Erectile dysfunction: The Viagra revolution

Content provided by the Faculty of the Harvard Medical School

Erectile dysfunction: The Viagra revolution

It was a problem that few men talked about, preferring silent suffering to the shame and embarrassment associated with impotence. In 1992, an expert panel convened by the National Institutes of Health tried to remove the stigma by offering the term “erectile dysfunction” (ED) to replace “impotence,” which is derived from the Latin for “loss of power.” It was a good idea, but it didn’t help. But everything changed in the spring of 1998, when sildenafil (Viagra) burst on the scene. Within days, male sexuality was making headlines, and within weeks, sales of the little blue pill were making history.

Viagra has helped countless men with impotence, and it has spawned the development of two similar drugs, vardenafil (Levitra) and tadalafil (Cialis). But ED pills have created a stigma of their own; many men who cannot use or who don’t respond to them feel a new sense of shame and frustration. It’s a pity since effective alternatives are available.

What causes impotence, and how do Viagra, Levitra, and Cialis help? And what can men do if these popular medications fail?

The normal erection

Erections are so complex that it’s a wonder they don’t fail more often. An erection is basically a hydraulic event. Blood enters the penis through arteries that carry blood to the two corpora cavernosa, shafts of spongy tissue (see Figure 1) that contain many vascular channels called sinusoids. From there, blood collects in venules and is carried away from the penis in larger veins. An erection occurs when the smooth muscles in the walls of the arteries relax. The arteries widen, bringing more blood to the sinusoids. The corpora cavernosa swell, producing pressure that compresses and narrows the venules, preventing the extra blood from leaving the erect penis (see Figure 2). During detumescence the process is reversed: The arteries narrow, reducing blood flow, and the veins widen, draining blood from the penis, which returns to its flaccid state.

Since an erection depends on blood flow, it’s clear that healthy arteries and veins are required for normal function. But there’s more to it than that; a healthy nervous system and normal hormones are essential as well.

The nervous system contributes in two ways. The brain is responsible for sexual desire, or libido. The impulses of sexual arousal are transmitted through the spinal cord to the pelvis, where they link up with the nerves of the autonomic nervous system. Sensory nerves from the skin of the penis and other erogenous tissues also connect here. In turn, the autonomic nervous system relays messages to the arteries, where they signal the smooth muscles to relax and admit more blood. The nervous system is also responsible for ejaculation. It tells the muscles in the epididymis, vas deferens, seminal vesicles, and prostate to contract, propelling semen forward. At the same time, nerve impulses tighten the muscles at the neck of the bladder so that semen flows out through the urethra instead of back into the bladder.

Nerves communicate with one another by releasing tiny chemical mediators, including nitric oxide. The arteries also release nitric oxide, which is responsible for relaxing their muscles, thus widening the channels.

As if the interplay between nerves and blood vessels was not already complex, normal levels of testosterone are also required for proper erectile function; other hormones play a role, too. Despite the clear importance of hormones, however, doctors don’t know exactly how they contribute to normal libido and potency.

What is impotence?

In simple terms, impotence is the failure to achieve a normal erection. But since nearly every man experiences erectile failure from time to time, doctors restrict a formal designation of impotence to cases in which a man is unable to develop and sustain an erection adequate for intercourse in at least 25% of attempts.

Who is at risk?

Whether it’s called impotence or erectile dysfunction, it’s an extremely common problem. Age is the strongest predictor. A 2002 nationwide survey found that only 8% of men in their 40s reported significant erectile dysfunction, but the prevalence rose to 19% for men in their 50s and to 39% for men 60 and older. All in all, nearly a quarter of American men older than 40 reported that they were frequently unable to get and keep a satisfactory erection. That means tens of millions of men need help; fortunately, most can benefit from treatment.

Although advancing age is strongly linked to erectile dysfunction, normal aging is not responsible. It is true that testosterone levels tend to decline with age, but they remain within the normal range in most older men. It’s also true that tissues become less elastic with age, nerve conduction slows, and emotional stress mounts. But none of these events accounts for the staggeringly high prevalence of impotence in older men. Instead, the culprits are diseases that damage blood vessels and nerves; diabetes, hypertension, and atherosclerosis are the leading examples. The medications used to treat them also play a role.

