The headlines spelled the end of a short-lived scientific hope: “Male birth control study nixed after men can’t handle side effects women face daily,” USA Today announced. “Men Back Out of Male Birth Control Study Because They Couldn’t Handle the ‘Changes in Mood,’” proclaimed People.
It was a high-profile — and highly embarrassing — end to a clinical trial that researchers hoped would usher in a new era of birth control. But the headlines obscured more complicated truths about the hard work of developing male contraceptives, and running clinical trials to assess their effectiveness. Years later, the field is still navigating the fallout.
Male contraceptive research has never garnered as much interest or investment as female birth control studies. But the 2016 study dashed nascent hopes of industry collaboration and the money that would come with it. “It depressed the whole field for a while,” said Diana Blithe, chief of the NIH Contraceptive Development Program, who was not involved in the study. Though other news outlets attempted to correct the record — men were not wimps; they actually liked the birth control — the damage was done. Even now, male birth control still sounds like “you are basically offering people a potential lawsuit,” said Heather Vahdat, executive director of the Male Contraceptive Initiative.
Despite the setbacks, researchers have spent the better part of the last decade quietly rebuilding. By continuing to develop, test, and hopefully one day market a male contraceptive, they aim to usher in a new vision of what feminist bioethicist Lisa Campo-Engelstein has called “contraceptive justice” — a world in which every person has a safe, reliable, and even likeable means of controlling reproduction.
Given there are a dozen or so different methods of female birth control, developing options for the other half of humanity might not seem like a pressing problem. But many women hate their contraceptives, citing familiar issues including changes to libido, weight, and mood. That ongoing burden is why news outlets were so quick to mock the male participants of the 2016 study: From the day the pill debuted in 1960, women have borne the brunt of family planning — and wielded much of the control. Men, who have just condoms and vasectomy at their disposal, have been largely excluded from both the pain and promise of reproductive autonomy.
In fact, even researchers within reproductive health have, at times, expressed skepticism of its relevance. “I used to say, male contraceptive — it had to turn the penis purple and [make it] glow in the dark,” said Mitchell Creinin, a professor of obstetrics and gynecology at the University of California, Davis, who now researches both female and male contraceptives. “The purple was so she knew he was taking it and the glow in the dark was the added benefit.”
But popular misconceptions around male birth control research have obscured some good news. These days, men around the globe seem not only receptive to contraceptives, but enthusiastic about their use. “[I’ve asked patients,] if there was a one in a million chance that you would die, would you take this?” said John Amory, a physician at the University of Washington Medical Center. “They said, ‘If it meant I didn’t have to use a condom, I’d take one in 100.’” The World Health Organization now estimates about 39% of men in the U.S. would use a new contraceptive within a year of its release. (In countries like Kenya, that number is as high as 76%.)
Fortunately, researchers think they are closer than ever to delivering on the holy grail of hormonal male birth control, with promising — if early — evidence of a contraceptive gel called NES/T and more products in the pipeline.
“I am not always the cup half-full person,” Blithe said. But emerging Phase 2 NES/T clinical trial data has transformed her into something of an optimist. “I am way half-full — I am three-quarters full. This is really working so much better than we expected.”
Science has promised that male birth control is about five to 10 years away since at least the 1970s. Most ideas never made it out of the lab. Chemotherapies, fungicides, chemicals to paralyze sperm, magnetic valves surgically inserted into the testes, ultrasound waves, a cottonseed byproduct called gossypol — “enormous numbers of things have been tried,” Wayne Bardin, the director of the Population Council, said back in 1983.
But they often proved ineffective, dangerous, irreversible, or, in the case of the magnetic valves, wildly off-putting to consumers.
“It never seemed unsolvable. We always thought we’d figure this out.”
John Amory, physician at the University of Washington Medical Center
The failed products had a herculean task: rein in the tens of millions of new sperm cells produced each day. “It never seemed unsolvable,” Amory said. “We always thought we’d figure this out.” But it’s math that makes interfering in female reproduction — by modulating a single egg released each month — seem simple.
Over time, researchers zeroed in on contraceptive methods that manipulate steroids produced in the gonads — specifically, testosterone. Creating sperm requires the body to produce and maintain high levels of testosterone in the testes. Scientists found they could, in essence, spoof the male reproductive system. When more testosterone is injected into the body, the hormonal signals between the brain and the testes shuts down, and both testosterone production and sperm production drops dramatically.
In the 1990s, WHO researchers published the results of two large-scale trials of testosterone as a standalone contraceptive. The first trial involved giving male participants weekly injections until they had zero detectable sperm left. Then, the research team watched what happened when the participants and their female partners stopped using all other means of birth control. The results were OK: 70% of participants got to the sperm “suppression” phase, and over a year of observation, there was a single pregnancy among 119 couples.
