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Are We Finally Ready for the Male Pill?

April 26, 2018

Daniel Dudley, 28, is a busy man. The doctor-in-training is an active hiker, an amateur chef—he’s currently learning Indian cooking—and a proud “father” to two dwarf rabbits whose antics he chronicles under the Instagram handle, bunnyzaddy. He’s also at least partially responsible for the creation of a new male contraceptive.

Over the last five years, Dudley has volunteered for three separate clinical trials of three different male contraceptive methods. He’s taken a daily pill for a month, rubbed a hormonal gel on his chest, and had an injection of hormones into his left butt cheek. If all the methods were available today, he’d choose the injection for its long-lasting convenience. “I would totally use it,” he says.

Dudley, who is currently in a long-distance relationship, wants to do his part to increase contraception options for men and take the burden of pregnancy prevention off women, “which is an injustice,” the medical student at the University of Washington says. “There’s been much less money and effort put into safely and effectively lowering men’s fertility.”

Women currently bear the greatest responsibility for preventing pregnancy, with nearly a dozen options for birth control, including longer-term solutions like the IUD and the implant and short-term strategies like the diaphragm and the vaginal ring. For several decades, men have had only two: the condom (with a failure rate of close to 20%) and the vasectomy, which is considered largely irreversible and involves minor surgery. There has not been a new commercial contraceptive for men in several decades.

That may change, thanks to new clinical trials and shifting perceptions of gender responsibilities. Today there’s a renewed reckoning over the negotiations surrounding the bedroom, including overdue conversations about consent. Scientists are hoping that the time is right to change the current contraception imbalance, and are launching clinical trials of different methods including pills and gels this year with the hopes that they will attract drug companies with promising results. Industry analysts believe there’s money to made. If a new male contraceptive method is approved in the next five years, the market is projected to be around $1 billion by 2024, and could grow at rate of 6% over the next ten years, according to Global Market Insights. Finally, there’s a pressing need: In the United States alone, 45% of pregnancies are unplanned, and yet public health strategy to prevent them largely ignores 50% of the population.

 

The arrival of the female birth control pill, in 1960, started a sexual revolution, helping women level the playing field. Its debut in the U.S. market changed society in unanticipated ways too. College enrollment was 20% higher among American women who could access the pill legally by age 18 in 1970 compared with women who could not, and one-third of the wage gains women have made since the 1960s are considered a result of oral contraceptives access, according to a Planned Parenthood report.

But female methods have not solved the world’s unplanned pregnancy problem: in the U.S. studies suggest it’s common for women to cycle through multiple types of birth control before settling on one that works. While women often struggle with birth control satisfaction, the burden of pregnancy prevention almost always falls on them, with 62% of all women of reproductive age currently using a contraceptive method. Even when it comes to permanent measures, female sterilization remains a much more common procedure than vasectomy in the U.S.

Not only do women endure all the physical risks when a birth control method fails, they assume the social ones too: A 2018 Denmark study found that a woman’s income sharply declines after having her first child—a drop not experienced by men—that ultimately causes women to earn 20% less than men throughout the rest of their career.

Adrienne Ton, 25, who is studying to become a family nurse practitioner at Columbia University, and is currently dating Dudley, says women may initially find it difficult to relinquish some control over pregnancy prevention, but that it can create more balance in a relationship. “Women are so used to carrying that burden, and are socialized to think it’s our responsibility” she says. “But I think women would be willing to have more protection.” Ton says at first she was nervous about Dudley’s trials, but that she thinks it’s “amazing” he’s willing to volunteer.

Isabella Connelley and Bethan Mooney for TIME

Past surveys suggest that at least 50% of men would use new male contraceptives, with men in stable relationships being the most open to taking a daily pill. While some scientists are exploring hormonal options for men that suppress testosterone and sperm production, other researchers are exploring non-hormonal options. In India, an injection procedure that stops sperm from escaping the testes is awaiting government approval, and in the U.S. a start-up and a non-profit organization are working on similar approaches.

