Vol. 161.

5-11, January 1999

Printed In U.S.A.

Review Article

THE EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF ERECTILE

DYSFUNCTION
ARNOLD MELMAN AND J. CLIVE GINGELL
From the Department of Urology, Albert Einstein College of MedicinelMontefiore Medical Center, Bronx, New York, and the Department
of Urology, Southmead Hospital, Bristol, United Kingdom

ABSTRACT

Purpose: Published studies on the epidemiology of erectile dysfunction and the physiology1
pathophysiology of erectile function are reviewed.
Materials and Methods: A literature search of more than 400 studies of the epidemiology and
pathophysiology of impotence and erectile dysfunction published during the last 3 decades was
conducted and the most pertinent articles are discussed.
Results: It has been estimated that the prevalence of erectile dysfunction of all degrees is 52%
in men 40 to 70 years old, with higher rates in those older t h a n 70 years. Erectile dysfunction has
a significant negative impact on quality of life. Risk factors for erectile dysfunction include aging,
chronic illnesses, various medications and cigarette smoking. A nitric oxidelcyclic guanosine
monophosphate mechanism has a n important role in mediating the corporal smooth muscle
relaxation necessary for erectile function. Other mechanisms involving neuropeptides, gap junc-
tions and ion channels also may modulate corporal smooth muscle tone. Erectile dysfunction can
be due to vasculogenic, neurogenic, hormonal a n d o r psychogenic factors as well a s alterations in
the nitric oxidelcyclic guanosine monophosphate pathway or other regulatory mechanisms,
resulting in a n imbalance in corporal smooth muscle contraction and relaxation.
Conclusions: Erectile dysfunction is a common condition associated with aging, chronic ill-
nesses and various modifiable risk factors. Normal penile erection is a hemodynamic process that
is dependent on corporal smooth muscle relaxation mediated by parasympathetic neurotrans-
mission, nitric oxide, and possibly other regulatory factors and electrophysiological events. As
more knowledge is gained of the physiology and regulatory factors that mediate normal erectile
function, t h e mechanisms involved in the pathophysiology of erectile dysfunction should be
further elucidated.
KEY WORDS:impotence, pathology, penile erection, physiology
In 1992 a National Institutes of Health Consensus Panel Although the survey by Kinsey et a1 has its limitations due to
defined erectile dysfunction as the inability to achieve or the population studied and the fact that attitudes toward
maintain a n erection sufficient for satisfactory sexual func- sexual issues were markedly different in 1948 than those
ti0n.l Before this time erectile dysfunction was included in prevalent today, this study represents a historical starting
the general term impotence, which also referred to other point for epidemiological data on the prevalence of erectile
disorders of male sexual function, such as orgasmic and ejac- dysfunction in the general population. We review the results
ulatory dysfunction. Important advances in our understand- of the survey by Kinsey et a1 and subsequent reports of the
ing of the physiology of penile erection and the pathophysi- prevalence of erectile dysfunction in the United States, to-
ology of erectile dysfunction have been reported during the gether with those of the limited number of studies conducted
last several years. Whereas 2 decades ago erectile dysfunc- in other countries. Also reviewed are pertinent articles ad-
tion was considered primarily a psychological disorder,"," it dressing risk factors associated with erectile dysfunction, the
is now known that the majority of men have a n underlying mechanism of normal penile erection and the pathophysiol-
organic cause.4 As a result progress has been made identify- ogy of erectile dysfunction.
ing the factors affecting the frequency and distribution of
erectile dysfunction.