The causes of erectile dysfunction

Since so many parts of the body must work just right to produce an erection, it’s hardly surprising that many problems can arise.

Medications. Impotence is a side effect of many drugs. Older men are particularly vulnerable because they often take more than one drug that might cause erectile dysfunction, and their medical problems may also cause impotence.

There is no simple way to tell if a medication is to blame. Instead, it’s a trial-and-error process of removing a medication, then waiting two to six weeks to see if potency returns. Many suspect medications, however, are important for health. Only a physician should juggle prescription drugs, but the patient has an important role, too. His first task is to report the problem. Then he should give the doctor a list of all his medications, both prescription and over-the-counter. It sounds obvious, but many men just don’t bring up the subject, and many doctors neglect to ask.

It’s been estimated that up to 25% of all erectile dysfunction is related to drugs. Even if this figure is high, medication is always the first cause to consider; it is also the most easily corrected. Table 1 contains a partial list of medications that have been implicated.

Vascular disease. Since erections depend on the arteries that supply blood to the penis, arterial disease is the most common cause of impotence. Atherosclerosis (“hardening of the arteries”) heads the list; high blood pressure, abnormal cholesterol levels, diabetes, and smoking all increase a man’s risk of developing atherosclerosis and impotence.

Neurological impotence. Disorders of the nervous system are frequently responsible. Diabetes is the most common culprit; nerves can also be damaged by alcoholism, multiple sclerosis, and spinal cord injuries.

Diabetes. A common cause of impotence, diabetes can interfere with erections by damaging blood vessels or nerves. Up to 50% of diabetics become impotent.

Prostate cancer and the treatment of prostate disease. Although the prostate itself has no role in producing erections, it sits near the nerves that are essential. Advanced prostate cancer can invade these nerves, causing impotence. Much more often, impotence is a side effect of surgical, radiation, or drug treatments for prostate cancer. Less commonly, surgery for benign prostatic hyperplasia (BPH) can interfere with erections.

Endocrine disorders. Many impotent men blame their hormones, but endocrine disorders account for no more than 15%–20% of all cases of erectile dysfunction. Hypogonadism (testicular failure) produces lower testosterone levels and is the most important endocrine cause of diminished libido and erectile dysfunction. An abnormally high level of prolactin, usually caused by a tumor of the pituitary gland, occupies second place. Less often, diseases of the thyroid or adrenal glands account for impotence.

Psychological causes. Impotence was once blamed on anxiety or depression. Indeed, many impotent men have psychological disorders, but mental distress results from impotence rather than the other way around. Still, psychological factors are responsible for about 15% of all impotence. Men who become impotent suddenly or who are impotent with one partner but not others are likely to have psychological impotence. An even more important clue is the presence of erections at night or on first awakening. Most healthy men experience three to five erections at night. The organic or physical causes of impotence impair nocturnal erections, but the psychological causes do not.

Figure 1: Anatomy of the penis The penis is made up of three cylindrical bodies, the corpus spongiosum (spongy body) — which contains the urethra and includes the glans (head) of the penis — and two corpora cavernosa (erectile bodies) that extend from within the body out to the end of the penis to support erection. Blood enters the corpora cavernosa through the central arteries (See also Figure 2).

Alcohol, smoking, and substance abuse. Some men may be tempted to turn to alcohol to help things along. It’s a bad idea. Alcohol can depress sexual reflexes; as Shakespeare explained, excess alcohol “provokes the desire but takes away the performance.” And with prolonged use, drinking can damage the liver, raising estrogen levels and causing permanent impotence, among other hazards. Street drugs such as cocaine, heroin, barbiturates, and amphetamines can all cause sexual dysfunction. By causing vascular disease, smoking, too, can contribute to impotence.

Obesity and lack of exercise. Men who experience erectile dysfunction may be tempted to blame it on age, hormones, or illness. But sometimes they should blame themselves. A Harvard study found that obesity increases the risk of impotence. A man with a 42-inch waist is twice as likely to develop the problem as a gent with a 32-inch waist. And the researchers also report that men who invest 30 minutes a day in exercise are 40% less likely to develop erectile dysfunction than sedentary men. In fact, lifestyle changes can help improve sexual function in some men.

