Exploring Potential Methods of Male Contraception
Exploring Potential Methods of Male Contraception
Lise Bejtlich Thomas Jefferson High School for Science and Technology
This article placed 1st in the 2022 Teknos Summer Writing Contest.
Contraception has been a major topic of debate in religious, political, and social spheres for decades. The first birth control pill was approved by the Federal Drug Administration (FDA) in 1960, and despite intense controversy, more than 1.2 million prescriptions had been written within two years [7]. Since then, rapid scientific and technological advancements have made hormonal contraception much safer—particularly by minimizing the significant risk of blood clots—and more accessible. Today, birth control is available in a wide variety of forms, including patches, injections, and even implants. But there’s a catch: every product on the market is exclusively for women.
Besides the fact that women have traditionally shouldered social responsibilities related to childbearing, there are several significant differences between men and women with regard to reproductive physiology. Women are only able to become pregnant during ovulation, a one-to-two-day window every month. At that time, gonadotropin-releasing hormone (GnRH) produced in the hypothalamus triggers the pituitary gland to increase levels of luteinizing hormone (LH) [8] and follicle-stimulating hormone (FSH), which lead to the release of an egg from the ovaries [9]. In order to prevent pregnancy, hormonal contraceptive methods primarily contain progestins. These chemicals mimic the effects of the naturally-produced hormone progesterone, which blocks sperm from the uterus by thickening mucus in the cervix after ovulation has ended [5]. Additionally, progestins inhibit GnRH and LH, thus suppressing ovulation, although the endocrine pathway is not well understood. Some medications also include estradiol (synthetic estrogen), which inhibits FSH. By using a contraceptive and artificially extending these sperm-unfriendly circumstances throughout the entire menstrual cycle, it is possible to prevent pregnancy up to 99% of the time, and a woman may choose to halt contraception at any time and restore her reproductive ability almost immediately.
Since men normally possess reproductive function at all times from the onset of puberty towards the end of their lives, inducing a reversible state of temporary infertility requires a novel change in the reproductive environment. The primary challenge is that testosterone drives the production of fertile sperm, but it is so closely connected to bone strength that completely suppressing it would result in undesirable and potentially dangerous side effects [4]. In recent years, a number of researchers have worked towards solving the testosterone problem, though no products as of yet are close to being brought to market. This paper will explain three methods currently in development and discuss another future option.
The most widely promoted treatment is dimethandrolone undecanoate (DMAU), a synthetic androgen developed by the National Institutes of Health which suppresses FSH and LH while preserving normal functions dependent on the presence of testosterone. In men, the testicular Leydig cells respond to LH by producing testosterone, and the testicular Sertoli cells respond to FSH by aiding in the process of creating sperm cells [10]. DMAU significantly and reversibly reduces testicular function by inhibiting both. Unfortunately, although DMAU has worked well in rabbits [2] and been verified for safety in adult men [11], there is currently no data as to whether it truly suppresses sperm count, and whether there are reliably few side effects. There were only a handful of primary or secondary studies testing it at all within the past five years. This is likely due in part to a study in 2010 that determined that DMAU had a relatively high risk of liver toxicity, particularly cholestatic hepatitis [6], a blockage of bile flow caused by overuse by many synthetic androgens—similar to the damaging effects of athletic performance-enhancing drugs. This potential for androgenic damage to the liver, compared to the lower risk of estrogen metabolism, indicates that developing effective oral contraception for men is much more challenging than for women.
One potential option to mitigate oral ingestion risks is the introduction of a physical barrier for the sperm. A private company, the Parsemus Foundation, has developed and researched a high-weight polymer known as Vasalgel. Similarly to a previously studied product called RISUG (Reversible Inhibition of Sperm Under Guidance), this gel is directly injected into the vas deferens tubes which connect the testicles to the urethra, preventing the movement of sperm. In one 2017 study, Vasalgel appeared safe and effective in rhesus monkeys [3]—but that very same year, another study showed that sperm function was significantly impaired after the reversal procedure, a sodium bicarbonate injection [12]. Even if the gel functioned perfectly, there is a necessity in public health to provide contraceptive measures that are both easy to access and easy to quit, if the patient so desires. Non-self-administration procedures exist for women, such as the arm implant and the intrauterine device (IUD), but they are not the only options, and should not be.
Returning to oral contraceptives, it is evident that extreme specificity is necessary when attempting to develop male contraception. At this point in scientific progress, it is generally not safe or feasible to interfere with testosterone entirely, or even with major related chemicals like FSH and LH. Thus, the most recent significant development in the field of male contraception is an extremely specific antagonist that targets receptors for retinoic acid. In general, retinoic acid is important in cell growth, differentiation, and embryonic development, and plays a significant role in sperm generation in adult men. However, researchers identified that there are three different receptors of retinoic acid (RAR-ɑ, RAR-β, and RAR-ɣ) which all bind to the same ligand, but with very slightly different structures. One molecule was successfully identified as inhibiting RAR-ɑ alone—important to ensure minimal side effects from inhibiting beta and gamma receptors. Inhibiting RAR-ɑ in mice was enough to prevent pregnancy with 99% efficacy, and fertility returned 4-6 weeks after halting treatment. Although the paper was presented at the American Chemical Society in March 2022, it is not yet available online. The researchers hope to begin human trials later in 2022, first focusing on safety before considering efficacy [1].
