Diagnosis of erectile dysfunction

Diagnosis of erectile dysfunction

The proper goal-oriented evaluation of a man proactive and complaining of
erectile dysfunction requires a sympatheticallyelicited history, a focused
physical examination and various carefully selected special investigations.

HISTORY

To obtain a clear history, it is important that the patient himself
understands the distinction between loss of libido, erectiledysfunction and
ejaculatory disturbance. This often may require some preliminary explanation.
The onset, consistency andseverity of the complaint need to be established.
Recently, the development of self-administered symptom scores by O'Learyand
colleagues (Table I, see Appendix, page 41) and Rosen and colleagues (Table II,
see Appendix, page 43) have facilitatedquantitative history-taking for
erectile dysfunction.

Because sexual function is intimately related to the appropriate response of
the sexual partner, tactful enquiries need to bemade concerning previous and
on-going relationships, and the attitude of the partner towards the problem.
Underlyingrelationship problems are a common cause of erectile dysfunction,
and this possibility needs to be tactfully explored in allcases. Although,
by tradition, the question concerning the presence or absence of early morning
erections has been proposedas a means to distinguish between psychogenic and
organic erectile dysfunction, the value of this enquiry has recently
beenquestioned. Many normal individuals do not regularly wake up with early
morning erections, although the presence of apositive history of a firm
erection on waking would make organic erectile dysfunction less likely. Although
these symptomscores are admirable in their own way, they in fact tend to
focus on the functional component of erectile dysfunction ratherthan its
impact on the quality of life of the sufferer. This issue has recently been
addressed by Wagner and colleagues, whohave attempted to quantify the impact
of erectile dysfunction on the sufferer (Table III, see Appendix, page 46).

A careful drug history is particularly important as a considerable number of
pharmacological agents are associated with thedevelopment of erectile
dysfunction. Most potent in this respect are the agents used in the treatment of
prostate cancer, suchas LHRH analogues, which cause loss of libido and
erectile dysfunction. Many other agents have less profound, but none theless
significant, effects. Some of the more commonly encountered compounds implicated
are listed in Table 6.Antihypertensive agents, such as P-blockers and
thiazide diuretics, are the most commonly implicated agents.
Antidepressants,especially monoamine oxidase inhibitors and tricyclic
compounds, are also common causes of erectile dysfunction. Serotoninreuptake
inhibitors may not only cause erectile dysfunction, but also retard
ejaculation.

The question of smoking and alcohol intake needs to be addressed. William
Shakespeare himself noted that alcoholincreases the desire, but diminishes
sexual performance. Smoking should be strongly discouraged and, in some cases,
the useof skin patches containing nicotine suggested.

Specific enquiry should be made concerning concomitant conditions,
particularly those affecting the vascular orneurological systems such as
angina, hypertension, diabetes mellitus, thyroid disease, renal

Table 6 Drugs associated with erectile dysfunctionMajor tranquilizers

phenothiazines, e.g. fluphenazinechlorpromazine, promazine,
mesoridazinebutyrophenones, e.g. haloperidolthioxanthenes, e.g.
thiothixeneAntidepressants

tricyclics, e.g. nortriptyline, amitriptyline,

calcium antagonistsdesipramine, doxepin

Antihypertensives

diuretics, e.g. thiazides, spironolactonevasodilators, e.g.
hydralazinecentral sympatholytics, e.g. methyldopa,clonidine,
reserpine

ganglion blockers, e.g. guanethidine, bethanidineP-blockers, e.g.
propranolol, metoprolol, atenolol

ACE inhibitors

PREVIOUS SURGERY

15

PREVIOUS SURGERY

Various forms of pelvic surgery, particularly radical prostatectomy,
cystoprostatectomy and abdominoperineal resection, are allstrongly
associated with subsequent erectile dysfunction.

DEPRESSION

Reactive or endogenous depression is strongly associated with erectile
dysfunction: nearly 90% of severely depressed menreport complete impotence.
Treatment with antidepressants may sometimes improve the situation, although
both monoamineoxidase inhibitors and tricyclic antidepressants may in
themselves cause erectile dysfunction. Selective serotonin
reuptakeinhibitors, such as fluoxetine (Prozac®) may not only cause erectile
dysfunction, but may also retard ejaculation.

Risk factors for erectile dysfunction

Risk factors for erectile dysfunction

Risk factors for organic erectile dysfunction (see Table 1, page 20) mainly
stem from the fact that the erectile mechanism is avasodilatory response
dependent on smooth muscle function under neurogenic control. Aging, which has
the strongestassociation with erectile dysfunction, probably exerts its
effects mainly through impaired vasodilatory and venoocclusivemechanisms.
Atheroma of the internal iliac arteries and their pudendal branches may be one
factor, but age-relateddegeneration of intracorporeal smooth muscle
mechanisms is probably more important. Venous leakage, another
age-relatedphenomenon, may in itself be a manifestation of deterioration of
intracorporeal smooth muscle function.

DIABETES MELLITUS

This disease is an important risk factor for erectile dysfunction. Damage to
small blood vessels is the main etiology and,therefore, erectile dysfunction
often occurs in association with diabetic retinopathy. Diabetic peripheral
autonomic neuropathyis a further contributory factor. Erectile dysfunction
may develop as a result of the progressive loss of small unmyelinated
so-called C fibers secondary to diabetes. Several groups have reported that
diabetes is associated with loss of NO synthase fromNANC nerve endings and
endothelial cells in the corpora. This may explain the pathophysiological basis
of the erectiledysfunction that so commonly accompanies diabetes.

