Why We Can’t Have the Male Pill
The trouble began, as it so often does, with a bottle of Chivas Regal.
Back in the 1950s, scientists at Sterling Drug, a now-defunct pharmaceutical company, synthesized a class of chemicals that made male rats temporarily infertile. They thought they might be onto something big: the first-ever birth control pill—for men. After identifying several promising compounds, including one known as WIN 18,446, a trio of researchers began testing them on a ready population, inmates at the Oregon State Penitentiary.
The results were astonishing. Within 12 weeks, the inmates’ sperm counts had plummeted. When the men stopped taking the drugs, sperm production returned to normal. Better yet, they experienced few side effects.
Then one of the participants drank some contraband Scotch and became unusually, violently ill. He confessed his transgression to the researchers, and follow-up studies confirmed his account: WIN 18,446 didn’t mix well with booze. Men who combined the two reported heart palpitations, sweating, nausea, and vomiting. The research was quietly abandoned.
For years, headlines have promised an imminent breakthrough in male contraception. Time and again, these efforts have fallen short. Last October, for instance, researchers reported that a hormone cocktail they’d been testing curbed sperm production and prevented pregnancies. But they’d had to halt the study early because men were reporting troubling side effects, including mood changes and depression.
“The joke in the field is that the male contraceptive has been five years away for the last 40 years,” says John Amory, a research physician at the University of Washington School of Medicine who has been working on the challenge for two decades. A new form of male birth control would be a public-health triumph and could snag a significant piece of the contraceptive market—which is expected to surpass $33 billion by 2023, according to research firm Global Market Insights Inc.—or possibly expand it further. In a 2002 German survey of 9,000 men in nine countries, including Brazil, France, Germany, Mexico, and the U.S., more than 55 percent of the respondents said they’d be willing to use a new form of male birth control. A later study by Johns Hopkins University estimated that the demand could yield 44 million customers in those nine countries alone. And yet major pharmaceutical companies have mostly abandoned the chase.
That has left a scrappy tribe of scientists to fill the void. They’ve dreamed up a vast array of ideas, from the conventional—hormone gels, implants, and injections designed to temporarily suppress sperm production—to the decidedly unorthodox. (Men, prepare to have lasers beamed at your testes.)
For his part, Amory is trying to resurrect the drug that showed so much potential in prisoners. But turning WIN 18,446 into a contraceptive has, like other such quests, proven difficult—as stubbornly elusive as discovering alien life or harnessing energy from nuclear fusion. “When I was in high school, I thought I was going to become a physicist and work on developing fusion,” Amory says. “Then I started working on this, and now I wonder what we’re going to have first: workable fusion or a male pill?”
When it comes to preventing pregnancy, women have a multitude of choices. There are diaphragms and sponges; cervical caps and female condoms; spermicidal gels, foams, films, creams, and suppositories; hormone-delivery systems involving pills, implants, injections, patches, vaginal rings, and IUDs. These options are far from perfect—and they remain inaccessible and unaffordable for many women—but at least they exist.
Men have only two choices: condoms, which have a real-world failure rate of about 18 percent, and vasectomy, a surgical procedure that’s often permanent. A new contraceptive could give men more control over their reproductive futures, alleviate a burden that’s overwhelmingly borne by women, and reduce the rate of unintended pregnancies, which is about 40 percent worldwide, according to the nonprofit Guttmacher Institute. Women have sometimes argued—not unconvincingly—that the lack of a male pill reflects a double standard, but the scientific and regulatory challenges involved in creating a viable male contraceptive are vexing on their own.
After the U.S. Food and Drug Administration approved the first female birth control pill, which used a mixture of hormones to suppress ovulation, in 1960, researchers explored taking a hormone-based approach to men. Clinical trials in the ensuing decades showed that dosing men with testosterone or combinations of testosterone and progestin temporarily inhibited sperm production, but that the strategy had drawbacks. Testosterone is rapidly cleared from the body when taken orally, so a hormonal contraceptive for men would likely have to be delivered via injection, implant, or topical gel, rather than as a pill. What’s more, the hormones don’t work in all men, and because they don’t only affect the gonads, they can, as with the female pill, cause nasty side effects that have nothing to do with fertility.
Research into hormonal solutions continues, but the challenges have prompted some investigators to seek drugs that target sperm more directly. Scientists at the University of Kansas and the University of Minnesota are studying a compound called H2-gamendazole, which prevents sperm from maturing properly, while Eppin Pharma Inc., a small North Carolina company, is developing a drug that would stop sperm from swimming by binding to a protein on the surface of the cells.
