Last month, researchers presenting at the annual meeting of the Endocrine Society revealed the early trial success of a once-daily contraceptive pill — for men. The announcement got a ton of news coverage, and raised a collective query of, “What took so long?” It’s been almost six decades since the FDA approved the first birth-control pill for women, and scientists have been promising an option for men for almost as long. They’ve tested injections, gels, implants, plant-based supplements and a handful of oral pill formulations, but research teams have repeatedly encountered political and biological roadblocks.
“Women ovulate once a month,” Stephanie Page, a professor of medicine at the University of Washington in Seattle, and the senior investigator on the most recent clinical trial, explains. “Men are making millions of sperm a day. It’s a much different biological challenge.”
Page says the new formula — dimethandrolone undecanoate, or DMAU — builds on the work scientists have done since the 1950s, and solves many of the biological problems that have derailed past attempts. And while Page predicts a male hormonal birth-control option will hit shelves in the next five to ten years, it’s important to remember: We’ve heard this before.
1950s
Some of the first — let’s call them questionable — trials of the newly created hormonal contraceptive, then administered via injection, were conducted on patients in an insane asylum. Researchers (who were, to put it bluntly, playing fast-and-loose with medical ethics) tested the drug, a mix of estrogen and progestin they hoped would put fertility on hold, on both women and men.
Birth-control crusader Margaret Sanger, then in her 80s, was furious; not because the drug she’d paid to have developed was being tested on people who likely couldn’t consent to being part of a clinical trial — but because she wanted the pill to be a women-only option, said Jonathan Eig, author of The Birth of the Pill: How Four Crusaders Reinvented Sex and Launched a Revolution.
“Once they were in the asylum, where there were both male and female patients, they figured it wouldn’t cost anything to test the progestin injection on men,” Eig explained. “The side effects for men weren’t that different from the side effects for women. There was some nausea, complaints about libido, some augmented breast size. As soon as Sanger found out they were testing it on men, she shut it down. She said, ‘We’re not paying you to do research for men. We’re only interested in women.’”
That may seem like a mistake in hindsight, Eig says. But Sanger’s priority was making sure the resulting pill would be a tool placed exclusively in the hands of women. “The point was control,” Eig says. “Women had to be the ones in control, otherwise they would still be reliant on men. If you’d just come up with a better condom and men remained in charge, it’s quite possible that women wouldn’t have ended up in the driver’s seat, especially not as quickly.”
1960s –1980s
Beginning pretty much the moment it was approved for use by American women in 1960, the pill changed the world.
Rates of women attending college, filling open jobs, and climbing the corporate ladder began to skyrocket. Some researchers saw this success as a great reason to develop more options — namely, an alternative for men.
Elsimar Coutinho, a Brazilian fertility doctor, was particularly interested in a plant-based, non-hormonal drug called gossypol.
Coutinho’s research into gossypol, which spanned more than three decades, was dismissed far more often than it was embraced.
After a 1972 Chinese clinical trial in which 8,806 men took gossypol pills that successfully reduced sperm counts but also caused worrisome side effects, Coutinho presented his findings at the 1974 World Population Conference. He was shouted down, he told The New Republic, by an audience of mostly women, who he says were “determined not to relinquish control” to a birth-control option aimed at men.
In 1986, the World Heath Organization deemed gossypol unacceptable as an antifertility drug, due in large part to evidence that it was toxic to rats and monkeys, and carried a 25 percent chance of irreversible sterility.
1990s–2000s
Coutinho continued conducting international trials until 2001, when a potential deal with a major Brazilian drug company fizzled out.
“Economics have been a factor because the [female] pill was so successful,” Eig says. “That created less incentive to develop a male pill. Why mess with something that’s making you a fortune if you’re a drug manufacturer?”
Despite scientific and economic roadblocks, research into male hormonal contraceptives crept forward, laying the foundation researchers built on to ultimately create the newest pill.
