The creators of a male birth control gel designed to inhibit sperm production—while maintaining healthy testosterone levels in the bloodstream—will soon start recruiting 420 couples from around the world to enroll in a new clinical trial.

Male participants will apply the hormonal gel to both shoulders once a day. Then, after lab testing indicates their sperm counts have been suppressed to extremely low levels (which could take two to three months), the couples will be tracked for a year while they use the gel as their lone form of contraception.

The project, led by the U.S. National Institutes of Health and the Population Council, is expected to begin signing up couples in early 2018, along with collaborating partners at nine locations in the U.K., Sweden, Italy, Chile, Kenya and several medical centers in the U.S. Once these sites get institutional and national review board sign-offs, the study will test whether the latest version of a hormonal birth control system for men can overcome the myriad obstacles that have sidelined earlier efforts. Just last year a clinical trial of a hormonal male contraceptive shot was shut down after some participants suffered concerning side effects.

Right now, options for male birth control are few—condoms, vasectomy and withdrawal—and there is no equivalent of “the Pill,” a hormonal contraceptive used by women, that would limit sperm production. Yet vasectomy requires surgery and is not always reversible, condoms are often used inconsistently and withdrawal is unreliable.

That’s why the NIH team has turned to its new experimental gel. It introduces into the bloodstream a combination of the hormones progestin—which suppresses sperm creation in the body—and testosterone. An earlier version of this approach appeared promising in a small, six-month pilot trial, in which gel application reduced sperm production while maintaining healthy testosterone levels. In about 89 percent of users, sperm counts were reduced to one million per milliliter or less (a point typically considered to indicate successful sperm suppression). “That number—89 percent—may sound low, but we suspect that there was some level of noncompliance, since the men in that pilot trial were not using this for contraceptive purposes,” says Diana Blithe, who is leading the gel trial as chief of the contraceptive development program at the NIH’s National Institute of Child Health and Human Development. By way of comparison, among women the typical failure rate for oral contraceptives hovers around 9 percent due to noncompliance and imperfect use, putting it in striking distance of the male gel sperm-suppression numbers.

Researchers have been trying for decades to deliver on male hormonal birth control. Theoretically this would inhibit sperm production in men, much as the Pill blocks women’s ovaries from releasing eggs. But in practice it is far more complex. In women the Pill essentially tricks the body into acting as though it already is pregnant, making it temporarily infertile. Among men a hormonal contraceptive could inhibit testosterone production in the testes, reducing sperm levels. It would, however, simultaneously decrease testosterone in the blood—which would cause intolerable side effects that include impeded ejaculation as well as altered libido and muscle mass. So the biggest hurdle to developing a male contraceptive pill has been the difficulty of providing replacement testosterone in oral form, Blithe says. The hormone would leave the body too quickly, rendering such a pill impractical because men would have to take it too many times a day.

Blithe’s contraceptive gel aims to get around those problems by steadily adding testosterone back into the bloodstream through the skin—at levels low enough to avoid promoting sperm production in the testes but high enough to prevent problematic side effects. “The amount of testosterone needed for sperm production in the testes is believed to be about 50 to 100 times greater than what is needed in the blood for other functions,” she notes.

Her team’s effort comes on the heels of a troubled, high-profile male contraceptive trial. Last year a study headed by the World Health Organization and a reproductive health institute called CONRAD reported a hormone injection suppressing sperm production in men was about 96 percent effective. (The NIH had no role in that project.) The shot—which men needed to receive every two months—included testosterone and progestin. Despite the injection’s effectiveness, the study was halted early when male volunteers experienced side effects including depression, acne and mood swings. Twenty of the 320 participants in that trial dropped out citing problems such as mood changes, erectile dysfunction or pain. One participant’s sperm levels had not returned to normal four years after an injection and remain at levels considered subfertile, says Douglas Colvard, a reproductive expert at CONRAD and one of the lead investigators of the hormonal shot effort.

Yet even with those side effects there was still a lot of interest in the product. The remaining trial participants mostly praised the injections and said they were still interested in continuing to use them, even after the scientists brought the test to a halt.

Blithe and her team expect their approach to be largely free of the side effects seen with the injection, because the daily gel applications would release the hormones more consistently. The most common side effect would likely be acne, according to Blithe. In the pilot work a small number of men reported acne, increased appetite, decreased libido, mood swings, headaches or insomnia—side effects also seen among women who take oral contraception. Unlike the gel, Blithe notes, the shots contained large levels of hormones that were introduced every eight weeks and then decreased in the body at varying rates until the next injection, likely contributing to the negative side effects.

Colvard, who is not involved with the gel effort, says it seems promising. “We don’t know for a fact that the fluctuating hormones in [our] study were the only cause of the side effects that occurred, but it’s plausible, given that behavioral changes occur during different hormonal cycles in men—like when teenagers hit puberty,” he says. For now his group is analyzing links between some of the mood swings seen in its study and hormonal fluctuations in the weeks following the injections, he says.

Aaron Hamlin, executive director of the Male Contraception Initiative—a nonprofit organization that funds and advocates for nonhormonal male birth control—says a gel that continuously delivers a hormone makes sense. “If you are able to spread the dosage out over more time, intuitively it seems like a better approach than having spikes that occur every so often, like with the shot,” he says. But he cautions that reversible nonhormonal methods—those that block sperm from fertilizing eggs without introducing hormones into the body—would still be preferable, because any hormone-based intervention would be subject to months-long delays between when a man starts using it and when his sperm production is sufficiently suppressed. The body, Hamlin notes, must also clear a reserve of sperm that existed before the treatment began. He is also concerned about the side effects of hormonal birth control, and the consideration that it may not adequately suppress sperm count in all men.

Yet nonhormonal methods (beyond vasectomies and condoms) that seek to impede egg fertilization have yet to reach the same level of testing in men. Animal tests have been performed with a couple of products including a compound called H2-gamendazole, which keeps sperm from reaching maturity so they are not fully developed when they are ejaculated—causing men to essentially “shoot blanks.” Another nonhormonal product, called Vasalgel, is a polymer hydrogel that physically blocks sperm in the vas deferens so they cannot reach an egg. Researchers published promising results with Vasalgel in rabbits and monkeys earlier this year but its maker says it has no timeline for human clinical trials. Yet another product, Gendarussa, was created by researchers at Airlangga University in Indonesia. It prevents sperm from fertilizing an egg via a mechanism that remains unclear—and the Indonesian team has not published results from its phase I human trials—so it is hard for outsiders to assess the product’s success or science, Blithe and Colvard say. Gendarussa has, however, received clearance from the Indonesian equivalent of the U.S. Food and Drug Administration to proceed with phase II trials, says Paul Feldblum, a senior epidemiologist in global health research at FHI 360, a human development organization that helped develop some protocols for the trial’s next phase. Gendarussa’s creators did not respond to a request for comment.

Despite their different methods, all these products have one thing in common: They are designed to fill the massive need for more contraceptive options. In 2012, 40 percent of all pregnancies worldwide were unintended, according to the Guttmacher Institute. New forms of birth control, reproductive specialists hope, could help slash those numbers.