Historically. the prevalence of erectile dysfunction has EPIDEhlIOLOGY
been difficult 'to estimate due t o the fact that it is not life Prevalence. Data from studies of the prevalence of erectile
threatening, patients often do not seek treatment and liter- dysfunction in the general population based on surveys of
ature terminology for the condition has been confusing. The samples of men indicate that the results are dependent on
most extensive epidemiological study of male sexual behavior the definition used for erectile dysfunction.' The period of
in the United States conducted by Kinsey et a1 was pub- data retrieval and the population surveyed also affect prev-
lished in 1948.5 Although this study included more than alence estimates. As mentioned previously the first extensive
15,000 men 10 to 80 years old, the number of men older than epidemiological study of male sexual behavior in the United
25 years was 4,108 and only 306 were older than 55 years. States was reported in 1948 by Kinsey et al.5 Their survey
5
6 EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION
included 15,781 men 10 to 80 years old. However, only 4,108 3chieving an erection during sexual stimulation and that
of these men were 25 years old or older and only 306 were 20%had some difficulty maintaining erections long enough
older than 55 years. The authors concluded that the preva- For sexual intercourse. Shirai et a1 estimated the prevalence
lence of erectile dysfunction was less than 1%in men younger 3f erectile dysfunction to be 26% in Japan based on a compi-
than 30, less than 3 4 in those younger than 45,6.7%in those lation of data on the number of men affected with certain
45 to 55,25%in those 65 and up to 80%in those 80 years old. conditions associated with erectile dysfunction and the esti-
However, due to the small sample numbers the prevalence mated prevalence of erectile dysfunction in these popula-
estimates determined by this study for men older than 55 tions.12 In a survey of 411 Danish men 51 years old 19% had
years should be interpreted with caution. experienced erectile dysfunction obstructing sexual inter-
Since 1949 various studies have investigated the preva- course a t least occasionally during the previous year.':J Al-
lence of erectile dysfunction in small samples of men. Spector though the populations studied and methods used varied
and Carey reviewed the results of 23 studies conducted be- considerably, the results of recent epidemiology studies indi-
tween 1948 and 1988." In studies with community samples cate that erectile dysfunction is a common problem that is
the prevalence of erectile dysfunction was 4 to 9%.In married associated with age and has a significant impact on quality of
men 60 years old or older Diokno et a1 reported a prevalence life. Further studies on the worldwide prevalence of erectile
rate of erectile impotence of 35%significantly associated with dysfunction with respect to racial, ethnic, socioeconomic and
history of heart attack, urinary incontinence and use of sed- cultural variability are needed.'
atives.' Risk factors associated with erectile dysfunction. For sim-
More recently Feldman et al reported on the prevalence of plicity erectile dysfunction can be classified as either organic
impotence in a general population using results from the Mas- or psychogenic.'& Organic erectile dysfunction is due to vas-
sachusetts Male Agmg Study.* This study conducted from 1987 culogenic, neurogenic, hormonal or cavernosal smooth mus-
to 1989 was a random sample survey of 1,290 noninstitution- cle abnormalities or lesions, whereas psychogenic erectile
alized men 40 to 70 years old in 11randomly selected cities and dysfunction is due to central inhibition of the erectile mech-
towns in the area of Boston, Massachusetts. Based on subject anism without a physical injury. In most patients with erec-
responses to a self-administered sexual activity questionnaire, tile dysfunction organic and psychogenic components exist.
the prevalence of minimal, moderate and complete impotence The most common cause of the organic component of erectile
was 17, 25 and 1092, respectively, yielding a prevalence of im- dysfunction is vascular (arterial or venous) abnormalities's
potence of all degrees of 52%.Based on these data and United oRen associated with atherosclerosis and diabetes melli-
States population projections for the year 2005 of more than 50 tus.16-19 Atherosclerotic disease is the cause of approxi-
million men 40 to 70 years old,9 erectile dysfunction will affect mately 40% of erectile dysfunction in men older than 50
more than 25 million men, and millions more of those older years.20 In patients with diabetes mellitus irrespective of
than 70 years. Subject age was the variable most strongly type the prevalence of erectile dysfunction is approximately
associated with erectile dysfunction in the Massachusetts Male 50% (range 20 to 75) with the prevalence dependent on pa-
Agmg Study.8 Estimated prevalence rates were 39% in men 40 tient age, duration of diabetes and disease severity."'-27
and 6 7 4 in those 70 years old. In fact, the results indicated that Other conditions associated with a high prevalence of erectile
the probability of complete erectile dysfunction increased from dysfunction include chronic renal failure,2*,29 hepatic fail-
5%,at 40 to 15%at 70 years old. Within this same age range the ure,30 multiple sclerosis,31,32 Alzheimer's disease33 and
probability of moderate impotence increased from 17 to 34% chronic obstructive lung disease.34 Endocrine disorders, such
and minimal erectile dysfunction remained unchanged a t 17%. as hypogonadism, hyperprolactinemia, hypothyroidism and
