Erectile dysfunction is defined as the persistent inability to achieve or maintain penile erection sufficient for sexual intercourse. In the past, patients have underreported this problem because of embarrassment and the belief that little could be done to alleviate it. The availability and marketing of new therapies for erectile dysfunction have greatly increased public awareness of this problem.

An estimated 10 million to 20 million American men have some degree of erectile dysfunction, the incidence of which increases markedly with age. Between the ages of 40 and 70 years, the probability of complete erectile dysfunction triples from 5.1 percent to 15 percent.¹

Physiology of Erection

[ corrected] Penile erection is mainly mediated by the parasympathetic nervous system, which when stimulated causes arterial dilation and relaxation of the cavernosal smooth muscle. The increased blood flow into the corpora cavernosa in association with reduced venous outflow results in penile rigidity.

Attention has recently been focused on the chemical mediators of erection. These include prostaglandin E, acetylcholine, vasoactive intestinal peptide and nitric oxide. The most physiologically important mediator is nitric oxide.² This substance is released from nerve endings and vascular endothelium and functions by activating guanylate cyclase, which converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP).³ cGMP becomes the secondary messenger that causes smooth muscle relaxation, resulting in venous engorgement and penile tumescence.

Patient Evaluation

HISTORY AND PHYSICAL EXAMINATION

The history should include the frequency and duration of symptoms, the presence or absence of morning erections and the quality of the relationship with the sexual partner. The sudden onset of erectile dysfunction in association with normal morning erections or a poor relationship suggests psychogenic impotence.⁴

A detailed medical history may reveal that the disorder is due to a chronic disease such as atherosclerosis, hypertension or diabetes mellitus. Inquiry about decreased libido and symptoms of hypothyroidism or hyperthyroidism may reveal a reversible cause (Table 1).^5–7

Because as many as 25 percent of cases of erectile dysfunction are due to medication side effects,⁴ the patient's drug therapy should be reviewed. Common pharmacologic causes of this disorder include antihypertensive drugs, most notably the centrally acting agents, beta blockers and diuretics. Antipsychotic and antidepressant drugs are also frequently implicated. Other drugs that can cause erectile dysfunction include spironolactone (Aldactone), cimetidine (Tagamet) and finasteride (Proscar).^5,7 Excessive alcohol intake, heroin use and cigarette smoking are also known causes (Table 2).^4,7,8

During the physical examination, signs of hypogonadism, such as gynecomastia or the loss of axillary and pubic hair, should be noted.⁴ The genital examination should include an evaluation of the size and consistency of the testes. The penis should be examined for any fibrosis and plaques indicative of Peyronie's disease.⁸ Finally, the bulbocavernosus and cremasteric reflexes should be assessed to eliminate a neurologic cause of the erectile dysfunction. The bulbocavernosus reflex is elicited by squeezing the glans penis while observing for contraction of the external anal sphincter. This may be visualized or felt during a digital rectal examination.

LABORATORY TESTS

The laboratory evaluation should be directed by the history and physical examination findings. The patient should be screened for any undiagnosed medical disease that may be the underlying cause of erectile dysfunction. A urinalysis, complete blood count and basic chemistry panel will help to rule out most metabolic and renal diseases.^5,8 In elderly men, because thyroid disease can present subtly, the thyroid-stimulating hormone level should be measured to rule out thyroid dysfunction. In one study⁶ of men who underwent an endocrinologic evaluation for erectile dysfunction, 6 percent were found to have hypothyroidism, and their erectile function improved with treatment.

Some authors advocate measuring prolactin and free testosterone levels as part of the initial evaluation.^4,5 The value of this routine testing is uncertain, however, because the incidence of endocrinopathy presenting as erectile dysfunction is reportedly only 2 percent.⁸ A reasonable strategy is to obtain a free testosterone level in all men aged 50 and older and in those younger than 50 who have symptoms or signs of hypogonadism such as decreased libido, bilateral testicular atrophy or a reduced amount of body hair.⁹ The prolactin level should be measured if the free testosterone level is low, the patient has a substantial loss of libido or a prolactinoma is suspected on the basis of a history of headache with visual field cuts.¹⁰ Measurement of luteinizing hormone levels can be reserved for use in distinguishing primary from secondary hypogonadism in men with low testosterone levels.⁹

Treatment Strategies

If an underlying medical condition has been diagnosed, treatment of that disease is appropriate; however, therapy for chronic diseases such as diabetes, hypertension and atherosclerosis does not guarantee the return of erectile function. Any evidence of hypogonadism, hypothyroidism or other endocrine causes should be thoroughly investigated and treated. As a risk factor for atherosclerosis and a common underlying cofactor, smoking should be avoided. If the patient smokes, methods of smoking cessation should be explored. Consideration should be given to changing prescription drugs that could be contributing to the problem (Table 2).

Many specific therapeutic options are now available for erectile dysfunction, with varying degrees of patient satisfaction. These include established nonpharmacologic treatments such as vacuum erection devices, penile prostheses or penile revascularization. Referral to a psychologist or psychiatrist with expertise in sexual dysfunction may be beneficial for patients with psychogenic erectile dysfunction.⁸ Currently available pharmacotherapeutic agents are compared in Table 3.

