An injectable male contraceptive combining long-acting testosterone and progestogen achieved near-complete yet reversible suppression of sperm production, according to findings of a prospective phase II study.

“In the past 4 decades, studies have demonstrated that reversible hormonal suppression of spermatogenesis in men can prevent pregnancies in their female partners, although commercial product development has stalled,” wrote Hermann M. Behre, MD, of the Center for Reproductive Medicine and Andrology, Martin Luther University, Germany, and coauthors.

In this international multicenter study, 320 healthy men aged 18-45 in stable, monogamous, heterosexual partnerships – without known fertility problems but with no desire for pregnancy in the next 2 years – were given intramuscular injections of 200-mg norethisterone enanthate combined with 1,000-mg testosterone undecanoate every 8 weeks.

The study involved phases. There was an initial suppression phase of treatment of up to 32 weeks, during which couples were told to use alternative nonhormonal contraception. Once two consecutive tests showed sperm concentrations at or below 1 million/mL, the couples began the 56-week efficacy phase where injections continued but couples were advised to not use any other form of contraception. This was followed by a recovery phase initiated when sperm concentrations returned above 1 million/mL.

By 24 weeks after the first injection, 95.9% of those who received at least one injection showed sperm suppression to a concentration of less than or equal to 1 million/mL, according to a paper published online Oct. 27 in the Journal of Clinical Endocrinology & Metabolism.

There were four pregnancies during the efficacy phase of the trial, representing a rate of 1.57 per 100 continuing users, but all occurred before the 16th week of the efficacy phase. Three of these four participants had sperm concentrations at or below 1 million/mL but none was azoospermic around the estimated conception date.

“Effective and safe male contraception continues to be elusive,” said Sarah W. Prager, MD, who was asked to comment on the findings. “This study shows that only 75% of men who are already signing up to participate in a male contraceptive research study would be willing to use the proposed method. Additionally, there seem to still be some significant negative side effects, 61% of which were assessed to be directly related to the male contraceptive study drugs.

“A failure rate of 4% in a study setting is significantly lower than most female contraceptive methods, and many women would potentially not feel comfortable relying on a method with that type of failure rate. Finally, male contraception that is not directly witnessed by a female partner could be suspect, and hard to rely on for any but women in long term, monogamous relationships, according to Dr. Prager, associate professor of obstetrics and gynecology and director of the Ryan Family Planning Program at the University of Washington, Seattle.

“Continuing to seek effective and safe male contraception is a worthy endeavor, but this study tells me that we still have a ways to go before male hormonal contraception can be operationalized,” she said in an interview.

Further findings from the study showed that there were six cases of sperm rebound during the efficacy phase, with sperm concentrations ranging from 2 million to 16.6 million/mL. Overall, the treatment showed a combined failure rate of 7.5%, which included nonsuppression by the end of the suppression phase, sperm rebound during the efficacy phase, or pregnancy during the efficacy phase.

By week 52 of the recovery phase, the cumulative rate of recovery of spermatogenesis to a concentration of at least 15 million/mL was 94.8 per 100 continuing users (J Clin Endocrin Metab. 2016, Oct 27. doi: 10.1210/jc.2016-2141).

However, eight men had not recovered spermatogenesis enough to meet the criteria for return to fertility; five of these showed restored sperm counts by week 74 of the recovery phase, two declined further follow-up, and one did not recover within 4 years of the last injection.

Nearly half of all participants reported acne, and 38.1% reported an increase in libido. There were also 65 reports of emotional disorders, although the authors noted that 62 of these reports all came from the same center in Indonesia. Other adverse events included injection site pain (23.1%), myalgia (16.3%), and gynecomastia (5.6%).

While the potential behavioral effects of the regimen were known, the trial was terminated early. The authors argued that similar effects have been observed both in the intervention and placebo arms of previous trials of this combination, which were designed to look only at suppression of spermatogenesis.

“Contraceptive efficacy studies cannot involve placebo groups for obvious ethical reasons,” they wrote. “Therefore, a definitive answer as to whether the potential risks of this hormonal combination for male contraception outweigh the potential benefits cannot be made based on the present results.”

The study was supported by United Nations Development Programme/United Nations Population Fund/United Nations International Children’s Emergency Fund/ World Health Organization/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction (Human Reproduction Programme, World Health Organization, Geneva, Switzerland), and CONRAD (Eastern Virginia Medical School, Arlington, Va.) using funding from the Bill & Melinda Gates Foundation and U.S. Agency for International Development). No relevant conflicts of interest were declared. Dr. Prager reported having no relevant financial conflicts of interest.