In a study published in 1995 Jcinler et a1 estimated the hyperthyroidism, also may result in erectile dysfunction35
prevalence of erectile dysfunction and the effects of age, but are the cause in only a small proportion of cases in the
ethnicity and geographic location on erectile dysfunction and overall population. Psychogenic erectile dysfunction, which is
quality of life.l0 This survey was conducted in men older than most prevalent in younger men (up to 70% of patients
40 years during a free screening program for prostate cancer younger than 35 years), accounts for approximately 10% of
in Madison, Wisconsin, New York, New York and New Or- erectile dysfunction in men older than 50 years.36
leans, Louisiana. Thus, this nonrandomly selected sample Trauma, irradiation or surgery involving the pelvic region
may not represent the general United States population. Of frequently can result in erectile dysfunction. Erectile dys-
the 1,517 men who responded to a self-administered ques- function induced by pelvic trauma can be caused by the
tionnaire 1,068 (70.4%)were white, 378 (24.9%)black, 47 injury itself or surgical procedures for repair. External beam
(3.1%)Hispanic, 18 (1.2%)Arabic and 6 (0.4%)of other ethnic radiation therapy in patients with localized prostate cancer
origins. Of these men 129 (8.5%)had had no sexual erections has been reported to cause erectile dysfunction in a t least
during the previous 12 months. Of the 1,388 men with erec- 25% of those treated.37 Furthermore, in a study in which 15
tions during the previous 12 months. Of the 1,388 men with of 16 patients had erectile dysfunction following external
erections during the previous 12 months 172 (12.4%)had beam radiotherapy the etiology was often vasculogenic in
had erections less than 1 in 5 times when sexually stimulated nature.38 Erectile dysfunction also is associated with urolog-
during the previous month and 273 (19.7%)had had erec- ical surgery for benign conditions of the prostate. For exam-
tions less than half the time. The prevalence of erectile dys- ple Lindner et a1 reported an incidence of erectile dysfunction
function was significantly associated with age (p <0.001) and of 13% in patients who underwent transurethral prostatec-
correlated with lowered quality of life (p <0.001). Interest- t ~ m y In. ~another
~ study of patients who underwent trans-
ingly, men younger than 55 years in Madison had a higher urethral resection of the prostate the incidence of erectile
prevalence of erectile dysfunction than those in New York or dysfunction 6 months after the procedure was 11%but 57% of
New Orleans but increasing age of men in Madison was not those who retained potency had a decrease from preoperative
associated with the same extent of increased prevalence as levels of f u n ~ t i o n . ~
Results
'J from a recent study in which no
for men in the other 2 cities. In that study the prevalence of decrease in erectile function was demonstrated following
erectile dysfunction was independent of subject ethnicity. transurethral resection of the prostate suggested that pa-
Only a few epidemiological studies have been conducted in tients often erroneously equate retrograde ejaculation with
which the prevalence of erectile dysfunction in countries erectile d y s f ~ n c t i o n . ~ ~
other than the United States has been evaluated. The results Various medications and substances of abuse are com-
of a small survey of 109 men in the United Kingdom who monly associated with erectile dysfunction.4"4:' The inci-
were 16 years old or older were published in 1986.II Data dence of drug related erectile dysfunction may be as high as
indicated that 32% of the men reported some difficulty in 25%.""Drugs that may cause erectile dysfunction include
 EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF ERECTILE DYSFL'NCTION 7
certain antihypertensive medications, hormones, antidepres- a thick bilayer fibrous sheath, the tunica albuginea, whose
sants, tranquilizers, alcohol, tobacco, heroin and cocaine. The
fibers unite medial to form a perforated septum that allows
incidence of erectile dysfunction in patients receiving various
the 2 bodies to function as a unit. The corpus sponposum has
types of antihypertensive drugs was examined in the Treat- a thinner tunica albuginea. The 3 corporal bodies are sur-
ment of Mild Hypertension S t ~ d y . ~ ~This, 4 5 study was a
rounded by deep fibrous tissue, Buck's fascia. Cavernosal
4-year, double-blind, placebo controlled trial of hypertensive
tissue is sponge-like with a mesh of interconnected cavern-
subjects treated with placebo or 1of 5 antihypertensive drugs
osal spaces also known as sinusoidal or lacunar spaces. These
(that is acebutolol, amlodipine, chlorthalidone, doxazosin and
cavernosal spaces are lined with vascular endothelium and
enalapril). Sexual function was assessed annually with ques-separated by trabeculae composed of bundles of smooth mus-
tions on sexual activity, and the ability to achieve and main-
cle fibers with an extracellular matrix of collagen, elastin and
tain erections. At 24 months the incidence of a n inability to
fibroblasts. Gap junctions, hexamer protein lined aqueous
achieve an erection ranged from 2.8% in the doxazosin (a- intercellular channels, connect the smooth muscle cells of the
blocker) group to 15.7% in the chlorthalidone (diuretic)group
corpora c a ~ e r n o s aThe
. ~ ~blood supply to the penis originates
compared with 4.9% in the placebo group.45 The incidence of predominantly from the internal pudendal artery, which af-
an inability to maintain an erection ranged from 4.28 in theter giving off the perineal artery becomes the penile artery.
