From mice to men: will a proof-of-concept male contraceptive progress to primetime?

Published 23 February 2023

A widely reported preclinical study has found that a single dose of a drug which switches off a signalling protein can immobilise mouse sperm for up to two and half hours. Researchers said it showed promise as an easy-to-use on-demand contraceptive for men.

It's now more than three decades since research stepped forward in male contraception with endocrine studies largely inspired by the WHO’s human reproduction programme. Yet today, with the WHO’s ‘anticipation of marketing’ no earlier than ten years, the condom is still the only reversible contraceptive available to men. There are, however, promising hormonal methods in development, notably a hormone-based gel which includes testosterone and segesterone acetate, a synthetic hormone developed by the Population Council and known as NES. The NES/T combined gel is now reported to be completing phase II trials.(1) So far, no male contraceptive has ever reached phase III in its development, though NES/T may well be the first.

However, there has been much interest of late not in a late phase trial but in a preclinical study of a male contraceptive which appears to work not by suppressing hormonal activity but by temporarily immobilising the action of sperm cells.(2) The study authors say their work - in a mouse model - provides proof of concept that inhibition of a sperm cell-specific form of adenylyl cyclase (sAC), an enzyme regulating the initial signalling events for activation of motility and capacitation, holds the potential to provide a safe, on-demand, non-hormonal and reversible oral contraceptive for men. Yet male contraception was not the first target for sAC. Thus, while working on sAC inhibitors as a treatment for an eye condition, a lab researcher at Weill Cornell Medical College in New York found that mice given a drug which inactivates sAC produce sperm cells which are unable to swim forward. The suggestion of a reversible contraceptive was enhanced by another group’s study that men who lacked the gene encoding sAC were infertile but otherwise healthy.

The newly reported study found that a single dose of a sAC inhibitor called TDI-11861 immobilises mouse sperm for up to 2.5 hours and that the effects persist in the female reproductive tract after mating. After three hours, some sperm began to regain motility; by 24 hours, nearly all sperms had recovered normal movement. When male mice treated with TDI-11861 were paired with female mice, they showed normal mating behaviour but did not impregnate the females, despite 52 different mating attempts. By contrast, male mice treated with an inactive control substance impregnated almost one-third of their female mates.

‘Our inhibitor works within 30 minutes to an hour,’ said the study’s first author in a press statement. ‘Every other experimental hormonal or non-hormonal male contraceptive takes weeks to bring sperm count down or render them unable to fertilise eggs.’ She added that it needs several weeks to reverse the effects of other hormonal and non-hormonal male contraceptives in development. But, because the effects of sAC inhibitors ‘wear off within hours’, men would take it only when and as often as needed - which ‘could allow men to make day-to-day decisions about their fertility’. The authors further noted that their studies now define sAC inhibitors as ‘leads for on-demand contraceptives for men’, and appear to meet ‘previously untested paradigms in contraception’, namely on-demand contraception after a single dose and a pharmacological intervention for men.

While other members of the group described the results as a possible game-changer, caution seems the more usual response in male contraception. Indeed, in this latest report, it still seems a long way from mice to men. Historically, developments from studies of hormonal methods have been inhibited by side effects, inconvenient routes of administration, and importantly a lack of commercial interest. And there’s always the ever-present question of whether a man would actually use any male method compliantly. The WHO, as it continues its ever-ongoing programme, is now enquiring just how willing male partners would be to use new male methods - and what attitudes their female partners might have.(3) ‘The burden of contraception will continue to be borne by their female partners until new male contraceptives are developed,’ the WHO reports.

New methods of male contraception is one of several strategic goals defined by the Male Reproductive Health Initiative, for which ‘there is an urgent need’. Indeed, at the SIG Andrology Campus meeting in Budapest in 2022 Richard Anderson, whose group in Edinburgh is involved in the clinical trials of the NES/T gel, said that there is enthusiasm for new methods among both men and women but current options were still not attractive. Meanwhile, the next step for the sAC inhibitor, according to the Weill Cornell press release, is to repeat the experiments in a different preclinical model. These experiments, it added, would lay the groundwork for human clinical trials that would test the effect of sAC inhibition on sperm motility in healthy men.

1. Thirumalai A, Amory JK. Emerging approaches to male contraception. Fertil Steril 2021; 115: 1369–1376.
2. Balbach M, Rossetti T, Ferreira J, et al. On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nature Communications 2023.
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