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
of these men were 25 years old or older and only 306 were
older than 55 years. The authors concluded that the preva-
lence of erectile dysfunction was less than 1%in men younger
than 30, less than 3 4 in those younger than 45,6.7%in those
45 to 55,25%in those 65 and up to 80%in those 80 years old.
However, due to the small sample numbers the prevalence
estimates determined by this study for men older than 55
years should be interpreted with caution.
Since 1949 various studies have investigated the preva-
lence of erectile dysfunction in small samples of men. Spector
and Carey reviewed the results of 23 studies conducted be-
tween 1948 and 1988." In studies with community samples
the prevalence of erectile dysfunction was 4 to 9%.In married
men 60 years old or older Diokno et a1 reported a prevalence
rate of erectile impotence of 35%significantly associated with
history of heart attack, urinary incontinence and use of sed-
atives.'
More recently Feldman et al reported on the prevalence of
impotence in a general population using results from the Mas-
sachusetts Male Agmg Study.* This study conducted from 1987
to 1989 was a random sample survey of 1,290 noninstitution-
alized men 40 to 70 years old in 11randomly selected cities and
towns in the area of Boston, Massachusetts. Based on subject
responses to a self-administered sexual activity questionnaire,
the prevalence of minimal, moderate and complete impotence
was 17, 25 and 1092, respectively, yielding a prevalence of im-
potence of all degrees of 52%.Based on these data and United
States population projections for the year 2005 of more than 50
million men 40 to 70 years old,9 erectile dysfunction will affect
more than 25 million men, and millions more of those older
than 70 years. Subject age was the variable most strongly
associated with erectile dysfunction in the Massachusetts Male
Agmg Study.8 Estimated prevalence rates were 39% in men 40
and 6 7 4 in those 70 years old. In fact, the results indicated that
the probability of complete erectile dysfunction increased from
5%,at 40 to 15%at 70 years old. Within this same age range the
probability of moderate impotence increased from 17 to 34%
and minimal erectile dysfunction remained unchanged a t 17%.
In a study published in 1995 Jcinler et a1 estimated the
prevalence of erectile dysfunction and the effects of age,
ethnicity and geographic location on erectile dysfunction and
quality of life.l0 This survey was conducted in men older than
40 years during a free screening program for prostate cancer
in Madison, Wisconsin, New York, New York and New Or-
leans, Louisiana. Thus, this nonrandomly selected sample
may not represent the general United States population. Of
the 1,517 men who responded to a self-administered ques-
tionnaire 1,068 (70.4%)were white, 378 (24.9%)black, 47
(3.1%)Hispanic, 18 (1.2%)Arabic and 6 (0.4%)of other ethnic
origins. Of these men 129 (8.5%)had had no sexual erections
during the previous 12 months. Of the 1,388 men with erec-
tions during the previous 12 months. Of the 1,388 men with
erections during the previous 12 months 172 (12.4%)had
had erections less than 1 in 5 times when sexually stimulated
during the previous month and 273 (19.7%)had had erec-
tions less than half the time. The prevalence of erectile dys-
function was significantly associated with age (p <0.001) and
correlated with lowered quality of life (p <0.001). Interest-
ingly, men younger than 55 years in Madison had a higher
prevalence of erectile dysfunction than those in New York or
New Orleans but increasing age of men in Madison was not
associated with the same extent of increased prevalence as
for men in the other 2 cities. In that study the prevalence of
erectile dysfunction was independent of subject ethnicity.
Only a few epidemiological studies have been conducted in
which the prevalence of erectile dysfunction in countries
other than the United States has been evaluated. The results
of a small survey of 109 men in the United Kingdom who
were 16 years old or older were published in 1986.II Data
indicated that 32% of the men reported some difficulty in
3chieving an erection during sexual stimulation and that
20%had some difficulty maintaining erections long enough
For sexual intercourse. Shirai et a1 estimated the prevalence
3f erectile dysfunction to be 26% in Japan based on a compi-
lation of data on the number of men affected with certain
conditions associated with erectile dysfunction and the esti-
mated prevalence of erectile dysfunction in these popula-
tions.12 In a survey of 411 Danish men 51 years old 19% had
experienced erectile dysfunction obstructing sexual inter-
course a t least occasionally during the previous year.':J Al-
though the populations studied and methods used varied
considerably, the results of recent epidemiology studies indi-
cate that erectile dysfunction is a common problem that is
associated with age and has a significant impact on quality of
life. Further studies on the worldwide prevalence of erectile
dysfunction with respect to racial, ethnic, socioeconomic and
cultural variability are needed.'
