Birth control for men

Alex Springer, 28, works at a biotech company in the Seattle area. Each morning he wakes up, takes a shower, and puts on deodorant. Then he pumps a squirt of gel into his hands and rubs it on both shoulders. It dries in about 30 s, after which he gets dressed and starts his day.

And just like that, Springer and his partner are protected from pregnancy.

“It just kind of becomes part of the routine,” he says.

Springer and his partner, Mel Hopkins, intend to have children one day, but not now. Hopkins has type 1 diabetes, and hormonal birth control methods interfere with her ability to manage her blood sugar levels. They wanted a contraceptive option for Springer—and for now, they have one.

Springer and Hopkins are one of thousands of couples around the globe participating in a Phase 2 trial for the NES/T gel, a topical contraceptive that combines Nestorone—a synthetic progestin—and testosterone. Together, these hormones suppress sperm production. Efficacy has been much higher than expected, says Stephanie Page, lead investigator at the Seattle site of the NES/T study and a professor at the University of Washington’s school of medicine. She says that the gel may have a lower failure rate than that of birth control pills with typical use. But hormonal birth control that targets sperm has gotten to Phase 2 trials before. Despite decades of research, no method has made it to market.

Past impediments included concerns about side effects and efficacy. But the NES/T trial differs from past ones in significant ways. NES/T is not an injection, and it’s self-administered. The trial also has checks in place for mental health. Side effects so far have been minimal.

Whether the NES/T gel makes it to market or not, people want sperm-​blocking birth control options other than condoms and vasectomies. And the recent US Supreme Court decision that the US Constitution does not confer the right to abortion has renewed those calls.

“In light of the changing legislative landscape and access to abortion and other female contraceptive methods . . . I think the onus is really on men to start to take a little bit more responsibility for family planning and contraceptive use,” Springer says.

Although Springer is testing a hormone-based drug, many would like options that don’t rely on hormones. By affecting a specific target in the sperm cycle, nonhormonal methods could sidestep the side effects that often come with hormonal drugs. They could also be more effective. In most studies, hormones don’t adequately suppress sperm to contraceptive levels for 10–15% of users, which may be due to genetic or environmental differences or to adherence with some methods, according to Page. Depending on the mechanism, nonhormonal drugs could take effect and wear off faster.

None of the current nonhormonal birth control candidates that block sperm have been tested in humans. But they are inching closer to clinical trials; some could start as early as next year. They are moving forward alongside a number of hormonal candidates. NES/T is the furthest along and could enter Phase 3 trials in 1–2 years, according to Page. Many people are wondering: Will this batch of options break through the barriers that have stymied sperm-targeting contraception so far?

Desire for options

When “the pill,” a hormonal birth control regimen for women, was approved in the US in 1960, the subject of contraception was taboo. Birth control was illegal in at least one state.

Shortly after the pill’s introduction, federal law was amended to significantly increase US Food and Drug Administration oversight of drug approvals. Some research on sperm-targeting birth control had been done in years prior, and it picked up again on not long after the pill was approved. Attempts always stalled, but over time, demand seems to have strengthened.

“We know that men who get vasectomies sometimes have regret about their vasectomy. We know that as much as men may not like condoms, female partners also don’t like condoms,” says Brian T. Nguyen, an assistant professor of clinical obstetrics and gynecology at the University of Southern California. Nguyen also founded the Expanding Male Engagement in Reproductive and Gender Equity (EMERGE) Lab. “So, it’s kind of this two-way street that both men and women are looking forward to male contraception.”

A 2000 study conducted across four cities in three countries showed that 44–83% of men would definitely or probably use a hormonal birth control pill (Hum. Reprod., DOI: 10.1093/humrep/15.3.637). The same year, in an international survey of nearly 2,000 women, only 2% answered that they wouldn’t trust a male partner to use hormonal contraception (Hum. Reprod., DOI: 10.1093/humrep/15.3.646). And an ongoing study involving a survey of over 13,000 men from six countries has so far found that 39% of men in the US and up to 76% of men in both Nigeria and Bangladesh would be willing to use novel male contraceptive technology within a year, according to Steve Kretschmer, one of the founders of consultancy group Outsight 4 Development, which is conducting the study. The study is funded by the Bill and Melinda Gates Foundation and Male Contraceptive Initiative, an advocacy organization and funder of nonhormonal reversible contraceptives that can be marketed to men.

