Written by Rebecca A.D. Cuellar, PhD, and Gunda I. Georg, PhD, The University of Minnesota’s Institute for Therapeutics Discovery & Development
Why is it that so much more emphasis and so many more resources are invested in developing contraceptives for women and not men? True, pregnancy has long been thought to be a woman’s problem but, as noted in the blog, “It Takes Two,” men are willing to share responsibility for family planning. There’s also the numbers game. To prevent pregnancy, you only have to keep one or a few eggs from being fertilized while millions of sperm are in play. Focusing on the female physiology means addressing a woman’s fertility for about 40 years. For men, the fertility window is around 68 years.
Another key reason? A multitude of direct physical risks are associated with pregnancy and childbirth, so the benefits of preventing pregnancy outweigh the risks of prescribing female birth control. Because men have no comparable physical risk of pregnancy/childbirth, any male contraceptive has to be universally and exquisitely without risk to justify administration to an otherwise healthy man.
In order to control male fertility non-hormonally, we must understand what we are trying to prevent. It is not merely the single moment of fertilization that needs addressing; we need to explore what happens throughout the sperm’s 88-day lifespan—from its formation through its potential fusion with an egg.
Days 1-15: Sperm Generation and Proliferation The estimated 300 meters of tightly coiled seminiferous tubules found in the testes are, in essence, sperm factories. The outer epithelium of these tubules are lined with tightly packed Sertoli cells that provide hormone nourishment to the developing sperm. Retinoic acid receptor alpha (RARa) antagonists are one molecular class that targets sperm alignment between the Sertoli cells’ tight junctions. Improperly aligned sperm do not progress to maturity.
Sertoli cells also protect the sperm-to-be by forming the blood-testis-barrier (BTB) that shields the sperm from the immune system and exposure to potentially harmful agents. The BTB is a key obstacle that scientists confront in trying to develop male contraceptives aimed at inhibiting spermatogenesis.
Days 16-40: Sperm DNA Established and Tail Formed During this phase, genetic determination occurs. Additionally, as the spermatocytes move from the outer epithelium towards the inner lumen, they change from spherical shapes to the classically recognized tailed structure. Contraceptive intervention during this phase could result in sperm that would be unable to move toward the egg. Exact mechanistic determination is still underway, but H2-Gamendazole is one such advanced contraceptive prospect currently in trials that targets sperm formation.
Days 41-74: Sperm Forward Motility Gained After reaching the lumen of the testis, spermatids move via peristaltic contractions towards the epididymis where they gain the ability to move on their own. One identified protein that can impair sperm motility in this phase is the cation channel of sperm (CatSper). Here at the University of Minnesota, a very active research effort is focused on identifying CatSper inhibitors. Such inhibitors would prevent the sperm from making significant forward progression. Other sperm motility research focuses on GAPDH-S inhibitors and, Na,K-ATPase inhibitors.
Days 75-82: Sperm Release From the epididymis, sperm are transported into the vas deferens where they receive continuing nourishment from secretions of the seminal vesicles, prostate, and Cowper glands. Now fully mature, sperm reside here until they enter the ejaculatory duct and exit the male body. As noted in “New Male Contraceptives: What’s in the Near-term Pipeline?,” several products under development would block sperm passage by inserting a polymer-based plug into the vas deferens.
Days 83-88: Sperm-Egg Fusion: Once introduced into the female reproductive tract, sperm undergo further maturation, known as hyperactivation and capacitation. Hyperactive motility enables a sperm to make strong forward progress toward the egg, while changes to its acrosomal cap enables it to bind to and penetrate the egg’s zona pellucida. TSSK (testis-specific serine/threonine kinase) plays a crucial role in this requisite acrosome reaction. TSSK has become an intriguing contraceptive molecular target because sperm with inhibited TSSK remain perfectly motile but are unable to attach to and fertilize the egg. Izumo and Juno in the sperm and egg, respectively, have also been identified as immuno-localized proteins responsible for sperm-egg fusion. Research efforts are targeting these proteins as well.
A final hurdle worth mentioning—sperm can survive for up to five days in the female reproductive tract. Any male contraceptive prospect that focuses on the sperm-egg fusion phase needs to be effective during this wide window. It cannot break down in the vagina’s acidic environment en route to the egg.
In the 56 years since the advent of modern female contraceptive methods, commercially available male contraceptive options have centered only on the sperm release phase. With today’s technological advancements, molecular biologists and medicinal chemists are now targeting multiple points along a sperm’s 3-month circuitous journey. That is exciting, bold, and way overdue.
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