Male Choice.

The search for new contraceptives for men

In his memoirs, legendary 18th-century lover Giacomo Casanova recommended the use of condoms--which he called "English riding coats"--to protect against unwanted pregnancies.

Even with all that's changed in the world, today's Casanovas have few more contraceptive choices for themselves than the original did. It's primarily abstinence, withdrawal, or condoms for men, whether they have many partners or just one. A surgical approach to contraception for men, vasectomy, which became available in the early part of the 20th century, presents the only notable addition.

In contrast, the number of contraceptive choices available to women has dramatically increased during this century, especially forms of so-called hormonal contraception such as birth control pills.

"We think there's a need for more alternatives for men," says Robert Spirtas of the Contraception and Reproductive Health Branch of the National Institute of Child Health and Human Development in Bethesda, Md. "Some women are uncomfortable with or can't take hormonal contraception. At the same time, recent research has shown that many men in committed relationships would be willing to take a contraceptive pill."

Although the contraceptive gender gap rests partly on financial concerns, biology also contributes, says Frances Hayes of Massachusetts General Hospital in Boston. Because of potential liability issues and the safe and effective female contraceptives, many drug companies have assumed that male contraceptives are unwise or unnecessary, she says. Moreover, men are constantly fertile, making it more difficult to design a contraceptive for them than for women, who are fertile for only a short time each month.

In the past few years, however, two European pharmaceutical companies and two large private foundations have begun to investigate male contraceptives. Federal agencies are also now interested in stimulating such research, says Spirtas.

"There has been a groundswell of interest" in research on male contraceptives, agrees John K. Amory of the University of Washington in Seattle. "More candidate compounds are being introduced, and there is real optimism that male hormonal contraception will soon be available commercially."

Most researchers agree that the ideal male contraceptive would be safe, effective, and reversible. In addition, it would be self-administered with little training and require neither elaborate surgical procedures nor prolonged periods of abstinence before becoming effective.

Duplicating in men the success of the female birth control pill isn't simple. "Female mammals turn off ovulation during pregnancy and lactation, and you can imitate that process," says Malcolm Potts of the University of California, Berkeley. "There's no analogous system to interrupt in the male."

Following the lead of the female pill, which alters concentrations of hormones coursing through a woman's blood and reproductive organs, groups trying to develop a male "pill" have tested drugs that block men's circulating hormones.

One approach is to give a man doses of testosterone that result in blood concentrations that are significantly higher than normal. This causes his pituitary gland to slow the release of two hormones that produce the signals necessary for sperm development. These two hormones--follicle stimulating hormone, or FSH, and luteinizing hormone, or LH--act in a feedback loop to maintain normal concentrations of testosterone in a man's blood.

Although some testosterone produced in the testes makes its way into the blood, it's the testosterone within the testes that's critical for sperm formation.

A large, international trial sponsored by the Geneva-based World Health Organization was completed about 5 years ago. Men received weekly injections of testosterone over 2 years. The treatment was about 97 percent effective in preventing pregnancy among 400 couples. This success rate is higher than that of condoms but not quite as good as that of the female birth control pill.

In some men, however, the high dose of testosterone needed to exert a contraceptive effect triggered acne and a slight weight gain and lowered the concentration of high-density lipoprotein (HDL), the heart-protecting cholesterol, in the blood.

Most researchers have turned to other reproductive hormones called progestins to block testosterone production in the testes--and thus sperm formation. Success with this method, however, leads to a drop in testosterone concentrations in the blood. To prevent the resulting side effects--such as loss of libido --researchers have given men in the contraceptive trials low doses of testosterone, which maintain normal blood concentrations of the hormone.

Last year, a team of British researchers reported in the January JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM a test in which 24 men took daily pills containing the progestin desogestrel and wore a testosterone-delivering skin patch. After 24 weeks, 23 of these volunteers had suppressed their sperm production to below 3 million sperm per milliliter of ejaculate, a count that most researchers consider incapable of producing a pregnancy.

Similarly, in the July HUMAN REPRODUCTION this year, a Scottish team reported that after 8 weeks, up to 70 percent of men taking desogestrel and testosterone had sperm counts in the infertile range. These men took desogestrel pills and received the testosterone from pellets implanted under their skin. Side effects were minimal, the team reported.

The results are "certainly very encouraging," says lead researcher David T. Baird of the University of Edinburgh. "We could have a male pill within 5 years."

In a follow-up study reported this month at the World Congress of Obstetrics and Gynecology in Washington, D.C., 30 men in Edinburgh and 36 in Shanghai took pills containing either 150 micrograms or 300 micrograms of desorgestrel daily and were given injections of 200 micrograms of testosterone in time-release pellets every 12 weeks.

After 16 weeks, no men taking the higher dose of desorgestrel had detectable sperm production. After 24 weeks of the lower dose, 85 percent of the Scottish men made no sperm, compared with 61 percent of the Chinese men. This is the first large study to demonstrate complete sperm suppression in two different ethnic groups, according to Richard Anderson, also of the University of Edinburgh.

Other researchers are replacing the progestins in such experiments with drugs that block the action of a hormone known as gonadotropin releasing hormone, or GnRH. Combined with testosterone, such GnRH blockers inhibit sperm production faster than testosterone alone or progestin-testosterone combinations do. Because the currently available GnRH blockers are expensive and must be injected into the fatty tissue just below the skin, scientists are developing a GnRH blocker that men can take orally, Amory notes. "This compound will require further testing, but it's an exciting candidate for future contraceptive trials," he says.