And then there’s Amory, who happened upon WIN 18,446 by accident. After arriving at the University of Washington in 1997, he began a practice that soon proved paradoxical. As a clinician, he often treated infertile men who desperately wanted children, while as a researcher he sought to develop a hormone cocktail that would prevent men from becoming fathers. Then, in the fall of 2006, he came across a paragraph about the Oregon prison experiments in a profile of two pioneering fertility scientists.
“It’s a fascinating story,” he says one rainy March morning in his office at the university’s labyrinthine health sciences building. Amory is a 50-year-old former rower and Eagle Scout, with the lanky build and cheerful, wholesome demeanor to match. He’s also an unabashed history buff and enthusiastic storyteller, and he calls up a carefully curated series of graphs to help him narrate the saga of WIN 18,446.
Initially, he says, the Sterling Drug scientists created the compound to treat parasitic infections. But when they tested it in rats, they noticed that the animals became infertile. “Then they stopped the drug, and the rats regained their fertility,” he says. “So they’re like, ‘Hey, maybe this could be a male contraceptive.’ This was before there was a pill for women.” Of course, rodents don’t drink, so it wasn’t until men started taking WIN 18,446 that researchers discovered it interacted dangerously with booze.
WIN’s side effects sounded familiar to Amory. In his clinical practice, he’d occasionally prescribed Antabuse (disulfiram) to patients who struggled with alcohol addiction. The drug blocks a form of the enzyme acetaldehyde dehydrogenase (ALDH), which helps the body metabolize alcohol; drinking while taking disulfiram leads to an extremely unpleasant, and occasionally fatal, constellation of hangover-like symptoms. But ALDH also plays a role in converting vitamin A to retinoic acid, which is required for sperm production. The pieces clicked into place: Amory realized that WIN 18,446 might inhibit ALDH, which would explain why it caused sperm counts to drop and why men taking it had adverse reactions to alcohol.
He tested his hypothesis in rabbits, dosing them with a WIN-laced banana-crème-flavored syrup. “Rabbits are brilliant, because their sperm counts are very similar to humans. They’re mammals just like humans, and you can train them to ejaculate into an artificial vagina,” he says, cuing up a video on his computer. “This is me making an artificial vagina.” (The faux orifice, it turns out, can be assembled from an ultrasound-probe cover and a thermos filled with water heated to about 100F, the approximate internal temperature of a female rabbit.)
After four weeks, the retinoic acid levels in the rabbits’ testes plummeted; sperm production soon followed. “You can see what happened to their sperm counts,” Amory says, whistling as he traces a plunging graph line with his finger. “They go right down to zero. And then we stop the drug, and they come right back up.” The results suggested he’d been right: WIN seemed to hobble sperm production by disrupting the synthesis of retinoic acid.
He concluded that WIN represented an elegant strategy for male contraception—it just needed to be better targeted. There are almost 20 different forms of ALDH; the liver relies primarily on ALDH2 to metabolize alcohol, while the testes use ALDH1A2 to make retinoic acid. WIN disrupted both forms of the enzyme; what they needed was a drug that blocked only ALDH1A2.
To help him tweak WIN, he turned to Alex Goldstein, a bespectacled, redheaded chemist who has become his collaborator and co-investigator. Over two years, Goldstein made about 100 versions of the compound, but none was selective enough. “So we went to plan B,” he says. With the help of a drug-screening robot, their team tested 55,000 additional chemical compounds, identifying about 300 that inhibited ALDH1A2. A leading contender soon emerged, with preliminary experiments suggesting it was more specific than WIN, and more potent.
Last year they put the compound, called CM-121, to the test, giving 10 mice daily doses for five weeks, measuring the animals’ retinoic acid levels, and counting the sperm in their testes. The results were disappointing. Within five hours of each dose, retinoic acid levels did indeed drop—then quickly returned to normal. Sperm production continued apace.
Fudge, Amory thought. (“I have two small boys, so I try not to swear,” he says.) He’d really thought it would work. But he understands the field too well to call it his biggest setback. “Oh, gosh,” he says, sighing, “it’s all setbacks.”
Drug development is an inherently difficult enterprise. Only 10 percent of the drugs that enter Phase I trials—the studies in which scientists evaluate dosing and basic safety in humans—ever make it to pharmacy shelves, and it can easily cost hundreds of millions of dollars to bring a drug to market. Male contraception is a particular challenge. Contraceptives have to be extraordinarily reliable. Many drugs would be considered successes if they worked half the time, but few people would use birth control that failed so frequently.
Then there are the basic facts of reproductive biology. Most healthy women of reproductive age release one egg per month and stop ovulating when they’re pregnant; they can suppress ovulation by taking hormones that mimic pregnancy, which is essentially what the pill does. But there’s no natural off switch for sperm production; men make sperm from puberty until death. “Spermatogenesis is a pretty formidable foe,” Amory says. “Your body has evolved over eons to make a lot of sperm. In fact, most men make a thousand sperm every second.”
