Sperm-Slowing Male Contraceptive Reversibly Inhibits Mouse Fertility

A new non-hormonal male contraceptive temporarily suppresses fertility in mice, a study has shown. The innovative treatment targets a compound that sperm require to remain motile. After exposure to the compound, called TDI-11861, sperm were immobilized for several hours, before returning to normal mobility after 24 hours. Researchers at Weill Cornell Medicine, led by Dr. Jochen Buck and Dr. Lonny Levin, hope that it could one day lead to a reversible, on-demand male contraceptive that would be more practical than other proposed treatments.

Contraceptives for men: 3000 years of failure to innovate

The task of avoiding accidental impregnation remains, despite decades of drug development, a responsibility left almost entirely up to women. Apart from vasectomies (first conducted in humans in 1899 by the masturbation-obsessed eugenicist Henry Clay Sharp) and condoms (first worn by Ancient Egyptians), almost all contraceptive strategies aim to alter female physiology to reduce fertility.

But that imbalance is being addressed, at last, by new scientific advances. Proposed strategies involve non-hormonal methods like gene disruption, employing retinoic acid inhibitors or the use of the sperm-deforming herb Triptonide (cribbed from Chinese medicine, where it is known as Thunder God Vine). Hormonal interventions are more advanced – a clinical trial of a Nestorone®/Testosterone gel is currently in advanced trials – but a shared limitation of all these approaches is their timing. Months of prior applications are needed to effectively reduce fertility.

This has left, write Buck, Levin and colleagues in a new publication in Nature Communications, significant room for a rapid-acting and reversible male contraceptive to be developed. The team has staked its claim by developing an inhibitor molecule that targets a protein called soluble adenylyl cyclase (sAC).

sAC: Kickstarting sperm motility

To understand why Buck and Levin believe their compound is a winner, we need to understand how sperm get ready for their big day. Prior to ejaculation, sperm are found in a dormant state in a region of the scrotum called the cauda epididymis. To be activated and ejaculated, the sperm are mixed with semen, where higher levels of bicarbonate kickstart sAC, which boots sperm into gear for fertilization, activating their motility.

Mice that have been genetically modified to lack sAC are infertile. sAC is unusual among male contraceptive targets as it is not just expressed in the testes, which opens up the risk of side effects. Buck and Levin’s team write that studies of men lacking sAC from birth show that the side effects are few and far between, and the most impactful ones, like an increased risk of kidney stones, only come into play after an extended period of sAC absence. If the molecule can be suppressed for just a short period of time, exposed males should remain risk-free.

Enter TDI-11861, a temporary contraceptive.

The compound was first trialed in sperm isolated both from male mice’s testes and from female mice’s vaginas post-copulation. Both sets of sperm were inhibited by the new compound, immobilizing sperm for up to two and a half hours, enough to inhibit even the most resilient and extended copulation sessions. After 3 hours, some sperm showed restored mobility and virtually all were back swimming 24 hours after administration. Chris Lindsey, a program officer for the National Institute of Child Health and Human Development's Contraception Research Branch, which helped fund the research, said that this could give the compound an “on-demand” mechanism of action. “It’s one of the things we’re most excited about,” said Lindsey.

Inhibiting mouse fertility

But would the compound have a similar efficacy outside of petri dishes? The team exposed groups of mice to their compound via injection. 52 male mice who were exposed to the inhibitor between 30 minutes and 150 minutes prior to copulation were completely unable to impregnate female mice. An additional 45 mice, who were injected between 30 and 180 minutes after copulation produced just 1 impregnation. In comparison, 15 out of 50 mice who were unexposed were able to impregnate female mice during a similar 2-hour window. When 15 exposed mice were left alone to do the deed for a period between 1 and 5 days after injection, their impregnation rate was 87%, only slightly below that of unexposed mice over the same period (93%), showing that the inhibitor’s effects remained temporary. “It's anecdotally parallel to Viagra,” said Lindsey. “Conceptually, you could take this with a meal, maybe an hour or so before you go and have sex, and you'd be rendering yourself infertile for that brief period. And you’d return to normal afterward.” 

"This is a remarkable study, showing very high contraceptive activity of this approach, inhibiting [sAC]," said Richard Anderson, Elsie Inglis Professor of Clinical Reproductive Science at the University of Edinburgh, "Importantly, as well as showing that it works in mice, and seemingly is fully reversible without detected toxicity, they also show that human sperm are similarly affected. These are very exciting data, and truly do pave a way towards the very novel approach of effective on-demand male contraception." 

While Buck and Levin’s unusual approach may be the first steps toward a contraceptive approach that could let partners make day-to-day decisions about their fertility, mice remain mice, and this research remains at an early stage. The team hopes to trial their compound in other model animals, before beginning the journey toward trials in humans. A male “pill” will have to wait a while longer. 

Reference: Balbach M, Rosetti T, Ferreira J et al. On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nat. Comms. 2023; 14(637). doi:10.1038/s41467-023-36119-6