Risk factors associated with erectile dysfunction. For sim-
plicity erectile dysfunction can be classified as either organic
or psychogenic.'& Organic erectile dysfunction is due to vas-
culogenic, neurogenic, hormonal or cavernosal smooth mus-
cle abnormalities or lesions, whereas psychogenic erectile
dysfunction is due to central inhibition of the erectile mech-
anism without a physical injury. In most patients with erec-
tile dysfunction organic and psychogenic components exist.
The most common cause of the organic component of erectile
dysfunction is vascular (arterial or venous) abnormalities's
oRen associated with atherosclerosis and diabetes melli-
tus.16-19 Atherosclerotic disease is the cause of approxi-
mately 40% of erectile dysfunction in men older than 50
years.20 In patients with diabetes mellitus irrespective of
type the prevalence of erectile dysfunction is approximately
50% (range 20 to 75) with the prevalence dependent on pa-
tient age, duration of diabetes and disease severity."'-27
Other conditions associated with a high prevalence of erectile
dysfunction include chronic renal failure,2*,29 hepatic fail-
ure,30 multiple sclerosis,31,32 Alzheimer's disease33 and
chronic obstructive lung disease.34 Endocrine disorders, such
as hypogonadism, hyperprolactinemia, hypothyroidism and
hyperthyroidism, also may result in erectile dysfunction35
but are the cause in only a small proportion of cases in the
overall population. Psychogenic erectile dysfunction, which is
most prevalent in younger men (up to 70% of patients
younger than 35 years), accounts for approximately 10% of
erectile dysfunction in men older than 50 years.36
Trauma, irradiation or surgery involving the pelvic region
frequently can result in erectile dysfunction. Erectile dys-
function induced by pelvic trauma can be caused by the
injury itself or surgical procedures for repair. External beam
radiation therapy in patients with localized prostate cancer
has been reported to cause erectile dysfunction in a t least
25% of those treated.37 Furthermore, in a study in which 15
of 16 patients had erectile dysfunction following external
beam radiotherapy the etiology was often vasculogenic in
nature.38 Erectile dysfunction also is associated with urolog-
ical surgery for benign conditions of the prostate. For exam-
ple Lindner et a1 reported an incidence of erectile dysfunction
of 13% in patients who underwent transurethral prostatec-
t ~ m y In. ~another
~ study of patients who underwent trans-
urethral resection of the prostate the incidence of erectile
dysfunction 6 months after the procedure was 11%but 57% of
those who retained potency had a decrease from preoperative
levels of f u n ~ t i o n . ~
Results
'J from a recent study in which no
decrease in erectile function was demonstrated following
transurethral resection of the prostate suggested that pa-
tients often erroneously equate retrograde ejaculation with
erectile d y s f ~ n c t i o n . ~ ~
Various medications and substances of abuse are com-
monly associated with erectile dysfunction.4"4:' The inci-
dence of drug related erectile dysfunction may be as high as
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
guanosine monophosphate induced penile corporal smooth
muscle relaxation a r e unknown. However, it has been pro-
posed t h a t cyclic guanosine monophosphate activates protein
kinase G, leading to the phosphorylation of proteins regulat-
ing corporal smooth muscle tone.5*‘32Nitric oxide is synthe-
sized by enzymatic oxidation of t h e terminal nitrogen atom of
the guanidinium moiety of the amino acid L-arginine by
nitric oxide synthase. Nitric oxide is released by endothelial
cells and efferent neuronal cells in response to erectogenic
stimuli. Endothelial nitric oxide synthase is a constitutive
enzyme t h a t is biochemically distinct from the neuronal en-
z ~ m eAn . ~inducible
~ form of nitric oxide synthase also may
exist in smooth muscle cells.5.xThe role of these nitric oxide
synthase isozymes in the physiological erectile process re-