Now, a scientific interlude: A male hormonal contraceptive works in a similar way as the female version. It targets the production of sperm in the testicles, which is directly related to testosterone levels in the body. Once sperm are lowered to a specific number per milliliter of semen, pregnancy becomes nearly impossible.
To oversimplify: if you reduce the amount of testosterone being produced in the testicles, the amount of sperm being produced goes down, too.
Scientists ran into a couple of problems early on. Testosterone is important for more than just sperm production; it also impacts bone mass, muscle mass, hair growth, vocal tone, and a number of other functions in the male body.
Scientists were tasked with essentially tricking the brain into thinking the body already has plenty of testosterone, by supplying it orally. The body then ceases testosterone production, removing the high-testosterone environment sperm need to mature in the testicles.
“It’s been a tricky challenge to deliver testosterone by mouth, so most of the science was being developed throughout the ’80s and ’90s focused on implants and injections,” says Page.
When a testosterone androgen is given orally, Page explains, it has a very short half-life in the body, meaning two or three daily doses are necessary. Earlier studies also found that while testosterone alone effectively reduced sperm counts in 60 percent of men, when they added progestin, it became an almost universally effective contraceptive; just like the female pill, which contains both progestin and estrogen. But for the men, that meant administering two different hormones, potentially via injection, multiple times a day.
“The early modifications made to try to increase [the oral version’s] time in the bloodstream were associated with severe liver trouble,” Page says. “There actually was a version — called Methyltestosterone — approved by the FDA, but it’s associated with hepatoxicity, so no one prescribes that.”
2018
Page and her team at the University of Washington, alongside researchers at UCLA’s LA BioMed, built on the science of the past five decades to develop DMAU.
“DMAU is a modified testosterone,” Page explains. “We’re giving them basically synthetic testosterone. So testosterone levels in the bloodstream are low, but the androgen prevents [men] from feeling the effects of low testosterone. We’re providing a substitute, so the testicle doesn’t make any [testosterone,] but it shouldn’t really matter except for the sperm.”
To solve the problem of testosterone’s short half-life, DMAU contains the long-chain fatty acid undecanoate, which slows the clearance of the hormone from the body without damaging, as far as researchers can tell, the liver or kidneys.
The compound also combines the progestin and androgen receptors, meaning rather than, Page says, “one pill with both things in it, this is one pill with one drug that does both jobs.”
The first job is convincing the brain there’s sufficient testosterone present. The second is reducing sperm count — by a lot.
“A normal sperm count is 15 million to 150 million sperm per milliliter,” Page says. “Earlier studies tell us if we can get it to less than 1 million per mL, that is 90 to 97 percent effective as a contraceptive for a couple. In other words, as good as the female pill.”
While DMAU’s creators expect it to reliably reduce sperm count to that “magic million” mark, the monthlong clinical trial presented at the Endocrine Society was really about establishing the drug’s acute safety, finding the right dose, and looking at hormone levels.
“We’re very optimistic and confident that when we do our three month study, we’ll see good suppression of sperm production,” Page says.
“We’ve got a ton of work to do, and certainly we’ll need support from either the pharmaceutical industry or businesses or other funding agencies, but it’s realistic to think we might have it on the market in the next five to ten years.”
Whether it will catch on the way the pill for women did in the ’60s remains to be seen, and will depend, says Eig, on how we shape the national conversation around it.
“Men have now been conditioned over the past half a century to believe that this is a woman’s responsibility,” he says. “One of the side effects of the pill for women is that it has created the impression that men can take a back seat. We’re going to have to overcome decades and decades of cultural bias, and men and women will have to start shifting that dynamic so it’s seen as a decision that we make together.”
But if the accompanying ad campaigns for a male hormonal contraceptive are anywhere as influential as ads for erectile dysfunction have been in recent years, Eig says, we’ve got nothing to worry about.
“We know that Madison Avenue is still really good at changing people’s behaviors,” he says. “I think if it’s marketed correctly you’ll be able to convince men this is a good idea. I think if I were young and single and I knew I could take responsibility and not have to worry about anyone getting pregnant, that could be pretty convincing.”
