm.nih.gov/pubmed/10396490

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39. El-Nashaar A, Shamloul R. Antibiotic treatment can delay ejaculation in patients with premature
ejaculation and chronic bacterial prostatitis. J Sex Med 2007 Mar;4(2):491-6.
http://www.ncbi.nlm.nih.gov/pubmed/17367444
40. Rowland D, Perelman M, Althof S, et al. Self-reported premature ejaculation and aspects of sexual
functioning and satisfaction. J Sex Med 2004 Sep;1(2):225-32.
http://www.ncbi.nlm.nih.gov/pubmed/16429622
41. Rowland DL, Patrick DL, Rothman M, et al. The psychological burden of premature ejaculation.
J Urol 2007 Mar;177(3):1065-70.
http://www.ncbi.nlm.nih.gov/pubmed/17296413
42. Symonds T, Roblin D, Hart K, et al. How does premature ejaculation impact a man’s life? J Sex Marital
Ther 2003 Oct-Dec;29(5):361-70.
http://www.ncbi.nlm.nih.gov/pubmed/14504007
43. Riley A, Segraves RT. Treatment of premature ejaculation. Int J Clin Pract 2006 Jun;60(6):694-7.
http://www.ncbi.nlm.nih.gov/pubmed/16805755
44. Byers ES, Grenier G. Premature or rapid ejaculation: heterosexual couples’ perceptions of men’s
ejaculatory behavior. Arch Sex Behav 2003 Jun;32(3):261-70.
http://www.ncbi.nlm.nih.gov/pubmed/12807298
45. Sotomayor M. The burden of premature ejaculation: the patient’s perspective. J Sex Med 2005
May;2(Suppl 2):110-4.
http://www.ncbi.nlm.nih.gov/pubmed/16422797
46. Solursh DS, Ernst JL, Lewis RW, et al. The human sexuality education of physicians in North American
medical schools. Int J Impot Res 2003 Oct;15(Suppl 5):S41-5.
http://www.ncbi.nlm.nih.gov/pubmed/14551576
47. Sharlip I. Diagnosis and treatment of premature ejaculation: the physician’s perspective. J Sex Med
2005 May;2(Suppl 2):103-9.
http://www.ncbi.nlm.nih.gov/pubmed/16422796
48. Shabsigh R. Diagnosing premature ejaculation: a review. J Sex Med 2006 Sep;3(4):318-23.
http://www.ncbi.nlm.nih.gov/pubmed/16939476
49. Rowland DL, Slob AK. Premature ejaculation: psychophysiological considerations in theory, research,
and treatment. Annu Rev Sex Res 1997;8:224-53.
http://www.ncbi.nlm.nih.gov/pubmed/10051895
50. Althof SE. Prevalence, characteristics and implications of premature ejaculation/rapid ejaculation.
J Urol 2006 Mar;175(3 Pt 1):842-8.
http://www.ncbi.nlm.nih.gov/pubmed/16469562
51. Althof SE, Symonds T. Patient reported outcomes used in the assessment of premature ejaculation.
Urol Clin North Am 2007 Nov;34(4):581-9, vii.
http://www.ncbi.nlm.nih.gov/pubmed/17983898
52. Patrick DL, Rowland D, Rothman M. Interrelationships among measures of premature ejaculation: the
central role of perceived control. J Sex Med 2007 May;4(3):780-8.
http://www.ncbi.nlm.nih.gov/pubmed/17419817
53. Althof SE, Abdo CH, Dean J, et al. International Society for Sexual Medicine's guidelines for the
diagnosis and treatment of premature ejaculation. J Sex Med 2010 Sep;7(9):2947-69.
http://www.ncbi.nlm.nih.gov/pubmed/21050394
54. Rosen RC, McMahon CG, Niederberger C, et al. Correlates to the clinical diagnosis of premature
ejaculation: results from a large observational study of men and their partners. J Urol 2007 Mar;177(3):
1059-64;discussion 1064.
http://www.ncbi.nlm.nih.gov/pubmed/17296411
55. Kempeneers P, Andrianne R, Bauwens S, et al. Functional and psychological characteristics of Belgian
men with premature ejaculation and their partners. Arch Sex Behav 2013 Jan;42(1):51-66.
http://www.ncbi.nlm.nih.gov/pubmed/22695640
56. Symonds T, Perelman M, Althof S, et al. Further evidence of the reliability and validity of the premature
ejaculation diagnostic tool. Int J Impot Res 2007 Sep-Oct;19(5):521-5.
http://www.ncbi.nlm.nih.gov/pubmed/17568761
57. Symonds T, Perelman MA, Althof S, et al. Development and validation of a premature ejaculation
diagnostic tool. Eur Urol 2007 Aug;52(2):565-73.
http://www.ncbi.nlm.nih.gov/pubmed/17275165
58. Arafa M, Shamloul R. Development and evaluation of the Arabic Index of Premature Ejaculation (AIPE).
J Sex Med 2007 Nov;4(6):1750-6.
http://www.ncbi.nlm.nih.gov/pubmed/17970977

