Men are sometimes called the forgotten half of contraception. While women's options were greatly expanded in the past century, men still have the same choices their great-granddaddies had: condoms or vasectomies. Some reasons for the discrepancy may be social, based on assumptions about which sex is more likely to accept the responsibility for pregnancy. But efforts to devise a male counterpart to the birth-control pill face biological hurdles as well.
Sperm continuously mature within microscopic tubules in the testicles (shown above in rats). In humans it takes 74 days for one sperm cell to complete its development. Photograph courtesy of A. Kent Christensen.
"It's a lot easier to interfere with the ovulation of one egg per month than it is to interfere with the production of trillions of sperm a month," says John Amory, an endocrinologist at the University of Washington. "Men are sperm-making machines. They produce a thousand sperm every heartbeat, and we're trying to get that to zero."
Amory's group is part of an international team testing the ability of androgens—male hormones—to lower sperm counts. Androgens such as testosterone are degraded in the liver when they're taken as pills, so the study's subjects, 120 monogamous young men in six cities in North America and Europe, receive a monthly injection in their buttocks instead. They also get time-release capsules of another reproductive hormone, progestin, implanted under their skin. The hormone combination interrupts the signaling pathway that prompts sperm production, and in 60 percent of men, sperm counts drop to zero. In another third, the counts fall below 3 million (a typical ejaculate has 20 million to 200 million sperm per milliliter).
The treatment takes two to three months to bring sperm counts down. But once sperm production is completely suppressed, the pregnancy rate among couples is less than 1 percent—comparable to that achieved with birth-control pills. Sperm counts rebound a few months after the men stop treatment.
The trouble is that fully 40 percent of men in this and other androgen studies don't reach zero sperm counts. Just a few million stragglers per milliliter of ejaculate could result in an unacceptably high risk of pregnancy. "It's a lot to ask a man to take a drug for this period of time and not have it work," says Amory. "The Holy Grail of this field is to get something that works all the time for everybody."
Unlike men, women already have a built-in system for shutting down fertility. Every month, the pituitary gland tells their ovaries when to release an egg—and when not to, which is most of the time. Birth-control pills use combinations of hormones to mimic the system's off switch. But male gametes don't have an endogenous stop sign. There is no natural way to turn off the testicles. Rather than orchestrate a cycle of fertility, male reproductive hormones ensure constant potency. Scientists can only fiddle with those hormones and hope the gonads get the message.
And men, long viewed by medical science as the "simpler" sex, are revealing some surprising physiological complexities. For example, no one understands the function of progestins in the male reproductive system. Women's bodies make progestins such as progesterone to suppress ovulation during pregnancy. "But men have progestin receptors, too, and they make progestin," says Amory. "Why, nobody knows. Progestin is the endocrine version of the male nipple."
Yet such substances could be the key to getting men's sperm counts to zero. Studies have shown that progestins can act synergistically with testosterone derivatives to suppress sperm production more effectively than any hormone can alone. They also help to reduce testosterone's side effects, such as weight gain, acne, and a reduction in the good cholesterol that protects against heart disease.
Even if those side effects are eliminated, some men will still balk, understandably, at the schedule of weekly or monthly shots. So researchers are looking for other methods of androgen delivery. The Population Council in New York City, a nonprofit group, is testing time-release capsules implanted under the skin of the upper arm that last for a year. Other studies focus on longer-lasting injections, transdermal patches, and oral-dose androgens. "The question is whether a man would take a pill once a day versus getting a shot once a week versus getting an implant or a patch," says Robert Spirtas, an epidemiologist at the National Institute of Child Health and Human Development. "I think we've become more of a pill-taking society."
If and when a male pill makes it to market, there's one side effect researchers won't be able to avoid. Sperm cells make up most of the volume of the testes, and treatment with male hormones shrinks the gonads by about 20 percent. The effect reverses once treatment stops, but "most of the guys don't really mind," says Amory. "They only notice because we're measuring their testicles."
A few labs are experimenting with approaches that don't involve hormones. At the North Shore University Hospital in Manhasset, New York, molecular biologist Susan Benoff is exploring a class of hypertension drugs for use in male contraception. In 1993, while working in the fertility clinic, she observed that many of the male patients were taking so-called calcium channel blockers to treat their high blood pressure. The sperm of these men couldn't fertilize eggs in vitro. Benoff has since discovered why: The drugs cloak sperm in a cholesterol coating that blocks their ability to penetrate an egg. Although the effects of calcium channel blockers are too broad to recommend them for contraception, "you can target these drugs to specific tissues," Benoff says. She is screening candidates for testes-specific compounds.
The recent discovery of a gene that regulates sperm movement may someday lead to a contraceptive that works by immobilizing sperm rather than by shutting down sperm production. But that's the most distant possibility. More imminent is a joint venture launched last July between European pharmaceutical giants Organon and Schering AG with the express purpose of putting a hormone-based male contraceptive on the market. Now that basic medical research is pointing them in a profitable direction, drugmakers may be less reluctant to pick up the tab for further contraceptive development. "They're talking in terms of years," says Spirtas. "Most of the other programs will probably take decades."
Visit the Web site of the Population Council (www.popcouncil.org) for a look at the history of male contraceptive development.
