Up, Up & Away

Dr. Irwin Goldstein is testing the future, and it's one hell of an improvement. For more than two decades, Dr. Goldstein, a professor of urology at Boston University School of Medicine, has been one of a small group of internationally recognized medical pioneers researching that shadowy male nightmare, impotence. Within days of the celebrated 1983 American Urological Association meeting at which G.S. Brindley, an audacious British researcher, dropped his pants for a personal demonstration of his penis injection therapy, Goldstein had his own patients using the needle. The technique is now the most widely employed in impotence treatment. Over the years, Goldstein has applied virtually every worthwhile remedy in recent medical history--including permanently erect and pump-operated implants, vacuum tubes, surgical bypasses to improve blood flow to the noble organ, and those erection-stimulating injections. But what he's now testing on a grateful collection of New Englander volunteers is the incandescent dream of millions of men who wilt as romance blooms.

A pill. A simple, portable, familiar, aspirin-like answer to a wretched problem. Though hundreds of thousands of men have satisfactorily regained their sex life with existing therapies, those techniques have their drawbacks. For many, if not most, beleaguered men, a pill could mean avoiding the permanent commitment of implant surgery; the sometimes dubious pleasure and wobbly erections caused by pumping oneself up with a vacuum tube; and the logistics and occasional pain of the needle--which can involve fumbling in the bathroom, trying to inject the right amount of medicine into the right place in one's penis.

Instead, a man who would otherwise be unable to perform in the grand love dance could unobtrusively swallow a small pill with a gulp of champagne, throw another log on the fire and in as little as 20 minutes be as hard as a cucumber--despite physical problems, psychological problems or almost any other problems.

"We're in the midst of an exciting revolution," says Goldstein enthusiastically, "a new area of sexual medicine called sexual pharmacology."

What Goldstein means is a drugstore for the penis. Erections are produced with drugs that are delivered to one's member, or to the controlling brain, in simple ways--pills, tiny pellets, perhaps creams, or through an occasional shot, like a flu vaccination. "Each week there's a new, innovative mechanism and a new delivery system," Goldstein says. Most of these near-miraculous drug therapies are in various stages of testing, but some could be approved by the Food and Drug Administration within the next year. Farthest down the road is the prospect of the simplest technique so far envisioned: the shot, a gene-therapy injection every three to six months that would keep a man's system primed.

But for the immediate future, the pill is the best and brightest hope for many men faced with impotence. Terry Payton is the urological nurse clinician in Goldstein's office. Since the Seventies Payton's role has been to provide tech support to thousands of Goldstein's patients--using therapies both approved and still in testing. "Stand by," says Payton, raising both eyebrows. "The pill is going to change everything. Everything."

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Most men do not know the most important and heartwarming facts about male impotence, which is less prejudicially described these days as erectile dysfunction.

First, a lot--a whole lot--of men experience it sooner or later, and usually long before they've lost their intellectual fascination with lust. According to the National Institutes of Health, as many as 20 million American men regularly have so much trouble getting a workmanlike erection that they can't have intercourse. Other sources estimate that 140 million men worldwide are affected. Even a sex-crazed teenager can be impotent in the clutch, but as men age, the numbers turn grimmer. The most detailed survey so far--the Massachusetts Male Aging Study--found that among men 40 to 70 years old, more than half had a problem getting and staying hard.

Second, despite the mythology, while psychological factors can often be part of the predicament, most men are impotent primarily because they have a physical problem with their plumbing. This is not a disease of unmanly mental hang-ups or problems getting over separation from your mother; it's one of plumbing--bad arteries and veins, for the most part. Masters and Johnson were dead wrong (as William Masters later gamely admitted) when they announced in the Sixties that more than 90 percent of male impotence is psychologically based. Today, the Impotence Institute of America estimates that impotence has a physical cause in 85 percent of sufferers.

Third, even before the new generation of drugs arrives, these physical problems can usually be remedied one way or another. And insurance companies now cover some of the bills.