doxazosin group to 17.1% in the chlorthalidone group versus The penile artery branches into the bulbar, urethral (spon-
6.8% in the placebo group. giosal), dorsal and cavernous arteries. The cavernous artery
Results of the Massachusetts Male Aging Study also indi- enters the corpora cavernosa and subsequently divides into
cated a higher probability of erectile dysfunction in associa-
many branches called the helicine arteries, which open
into the cavernosal spaces. The 3 sets of veins that drain
tion with certain treated medical conditions.8 After adjusting
for patient age the probability of complete erectile dysfunc-
blood from the penis are the superficial, intermediate and
tion was 39% in men with treated heart disease, 28% with deep veins. The deep veins drain the corpora cavernosa and
treated diabetes and 15% with treated hypertension versus corpus spongiosum. The penis is innervated mainly by the
9.6% in the entire population surveyed. Untreated ulcer, sympathetic nervous system which originates in the thora-
untreated arthritis and untreated allergy with probabilitiescolumbar spinal cord and the parasympathetic nervous sys-
of 18, 15 and 12%~, tem which originates in the sacral spinal cord.
respectively, also demonstrated an asso-
ciation with erectile dysfunction. Furthermore, the probabil- Hemodynamics. The physiology of penile erection has been
ity of erectile dysfunction in these diseases was further in-
reviewed extensively.4H Penile erection and detumescence
creased in patients who smoked cigarettes. For instance the are hernodynamic events regulated by corporal smooth mus-
probability of complete erectile dysfunction was 21% in non-cle relaxation and contraction, respectively. In the flaccid
smoking individuals with treated heart disease compared state a dominant sympathetic influence prevails, and arterial
with 56% in smokers with treated heart disease. However, and corporal smooth muscle is tonically contracted. As a
result only a minimal amount of blood flows through the
the probability of complete erectile dysfunction in the entire
population was not significantly different in smokers (110) cavernous artery into the cavernosal spaces. After sexual
and nonsmokers (9.3%). The effect of cigarette smoking on stimulation parasympathetic activity causes a decrease in
peripheral resistance due to vasodilatation and increased
the prevalence of erectile dysfunction also was evaluated in a
cross-sectional survey of 4,462 male military veterans 31 toblood flow through the cavernous and helicine arteries. The
49 years old.46 The odds ratio of the association between intracavernous pressure increases without any increase in
cigarette smoking and reported erectile dysfunction was 1.5 systemic pressure. Relaxation of the trabecular smooth mus-
cle causes increased compliance of the cavernosal spaces,
(95% confidence interval 1.0 to 2.2) after adjusting for age,
race, marital status, vascular disease, psychiatric disease,leading to penile engorgement and erection. In the full erec-
hormonal factors and substance abuse. tile state increased blood volume and compression of the
In the Massachusetts Male Aging Study after age adjust- relaxed trabecular smooth muscle against the relatively r i p d
ment men with the highest levels of anger suppression and tunica albuginea lead to a reduction in venous outflow (re-
anger expression had higher probabilities of moderate (35%) ferred to a s the veno-occlusive mechanism). Voluntary or
and complete (16 to 19%) erectile dysfunction than the over-reflexogenic contraction of the ischiocavernous and bulbocav-
all study population (9.6%L8In addition, indexes of person- ernous muscles causes intracavernosal pressure to increase
ality dominance and depression correlated with erectile dys-above systemic pressure. A rigid erection occurs and blood
flow through the cavernous artery ceases. Detumescence re-
