How to Assess and Treat Erectile Dysfunction

Erectile dysfunction is an important part of the total clinical picture in primary care, the author emphasizes, not only for its psychosocial significance but as a possible early indicator of general vascular compromise. He discusses how to examine and interview patients who are having erectile problems, determine what tests they need, and direct them in the safe and effective use of phosphodiesterase inhibitor drugs or other therapies.

By Jeff Unger, MD

Erectile dysfunction (ED) is defined as the inability to maintain a sufficiently rigid erection for vaginal penetration and ejaculation, or successful intercourse. Epidemiologic studies suggest that between 5% to 20% of all men suffer from moderate to severe ED, yet less than 70% of them seek treatment for a disorder that can very often be successfully treated in the primary care setting. In the Massachusetts Male Aging Study, 52% of 1709 men (ages 40 to 69) surveyed reported ED, with 10% having complete, 25% moderate, and 17% minimal ED. The probability of having complete ED tripled after age 70, compared to men in their 40s. Even younger men can have ED. About 7% of American men aged 18 to 29 years have reported ED, as well as 18% of men aged 50 to 59 years. Erectile dysfunction has a negative impact on quality of life and often results in fear, loss of self-image, low sexual satisfaction, and depression.

Erectile dysfunction is seen less often in men who are physically active. Of the 31,742 men enrolled in the Health Professionals Follow-up Study (www.hsph.harvard.edu/hpfs/), those who were physically active reported 30% less ED compared with men who were inactive. Physically active was defined as the equivalent of running three hours or more per week or playing singles tennis five hours a week. Other behaviors such as smoking and watching more than 20 hours of television a week were strongly associated with ED. The condition was also found to be more prevalent in men who are obese, men with diabetes or previous stroke, and men who take antidepressants or beta blockers. Risk factors for ED were found to be nearly the same as those associated with cardiovascular disease.

Primary care physicians who manage patients with chronic diseases should be aware of the comorbid association between ED and disorders such as coronary artery disease, hypertension, hyperlipidemia, depression, and diabetes. Current clinical research suggests that the penile vascular bed may be a sensitive indicator of early systemic endothelial cell dysfunction. Erectile dysfunction could be one of the initial signs of oxidative stress that occurs before the development of cardiovascular disease. Aggressive medical management of existing cardiovascular risk factors (hyperlipidemia, hypertension, smoking, obesity, and diabetes) in men with ED is becoming an important adjunct to standard medical treatment. Thus, asking men about ED as part of the review of symptoms is an effective means of practicing preventive vascular medicine.
 

PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION

Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase, which increases synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in an erection.

The tissue concentration of cGMP is regulated by the rates of both synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the corpus cavernosum is the cGMP-specific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual arousal.

Erectile dysfunction may be classified as psychogenic, organic, or mixed psychogenic and organic, which is the most common form of the disorder. The table below lists the causes of ED that are most often seen in a primary care setting. Sexual function progressively decreases with aging. Erections become less rigid, ejaculation is less forceful, and the ejaculatory volume decreases. In addition, the refractory period between erections lengthens. Penile sensation and serum testosterone levels decrease with age.

About 50% of men with diabetes have ED. Diabetes affects the small vessels of the penis and may also affect its endothelial cells, resulting in reduced levels of nitric oxide. Patients with chronic diseases may have ED that is multifactorial in etiology. Such patients may have vascular insufficiency, low levels of free testosterone, autonomic and sensory neuropathy, and psychological stress. They may also be taking medications that can reduce potency.

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DIAGNOSING ERECTILE DYSFUNCTION

When patients present with ED, a thorough medical, sexual, pharmacologic, and psychosocial history should be taken. The psychosocial history may reveal issues related to sexual conflict between couples. For example, a patient whose partner is menopausal may be discouraged from having sexual activity because of a fear of inducing vaginal pain during intercourse. The use of nicotine, alcohol, or illicit drugs should be avoided during treatment for ED. Patients may be upset that their erections appear to be less firm than they were when they were younger, even though they are still able to produce and maintain erections that are satisfactory for successful intercourse. Such patients may require only reassurance rather than pharmacologic therapy. Patients who are depressed may experience improvement in their libido and sexual performance once their psychological issues are resolved.

When a patient expresses concerns about ED, certain specific questions must be asked. Patients should be questioned as to when their last successful intercourse occurred, with success being defined as the ability to obtain and maintain an erection that is satisfactory for vaginal penetration and ejaculation. The box at left lists several questions that are helpful in evaluating whether ED is related to an organic, psychogenic, or mixed etiology. Patients with organic ED often note a gradual onset of symptoms, whereas those with psychogenic causes report an acute onset. Patients with organic disease have infrequent nocturnal or morning erections, whereas those with psychogenic ED may experience such erections frequently. Penile sensation may be reduced in patients with ED related to neurogenic causes.