All hormonal contraceptives for men that rely on testosterone face some disadvantages. Few researchers have had any success getting testosterone into the blood stream via a pill because the digestive system quickly breaks down the hormone and toxic byproducts can accumulate in the liver. Also, there's concern that hormonal contraceptives may increase a man's risk of prostate cancer.

Researchers say they might be able to improve hormonal contraceptives by replacing testosterone in their formulations with so-called designer hormones, chemicals that have the effect of the hormone on some organs but don't affect others (SN: 10/16/99, p. 252). The New York-based Population Council is beginning trials of such a testosterone analogue, called 7 alpha-methyl-19-nortestosterone. In rats, the compound doesn't stimulate prostate growth, though it does block sperm production.

A disadvantage of any contraceptive that reduces testosterone in the testes is that it may take months to become truly effective and just as long to wear off when treatment ends. Blocking testosterone prevents only the initial step of sperm development, the release of precursor cells in the hundreds of seminiferous tubules of the testes. But sperm in one tubule are at a different stage of development than in the next, and after precursor release, sperm development is independent of testosterone. From start to finish--in the seminiferous tubules and then in the epididymis, a coiled tube just outside the testes--a cycle of sperm production takes about 72 days.

While some scientists try to perfect methods of blocking sperm production by administering hormones, others predict that contraceptive compounds that act directly on sperm growth, maturation, and function could provide a better alternative. Agents that could disrupt the late stages of sperm development would be effective faster than testosterone-blocking contraceptives, and presumably their contraceptive effect could be reversed more quickly. Some of these contraceptives might be able to block sperm function without disturbing testosterone production, thus avoiding side effects.

In September 1999, the National Institutes of Health sponsored a workshop that examined potential new targets for male contraceptives. Speakers pointed out that interfering with cellular processes that participate only in sperm development is the best way to develop contraceptives.

Researchers are investigating ways to interfere with the effects of FSH and LH on sperm precursor cells without inhibiting the production of testosterone in the testes. Studies in rats suggest that maturing sperm cells die quickly when the hormones disappear, says Ronald Swerdloff of the Harbor-UCLA Medical Center in Los Angeles. When the hormones return, sperm development begins again. A hormone known as inhibin and perhaps anti-bodies directed at FSH can selectively inhibit FSH action in the testes.

Another strategy focuses on meiosis. In this process, a cell divides to become two eggs or two sperm, each with only a single set of chromosomes instead of the usual double set. Researchers working with mice have identified two proteins that are involved in this process but not in normal cell division. Interfering with their action may have contraceptive action without side effects.

Other opportunities for contraceptive activity arise from compounds that induce premature release of sperm from the testes to the epididymis. A chemical known as lonidamine prevents developing sperm from staying attached to the cells lining the seminiferous tubule and causes infertility in rats and men, says the Population Council's C. Yan Cheng. However, lonidamine's side effects--it can damage the kidneys--preclude its use as a contraceptive, he says.

He and his colleagues have developed two less toxic compounds that share the core structure of lonidamine, Cheng reported in June at the Endocrine Society meeting in Toronto. Rats given the drugs orally become infertile, with no signs of side effects, and their fertility returns once the drugs are discontinued, he says.

Other possibilities for fast-acting and easily reversed contraceptives come from compounds known to interfere with chemicals that initiate the movement of sperm tails or that allow sperm to penetrate the coverings of the egg.

Another possible approach is called immunocontraception. Scientists propose that either women or men can be immunized against proteins vital to fertility. The Population Council is beginning trials in men of a compound that induces the immune system to form antibodies against GnRH. Studies in male rats and rabbits have shown that this compound is effective as a reversible contraceptive and has few side effects.

In a recent survey of about 1,800 men living in Edinburgh, Shanghai, Hong Kong, and Cape Town, South Africa, up to 83 percent said they would use a male contraceptive pill. Overall, pills were more acceptable than injectable or implantable contraceptives, the researchers reported in the March HUMAN REPRODUCTION.

Acceptability isn't the only problem. Money and politics have always been issues in fertility research. "Contraception is sometimes considered risky by companies in the wake of lawsuits" over female methods of contraception, says Amory. He adds, "Government funding for such research is opposed by some religious and voter groups."

Although governments, nonprofit organizations, and pharmaceutical companies are devoting more funding to male contraceptives than ever before, it's hard to predict when a birth control pill will be available for men. "Each time a new paper [on male contraceptives] comes out, it makes headlines," says Hayes.

But the headlines don't necessarily translate into advances that make hormonal contraceptives for men acceptable as well as effective, she says. Compliance with hormonal regimens is a problem. Even in clinical studies, men sometimes find the complicated schedule of pills and patches or injections difficult to handle, Hayes says.

"We know hormonal regimens work" to stop men's sperm production, says Swerdloff. "Now, we're trying to decide what's the best formulation to get the most effective and user-friendly contraceptives. People are beginning to feel more comfortable with male contraceptives. Politically, it's easier to fund [government] research. And pharmaceutical companies are beginning to believe this will generate revenue."

Whether the wedding of the new scientific understanding of the male reproductive system and growing research-funding opportunities will produce an acceptable, practical male contraceptive is still unclear. If it succeeds, many couples will celebrate the new arrival.