mains to be elucidated. However, data suggest t h a t oxygen
tension h a s a role in the regulation of penile erection via its
modulation of nitric oxide synthesis in the corpus caverno-
sum.59 Furthermore, advanced glycosylation end products
have been shown t o quench nitric oxide mediated human
corporal smooth muscle relaxation.60
Neuropeptides. Corporal endothelial cells synthesize and re-
lease endothelin, which is a potent and long actingvasoconstric-
tor.61 Thus, endothelin may contribute to the maintenance of
tone of the penile smooth muscle that characterizes the flaccid
state. The mechanisms involved in endothelin induced penile
smooth muscle contraction have not been determined. How-
ever, it has been suggested that endothelin-l may augment the
contractile responses induced by other vasomodulators in the
human corpus cavernosum.@l
Another neuropeptide that may interact with the nitric oxide
dependent pathways of erectile function is vasoactive intestinal
polypeptide. Immunohistochemical studies have indicated that
vasoactive intestinal polypeptide is present in autonomic
nerves of the smooth muscle of the corpus cavernosum and
corpus spongiosum, the tunica albuginea, and penile arteries
and veins.47 In vitro studies indicate that vasoactive intestinal
polypeptide has an inhibitory and relaxation producing effect on
human corpus cavernosum However, vasoactive in-
testinal polypeptide did not produce a n erection in normal VOI-
unteers when injected intracavernosally65 suggesting that va-
soactive intestinal polypeptide does not have a major role in
penile erection. Current evidence indicates that nitric oxide is
the principal mediator of penile erection. Future studies may
elucidate whether other neuropeptides or factors interact with
nitric oxide mechanisms.
Electrophysiology. Studies suggest that neuronal innerva-
tion of the corpus cavernosum is not dense enough to account
for t h e rapid and coordinated responses of smooth muscle
during penile erection and d e t u m e ~ c e n c e . Based
~ ~ ~ ~on
~)~~~
the electrical activity of cavernous smooth muscle observed
during studies using electromyographic recordings,67 it has
been proposed that electrical events may contribute to the
modulation of corpus cavernosum smooth muscle tone.47
There is mounting evidence that gap junctions (aqueous in-
tercellular channels t h a t permit the transit of current carry-
ing ions and second messenger molecules), calcium channels
and potassium channels have a critical role in the modula-
tion of corpus cavernosal smooth muscle tone.47.66.68-71 In
the cavernosal smooth muscle increases in the concentration
of intracellular calcium ions must occur before contraction,
and a continuous transmembrane calcium ion flux is re-
quired for contraction to be maintained.j7,67,6g.70.72-74 Eleva-
tions in intracellular calcium ion levels may occur a s a result
of receptor and nonreceptor mediated mechanisms. As shown
in figure 175norepineprine may activate t h e al-adrenergic
receptor, which leads to activation of phospholipase C. Phos-
pholipase C then cleaves membrane bound phosphatidylino-
sitol into t h e second messengers inositoltriphosphate 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
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-
glycerol activates protein kinase C, which modulates calcium
channels, potassium channels and gap junctions. In the case
of corporal smooth muscle relaxation transmembrane cal-
cium ion flux decreases and intracellular calcium ions are
sequestered. For example nitric oxide enters smooth muscle
cells and activates guanylate cyclase, which catalyzes the
formation of cyclic guanosine monophosphate. Subsequently
cyclic guanosine monophosphate is thought to activate pro-
tein kinase G, which modulates ion channels and gap junc-
tions. In addition, such substances as prostaglandin E l can
bind to receptors that stimulate the adenylate cyclase, which
catalyzes the formation of cyclic adenosine monophosphate.
This second messenger then stimulates protein kinase A.