Patients who notice a curvature of the penis during an erection may have plaque formation within the tunica albuginea, resulting in Peyronie's disease. Some younger men may have perfectly normal erections but feel that they are experiencing longer refractory times. Finally, one of the most common causes of ED in younger men is pressure damage to the pudendal nerve due to long-distance bicycle riding. Simply changing to a wider, softer bike seat may resolve sexual dysfunction in these individuals.

EXAMINING THE PATIENT

Physical examination should include careful inspection of the penis, testicles, and femoral blood vessels. When evaluating the penis, carefully palpate the corpora cavernosum and note the presence of any scar tissue that would indicate Peyronie's disease. Place a vibrating tuning fork on the glans penis. If the patient is unable to perceive vibration, a neurologic abnormality may be present. Testicular size and symmetry should be noted. Palpate the femoral arteries and listen for bruits. Finally, a prostate examination should be performed to assess for pain, nodularity, and enlargement, which would indicate pathology.

An ED specialist may order extensive testing on patients to determine the etiology of their sexual dysfunction (see table, below). However, in the primary care setting, most cases of ED can be evaluated and treated successfully with minimal lab studies. A lipid panel, thyroid studies, free testosterone level, and serum prolactin level should be obtained. Pituitary adenomas may cause elevations in serum prolactin, which can, in turn, result in ED. Patients with ED and an elevated prolactin level should be further evaluated for pituitary tumors. Hypothyroidism may also cause prolactinemia.

If a patient does not respond to a recommended therapy or if he insists on knowing the exact reason for his ED, referral for specialty evaluation is certainly warranted. Other indications for specialty referral include complex gonadal and endocrine disorders, a central nervous system lesion, severe psychogenic disease, Peyronie's disease, post-traumatic injury, and primary erectile dysfunction.

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TREATING ERECTILE DYSFUNCTION

Prior to the introduction of the PDE5 inhibitors, patients with ED were frequently referred to urologists for penile implants or training in the use of vacuum devices. However, the introduction of sildenafil (Viagra) in 1998 has given primary care physicians direct access to simple and successful pharmacologic therapy for ED. To date, more than 25 million men have been treated with PDE5 inhibitor drugs. Vardenafil (Levitra) has been approved by the FDA and is now available in pharmacies. Tadalafil (Cialis) was approved in November 2003.

The PDE5 inhibitors have unique chemical, pharmacokinetic, efficacy, and safety profiles. When sexual stimulation releases nitric oxide into the penile smooth muscle, inhibition of PDE5 causes a marked elevation of cGMP concentrations in the glans penis, corpus cavernosum, and corpus spongiosum, resulting in increased smooth muscle relaxation and a firmer erection. These drugs have no effect on the penis in the absence of sexual stimulation or when concentrations of nitric oxide or cGMP are low. They may be used in patients with any form of ED. The table below shows the efficacy of the currently available PDE5 inhibitors on men with various forms of ED.

Sildenafil, vardenafil, and tadalafil are potent PDE5 inhibitors. Existing data indicates that all three drugs have similar clinical efficacy. Both sildenafil and vardenafil appear to inhibit another type of phosphodiesterase, PDE6, which is located in the eye. Although PDE6 inhibition is associated with transient visual disturbances, no long-term visual complications have been noted in sildenafil-treated patients. Patients who do experience a blue haze in their visual field with sildenafil may not experience this side effect with vardenafil.

Tadalafil does not inhibit PDE6, but it does inhibit PDE11, which is found in the anterior pituitary, testes, prostate, cardiac myocytes, and cells of the heart's conduction system. The functional significance of pharmacologic PDE11 inhibition is unknown, and the safety implications are unresolved. To date, the effects of PDE5 inhibitors on cardiac contractility are unknown.

Phosphodiesterase type 5 is found in the penis and in arterial and venous smooth muscle. If nitric oxide is made available systemically in the presence of a PDE5 inhibitor, a significant drop in blood pressure may occur. Thus, all three PDE5 inhibitors are absolutely contraindicated in men taking nitrates. The table below compares the pharmacodynamics of sildenafil, vardenafil, and tadalafil.

In general, men with cardiac disease should be cautioned about using these drugs. Management of ED in cardiac patients is summarized in the table below.

The PDE5 inhibitors have similar side effects, including headaches, flushing, and dyspepsia. Myalgia, back pain, and pain in the extremities may also occur in 15% to 40% of men taking tadalafil.