If researchers do find a promising drug, they’ll also need to persuade regulators to approve it. No one’s quite sure what that will take. Male contraceptive drugs represent an entirely new product category, and the FDA hasn’t yet laid out clear guidelines for them. Will regulators measure a male contraceptive drug against the female pill or simply compare it to the male-directed approaches now available? Will they want a male pill to be as effective as a vasectomy or simply more reliable than a condom? “Nobody really knows, because nobody’s gotten to that point,” says Zahed Subhan, chief executive officer of Eppin Pharma, the North Carolina company that’s testing a drug that aims to interfere with sperm movement.
There’s reason to believe it will prove tougher to win approval for the first male pill than it was for the female one. Research and regulatory standards have evolved considerably in the past 60 years—the Oregon prisoner tests likely wouldn’t pass muster today, nor would some early trials for the first female pill. (In one crucial study performed with low-income women in Puerto Rico, participants weren’t fully informed of the potential risks, and their reports of side effects were largely dismissed.) Some scientists have also speculated that the original formulation of the female pill, which contained much higher doses of hormones than current products do, wouldn’t be approved today.
Moreover, while female contraceptives aren’t without dangers, pregnancy entails serious health risks. This means regulators charged with making a risk-benefit calculation may conclude in some cases that unplanned pregnancies pose a greater hazard to women than the side effects of a new birth control product would. The female pill also has some noncontraceptive health benefits. The first birth control pill, Enovid, initially won FDA approval in 1957 to treat menstrual disorders; it wasn’t approved as a contraceptive until three years later.
That men don’t bear the medical risks of pregnancy may change the calculus for regulators assessing a male contraceptive. So might the fact that men, with their long reproductive lifespans, could find themselves using birth control for decades longer than women typically take the pill. Unless researchers manage to find a contraceptive with real health benefits for men, regulators will probably have a low tolerance for side effects. “A male contraceptive solution just has to be squeaky clean,” Subhan says.
If a drug were approved and serious side effects popped up, pharmaceutical companies could face costly lawsuits. Litigation is always a risk for drugmakers, but medications designed to be taken by young, otherwise healthy patients for long periods of time, especially those affecting the reproductive system, could be particular targets. Women have filed, and sometimes won, high-profile lawsuits over female contraceptives, alleging that certain drugs and devices have caused a variety of serious injuries—including blood clots, uterine damage, birth defects, miscarriages, and infertility—or that contraceptive failures have left them with unwanted pregnancies.
The scale and spread of the challenges may explain why pharmaceutical companies that once had active research programs had dropped them by about a decade ago. “The drug company funding has kind of dried up,” says Amory, who previously received financing from Organon BioSciences, Schering, and Bayer. “It seemed to some that they decided that the risk-benefit wasn’t favorable.” Although surveys show that men are interested in male contraception, because they don’t get pregnant they may be less motivated to take on the attendant hassles and risks. It’s also not clear if a new male contraceptive would expand the contraceptives market or cannibalize it. Companies profiting from existing solutions might be reluctant to invest in competing products.
Scientists at universities, nonprofits, and startups aren’t scaring so easily. “Everybody in the male birth control area is an underdog,” Goldstein says. Amory and Goldstein’s work on WIN had been funded by the National Institutes of Health, but their grant—$1.5 million over five years—ran out at the end of June, and they don’t have more money lined up yet. Even an identical grant wouldn’t be nearly enough to develop an FDA-approved drug ready for widespread use. Their plan is to find a better, more potent candidate, assemble evidence that it’s safe and effective, and approach pharmaceutical companies about a partnership.
But that will take time. “Science is tough that way,” Amory says. “Most things don’t work.”
Some entrepreneurs say the path forward requires wholly rethinking male birth control.
“What is a male contraceptive?” asks Kevin Eisenfrats, the 24-year-old co-founder and CEO of Contraline Inc., a startup based in Charlottesville, Va. “Is it a drug, or is it a medical device?” Just inside the front door of the company’s two-story brick building, not far from the University of Virginia, a custom mural—a silhouette of a man and woman walking into the sunset—is splashed across a side wall. A bowl of Contraline-branded, sperm-shaped foam stress balls sits on the reception counter.
Eisenfrats, who has long eyelashes and a spray of freckles on his nose, takes a seat at a cluttered conference table and delivers his elevator pitch. “What we’re developing is a nonsurgical and reversible alternative to a vasectomy,” he says. Contraline has created a hydrogel, called Echo-V, that can be injected into the vas deferens, the thin tube that transports sperm from the testes to the urethra. Upon injection, the gel solidifies, blocking the flow of sperm but allowing other fluid to pass through. Ideally, he says, when a man is ready to have children, a doctor would dissolve the gel.
