Rebuilding The Male Machine

PHYSICIANS HAVE SPENT CENTUries trying to pump life into flagging male sex organs. Until recently, the treatments were crude and the options limited. But impotence research has come of age in the past two decades, and the arsenal is exploding. If several new drugs fulfill their promise, ""taking the pill'' could soon have a whole new meaning.

As recently as the 1970s, no one knew exactly how erections came about, but the workings of the penis are now well understood. The shaft houses a pair of erectile chambers filled with spongelike tissue that expands dramatically when filled with blood (chart). The chambers would be engorged all the time if blood entered them as freely as it does other tissues. So the body walls them off. Smooth-muscle cells constrict the local arteries, keeping blood flow to a trickle. Similar cells surround the blood-filled spaces in the erectile tissue, preventing any buildup. As long as all these smooth-muscle cells are flexed, the penis stays flaccid.

In a healthy male, that arrangement is easily reversed. Sexual stimulation triggers the release of a neurotransmitter called nitric oxide, which sets off production of several other substances. One of them, a chemical called cyclic GMP, has a knack for relaxing smooth-muscle cells. When doused by cyclic GMP, the cells loosen their grip on the erectile chambers, and the spongelike tissue starts to swell. If nearby veins continued to siphon off excess blood, the effects would be pretty modest. But the swelling tissue pinches those veins against the wall of the erectile chamber, temporarily pinching them shut. ""It's like filling a bathtub,'' says Dr. Harin Padma-Nathan, director of the Male Clinic in Santa Monica, Calif., and an associate clinical professor at the University of Southern California. ""You turn on the faucet, and you put a plug in the drain.''

Until they understood this sophisticated plumbing system, experts usually blamed erectile problems on psychological ones. Today other factors appear more important. It's well known, for example, that bike injuries and prostate operations can damage the nerves that control the penile smooth-muscle cells. So can diseases like diabetes, alcoholism or multiple sclerosis. And even when the erectile nerves are intact, drugs prescribed for depression, high blood pressure and other conditions can keep them from firing properly. But the most common cause of impotence is arteriosclerosis, the vascular hardening that leads to heart attack and stroke. Virtually anything that raises the risk of coronary heart disease--smoking, poor diet, a chronic lack of exercise--can also cause problems below the belt.

Urologists are rarely able to fix damaged nerves or arteries, but they can usually help men compensate. Until recently, implants and vacuum pumps were all they could offer. But everything changed in 1982, when a surgeon named Ronald Virag accidentally injected a smooth-muscle relaxer called papaverine into the pelvic artery of an anesthetized patient. The man on the table spiked a three-hour erection, inspiring Virag and others to try the same trick on men with erectile problems. It worked. Home injections of papaverine and other smooth-muscle relaxers, such as alprostadil, have since become standard treatments for impotence. The trend began with the off-label use of existing drugs, but pharmaceutical companies are now racing to patent unique formulations.

The first to reach the market was Caverject, an injectable form of alprostadil that Pharmacia & Upjohn introduced in 1995. A similar injectable called Edex received FDA approval this year. And a California company called Vivus has introduced the same drug in a soft pellet called MUSE, which is inserted into the urethra with an applicator. By dilating arteries and relaxing the erectile tissue, these drugs quickly trigger involuntary erections that can last an hour or more. They can also cause pain and, in rare cases, priapism--an excruciating, nonstop erection that destroys penile tissue unless the user gets an antidote. And for all their efficiency, these treatments definitely lack subtlety. ""If you're taking an injection therapy or MUSE,'' boasts Vivus president Leland Wilson, ""you can be doing the dishes or washing your car. You'll have an erection regardless.'' What fun.

The ideal remedy would be easier to take, and would make erections possible instead of compulsory. That's where the pills come in. Three are now in the final stages of development. They have different mechanisms of action, but none requires any fancy equipment, and each can improve sexual function without interfering with dish washing. TAP Holdings' Spontane (apomorphine) is a non-narcotic morphine relative that stimulates the brain centers involved in erection. In premarketing studies, 70 percent of mildly impotent users have found it useful. Zonagen's Vasomax (phentolamine) gently dilates penile blood vessels by blocking the effects of adrenaline. Urologists have long included phentolamine in injectable cocktails, but this will be its first time out in pill form. Like Spontane, it's intended for men with mild problems, but studies suggest only 40 percent benefit. The third pill, Pfizer's Viagra, looks like the star of its class. When it hits the market, says Dr. John Mulcahy of Indiana University, ""most physicians will just say, "You have impotence? Try it'.''

Viagra's active ingredient, sildenafil, was originally studied as a treatment for high blood pressure. It didn't solve that problem, but it had powerful effects on the penis. By blocking the enzyme that breaks down cyclic GMP, it boosts that chemical's relaxing effect on the penile smooth-muscle cells. Premarketing studies have included men with varying degrees of impotence, and 60 to 80 percent have benefited. The drug's most common side effects include indigestion and headaches, and some users report visual disturbances, such as a loss of color perception or a halo effect. But those effects are transitory. Experts are hopeful that low-dose combinations of the new pills will boost benefits and reduce side effects. And researchers are now exploring gene-based therapies that may someday prevent impotence altogether. Until then, an occasional headache may be the price of admission.

Erectile chambers would be engorged all the time if blood entered them as freely as it does other tissues. So smooth muscle cells keep a tight grip on the incoming arteries and blood-filled spaces.

Sexual excitement triggers the release of chemicals that relax smooth muscle cells. Arteries widen and spaces in the erectile chambers fill with blood. The expanding tissue shuts veins, trapping blood.

Arteriosclerosis is the leading cause of impotence. Anything that damages the circulatory system--smoking, inactivity, poor diet-can cause problems below the belt.

Injury, surgery or disease can damage the nerves that trigger erections. Drugs used for other conditions sometimes prevent the nerves from firing properly.