HYPERTENSION

This is frequently associated with erectile dysfunction. Approximately
one-third of men beyond middle age have a diastolicblood pressure >90
mmHg. Hypertension causes damage to small blood vessels and this may adversely
affect intracorporealvasodilatory mechanisms. Moreover, many of the agents
used to control hypertension, especially P-blockers and diuretics,
areassociated with the development of erectile dysfunction. It has been
postulated that, because high intracorporeal pressures arerequired to
produce penile rigidity, the reduction of blood pressure by any agent is likely
to increase the incidence of erectiledysfunction. However, a-blockers,
perhaps through the induction of intracorporeal vasodilatation, appear to
enhance erection,while still lowering both systolic and diastolic blood
pressures.

HYPERLIPIDEMIA

This disease often occurs in association with hypertension and is also a
cause of damage to the peripheral vascular system.Hypercholesterolemia and
elevated serum triglyceride levels are both also associated with erectile
dysfunction.

SMOKING

Although there have been few epidemiological studies to confirm this, it
appears likely that heavy smoking is associated witherectile dysfunction
because of its deleterious effects on blood vessels and its action leading to an
increase of plateletstickiness.

PEYRONIE'S DISEASE

Fibrosis developing in the corpora albuginea may result in permanent scarring
and consequent deformity of erection. Whenthe fibrosis is severe (Figure
38), penetrative intercourse may be impossible. As a result of the loss of
tunica elasticity, Peyronie'sdisease may also be associated with venous
leak-induced erectile dysfunction.

Epidemiology of erectile dysfunction

Epidemiology of erectile dysfunction

Ever since the ground-breaking work of Kinsey, the prevalence of erectile
dysfunction has been a subject of debate. Althoughit is certain that many
millions of men are affected by the condition, there is a surprising dearth of
high-qualityepidemiological data with which to quantify accurately the
extent of the problem. A figure of one man in ten has often beenquoted as an
estimate of the prevalence of erectile dysfunction, but the frequency and
severity of the disorder vary markedlywith age. Erectile dysfunction is
uncommon in young men (with the exception of intermittent psychogenic
problems),becomes more common in middle age, and is highly prevalent in men
more than 60 years of age. Thus, to some extent,erectile dysfunction is a
natural expression of aging, but one that men are increasingly less willing to
accept without seekingtreatment. As the world's population ages over the
next few decades (Figure 35), the number of men who will suffer
erectiledysfunction seems certain to rise.

One problem for epidemiologists trying to quantify the extent and impact of
erectile dysfunction is the frequentunwillingness of men to discuss the
problem frankly. The accuracy of almost all data in this disease area is
therefore impairedby the reluctance of many, particularly older, men to
respond to what they regard as overly personal questions. However, withthe
development of simple questionnaires which can be self-administered, and the
gradual breakdown of social taboossurrounding the open discussion of sexual
issues, it is possible to anticipate higher-quality information in the
future.

At this time, however, the best data available concerning the prevalence of
erectile dysfunction are derived from theMassachusetts Male Aging Study
(Figure 36). The findings of this study may be summarized as follows. A total of
1290 menaged 40-70 years were included in the study; erectile dysfunction
was very common, with 52% of men reporting some degreeof erectile
dysfunction—mild in 17.1%, moderate in 25.2% and complete in 9.6%. Complete
erectile dysfunction wasreported by 5% of men at 40 years of age, rising to
15% at age 70 years. Loss of firm erections is often extremely bothersometo
men. Figure 37 demonstrates the degree of worry, the loss of confidence, the
negative feelings and the depression that canresult.

PRIAPISM AND POSTPRIAPISM ERECTILE DYSFUNCTION

12 PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION

PRIAPISM AND POSTPRIAPISM ERECTILE DYSFUNCTION

Priapism may be defined as an involuntary erection that lasts for more than
4-6 h. The condition may be spontaneous orsecondary to intracavernous
pharmacotherapy. Spontaneous priapism may be idiopathic or associated with blood
disorderssuch as sickle cell anemia, leukemia or other malignancies (Figure
34).

After 4-6 h, a persistent erection usually becomes painful, but late
presentation is not uncommon because of embarrassment.Initial therapy
involves corporeal aspiration and injection of adrenergic vasoconstrictor
substances such as phenylephrine ormetaraminol (Aramine®). Because these
potent vasoactive agents frequently enter the circulation after intracorporeal
injection,blood pressure should be carefully monitored during therapy.

Although pharmacotherapy with aspiration and injection of vasoactive agents
is often successful within 6-12 h of onset ofpriapism, beyond that time
period the efficacy of any therapy is rapidly diminished. Initial high-flow
priapism is followed bylower flow and progressive deoxygenation of the
corpora. In these later cases, aspiration of the corpora reveals
darkdeoxygenated blood. Progressive ischemia to the intracorporeal smooth
muscle renders the helicine arteries and walls of thetrabecular spaces
progressively less capable of developing sufficient vasoconstriction necessary
to restore and maintainflaccidity.

The consequence of untreated priapism or priapism unresponsive to therapy is
the development of corporeal fibrosis. Thisresults in erectile dysfunction
which is difficult, and sometimes impossible, to treat. Even insertion of a
penile prosthesis maybe technically difficult in such cases because the
fibrosis renders dilatation of the corporeal space problematical.

PSYCHOGENIC CAUSES

Psychological causes were once widely assumed to be the predominant cause of
erectile dysfunction. However, if the correctdefinition of erectile
dysfunction is applied, namely, the persistent loss of penile rigidity in all
circumstances, thenpsychogenic erectile dysfunction proves to be less common
than its organic counterpart, especially in older men. Psychogenicerectile
dysfunction typically occurs in younger men, and is variable and often
associated with performance anxiety. Increasedsympathetic vasoconstrictor
tone and raised circulating norepinephrine levels are most probably involved.
Psychogenicfactors also come into play in other forms of erectile
dysfunction, as failure of erection itself induces anxiety, loss
ofconfidence and sometimes relationship difficulties. The conviction that an
erection will not develop when required, therefore,becomes a self-fulfilling
prophesy.