42 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

59. Serefoglu EC, Yaman O, Cayan S, et al. The Comparison of Premature Ejaculation Assessment
Questionnaires and Their Sensitivity for the Four Premature Ejaculation Syndromes: Results from the
Turkish Society of Andrology Sexual Health Survey. J Sex Med 2011 Apr;8(4):1177-85.
http://www.ncbi.nlm.nih.gov/pubmed/21269396
60. McMahon CG. Ejaculatory latency vs. patient-reported outcomes (PROs) as study end points in
premature ejaculation clinical trials. Eur Urol 2007 Aug;52(2):321-3.
http://www.ncbi.nlm.nih.gov/pubmed/17445975
61. Althof S, Rosen R, Symonds T, et al. Development and validation of a new questionnaire to assess
sexual satisfaction, control, and distress associated with premature ejaculation. J Sex Med 2006
May;3(3):465-75.
http://www.ncbi.nlm.nih.gov/pubmed/16681472
62. Rosen RC, Catania JA, Althof SE, et al. Development and validation of four-item version of Male
Sexual Health Questionnaire to assess ejaculatory dysfunction. Urology 2007 May;69(5):805-9.
http://www.ncbi.nlm.nih.gov/pubmed/17482908

4.8 Treatment
In men for whom PE causes few, if any problems, treatment is limited to psychosexual counselling and
education. Before beginning treatment, it is essential to discuss patient expectations thoroughly. Furthermore,
it is important to treat first, if present, erectile dysfunction especially and prostatitis.

Various behavioural techniques have been beneficial in treating PE and are indicated for patients uncomfortable
with pharmacological therapy. In lifelong PE, behavioural techniques are not recommended for first-line
treatment. They are time-intensive, require the support of a partner and can be difficult to perform. In addition,
long-term outcomes of behavioural techniques for PE are unknown.

Pharmacotherapy is the basis of treatment in lifelong PE. Dapoxetine is the only on-demand pharmacological
treatment approved for PE in European countries; all other medications used in PE are off-label indications.
Chronic antidepressants including selective serotonin reuptake inhibitors (SSRIs) and clomipramine, a tricyclic
antidepressant and on-demand topical anaesthetic agents have consistently shown efficacy in PE. Long-term
outcomes for pharmacological treatments are unknown.

An evidence-based analysis of all current treatment modalities was performed. Levels of evidence and grade of
recommendation are provided and a treatment algorithm is presented (Figure 4).

4.8.1 Psychological/behavioural strategies

Behavioural strategies mainly include the ‘stop-start’ programme developed by Semans (1) and its
modification, the ‘squeeze’ technique, proposed by Masters and Johnson:
• In the ‘stop-start’ programme, the partner stimulates the penis until the patient feels the urge to
ejaculate. At this point, he instructs his partner to stop, waits for the sensation to pass and then
stimulation is resumed.
• The ‘squeeze’ technique is similar but the partner applies manual pressure to the glans just before
ejaculation until the patient loses his urge.

Both these procedures are typically applied in a cycle of three pauses before proceeding to orgasm.
Behavioural strategies are based on the hypothesis that PE occurs because the man fails to appreciate the
sensations of heightened arousal and to recognise the feelings of ejaculatory inevitability. Re-training may
attenuate stimulus-response connections by gradually exposing the patient to progressively more intense
and more prolonged stimulation, while maintaining the intensity and duration of the stimulus just below the
threshold for triggering the response. There are several modifications of these techniques making comparison
difficult.

Masturbation before anticipation of sexual intercourse is a technique used by younger men. Following
masturbation, the penis is desensitized resulting in greater ejaculatory delay after the refractory period is over.
In a different approach, the man learns to recognise the signs of increased sexual arousal and how to keep his
level of sexual excitement below the intensity that elicits the ejaculatory reflex. Efficacy is similar to the ‘start-
stop’ programme (2).

