TRIPTONIDE, a natural compound that can either be purified from the Chinese Tripterygium wilfordii Hook F herb or produced through chemical synthesis, has proved to be an effective, safe, and reversible male contraceptive agent in preclinical animal models. These findings are of particular therapeutic importance because there are currently no nonhormonal male contraceptives available.
Dr Wei Yan, an investigator with The Lundquist Institute, Torrance, California, USA and research colleagues initially administered triptonide at five doses via oral gavage to adult mice between the ages of 8–12 weeks. Mice from each of the dosing groups were sacrificed at weekly intervals to investigate various epididymal sperm parameters. The shortest time required to induce deformed sperm with a complete lack of forward motility (approximately 100% penetrance) was 3–4 weeks at a single daily dose of 0.8 mg/kg/body weight. Similarly, studies in male cynomolgus monkeys revealed that single daily oral doses of 0.1 mg/kg/body weight triptonide resulted in sperm deformation and reduced sperm counts and motility after 5–6 weeks.
Further investigation demonstrated that male fertility was regained within approximately 4–6 weeks of triptonide treatment cessation. Lastly, neither short- nor long-term triptonide treatment was found to cause discernible systematic toxic effects (as revealed by histological examination of vital organs in mice and haematological and serum biochemical assays in monkeys).
In order to determine the molecular mechanism that underlies the effect of triptonide treatment, the drug affinity responsive target stability assay was employed. Triptonide appeared to bind junction plakoglobin and therefore disrupted its downstream interactions with SPEM1 during spermiogenesis. This ultimately results in a phenotype similar to that of Spem1 gene knockout mice models, which are characterised by sperm deformation and male infertility.
Going forward, targeting late spermiogenesis would therefore be an effective strategy for the development of nonhormonal male contraceptives.
Commenting on the wider relevance of the research findings, Dr Yan stated: “We are very excited that the new idea worked and that this compound appears to be an ideal male contraceptive. Our results using noninjurious studies on lower primates suggest triptonide will be an effective treatment for human males as well. Hopefully, we will be able to start human clinical trials soon to make the nonhormonal male contraceptive a reality.”