Establishing the cause of erectile dysfunction is best approached by considering the
   normal controls of erection.29,30

   Vascular insufficiency Inadequate erection caused by major vascular
   insufficiency occurs with aortoiliac atherosclerosis; it is usually accompanied by
   claudication and by diminished or absent femoral pulses.

   The possibility that erectile dysfunction is caused by disease of smaller arteries can
   be pursued with modern hemodynamic techniques. Doppler and ultrasound study can
   delineate arterial, sinusoidal, or venous inadequacy. Because these methods are not
   widely available, the differential diagnosis is still guided by clinical findings. If
   injection of papaverine into the corpora cavernosa induces a normal erection within
   10 minutes, there is no need for further evaluation of the vascular component.

   Peripheral neuropathy Peripheral neurogenic erectile dysfunction occurs as a
   result of spinal cord trauma. It also occurs in the various syndromes of autonomic
   insufficiency and in about 50 percent of men with insulin-dependent diabetes
   mellitus.31 The medical history of men who have diabetes usually discloses other
   signs of neuropathy, such as postural hypotension, diarrhea, and incontinence. The
   erectile defect associated with diabetes may be impaired relaxation of smooth muscle
   of the corpora cavernosa. In vitro, smooth muscle relaxation is impaired by either
   direct electrical or neurochemical stimulation.32 The absence of nocturnal penile
   tumescence has been used to identify cases of neurologic erectile dysfunction.

   Drugs Many drug-related causes of erectile dysfunction involve the complex
   interconnections of the erotogenic pathways. Antihypertensive drugs, tranquilizers,
   antidepressants, and many other agents may all cause decreased erectile capacity
   [see Table 1]. 33 Hypertension and antihypertensive medications are frequent
   causes of erectile dysfunction.34 In one group of hypertensive patients, 17 percent
   reported some decrease in potency before they had begun any treatment. Diuretics,
   centrally active sympatholytics (including clonidine, methyldopa, and reserpine), and
   peripherally active agents may all induce partial or complete erectile dysfunction;
   some agents (e.g., guanethidine) can cause retrograde ejaculation. Beta blockers may
   produce erectile dysfunction with or without fatigue and depression. The
   mechanisms by which these drugs produce erectile dysfunction are not well
   understood, and it is impossible to predict which agent will affect which patient. Trial
   and error are therefore necessary to distinguish between the pharmacological causes
   of erectile dysfunction and the psychological influences of the disease and its
   treatment. Fortunately, angiotensin-converting enzyme inhibitors and calcium
   channel blockers do not seem to interfere with erectile function.

   Occasionally, drugs cause erectile dysfunction by affecting the hormonal control of
   erection. For example, spironolactone and cimetidine act as antiandrogens.

   Alcohol consumption Alcohol can cause erectile dysfunction by many
   mechanisms, but it is extremely difficult to untangle its pharmacological effects from
   its emotional and social impact. Alcohol is a direct central nervous system depressant.
   It can impair testosterone biosynthesis directly or through liver disease (see below).
   Alcohol dependence can be associated with spousal abuse or general violence,
   which may contribute to its negative psychological impact on sexual function.

   Epilepsy Erectile dysfunction may accompany temporal lobe epilepsy. Some
   patients with this disorder have hyperprolactinemia, but in other patients, the erectile
   difficulty has no obvious cause and may reflect abnormalities in still unknown
   pathways related to erectile function.

   Systemic disorders Several systemic disorders, including alcoholism, cirrhosis,
   and uremia, can produce hypogonadism associated with a low testosterone level.
   Although the mechanisms involved remain to be elucidated, the underlying disorder
   should be corrected whenever possible. Some evidence suggests that uremia
   adversely affects steroidogenesis, producing a consequent rise in gonadotropin level.
   Therapy with clomiphene has been beneficial, but confirmation of its effects is still
   needed. Hyperprolactinemia and a low testosterone level occur in chronic renal
   failure, and bromocriptine therapy [see Subsection V] can be helpful in lowering
   the prolactin level.

   Psychogenic factors Psychogenic factors are thought to be the most frequent
   cause of erectile dysfunction. Anxiety, fatigue, interpersonal stresses, and chronic
   illness are common underlying factors. Depression requires separate mention
   because of its frequency; erectile dysfunction may be the presenting complaint that
   leads to correct diagnosis and treatment. Endocrine abnormalities The principal
   endocrine abnormalities that lead to erectile dysfunction include testosterone
   deficiency from pituitary or testicular disease, estrogen excess (e.g., caused by liver
   disease), and hyperprolactinemic syndromes. Prolactin excess exerts an
   antigonadotropic effect manifested mainly by erectile dysfunction, which is usually
   associated with a low plasma testosterone level. However, even after the plasma
   testosterone level has been normalized, erectile dysfunction can persist until the
   hyperprolactinemia is corrected. Hyperthyroidism, Cushing's syndrome, and
   myxedema can each cause reversible erectile dysfunction.

   When should evaluation for an endocrine cause of erectile dysfunction be
   undertaken? Patients with psychogenic erectile dysfunction are often capable of
   erection in some circumstances-for example, when masturbating or when having sex
   with a different partner. Endocrine erectile dysfunction, on the other hand, tends to
   develop gradually and then to be constant. Plasma testosterone and prolactin levels
   should be measured in any patient who has been impotent in most circumstances for
   more than three months. Abnormal levels of these hormones may be indicative of
   treatable organic disease. If a low testosterone level is found, pituitary evaluation,
   including measurement of serum FSH, LH, and prolactin levels, is warranted.

