A joke among researchers in the field of male contraception is that a clinically approved alternative to condoms or vasectomy has been five to 10 years away for the past 40 years. The so-close-yet-so-far state of male contraceptive development has persisted in large part because of three serious hurdles: the technical challenges of keeping millions of sperm at bay, the stringent safety standards that a drug intended for long-term use in healthy people must meet, and, ultimately, the question of whether men will use it.

Any sex-ed grad can tell you: the only two effective contraceptives for men today are condoms and vasectomy. Condoms have been around for at least 300 years, with early versions made of animal intestines. Today's rubber prophylactics are relatively cheap and widely available, offer bonus protection against sexually transmitted infections, and are 98 percent effective against pregnancy if used properly. On the other hand, surgery to cut the vas deferens (sperm ducts) is nearly foolproof in pregnancy prevention but is usually considered irreversible and tantamount to sterilization. "It's appalling that besides condoms men only have a surgical nonreversible method," says Regine Sitruk-Ware, a reproductive endocrinologist at the Population Council in New York City.

For decades the promise seemed to lie in a hormonal approach—an analogue to the female birth control pill—that would adjust the hormones controlling sperm production. Inconsistent results among men and side effects associated with long-term testosterone use have, however, led some researchers lately to set their sights elsewhere. Newer, nonhormonal methods target various developmental nodes in the formation of sperm, their motility and their egg-penetrating capabilities. There is also work on a form of reversible vasectomy which involves blocking the vas deferens with a polymer gel that may later be dissolved.

Most of the new alternatives under development are geared toward men in long-term relationships who seek a dependable, reversible form of contraception. Increasingly, men want more control over their fertility, and many would like to share the burden of contraception with their female partners. For couples in which the woman cannot handle female birth control for whatever reason—in some women, hormonal contraceptives can cause significant side effects such as bleeding, reduced libido and increased cardiovascular risks; IUDs (intrauterine devices) can cause severe cramps; diaphragms can kill spontaneity and require manual insertion—male contraception may be the best or only option. "It's really an unmet need," Sitruk-Ware says.

About half of pregnancies in the U.S. are unplanned and half of these end in abortion. An effective male contraceptive might have salutary implications for population growth worldwide, but for William Bremner, who leads the Center for Research in Reproduction and Contraception at the University of Washington (U.W.) in Seattle, the goal is providing options to individual couples. "If people had effective methods and real choices, there would be fewer unwanted children and markedly fewer abortions," he says.

Worthy intentions, notwithstanding, the reality is that funding has been a continual challenge for the field. The National Institutes of Health (NIH) currently provides nearly all of the funding for male contraception research in the U.S.—and for some international studies, too. Researchers agree that for a new contraceptive to come to market, support from pharmaceutical companies is a practical necessity, but interest in the industry has been waning in recent years. A major blow came in 2006 when two major companies that had been on board, Schering AG and Organon, shut down their joint hormonal male contraceptive program soon after Schering's acquisition by Bayer. That meant the end of a major funding stream as well as the loss of any research advances that had been made by the project. "Unfortunately, the people who were working on it are under obligation to keep confidential the information, in case they ever go back to it," says Diana Blithe, director of the Male Contraceptive Development Program at the NIH.

Hobbling sperm without hormones
Although none have reached clinical trial stage, nonhormonal methods of male contraception are gaining traction. About three or four years ago, John Amory, a researcher and clinician at U.W. who has been working on hormonal methods for many years, became interested in a nonhormonal target: retinoic acid, a metabolite of vitamin A that is essential for spermatogenesis. In animal models the compound bisdichloroacetyldiamine safely and reversibly induces infertility by inhibiting an enzyme, aldehyde dehydrogenase 1a2, required for retinoic acid synthesis in the testes. Unfortunately, bisdichloroacetyldiamine also inhibits a similar enzyme, aldehyde dehydrogenase 2, required for alcohol metabolism in the liver—meaning that animals on bisdichloroacetyldiamine were unable to process alcohol. "And some would say that if it weren't for alcohol no one would need a contraceptive anyway," jokes Amory, who is working on ways to more specifically inhibit aldehyde dehydrogenase 1a2. In another approach, detailed June 1 in Endocrinology, Debra Wolgemuth's lab at Columbia University used a synthetic retinoid to block retinoid acid receptors, achieving reversible infertility in mice.

Several labs are also looking at ways to thwart sperms' ability to find and swim toward the egg. A group of proteins known as CatSpers controls hyperactivation—the frenzied flagellar beating of sperm tails after ejaculation. Two studies published in March found that progesterone and high-pH, or alkalinity, around an egg act on CatSpers to turn on hyperactivation. Because CatSpers are believed to be found only on sperm, drugs targeted specifically to these proteins would presumably have few side effects elsewhere in the body.

Other agents being investigated, including gamendazole and adjudin, target the Sertoli cells within the testes that provide crucial nourishment to growing sperm. None of these nonhormonal drugs will be tested in humans for at least another two or three years, Sitruk-Ware says. Once a contraceptive target is determined, researchers can use high-throughput screening technology to check thousands of compounds for drug potential.

The dark horse

The most tireless advocate for new male contraceptives may be Elaine Lissner, director of the one-woman operation Male Contraception Information Project, which tries to raise public awareness of nonhormonal male contraceptives. In particular, she has been trumpeting a particular method known as reversible inhibition of sperm under guidance (RISUG). Developed and currently undergoing clinical trials in India, RISUG involves a small incision in the scrotum and injection of a polymer gel into the vas deferens, the same tubes severed in vasectomy. (Vasectomy is reversible in some cases with expensive microsurgery to reconnect the vas deferens. Complications such as anti-sperm antibodies that form when sperm leaks into the body during vasectomy, however, make reversal more than a problem of plumbing.) The porous polymer does not block the flow of sperm but purportedly renders sperm inert by disrupting the chemistry of their cell membranes. Although many researchers appreciate Lissner's advocacy efforts, they do not necessarily share her enthusiasm for RISUG, which is still untested the U.S.