Diagnosis

Doctors can learn a great deal about impotence from a thorough medical history and physical exam. Men should report when and how their sexual dysfunction began and whether it involves loss of desire, erectile dysfunction, or difficulties with ejaculation and orgasm. Patients should review their previous illnesses and operations as well as their current medications. It is particularly important to note the presence or absence of nocturnal erections as well as any symptoms of stress or depression.

Many men with impotence have normal physical exams, but others may display clues to underlying causes. Doctors should check blood pressures with the patient lying and standing. They should evaluate the circulation to the legs, often a clue to vascular diseases. Abnormally small testicles or enlarged breasts are among the possible hints of hormonal abnormalities. A digital rectal exam (DRE) should be performed to check the prostate. Men who choose to be screened for prostate cancer should also have a PSA test. Neurological testing should include simple checks of the sensation and reflexes in the legs, as well as tests of rectal sensation and reflexes involving the muscles that support the scrotum.

Figure 2: In working order When a man is sexually stimulated, chemical signals from the brain cause the penile arteries to widen, allowing more blood to enter the erectile bodies known as the corpora cavernosa. The tissues swell with blood, causing an erection. At the same time, the blood-engorged tissues compress the veins, keeping blood in the penis and maintaining the erection.

Laboratory tests can also show potential causes of impotence. Doctors can order blood tests to check for diabetes and to measure levels of testosterone, prolactin, and thyroid stimulating hormone (TSH).

If these studies fail to diagnose why a man is impotent, more elaborate testing may be indicated. Urologists and endocrinologists have developed a wide array of tests, but they are not used very often. Instead, the next step is often a trial of Viagra, Levitra, or Cialis.

Before taking ED pills

Most men with erectile dysfunction want to try a pill. It’s a good way to proceed, but before a doctor writes the prescription, he should ask himself if there are underlying problems that can be corrected. In the case of impotence, unfortunately, it’s difficult. When medications are to blame, they can and should be changed or discontinued if at all possible. If psychological factors are the problem, counseling or sex therapy can address the cause. Hormonal abnormalities can also be corrected. Men with low testosterone levels can receive hormone replacement, but they should always be checked for signs of prostate cancer before starting testosterone therapy. Men with normal levels will not benefit from testosterone, and they are still subject to potentially serious side effects from therapy. Men with high prolactin levels or thyroid abnormalities can receive specific treatment for those problems.

In more than half the cases of impotence, however, the underlying problem cannot be corrected. Vascular and neurological impotence, diabetes, and impotence caused by prostate surgery or radiation therapy fall into this category. That’s where “the big three” come in.

How do the ED pills work?

These medications are simple to take, but their actions are complex. That’s not surprising, since an erection itself is so complicated. The crucial chemical for both spontaneous and medication-assisted erections is nitric oxide, which transmits the impulses of arousal between nerves and also relaxes muscle cells in the penile arteries, causing them to widen and admit more blood (see Figure 2).

Nitric oxide is essential for a normal erection, but it does not act alone. It signals the arterial cells to produce cyclic guanosine monophosphate (cGMP), the chemical that increases the flow of blood to the penis. But the tissues of the penis also produce phosphodiesterase-5 (PDE5), an enzyme that breaks down cGMP.

In normal circumstances, the penis generates enough cGMP to produce a rigid erection and enough PDE5 to end the erection when ejaculation is complete. But in many men with erectile dysfunction, this intricate system is out of balance, and one of the ED pills often sets things right. They all inhibit PDE5, increasing the supply of cGMP; in many men, the extra cGMP will allow firm and sustainable erections to develop in response to sexual stimulation.

Are they effective?

They are. And despite dueling ads on television, the three medications have similar success rates. In all, about 70% of men respond well to the drugs; but the rates vary according to what is responsible for the erectile dysfunction. Men with impotence of no identifiable organic cause fare best, with a 90% success rate. In contrast, only 50% of men with diabetes respond well. Men who have been treated for prostate cancer present special problems.

