Better male birth control is on the horizon

In 1960, a new drug revolutionized society from the bedroom to the streets. The introduction of a hormonal contraceptive, the birth control pill, gave women reproductive autonomy and a more effective way to plan a family. Since then, many more options have arrived: different pill formulations; hormonal implants, patches and vaginal rings; IUDs and barrier methods.

But over the last 60 years, exactly zero new options have been developed for men. They are stuck with only two choices, condoms or vasectomies. Both have their issues: Condoms, their relatively high failure rate (as high as 12 percent); vasectomies, their permanency. Neither offer men the same level of fertility control as options for women, says Alexandra Joice Berger, a urologist at Brigham and Women’s Hospital in Boston.

New forms of male birth control are badly needed. “Male contraception is a particularly big concern in many states in the U.S. where access to women’s services is not guaranteed anymore,” says Jesse Mills, director of UCLA’s Men’s Clinic. The Supreme Court’s Dobbs ruling that overturned Roe v. Wade in 2022 has curtailed access to abortion in some states and raised concerns about access to birth control. That seems to have changed public opinion about male contraception.

Although fear of permanent infertility has made some men wary of trying a male birth control, surveys show a sizable portion of men want new contraceptives, and women trust their partners to use them responsibly. In a recently published survey of more than 15,000 men in seven countries, 49 percent of U.S. men said they would use a new male contraceptive within the first year of availability (compared with 39 percent before Roe v. Wade was overturned). In some countries, such as Nigeria and Bangladesh, that willingness reached 76 percent. Meanwhile, about 50 to 85 percent of surveyed women trust their male partners to take contraceptives responsibly, depending on the country.

New options could arrive in the not-too-distant future. We’re within touching distance of the first fertility-controlling, nonpermanent male contraceptive, which could enter pharmacies within five to 10 years. There could even be two. Research looks promising for a daily hormonal gel called NES/T that suppresses sperm production and for an injectable gel called ADAM that blocks the plumbing of sperm transmission. Other options, including drugs that work for just a few hours at a time, are also in development.

Given the diversity of people and lifestyles, multiple methods of male contraception are needed “to fulfill the needs of all potential users,” says Brian Nguyen, a gynecologist at the University of Southern California’s Keck School of Medicine.

Here’s the major snag: regulatory approval. No male contraceptive has ever gained approval from the U.S. Food and Drug Administration. While the risk of side effects from contraceptives in testing so far appears to be low, all of these scientific advances will be for naught if researchers can’t convince the FDA to use different safety standards for contraception for men (who don’t face health risks from pregnancy) than they do for women.

Stopping sperm production

In 2022, Oscar Ahlqvist, a 34-year-old health care worker in Sweden, enrolled in a clinical trial testing the efficacy and safety of the NES/T hormonal contraceptive. “My girlfriend Kerstin doesn’t handle birth control well and has bad side effects,” Ahlqvist says. “I wanted to share the burden of birth control.”

Ahlqvist is one of about 400 men who participated in the NES/T trial, conducted in 16 sites globally, including the United States. Every day for more than a year, Ahlqvist and other participants rubbed a medicated gel containing Nestorone and testosterone into each shoulder. Nestorone, a synthetic version of the hormone progesterone, sets off a chain reaction that blocks the production of androgen sex hormones in the testes that are needed to produce sperm. Because Nestorone inhibits testosterone production, the gel adds back in just enough testosterone to maintain a man’s libido and sexual function.

NES/T is long-acting. It takes four to 12 weeks of daily applications to lower sperm production to less than 1 million sperm per milliliter, the threshold to prevent pregnancy. After stopping NES/T, normal sperm production resumes within six months.

Overall, the findings have been “really terrific,” even exceeding expectations, says Diana Blithe, chief of the Contraceptive Development Program at the National Institutes of Health in Bethesda, Md., who led the Phase IIb trial that Ahlqvist participated in. Blithe couldn’t share specific data, but published results are expected early this year.