In their next study, WHO scientists decided to see what happened if some sperm remained. Using an otherwise identical study design, they offered participants the chance to have otherwise unprotected sex as soon as the male partner’s sperm counts dropped below 3 million sperm per milliliter of ejaculate. (Now, the standard for male contraceptives is 1 million or fewer.) The results suggested that even with some sperm still present, pregnancy rates could be curbed.
The trouble was, for reasons that are still unclear, the testosterone injections didn’t work equally well for everyone. Almost all East Asian men studied saw their sperm levels plummet, but many of their Caucasian counterparts were “non-responders” who couldn’t reach the sperm suppression phase. (“This is a real problem for drug companies,” Amory told The Los Angeles Times in 2006. “We don’t have the same problem with women.”)
That’s how, in 2008, WHO and the nonprofit reproductive research group CONRAD began recruiting participants for a new clinical trial — this time, of an injectable combination of testosterone and another hormone called norethisterone enanthate. They hoped the mix, known as TU/NET-EN, would make the contraceptive more effective for more participants.
By all accounts, it worked.
Across 10 global study sites, the researchers found that 96% of men receiving the injections achieved a sperm concentration of less than a million, rendering them effectively infertile. In a trial with 266 couples, four pregnancies were reported, which is on par with other birth control methods. What’s more, most male participants reported liking the method — and said they would continue to take the product, if given the chance.
These were findings that should have paved the way for pharmaceutical industry interest: Controlling sperm counts was not only possible, it was a viable method of pregnancy prevention. “As a contraceptive trial it was extremely successful,” said co-author Richard Anderson of the MRC Centre for Reproductive Health at the University of Edinburgh.
Then the reports of side effects started rolling in.
If the fallout was definitive, the events that led up to the study’s cancellation felt far less clear. There were 1,491 individual incidents reported, ranging from headaches to acne, and just under two-thirds of those were deemed related to the experiment itself. But a few of the reports were more serious than the subsequent news reports let on: One participant developed depression and another attempted a drug overdose. (A third died by suicide, though investigators concluded that the death was unrelated to the trial.)
The researchers weren’t sure what to make of it: They were troubling findings, but 62 of the 65 reports of emotional side effects also came from a single study site in Indonesia, calling into question whether the problem was in the drug itself, or the research methods. (Notably, key hormone analyses from the Indonesia study site have never been completed.)
The study’s two safety review panels were confused, too. When they convened for independent evaluations, one panel said the study could continue, and one didn’t. “It was a bit controversial,” recalled Michael Mbizvo, the former director of reproductive health and research at the WHO. In the end, the trial was cut short.
The 2016 study cast a long shadow. Previously, contraceptive studies did not routinely screen participants for mood. Now, it’s common practice, so researchers have a baseline to compare incidents against. Researchers have also moved away — at least for now — from injectable contraceptives, on the suspicion that participants in the 2016 trial may have struggled emotionally because the time between doses allowed their hormones to rise and fall more dramatically than they would with, say, a daily pill.
The last major industry investment in male contraceptives ended back in 2006. Two European companies, Organon and Schering, saw a product — a combined testosterone-progesterone implant, coupled with regular injections — through its Phase 2 trial. It appeared effective, but the companies concluded that the product would not have enough widespread appeal and decided not to fund a Phase 3 trial. That same year, the New Jersey-based firm Wyeth Pharmaceuticals announced it was “discontinuing its entire research program for new male and female contraceptive drugs,” the Los Angeles Times reported, citing “[f]inancial pressures, scientific difficulties and an unknown market.”
Many had hoped that TU/NET-EN would change the narrative. For a time, at least, it only seemed to make things worse.
Anderson has little interest in looking back on it. “Frankly, enough is enough,” he told STAT in an email. What he wants to talk about is what comes next.
In spring 2020, John Reynolds-Wright had one goal: to keep patients enrolled in a clinical trial of a new male contraceptive, despite a pandemic lockdown.
Reynolds-Wright, a clinical research fellow at the MRC Centre for Reproductive Health, jumped into a car with a nurse colleague and drove big figure eights along Scotland’s “central belt,” which runs from Edinburgh to Glasgow, to get the birth control where it needed to go.
At each stop, they dropped off 5-milliliter pumps of the contraceptive gel — called NES/T — and picked up sperm samples, to be analyzed back in Anderson’s lab.
Like other male contraceptive products before it, NES/T works by combining testosterone and another hormone, Nestorone, to suppress sperm production. But this drug comes in the form of roughly a teaspoon of gel, applied daily to the skin on the shoulders and back — where it can be covered by a shirt until it’s absorbed.