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The first real treatment--and likely to remain the treatment of last resort--was the implant. Semirigid implants, as their name describes, are two bend-able rods that will get a man into a vagina but can sometimes be hard to hide under a business suit. Inflatable, hydraulic implants, refined over more than 20 years of use, give a dependable, solid erection come hell or high water and with a minimum of fuss--discreet squeezes of a pump mechanism hidden in the scrotum take a man up or down. Each year about 20,000 American men opt for some sort of implant, costing from $10,000 to $15,000, according to the Harvard Health Letter. The AUA recently estimated that the patient satisfaction rate for the more advanced hydraulic implants ranged from 83 percent to almost 96 percent, depending on the type of device.

Less formal, off-the-record conversations with several women involved with implanted men showed that they too were pretty damned satisfied with implants. Predictability and longevity--because the penis stays hard after ejaculation--were big factors for women. One claimed that she had not yet given in to her recurring fantasy to inflate her boyfriend as he sleeps, for a midnight ride.

The downside is certainly worth pondering, however. Implant surgery changes the penis permanently. Tissue is damaged when the implant is put in place, diminishing the ability to achieve an erection naturally. The implants can become infected, the machinery can break down, some men end up with shorter or far different erections than they're accustomed to and the recovery from surgery is by all accounts agonizing--what Goldstein calls the "mad month." After recovery, a few men also become what some researchers call "timid pumpers"--men too squeamish to properly rock and roll with the device.

Surprisingly, another widely used mechanical solution--involving no surgery--is the medical version of those plastic vacuum tubes alleged to enlarge the penis. In fact, a vacuum pulls blood into any bodily appendage. "If you put your earlobe in a negative atmosphere," notes Goldstein, "you draw blood into it." The AUA reports that three quarters of the men who start using vacuum devices are happy enough to keep using them, and that in one study, 84 percent of the men--and almost 90 percent of their partners--said they were satisfied with the technique. Comfortably married couples seem to like these best, and one manufacturer alone recently reported having sold more than 300,000 vacuum devices at $400 a pop.

Drawbacks include having to haul the machine around, the interruption in foreplay while the man pumps up and the need to have skilled, personal instruction to make it function correctly. Erections last about a half hour and require a tension ring around the base of the penis in order to hold the blood in place. This often makes for an erection that's wobbly at the base, since no blood is stored on the other side of the ring.

Other current therapies rely on an irony of the penis: It must relax in order to get hard. In ordinary circumstances, as a man becomes focused on the object of his affection, his brain tells nerves to release substances that relax spongy tissue in two long tunnels running the length of the penis. Blood pumps in, the penis swells and this swelling pinches off the normal exit veins--trapping the blood and maintaining an erection until ejaculation. If the nerves don't get the message, or if blocked or crushed arteries don't let enough blood in, or if damaged veins let the blood leak out too soon, nothing, or not much, happens, and the spongy-tissue cells stay constricted like tiny sphincters.

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But it has long been known that smooth-muscle tissue--common in other parts of the body as well as in the spongy tunnels of the penis--can (continued on page 96)Up, Up & Away(continued from page 94) be relaxed by direct contact with certain drugs. What the brave Brindley demonstrated on himself--and allowed urologists in the front rows of the auditorium to examine by hand, to be sure he wasn't hiding an implant-- was the injection of a drug directly into the smooth-muscle cells in the tunnels of the penis. By 1995, Caverject (Pharmacia & Upjohn Co.'s brand name for a synthetic prostaglandin called alprostadil) had become the first drug approved by the FDA for treating impotence.

Alprostadil is also the active drug in the tiny pellets called the Medicated Urethral System for Erection, or MUSE, for which Vivus Pharmaceuticals (based in Menlo Park, California) received FDA approval early in 1997. The product, which resembles a rabbit food pellet, is released a little over an inch up the man's urethral tube using a simple disposable plastic plunger. The pellets come in four dosage levels and deliver 80 percent of the goods to the smooth muscles within ten minutes. The erections can last up to an hour, depending on the dose. Vivus recommends using its product no more than twice every 24 hours, which may appeal to men for financial reasons. These erections are expected to cost $19 to $24 each, depending on the dosage.