“Effectiveness is good. Reversibility is really good — we can be very reassuring about returning fertility [after stopping treatment]. We don’t see any problems,” Blithe says. Side effects also appear to be minimal. Some men had acne and mild mood alterations, but few participants dropped out of the trial because of severe side effects.

Ahlqvist says he would “definitely recommend NES/T to everyone who has the opportunity to try it.” The only side effects he felt were feeling “pretty down” during the first month he started using the gel and the first month after stopping it.

John Amory, a reproductive health researcher at the University of Washington in Seattle who has seen the trial’s results, says he’s “hesitantly optimistic.” His hesitancy comes from concerns that side effects could still derail NES/T during further testing. In 2016, a clinical trial of a promising two-hormone male birth control was stopped early after too many participants reported adverse side effects like mood disorders.

“Concerns around side effects are partly what’s causing holdups in male contraceptive development,” he says.

Amory also questions how reliable NES/T will be in the real world. “Adherence is critical — if men don’t use it every day, it won’t work.” And the fact that it takes one to two months of daily use before NES/T kicks in might deter some people from trying it, he says. In contrast, women are protected from pregnancy within two to seven days of starting the pill.

The success of NES/T will live or die in the next stage of testing, if it gets that far. In a Phase III trial, efficacy and safety would be tested in a wider array of men and in more real-world settings in which participants are less supervised by medical experts. It would be the final test before regulatory approval.

If such testing gets funding and the go-ahead, it could start this year, Blithe says. Even if all goes well, she estimates it will be another eight to 10 years before NES/T is available. Two decades after the first NES/T study, “we’ve just finished the Phase IIb trial. It takes a long time to do this,” she says, almost apologetically.

Other candidates that block sperm production are further behind in development. And some scientists are reviving older, abandoned candidates. In a trial more than 60 years ago, a compound that inhibits retinoic acid, which plays crucial roles in the production of mature sperm, proved to be safe and effective, but the work was never followed up.

“They found you can’t drink [alcohol] when you take it,” Amory says. “The joke is if you can’t drink, then you wouldn’t need it.” He’s developing new agents to block the creation of retinoic acid without causing sensitivity to alcohol, though he hasn’t found a compound suitable for testing in humans yet.

Blocking sperm transmission

For men who don’t want to take a drug that interferes with their hormones or sperm production, another option is a physical barrier that blocks sperm transmission. In the works are occlusion gels. A doctor injects a hydrogel into the vas deferens, the 30-centimeter-long tube that transports sperm from the testicles to ejaculatory ducts. In the body, the hydrogel morphs into a thick, semisolid substance that acts like a dam to keep sperm out of semen during ejaculation. It’s similar to a vasectomy, but doesn’t require cutting the vas deferens.

The benefit of occlusion gels, Mills says, is the very low potential of adverse side effects compared with a hormonal contraceptive. The hydrogel is inert, acts only locally in the vas deferens and — at least theoretically — can be easily reversed with a second injection to break down the gel. The main risk comes with the injection, which needs a highly skilled provider to avoid unintended damage or entering the wrong spot.

Two companies have occlusion gels in the pipeline. Virginia-based Contraline is testing its product, ADAM, in an ongoing Phase I clinical trial in Australia. The main aim is testing safety. Preliminary data from 12 months in show that none of the 25 participants had adverse side effects and there were no unintended pregnancies.

“It’s a very small trial, but it seems 100 percent reversible and safe,” says Berger, who was not involved with the study.

Meanwhile, NEXT Life Sciences, based in California, is predicting regulatory approval of its product, Plan A, by 2026. That’s “kind of crazy,” Berger says, since Plan A has so far been studied only in lab animals. But medical devices like Plan A and ADAM go through a much faster regulatory approval process than medications like NES/T.

On-demand contraceptives

The long-term dream is to develop on-demand, temporary fertility blockers. A man could pop a pill, wait half an hour and then be good to go without the risk of getting his partner pregnant. Such a drug would temporarily stop sperm’s ability to swim so fertilization isn’t possible. The sperm then return to normal once the drug wears off a few hours later, says Jochen Buck, a pharmacologist at Weill Cornell Graduate School of Medical Sciences in New York City.