Psychological factors may be associated with PE and should be addressed in treatment. These factors, if
any, mainly relate to anxiety, but could also include relationship factors. The limited studies available suggest
that behavioural therapy, as well as functional sexological treatment lead to improvements in the duration of
intercourse and sexual satisfaction.

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 43

Overall, short-term success rates of 50-60% have been reported (3,4). However, there is no controlled research
to support the efficacy of behavioural techniques, while a double-blind, randomized, crossover study showed
that pharmacological treatment (chlomipramine, sertraline, paroxetine and sildenafil) resulted in greater IELT
prolongation than behavioural therapy (5). Furthermore, clinical experience suggests that improvements
achieved with these techniques are generally not maintained long term (6,7). Behavioural therapy may be most
effective when used to 'add value' to medical interventions, although this suggestion requires proof from further
randomized clinical trials. Validated assessment instruments need to be used as end-points. Longer follow-up
periods are necessary to confirm these findings.

4.8.1.1 Guideline recommendation

Treatment of PE LE GR
Psychological/behavioural therapies 3 C

4.8.2 Dapoxetine
Dapoxetine hydrochloride is a short-acting SSRI, with a pharmacokinetic profile suitable for on-demand
treatment for PE. It has a rapid Tmax (1.3 hours) and a short half-life (95% clearance rate after 24 hours) (8).
Dapoxetine has been investigated in 6081 subjects to date (9). It is approved for on-demand treatment of PE in
European countries and elsewhere, but not in the USA.

Both available doses of dapoxetine (30 mg and 60 mg) have shown 2.5- and 3.0-fold increases, respectively,
in IELT overall, rising to 3.4- and 4.3-fold in patients with baseline average IELT < 0.5 minutes (10,11). In
RCTs, dapoxetine, 30 mg or 60 mg 1-2 hours before intercourse, was effective from the first dose on IELT
and increased ejaculatory control, decreased distress, and increased satisfaction. Dapoxetine has shown a
similar efficacy profile in men with lifelong and acquired PE (11). Treatment-related side-effects were dose-
dependent and included nausea, diarrhoea, headache and dizziness. Side-effects were responsible for study
discontinuation in 4% (30 mg) and 10% (60 mg) of subjects (12). There was no indication of an increased risk
of suicidal ideation or suicide attempts and little indication of withdrawal symptoms with abrupt dapoxetine
cessation (13).

Regarding a combination of PDE5 inhibitors with dapoxetine, the addition of dapoxetine to a given regimen of
PDE5I inhibitor may increase the risk of possible prodromal symptoms that may progress to syncope compared
to both PDE5I inhibitors and SSRIs administered alone. Generally, when dapoxetine is co-administered with a
PDE5I inhibitor, it is well tolerated, with a safety profile consistent with previous phase 3 studies of dapoxetine
alone (14). A low rate of vasovagal syncope was reported in phase 3 studies. According to the summary of
product characteristics, orthostatic vital signs (blood pressure and heart rate) must be measured prior to
starting dapoxetine. No cases of syncope were observed in a post-marketing observational study, which had
identified patients at risk for orthostatic reaction using the patient's medical history and orthostatic testing (15).

The mechanism of action of short-acting SSRIs in PE is still speculative. Dapoxetine resembles the
antidepressant SSRIs in the following ways: the drug binds specifically to the 5-HT reuptake transporter
at subnanomolar levels, has only a limited affinity for 5-HT receptors and is a weak antagonist of the
1A-adrenoceptors, dopamine D1 and 5-HT2B receptors. The rapid absorption of dapoxetine might lead to
an abrupt increase in extracellular 5HT following administration that might be sufficient to overwhelm the
compensating autoregulation processes. Does the mechanism of action of short-acting SSRIs differ from that
of the conventional chronic SSRI mechanism of action? Either such agents do not cause the autoreceptor
activation and compensation reported using chronic SSRIs, or these effects occur but they simply cannot
prevent the action of short-acting SSRIs (16).

4.8.2.1 Guideline recommendation

On-demand treatment of PE LE GR
Dapoxetine on demand 1a A

4.8.3 Off-label use of antidepressants: SSRIs and clomipramine

Ejaculation is commanded by a spinal ejaculation generator (17,18) under excitatory or inhibitory influences
from the brain and the periphery (19). 5-hydroxytryptamine (5-HT or serotonin) is involved in ejaculatory control,
with its ejaculation-retarding effects likely to be attributable to activation of 5-HT1B and 5-HT2C receptors,
both spinally and supraspinally. By contrast, stimulation of 5-HT1A receptors precipitates ejaculation (20).