Recently, the pill method Dudley tested showed promise: Researchers gave Dudley and 82 other men a drug called dimethandrolone undecanoate, or DMAU, which lowers certain hormones like testosterone that are required for sperm production. The small study found that the once-daily pill appeared safe, and among men who took the highest dose, it was able to suppress hormones needed for sperm development to extremely low levels with no serious side effects.

The scientists behind the DMAU pill trial—from the University of Washington, Los Angeles Biomedical Research Institute and elsewhere—have worked in the field for years and say there’s welcome and unprecedented energy around their research today. “We have a lot of positive momentum right now,” says study author Dr. Stephanie Page, the division head for metabolism and endocrinology at the University of Washington School of Medicine. “I think the field may be in a different place because the public is expressing quite a bit of interest. There are changes happening socially. It seems different from 15 years ago.”

Like Dudley, Kristoffer Thordarson—a California native and self-described “beach bum”—is currently studying microbiology at the University of Washington, and has volunteered in multiple clinical trials for male birth control methods. At the end of January, Thordarson, 22, got a DMAU-containing injection into his right abdomen to lower his sperm count to nearly negligibleunless he got the placebo, that is. He was told not to use the method as contraception just in case. “It felt like I was being stung by a bee,” he says.

Thordarson and Dudley agree that the pain from the needle is a worthy burden to bear if it means they’re doing their part to progress the science behind male contraceptives, and in their opinion, right a wrong. “I think having both men and women be responsible for preventing unwanted pregnancies will alleviate a lot of the misogyny and crap that women face,” says Thordarson.

In the pill study Dudley participated in, men experienced drops in testosterone to levels that classified their bodies as medically castrated. The men didn’t experience serious side effects, however, because DMAU mimics testosterone throughout the body. Eight of the men taking the drug reported decreased libido and five men taking the drug reported acne. The researchers plan to test the effects of the pill on another 100 men before moving on to a longer trial with couples.

In the meantime, the National Institutes of Health (NIH) and the Population Council, with the help of several universities around the world, are planning to kick off one of the largest male contraceptive trials to date in June for a gel contraceptive. Research behind the gel method is moving faster than the pill, largely because when taken orally, lab-made testosterone (which is used in male contraceptives) clears the body quickly, and researchers say gels get absorbed into the skin and stay in the bloodstream longer than pill versions so far.

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The gel trial will enroll over 400 couples in six countries, and require men to rub the gel onto their upper arms and shoulders once a day. The gel contains a synthetic progestin called nestorone—which blocks the testes from making enough testosterone to produce sperm—and a synthetic testosterone, which will counteract subsequent hormonal imbalances. Once the men’s sperm count has reached a low enough level, the men and women will agree to rely solely on the gel as their birth control. The study sites—including Page’s lab—are starting recruitment, and the plan is for the trial to launch this summer.

 

The much-maligned condom, in some form, has been around since Imperial Rome, though the first recorded descriptions appeared in the 16th century. The condom evolved from animal intestine to latex, and gained mass appeal during times of war. The German military began supplying members with condoms during World War I to prevent sexually transmitted diseases, and by 1918 condoms were legalized in the U.S. for disease prevention.

Men’s other birth control option, the vasectomy, was first described in the 19th century as a procedure for dogs, before becoming a method to treat enlarged prostates or as an alternative to castration. During the first half of the 20th century, vasectomies were used as part of state-backed eugenics programs whereby criminals in prisons were forced to have vasectomies. By the second half of the century, men started to get the procedure electively, and today it is estimated that between 175,000 to 550,000 vasectomies are performed every year in the U.S.