Birth control beyond hormones

Hormonal birth control like the NES/T gel works by stopping the creation of sperm. The testosterone in the drug, alone or in combination with other hormones like progestin, suppresses other hormones that drive sperm production.

But hormones act throughout the body. For some people, that can make hormonal methods difficult or even impossible to tolerate.

“When you give somebody an exogenous hormone, you’re changing the expression or influencing the expression of hundreds and potentially thousands of genes,” says Daniel S. Johnston, chief of the Contraception Research Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), part of the US National Institutes of Health. “If there’s 20,000 genes, and I’m ballparking, you’re potentially changing the expression of 5% of them.”

One roadblock to developing sperm-​blocking hormonal birth control has been its side effects. In 2016, a large Phase 2 trial of a hormonal injection with big funders—including the United Nations and the World Health Organization—was stopped early (J. Clin. Endocrinol. Metab. 2016, DOI: 10.1210/jc.2016-2141). The study authors note in their publication that “the frequencies of mild to moderate mood disorders were relatively high.”

Some women taking the pill or using other hormonal contraceptives have had the same side effects that some men have had in studies. But regulatory standards have changed since 1960, when the pill was approved. And given the health risks that come with pregnancy, regulatory bodies may consider more potential side effects to be acceptable for someone who can become pregnant than for someone who cannot.“It’s absolutely true that the side effects are similar. And similarly, not everybody has side effects with hormonal methods for both women and men—many people take them without issue at all,” Page says. “And so I think there’s a double standard in terms of what regulatory bodies are looking for.”

Another issue with hormonal methods is that they don’t adequately suppress sperm for some people. And there’s a lot of sperm to suppress: 1,000 sperm are produced per heartbeat, says Gunda Georg, a medicinal chemist at the University of Minnesota Twin Cities. Compared with one egg released a month, that’s a daunting problem.

And while data indicate that men are largely willing and interested in taking birth control, hormonal methods make some men wary.

“What I have learned over a few . . . conversations with men, they are really very, very, very sensitive when it comes to ‘Ooh, does that affect my testosterone levels?’ ” says Nadja Mannowetz, cofounder and chief scientific officer of YourChoice Therapeutics, which is developing a contraceptive that targets sperm. “This is really the first question—not necessarily ‘Is this effective’ or something like that. It’s really more like, ‘Oh, will I still be a man?’ ”

Researchers see an opportunity to create birth control that uses nonhormonal methods to target molecules involved in the production or function of sperm. Some candidates target proteins that play key roles in generating sperm. Others target proteins that are important later in the sperm’s journey, like those that enable sperm to swim properly. YourChoice’s lead candidate targets a protein called retinoic acid receptor (RAR-α), which is involved in sperm production.

RAR-α is part of the vitamin A pathway. Certain cells in the body convert vitamin A (also known as retinol) from food into retinoic acid, which is involved in cell growth, differentiation, and more.

Normally, retinoic acid binds to RAR-α, which results in the expression of some genes related to sperm production. YourChoice’s drug, YCT-529, binds to RAR-α so that retinoic acid can’t. As a consequence, some genes needed for sperm production don’t get expressed.

Jean-Ju Chung, a cell biologist at the Yale School of Medicine who works on sperm ion channels, is taking another approach by zeroing in on a target that affects how sperm swim. For sperm to complete the long journey to an egg, they have to move their flagella—their tails—vigorously and in an asymmetric pattern. Sperm gain this quality, called hyperactivated motility, after ejaculation as they progress toward the egg.

“If sperm are able to swim only straight, they’re going to stop,” Chung says.

Chung is targeting a protein called CatSper, a calcium ion channel in the sperm flagellum that is key to hyperactivated motility. In animal models such as mice, editing out the gene that encodes CatSper prevents sperm from attaining hyperactivated motility, so they swim only symmetrically, Chung says. Even if sperm could somehow get to an egg with their faulty swimming, CatSper is also important for other processes key to conception, like the reaction that allows sperm to penetrate the egg coating. Without CatSper, that step is blocked.

Eppin Pharma also has a drug in the works that interferes with sperm function. The small molecule, EP055, binds to EPPIN (epididymal protease inhibitor), a protein on the sperm surface. In binding, it prevents steps that make the sperm functional, like a rise in pH, an influx of calcium ions in the sperm cell, and hyperactivation of sperm motility.

Targeting sperm motility has a potential advantage: such drugs would take effect more quickly than drugs that cut off sperm production from the start, which take months to achieve a contraceptive effect.