   One study that employed the plasma testosterone assay to screen patients with
   erectile dysfunction suggests that psychogenic erectile dysfunction may not occur as
   frequently as has been alleged.35 Of 105 patients tested, 37 were found to have
   organic hypogonadism. Of these, 20 patients had hypothalamic-pituitary deficiency,
   seven had testicular failure, eight suffered from hyperprolactinemia, and two had
   occult hyperthyroidism. Although these relative frequencies may not be
   representative, the screening approach using the plasma testosterone assay was
   nonetheless invaluable.

   EVALUATION AND TREATMENT OF ERECTILE dysfunction

   As specific, treatable causes of erectile dysfunction are further defined, it becomes
   imperative to follow a protocol capable of detecting the principal cause of
   dysfunction in each patient. The starting point is a careful history and physical
   examination, combined with a detailed sexual history. The patient should be asked
   about duration of the symptom, the circumstances in which it is manifested, the
   potential role of disease or medication, and the possibility of alcoholism or
   depression. Physical examination should include testing peripheral reflexes and
   pinprick sensation in the perianal area. If any of the specific conditions already
   mentioned is suggested, the appropriate therapy is clear. It is extremely important to
   review all medications being taken and to prescribe a substitute for any that may be
   contributing to erectile dysfunction. In many patients, no clear etiology is determined;
   two additonal tests are then indicated.

   The gold standard for noninvasive testing is the recording of nocturnal penile
   tumescence.36 This test can be done in a sleep laboratory, but several devices are
   available for use at home. With the RigiScan, measurements of pressure at the base
   and tip of the penis are recorded during natural sleep; the record is read by a
   computer, and a profile of pressures is printed out for quantitative interpretation.37 In
   this and other direct measurements, one can distinguish between the presence of
   some erection and the sustained achievement of sufficient pressure for vaginal
   penetration. Alternatively, a urologist can inject papaverine, papaverine plus
   phentolamine, or prostaglandin E1directly into the penile corpora. A firm erection
   achieved in this way indicates that the vascular component of erection is adequate
   and also provides an effective therapeutic alternative. The failure to induce erection
   should be followed by definitive vascular studies.

   There is appropriate therapy for erectile dysfunction of a specific cause (see below).
   When no specific diagnosis is made, several options exist. Long-term follow-up
   studies indicate a generally high degree of patient and partner satisfaction with intrac
   avernous injection of vasoactive drugs.38,39 Injection of papaverine alone or
   papaverine with phentolamine induces an erection lasting 30 to 120 minutes in about
   70 percent of patients. Side effects include pain, ecchymosis, and occasional
   episodes of priapism that require pharmacological intervention.40,41 Similar results
   have been obtained with injections of prostaglandin E1.42 Intracavernous injection of
   the synthetic prostaglandin E1 alpros tadil is approved by the FDA for treatment of
   erectile dysfunction.43,44 Intraurethral instillation of alprostadil by a drug-delivery
   system, MUSE (medicated urethral system for erection), is reportedly effective in
   inducing satisfactory erection in two thirds of men with erectile dysfunction of
   diverse causes.45 It is probably a bit less effective than the direct injection.

   An alternative to this invasive approach is the use of a plastic tube and suction pump
   to create a vacuum around the penis.46,47 When an erection results, a rubber band is
   placed at the base of the penis and satisfactory coitus can occur. A third choice is
   surgical implantation of one of several types of prostheses. These have been used
   successfully by many couples.48 Sex therapy is especially helpful for psychogenic
   erectile dysfunction. Supportive counseling and reassurance are a necessary adjunct
   for all patients with erectile dysfunction, particularly because anxiety and fear of
   failure compound any partial erectile difficulty. Two drugs for oral treatment of
   erectile dysfunction are under consideration by the FDA. A new drug application has
   been submitted for sildenafil, and an oral form of phentolamine is in phase III trials.

   Aging and Erectile Dysfunction

   The most frequent clinical presentation of erectile dysfunction is in apparently normal
   men older than 50 years. The clinical significance of any gradual decline in testicular
   function in men older than 50 years is receiving renewed study. Although there is
   much individual variation, aging men generally experience a gradual decline in
   sexual activity. In some studies, the decrease in erectile function has been associated
   with decreased plasma levels of free testosterone.49 Other studies have found that
   although sexual dysfunction and hypogonadism each increase with age, they are not
   associated.17 Detailed correlative and, especially, longitudinal studies of
   psychosexual behavior are not yet available; thus, the question whether such changes
   are inevitable accompaniments of aging or whether they reflect a partial decline in
   testosterone secretion has not been answered definitively.

   Diminished erectile capacity in older men should be evaluated in the total context of
   other illnesses, interpersonal relationships, physical examination, and drugs being
   taken. If there is no absolute barrier to sexual function and if the plasma testoste rone
   level is low normal or borderline (i.e., between 150 and 200 ng/dl), testosterone
   therapy can be considered. If FSH and LH levels are low, particularly if the plasma
   testosterone level is strikingly depressed (i.e., < 100 ng/dl), serum prolactin and
   thyroxine levels should be measured to exclude pituitary insufficiency [see
   Subsection V]. A rectal examination should be done, and both prostate-specific
   antigen and prostatic acid phosphatase levels should be measured to exclude early
   prostate carcinoma. If the resulting data are reassuring, testosterone enanthate, 200
   mg intramuscularly monthly, can be tried for three months. If genuine improvement
   in potency is obtained, long-term therapy can be considered after the patient is
   informed of the risks and benefits. In patients committed to long-term treatment,
   periodic rectal examination and prostate-specific antigen determination are indicated
   because testosterone therapy may stimulate a focus of prostate carcinoma.50 In view
   of this concern, other treatments for erectile dysfunction should be given serious
   consideration in the choice of therapy.