Art courtesy of Noora Said.
Oral birth control, commonly referred to as “the pill,” is prescribed to millions of women in the United States as a convenient and effective way to prevent pregnancy, treat acne, regulate periods, and more. While the pill in the 1950s marked a triumph for women’s reproductive rights, the history of birth control is one deeply rooted in injustice. From the propagation of eugenics ideology to the mass sterilization of Puerto Rican women during the Rio Piedras clinical trials, the development of oral contraception directly targeted impoverished Black and Brown communities in the United States.
Even today, the economic and health-related burdens associated with preventing pregnancy fall predominantly on women. This has long been due to the lack of birth control options available to men. While women have over ten birth control options including barrier (condoms, diaphragms, and sponges), hormonal (pills, patches, shots, and rings), and long acting, reversible contraceptive methods (IUDs and implants), men only have two: condoms and vasectomies.
After twenty years of studying sperm formation, researchers at the Lundquist Institute at Harbor-UCLA Medical Center have recently discovered that triptonide, a compound purified from the Chinese herb Tripterygium wilfordii Hook F, can demonstrate reversible contraceptive abilities in men. With this finding, a reversible non-hormonal male contraceptive may be on the horizon, making equitable reproductive health a possibility.
For over five decades, researchers have been working on developing contraceptive pills for men with no success. Previously, the mainstream approach for developing male contraceptives involved blocking sperm production. The belief was that if sperm counts were reduced to zero, there would be no sperm available to fertilize eggs and, therefore, pregnancy would be prevented. The problem with this approach, however, is that it requires depletion of sperm precursor cells, which is hard to achieve and tends to cause significant side effects.
Wei Yan, principal investigator of the study, explored a new, innovative approach for developing male contraceptives. Instead of depleting all sperm cells, Yan sought to disable sperm by causing deformation during spermiogenesis, the maturation process of spermatids (immature male germ cells) into sperm. By disrupting the final steps of sperm assembly, Yan theorized that sperm would become incompetent, or unable to fertilize eggs, due to their malformation, while sperm count and testis size would be largely preserved.
Towards this goal, the researchers combed databases containing thousands of drug candidates with documented side effects in search of a compound with sperm deforming effects. Tripterygium wilfordii Hook F, sometimes called thunder god vine, has long been used in traditional Chinese medicine to treat autoimmune and inflammatory diseases like rheumatoid arthritis and lupus. Ever since the first reported cases of infertility in men after taking this herbal medicine, researchers have spent years isolating and purifying different compounds of this herb in an effort to identify which specific compound caused deformed sperm. However, many of these purified compounds caused severe liver toxicity or had limited reversibility of contraceptive ability. In hopes of isolating a compound of the herb that demonstrated reversibility in male fertility without serious side effects, the researchers persisted in their testing and ultimately observed that triptonide displayed the desired contraceptive properties.
After administering triptonide at different doses to adult male mice, the researchers found that between three and four weeks, daily oral consumption of triptonide at a dose of 0.8mg/kg body weight (BW) induced deformed sperm with limited forward motility, successfully causing infertility. Repeating this experiment with cynomolgus monkeys, the researchers similarly observed that daily intake of triptonide at 0.1mg/kg BW for five to six weeks led to male infertility due to disabled sperm. In both mice and monkeys, the induced infertility was found to be fully reversible, meaning that fertility was regained between four to six weeks after stopping consumption of the contraceptive. This reversibility in contraceptive effects is essential in granting the consumer more flexibility over his own fertility.
The testes of both mice and monkeys maintained normal morphology without any severe cell depletion, meaning sperm counts remained relatively normal during triptonide treatment. The difference between triptonide-treated and control animals was that the former displayed deformed sperm, particularly a “head-bent-back” phenotype with complete inability of forward motility.
To understand what this looks like, picture sperm as a tadpole, containing both a head and a tail. Spermatids, the precursors to sperm, are round and do not have a tail. In order to mature into sperm, spermatids undergo an elongation process in which the head becomes compacted and the tail forms through gradual elongation. This coordinated process is controlled by the gene SPEM1, which allows the tail and head to grow proportionally.
Normally, SPEM1 interacts with a protein called junction plakoglobin; however, in the presence of triptonide, this interaction is blocked due to junction plakoglobin’s higher binding affinity to triptonide. When SPEM1 and junction plakoglobin are unable to bind, the elongation process of spermatids is disrupted. “The consequence [of inhibiting the SPEM1 gene] is that you’re going to have a head that is all bent back and sometimes the tail actually starts wrapping around the head,” Yan said.
Deformed sperm are unable to fertilize eggs because of their inability to swim vigorously to meet the egg and because defective sperm tails are not strong enough to penetrate the egg during fertilization. With the inhibition of SPEM1, spermiogenesis lacks a checkpoint mechanism to eliminate deformed spermatids. Importantly, this missing “quality control” is advantageous to birth control safety because normal sperm counts are preserved.
Because two abundant compounds of the Chinese herb—triptolide and triptochloride—are known for causing liver toxicity, many grant reviewers rejected Yan’s applications because of the herb’s notorious reputation.
“At a certain point, I wanted to give up because [the project] just didn’t go anywhere without funding,” Yan said. “I was lucky enough to secure private funding.”
Now that triptonide has successfully displayed reversible contraceptive effects in both male mice and monkeys without side effects, when can it be used by human men? Before any clinical trials, the Food and Drug Administration (FDA) must approve the drug’s Investigational New Drug (IND) status. Before that, pharmacokinetics and toxicology studies must be conducted to further assess safety and metabolism of the drug in the body. Ultimately, securing further funding is the prerequisite to move this project forward.
So why has it taken so long to make progress in developing male contraceptives? While funding poses a challenge, Yan believes the underlying reason is because of lack of success with popular methodologies. As described previously, the standard research approach for inducing male infertility has historically been sperm depletion. Finding a chemical that can deplete all sperm cells without causing adverse effects has proven difficult.
“A popular joke in the field is that male contraceptives have been five years away for fifty years,” Yan said. With the success of treating animals with triptonide, Yan hopes that he can find enough financial support to bring triptonide drugs onto the market. Not only will this achievement allow for shared contraceptive responsibility between men and women, but it will also provide men with more autonomy over their reproductive health. After all, according to Yan, “to control your own fertility is a basic human right.”
Chang, Z., Qin, W., Zheng, H., Schegg, K., Han, L., Liu, X., … & Yan, W. (2021). Triptonide is a reversible non-hormonal male contraceptive agent in mice and non-human primates. Nature communications, 12(1), 1-14.