The modern search for a third male contraceptive kicked off clinical trials in the early 1970s when both the U.S. and Chinese government launched studies on potential sperm-suppressing compounds that could be taken by pill. Chinese researchers ran trials of gossypol, a chemical that’s derived from seeds of cotton plants, in over 8,000 men. Daily gossypol pills lowered men’s sperm count, but some of the men did not return to their usual fertility levels after ending the pills, and several experienced severe drops in their potassium. Ultimately the work was discontinued over concerns about the side effects.

Also in the early 1970s, researchers backed by the NIH started experimenting with injectable male hormonal birth control options. Early studies showed that with the right combination of testosterone and the synthetic hormone progestin, a man’s sperm count could be substantially lowered.

Pharmaceutical companies Organon and Schering teamed up on a clinical trial in the early 2000s: Around 300 men were given progestogen implants and injections of testosterone, and though the men experienced side effects like acne, weight gain and mood issues, they also experienced dramatic drops in sperm counts.

But after the pharmaceutical giant Bayer bought Schering in 2006 (Bayer is one of the top sellers of female birth control, with brands like Mirena and Yaz), both companies closed their research programs. “Once the acquisition was finalized, [Bayer] conducted a thorough review of the product portfolio to ensure that the business was investing resources in therapeutic areas that would bring the greatest benefits to patients while ensuring the company was operating in a financially responsible manner,” says Courtney Mallon, deputy director of U.S. Pharmaceuticals Product Communications for Bayer, in an email to TIME. “Ultimately, the decision was made to halt male contraceptive research and we currently do not have plans to pursue in the future.”

Another former company called Sterling Drug tested a fertility-suppressing compound called WIN 18,446. As Bloomberg Businessweek reported, the researchers discovered their method didn’t mix well with alcohol. An inmate at Oregon State Penitentiary who was partaking in the trial drank contraband scotch and became “violently ill.” A few scientists are keeping that research going on a small scale, but they lack funding from pharmaceutical companies or government grants.

 

For regulators, the future of male contraceptives may come down to one question: How much physical risk should a man carry? From a regulation perspective, scientists say it’s harder to justify—even if it’s a harsh or a dated view—that a healthy person should take a medication, and deal with its side effects, to prevent an outcome from happening to someone else.

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The results from a trial published in 2016 illustrate the problem. The study, which began ten years ago, was one of the largest male contraceptive trials and launched in 10 study sites around the globe with support from groups like the World Health Organization (WHO) and United Nations Development Programme. On paper, the trial results showed the contraceptive—which used a combination of a long-acting testosterone and a derivative of the female hormonal progesterone—was an early success. The 320 men, with the consent of their female partners, agreed to undergo injections every two months of the hormones which were designed to substantially lower their sperm count, and then use that method as their primary form of birth control. The findings were stunning: hormonal injections given to the men were 96% effective at suppressing their sperm and preventing pregnancy, and the vast majority of men said they would use it if it came to market (likely in pill form).

And yet despite the method’s popularity, and how well it worked, an independent panel appointed by the WHO argued that the side effects experienced by some of the men—including mood swings and depression—were unsafe. “I did not agree,” says study co-author Gabriela Noé, a male contraceptive researcher at the Instituto Chileno de Medicina Reproductiva in Santiago, Chile. “It’s true there were side effects, but they were mild and well-tolerated.”

Researchers say the closure of the study may say less about men’s willingness to “put up” with the same side effects women do, and more about whether regulators think they should. In fact, over 80% of the men in the shuttered trial said they would use the method if it were available. “There’s this idea that men won’t tolerate any side effects,” says Page. “But we certainly don’t know that.”

The decision to end the trial—which was published in 2016 in the Journal of Clinical Endocrinology & Metabolism—sparked criticism among the reproductive health community, with some arguing that women regularly deal with significant side effects from their hormonal birth control, including mood swings, depression, acne, strokes, low libido, blood clots and more.

“The side effects were no different from female hormonal contraception,” says study co-author David J. Handelsman, a professor of reproductive endocrinology and andrology at the University of Sydney, adding that he was “definitely not” in agreement that the trial should end. Interviews with nine of the report’s authors revealed that many of the study authors did not agree with the panel’s decision or were disappointed by it.