The idea isn’t novel. It’s inspired by a technique known as reversible inhibition of sperm under guidance (Risug), invented in India in the 1970s. The Parsemus Foundation, a nonprofit based in Berkeley, Calif., is developing a similar product, called Vasalgel. But while Risug requires doctors to make a small opening in the skin of the scrotum to access the vas deferens, Contraline has invented a procedure, which it has dubbed “vasintomy,” that allows doctors to implant the gel nonsurgically, injecting it directly through the skin using an ultrasound to guide its placement. “No scalpels or sutures required,” Eisenfrats says. “It’s maybe a three-minute overall procedure.”
He hatched the idea while he was a senior at the University of Virginia School of Engineering & Applied Science and initially planned to market Echo-V to pet owners as an alternative to neutering. The veterinarians he reached out to were enthusiastic about the idea—just not for their animal patients. “They were saying, ‘Well, this is really cool. It sounds great, but can my husband get it?’ ” he says with a laugh.
Because Echo-V qualifies as a medical device, Contraline may have an advantage over rivals working on a male pill. The FDA typically requires more and larger clinical trials for drugs than it does for devices; it takes 12 years, on average, to bring a new drug to market, compared with three to seven years for a new medical device. The expense therefore tends to be much higher for drugs.
Contraline, which was launched in March 2015, hasn’t had trouble attracting investors, raising $700,000 in a preliminary seed round last year, followed this spring by a second seed round of $2.3 million led by Peter Thiel’s Founders Fund. (“At Contraline, we only do seeds,” Eisenfrats jokes.)
Other organizations are also exploring alternative funding models and research concepts. The Parsemus Foundation solicits tax-deductible donations from the public and accepts payment in bitcoin. Last year the foundation, which has 52,000 people on its mailing list, suggested supporters each donate “an hour’s wages” to raise the $127,000 it needed to manufacture the gel for its first clinical trial. (The campaign closed with $85,000, and a trial is planned for 2018.) The Male Contraception Initiative, a nonprofit, has also run a crowdfunding campaign for researchers.
As for more radical scientific approaches, British researchers are working on a so-called clean-sheets pill that would stop men from ejaculating during orgasm. A German company has devised an implantable valve—advertised to be “small as a gummy bear” and “100% vegan”—that would let men turn the flow of sperm on and off with the flick of an actual switch. And a Chinese team has piloted an approach that involves injecting gold nanoparticles into the testes and heating them with an infrared laser. None are likely to be commercially available soon—indeed, they haven’t yet been tested in humans, though Clemens Bimek, the German who developed the spermatic duct valve, reportedly had several prototypes implanted in his scrotum.
Contraline’s research team is racing to be one of the first to market with a viable solution. The company is tinkering with the gel’s formulation, assessing its efficacy and biocompatibility, designing an injection device, and refining the injection and reversal procedures. Eisenfrats says he plans to begin a preclinical trial in large animals next year, begin human trials in 2019, and earn FDA approval in 2021.
It’s an ambitious timeline. The developers of Risug and Vasalgel have been at it longer than Eisenfrats, and they’ve both faced setbacks and delays—hopes for Risug have been high for the past 15 years. Still, Eisenfrats is confident Contraline can pull it off. “Some people think it’s a little aggressive, but I wouldn’t say anyone has ever called bullshit on it,” he says. “It’s doable. The pathway we’re taking makes sense.”
On the back wall of Contraline’s first-floor laboratory, two posters depict artifacts from the strange and slightly horrifying history of contraception: a condom made from animal intestines, a screw-like device designed to be inserted into the uterus, a box of “anti-baby” tablets, a lemon. “This is what was in the past,” Eisenfrats says, pointing. “And this,” he adds, turning and gesturing at his gleaming new lab, still being stocked with equipment, “is where we’re going.”
One afternoon this spring, Amory and six members of his research team gather for a lab meeting in a small, windowless room down the hall from his office. Goldstein, the chemist, clicks through slides crammed with chemical names and structures. He’s been synthesizing new compounds, looking for one more potent than CM-121, the former lead contender. Of the hundreds he’s made so far, several seem strongly and selectively to inhibit ALDH1A2. “That’s good,” Amory says. “That’s a bunch of good inhibitors.”
He has stopped predicting when his team might be ready to start human trials, let alone have a pill ready for sale. And he’s fine with the possibility that they won’t be the first to break through—that Contraline or someone else might beat them to market. “I don’t feel like we’re in a race or that it’s a competition,” he says. Rather, he hopes that someday a wide variety of options will be available to men, including his two sons.
“My dream is to send them off to college with a five-year, reversible, male contraceptive implant,” Amory jokes. But his boys seem to be growing up faster than the field is moving. “I have an eighth-grader now, so I’m not sure I’m going to make that deadline.”