A New Age for Birth Control: Reversible Male Contraceptives on the Horizon

In November of 2016, you may have seen a version of a headline like this: “Male birth control study nixed after men can’t handle side effects women face daily” [1]. Steeped in some truth (a study was indeed cancelled after men experienced harsh side effects similar to what many women experience [2]) and masked by outrage (from readers and authors who didn’t know that the severity of side effects far exceeded those felt by women), the news clearly struck a chord with many people who wish for the burden of birth control to be shared by men and women. Highly effective and reversible birth control has been available for women since 1960, when the FDA approved Enovid® (“the pill”) for use as a contraceptive [3]. For men, currently the best options are condoms (which are only 82% effective [4]) and vasectomies (which are only partially reversible [5]). Despite the current lack of options, there are many potential approaches to male birth control that are currently in development. Some, like the study mentioned above, utilize hormones to stop the production of sperm. Others use non-hormonal methods to physically block the delivery of sperm.

To fully understand the methods that are currently in development, we first need to understand the male reproductive system and generation of sperm. In the testes there exist multiple specialized cells including sperm stem cells, Sertoli cells, and Leydig cells. These cells all remain in close contact with each other, sending and receiving hormonal signals that ultimately result in the production of sperm from the sperm stem cell. These mature sperm then travel through the vas deferens for ejaculation. Hormonal methods of birth control aim to stop the production of sperm, whereas physical methods of birth control aim to stop sperm traveling through the vas deferens.

To prevent spermatogenesis, or the production of sperm, hormonal birth control interferes with the normal hormonal signals involved. Normally, spermatogenesis requires a very high local concentration of testosterone by sequestering the testosterone with a specific receptor made by Sertoli cells. These receptors grab and hold on to the testosterone, keeping it close to the cells that need it. The testosterone itself comes from the nearby Leydig cells, which know to make testosterone after getting a signal from Gonadotropin Releasing Hormone (GnRH) that is released from the hypothalamus in the brain. When GnRH is released, it stimulates Leydig cells to make testosterone, which Sertoli Cells keeps nearby for sperm production. Interestingly, the release of GnRH is part of a negative feedback loop. When there is enough testosterone from the Leydig cells, the release of GnRH in the hypothalamus stops, preventing excess production of testosterone. When testosterone levels fall, GnRH release is stimulated and the loop starts again (Figure 1) [6].

Figure 1: The negative feedback loop of sperm production. (Image credit and compiled by Stephanie DeMarco)

This feedback loop provides the basis for many of the male hormonal birth control methods currently being tested. Administering excess testosterone through an injection or pill prevents the secretion of GnRH, and subsequently the production and sequestration of testosterone that is required for the production of sperm. Similar to testosterone feedback, administration of progestins, a synthetic hormone, can also inhibit the secretion of GnRH, and many combination therapies include both testosterone and progestin to prevent the development of sperm [6].

There are side effects associated with the administration of testosterone and progestins, however. The study that was pulled last year [2] was administering an injection of a combination of progestins and testosterone, and they found almost all of their participants experienced severe side effects including depression, acne, pain at the injection site, moodiness and increased libido. Many clinical trials are now aiming to determine both the best method of administration (orally, by injection, by implant, or as a gel) and the best dosages to maximize efficacy and minimize side effects.

In addition to hormonal methods, there are also reversible physical methods in trials that rely on blocking the transport of mature sperm through the vas deferens, similar to how a vasectomy physically cuts the vas deferens, but with a better reversibility rate. Internationally, a compound called RISUG® has undergone multiple trials in India, with patients from the first trials currently in their 15th year of protection. RISUG® is a gel that solidifies when injected into the vas deferens. Not only does it provide a physical barrier to sperm, but the gel also contains ions that interfere with the sperm so that any sperm that does get through is non-viable. To reverse the treatment, a second injection is administered that dissolves the gel; however, this reversal has not yet been tested in humans, only primates [7, 8]. A similar product, Vasalgel™, is currently in development in the United States, and is expected to start clinical trials sometime in 2017 [8].

While we likely won’t see approval of any of these methods in 2017, the new year should bring with it new developments in each of these technologies. Vasalgel™ is expected to start its first clinical trials in America, RISUG® will continue to expand its Phase III clinical trials, and multiple ventures will seek out the perfect combination of testosterone and progestins. Obviously, this will be no easy task, especially in light of the harsh side effects that made headlines last year. However, this research is still incredibly important in closing the gender gap for responsible reproductive health. It’s been 57 years since the female pill was approved, and hopefully soon we’ll see a convenient and reversible method for men too.

Lynnea Rae Waters (lynnearaewaters.weebly.com)
lynneawaters@gmail.com
Guest Contributor, Signal to Noise Magazine
PhD Candidate, UCLA Molecular Biology IDP: Immunity, Microbes and Molecular Pathogenesis

References:

[1] Hafner, J. Male birth control study nixed after men can’t handle side effects women face daily. USA Today (2016, Nov 2).

[2] Behre, H. M. et al. Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men. J Clin Endocrinol Metab 101(12), 4779-4788 (2016).

[3] Christin-Maitre, S. History of oral contraceptive drugs and their use worldwide. Best Practice & Research Clinical Endocrinology and Metabolism 27(1), 3-12 (2013).

[4] Center for Disease Control. Effectiveness of family planning methods (2011).

[5] Belker, A. M., Thomas, A. J. Jr., Fuchs, E. F., Konnak, J. W. & Sharlip, I. D. Results of 1469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. J Urol 145(3), 505-511 (1991).

[6] Wang, C. & Swerdloff, R. S. Hormonal approaches to male contraception. Cur Opin Urol 20(6), 520-524 (2010).

[7] Parsemus Foundation. Vasalgel, a multi-year contraceptive (2016).

[8] Lohiya, N. K. et al. RISUG: An intravasal injectable male contraceptive. Indian J Med Res 140(7), 63-72 (2014).