NEUROGENIC CAUSES

AN ATLAS OF ERECTILE DYSFUNCTION 11

NEUROGENIC CAUSES

The dependence of normal erectile and ejaculatory function on intact neural
pathways to and from the brain has already beenmentioned. Not surprisingly a
considerable number of neurological disorders may result in erectile dysfunction
(Table 3).Those involving the central nervous system include cerebrovascular
accidents, Parkinson's disease and multiple sclerosis.Damage or degeneration
of peripheral nerves supplying the corpora also results in erectile dysfunction.
Examples includediabetic neuropathy, cauda equina lesions due to a prolapsed
intervertebral disk, and iatrogenic neural injury during
abdominoperineal resection of the rectum. The unusual, but interesting,
disorder known as multiple system atrophy ischaracterized by degeneration of
both the sympathetic and parasympathetic central and peripheral autonomic
neurons, as wellas of Onuf's nucleus in the sacral spinal cord (Figure 31).
The result is progressive and disabling ortho static hypotension,urinary
incontinence and erectile dysfunction, together with ejaculatory failure.

ENDOCRINOLOGICAL CAUSES

Testosterone secreted from the Leydig cells of the testes under the influence
of luteinizing hormone (LH) is necessary fornormal male sexuality and sexual
function (Table 4). Medications such as luteinizing hormone-releasing hormone
(LHRH)agonists or stilbestrol, which lower circulating testosterone, result
in loss of libido and in erectile dysfunction. Patients whoare hypogonadal
as a result of pituitary or testicular dysfunction frequently suffer from
erectile dysfunction, which respondsto treatment with exogenous androgens.
More contentious is the suggestion that waning testosterone levels in men of
middleage and beyond (Figure 32), the socalled 'male menopause', are a
frequent cause of erectile dysfunction and, therefore,boosting serum
testosterone levels has therapeutic benefits (Table 5). However, there is some
evidence from experimentalanimal models that androgens are necessary for the
support of intracavernosal smooth muscle function and maintenance ofNO
synthase levels. Exogenous androgens are certainly capable of enhancing the
libido, which is an important component ofsexuality.

Dihydrotestosterone (DHT), the potent androgenic metabolite of testosterone
produced by the enzyme 5a-reductase, iscrucial for the normal development of
the male external genitalia, seminal vesicles and prostate, but is not essential
for eitherthe libido or erectile function. Compounds such as finasteride,
which inhibit the activity of 5a-reductase type II, result inshrinkage of
the prostate by 20-30%, but have been reported to cause erectile dysfunction in
only around 3-5% of patients.However, in the 4-year placebo-controlled study
of finasteride recently reported by McConnell and colleagues, nearly 14%
ofpatients taking the active drug experienced some form of sexual
dysfunction.

Prolactin, which is released from the pituitary gland, acts as an inhibitory
factor in male sexual function.Hyperprolactinemia, either idiopathic or,
less commonly, the result of a tumor such as a pituitary prolactinoma (Figure
33), isassociated with erectile dysfunction, as is the more common entity of
idiopathic hyperprolactinemia. Correction of the raisedprolactin levels
using bromocriptine may sometimes restore potency in such patients.

Table 3 Neurogenic pathophysiology of organic erectile dysfunction

Diabetes, alcoholism/vitamin deficiencies contribute to somatic/autonomic
neuropathyDemyelinating diseases (e.g. multiple sclerosis) decrease penile
sensation

Aging elevates sensory thresholds to vibratory/electrical stimulation

Pelvic/retroperitoneal surgery (e.g. radical prostatectomy) may damage the
autonomic nervous system controlling the physiology ofpenile
erection/ejaculation_

Table 4 Endocrinological pathophysiology of organic erectile
dysfunctionLow testosterone levels associated with decreased libido

Decline in nitric oxide synthase activity in castrated animals reversed by
androgen supplementationNitric oxide synthase mRNA increases with androgen
supplementation

Hypogonadism may be due to primary testicular failure, decreased secretion of
gonadotropin releasing hormone (e.g.

hyperprolactinemia), or alterations in steroid hormone protein binding (e.g.
alcoholism, liver failure)_

Table 5 Age-related pathophysiology of organic erectile dysfunction

Cellular senescence alters collagen content in corpora cavernosa/tunica
albuginea, leading to venous occlusive dysfunction/decreasedneuronal
transmission to cavernosal smooth muscle

Aging alters endothelial function, leading to decreased basal nitric oxide
release and up-regulation of basal endothelin-1

Reproductive aging in animals impairs neurogenic erectile response: increase
in latency period to attain an erection/decrease in maximalintracavernosal
pressure; loss of function integrity of endoluminal structures; imbalance in
expression of vasoconstricting/vasorelaxingmodulators of penile
erection/decrease in nitric oxide synthase/increase in endothelin-1 levels_

PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION Neurological diseases

10 PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION

Age

hyperprolactinemiaNeurological diseases

multiple sclerosis

multiple system atrophy

Parkinson's disease

spinal cord injuryOther

acquired immunodeficiency syndrome (AIDS)

Table 2 Vascular pathophysiology of organic erectile dysfunction

Vascular etiology of erectile dysfunction present in 60% of patients. Small
vessel vascular disease (e.g. diabetes) and large vesselarteriosclerosis
(e.g. hypertension) cause arterial insufficiency/erectile dysfunction; erectile
dysfunction occurs in 25% of men treated forhypertension and 60% of
diabetics

Tobacco alters penile arterial hemodynamics, causing erectile dysfunction in
a high proportion of elderly smokers; pelvic radiation leadsto
fibrosis/stenosis of pelvic arteries and accelerates existing arteriosclerosis;
venous occlusive dysfunction may be due to decreaseddistensibility of
corpora cavernosa or inherent abnormalities in tunica albuginea

Vascular endothelial growth factor may play a role in modulation of normal
vascularity of penile architecture_

or the cavernosal venous system (Figure 29). The etiology of this is obscure,
but is more likely to be a primary disorder ofintracavernosal smooth muscle
than a problem primarily related to the penile veins themselves.