Jochen Buck and Lonny Levin at Weill Cornell Medicine are working on a contraceptive that can be taken on demand and halt fertility almost immediately. Their compound would target an enzyme called soluble adenylyl cyclase (sAC), which catalyzes the creation of cyclic adenosine monophosphate (cAMP), a messenger molecule needed for sperm motility. Their drug candidate would inhibit sAC, preventing cAMP from being produced, and stopping sperm from swimming altogether.

They envision that people will take the compound as needed, like the erectile dysfunction drug Viagra. It might be taken around 30 min before sex, and it could last a few hours, a day, or even a weekend. But users wouldn’t need to take it every day.

“When you take a pill every day for the rest of your life, you have such a concern for chronic things going wrong,” Levin says. But even if someone takes it multiple times a week, their drug candidate won’t stay in the body very long, he says.

This category of drug wouldn’t interfere with sperm production, so sperm counts would be normal; just the function would be impaired.

“Of course, if you can control both number and the motility, probably that’s going to be more comprehensive,” Chung says. But she adds that if she had to choose one, she’d choose hampering sperm function because low numbers of healthy sperm can still lead to pregnancy, and a drug targeting sperm creation will require a longer wait to be effective.

An obstacle-laden path

There are, it seems from preclinical data, effective drug candidates that target parts of the sperm cycle. But so far, each comes with some concerns.

“If the bugaboo of hormonal contraceptive is that it doesn’t work in everybody, the bugaboo of nonhormonal contraceptives is toxicity,” says John Amory, an internist and contraceptive researcher at the University of Washington. He’s also working on a nonhormonal drug involved in the vitamin A pathway. “A lot of things that will kill sperm will harm other things as well,” he says.

Multiple contraceptive targets that researchers are studying, like sAC and RAR-α, are found in several places throughout the body. If a drug targets a protein in the testes that also exists in, say, the brain, harmful side effects are possible.

CatSper, the intended target of Chung’s lab, seems to be completely sperm specific. What’s holding it back is that it so far can’t be expressed on its own in a model system—like a cultured human cell line—that would allow drugs designed to block it to be tested ahead of human studies.

The NICHD’s Johnston has some reservations about targeting RAR-α. RAR-α is expressed in parts of the body other than the testes, and it’s possible that a drug targeting that protein would affect it in multiple places. Some published papers have suggested that targeting RAR-α could cause undesired changes in the immune system and possibly other parts of the body, like the heart and eyes, Johnston says.

Georg, who developed YCT-529, notes that in animal studies, levels of the compound outside the testes are low, suggesting it does stay on target.

Johnston says he hopes YourChoice’s drug candidate works—he hopes all the testicular contraceptive candidates work. “But there are papers that . . . give me a couple concerns about RAR-α,” Johnston says. “There are very few products that I have no concerns about.” There will be no perfect candidate, he says.

While some side effects can be measured in animals, one that’s hard to predict until a drug is tested in humans is changes in mental health. Mood changes are a notable side effect for hormonal contraceptives currently marketed to women. Researchers hope that drugs that target specific sperm proteins would avoid mood effects since they are not as broad acting as hormones.

Barriers to approval

The landscape is rife with questions that won’t be answered until clinical trials. But even with answers, contraceptives that can be marketed to men face a tougher path to approval than many other types of drugs.

“It’s not a disease to be fertile,” Georg says.

There is a risk-benefit analysis for every drug. For conditions like cancer, Alzheimer’s disease, or diabetes—in which the health impacts on the person who would receive treatment are clear—a drug has to only make a dent in the symptoms to potentially be worth the risk of side effects. For birth control, it’s a different calculation.

“If it’s a chemotherapy drug, 80%’s great, right?” says Logan Nickels, research director at Male Contraceptive Initiative. “If it’s a contraceptive, 80% is lower than the condom. It’s out the door.”

This calculation is also different for people who can become pregnant. Fertility may not be a disease, but pregnancy is still potentially life threatening. In 2017, nearly 300,000 people died from causes related to pregnancy and childbirth, according to the World Health Organization.

“The birth control pill that women take actually kills a small number of women,” Amory says. “And that’s always been justified because the risk of unintended pregnancy is actually higher than the risk of the contraceptive.”

Convincing pharmaceutical companies that there is, in addition to the risk, significant benefit to advancing sperm-​targeting drug candidates is an obstacle. But one point is that unintended pregnancies can have negative outcomes for both partners.