function. After adjusting for age men with the highest levels
of dominance had lower probabilities of moderate (15%) and sults as increased sympathetic nervous system activity in-
complete (7.9%')erectile dysfunction, whereas men with the creases the tone of the helicine arteries and contraction of
greatest degree of depression had a higher probability of trabecular smooth muscle. Arterial blood flow resumes a t the
moderate or complete erectile dysfunction (90%1 compared prestimulation level, venous outflow channels reopen. intra-
with those who were least depressed (25%).The probability cavernosal pressure rapidly declines and the veno-occlusive
of complete erectile dysfunction inversely correlated with mechanism is inactivated. returning the penis to the flaccid
serum high density lipoprotein cholesterol and serum dehy- state. Thus, the normal penile erectile mechanism is depen-
droepiandrosterone sulfate. Thus, epidemiological studies dent on a delicate balance between corporal smooth muscle
provide valuable data on disease, drug and psychological contraction and relaxation.J",""
variables associated with erectile dysfunction, some of which Neurotransrnission. Corporal smooth muscle contraction is
modulated by the sympathetic nervous system via the re-
are modifiable. Elimination of these modifiable risk factors,
such a s cigarette smoking, alcohol consumption and certain lease of norepinephrine and activation of postsynaptic t r l -
medications (see Appendix), could have a significant impact adrenergic receptors.51.5z On the other hand, relaxation is
mediated by acetylcholine released by the parasympathetic
on the prevalence of erectile dysfunction and as a result the
costs of erectile dysfunction management. nervous system and a second neurotransmitter, nitric oxide
or a nitric oxide releasing substance.".' Nitric oxide, originally
called endothelium-derived relaxing factor, was shown to
PENILE ERECTION PHYSIOLOGY AND PATHOPHYSIOLOGY induce relaxation of vascular smooth muscle.54 Subsequently
Anatomy. The penis is composed of 2 dorsal cylindrical Ignarro et a1 reported that nitric oxide induced the formation
bodies, the corpora cavernosa, and the ventral corpus spon- of cyclic guanosine monophosphate in the vascular system.55
giosum which encloses the urethra and expands distal to Nitric oxide stimulates soluble guanylate cyclase after bind-
form the glans penis. The corpora cavernosa are enclosed in ing to the iron atom of the heme moiety of the enzyme.% The
8 EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION

exact mechanisms that are involved in nitric oxiddcyclic corpus spongiosum, the tunica albuginea, and penile arteries
guanosine monophosphate induced penile corporal smooth and veins.47 In vitro studies indicate that vasoactive intestinal
muscle relaxation a r e unknown. However, it has been pro- polypeptide has an inhibitory and relaxation producing effect on
posed t h a t cyclic guanosine monophosphate activates protein human corpus cavernosum However, vasoactive in-
kinase G, leading to the phosphorylation of proteins regulat- testinal polypeptide did not produce a n erection in normal VOI-
ing corporal smooth muscle tone.5*‘32Nitric oxide is synthe- unteers when injected intracavernosally65 suggesting that va-
sized by enzymatic oxidation of t h e terminal nitrogen atom of soactive intestinal polypeptide does not have a major role in
the guanidinium moiety of the amino acid L-arginine by penile erection. Current evidence indicates that nitric oxide is
nitric oxide synthase. Nitric oxide is released by endothelial the principal mediator of penile erection. Future studies may
cells and efferent neuronal cells in response to erectogenic elucidate whether other neuropeptides or factors interact with
stimuli. Endothelial nitric oxide synthase is a constitutive nitric oxide mechanisms.