Intracavernosal Alprostadil

Intracavernosal administration of alprostadil (Caverject) has reported success rates of 67 to 85 percent and has been used in the treatment of erectile dysfunction for several years.¹¹ When injected directly into the corpus cavernosum, alprostadil (prostaglandin E₁) acts on the arteriolar smooth muscle cells, causing them to relax and produce an erection, usually within several minutes. Its mechanism of action is to stimulate an increase in the levels of intracellular cyclic nucleotides that cause relaxation. The usual dose is between 5 and 40 μg per injection. The current average wholesale price ranges from about $86 for six of the 5-mg doses to approximately $163 for six of the 40-μg doses.¹² Patients usually start at 2.5 μg and titrate up in 5-μg increments for effect, with a maximum dose of 60 μg. No more than three injections per week are recommended, with a minimum period of 24 hours between injections.¹³ Initial dosing and required adjustments should be carried out in the physician's office.

Pain, hematoma and prolonged erection are reported adverse reactions that may limit compliance. Prolonged erection (more than four hours' duration) and priapism (more than six hours' duration) were reported in just 4 percent and less than 1 percent of patients, respectively.¹³ In a study of patients receiving intracavernosal injections of alprostadil for erectile dysfunction, 56 percent discontinued therapy within one year, and 68 percent discontinued within two years.¹⁴ Intracavernosal alprostadil is contraindicated in patients with penile deformity, patients having conditions that predispose them to priapism (sickle cell disease or trait, leukemia, multiple myeloma, polycythemia or thrombocythemia), those with a known hypersensitivity to alprostadil or those who have been advised for medical reasons to avoid sexual intercourse.

Given the relatively high rate of prolonged erection or priapism with this form of alprostadil, prescribing physicians should be aware of appropriate management of these conditions. This includes aspiration of the corpora, followed by intracavernous injection with an alpha-adrenergic agonist such as phenylephrine (Neo-Synephrine). Surgery is occasionally necessary.

Transurethral Alprostadil

Transurethral alprostadil provides the same significant improvement in erectile function as injectable alprostadil with a better tolerated method of delivery. In one large study,¹⁵ 65 percent of patients reported successful and satisfactory intercourse. This form of alprostadil is thought to diffuse into the corpus spongiosum and then into the corpus cavernosum. Once the drug enters the cavernosum, the arteriolar smooth muscle relaxes, resulting in erection. In a large double-blind, placebo-controlled study, the most common reported side effect was penile pain (10.8 percent), which was not judged by patients to prevent its use.¹⁵

The average wholesale price of alprostadil for transurethral administration ranges from $118.50 for six of the 125-μg suppositories to $143.25 for six of the 1,000-μg suppositories.¹² Dosage is initially 125 to 250 μg, with adjustment up or down as indicated. However, in the study cited above,¹⁵ few patients responded to less than 500 mg. The treating physician should determine the minimal effective dose. The drug is available in 125-, 250-, 500- and 1,000-μg suppositories. More flexibility is available with this form of alprostadil because it can be used twice in a 24-hour period.¹⁶

Penile pain (11 to 32 percent) and minor urethral discomfort are the most common reported adverse effects of transurethral administration, with dizziness (2 percent) and symptomatic hypotension (3 percent) being the most serious.¹⁶ As with transcavernosal alprostadil, the transurethral form of the drug is contraindicated in patients with an abnormally formed penis, those having conditions that predispose them to priapism, those with a known hypersensitivity to alprostadil and those who have been advised for medical reasons to avoid sexual intercourse. Because it is a smooth muscle relaxant, transurethral alprostadil should not be used during sexual intercourse with a pregnant woman.¹⁶

Sildenafil

Sildenafil (Viagra), whose labeling was approved by the U.S. Food and Drug Administration (FDA) in March 1998, is the first oral medication to be marketed for the treatment of erectile dysfunction. Sildenafil inhibits the conversion of cGMP to guanosine monophosphate in the corpus cavernosum, thereby increasing the available concentration of cGMP. This reaction is largely catalyzed by the enzyme phosphodiesterase type 5. Sildenafil inhibits this enzyme, resulting in relaxation of the cavernosal smooth muscle.¹⁷ Sildenafil is absorbed rapidly, with peak plasma levels achieved within an hour. It undergoes hepatic metabolism and has a half-life of about four hours.

Because of its unique locally acting mechanism of potentiating the physiologic response to sexual arousal, sildenafil is effective in men with erectile dysfunction of organic, psychogenic or combined causes. The use of sildenafil in women is under study but has not yet been approved.

SAFETY AND TOLERABILITY

The most common side effects of sildenafil are headache, flushing and dyspepsia (Table 4).¹⁷ A small percentage of patients report an alteration in color perception. Postmarketing reports released by the manufacturer indicate infrequent occurrences of priapism. Because of the presence of phosphodiesterase in the retina, patients with retinitis pigmentosa should not be given sildenafil.