Intracavernosal smooth muscle fibrosis

Full erection depends on achieving complete intracorporeal vasodilatation.
This, in turn, depends on normally functioningcorporeal smooth muscle. Aging
and/or ischemia may result in degeneration of smooth muscle cells, thereby
impairing theability to respond to vasodilator signals. During flaccidity,
the oxygen saturation of the blood within the lacunar spaces is low(40
mmHg). During erection, however, the inflow of arterial blood raises the oxygen
saturation of lacunar blood to >90

mmHg.

The current evidence suggests that the development of intermittent erections
may be an important mechanism formaintaining full oxygenation and, thus,
function of cavernosal smooth muscle. Conditions of low oxygenation promote
theproduction and release of transforming growth factor^. This molecule, in
turn, results in the formation of collagen, with theresultant development of
intracorporeal fibrosis (Figure 30). This may help to explain the physiological
importance of thephenomenon of intermittent nocturnal penile tumescence.
This is an important concept because it suggests that loss oferection due to
any cause may be compounded by loss of cavernosal smooth muscle function and
fibrosis. Clearly, suchconsiderations may have an impact on the timing of
treatment decisions in circumstances such as erectile dysfunctionfollowing
radical prostatectomy.

Failure of intracavernosal neurotransmission

The molecular mechanisms of vasodilatation and vasoconstriction that underlie
erection and detumescence have only recentlybeen elucidated. Bearing in mind
their complexity, it would be surprising if specific abnormalities of
neurotransmission didnot translate into clinical erectile dysfunction. As
yet, however, none have been specifically described, but failure of
NOproduction due to lack of NO synthase or abnormalities of receptor or
second-messenger function may well underlie somecases. More research is
needed in this rapidly evolving area.

Pathophysiology of erectile dysfunction

Pathophysiology of erectile dysfunction

Given the complexity of the system, it is not surprising that a wide variety
of diverse disorders may result in erectiledysfunction (Table 1). Often, the
cause is multifactorial, but vasculogenic causes are the most commonly
implicated.

VASCULOGENIC CAUSES

Arterial insufficiency

Because the development and maintenance of a rigid erection depend on
achieving a high intracavernosal pressure, it is notsurprising that
disorders affecting the peripheral arterial blood flow are strongly associated
with erectile dysfunction (Table 2).The most common cause is atheroma
involving either the common or internal iliac arteries or their more distal
branches(Figure 28). The risk factors for this are similar to those for
coronary artery disease (including smoking, hypertension,hyperlipidemia,
diabetes mellitus and obesity). Narrowing or occlusion of the internal pudendal
arteries reduces perfusionpressure to the corpora, resulting in a failure to
achieve full rigidity. In the absence of such pressure, the normal
veno-occlusive mechanisms cannot operate and, thus, the problem is
compounded by secondary venous leakage. Obliterativedisease of the aorta may
also result in erectile dysfunction.

Venous leakage

In the presence of a normal arterial inflow, normal veno-occlusive mechanisms
should slow egress of blood from the corporato a virtual trickle during full
erection. Failure to do so results in a flaccid erection and leakage of blood,
either into the deepdorsal vein

Table 1 Risk factors for erectile dysfunction

Age_

Vascular factors

myocardial infarction

coronary artery bypass surgery

cerebral vascular accident

peripheral vascular disease

hypertension

hyperlipidemia

smokingMetabolic diseases

diabetes mellitus

renal failure

thyrotoxicosis

hypothyroidism

depression

alcoholism

chronic liver disease

adrenal disorders

hypogonadism

ORGASM AND EJACULATION

8 AN ATLAS OF ERECTILE DYSFUNCTION

ORGASM AND EJACULATION

Orgasm and ejaculation are the result of a sudden increase in sympathetic
efferent activity. This has a number of effects: theprostate, seminal
vesicles and vasa deferentia contract, emptying their contents into the
prostatic urethra. The bladder neckcloses tightly to prevent retrograde
ejaculation, and the external urethral sphincter relaxes. Semen is ejaculated in
a pulsatilefashion as a result of rhythmic contractions of the
bulbocavernosus muscles (Figure 27).

MECHANISMS OF ERECTION - continuation

MECHANISMS OF ERECTION 7

REGULATION OF INTRACAVERNOSAL SMOOTH MUSCLE CONTRACTILITY

Two principal mechanisms control the tone of penile smooth muscle cells:

(1) Neurogenic control, in which adrenergic, cholinergic and NANC fibers
all play a role; and

(2) Endothelial control, by neurotransmitter substances released by the
endothelium lining the helicine arteries and lacunarspaces.