enzyme t h a t is biochemically distinct from the neuronal en- Electrophysiology. Studies suggest that neuronal innerva-
z ~ m eAn . ~inducible
~ form of nitric oxide synthase also may tion of the corpus cavernosum is not dense enough to account
exist in smooth muscle cells.5.xThe role of these nitric oxide for t h e rapid and coordinated responses of smooth muscle
synthase isozymes in the physiological erectile process re- during penile erection and d e t u m e ~ c e n c e . Based
~ ~ ~ ~on
~)~~~
mains to be elucidated. However, data suggest t h a t oxygen the electrical activity of cavernous smooth muscle observed
tension h a s a role in the regulation of penile erection via its during studies using electromyographic recordings,67 it has
modulation of nitric oxide synthesis in the corpus caverno- been proposed that electrical events may contribute to the
sum.59 Furthermore, advanced glycosylation end products modulation of corpus cavernosum smooth muscle tone.47
have been shown t o quench nitric oxide mediated human There is mounting evidence that gap junctions (aqueous in-
corporal smooth muscle relaxation.60 tercellular channels t h a t permit the transit of current carry-
Neuropeptides. Corporal endothelial cells synthesize and re- ing ions and second messenger molecules), calcium channels
lease endothelin, which is a potent and long actingvasoconstric- and potassium channels have a critical role in the modula-
tor.61 Thus, endothelin may contribute to the maintenance of tion of corpus cavernosal smooth muscle tone.47.66.68-71 In
tone of the penile smooth muscle that characterizes the flaccid the cavernosal smooth muscle increases in the concentration
state. The mechanisms involved in endothelin induced penile of intracellular calcium ions must occur before contraction,
smooth muscle contraction have not been determined. How- and a continuous transmembrane calcium ion flux is re-
ever, it has been suggested that endothelin-l may augment the quired for contraction to be maintained.j7,67,6g.70.72-74 Eleva-
contractile responses induced by other vasomodulators in the tions in intracellular calcium ion levels may occur a s a result
human corpus cavernosum.@l of receptor and nonreceptor mediated mechanisms. As shown
Another neuropeptide that may interact with the nitric oxide in figure 175norepineprine may activate t h e al-adrenergic
dependent pathways of erectile function is vasoactive intestinal receptor, which leads to activation of phospholipase C. Phos-
polypeptide. Immunohistochemical studies have indicated that pholipase C then cleaves membrane bound phosphatidylino-
vasoactive intestinal polypeptide is present in autonomic sitol into t h e second messengers inositoltriphosphate and
nerves of the smooth muscle of the corpus cavernosum and diacylglycerol. Inositoltriphosphate mobilizes calcium ions

K+ K’
Factors that modulate Factors that modulate
Vasoconstriction Vasorelaxation
FIG.1. Major mechanisms regulatin corporal smooth muscle tone, including 2 corporeal sniooth muscle cells interconnected by gap junction.
Ca’+, calcium ions. DAG, diacylglycerof. CAMP,cyclic adenosine mono hosphate. cGMP, cyclic guanosine monophosphate. IP,, inositoltriphos-
6.
phate. K’,potassium ions. PKA,protein kinase A. PKG, protein kinase PGE, prostaglandin E l . ATP, adenosine triphosphatase. K - , potassium
ions. Reproduced with pemissi0n.7~
 EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION 9

FIG.2. Critical amount of smooth muscle relaxation is required to convert tonically or actively contracted flaccid penis to erect state.
Impaired relaxation and/or augmented contractility may result in organic erectile dysfunction.Reprinted with permission."

from the mitochondria and endoplasmic reticulum. Diacyl- beginning to be elucidated, it has been established that the
glycerol activates protein kinase C, which modulates calcium nitric oxidelcyclic guanosine monophosphate mechanism has
channels, potassium channels and gap junctions. In the case a significant role in mediating erectile function. The exact
of corporal smooth muscle relaxation transmembrane cal- etiological mechanisms responsible for abnormal erectile re-
cium ion flux decreases and intracellular calcium ions are sponse have yet to be determined. However, organic and
sequestered. For example nitric oxide enters smooth muscle psychogenic factors may cause alterations in the nitric oxidel
cells and activates guanylate cyclase, which catalyzes the cyclic guanosine monophosphate pathway and impair smooth
formation of cyclic guanosine monophosphate. Subsequently muscle relaxation and/or increase smooth muscle contrac-
cyclic guanosine monophosphate is thought to activate pro- tion, thereby resulting in erectile dysfunction. Taub e t a1
tein kinase G, which modulates ion channels and gap junc- reported that the relationship between contraction and re-
tions. In addition, such substances as prostaglandin E l can laxation of corporal tissue strips of humans and rabbits was