There are other reasons why pharmaceutical companies have not been quick to invest in bringing male contraceptives to market. Creating a male method is an onerous process. Female birth control largely works by preventing the ovulation of one egg, once a month. But men produce millions of sperm every day, and bringing that number down to zero involves the careful experimentation of various hormones, dosing and intervals, and it takes awhile to get it right.

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“Hopefully we will have results that are exciting and effective enough that a company will come and partner,” says Diana Blithe, the chief of the Contraceptive Development Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, who is supporting the upcoming gel trial. “I think [companies] are looking for assurance that it’s going to work and men are going to use it.”

Devin Patterson, 33, a data architect in Grand Rapids, Michigan describes himself as “someone with a strong leaning towards the child-free lifestyle,” and says he would consider using a male contraceptive beyond condoms—hormonal or non-hormonal—if it was available, side effects included. “It comes down to choice,” he says. “I’d like to have a choice, and options. I don’t know why it has to be [women’s] problem and I would like control of my own destiny.”

 

Researchers and investors are betting that non-hormonal contraceptives could become popular among men, allowing men to go a decade between procedures. In India, researchers have tested a sperm-blocking product called RISUG (Reversible Inhibition of Sperm Under Guidance) in human clinical trials with success. The procedure is at least 98% effective at suppressing sperm, and so far has been tested in around 500 men where it has prevented pregnancies in their partners for up to 10 years.

It’s inspired similar versions in the U.S. The nonprofit Parsemus Foundation acquired the rights to produce RISUG in 2010 and have since created Vasalgel, which may begin a clinical trial in humans in 2019. Vasalgel consists of a polymer gel injected into the vas deferens — the tube through which sperm swims — that blocks sperm from escaping. It’s long-acting but reversible, and could safely be used for several years, the group says. In a study published in February 2017, researchers tested Vasalgel in 16 adult male monkeys, and found that it was effective at preventing pregnancy during the monkeys’ mating seasons.

“I care about my wife, and if we were on birth control that’s the method we would choose,” says Kaplan Akincilar, 37, an audio and video engineer in New York and father of one who has been following Vasalgel research. “I can’t believe it’s taken this long for an alternative to condoms to even be an option.”

Contraline, a startup in Charlottesville, Virginia, is developing a method that’s somewhat similar to RISUG and Vasalgel. Contraline uses a non-surgical procedure to inject a solution that hardens into a hydrogel in the van deferens in seconds, blocking sperm. The company has yet to launch human clinical trials, but has been popular among investors, raising $2.25 million in a funding round led by Peter Thiel’s Founders Fund in 2017.

Though Contraline CEO Kevin Eisenfrats would not release the number of men who have contacted the company, he says over 70% of people who have reached out have expressed interest in participating in the company’s future clinical trials. “We thought it would be women signing their boyfriends or husbands up, but it’s been primarily men signing themselves up,” says Eisenfrats, adding that the company largely hears from men ages in their 20s and 30s. “I think there’s a huge interest from millennials.”

For men like Akincilar, a non-hormonal option that’s reversible is appealing, though he says he’s unsure other men will be onboard. “I’ve asked people I work with if they would do it and they’re like, ‘absolutely not, I would not take a shot to the balls,’” he says.

Researchers remain optimistic the field is on track to bring a male birth control method to market within ten years, but argue they need more support to make it a reality, ideally from pharmaceutical companies. Large, costly studies in thousands of couples are likely needed. Unknown regulatory hurdles also remain. If a male pill makes it to federal consideration, will regulators agree that the payoff—even if there are side effects—is worth it?

“I think as research continues, more men will be open to it—particularly men broadly interested in social justice, or personally interested in helping a female partner,” says Dudley.

“Our society is moving towards more gender equality in many areas,” he adds. “This is an obvious next step.”