Written by John K. Amory MD, MPH and William J. Bremner MD, PhD, University of Washington
While women usually produce a single egg every month, men make over 1,000 sperm every second—upwards of a hundred million in a day! Given those numbers, developing a male contraceptive that can suppress all those sperm is a formidable challenge. Nonetheless, several groups are up to the task, researching novel methods of contraception for men from three angles:
Hormonal contraceptives to suppress brain signals that direct the testes to make sperm
Non-hormonal contraceptives that inhibit sperm production in the testes or their maturation prior to ejaculation, and
Novel ways to plug the vas deferens.
Addressing male contraception hormonally
Here at the University of Washington and at the University of California-Los Angeles, we are working on daily topical applications of a testosterone/progestin combination gel. Trials will start soon in six countries where over 120 men and their partners will be enrolled. Earlier tests of this combination gel found 89% of men achieving sperm concentrations below 1 million—a very low level of sperm production with comparable contraceptive efficacy to the female oral contraceptive pill. Importantly, most study participants were very satisfied with the regimen and reported that they would use it if it were commercially available.
A newer hormone, dimethandrolone undecanoate (DMAU), which acts as both a progestin and an androgen, could serve as a single-agent contraceptive. Early clinical testing of this compound is ongoing.
The most common immediate side effects noted in male hormonal contraceptive studies are acne, decreased HDL “good” cholesterol, and mood changes; the long-term health impact of male hormonal contraceptives is still unknown. Knowing this, other researchers are pursuing non-hormonal options.
Evaluating non-hormonal options
Most non-hormonal contraceptives attack sperm production or function in the testes. While several new generation compounds have shown efficacy in animal testing, none has yet been tested in men. These include Adjudin, a compound that disrupts the process of sperm maturation by breaking the adhesion of immature sperm (spermatids) to Sertoli cells that ‘nurse’ developing sperm. To ensure that Adjudin effectively reaches the Sertoli cells without affecting other cells in the body, researchers at the Population Council have attached Adjudin to a slightly modified hormone specific to Sertoli cells. Before Adjudin can be studied in humans, researchers will have to develop an effective (and affordable) way to inhibit an autoimmune response to the modified hormone carrier. Adjudin would likely be administered by patch or implant.
H2-Gamendazole, which would be taken orally, is an anti-sperm compound that interferes with sperm maturation by inhibiting growth of the sperm head and tail. The unfinished sperm fragments are then reabsorbed into the body. Researchers are currently investigating potential tissue toxicity of gamendazole and how the female partner may be impacted physiologically if the compound remains in the semen. Using lower dosages of the compound in future trials may address these concerns.
Another way to deter sperm maturation is by inhibiting the conversion of retinol (Vitamin A) to retinoic acid, a process necessary for spermatogenesis. WIN 18,446 prevents such conversion by inhibiting the testes-specific enzyme, ALDH1A2. Unfortunately, WIN 18,446 interferes with alcohol metabolism so men who take WIN 18,446 and drink alcohol get violently ill. Here at the UW, we are focusing on development of novel, specific inhibitors of ALDH1A2 that don’t interfere with alcohol metabolism. Given the need for nearly complete suppression of sperm production, progress has been slow.
BMS-189453 also targets retinoic acid by working as a retinoic acid antagonist. The compound blocks retinoic acid receptors in Sertoli cells, thus disrupting sperm maturation. Already shown to be effective in mice, the drug will next be tested in primates.
Sperm cells contain novel proteins, some of which are ion transporters (e.g., CatSper; V4 Na K-ATPase) that play an important role in sperm motility. Compounds that specifically inhibit these transporters could theoretically function as contraceptives. Such compounds could be taken by men or women.
Long-acting, non-surgical, reversible contraception – an option for men?
Notably missing from the limited range of male contraceptive options is a long-acting, reversible method. Research into a “reversible vasectomy” began in the early 1990s with the development of RISUG, a temporary plug for the vas deferens that could be removed or dissolved by an injection at a later date. Initial studies of RISUG showed excellent contraceptive efficacy. Other efforts in this space currently include the Parsemus Foundation’s Vasalgel and Contraline’sEcho-V. Both approaches involve injections of polymer solutions into the vas deferens to block sperm passage. While neither product has yet been studied in humans, results from animal studies look promising.
Moving from R&D to Product Introduction
While articles on male contraception always seem to note that a new male method is “just 10 years away” from commercialization, we remain truly excited about ongoing R&D prospects. Non-surgical vasectomy options may become a reality in the next five years, with reversible options substantiated by 2025. We are hopeful that hormonal options will be commercialized in the next 10 years with novel, non-hormonal methods ready within 20. This optimism is based both on ongoing clinical research and also on new targets and models only starting to be researched. Our colleague, Dr. Martin Matzuk, will focus on these new areas in the next blog.
It is truly incredible that men can produce 1,000 sperm each second. The ability of scientists to discover ways to keep that production at bay will be instrumental in significantly changing the contraceptive landscape for men in the years ahead.
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