By Natale Hall

The use of contraception among humans is a practice nearly as old as human civilization itself. The earliest known record of pregnancy prevention was described in an ancient Egyptian papyrus roll dating back to 1850 B.C.¹ Over the next thousand years, birth control evolved (thankfully) from inserting acacia leaves into the vagina to a variety of hormonal and non-hormonal options women can choose from today. However, despite centuries of research investigating how best to regulate female reproduction and physiology to prevent conception, the family planning industry is severely lacking in reliable and realistic male birth control options. In fact, there have been no new FDA-approved reversible methods of male birth control since the invention of the condom in the 1850s. However, recent studies indicate the concept of male contraception is no longer as radical as it once was, with several multinational surveys indicating that more than half of male participants would take birth control if available.^2,3 Luckily, for those men, several emerging non-hormonal and hormonal male birth control options may see FDA approval in the coming years. One such option includes an inhibitor of soluble adenylyl cyclase (sAC), which could be the first on-demand male contraceptive in history. 

In mammals, bicarbonate-regulated soluble adenylyl cyclase (sAC) is one of two families of adenylyl cyclase that produces cyclic AMP (cAMP), an important signaling molecule in the body.⁴ sAC plays a vital role in sperm capacitation, a series of physiological changes that allows sperm to fuse with and fertilize an egg. Sperm is produced in the testicles and then stored in the cauda epididymis under a tightly regulated bicarbonate concentration of around 5 mM. During ejaculation, sperm mixes with semen, which has a much higher bicarbonate concentration of approximately 25 mM. Exposure to these high bicarbonate levels activates sAC in the sperm cells and begins a signaling cascade resulting in sperm capacitation, as shown in Figure 1.⁵ The increase in bicarbonate concentration in the sperm environment during ejaculation emphasizes the need for sAC in the fertilization capacity of sperm. Studies from as early as 2004 reported sAC knockout mice were sterile and produced sperm displaying significant defects in motility.⁶ Since then, the goal has been to produce temporary infertility in males through targeting and inactivating sAC activity. After 20 years, a viable method has been developed: an inhibitor of sAC called TDI-11861.

Developed by researchers at the Tri-Institutional Therapeutics Discovery Institute,⁷ TDI-11861 inhibits sAC activity by binding to two different sites on the enzyme. The first site that TDI-11861 blocks is the bicarbonate binding pocket of sAC. This prevents enzyme activation when exposed to the high bicarbonate concentration during ejaculation, subsequently arresting sperm capacitation. TDI-11861 also binds to the active site of sAC, inhibiting cAMP formation and downstream signaling. When tested in vitro using mouse and human sperm cells, TDI-11861 was found to lower intracellular cAMP levels, decrease sperm flagellar beat frequency, stop the sperm from “swimming,” and prevent the fusion of the sperm with the egg plasma membrane during fertilization. Comparable results followed after male mice were given an oral dose of TDI-11861 both in vivo, when sperm were surgically removed, and ex vivo, when sperm were ejaculated. After such promising results, the only remaining question is will TDI-11861 successfully stop conception?

And the answer? Not only is TDI-11861 effective in preventing pregnancy, but so far it is outperforming every known method of birth control on the market! When 52 male mice were injected with the compound and paired with reproductively mature females from 30 minutes to 2.5 hours post-injection, there were zero pregnancies.⁷ In other words, TDI-11861 demonstrated a contraceptive efficacy of 100% for up to 2.5 hours, higher than the most effective female birth control (the implant) which is about 99% effective, and much higher than the most common female birth control (the oral contraceptive pill) which is about 91% effective, as displayed in Figure 2. Although the efficacy of TDI-11861 decreases to about 91% at 3 hours post-injection,⁷ the drug’s effectiveness is still on par with the aforementioned female birth control options. Another noteworthy result is when TDI-11861 was administered to male mice, it resulted in no measured side effects on long-term sperm function, male fertility, conception, physiology of other systems, and behavior.⁷ If the absence of side effects translates to humans,  it is a significant advantage over female contraception methods, each of which has numerous side effects including irregular menstruation, nausea, headaches, emotional instability, bone density loss, weight gain, and even increased risk of blood clots.⁸ Finally, the intended use of TDI-11861 is unique for an oral contraceptive and is designed to be taken about 30 minutes to 2 hours before sexual intercourse. By taking TDI-11861 on-demand when needed, men will have complete agency over their role in pregnancy prevention without the long-term commitment many women make to their birth control method. Skeptical about men adhering to an as-needed pill? Millions of men manage to take Viagra, which works in an analogous way.

