Current estimates indicate that about 50% of all pregnancies worldwide are unplanned. For men, the two available contraceptive options include a vasectomy or condoms, both of which are associated with certain limitations.
In a recent Nature Communications study, researchers identify a soluble adenylyl cyclase (sAC) inhibitor that has the potential to be used as an on-demand oral contraceptive for men.
Recent advances in male contraceptives
Several hormonal contraceptives have been investigated for their ability to interfere with spermatogenesis and ultimately limit the production of sperm. Despite success rates of up to 94% in clinical trials, most of these therapeutics were not pursued due to adverse side effects. Currently, a topical nestorone-testosterone gel is being investigated in many countries throughout the world.
Several non-hormonal strategies have also been investigated, such as Triptonide, which is an herb that causes sperm deformation that ultimately sterilized mice and nonhuman primates in preclinical trials. Epididymal peptidase inhibitors (EPPIN) are also non-hormonal agents that have been shown to block the activity of sperm in non-human primates.
The aforementioned hormonal and non-hormonal therapeutic strategies require several months of continuous treatment before they are considered to be effective. Furthermore, a similar period of time is required after cessation of the treatment for their effects to be reversible.
What is sAC?
Within the testes, specifically the cauda epididymis, mature sperm are stored in stable bicarbonate environment that is maintained at a concentration of about 5 millimolar (mM). During ejaculation, the exposure of sperm to semen leads to a rapid exposure to much higher bicarbonate levels of about 25 mM and subsequent activation of sAC.
Cyclic adenosine monophosphate (cAMP) is a crucial component throughout the sperm life cycle. The activation of sAC upon ejaculation leads to a rise in cAMP levels, which activates sperm motility and capacitation, both of which are crucial for the ability of sperm to fertilize the oocyte.
Notably, previous studies have indicated that despite the widespread distribution of sAC in mammalian tissues, distinct sAC isoforms can be found in sperm. Thus, inhibiting sAC could provide a safe approach for male contraception with limited off-target effects.
Oral sAC inhibitor is non-toxic and effective
Previously, the researchers of the current study identified several small molecule inhibitors that specifically target sAC in vitro to ultimately block several processes in both mouse and human sperm that are needed for fertilization. From this data, the researchers utilized their structure-assisted drug design efforts to identify a potent sAC inhibitor that exhibited drug-like properties and could withstand exposure to an inhibitor-free environment, such as the vagina after ejaculation.
These efforts led to the identification of TDI-11861, which tightly binds to sAC and inhibits adenylyl cyclase activity in vitro at a low concentration. In addition to being a more potent inhibitor, TDI-11861 was also found to exhibit a 200-fold longer residence time after binding to sAC.
Furthermore, this investigative drug was not found to pose any mutagenic or cytotoxic risks in vitro. When used to treat mice every day for seven days at 15-fold greater concentrations than its optimal in vitro dose, TDI-11861 was similarly non-toxic to the testis and epididymis, nor did its treatment increase the risk of kidney stone formation.
The efficacy of a single oral dose of TDI-11861 in mice was confirmed by the lack of increased cAMP levels one and three hours after treatment.
When isolated sperm from treated mice were diluted by 100-fold to mimic the inhibitor-free environment of the female reproductive tract, TDI-11861-treated sperm remained unresponsible to bicarbonate. This differed from a less potent sAC inhibitor TDI-10229, in which isolated sperm that were subsequently exposed to an inhibitor-free environment recovered their bicarbonate-induced cAMP responsiveness.
In addition to the increased stability of TDI-11861, a single oral treatment successfully inhibited the motility of sperm without inducing any cytotoxic effects on the sperm cells. Furthermore, TDI-11861 treatment did not cause any adverse effects in the behavior or ejaculation of the male animals.
The current study discusses the efficacy of a highly specific, non-toxic, non-hormonal, and on-demand sAC inhibitor that can act as an effective male contraceptive in vivo. Although these conclusions were based on mouse studies, the researchers anticipate that the sAC inhibitor will remain in the human vagina after ejaculation, thus limiting the ability of sAC-inhibited sperm to survive after sex.
As compared to all other existing pharmacological contraceptives for both men and women, the sAC inhibitor discovered in the current study does not require chronic treatment to be effective and renders a man to be infertile within 30 minutes of a single dose. Furthermore, fertility is restored the following day, which also differs significantly from current contraceptives that require several weeks to months to recover normal sperm activity.
Although future clinical trials are needed to confirm the safety and efficacy of this drug in humans, this innovative contraceptive strategy has the potential to revolutionize family planning.
- Balbach, M., Rossetti, T., Ferreira, J., et al. (2023). On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nature Communications 14; 637. doi:10.1038/s41467-023-36119-6.