Like protein kinase C and G protein kinase A modulates ion
channels and gap junctions, possibly via the phosphorylation
of target proteins. In general, events linked to calcium mo-
bilization and muscle contraction favor increases in the level
of intercellular communication, whereas events linked t o the
activation of cyclic adenosine monophosphate and muscle
relaxation decrease the level of intercellular communica-
tion.7"
Gap junction proteins have been implicated in the initia-
tion, maintenance and modulation of corporal smooth muscle
t0ne."~.fi~-7"Connexin43, the membrane spanning protein of
the gap junctions of human corporal smooth muscle, has a
vital role in contraction and relaxation responses.s2 Further-
more, a recent study indicated that the expression of con-
nexin43 messenger ribonucleic acid (mRNA) varied 2 to
8-fold in corporal tissue isolated from patients with organic
erectile dysfunction.7fi Interestingly, connexin43 mRNA ex-
pression is thought to be a significant point for the regulation
of intercellular communication in the smooth muscle cells of
other tissues, such a s myometrial smooth m u s ~ l e . Fur- ~~.
ther studies are needed t o determine whether connexin43
mRNA has a similar role in the physiology and pathophysi-
010gy of erectile function.
Puthophysiology. For penile erection and detumescence to
occur the smooth muscle of the corpus cavernosum must be
exposed to a myriad of hormones, neurotransmitters, ions
and second messenger molecules that interact in a complex
manner to modulate tone. Although the mechanisms in-
volved in these complicated physiological processes are only
9
beginning to be elucidated, it has been established that the
nitric oxidelcyclic guanosine monophosphate mechanism has
a significant role in mediating erectile function. The exact
etiological mechanisms responsible for abnormal erectile re-
sponse have yet to be determined. However, organic and
psychogenic factors may cause alterations in the nitric oxidel
cyclic guanosine monophosphate pathway and impair smooth
muscle relaxation and/or increase smooth muscle contrac-
tion, thereby resulting in erectile dysfunction. Taub e t a1
reported that the relationship between contraction and re-
laxation of corporal tissue strips of humans and rabbits was
described by a first order linear equation and characterized
by a n inverse relationship.49 Moreover, the slope of the re-
gression line was indistinguishable from unity for tissues
obtained from 2 individuals with normal erectile function,
whereas the slope of the regression line was significantly
greater than unity for tissues obtained from 10 patients with
organic erectile dysfunction. Although these preliminary re-
sults need to be confirmed in a larger number of subjects,
they suggest that the normal inverse relationship between
corporal smooth muscle contraction and relaxation can be-
come exaggerated in patients with erectile dysfunction. A
schema of the potential consequences of an imbalance be-
tween corporal smooth muscle contraction and relaxation is
given in figure 2.5u
CONCLUSIONS
Erectile dysfunction is a common condition that is associ-
ated with aging but not invariably a consequence of aging. In
addition to aging, risk factors for erectile dysfunction include
illnesses, such as diabetes mellitus and atherosclerosis, pel-
vic lesions and surgery, various medications, such as some
~antihypertensives
~ and antidepressants, and cigarette smok-
ing. Erectile dysfunction has a negative impact on quality of
life. Evidence indicates that nonadrenergidnoncholinergic
neurotransmission has a vital role in mediating penile erec-
tion via a nitric oxiddcyclic guanosine monophosphate mech-
anism. Other neuropeptides, gap junctions and ion channels
may contribute to the modulation of corpus cavernosum
smooth muscle tone necessary for penile erection and detu-
mescence. Erectile dysfunction can be caused by vasculo-
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.
Antihypertensives (for example thiazide diuretics) 23. Kolodny, R. C., Kahn, C. B., Goldstein. H. H. and Barnett, D. M.:
Antidepressants (for example tricyclic antidepressants, Sexual dysfunction in diabetic men. Diabetes, 23: 306, 1974.
monoamine oxidase inhibitors, lithium. serotonin re- 24. McCulloch, D. K.,Campbell. I. W.. Wu, F. C.. Prescott, R. .J. and
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