ADRENERGIC VASOCONSTRICTOR MECHANISMS

Catecholamine-containing adrenergic nerves have been demonstrated in the
cavernosal and helicine arteries as well as incavernosal smooth muscle of
humans. Norepinephrine is released from dense-core vesicles of sympathetic nerve
terminals tointeract with a-adrenoceptors located on cavernosal smooth
muscle membranes (Figure 18). The main mediator of penilesmooth muscle
contraction appears to be the a1-adrenoceptor, all three subtypes (a1A, a1B and
a1D) of which have beendetected in the human corpus cavernosum. There is
some evidence that the (a1A subtype is functionally predominant.
Theinteraction of norepinephrine with the a1-adrenoceptor results in an
increase in intracellular calcium via a guanidinenucleotide-binding protein
(G protein) mechanism amplified through inositol phosphate (IP3) and
diacylglycerol (DAG)pathways (Figure 19). Sympathetic nerve activity is
therefore involved in both inducing detumescence and active maintenanceof
intracavernosal smooth muscle tone when the penis is in its normal flaccid
state. This is the basis for the clinicaleffectiveness of drugs such as
phentolamine (Vasomax®).

CHOLINERGIC MECHANISMS

Erection is initiated by increased neural activity in the parasympathetic
nerves originating from the S2-S4 spinal segments.The preganglionic
neurotransmitter is acetylcholine, but the postganglionic nerve endings
mediating vasodilation are NANC.Acetylcholine may, however, modulate
noradrenergic vasoconstrictor tone by acting upon prejunctional muscarinic
receptorson adjacent sympathetic nerve endings.

NON-ADRENERGIC NON-CHOLINERGIC MECHANISMS

The principal neurotransmitter mediating trabecular smooth muscle relaxation
is NANC. Originally, the 28 amino-acidpeptide VIP was put forward as the
candidate molecule, but it is now recognized that nitric oxide (NO) is the most
importantmolecular mediator of erection. NO synthase is present in the
pelvic nerves (Figure 20) and in the peripheral autonomic nerveendings
innervating the corpora (Figures 21 and 22). Release of NO leads to the
accumulation of cGMP within trabecularsmooth muscle cells and
hyperpolarization of the cell membrane. The resultant reduction in intracellular
calcium leads tosmooth muscle cell relaxation which, as already mentioned,
spreads rapidly from cell to cell through so-called gap
junctions.Vasodilatory responses are terminated by degradation of cGMP,
mainly by the enzyme PDE5.

ENDOTHELIAL MECHANISMS

Endothelium-derived relaxation factors were first described in the rabbit
aorta by Furchgott in 1980. A similar mechanism inwhich lacunar endothelium
releases a substance that relaxes trabecular smooth muscle also occurs in the
corpora. Again, themain relaxing factor is NO, produced by NO synthase,
which exerts an effect by stimulating the activity of guanylate
cyclase,resulting in an accumulation of cGMP and a decrease in cytoplasmic
free calcium.

Other molecules play a part in tumescence and detumescence, including
endothelin-1, which has a powerfulvasoconstrictory effect. In contrast, the
action of PGE1 is to relax trabecular smooth muscle. Other prostaglandins, such
asPGI2, may also play a role in preventing intracorporeal coagulation by
their antiplatelet aggregation activity.

HEMODYNAMICS OF ERECTION

Penile erection is a hemodynamic response to a combination of humoral,
neurogenic and local signals. Vasodilatory signalingcoincides with reduced
vasoconstrictor activity. The result is increased flow through the dilating
cavernosal arteries. At thesame time, the smooth muscle helicine arteries
and lacunar spaces relax, thereby allowing blood to fill the
intracorporealspace (Figures 23 and 24). Cavernosal filling compresses the
obliquely running subtunical venules against the sturdy tunicaalbuginea,
resulting in a hundred-fold increase in resistance to venous outflow (Figure
25). Intracavernosal blood pressuresoon rises to approximate that of
systolic blood pressure, thereby producing penile erection (Figure 26).

Mechanisms of erection

Mechanisms of erection

Intracavernosal smooth muscle tone is by far the most important determinant
of intracavernosal blood flow. Approximatelyhalf of the cavernosal volume is
composed of smooth muscle, with the remainder consisting of either lacunar
spaces orcollagen. Collagen fibers are largely responsible for the passive
mechanical properties of cavernosal tissue. In contrast, activecontraction
of cavernosal smooth muscle is dependent upon a number of factors, including the
level of agonists(neurotransmitters, hormones and endothelium-derived
factors), adequate expression of receptors, integrity of
transductionmechanisms, calcium homeostasis, interaction of contractile
proteins, and intimate intracellular communication betweensmooth muscle
cells (gap junctions).

Cavernosal smooth muscle cells contain abundant amounts of the contractile
proteins, actin and myosin. Followingphosphorylation of myosin by adenosine
triphosphate (ATP), attachments (crossbridges) form between the light chains
ofthese two proteins and these attachments provide the mechanism for
contractile tone of smooth muscle. The expenditure ofenergy for maintaining
this state of tone is almost zero, but there is an absolute requirement for a
high concentration ofcytoplasmic free calcium.

Adequate calcium homeostasis is, therefore, fundamental to the normal
regulation of smooth muscle tone. Three majormechanisms are involved:

(1) Influx of extracellular calcium through voltageregulated
channels;

(2) Activation of membrane-bound receptors which allow extracellular
calcium to enter through receptor-operated channels;

(3) Activation of signal pathways which allow intracellular release of
calcium from the sarcoplasmic reticulum.

Relaxation of cavernosal smooth muscle may be thought of as 'resetting' the
contractile machinery. This is mainlyaccomplished by lowering intracellular
calcium. There are a number of mechanisms by which this may be achieved but,
ingeneral, all pathways depend on either the accumulation of cyclic
adenosine monophosphate (cAMP) or cyclic guanosinemonophosphate (cGMP), or
the activation of potassium channels with consequent hyperpolarization of the
cellular membrane(Figure 16).