It's a little early to tell how popular this system will be among the erection-challenged. In a clinical study, Vivus found that as many as 96 percent of the men thought MUSE was easy to use-- not a description that would come to mind for most men using injections. And in a three-month home trial of MUSE, testing almost 1000 couples, 65 percent of the men had erections, compared with 19 percent using the technique but receiving only a placebo. About 11 percent of the men experienced the most common side effect-- described by Vivus as "transient penile pain"--and the discomfort was enough that about one percent of the men stopped using the technique during the tests.

As for injection therapy, there are other drugs still not formally approved but commonly prescribed by knowledgeable doctors. These include two other smooth-muscle relaxers: phentolamine and papaverine. Increasingly, such drugs are being used in combination with alprostadil. Among the differences is cost. Caverject is as much as $25 a hard-on, while the two other drugs cost about $3 a shot.

The most widely mentioned side effect of injections is occasional pain in the penis, though care must also be taken to avoid infection and to be on guard for a prolonged erection, which can cause permanent damage. Some studies also suggest that the injections can become less effective over time. Despite all this, something of a subculture of narco-studs has developed--featuring incredible tales of movie-celebrity swordsmen and septuagenarian party animals.

A recent article in the online magazine Slate includes a cartoon illustration of three older gents presumably discussing their latest sexual conquests over tea at the "Penile Injection Club" as part of a cautionary tale about messing with mother nature as we age. In fact, Slate reports, hundreds of thousands of American men of all ages now regularly inject themselves, taking advantage of the most widely prescribed impotence therapy today. According to the Harvard Health Letter, injections just plain work 94 percent of the time in impotent men, regardless of their problems. And patients report that injections work their wonders in 15 minutes or less.

"Who wants to give himself a shot there?" admits Frank, a former bus driver who has had trouble getting erections since he was a teenager. But after the pinprick of pain there are compelling advantages.

"It's been a blessing for me," Frank says, laughing. "I'm 51. I'll take anything I can get." After he started the injections (and before he and his long-suffering wife split up), his wife became extra excited when they were going to have sex, because she knew that it would be a prolonged event. Though doctors try to titrate dosages that will give their patients a one-hour erection, men commonly jack a bit more medicine into their syringes. Frank says that even without upping his dosage, he regularly enjoys three-hour erections from a shot. (If erections last four hours, men are advised to get to an emergency room for a counteracting injection of phenylephrine, before damage ensues.) And since he's begun seeing other women, Frank has yet to meet one who has been turned off by his sexual preparations, he says, particularly when they hear of the extended forecast.

Meanwhile, Frank's estranged wife has spread the word among his friends' wives that they too can experience a wildly improved sex life. But his pals with erection problems don't like the idea of a needle either. And Frank himself has been testing one of the new pills, which he finds a significant improvement over injection.

"There are a million people like us out there, and just a few have the will to go through with that," says Frank. Referring to his friends, he adds, "They're all waiting to see how the pill makes out. And then they're going to come in."

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Dr. Leroy Nyberg is director of urology programs at the NIH. If there is a federal impotence czar, Dr. Nyberg is he. According to Nyberg, the pill and earlier advances in impotence treatment are largely the results of efforts made by the medical-appliance and pharmaceutical industries, which studied first the early implant devices and then the dashing Brindley's injection erection and said, "'Hey, this is something we can work on.'"

Research into the causes of impotence, notes Nyberg, is still carried on by academic researchers. The health-products companies, he says, "just look at how we can treat impotence. So they didn't help us understand what causes it--but they made rapid progress in the way it can be treated."