Because the nerves that are essential for erections travel along the outside of the prostate, all forms of cancer treatment are likely to cause impotence. In round numbers, surgical removal of the gland (radical prostatectomy), external beam radiation therapy, and radioactive seed therapy (brachytherapy) will each cause erectile dysfunction in about 80% of patients. None of the ED pills will help men who have had standard surgery, but they may work in 25%–50% of men who have had the newer nerve-sparing operation. Improvement, though, is rare in the first nine months after surgery, in men older than 60, in men with complete impotence, and in men whose nerves have been spared on only one side of the prostate. The three medications can also help some men following radiotherapy, but more research is needed to determine which men are likely to benefit. Fortunately, though, many men who fail with oral drugs will respond to other treatments.

Are they safe?

They are. And in men without cardiovascular disease, they are very safe. The three rivals have similar side effects. The most common one is headache, which occurs in up to 16% of men. Other reactions include facial flushing, nasal congestion, indigestion, and diarrhea. About 4% of the men who take Cialis experience backache, which is mild and self-limited. A few Viagra or Levitra users have visual disturbances, typically in the form of impaired color vision or a bluish haze. Like the other common side effects, such visual abnormalities are mild and temporary. Still, men with retinitis pigmentosa, a rare eye disease, should check with their ophthalmologists before using these medications.

Headaches and blue vision are one thing, cardiac abnormalities, quite another. Are ED pills safe for the heart?

The drugs are safe for healthy hearts, but all men with cardiovascular disease should take special precautions, and some cannot use them under any circumstances. The problem is their effect on arteries. All arteries, not just those in the penis, generate nitric oxide, so any artery can widen in response to Viagra, Levitra, or Cialis. It doesn’t happen often because the ED pills specifically target PDE5, which is concentrated mainly in the penis. But other arteries contain some PDE5, which is why the drugs temporarily lower the blood pressure of healthy men by a small amount, typically 5–8 mm Hg.

Organic nitrates are drugs that widen arteries by increasing their supply of nitric oxide; that’s how they open the partially blocked coronary arteries in patients with angina. But because the nitrates and the ED pills all act on nitric oxide, the drugs don’t mix; healthy volunteers given Viagra followed an hour later by nitroglycerin see their blood pressures drop by 25–51 mm Hg, a potentially dangerous amount. All the experts agree that men who are taking nitrates cannot use the ED pills; this includes all preparations of nitroglycerin (short-acting, under-the-tongue tablets or sprays), long-acting nitrates (isosorbide dinitrate or Isordil, Sorbitrate, and others, and isosorbide mononitrate, Imdur, ISMO, and others), nitroglycerin patches and pastes, and amyl nitrite or amyl nitrate (so-called poppers, which some men use for sexual stimulation). Men who have taken Viagra or Levitra must not take nitrates for 24 hours; for Cialis, the ban extends to 48 hours, a disadvantage for men at risk for heart disease.

Faced with concern about ED pills and the heart, the FDA has urged caution in patients who have suffered heart attacks, strokes, or serious disturbances of the heart’s pumping rhythm in the previous six months, in men with a history of congestive heart failure or unstable angina, and in men with low blood pressure or uncontrolled high blood pressure (above 170/110 mm Hg). Because certain medications can boost the blood levels of these drugs, men taking erythromycin or certain antifungal or anti-HIV medications should use only low-dose PDE-5 inhibitors. Reduced dosage is also important for men with advanced age and for those with significant kidney or liver disease.

Differences

Although you’d never know it from their ads, Viagra, Levitra, and Cialis are very similar. But they do have some differences, which are summarized in Table 2.

Using an ED pill

Faced with all these warnings, should any man use Viagra, Levitra, or Cialis? Indeed, no one should use them needlessly or recklessly, but 20 million American men are plagued by impotence, and most can use them safely.

If nothing can be done to correct the cause of a man’s erectile dysfunction and if he has no problems that make oral medications risky, then a drug is worth a try. Each comes in several strengths; most doctors prescribe a middle dose initially, lowering it if it works well or increasing it if it does not. Men with potential problems should always start with the lowest dose, and every man should be alert for possible side effects. Men should avoid consuming alcohol before taking these drugs.

By itself, an ED pill will not produce an erection, but it will improve the erectile response to erotic stimulation. For best results, the drugs should be taken about an hour before sexual activity and should not be used more than once a day. These medications are not aphrodisiacs, and they should be used only to correct impotence, not to enhance sexual performance. Men who do not respond to a full dose on two or three different occasions should try other treatments.

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Last updated:	August 21, 2006