Tadalafil may be taken from 30 minutes to 12 hours before sexual activity with or without food; it may be effective for 24 to 36 hours after it is taken. The use of tadalafil plus excessive alcohol consumption may increase the risk of orthostatic hypotension. Sildenafil should be taken one hour before intercourse on an empty stomach; erections occur 30 minutes after dosing. The efficacy of sildenafil is reduced if it is taken after a high-fat meal has been eaten. Patients should take vardenafil 60 minutes before intercourse, with or without food. Men older than 65 should use an initial 5-mg dose of vardenafil or a 25-mg dose of sildenafil.

Patients who do not achieve satisfactory results with sildenafil may be switched to vardenafil. Data suggests that patient response to vardenafil may occur more frequently with initial doses than with sildenafil. Patients taking an alpha blocker such as doxazosin should avoid taking vardenafil and tadalifil at the same time because of a high risk of developing orthostatic hypotension. Sildenafil 25 mg may be used four hours after an alpha-blocker is taken.

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OTHER THERAPIES MAY BE NEEDED

Although the PDE5 inhibitors are highly effective in treating ED in the primary care setting, other drugs may have to be considered in some patients. Men with androgen deficiency due to hypogonadism may respond to testosterone replacement therapy. Daily use of transdermal testosterone raises serum testosterone levels to within normal range in 90% of men. The most common adverse effects are skin irritation and contact dermatitis. Testosterone patches are contraindicated in men with prostate cancer or benign prostatic hypertrophy. In men receiving testosterone replacement, lipid, prostate-specific antigen, and hematocrit levels should be measured every six months.

Transurethral alprostadil (Muse) has been shown to be effective in 43% of men with erectile dysfunction. The drug is inserted into the urethra with an applicator. The patient then massages the penis for five minutes to disperse the drug. Walking for five minutes after the drug is inserted may also be helpful in speeding the drug's onset of action. Although minimal systemic effects are noted, the drug may result in penile pain (82% of patients) and burning (12%). In addition, dose titration in the office setting (starting with 500 mcg) is necessary to determine the clinical response to a given dose of alprostadil and evaluate potential complications such as urethral bleeding, syncope, and priapism (a prolonged erection lasting more than two hours). Doses of alprostadil can range from 250 to 1000 mcg.

For patients who fail to achieve erections with PDE5 inhibitors or alprostadil, intracavernosal therapy should be considered. Alprostadil is the only intracavernous drug approved in the United States; it results in satisfactory erections in 70% to 90% of men. Doses should be titrated (from 5 to 40 mcg) in the office setting. Patients should be instructed on proper intracavernosal injection technique using an autoinjector syringe with a predetermined dosage. Following an injection, patients should be observed for 60 minutes to make certain that the erection is adequate for vaginal penetration and that the patient does not develop priapism. The patient's erection may appear adequate to the examiner but not to the patient, in which case the patient should be reassured that manual stimulation of the penis following intracavernosal injections should enhance the erection.

Dose titration usually occurs over two office visits. During the first visit, the physician will discuss intracavernosal injection technique with the patient and perform the initial injection. Time to erection is noted and any side effects are documented. On the second visit, the patient will administer the appropriate dose of alprostadil while the physician observes his technique. If a patient is unable to inject the penis, his partner can be instructed on the proper technique.

The most common side effect is a painful erection, which occurs in 17% to 34% of men. Priapism occurs in 4% of patients, and 3% develop fibrosis at the site of the injections. Patients who develop priapism can have the erection reversed with phenylephrine, which has a rapid onset of action of less than one minute and a duration of action of 7 to 20 minutes. The drug is administered by adding 10 mg (1 ml) of phenylephrine to 499 ml of saline. This yields a solution of 20 mcg/ml, of which 10 to 20 mcg is given via intracavernous injection every 5 to 10 minutes. Surgical intervention may be required if phenylephrine fails to produce detumescence of the erection.

Although no transdermal medications are currently FDA approved for ED in the United States, phase 2 and phase 3 studies are being conducted using alprostadil in combination with a dermal absorption enhancer. When used in a cohort of diabetic men, 53% reported improvement in sexual function, compared with 20% in the placebo group. Prostatectomy patients reported a 57% improvement, compared with 11% in the placebo group. In addition, patients who failed to respond to sildenafil reported a 45% improvement with transdermal alprostadil. No serious drug-related adverse events have been reported in these clinical trials. An intranasal preparation for ED, called PT-141, is also being tested in clinical trials.
 

SUCCESSFUL PHARMACOTHERAPY

Primary care physicians should be aware of the frequency with which patients experience ED. Over the past 30 years, successful pharmacotherapy has surpassed the need to refer patients to a urologist for surgical consideration. The drugs that are available in the primary care setting should result in satisfactory erections in the vast majority of patients, whether their ED results from organic or psychogenic causes or a combination of the two etiologies. Physicians should also remember that ED is often associated with systemic diseases resulting from diffuse endothelial dysfunction. The workup for ED patients should include an assessment of systemic disorders that tend to coexist with sexual dysfunction.

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