44 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

Selective serotonin reuptake inhibitors (SSRIs) are used to treat mood disorders, but can delay ejaculation
and are therefore widely used ‘off-label’ for PE. As for depression, SSRIs must be given for 1 to 2 weeks to be
effective in PE (20). Administration of chronic SSRIs causes prolonged increases in synaptic cleft serotonin,
which desensitizes the 5-HT1A and 5-HT1B receptors (21). Clomipramine, the most serotoninergic tricyclic
antidepressant, was first reported in 1973 as an effective PE treatment (22). SSRIs have revolutionized
treatment of PE, but they have also changed our understanding of PE since the first publication on paroxetine
in 1970 (23). Before dapoxetine, daily treatment with SSRIs was the first choice of treatment in PE. Commonly
used SSRIs include citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, all of which have a similar
pharmacological mechanism of action.

A systematic review and meta-analysis of all drug treatment studies reported that, despite methodological
problems in most studies, there still remained several, well-designed, double-blind, placebo-controlled trials
supporting the therapeutic effect of daily SSRIs on PE (24). Open-design studies and those using subjective
reporting or questionnaires showed greater variation in ejaculation delay than double-blind studies in which the
ejaculation delay was prospectively assessed with a stopwatch.

Based on this meta-analysis, SSRIs were expected to increase the geometric mean IELT by 2.6-fold to 13.2-
fold. Paroxetine was found to be superior to fluoxetine, clomipramine and sertraline. Sertraline was superior to
fluoxetine, whereas the efficacy of clomipramine was not significantly different from fluoxetine and sertraline.
Paroxetine was evaluated in doses of 20-40 mg, sertraline 25-200 mg, fluoxetine 10-60 mg and clomipramine
25-50 mg; there was no significant relationship between dose and response among the various drugs. There is
limited evidence that citalopram may be less efficacious compared to other SSRIs, while fluvoxamine may not
be effective (25,26).

Ejaculation delay may start a few days after drug intake, but it is more evident after 1 to 2 weeks since receptor
desensitization requires time to occur. Although efficacy may be maintained for several years, tachyphylaxis
(decreasing response to a drug following chronic administration) may occur after 6 to 12 months (22).
Common side-effects of SSRIs include fatigue, drowsiness, yawning, nausea, vomiting, dry mouth, diarrhoea
and perspiration; they are usually mild and gradually improve after 2 to 3 weeks (22). Decreased libido,
anorgasmia, anejaculation and ED have been also reported.

Because of a theoretical risk of suicidal ideation or suicide attempts, caution is suggested in prescribing SSRIs
to young adolescents with PE aged 18 years or less, and to men with PE and a comorbid depressive disorder,
particularly when associated with suicidal ideation. Patients should be advised to avoid sudden cessation or
rapid dose reduction of daily dosed SSRIs which may be associated with a SSRI withdrawal syndrome (12).

In one controlled trial, on-demand use of clomipramine (but not paroxetine), 3 to 5 hours before intercourse,
was reported to be efficacious, though IELT improvement was inferior compared to daily treatment with the
same drug (27). However, on-demand treatment may be combined with an initial trial of daily treatment or
concomitant low-dose daily treatment reducing adverse effects (28,29).

Individual countries’ regulatory authorities strongly advise against prescribing medication for indications if
the medication in question is not licensed/approved and prescription of off-label medication may present
difficulties for physicians.

4.8.3.1 Guideline recommendation

Chronic treatment of PE LE GR
Off-label chronic treatment i.e. daily with selective serotonin receptor inhibitors (SSRIs) and 1a A
clomipramine antidepressants

4.8.4 Topical anaesthetic agents

The use of local anaesthetics to delay ejaculation is the oldest form of pharmacological therapy for PE (30).
Several trials (31,32) support the hypothesis that topical desensitizing agents reduce the sensitivity of the glans
penis so delaying ejaculatory latency, but without adversely affecting the sensation of ejaculation.