The lure is a potential market of colossal dimension. As impotent men have lately emerged blinking from the closet and learned that they don't have to feel guilty about their plight, they have begun to spend money on remedial measures. Business Week estimates that in 1995, men in the U.S. spent around $665 million on therapies for erectile dysfunction. And that is a drop in the ocean compared with the anticipated demand among well-heeled aging baby boomers seeking a convenient magic potion to bring back that hunka hunka burnin' love.

Typically, a new drug takes about 15 years and $400 million to be brought to market. So researchers at Pfizer Inc.'s labs in Sandwich, England were intrigued when a drug they were testing to combat angina--heart pain from inadequate blood flow--failed at that task but turned out to improve blood flow to the penis instead. Subjects kept reporting that, screw their hearts, they had started having all these marvelous (continued on page 152)Up, Up & Away(continued from page 96) erections. Pfizer began tests to turn the drug into an erection pill, eventually trying it out on thousands of volunteers in the U.K., U.S. and Australia. The Pfizer pill has become the most widely watched of the oral drugs in development.

"There's been quite a response in the test-patient population," says Pfizer spokeswoman Kate Robins with considerable understatement. Various studies have already shown that sildenafil, which Pfizer is marketing under the name Viagra, has improved erections in 88 percent to 92 percent of the men tested, no matter the cause of their affliction. In one test, most men got an erection within 19 minutes after they popped the pills.

Pfizer plans to submit test data to the FDA sometime in 1997, Robins says, though she repeats the routine industry caution that "a drug can crash and burn at any time." Knowledgeable people in the industry cite government regulators' questioning tests or unexpected side effects as reasons why a drug never makes it to market. So far, says Robins and independent researchers familiar with the testing, side effects have been limited to a few cases of headaches, flushing and nausea.

Vasomax is the proposed trade name of another pill being developed to treat impotence, this one by Zonagen Inc. Based on phentolamine, one of the drugs currently used in an injectable form, Vasomax relaxes the smooth-muscle cells in the penis, allowing blood to rush in--even if through nervousness or other causes the man has released adrenaline. Adrenaline, which constricts the cells, kills erections. Zonagen recently began final testing on Vasomax.

Tap Pharmaceuticals, partly owned by health care giant Abbott Laboratories, is developing a pill that could open a new front in the treatment of impotence. Tap's pill, based on apomorphine, is placed under the tongue, not swallowed. But the real difference is in how it works. While the other oral drugs--and injections and proposed creams, for that matter--directly affect the crucial penile muscle cells, apomorphine operates on the brain. Just as parts of the brain influence sight and hearing, others direct neurotransmitiers that carry news of our urgent appetite to the penis, triggering an erection. Apomorphine works its wiles on one of these neurotransmitters. This intrigues researchers, because they know so little about such "centrally acting" drugs. Most research has been done on drugs that work directly on the penis.

Goldstein, who is testing the Pfizer and Zonagen pills on his patients, expects that both will make it to the marketplace, with one brand being more effective with particular kinds of impotence than the other.

Nyberg of the NIH is cautious but optimistic about oral drugs. "We know we can get drugs that work on the heart and we know that we can get drugs that work on the prostate--and have minimal side effects elsewhere," he says. "We're hopeful that we can also tailor these drugs, which are now pretty broad in their effects. I think eventually we will have an oral drug."

Gels and creams that are rubbed directly on the penis are also being tested, though some researchers think that these treatments may have a more limited market. The cream must penetrate several layers of skin and other tissue, which often means that the drug takes a roundabout route through the circulatory system. Researchers in one study of a cream that contained smooth muscle--relaxing drugs concluded that while the cream did bring out a bigger, better erection in most of the test subjects, it probably worked better for psychologically impaired rather than for physically impaired patients. Other creams that have been tested consistently produced that legendary bedtime bane, a headache. Researchers also worry that with anything one rubs on the penis, there could be side effects for one's partner as well.