Nitric oxide, produced from its precursor L-arginine by nitric oxide synthase
(NOS), appears to exert two effects within thecorpora (Figure 17):

(1) Activation of potassium-channel ATPase, resulting in
hyperpolarization of the smooth muscle cell membrane. Thishyperpolarization
prevents the opening of voltage-dependent calcium channels, thereby reducing
intracellular calcium;

(2) Activation of guanylate cyclase which catalyzes the conversion of
guanosine triphosphate (GTP) to cGMP. This triggersrelaxation by lowering
intracellular calcium.

Other muscle relaxants act via cAMP-dependent mechanisms and include
prostaglandin (PG) E1 and vasoactive intestinalpolypeptide (VIP). These
substances react with membrane receptors coupled to a G protein which stimulates
adenylatecyclase to produce cAMP, thus lowering intracellular calcium. The
presence of two distinct and separate pathways to induceintracorporeal
vasodilatation is probably a reflection of the importance of the erectile
mechanism in the perpetuation of thespecies.

The breakdown of cGMP, accomplished mainly by phosphodiesterase type 5
(PDE5), raises cytoplasmic free calciumlevels and reverses smooth muscle
relaxation. Compounds such as papaverine and the recently discovered, more
selective,molecule sildenafil inhibit intracorporeal PDE5, thereby
increasing the intracellular half-life of cGMP and, thus, promotingand
prolonging smooth muscle relaxation and erection.

The deep drainage system consists of the cavernosal and crural veins

AN ATLAS OF ERECTILE DYSFUNCTION 5

complex at the urethroprostatic junction. The deep drainage system consists
of the cavernosal and crural veins. Emissaryveins in the proximal third of
the penis join to form one or two cavernosal veins which pass between the bulb
and crus of thepenis to drain into the internal pudendal vein (Figure
11).

LYMPHATIC DRAINAGE

Lymph is drained from the penis by lymphatics which pass to the superficial
and deep inguinal lymph nodes of the femoraltriangle (Figure 12). In turn,
these nodes, which may become secondarily involved in patients who have
carcinoma of thepenis (Figure 13), drain to the external and internal iliac
lymphatic chains. Conditions that obstruct these lymphatic channels,such as
metastatic prostate cancer, may result in gross penile and scrotal edema.

NEUROANATOMY

Three sets of peripheral nerves are involved in penile erection and
subsequent detumescence: parasympathetic nerves from thesecond to fourth
sacral (S2-S4) segments, sympathetic nerves from the tenth thoracic to the
second lumbar (T10-L2)thoracolumbar outflow, and somatic fibers via the
pudendal nerves (Figure 14).

The sympathetic nerves reach the corpora, as well as the prostate and bladder
neck, via the hypogastric nerves, where theyare susceptible to injury in
retroperitoneal lymph node dissection performed for the treatment of metastatic
testicular cancer.Postganglionic noradrenergic fibers pass posterolateral to
the prostate in the so-called nerves of Walsh to enter the corporacavernosa
medially.

Parasympathetic nerves stem from the so-called sacral erection center and
their cell bodies lie in the intermediolateral nucleifrom S2 to S4. Exiting
through the sacral foramina, these nerves pass forward lateral to the rectum as
the nervi erigentes toreach the pelvic plexus. In this location,
preganglionic fibers relay in ganglia, and postganglionic non-adrenergic,
non-cholinergic (NANC) fibers pass in the cavernous nerves to the corpora
cavernosa. These nerves are vulnerable during proceduressuch as
abdominoperineal resection of the rectum and radical prostatectomy (Figure
15).

The pudendal nerves comprise motor efferent and sensory afferent fibers which
innervate the ischiocavernosus andbulbocavernosus muscles as well as the
penile and perineal skin. Pudendal motor neuron cell bodies are located in
Onuf'snucleus of the S2-S4 segments. The pudendal nerve enters the perineum
through the lesser sciatic notch at the posterior borderof the ischiorectal
fossa and runs in Alcock's canal towards the posterior aspect of the perineal
membrane. At this point, it givesoff the perineal nerve with branches to the
scrotum and the rectal nerve supplying the inferior rectal region.

The dorsal nerve of the penis emerges as the last branch of the pudendal
nerve. It then runs distally along the dorsal penileshaft lateral to the
dorsal artery. Multiple fascicles fan out distally, supplying proprioceptive and
sensory nerve terminals tothe dorsum of the tunica albuginea and skin of the
penile shaft and glans penis.

CENTRAL NERVOUS SYSTEM CONNECTIONS

Although reflex spinal erections may occur provided that the sacral reflexes
are intact (for example, after cervical or thoracicspinal injury), central
connections are paramount in engendering the normal male sexual response. These
central pathways,however, are as yet incompletely understood.

A number of areas in the brain are involved in the modulation of erection,
including the thalamic nuclei, rhinencephalon,limbic structures and
paraventricular nucleus. Messages are integrated in the medial preoptic area
where dopaminergicneurons are important. Norepinephrine (noradrenaline) and
serotonin have also been identified as neurotransmitters in thisregion.
Efferent pathways enter the medial forebrain bundle and pass caudally into the
mid-brain tegmental region near thelateral part of the substantia nigra.
Caudal to the mid-brain, the efferent pathway travels in the ventrolateral part
of the ponsand medulla, passing down to the sacral spinal centers via the
lateral funiculus of the spinal cord. Activation of theparasympathetic
neurons, located in the spinal cord, leads to intrapenile release of nitric
oxide, mainly by neural terminations.

Superimposed on this hypothalamo-spinal circuit are higher centers, including
the gyrus rectus, cingulate gyrus andhippocampus; these areas are all
capable of modifying the erectile response, although their exact function has
not yet beenelucidated. Diseases specifically affecting these structures
include Parkinson's disease, multiple system atrophy and stroke,all of which
are often associated with erectile dysfunction.

