When a presentation at ENDO 2024 highlighted a male contraceptive gel that suppresses sperm production faster than other hormone-focused methods of male birth control, the Boston Convention Center was abuzz. Containing segesterone acetate and testosterone and applied to both shoulders, this groundbreaking new birth control could prove revolutionary.
When the results from an ongoing multicenter Phase 2b clinical trial showing a novel male contraceptive gel suppresses sperm production faster than similar experimental hormone-based methods for male birth control were announced at ENDO 2024, a lot of ears perked up.
The gel combines two hormones: segesterone acetate (named Nestorone) and testosterone. And after the Dobbs decision, a lot of men, and women, seem to be eagerly awaiting such a method for choosing when to start a family.
“The development of a safe, highly effective and reliably reversible contraceptive method for men is an unmet need,” says senior researcher Diana Blithe, PhD, chief of the Contraceptive Development Program at the National Institutes of Health (NIH) in Bethesda, Md. “While studies have shown that some hormonal agents may be effective for male contraception, the slow onset of spermatogenic suppression is a limitation.”
According to a recent study, when the Dobbs decision was handed down, interest in a male contraceptive increased dramatically; the willingness to try a product within the first year of it coming onto the market rose from 39% to 49%, with 82 expressing interest in ever using a male method. And now that the trial is showing sperm suppression happens more quickly with this treatment, that interest may rise further. “A more rapid time to suppression may increase the attractiveness and acceptability of this drug to potential users,” Blithe says.
Goldilocks of Testosterone
The results presented at ENDO 2024 in Boston included data from 222 men who completed at least three weeks of daily treatment with the contraceptive gel. The gel contained eight milligrams of segesterone acetate and 74 milligrams of testosterone. Segesterone acetate is an ingredient of the Annovera vaginal birth control ring. Men applied the gel once daily to each shoulder blade (to reduce the risk of exposing the gel to others).
The treatment acts on the endocrine feedback loop between the pituitary and the gonads — secretion of luteinizing hormone (LH) from the pituitary causes the testes to make testosterone and follicle-stimulating hormone (FSH) is involved in sperm maturation. The segesterone acetate in the gel stops the pituitary from secreting LH and FSH, shutting down the production of testosterone. Local testosterone concentration in testes is higher than levels that circulate in the blood; when testosterone falls below a threshold, the testes stop producing sperm. But men would like to maintain a normal libido and muscle mass, so the gel replaces testosterone in the blood without it accumulating in the testes.
“The development of a safe, highly effective and reliably reversible contraceptive method for men is an unmet need. While studies have shown that some hormonal agents may be effective for male contraception, the slow onset of spermatogenic suppression is a limitation.” — Diana Blithe, PhD, chief, Contraceptive Development Program, National Institutes of Health, Bethesda, Maryland
“The sperm production stays shut off, but everything else functions normally because the blood is not seeing any kind of lower testosterone levels,” Blithe says. “It’s the differential between the concentration of testosterone that’s needed locally in the testes to recruit stem cells to make sperm and the testosterone that’s needed in the blood to support all the other functions that androgens support.”
Blithe explains that they found that Nestorone is a pure progestin – not a so-called “promiscuous” hormone like levonorgestrel that’s commonly used in female contraception. “[Levonorgestrel] binds to the progesterone receptor very strongly, but it also binds to the androgen receptor pretty strongly,” she says. “Those off-target effects, including other hormones that impact the glucocorticoid pathway, that can impact mood and things. It’s the off-target effects of hormones that might cause some bad side effects. Nestorone, we think, binds to the progesterone receptor and not so much to other receptors, so it’s good because we’re not seeing the kinds of side effects that we would worry about if it were impacting some of these other pathways.”
“Nestorone is the progestin. That shuts down the pituitary LH and FSH,” Blithe continues. “Testosterone is the second component, and that maintains everything in the normal functional range. We’re not too high, not too low, just the Goldilocks amount of testosterone that makes everything work well.”
Early in the study, the researchers measured for suppression of sperm production by obtaining sperm counts at four-week intervals. The threshold deemed effective for contraception was one million or fewer sperm per milliliter of semen, Blithe says.
Eighty-six percent of participants reached this sperm count by week 15, the researchers report. Among those men, sperm production was suppressed at a median, or midpoint, time of less than eight weeks of segesterone-testosterone treatment. Blithe says prior studies of male hormonal contraceptives given by injections showed a median time between nine and 15 weeks for sperm output to become suppressed.
“What we actually are seeing is by eight weeks, half the men are already fully suppressed. That was a surprise,” she says. “That’s where the publicity around this came out when we released that information to say, ‘This is working faster than we expected.’”
Family Time
The sperm suppression stage of the international phase 2b trial of segesterone-testosterone gel is complete. The study continues to test the contraceptive’s effectiveness, safety, acceptability, and reversibility of contraception after treatment stops.
Once the subjects stop using the product, they go into recovery and Blithe and her team take sperm samples to show how long it takes for the sperm to come back. “Once you start seeing them, then they go up to normal range pretty quickly,” she says.
Couples who completed the trial and decided it was the right time for them to start a family have done so successfully. “We’re not aware of anybody who’s trying and not able to, and there’s no reason to think that would be the case if it wasn’t the case before they started the study because their sperm come back,” Blithe says. “Their sperm parameters are normal when they leave us.”
Male Contraception: A Women’s Health Issue
Blithe says that the development of a male contraceptive is a women’s health issue, since women are the ones who get pregnant if they don’t have a contraceptive. And some women don’t always have the best experiences with contraceptives. “Lots of women really love their contraceptive methods and don’t want something else, but lots of women don’t love theirs and would love to have a hormone-free interval, or in some cases they actually can’t use hormonal methods. That really limits their options,” she says. “A male contraceptive for them is really critical.”
“The sperm production stays shut off, but everything else functions normally because the blood is not seeing any kind of lower testosterone levels. It’s the differential between the concentration of testosterone that’s needed locally in the testes to recruit stem cells to make sperm and the testosterone that’s needed in the blood to support all the other functions that androgens support.” — Diana Blithe, PhD, chief, Contraceptive Development Program, National Institutes of Health, Bethesda, Maryland
Blithe says some of the investigators have spent their careers developing contraception methods for women, which provided a perspective for the researchers who have worked on developing methods for me. “I think one of the things that our study in couples has taught me that I didn’t appreciate when we started was how much it means to a female partner to be able to be in a situation where she has a really effective method that doesn’t require her to use products that she doesn’t want or can’t use,” she says.
Blithe says the communication between investigators working on female contraception and their counterparts developing a male contraceptive has been crucial. She tells Endocrine News that she doesn’t see the study participants personally, but she hears from her teams that some female partners experience anxiety as they get to the end of the year of efficacy. The male partner stops using the gel and goes into recovery. The anxiety that some women experience at that point is much greater than the anxiety the women in the female method studies face for the same choice.
“That is probably something that none of us really thought about much ahead of time but see in practice in a way that it makes it more palpable that this is a method for women as well as potentially a method for men, who might not be in a relationship but might want to control their fertility,” she says. “It’s really two different aspects of trying to look at this progress in the field: who it benefits and how much it means to the people who are in the study.”
Blithe goes on to say that the study seems to mean a lot to the people participating in it. The participants are already eager for phase 3. “I always say my favorite comment when we ask about acceptability is, ‘Can I re-enroll?’ Because it’s almost a two-year commitment. That indicates, again, a great deal of acceptability of this method for many of the participants,” she says.
Bagley is the senior editor of Endocrine News. In the September issue, he wrote about the ongoing efforts to fund women’s health research.
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