Phase 2 clinical trials for the drug, a collaboration between Blithe’s team at the NIH and the nonprofit Population Council (which developed the hormone Nestorone), began in 2018 with 15 study sites. While the researchers cannot yet share the results, they say they’ve been surprised by the success so far. More than 110 couples have finished the yearlong trial. Blithe said the vast majority have found the drug to be safe, effective, and reversible — as evidenced by the couples who have gone on to successfully have children.
Even more of a surprise is that people seem to like using the product. Researchers, including Blithe, were skeptical that couples would accept a sticky gel that had to be applied every day. But some study participants were so keen on it, they asked to continue using NES/T after the trial ended (and were politely rebuffed).
The NES/T team still faces an arduous path forward. The Phase 2 trial is set to wrap up in 2024. The next step, a Phase 3 trial, will be expensive — on the order of $20 million, based on one dataset of more than 700 clinical trials. To bring the drug to market, Blithe and her team will likely need industry partners to pick up the tab.
While female contraceptives also have side effects, “that’s a devil they know,” Amory said of drugmakers. “They know they’re going to face lawsuits for blood clots, but they can sell enough to make up for it. There’s no precedent for male contraceptives.” A handful of small companies are plowing ahead anyway. For example, the biotech firm YourChoice Therapeutics is testing a non-hormonal pill in animals, and hopes to move to human trials by early 2023. Likewise, Eppin Pharma in Durham, N.C., is also developing a male contraceptive pill that targets sperm motility. But more financial support is likely needed.
Even if it is secured, NES/T proponents may face regulatory hurdles. A male hormonal contraceptive will likely be considered “first in class” drug by the FDA, which may lead to novel questions from regulators. “There is this thing about being the first one,” Amory said. “If you’re one step ahead of the crowd, you’re a leader. If you’re two steps ahead, you’re a martyr.” Researchers may also have to make the case that the percentage of men who achieve suppression, while not 100%, is enough.
Right now, the NES/T team is seeking guidance from the FDA about what, exactly, male contraceptive developers will have to demonstrate. “To do the right studies, we have to know what we’re going to need to show,” said Stephanie Page, co-director of the UW Medicine Diabetes Institute and one of the NES/T study site investigators. As it stands, the NES/T trial could theoretically wrap up successfully, only for the FDA to say they missed a crucial variable.
Blithe estimated that — even if everything goes right — it could take another decade to get the drug approved by the FDA, though significant industry investment might speed up the timeline. “It took us [more than] 15 years to get to where we are now,” she said, adding, “and it wasn’t like we were sitting on our hands during any of that time.”
Any male contraceptive will also have to contend with the tricky matter of trade-offs. Historically, the risks of female birth control have been weighed against the risks of pregnancy, which is potentially life-threatening. Because pregnancy poses no obvious health risks to the male partner, advocates worry the bar for acceptable side effects will be much higher.
In anticipation of regulatory reviews, bioethicists like Amory are working to reframe these conversations. They point out that there are no real empirical studies assessing whether or how unintended pregnancy impacts men and promoting a new model of shared risk, which argues that the risks and benefits of sex must be considered in terms of the couple.
Shared risk may upend generations of assumptions about gender, sex, and power. But a significant number of men seem eager to take on some responsibility, if they could just get their hands on a product. “My tombstone will say, ‘Men do want contraceptives and women will trust them,’” Vahdat of the Male Contraceptive Initiative said.
Anderson, for his part, said that while the NES/T gel may never “be the world’s number one contraceptive,” he believes it will one day hit the market — and help pave the way for future products.
There are plenty in the pipeline. Page has been investigating a synthetic steroid since 2006, and recently completed enrollment for a Phase 1 trial. Researchers are also studying Vasalgel, a polymer that is injected into the vas deferens to stop the flow of sperm. In 2022, the Parsemus Foundation announced that NEXT Life Sciences would be taking over development of the product, which has yet to enter into clinical trials in the United States. And many hope to one day develop non-hormonal contraceptives, which, among other benefits, could offer new options for trans people, some of whom cannot use hormonal birth control. Researchers also hope to one day combine contraceptive action with protection against sexually transmitted infections.
Not every drug will pan out, but each step will deliver new insights. Male contraceptive researchers are often treated as if “we’ve been toiling in obscurity for this length of time and nothing has come out of it,” Reynolds-Wright said. In reality, “lots of things have come out of it — just not the intended thing.” Early WHO studies gave rise to the no-scalpel vasectomy. And testosterone undecanoate is now used to treat hypogonadism. (Incidentally, this may be another path to market, Amory said: Get a drug approved for another use, and then make the case for contraception.)
Whether it’s NES/T or another product, Anderson is confident hormonal male contraception will one day be in widespread use. By the time it happens, he bets he’ll be retired.
“But,” he said, “I hope to read about it in the newspaper.”
This story is part of ongoing coverage of reproductive health care supported by a grant from the Commonwealth Fund.