Hormonal birth control methods are highly effective, but for many people who take them, they have undesirable side effects. But these could someday be avoided with the advent of fast-acting nonhormonal contraceptives. In a study published February 14 in Nature Communications, a group of Weill Cornell Medicine pharmacologists report a male contraceptive that prevented 100 percent of pregnancies in mice allowed to mate just 30 minutes after the drug was administered. And rather than altering hormone levels throughout the body, the compound works by paralyzing sperm, essentially making them dead in the water upon entry into the female reproductive tract.
“It is really encouraging that for the first time, there is a drug that can inhibit sperm function without affecting the production,” says Celia Santi, a sperm physiologist at Washington University School of Medicine in St. Louis—“and that can be used short-term, on-demand without any noticeable side effects.”
According to study author and Weill Cornell Medicine pharmacologist Lonny Levin, over 50 percent of pregnancies in the United States are unplanned. “That means that science has been doing a disservice to the public,” he says, and that more work needs to be done to make better birth control techniques. He knew it was possible to develop a working male contraceptive; several different methods have already made it to clinical trials. However, he also knew that developing a working method was only half the battle. Birth controls that are nearly 100 percent effective already exist for female patients, but these methods only work by supplying the user with hormones on a constant basis. The constant upkeep of methods like the pill can lead to misuse, and the unwanted side effects from the hormones in both the pill and other methods can cause people to give them up.
“Healthy people shouldn’t be taking drugs unless they need them,” Levin says. “That was our inspiration.”
Levin and Jochen Buck, a fellow pharmacologist at Weill Cornell Medicine, wanted to develop a fast-acting, orally ingested birth control meant to be taken only when needed, thereby avoiding the side effects seen in chronic hormonal methods, and only temporarily limiting fertility. Such a drug, which the authors call an “on-demand” birth control, hasn’t been developed.
Other male birth control drugs in development aim to limit the production of sperm but only become effective after several months of taking the drugs, and it takes another 8 to 12-week adjustment period before the person taking them becomes fertile again. So Levin and Buck decided to target the function of the sperm rather than the amount. “We deal with normal sperm,” Buck says. “We [needed to] prevent their on-switch from being turned on.”
Levin and Buck’s coauthor had discovered a potential molecule while doing research on a separate topic. The promising compound was an inhibitor for soluble adenylyl cyclase (sAC), an enzyme that exists in almost every cell across the body, but is particularly essential to the flagellum that a sperm cell uses to swim. Moreover, Buck says, sAC is the only cyclase enzyme that is regulated by bicarbonate, which binds to a specific site on the molecule. By using an inhibitor that binds to that site, they could target sAC without affecting the function of any other biomolecules. To make sure it would work as a drug, the scientists partnered with drug company TDI Therapeutics. Testing nearly 350 different sAC inhibitor cell lines on several different animal species, they looked for ones that were both safe and effective. Any that remotely interfered with important parts of the body and any that couldn’t survive in the bloodstream were immediately thrown out.
Sperm motility tracks before treatment with the inhibitor (top), one hour after exposure to the inhibitor (middle) and 24 hours after exposure (bottom).
MELANIE BALBACH, LEVIN/BUCK LABORATORY, WCMC
Once they narrowed down their options, they then needed to tinker with the molecules’ structure. A working male birth control drug needs to be potent and “sticky” enough to cling on to the right binding site even after entering the female reproductive tract, where the drug’s concentration becomes significantly diluted. However, after a few tweaks to the crystal structure, one of Levin and Buck’s coauthors got it to work in one of their cell lines. “He came and showed us [that] these things stay stuck,” Levin says. “And we were like, ‘damn, it’s going to work.’”
The team put their new sticky compound to the test both in vitro and in vivo. In the lab, they incubated human and mouse sperm in media that contained or lacked the inhibitor compound, finding that sperm exposed to the inhibitor displayed significantly lower flagellar beat frequencies. When they moved the treated sperm to a diluted solution without the presence of the inhibitor—mimicking the movement of the sperm to the female reproductive tract—the inhibitor continued to limit the sperm’s motility, meaning that it stayed stuck to the binding site.
The scientists then injected the compound into 50 male mice. They waited 30 minutes to allow the drug to work before putting each of those mice, along with 50 controls, into containers with fertile females. After giving the mice a mating period of a few hours, the scientists then removed the female mice and waited to see which of them got pregnant. In the control group, 30 percent of the females ended up pregnant. However, not one female mouse that mated with a treated male became pregnant. The team found that the male mice’s fertility returned to normal levels by the next day, indicating that the drug wasn’t having any permanent effect. The mice also didn’t display any other side effects from the drug, even when the team tried giving them repeat injections for several weeks. The scientists also tried administering the drug orally and found the same decrease in the flagellar beat frequency in the animals’ sperm as when they were injected with it.
Levin says he is incredibly excited about the potential their method holds, especially the short period of time it takes to work in comparison to the methods that take several weeks. “A man [could] take it with dinner and be [on a] contraceptive that night and through the next morning perhaps, and by a day later, they’ll be normally fertile again.” But he emphasizes that it will be at least a couple of years before their drug enters clinical trials. He and Buck are currently in the midst of testing the inhibitor in rabbits, which have a higher mating drive than mice, and making further tweaks to the compound itself to strengthen its survival in the bloodstream and make it a better candidate for oral ingestion.
Santi emphasizes the importance of innovations like this, particularly for groups like teenagers who may not have access to, or feel comfortable asking for, long term hormonal methods, or for people who have more casual relationships. “My hope is that there will be more awareness about the importance of contraceptives, especially in these times. That would be really great.”