Anatomy - The key structures mediating penile erection

Anatomy

The key structures mediating penile erection are the paired corpora cavernosa
or 'erectile bodies' (Figure 1). These cylindricalstructures form the bulk
of the penis and fill with arterial blood under pressure at the time of
erection. Fused distally for three-quarters of their length, they separate
proximally to fuse with each ischial tuberosity of the pelvis. Each corpus
cavernosumhas a thick fibrous sheath, the so-called tunica albuginea, which
surrounds the erectile tissue, made up of multiple lacunarspaces that are
inter-connected and lined by vascular endothelium (Figure 2). The trabeculae
constitute the walls of thesespaces, and comprise smooth muscle and a
fibroelastic framework of collagen in almost equal quantities.

The corpus spongiosum surrounds the urethra, which traverses the length of
the penis within this structure, lying in theventral groove formed by the
paired corpora cavernosa in the pendulous portion. At its proximal portion, it
expands to formthe bulb, which curves upwards through the urogenital
diaphragm to reach the apex of the prostate gland. Distally, the
corpusspongiosum expands to form the glans penis (Figure 3). The spongiosum
is composed of sinusoidal spaces of largerdimensions than those of the
corpora cavernosa and with less smooth muscle. The tunica albuginea surrounding
thespongiosum is flimsy compared with that of the corpora, but the
spongiosum is nevertheless capable of an erectile response.

The corpus spongiosum in the bulbar region is surrounded by the
bulbospongiosus muscles (Figure 4). These have twoimportant functions: to
facilitate ejaculation by their rhythmic contractions, and to empty the bulbar
urethra after voiding,thereby preventing postmicturition dribble.

The skin overlying the penis is exceptionally mobile and expandable to
accommodate the considerable increase in girth andlength that occurs during
erection. This lack of adherence makes it relatively susceptible to edema. In
its distal portion, thepenile skin extends forward to form the prepuce
before folding backwards and attaching to the corona of the glans
penis(Figure 5).

The pendulous portion of the penis is supported and stabilized by the
suspensory ligament (Figure 6). Division of thisstructure makes the penis
appear longer in its flaccid state, but this does not enhance the proportions of
the organ when erect.

ARTERIAL BLOOD SUPPLY

The blood supply to each corpus cavernosum is derived mainly from the
internal iliac artery, a branch of the atheroma-pronecommon iliac artery. In
the pelvis, the internal pudendal artery passes beneath the sacrospinous
ligament and over thesacrotuberous ligament, and gives off the perineal
artery in Alcock's canal, where it runs under the superficial
transverseperineal muscle and the symphysis pubis (Figure 7). After giving
off the perineal artery, it becomes the common penile artery(Figure 8). This
vessel pierces the pelvic floor adjacent to the inferior ramus of the ischium
near the bulb of the urethra andgives off the bulbar, urethral, dorsal and
cavernosal branches before reaching the corpus cavernosum to form one element
ofthe paired dorsal arteries (Figure 8).

The cavernosal artery on each side pierces the tunica albuginea at the hilum
of the penis. It then runs distally in the centerof each corpus while giving
off numerous helicine branches. These corkscrewshaped muscular vessels open
directly into thelacunar spaces (Figure 9). The tonic contraction of the
smooth muscle walls (Figure 10) normally allows only small amountsof blood
into the lacunar spaces, thereby maintaining penile flaccidity. Relaxation of
the muscular walls of these vesselsinitiates the hemodynamic changes that
result in penile erection.

VENOUS DRAINAGE

Blood leaves the penis via three venous systems: superficial, intermediate,
and deep. The superficial system allows blood frommultiple superficial veins
to drain into the superficial dorsal vein, which itself drains into the left
external branch of theinternal saphenous vein. The intermediate venous
system lies beneath Buck's fascia and comprises the deep dorsal vein andthe
multiple circumflex veins. This system drains blood from the glans, corpus
spongiosum and the distal two-thirds of thecorpora. The deep dorsal vein
runs in the groove dorsally between the corpora cavernosa. It enters the pelvis
beneath thesuspensory ligament, which suspends the corpora from the
undersurface of the pubic arch and drains into the dorsal venous

Review of Erectile Dysfunction

Section I:A Review of Erectile Dysfunction

Introduction 3

Anatomy 4

Arterial blood supply 4

Venous drainage 4

Lymphatic drainage 5

Neuroanatomy 5

Central nervous system connections 5

Mechanisms of erection 6

Regulation of intracavernosal smooth muscle contractility 6

Adrenergic vasoconstrictor mechanisms 7

Cholinergic mechanisms 7

Non-adrenergic non-cholinergic mechanisms 7

Endothelial mechanisms 7

Hemodynamics of erection 7

Orgasm and ejaculation 8

Pathophysiology of erectile dysfunction 9

Vasculogenic causes 9

Neurogenic causes 10

Endocrinological causes 11

Priapism and postpriapism erectile dysfunction 12

Psychogenic causes 12

Epidemiology of erectile dysfunction 13

Risk factors for erectile dysfunction 14

Diabetes mellitus 14

Hypertension 14

Hyperlipidemia 14

Smoking 14

Peyronie's disease 14

Previous surgery 15

Depression 15

Diagnosis of erectile dysfunction 16

History 16

Physical examination 17

Special investigations 17

Treatment options for erectile dysfunction 19

Psychosexual counseling 19

Medical therapies 19

Vacuum devices 22

Surgical therapies 22

Conclusions 24

Bibliography 25

Appendix 28

2

Introduction

Until recently, a man unable to develop or sustain an erection sufficient for
penetrative sexual intercourse has been referred toas 'impotent'. This term,
however, has negative connotations which imply a general loss of prowess in
other domains ofmental and physical function. Thus, nowadays, the more
specific term 'erectile dysfunction' is preferred.