4.8.4.1 Lidocaine-prilocaine cream

In a randomized, double-blind, placebo-controlled trial, lidocaine-prilocaine cream increased the IELT from 1
minute in the placebo group to 6.7 minutes in the treatment group (33). In another randomized, double-blind,
placebo-controlled trial, lidocaine-prilocaine cream significantly increased the stopwatch-measured IELT from

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 45

1.49 to 8.45 minutes while no difference was recorded in the placebo group (1.67 to 1.95 minutes) (34).

Lidocaine-prilocaine cream (5%) is applied for 20-30 minutes prior to intercourse. Prolonged application of
topical anaesthetic (30-45 minutes) may result in loss of erection due to numbness of the penis in a significant
percentage of men (33). A condom will prevent diffusion of the topical anaesthetic agent into the vaginal wall
causing numbness in the partner.

Alternatively, the condom may be removed prior to sexual intercourse and the penis washed clean of any
residual active compound. Although no significant side-effects have been reported, topical anaesthetics are
contraindicated in patients or partners with an allergy to any part of the product.

An experimental aerosol formulation of lidocaine, 7.5 mg, plus prilocaine, 2.5 mg (Topical Eutectic Mixture for
Premature Ejaculation [TEMPE]), was applied 5 minutes before sexual intercourse in 539 males. There was
an increase in the geometric mean IELT from a baseline of 0.58 minutes to 3.17 minutes during 3 months of
double-blind treatment; a 3.3-fold delay in ejaculation compared with placebo (p < 0.001) (35). 

4.8.4.2 Guideline recommendation

On-demand topical therapy for PE LE GR

Lidocaine-prilocaine cream 1b A

4.8.5 Tramadol
Tramadol is a centrally acting analgesic agent that combines opioid receptor activation and re-uptake inhibition
of serotonin and noradrenaline. Tramadol is readily absorbed after oral administration and has an elimination
half-life of 5-7 hours. For analgesic purposes, tramadol can be administered between 3 and 4 times daily in
tablets of 50-100 mg. Side-effects were reported at doses used for analgesic purposes (up to 400 mg daily)
and include constipation, sedation and dry mouth. Tramadol is a mild-opioid receptor agonist, but it also
displays antagonistic properties on transporters of noradrenaline and 5-HT (36). This mechanism of action
distinguishes tramadol from other opioids, including morphine. However, in May 2009, the US Food and
Drug Administration released a warning letter about tramadol's potential to cause addiction and difficulty in
breathing (37).

One placebo-controlled study reported that tramadol HCl significantly increased IELT compared with placebo
(38). A larger, randomized, double-blind, placebo-controlled, multicentre 12-week study was carried out to
evaluate the efficacy and safety of two doses of tramadol (62 and 89 mg) by orally disintegrating tablet (ODT) in
the treatment of PE (39). Previously, a bioequivalence study had previously been performed that demonstrated
equivalence between tramadol ODT and tramadol HCl. In patients with a history of lifelong PE and an IELT < 2
minutes, increases in the median IELT of 0.6 minutes (1.6-fold), 1.2 minutes (2.4-fold) and 1.5 minutes (2.5-
fold) were reported for placebo, 62 mg of tramadol ODT, and 89 mg of tramadol ODT, respectively. It should be
noted that there was no dose-response effect with tramadol. The tolerability during the 12-week study period
was acceptable.

Overall, tramadol has shown a moderate beneficial effect with a similar efficacy as dapoxetine. From what is
known about the neuropharmacology of ejaculation and the mechanism of action of tramadol, the delaying
effect on ejaculation could be explained by combined CNS µ-opioid receptor stimulation and increased
brain 5-HT availability. However, the beneficial effect of tramadol in PE is yet not supported by a high level of
evidence. In addition, efficacy and tolerability of tramadol would have to be confirmed in more patients and
longer term.

4.8.5.1 Guideline recommendation

On-demand treatment of PE LE GR
Tramadol on demand 2a B

4.8.6 Other drugs

4.8.6.1 Phosphodiesterase type 5 inhibitors
There is only one well-designed, randomized, double-blind, placebo-controlled study comparing sildenafil to
placebo (40). Although IELT was not significantly improved, sildenafil increased confidence, the perception
of ejaculatory control and overall sexual satisfaction, reduced anxiety and decreased the refractory time to
achieve a second erection after ejaculation.