RISUG's fighting chance, touted by its supporters, is its potential reversibility. In nonhuman primates, reversibility has been achieved by dissolving the polymer with an injected solvent. In Amory's view, however, "until they demonstrate reversibility in humans, it's really no different than a vasectomy," although, he adds, "I'd love it if this worked."

Lissner, who is not a scientist herself, bought the international rights to RISUG last year and has created a foundation called Parsemus to develop the procedure in the U.S. That means starting from square one, with toxicology testing and small animal studies. Lissner hopes to eventually get the procedure, now re-branded as Vasalgel, approved as a medical device in the U.S. Before that happens, however, Vasalgel, like all other contenders in the male contraceptive line-up will have to catch the eye of a funding source.

The current status of hormonal methods
The female birth control pill, which went on the market in 1960, increases levels of progesterone to suppress ovulation; similarly, a male hormonal contraceptive would increase levels of testosterone to suppress sperm production. Testosterone inhibits the release of two pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which control in the testes testosterone production and spermatogenesis, respectively. Thus, testosterone works in a negative feedback loop with LH and FSH to maintain relatively constant levels of testosterone in the blood. A male contraceptive that delivers extra testosterone into the bloodstream sends a signal to the pituitary to suppress the hormones that promote sperm production.

For women, the birth control pill replicates the body's natural state of infertility—pregnancy—and essentially fools the body into acting as if it were pregnant. "Men don't have an analogous time. After puberty they keep making sperm until they die," Amory explains.

Compared with the one-egg-per-month output of the female reproductive system, the roughly 1,000-sperm-per-heartbeat output of the male reproductive system is "a quantitatively challenging problem" for contraceptive research, Amory says. Thankfully for Amory's cohort, effective male contraception does not require complete obliteration of sperm production. Only about 5 percent of sperm are functional to begin with, Amory estimates, and very few of these high-quality sperm will survive the arduous journey to the egg. Lowering sperm count to less than one million per milliliter of ejaculate from the normal range of 20 million to 30 million per milliliter results in de facto infertility.

Though often referred to as the "male pill," male hormonal contraceptives in development are mostly synthetic testosterone delivered in the form of injections, slow-release implants or rub-on gels that absorb through the skin. (Oral ingestion of testosterone is less effective because much of the hormone is then broken down by the liver.) Adding progesterone (a female sex hormone), which also suppresses spermatogenesis, to a testosterone regimen improves contraceptive outcomes. The testosterone–progesterone combination achieves effective contraception for more than 90 percent of men—but for reasons that are still unclear, there are always some men for whom sperm production is insufficiently suppressed. For comparison, the female pill is about 98 percent effective when taken correctly.

In April a clinical trial of injections of long-acting progestin (synthetic progesterone) and testosterone was ended early due to higher than expected rates of minor side effects such as irritability and acne among the 321 participants. The trial was a collaboration between the World Health Organization and CONRAD, an Arlington, Va.–based nonprofit that supports reproductive health research. Douglas Colvard, deputy director of programs at CONRAD, expressed disappointment at the end of the trial but was optimistic there would be valuable data from the third of participants who had completed 12 months of injections.

A clinical trial of a contraceptive implant, led by the Population Council, the University of California, Los Angeles, and U.W., will begin late this year or early 2012, according to Sitruk-Ware. The implant, which is matchstick-size and placed under the skin of the upper arm, contains a modified synthetic steroid that resembles testosterone but should not have the same effect on prostate growth sometimes associated with testosterone treatments.

"The idea is a good one," Amory says of male hormonal contraception, "and it works most of the time, but not well enough for a pharmaceutical company to jump in and put some money and time into it."

Do men really want it?
When asked whether a new contraceptive will appeal to men, researchers are quick to point out that men are already responsible for 30 percent of contraception in developed countries (and 14 percent in developing countries), split about evenly between condoms and vasectomies. Even if that is the minority of sexual partners, those figures still add up to hundreds of millions of men.

A 2002 survey of 9,000 men in nine countries across four continents found that more than 55 percent of men would be willing to use a hormonal form of contraception. In a 1996 survey of nearly 2,000 women in Scotland, China and South Africa 87 percent thought that a hormonal male contraceptive was "a good idea" and 98 percent of women said they would trust their partners to use a hypothetical "male pill". "Of course, we don't really know for sure what people will do," Amory says. "All surveys have that limitation."

The risk–benefit analysis for male contraceptives is different from that of female contraceptives because at the end of the day, men are not the ones getting pregnant, Colvard says. For that reason, future male contraceptives may come with incentives other than pregnancy prevention: side benefits such as muscle gain, fat loss and even baldness prevention.

(Of course, infertility is a well-known side effect of testosterone doping in athletes. Although testosterone used for contraceptive purposes would show up on a drug test, according to Amory, the levels are far below those needed for significant muscle enhancement.)

Although many men may welcome new contraceptive options, there is not the same momentum that pushed female contraception. "We don't see groups of men going on the streets," Sitruk-Ware says. "On the other hand, when we do clinical trials in various countries the men are very interested."

For now, researchers and consumers can only assume that when presented with a full pipeline of new drugs and better data on the safety, efficacy and public acceptability of male contraceptives, pharmaceutical companies will eventually see an opportunity for their profit margins. The hope is, "If you make it, they will come," NIH's Blithe says.