bind to receptors that stimulate the adenylate cyclase, which described by a first order linear equation and characterized
catalyzes the formation of cyclic adenosine monophosphate. by a n inverse relationship.49 Moreover, the slope of the re-
This second messenger then stimulates protein kinase A. gression line was indistinguishable from unity for tissues
Like protein kinase C and G protein kinase A modulates ion obtained from 2 individuals with normal erectile function,
channels and gap junctions, possibly via the phosphorylation whereas the slope of the regression line was significantly
of target proteins. In general, events linked to calcium mo- greater than unity for tissues obtained from 10 patients with
bilization and muscle contraction favor increases in the level organic erectile dysfunction. Although these preliminary re-
of intercellular communication, whereas events linked t o the sults need to be confirmed in a larger number of subjects,
activation of cyclic adenosine monophosphate and muscle they suggest that the normal inverse relationship between
relaxation decrease the level of intercellular communica- corporal smooth muscle contraction and relaxation can be-
tion.7" come exaggerated in patients with erectile dysfunction. A
Gap junction proteins have been implicated in the initia- schema of the potential consequences of an imbalance be-
tion, maintenance and modulation of corporal smooth muscle tween corporal smooth muscle contraction and relaxation is
t0ne."~.fi~-7"Connexin43, the membrane spanning protein of given in figure 2.5u
the gap junctions of human corporal smooth muscle, has a
vital role in contraction and relaxation responses.s2 Further-
CONCLUSIONS
more, a recent study indicated that the expression of con-
nexin43 messenger ribonucleic acid (mRNA) varied 2 to Erectile dysfunction is a common condition that is associ-
8-fold in corporal tissue isolated from patients with organic ated with aging but not invariably a consequence of aging. In
erectile dysfunction.7fi Interestingly, connexin43 mRNA ex- addition to aging, risk factors for erectile dysfunction include
pression is thought to be a significant point for the regulation illnesses, such as diabetes mellitus and atherosclerosis, pel-
of intercellular communication in the smooth muscle cells of vic lesions and surgery, various medications, such as some
other tissues, such a s myometrial smooth m u s ~ l e . Fur- ~~. ~antihypertensives
~ and antidepressants, and cigarette smok-
ther studies are needed t o determine whether connexin43 ing. Erectile dysfunction has a negative impact on quality of
mRNA has a similar role in the physiology and pathophysi- life. Evidence indicates that nonadrenergidnoncholinergic
010gy of erectile function. neurotransmission has a vital role in mediating penile erec-
Puthophysiology. For penile erection and detumescence to tion via a nitric oxiddcyclic guanosine monophosphate mech-
occur the smooth muscle of the corpus cavernosum must be anism. Other neuropeptides, gap junctions and ion channels
exposed to a myriad of hormones, neurotransmitters, ions may contribute to the modulation of corpus cavernosum
and second messenger molecules that interact in a complex smooth muscle tone necessary for penile erection and detu-
manner to modulate tone. Although the mechanisms in- mescence. Erectile dysfunction can be caused by vasculo-
volved in these complicated physiological processes are only genic, neurogenic, hormonal and/or psychogenic factors,
10 EPIDEMIOLOGY AND PATHOPHYSIOLOGY O F ERECTILE DYSFUNCTION

which may result in alterations in regulatory mechanisms impotence in diabetes mellitus: vasculogenic versus neuro.
and a n imbalance in corporal smooth muscle contraction and genic factors. Neurourol. Urodyn.. 1 2 145, 1993.
relaxation. Advances being made in our understanding of the 19. Ryder. R. E.. Close, C. F., Moriarty, K. T.. Moore, K. T. and
physiology of penile erection should help to elucidate further Hardisty. C. A.: Impotence in diabetics: aetiology, implications
the mechanisms involved in the pathophysiology of erectile for treatment and preferred vacuum device. Diabetes Med., 9:
893, 1992.
dysfunction. 20. Kaiser, F. E., Viosca, S. P., Morley, J . E.. Mooradian, A. D..
Davis, S. S. and Korenman, S. G.: Impotence and aging: clin.
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E R E C T I L E DYSFUNCTION 1988.
21. Rubin, A. and Babbott. D.: Impotence in diabetes niellitus.
Cigarette smoking J.A.M.A., 168: 498, 1958.
Alcohol consumption 22. Rundles, R.W.: Diabetic neuropathy. General review with report
Drugs of 125 cases. Medicine, 2 4 111. 1945.
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Antidepressants (for example tricyclic antidepressants, Sexual dysfunction in diabetic men. Diabetes, 23: 306, 1974.
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Tranquilizers (for example phenothiazines, butyrophe- K. J.: Prevalence of self-reported erectile dysfunction in people
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