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.