"They haven't really worked," says Dr. Arnold Melman, professor and chairman of urology at Albert Einstein College of Medicine and Montefiore Medical Center in New York City. Dr. Melman, who has been a trailblazer in impotence research since 1971, is working on what he considers a better idea: gene therapy. The concept is preliminary but attractive.

"We're proposing that we change the threshold of erections," Melman says, "so that the [smooth muscles] will be more easily relaxed when sexual stimulus comes along." This would be done by changing the "tone" of the penis--by regularly augmenting the genes that control the threshold at which smooth muscles in the penis relax, allowing blood to rush in. Conceivably, what Melman calls a "little packet of extra genes" might be needed only every three to six months.

"It works in animals," says Melman. "We don't know if it will work in people." In Melman's animal studies, erections were significantly improved for up to three months with each treatment. "We think that's the next big wave," Melman says.

After the pills.

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Many reputed therapies that are passionately discussed in locker rooms have few admirers among researchers, even though some doctor may have endorsed them. Trazodone, for instance, an anti-depressant drug, can produce an erection as one of its side effects, notes Melman, but a recent study has shown it to be not much more effective than a placebo--in effect, no more useful than wishful thinking. Likewise yohimbine, an extract from the bark of an African tree, widely considered to be an aphrodisiac, does a lot for male rats. In the decade or so that it has been available over the counter, plenty of men believe they have been helped by it too. Yet the few careful studies on humans have been disappointing, particularly compared with more conventional therapies. In its guidelines to treating physical impotence, issued in November 1996, the AUA found a success rate for yohimbine so low--less than 25 percent--that it is statistically indistinguishable from a sugar pill.

Hormones are another hot topic. Urologists agree that testosterone imbalances can hurt the libido--that streetcar of sexual desire--but testosterone doesn't much affect erections per se. Also, testosterone problems are actually rare and easily diagnosed with standard tests. While testosterone was once believed in medical circles to be a major factor in impotence, today it's practically a nonissue.

So-called superhormones touted by some doctors--first melatonin and now DHEA--don't have many advocates among the advance guard of veteran impotence researchers either. While they may help the old libido to feel better generally, no serious studies have shown that either of these hormones can help a guy with real erection problems.

"There certainly are people out there, patients, who say, 'Hey, this worked on me,'" says Nyberg. "But how do we define what their impotence was? What was the cause of it? We just don't have good data to say yes or no."

Goldstein is more blunt, as are other researchers. Few, if any, of the men who pass through Goldstein's clinic are interested in fiddling with DHEA supplements when a shot--or now a pill--predictably delivers a hard, sometimes hours-long, guaranteed flag-waver. Goldstein describes the DHEA frenzy as "one of the bigger scams on the planet."

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One winter day, as a blizzard flogs the streets of Boston, Goldstein is an energetic ringmaster, moving from one patient to another in the X-ray department at Boston University Medical Center. Today he's assessing tests of the hydraulic workings of the men's penises. He and the nurses and technicians use various diagnostic aids, including machines that patients take home at night to attach to their penises. The next day, a computer readout graphs the time, size and hardness (or softness) of any nocturnal erections.

The tests today, however, are in-house. Many middle-aged and older men become impotent from years of smoking cigarettes, high blood pressure, high cholesterol or diabetes. But young men often lose their erections as a result of traumatic injuries to the groin. And it's no small problem. Goldstein estimates that 600,000 American men are impotent from such accidents.

Today Goldstein looks at young patients who could be candidates for bypass surgery, a treatment still in research and not yet fully endorsed by the AUA, which deems it "immature." Indeed, the AUA recommends that bypasses be performed only in such research environments as Goldstein's and Melman's.

As many serious cyclists know (Goldstein and his fellow researchers have interviewed more than a thousand cyclists), a bad fall on the bike's center bar can crush major blood vessels needed to fill the penis and cause an erection. Even the pressure of a bike's seat over time, for regular 100-mile riders, can foul up vital arteries down there.