Young men whose partners end an unintended pregnancy with abortion are more likely to complete their education than those whose partners continue to carry the pregnancy, Nguyen says. “Part of the issue is policy makers and pharmaceutical companies not recognizing that men do feel that there is an impact on them when their partner gets pregnant, particularly when their partner gets pregnant when they don’t want to.”

One school of thought, supported by many in the field, is that regulatory bodies should consider the couple’s health in addition to the individual’s. The risk-benefit analysis should take into account both parties involved in the pregnancy. In addition, Page of the NES/T trial argues that there is precedent for an individual risking their health to improve someone else’s.

“There is the concept of living organ donation, wherein the person giving an organ certainly undertakes a health risk for the benefit of somebody else,” she says. “There are situations that we do find that acceptable.”

On top of the potential risk to drug takers, drug companies also face risks. Contraceptives are common targets of litigation. A well-known example is Yaz and Yasmin, two ovulation-blocking contraceptive pills for which Bayer has settled over 18,000 lawsuits for alleged serious side effects like blood clots and heart attacks. Implants including NuvaRing, the Mirena intrauterine device, and Essure have also been the subjects of lawsuits.

“Pharmaceutical companies are increasingly risk averse,” Male Contraceptive Initiative’s Nickels says, noting that they rely on start-ups to take on the early risk and then buy the drug candidates after they’ve shown promise. “And I think that that’s all bad for male contraception, a field that historically has had a really hard time getting into people, much less proving that it’s going to be successful,” Nickels says.

But, he adds, there’s also money to be made.

“We’re talking about 4 billion men. Men are not a monolith. And if you can capture 1%, 10%, 8% of that market, that’s a lot of people,” Nickels says. “And so I think people understand that there’s a business case to be made as well. And that window for how much that opportunity is worth, in terms of risk, is getting closer and closer. And we’re getting to an inflection point.”

A rising tide?

In a 2012 C&EN article, Amory said that 10 years’ time sounded about right for a male contraceptive to be approved (C&EN, Sept. 24, 2012, page 35). He also recounted a common joke in the field—that people have been saying such a drug was 5–10 years away for decades. He repeated the joke this year.

Nickels is cautiously optimistic that the joke may be reaching the end of its lifetime. He doesn’t think a drug is 10 years away anymore. “I’ve talked to a number of people who have been here for 10 or 15 or 20 years. And they say that this is it—this is the time.”

As for which type will make it to market first, hormonal approaches have a healthy lead. And they have an advantage in terms of familiarity.

“We’re very, very comfortable with hormones,” Amory says. “They’re a devil we know.”

In the best-case scenario, the NES/T gel could be approved in 5 years, Page says, but 7 or 8 years is more likely. Nonhormonals are pretty far behind, but they are gaining ground. YourChoice is poised to start human trials of its lead candidate in 2023, which would be the first time nonhormonal contraceptives would be given to men in the US. Buck and Levin think they could be approved to start clinical trials on a sAC-targeting drug in 2–3 years. Eppin Pharma CEO Michael O’Rand says a clinical trial for his firm’s candidate could start next year or the year after, depending on funding.

Experts agree that it’s not a race to see which one will make it to the finish line; they want to see a broad push to get as many options approved as possible. And what people want is a choice.

One thing seems clear—an approval for one drug can only help the rest.

“A rising tide lifts all boats,” Levin says. “So if the NES/T trials work, and that’s out there, that would be great because that would absolutely reveal to the world that there’s a market.”

Already, evidence of a market is emerging. YourChoice’s Mannowetz recounts the company’s inbox being flooded with requests after Georg presented the company’s technology at the American Chemical Society Spring 2022 meeting.

“We have received so many emails from men who ask, ‘Where can I buy your product?’ Well, sorry, it’s still in development. ‘Can I buy stock in your company?’ Sorry, we are still a private company,” Mannowetz says. “And the third question, ‘When, where, and how can I participate in your clinical trial?’ ”

Page has also seen enthusiasm when enrolling participants in the NES/T clinical trial. “This idea that men won’t take any risk of side effects for contraception—that’s just not true,” she says. She emphasizes many users won’t have side effects. And participating men are interested in relieving their partner of the burden of birth control, she notes.

One of those people is Springer. He and his partner are approaching the end of their participation in the NES/T trial. They’re sad to see it go, he says.

“It’s become a part of our life. And now we have to figure out what other option is out there that will work for us,” he says. But he doesn’t think their situation is unique. Birth control options are unfeasible for lots of women, he says, and even for couples in which women have no limitations on what birth control they can take, reproductive responsibility should be shared.