Experimental Male Contraceptive Drug Stops Sperm Movement, Prevents Pregnancies In Preclinical Study

Researchers found that mice which were administered a drug that inactivates a certain enzyme produced sperm that cannot propel themselves forward. 

A new experimental male contraceptive drug candidate has been observed to temporarily stop the movement of sperm in their tracks and prevent pregnancies in preclinical models, according to a new study published February 14 in the journal Nature Communications. The study, led by Weill Cornell Medicine, demonstrates that an on-demand male contraceptive is possible, and it could be a "game-changer" for contraception, according to the study's co-senior authors Dr Jochen Buck and Dr Lonny Levin. 

Buck and Levin are professors of pharmacology at Weill Cornell Medicine. 

Why has research on male oral contraceptives been slow?

Condoms have existed for about 2,000 years, and vasectomies have been men's only options to date. In a statement released by Weill Cornell Medicine, Levin said that research on male oral contraceptives has stalled partly because potential contraceptives for men must clear a much higher bar for safety and side effects. 

Levin noted that since men do not bear the risks associated with carrying a pregnancy, it is assumed that men will have a low tolerance for potential contraceptive side effects. 

Research on an enzyme called sAC

Initially, Buck and Levin did not plan to find a male contraceptive, but when Levin challenged Buck to isolate an important cellular signalling protein called soluble adenylyl cyclase (sAC), Buck could not resist, and started working on the project. This is a chemical which has long eluded biochemists. It is an enzyme and mediates cell growth and differentiation in organisms. It took Buck two years to isolate sAC. 

Then, Buck and Levin decided to conduct further research on sAC, and merged their laboratories. 

Mice genetically engineered to lack sAC are infertile, the researchers found. 

In 2018, Dr Melanie Balbach, a postdoctoral associate working in the laboratory of Buck and Levin, made an interesting discovery while she was working on sAC inhibitors as a possible treatment for an eye condition. 

Inactivation of sAC produced non-motile sperm

Balbach found that mice which were administered a drug that inactivates sAC produced sperm that cannot propel themselves forward. 

Another team's report showed that men who lacked the gene encoding sAC were infertile but otherwise healthy. These findings reassured Buck, Levin and their colleagues that sAC inhibition might be a safe contraceptive option. 

According to the new study, a single dose of a sAC inhibitor called TDI-11861 immobilises mice sperm for up to two and a half hours. These effects were found to persist in the female reproductive tract after mating. Some sperm started regaining motility a few hours after the drug was administered. By 24 hours, nearly all sperm had recovered normal movement. 

Male mice who were treated with TDI-11861 exhibited normal mating behaviour when paired with female mice. However, the male mice did not impregnate females despite 52 different mating attempts. By contrast, male mice which were treated with an inactive control substance impregnated almost one-third of their mates. 

What makes the experimental drug unique?

In the statement, Balbach said the inhibitor works within 30 minutes to an hour, and every other experimental hormonal or non-hormonal male contraceptive takes weeks to bring sperm count down or render them unable to fertilise eggs. 

Balbach also said that it takes weeks to reverse the effects of other hormonal and non-hormonal male contraceptives in development, and since sAC inhibitors wear off within hours, and men would take it only when they need it, the drug could allow men to make day-to-day decisions about their fertility. 

According to Balbach and Levin, it took substantial medicinal chemistry to develop TD-11861, and this was accomplished in partnership with the Tri-Institutional Therapeutics Discovery Institute (TDI), which works with investigators from Weill Cornell Medicine and other institutes to hasten early-stage drug discovery. 

Dr Peter Meinke of TDI said the highly productive collaboration between TDI and the Buck/Levin laboratory clearly illustrates the power of partnering pharma-trained drug discovery scientists with academic innovators.

What is next?

Levin said the team is already working on making sAC inhibitors better suited for humans. 

Next, the researchers intend to repeat the experiments in a different preclinical model, so that the findings could lay the groundwork for human clinical trials that would test the effect of sAC inhibition on sperm motility in healthy human males, according to Buck. 

Dr Levin said that if the drug development and clinical trials are successful, he hopes to walk into a pharmacy and hear a man request "the male pill".