Beyond condoms

FOUR offspring is plenty for 37-year-old Glen Magdaleno of Los Angeles. “Children are grand, but they’re a bit of a hassle too,” he says. “I love my kids, but I just can’t have any more and still be a good parent.”

Not only would Magdaleno, a nursing attendant in a hospital orthopedic ward, be happy to share contraceptive responsibility with his wife, he’d also like for all men to have options beyond condoms, withdrawal or a vasectomy. To those ends, he recently volunteered at Harbor-UCLA Medical Center to test one of several male birth control drugs being developed around the world.

Every morning during the monthlong study, Magdaleno smeared hormone-laced gel over his upper body. The experimental drug was designed to penetrate his skin, enter his bloodstream and trick his body into shutting down testicular functioning -- a reward he considers well worth the bit of acne he encountered. “At first I was worried about my libido and other side effects, but then I got excited about the idea of making love without the consequences,” he says.

If widespread, Magdaleno’s enthusiasm would bode well for drug developers. Forty years after the introduction of the female birth control pill -- and despite sluggish progress in recent years -- researchers are still optimistic about the ultimate feasibility of a male contraceptive.

Drugs now in development all use hormonal methods similar to those used in many female contraceptives. Small studies have found their delivery -- a combination of implants, injections and gels -- to be generally safe, reversible and effective in lowering sperm counts.

Now researchers are fine-tuning the methods to make them convenient enough for men to use consistently. And several studies are planned or underway in the United States, Europe and Asia to look at the real-life effectiveness of male hormonal methods in couples using no other protection during sex.

That’s not to say a male birth control drug will hit the market in the next five or even 10 years. And the first product isn’t likely to be a daily pill.

A man’s reproductive system is even trickier to tame than a woman’s. “Theoretically, all it takes to impregnate is one sperm,” says Dr. Christina Wang, a professor and program director at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. Every day, men churn out tens of millions of sperm. Women, however, produce a single egg once a month. “It’s much more difficult to suppress sperm production,” Wang says. “And you have to suppress it every single day.”

Male hormonal methods work by adding testosterone or other male hormones to the bloodstream. The brain senses these extra hormones and, to keep the reproductive system in balance, sends chemical signals to shut down the testes, Wang says. This halts production of sperm cells. It also blocks normal production of testosterone -- responsible for male characteristics throughout the body, from facial hair to sex drive -- but the added male hormones serve to take up the slack.

Men can still ejaculate with suppressed sperm levels, but the hope is that they would be functionally infertile. Contraceptive researchers aim to reduce sperm counts from a normal average of 20 million to 200 million sperm per milliliter of semen to 1 million sperm per milliliter -- or even lower, says Dr. John Amory, a professor of medicine at the University of Washington who has been studying a testosterone gel. Studies suggest that lowering the sperm count that much could result in a contraceptive that’s as much as 99% effective.

Researchers have found they can boost the sperm-suppressing effects of the added male hormones by also administering progestin, a type of hormone used in female birth control pills and found naturally in small amounts in men. The progestin reinforces the chemical messages that shut down the testes.

Sperm production can then be suppressed with even less testosterone, which helps avoid some of the hormone’s side effects. Researchers are most worried about testosterone’s tendency to decrease levels of heart-healthy HDL cholesterol, which they’ve seen in some clinical trials, as well as possibly contributing to prostate cancer, which would require longer trials to study.

In the short term, testosterone’s side effects can be similar to those of steroid use, including mood changes, lean muscle weight gain, acne breakouts and a temporary shrinking of the testes -- the latter being a response to decreased sperm volume, Amory says.

The need for high doses of testosterone makes a male birth control pill tough to formulate, Wang says. Drops or spikes in hormonal levels can trigger sperm production, so a steady delivery method is crucial. Unlike estrogen, however, testosterone doesn’t work well in a daily pill. The hormone tends to immediately break down in the liver.

To bypass this route, researchers are instead experimenting with ways to administer hormones directly into the bloodstream -- including a combination of slow-release implants, long-lasting injections or daily gels.

Researchers in China are wrapping up the largest of these trials, a two-year efficacy study of approximately 1,000 volunteers, says Kirsten Vogelsong, a scientist at the World Health Organization, which sponsored the trial. The men received monthly testosterone shots and began having otherwise unprotected sex with their partners after researchers verified a drop in sperm count. Preliminary results suggest that most men remained infertile during the injection regimen, Vogelsong says, but a full report is expected sometime next year.

Also, the World Health Organization will help sponsor a smaller injection trial in Europe and Asia next year. Researchers plan to give 400 men bimonthly shots of testosterone and progestin at nine sites and follow them and their partners for a year, says Doug Colvard, associate director of CONRAD, a nonprofit reproductive health organization in Virginia.