46 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

Several open-label studies showed that sildenafil combined with an SSRI is superior to SSRI monotherapy:
• Sildenafil combined with paroxetine improved IELT significantly and satisfaction versus paroxetine
alone (41).
• Sildenafil combined with sertraline improved IELT and satisfaction significantly versus sertraline alone
(42).
• Sildenafil combined with paroxetine and psychological and behavioural counselling significantly
improved IELT and satisfaction in patients in whom other treatments failed (43).
• Finally, sildenafil combined with behavioural therapy significantly improved IELT and satisfaction
versus behavioural therapy alone (44).
There is limited data in PE on the efficacy of other PDE5Is (tadalafil and vardenafil) (45,46). Overall, the role of
PDE5Is in PE patients without ED is not established, with only minimal double-blind placebo controlled data
available.

4.8.6.2 Guideline recommendation

On-demand treatment of PE LE GR
PDE5 inhibitors 3 C

4.8.7 Guidelines on treatment of PE

Recommendations LE GR
Erectile dysfunction, other sexual dysfunction or genitourinary infection (e.g. prostatitis) should 2a B
be treated first.
Pharmacotherapy should be given as first-line treatment of lifelong PE. 1a A
Pharmacotherapy includes either dapoxetine on demand (a short-acting SSRI that is the 1a A
only approved pharmacological treatment for PE) or other off-label antidepressants, i.e. daily
SSRIs and clomipramine, that are not amenable to on-demand dosing. With all antidepressant
treatment for ED, recurrence is likely after treatment cessation.
Off-label topical anaesthetic agents can be offered as a viable alternative to oral treatment with 1b A
SSRIs.
Behavioural and sexological therapies have a role in the management of acquired PE. They are 3 C
most likely to be best used in combination with pharmacological treatment.
ED = erectile dysfunction; PE = premature ejaculation; SSRI = selective serotonin reuptake inhibitor.

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 47

Figure 4: Management of PE*

Clinical diagnosis of premature ejaculation based

on patient +/- partner history
• Time to ejaculation (IELT)
• Perceived degree of ejaculatory control
• Degree of bother/distress
• Onset and duration of PE
• Psychosocial/relationship issues
• Medical history
• Physical examination

Treatment of premature ejaculation

Patient counselling/education
Discussion of treatment options
If PE is secondary to ED, treat ED first or
concomitantly

• P harmacotherapy (recommended as first-line

treatment option in lifelong PE)
o Dapoxetine for on-demand use (the only
approved drug for PE)
o Off-label treatments include chronic daily use
of antidepressants (SSRIs or clomipramine)
and topical anaesthetics or oral tramadol on
demand
• Behavioural therapy, includes stop/start technique,
squeeze and sensate focus
• Combination treatment

* Adapted from Lue et al. 2004 (47).

ED = erectile dysfunction; PE = premature ejaculation; IELT = intravaginal ejaculatory latency time; SSRI =
selective serotonin receptor inhibitor.

4.9 References
1. Semans JH. Premature ejaculation: a new approach. South Med J 1956 Apr;49(4):353-8.
http://www.ncbi.nlm.nih.gov/pubmed/13311629
2. de Carufel F, Trudel G. Effects of a new functional-sexological treatment for premature ejaculation.
J Sex Marital Ther 2006 Mar-Apr;32(2):97-114.
http://www.ncbi.nlm.nih.gov/pubmed/16418103
3. Grenier G, Byers ES. Rapid ejaculation: a review of conceptual, etiological, and treatment issues.
Arch Sex Behav 1995 Aug;24(4):447-72.
http://www.ncbi.nlm.nih.gov/pubmed/7661658
4. Metz ME, Pryor JL, Nesvacil LJ, et al. Premature ejaculation: a psychophysiological review.
J Sex Marital Ther 1997 Spring;23(1):3-23.
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23. Waldinger MD, Hengeveld MW, Zwinderman AH. Paroxetine treatment of premature ejaculation: a
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24. Waldinger MD, Zwinderman AH, Schweitzer DH, et al. Relevance of methodological design for
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25. Waldinger MD, Zwinderman AH, Olivier B. SSRIs and ejaculation: a double-blind, randomized, fixed-
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5. CONCLUSION
Modern treatment of ED has been revolutionized by the worldwide availability of three PDE5Is for oral use:
sildenafil, tadalafil and vardenafil. These drugs have high efficacy and safety rates, even in difficult-to-treat
populations, such as patients with diabetes mellitus or who have undergone radical prostatectomy. Patients
should be encouraged to try all three PDE5Is. Patients should make up their own minds about which
compound has the best efficacy, while also considering other factors, such as time of onset, duration of action,
window of opportunity and how side-effects affect them individually.