The most important concern is the labeled contraindication for patients taking nitrates of any kind because of the potential for sudden severe hypotension. Patients taking nitrates have high levels of nitric oxide in the bloodstream. Sildenafil potentiates the effect of the nitrates by inhibiting the breakdown of cGMP, causing hypotension due to severe vasodilation.

The manufacturer has warned emergency physicians of this dangerous side effect in an effort to avoid the possibility of giving nitroglycerin to a patient with chest pain who presents to the emergency department after taking sildenafil. Paramedics across the country have also been cautioned to ask men with chest pain if sildenafil has been taken before they administer sublingual nitroglycerin. Recreational drugs such as amyl nitrite (“poppers”) are thought to have the same hypotensive effect when combined with sildenafil.

As of May 1999, postmarketing reports of sildenafil have not resulted in a change by the FDA concerning the safety of the drug. Although several patients have died after receiving prescriptions for sildenafil, it is unclear how many of these deaths resulted from appropriate use of the medication. Between late March and July 1998, 3.6 million outpatient prescriptions for sildenafil were dispensed. During the same period, 69 patients in the United States died after the confirmed use of sildenafil. No cause of death could be found in 21 of these cases. Of the remaining 48 deaths, 46 were attributed to cardiovascular events. Twelve of the men who died had taken nitroglycerin, either prescribed or self-administered. Postmarketing studies are continuing.¹⁸ A patient who has been advised not to have sex for medical reasons clearly should not be given a prescription for sildenafil.

Recently, the American College of Cardiology and the American Heart Association released a consensus statement regarding the use of sildenafil in patients with cardiovascular disease.¹⁹ The statement reiterates that nitrates should be avoided for 24 hours after the use of sildenafil and longer if the patient takes other drugs that are metabolized by the cytochrome P450 3A4 system or if the patient has renal or hepatic dysfunction. The panel's recommendations are summarized in Table 5.

The management of angina in patients who have taken sildenafil within 24 hours involves the use of non-nitrate antianginal drugs such as beta blockers. The use of heparin, narcotics, aspirin or calcium channel blockers for acute coronary artery syndromes is not contraindicated. If nitrates are inadvertently administered to a patient who has taken sildenafil and hypotension occurs, aggressive fluid resuscitation with the patient in the Trendelenburg position is the first step. An intravenous alpha-adrenergic agonist (phenylephrine) or an alpha- and beta-adrenergic agonist (norepinephrine) can be given if needed to support blood pressure. An intra-aortic balloon counterpulsation pump can be used if pharmacologic measures are ineffective.¹⁹

EFFICACY

The first published efficacy trial of sildenafil involved only 12 patients, but it is the only study that included objective measurements of penile rigidity.²⁰ In the first phase of this study, penile rigidity was measured using plethysmography during visual sexual stimulation in patients taking varying doses of sildenafil or placebo. In the men who took the 50-mg dose of sildenafil, the mean duration of erection was increased by 10 minutes at the base of the penis and six minutes at the tip of the penis compared with placebo. The second phase of this study involved a diary of erectile activity in which 10 of 12 patients reported improved erectile activity while receiving sildenafil.

The largest published trial of sildenafil evaluated efficacy based on the previously validated International Index of Erectile Function.²¹ In 312 men receiving sildenafil, mean scores for the frequency of penetration and maintenance of erections after penetration increased significantly.¹⁷ A clinically significant dose-response relationship was also demonstrated: erection appropriate for intercourse was attained in 72 percent of the men receiving 25 mg, 80 percent of those receiving 50 mg, and 85 percent of men those given 100 mg of sildenafil.¹⁷

Sildenafil was recently studied in a large series of diabetic men with erectile dysfunction and was found to be well tolerated and effective.²² In this randomized, controlled trial, 74 of 131 patients taking sildenafil reported improved erections compared with only 13 of 127 patients taking a placebo. The incidence of mild adverse effects was higher in the group taking sildenafil, but the incidence of cardiovascular events was similar in both groups.

PRESCRIBING AND PRICE

Sildenafil should initially be prescribed at 50 mg to be taken one hour before anticipated intercourse. The dose can be increased to 100 mg if needed. A 25-mg tablet is also available; this should be the starting dose for men older than 65 and in patients with hepatic or renal dysfunction. Sildenafil should not be used more than once a day and should not be used in combination with other drugs for erectile dysfunction. As of this writing, the drug cost to pharmacists is approximately $263 for 30 tablets of any size.²³ This translates to an average wholesale price of $8.75 per tablet, which has prompted some insurers to limit the number of tablets they will pay for on a monthly basis.

Final Comment

Erectile dysfunction is increasingly being recognized as a common, treatable disorder. The development of sildenafil has prompted an unprecedented number of men to seek treatment. Sildenafil may not be appropriate for all patients, but other therapeutic options discussed in this article may be of benefit. A thoughtful evaluation may reveal treatable causes and provide family physicians with an opportunity to become involved in the comprehensive health care of men who otherwise would not have sought medical attention.