Yet if everything else in the penis is working correctly, a bypass to restore blood flow can potentially fix the problem. Other conditions--such as hormonal imbalances, true psychological impotence and some cases of neurological damage--are also likely candidates for a long-term cure.

Goldstein's patients today are undergoing the dynamic infusion cavernosometry and cavernosography examination--better known around the office as the DICC (appropriately pronounced "dick") test. After they get a local anesthetic, they are injected with drugs that produce an erection. Then various procedures tell Goldstein if enough blood is coming in, if it's being properly trapped to maintain the erection and how the whole system is behaving. The details determine which therapies should work best for each patient.

One 16-year-old martial arts competitor is sitting on a gurney, penis in hand, watching it gradually deflate after the test. An opponent in a match had twice kicked him hard in the groin. The 16-year-old got a laugh from the fans in the bleachers when he yelled at the guy, "Stop kicking me in the balls." But in the months afterward, he had no erections. From Goldstein, he gets relatively good news. Goldstein wants to wait a couple of years, until the young man has grown more, but he can probably be permanently repaired with an arterial bypass to bring more blood to his wand.

A 27-year-old soccer player gets good news, too. He slipped and fell hard on a fence rail while retrieving a dead ball. Afterward, he went through a string of doctors who didn't know what to tell him until one referred him to Goldstein. "You're a go!" Goldstein now reassures him in a happy, booming voice. Everything works in his system except the incoming artery, which was crushed. An artery transferred from his stomach should bypass the obstruction and get his penis pumping up again.

Not so for other men this day.

Goldstein has been doing this surgery since 1981, trying to discover why it works in some cases but not in others. One fundamental has become gospel: If the erect penis leaks too much blood back out of the system, no bypass will restore the erection. And the long, complex surgery isn't worth it.

Across the street at Boston University's Center for Advanced Biomedical Research, researcher Robert Moreland spends his time trying to understand the critical ratio of smooth-muscle to connective tissue necessary for an erection. When there's too much connective tissue, the erectile chambers leak. By testing different drugs and environments on cultures of smooth-muscle cells grown from tissue removed during implant operations, Moreland and his colleagues hope, ultimately, to be able to find ways to restore a healthy balance. "We can't fix that now," says Moreland. "But we're getting there."

That may not be soon enough for Goldstein's next patient, a 28-year-old fisherman who slipped and straddled the rail of a boat. Sadly, he gets the news that his leaking can't be fixed with surgery. His best hope now is the needle--and if that doesn't work, an implant. "I feel very bad telling you all this," says Goldstein, as tears well in the young man's eyes. "This is a problem that is permanent."

But far from hopeless, as Goldstein's patients who have taken first injections, and now the pill, point out. What makes longer-term patients grumpy these days, in fact, is that the new oral drugs aren't on the market yet. After Pfizer's earliest tests of Viagra were completed in England, the test subjects petitioned the company to be allowed to stay on the pill. The men in Goldstein's test groups who are nearing the end of their programs--and facing a return to the needle or other treatments until one or more oral drugs get FDA approval--are no happier.

A former Army MP and law enforcement veteran admits that for him, the pill doesn't give as hard, or lasting, an erection as the injection. "But it's a lot more comfortable," he laughs. "It's a big joke between my girlfriend and me. She comes in with a glass and the two pills and says, 'It's time for your medication.'" He's also been stopped at Customs when inspectors have found what looked like drug paraphernalia in his bags. Now at the beginning of a test series, he's hoping approval comes by the time he's out of the program.

A 42-year-old financial officer in a state agency, who damaged himself during a simple bedroom misstep with his wife ("she zigged and I zagged"), is not so optimistic. He has less than two months left with the test pills. And despite experience with needles as a frequent blood donor, he hasn't gotten used to injecting his own penis.

"As for the pill's side effects," he sighs, "the primary one is anxiety--knowing that you're at the end of the testing, and that you could be getting kicked out of the program shortly."

Even without upping his dosage, he regularly enjoys three-hour erections from a shot.