On-demand contraceptives that act on sperm are not a new idea — they date back to the 1960s — but the trick has been finding drugs that are both effective and reversible. Recent advances in understanding the molecular machinery of male reproduction have led to several potential targets.

One is a protein called serine/threonine kinase 33, or STK33. Men with mutations in the gene that codes for STK33 are sterile due to defective sperm. A study published in Science in 2024 found that a molecule that binds to and blocks the function of STK33 can cause temporary infertility in mice.

Another target is soluble adenylyl cyclase, or sAC, an enzyme essential for sperm motility and maturation. In 2023, Buck and colleagues showed that blocking sAC renders male mice infertile until the drug wears off. The team is now searching for sAC-inhibiting compounds suitable to test in humans.

Buck credits industry-wide advances in drug design for recent successes. Methods such as X-ray crystallography reveal the molecular structures of proteins. By tweaking the structures in simulations, researchers can predict which modifications change how a drug binds to a targeted protein. This makes the search for drug candidates much faster and more precise than older methods of drug screening, Buck says.

“Thirty years ago, this kind of drug design wasn’t possible. We needed breakthroughs in chemistry to create extremely sophisticated drug candidates,” he says.

Buck is further ahead testing a vaginal ring for women that contains a sAC inhibitor. The ring prevents unwanted pregnancies by impeding sperm function, which he hopes will leapfrog the male contraceptive sAC inhibitor through development.

“So far it has a very low toxicology profile,” he says, and he expects clinical trials to start next year. A sAC inhibitor for men could be less than 10 years away from regulatory approval, if clinical trials go according to plan.

The hurdle of regulatory approval

With promising results for NES/T, experts are gearing up for the momentous task of applying for regulatory approval. One challenge is that the bar for male birth control medications is much higher than for female contraceptives.

The FDA approves or rejects a drug based on the health risks and benefits to the patient. For men preventing childbirth? “There’s no [health] benefit for them. Zero,” says Steve Kretschmer, founder and executive director of DesireLine, a health consultancy based in Istanbul. “There’s no drug that will be approved unless it has a perfect side effect profile.”

Women on hormonal birth control may endure a range of side effects, including headaches, mood changes and even blood clots. But the FDA has deemed those risks acceptable given the risks of childbirth.

Low-level concerns of hormonal side effects are one thing, but the specter of permanent infertility haunts the male birth control field. Gossypol, a promising male contraceptive tested in the 1970s, worked too well — by some estimates, 10 percent of men who took part in trials in China became sterile, even after stopping gossypol.

“Permanent infertility was my biggest concern before I went into the [NES/T] trial. What if my body doesn’t kick-start again after?” Ahlqvist says.

But permanent infertility is not an inherent risk of male birth control, Nguyen says, referencing recent trial data.

Preconceived notions about male birth control plus the regulatory challenges have contributed to why pharmaceutical companies are not rushing to develop male contraceptives, Amory says.

Though it might take a change in how the FDA weighs the risk of NES/T for it to ever reach the finish line, that shift could be a game changer for other drug approvals too.

“The question really is, is it possible to get the FDA to shift their criteria to be at the relationship level?” Kretschmer says. The idea is to take equity into account, in which a man gives informed consent and is willing to take on the risks for the benefit of his partner. He points to models the FDA could follow from the World Health Organization and the European Medicines Agency, which are more receptive to the shared-risk argument.

Despite NES/T being further along in the development pipeline, ADAM and other occlusion gels may become available sooner. They’re classified as medical devices, not drugs, Kretschmer says, which follow a different regulatory path. Most of the time, companies are not required to submit clinical data to demonstrate safety and efficacy for a medical device, speeding up the review process.

The best-case scenario, experts say, is that an occlusion gel wins approval within five years, and a hormonal contraceptive follows a few years later. If so, it would be the first new male contraceptives to hit the marketplace since goat-bladder condoms were used 5,000 years ago.