Although the problem is most commonly the result of isolated malfunction of
penile erection, diminished or absent libidoand delayed or absent orgasm and
ejaculation frequently coexist with erectile dysfunction, each in its own way
contributing tothe afflicted individual's sense of failure and personal
inadequacy.

Many millions of men world-wide are afflicted by erectile dysfunction.
Although the ability to develop and sustain anerection may not always result
in complete loss of sexual satisfaction, in most men, it creates a psychological
stress thatadversely affects the relationship with their partner. This, in
itself; often compounds the physical problem. In men of all ages;erectile
dysfunction diminishes the willingness to initiate or continue sexual
relationships, not only because of loss of self-esteem, but also because of
the fear of the humiliation associated with inadequate sexual performance and
the risk ofsubsequent rejection.

Erectile dysfunction is frequently regarded as an inevitable part of aging
and, thus, as a symptom simply to be acceptedwith stoicism. However; this
assumption is often incorrect. Erectile dysfunction is not uncommonly the result
of some otherillness, such as diabetes mellitus or hypertension, or a
consequence of the treatment of the latter disorder withantihypertensive
agents.

The correct diagnosis of erectile dysfunction depends on an accurate and
sympathetically elicited history which recognizesthat the physical component
may be only part of the problem. The psychological, interpersonal and wider
social ramificationsalso need to be tactfully assessed. Careful physical
examination and judicious stepwise use of investigations help to completethe
picture.

Now, for the first time; an increasing range of safe and effective treatment
options is available for men who suffer fromerectile dysfunction. Many of
these options, however, are poorly appreciated not only by patients; but also by
health-careprofessionals, many of whom still feel too embarrassed to address
this highly prevalent and distressing problem in a seriousand sympathetic
manner.

Erectile dysfunction often has a major impact on the self—esteem and quality
of life not only of the man, but also of hispartner. Thus, there are few
areas in medicine where so much remains to be done and with so much potential to
improve theoutlook for the many millions of sufferers as well as for their
partners.

Good communication is the byword of our time

Preface

Good communication is the byword of our time. Visual images convey
information more coherently and more effectivelythan words. With this in
mind, I have put together an updated Atlas of Erectile Dysfunction to make
available the latest state-of-the-art information as to the causes,
diagnosis and treatment options for this highly prevalent and often distressing
condition.Since both family and nurse practitioners are increasingly
involved in the care of men suffering from erectile dysfunction, Ihave
included some images of other conditions affecting the external genitalia; such
as condylomata acuminata and penilecarcinoma. These problems can
occasionally surface and cause confusion in an erectile dysfunction clinic or
the familypractitioner surgery.

It has been estimated that overall one in ten men suffers from erectile
dysfunction. Although never life-threatening in theusual sense of being
fatal, erectile dysfunction may yet have major effects on quality of life by
causing considerable loss ofselfesteem and often putting important life
relationships in jeopardy.

However, for the first time, we are now able to understand the causes,
pinpoint the diagnosis, and initiate safe and effectivetherapy for the many
sufferers with this disorder. Unfortunately, many doctors and other health-care
professionals stillbecome uneasy at the thought of a frank and open
discussion concerning matters of sexual dysfunction. Much of this taboo
isdue to a lack of understanding of the causes and awareness of the remedies
now available for the problem. It is my hoped-forintention that this second
edition of the atlas will provide clinicians with easy access to the information
that they require tobring up the subject with their patients and alleviate
the often considerable anxiety and distress endured not only by the manymen
afflicted by erectile dysfunction, but by their partners as well.

Roger S.Kirby

London

It is a great pleasure for me

Foreword

It is a great pleasure for me to introduce this recently updated and
beautifully constructed Atlas of Erectile Dysfunction. For manyyears, Roger
Kirby has been a prolific author and researcher known for his simple and
practical approaches to complexurological issues. This new endeavor is
further proof of the bright ideas and talent that he possesses.

Over the last two decades, innovative basic research into the functional
anatomy and physiology of the penis has vastlyimproved our understanding of
erectile function and dysfunction. Working together, scientists, clinical
researchers andpharmaceutical companies have brought on revolutionary
changes in the diagnosis and treatment of erectile dysfunction, tothe
benefit of millions of men and their partners. These rapid changes in the
understanding of the pathophysiology andmanagement algorithm have also
caused much confusion and debate among the medical community regarding the
mostappropriate and cost-effective approach to the management of erectile
dysfunction. Therefore, it is with great admiration andappreciation of my
dear colleague Roger Kirby that I acknowledge his tremendous achievement in
putting together such anextensive, yet straightforward, book on the current
state of the subject.

An Atlas of Erectile Dysfunction contains diagrams of basic anatomy
mechanisms, pharmacology and neurophysiology thatare clearly outlined and
easy to understand. The chapter on diagnosis is streamlined to give the reader
an excellent idea ofwhich tests are needed in cases where more detailed
examination is necessary. The discussions covering the various optionsare
well written, especially the sections discussing the new oral agents. The
illustrations of surgical treatments, such asrevascularization, penile
prosthetic surgery and reconstructive surgery for Peyronie's disease, are
somewhat simplified but,nevertheless, illustrate the key steps involved in
each technique.

Overall; this is an excellent reference book which is superbly illustrated by
numerous drawings and photographs in color. Thereader will not only
appreciate the major progress in erectile dysfunction research and management,
but will also enjoy thebeautiful illustrations which make this atlas a
must-read for anyone interested in this topic.