Finally, there is one potential option that has not yet been studied in a lab setting. To provide context, one of the most important organs in the testicular system is the epididymis, a complicated series of ducts which provides a specialized environment for the maturation of functional sperm cells. Both secretion and absorption of small molecules in the microenvironment are of great importance, impacting pH and osmolarity. There is a long list of genes that influence different aspects of the epididymal environment, related to everything from Na+ reabsorption (Erɑ, Nhe3) to dysfunction of clusterin, a ubiquitous protein associated with apoptosis (Apoer2) [13]. Most identified genes are linked to multiple systems of the body, so full suppression would likely lead to undesirable side effects, but it is possible that selectively blocking receptors in the reproductive system could lead to a reversible change in the epididymal environment and make it temporarily uninhabitable for sperm.
Considering the breadth, depth, and variety of research in the field, it is likely that in the coming years, medicinal contraception will no longer be limited to women. This will prove to be an enormous step forward for safety and equity in public health; women whose bodies react poorly to contraception may have the option of extra caution from their partners, and men will be able to exercise greater bodily autonomy. It remains to be seen whether the first product on the market will be hormonal, like DMAU, ultra-specific, like RAR-ɑ inhibition, or relatively invasive, like Vasalgel. Ultimately, any option will promote bodily autonomy, safer sex, and greater peace of mind.
References
[1] A non-hormonal pill could soon expand men’s birth control options. (2022). American Chemical Society. https://www.acs.org/content/acs/en/pressroom/newsreleases/2022/march/non-hormonal-pill-could-soon-expand-mens-birth-control-options.html
[2] Attardi, B.J., Engbring, J.A., Gropp, D. and Hild, S.A. (2011), Development of Dimethandrolone 17β-Undecanoate (DMAU) as an Oral Male Hormonal Contraceptive: Induction of Infertility and Recovery of Fertility in Adult Male Rabbits. Journal of Andrology, 32: 530-540. https://doi.org/10.2164/jandrol.110.011817
[3] Colagross-Schouten, A., Lemoy, M. J., Keesler, R. I., Lissner, E., & VandeVoort, C. A. (2017). The contraceptive efficacy of intravas injection of Vasalgel™ for adult male rhesus monkeys. Basic and Clinical Andrology, 27, 4. https://doi.org/10.1186/s12610-017-0048-9
[4] Harvard Health. (2019, August 29). Testosterone — What It Does And Doesn’t Do. https://www.health.harvard.edu/medications/testosterone--what-it-does-and-doesnt-do
[5] He, W., Li, X., Adekunbi, D. et al. Hypothalamic effects of progesterone on regulation of the pulsatile and surge release of luteinising hormone in female rats. Sci Rep 7, 8096 (2017). https://doi.org/10.1038/s41598-017-08805-1
[6] Hild, S. A., Attardi, B. J., Koduri, S., Till, B. A., & Reel, J. R. (2010). Effects of synthetic androgens on liver function using the rabbit as a model. Journal of Andrology, 31(5), 472–481. https://doi.org/10.2164/jandrol.109.009365
[7] Kao, A. (2000, June 1). History of Oral Contraception. Journal of Ethics | American Medical Association. https://journalofethics.ama-assn.org/article/history-oral-contraception/2000-06#:%7E:text=The%20Food%20and%20Drug%20Administration,as%20it%20is%20popularly%20known
[8] Karsch, F. J., Bowen, J. M., Caraty, A., Evans, N. P., & Moenter, S. M. (1997). Gonadotropin-releasing hormone requirements for ovulation. Biology of reproduction, 56(2), 303–309. https://doi.org/10.1095/biolreprod56.2.303
[9] Orlowski M., Sarao M. S. Physiology, Follicle Stimulating Hormone. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing (2022). https://www.ncbi.nlm.nih.gov/books/NBK535442/
[10] Sharpe, R. M., Fraser, H. M., Cooper, I., & Rommerts, F. F. (1981). Sertoli-Leydig cell communication via an LHRH-like factor. Nature, 290(5809), 785–787. https://doi.org/10.1038/290785a0
[11] Thirumalai, A., Ceponis, J., Amory, J. K., Swerdloff, R., Surampudi, V., Liu, P. Y., Bremner, W. J., Harvey, E., Blithe, D. L., Lee, M. S., Hull, L., Wang, C., & Page, S. T. (2019). Effects of 28 Days of Oral Dimethandrolone Undecanoate in Healthy Men: A Prototype Male Pill. The Journal of Clinical Endocrinology and Metabolism, 104(2), 423–432. https://doi.org/10.1210/jc.2018-01452
[12] Waller, D., Bolick, D., Lissner, E., Premanandan, C., & Gamerman, G. (2017). Reversibility of Vasalgel™ male contraceptive in a rabbit model. Basic and Clinical Andrology, 27, 8. https://doi.org/10.1186/s12610-017-0051-1
[13] Zhou, W. (2018). Characteristics of the Epididymal Luminal Environment Responsible for Sperm Maturation and Storage. Frontiers. https://www.frontiersin.org/articles/10.3389/fendo.2018.00059/full