A small study in Seattle suggests that testosterone might also be effective when applied onto the skin. Thirty-eight volunteers used a daily testosterone gel in addition to slow-release progestin implants, according to a report published by Amory and his colleagues in September. In 90% of the men, sperm counts dropped to infertile levels within six months, Amory says. Most of these levels returned to normal soon after the trial ended.

To continue this work, Amory and Wang are conducting a new gel-only trial in Seattle and Los Angeles. Volunteers like Magdaleno apply separate progestin and testosterone gels daily, and researchers monitor their sperm count over the course of a few weeks. The researchers hope to enroll 140 volunteers and publish results after the trial concludes next spring.

For men who dislike daily routines, once-a-year surgery might be more attractive. The Population Council, a nonprofit international research organization in New York, is working on a slow-release implant of a powerful testosterone derivative, says Dr. Regine Sitruk-Ware, executive director of product research and development. This compound -- administered through four small plastic rods that release hormones for up to a year -- could spare the prostate from long-term side effects, she says. In initial tests in Europe, South America and Los Angeles over the last five years, the drug blocked sperm production completely in 72 out of 87 volunteers. Researchers are now tinkering with the rubber material used in the implant and hope to test a new single-rod implant in clinical trials within a couple of years.

Still, questions about the scientific mechanisms remain. Puzzlingly, men of Asian descent seem to respond more quickly and completely to male hormones than do non-Asians, Amory says. And some men in all hormonal studies are simply “non-responders,” remaining fertile after standard treatments. “This is a real problem for drug companies,” he says. “We don’t have the same problem with women.” He hopes that larger clinical trials will tease out slight differences in biology, which could then guide development of other methods.

Even if a drug proves effective, however, it still needs to be convenient. At the end of a large, three-year European study, researchers decided the combination tested -- yearly progestin implants with testosterone injections every three months -- was not likely to be acceptable for “widespread everyday use,” according to a joint press release by the study’s sponsors, Schering AG of Germany and Organon of the Netherlands. Although both companies say they remain individually committed to bringing a male hormonal contraceptive to the market, they don’t plan to continue with further trials of this drug combination.

Also in September, Wyeth Pharmaceuticals in Madison, N.J., announced it was discontinuing its entire research program for new male and female contraceptive drugs. Financial pressures, scientific difficulties and an unknown market for male contraception were among the factors that contributed to the decision, says Gerald Burr, a spokesman for the company’s research and development program.

Indeed, most research in the United States is being done by nonprofit, academic or government organizations, says Diana Blithe, program director of male contraceptive development at the National Institute of Child Health and Human Development at the National Institutes of Health.

“Pharmaceutical companies have not chosen to pursue this aggressively,” she says. Male birth control is “both an untapped and untested market,” and many drug companies prefer to follow less risky avenues of research, she says.

Still, Glen Magdaleno is hoping a good birth control will be available for his sons, ages 7 and 9, by the time they’re old enough to need it. “This could be a great thing for my boys,” he says. “I’d be more than happy to make them take it.”

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What they said

Would men use it?

A survey of 9,000 men in nine countries, published in 2005 in the journal Human Reproduction, found that 55% were willing to use male hormonal contraceptives. Only 21% were unwilling.

Of those countries:

At 29%, Indonesia had the smallest percentage of men willing to use hormonal contraceptives.

At 71%, Spain had the largest percentage willing to use such methods.

Of all the countries, including Germany, France, Sweden, Argentina, Brazil and Mexico, the United States ranked sixth on the greatest-acceptance list, with 49% of men in this country willing to use hormonal contraceptives.

Among men who would use a hormonal method:

23% would prefer an annual implant.

22% would choose a daily pill.

And 12% would choose a monthly injection.

Men who were willing to use hormonal methods were more likely to have higher education levels, report a higher income, have no religious objections, live in a metropolitan area and be willing to undergo a vasectomy.

Kirsten Thompson, director of the Male Contraception Coalition, says the demand for new male contraception is clear. “Every week I get e-mails from men asking where they can get access to experimental products they read about.”

Would women trust them?

An earlier survey, published in 2000 in the journal of Human Reproduction, found support for a male contraceptive among 1,900 women attending family planning clinics in Scotland, China and South Africa.

More than 65% said responsibility for contraception fell too much on women.

More than 90% of Scottish and South African women considered the “male pill” a good idea, while 71% of women in Hong Kong and 87% of women in Shanghai thought it was a good idea.

2% said they would not trust their partner to use male hormonal contraceptive.

“You have to think of this in terms of couples in a stable relationship, where for some reason perhaps the woman can’t take oral contraceptives,” says Diana Blithe, program director of male contraceptive development at the National Institute of Child Health and Human Development. “In this country, 17% of men undergo vasectomies, which is much more drastic than hormonal methods. I think the market is there.”