Treatment options for patients who do not respond to oral drugs, or for whom drugs are contraindicated,
include intracavernous injections, vacuum constriction devices, or implantation of a penile prosthesis as a last
option.

It is very important that the physician warns the patient that sexual intercourse is a vigorous physical activity,
which increases heart rate and cardiac work. Physicians should assess a patient's cardiac fitness prior to
treating ED.

Any successful pharmacological treatment for erectile failure demands a degree of integrity of the penile
mechanisms of erection. Further studies of individual agents and synergistic activity of available substances
are underway. The search for the ideal pharmacological therapy for erectile failure aims to fulfil the following
characteristics: good efficacy, easy administration, freedom from toxicity and side-effects, with a rapid onset
and a possible long-acting effect.

Premature ejaculation is another very common male sexual dysfunction. Four major definitions of PE are
currently used and the most widely accepted classification of PE includes 'lifelong' (primary) and 'acquired'
(secondary) forms (syndromes).

Diagnosis of PE in everyday clinical practice is based on medical and sexual history assessing IELT, perceived
control, distress, and interpersonal difficulty related to the ejaculatory dysfunction. A targeted physical
examination is advisable but not mandatory.

Pharmacotherapy is the basis of treatment in lifelong PE, including dapoxetine on demand, the only approved
drug for the treatment of PE, off-label daily dosing of SSRIs and clomipramine and topical anaesthetics.
Behavioural techniques may be efficacious as a monotherapy or in combination with pharmacotherapy, but
they can be difficult to perform. In every case, recurrence is likely to occur after treatment withdrawal.

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 51

6. ABBREVIATIONS USED IN THE TEXT
This list is not comprehensive for the most common abbreviations

5-HT 5-hydroxytryptamine
AIPE Arabic Index of Premature Ejaculation
AUC area under curve (serum concentration time curve)
BMI body mass index
CAD coronary artery disease
cGMP cyclic guanosine monophosphate
CGRP calcitonin gene-related peptide
CHF congestive heart failure
Cmax maximal concentration
DICC dynamic infusion cavernosometry or cavernosography
DRE digital rectal examination
DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders IV-Text Revision
EAU European Association of Urology
ED erectile dysfunction
EMEA European Medicines Agency
FDA (US) Food and Drug Administration
FSH follicle-stimulating hormone
GAQ General Assessment Question
GR grade of recommendation
GSSAB Global Study of Sexual Attitudes and Behaviors
ICD-10 International Classification of Diseases-10
IELT intravaginal ejaculatory latency time
IIEF International Index for Erectile Function
IIEF-EF International Index for Erectile Function - erectile function domain
IPE Index of Premature Ejaculation
ISSM International Society for Sexual Medicine
LE level of evidence
LH luteinizing hormone
LVD left ventricular dysfunction
MET metabolic equivalent of energy expenditure in the resting state
MI myocardial infarction
MMAS Massachusetts Male Aging Study
MSHQ-EjD Male Sexual Health Questionnaire Ejaculatory Dysfunction
NHSLS National Health and Social Life Survey
NS nerve sparing
NO nitric oxide
NPTR nocturnal penile tumescence and rigidity
NSRP nerve-sparing radical prostatectomy
NYHA New York Heart Association
PCa prostate cancer
PDE5[I] phosphodiesterase type 5 [inhibitors]
PE premature ejaculation
PEDT Premature Ejaculation Diagnostic Tool
PEP Premature Ejaculation Profile
PEPA Premature Ejaculation Prevalence and Attitudes
PRO Patient reported outcome
PSA prostate-specific antigen
QoL quality of life
RP radical prostatectomy
SEP sexual encounter profile
SSRI selective serotonin reuptake inhibitor
TEMPE topical eutectic mixture for premature ejaculation
Tmax time to maximum plasma concentration
VCD vacuum constriction devices
VIP vasointestinal peptide

52 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013

Conflict of interest
All members of the Male Sexual Dysfunction guidelines writing panel have provided disclosure statements
of all relationships which they have and which may be perceived as a potential source of conflict of interest.
This information is kept on file in the European Association of Urology Central Office database. This guidelines
document was developed with the financial support of the European Association of Urology. No external
sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited
to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have
been provided.

MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013 53

54 MALE SEXUAL DYSFUNCTION - UPDATE MARCH 2013