While the idea of male birth control may have once seemed farfetched, today it is close to becoming a reality. One of the top contenders for a male contraceptive is TDI-11861, an inhibitor of an enzyme essential to sperm function. In pre-clinical mouse studies, TDI-11861 has shown powerful pregnancy prevention capabilities rivaling even the most effective birth control methods currently used by women, with none of the side effects. Although additional experiments must be conducted before moving to clinical trials, if the drug continues to succeed, it could become the first pharmacological contraceptive for men. Such a monumental development would no doubt usher in a new era of sexual and reproductive health in which the responsibility of preventing pregnancy does not fall entirely on women. As the saying goes, it takes two to tango, so why should it be any different for contraception?

TL;DR

• Reliable, realistic male birth control options are severely lacking.
• TDI-11861, a sAC inhibitor, suppresses sperm motility and effectively prevents pregnancy in mice.
• TDI-11861 would be the first nonhormonal pharmacological male contraceptive.

---

Reference

1. Lipsey, Richard G., et al. “Historical Record on the Control of Family Size.” Economic Transformations: General Purpose Technologies and Long-Term Economic Growth, Oxford University Press, Oxford, 2012, pp. 335–340.

2. Martin, C. W., Anderson, R. A., Cheng, L., Ho, P. C., van der Spuy, Z., Smith, K. B., Glasier, A. F., Everington, D., & Baird, D. T. (2000). Potential impact of hormonal male contraception: cross-cultural implications for development of novel preparations. Human reproduction (Oxford, England), 15(3), 637–645. https://doi.org/10.1093/humrep/15.3.637

3. Heinemann, K., Saad, F., Wiesemes, M., White, S., & Heinemann, L. (2005). Attitudes toward male fertility control: results of a multinational survey on four continents. Human reproduction (Oxford, England), 20(2), 549–556. https://doi.org/10.1093/humrep/deh574

4. Ritagliati, C., Ayoub, S., Balbach, M., Buck, J., & Levin, L. R. (2023). In vivo characterization of sAC null sperm. Frontiers in cell and developmental biology, 11, 1134051. https://doi.org/10.3389/fcell.2023.1134051

5. Wen, Z., Lei, Z., Tian, E., Wang, Y., Zhong, Y., & Ge, R. S. (2021). Inhibition of human sperm motility and capacitation by ziram is mediated by decreasing tyrosine protein kinase. Ecotoxicology and environmental safety, 218, 112281. Advance online publication. https://doi.org/10.1016/j.ecoenv.2021.112281

6.  Xie, F., Garcia, M. A., Carlson, A. E., Schuh, S. M., Babcock, D. F., Jaiswal, B. S., Gossen, J. A., Esposito, G., van Duin, M., & Conti, M. (2006). Soluble adenylyl cyclase (sAC) is indispensable for sperm function and fertilization. Developmental biology, 296(2), 353–362. https://doi.org/10.1016/j.ydbio.2006.05.038

7. Balbach, M., Rossetti, T., Ferreira, J., Ghanem, L., Ritagliati, C., Myers, R. W., Huggins, D. J., Steegborn, C., Miranda, I. C., Meinke, P. T., Buck, J., & Levin, L. R. (2023). On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nature communications, 14(1), 637. https://doi.org/10.1038/s41467-023-36119-6

8. Britton, L. E., Alspaugh, A., Greene, M. Z., & McLemore, M. R. (2020). CE: An Evidence-Based Update on Contraception. The American journal of nursing, 120(2), 22–33. https://doi.org/10.1097/01.NAJ.0000654304.29632.a7