On February 23, 2023, a senior researcher at the rehnquist Institute, a professor's research group at UCLA, and a research group at the Guangdong Institute of Family Planning Science and Technology jointly published a research report entitled "Triprenone is a reversible non-hormonal male contraceptive and non-human primer in male mice", which brought an ideal male contraceptive product.
It is reported that oral administration of triptolide can induce sperm malformation in male rats and male cynomolgus monkeys, so that sperm lose motility and fertilization ability, thus achieving contraceptive effect. Experiments show that the effective rate of this method is close to 100%, and there is no obvious side effect. Once the drug is stopped, the male fertility can be completely restored. The target and contraceptive mechanism of triptolide were also preliminarily expounded, and it was considered that triptolide was a candidate drug for non-hormonal male contraception with great transformation and application prospects.
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As early as 2009, Professor Wei Yan put forward the idea of developing male non-hormonal contraceptives with the goal of haploid stage of spermatogenesis [2]. In the process of searching for compounds that can act on key proteins in the late stage of sperm assembly, nearly 100 kinds of compounds (F, figure 1A) purified from Tripterygium wilfordii hook. F attracted the attention of Professor Wei Yan. As a traditional Chinese medicine, tripterygium wilfordii is often used to treat rheumatoid arthritis, nephritis and lupus erythematosus. [3], but long-term use of this medicine often causes male infertility [4]. This has attracted the attention of researchers, trying to find "anti-sperm" components from tripterygium wilfordii extract [5-9].
Figure 1. (1): Tripterygium wilfordii. (b, c): the offspring of male rats and male cynomolgus monkeys whose fertility recovered after drug withdrawal.
Although triptolide and triptolide are two compounds with high content in Tripterygium wilfordii, they show serious hepatotoxicity and fertility irreversibility in the study [10- 13]. On 20 12, Professor Wei Yan found that Tripitong has good contraceptive effect and reversibility in male rats through continuous exploration. In order to further test the effectiveness of this compound in primates, our research team cooperated with Tang's research team.
In this new study, the researchers first discussed the contraceptive effect and long-term effect of triptolide on male mice and cynomolgus monkeys. Male adult mice were given triptolide 0.8 mg/kg (the lowest effective dose) every day for 4 weeks, and their sperm were severely deformed and lost vitality, which could not make the fertile female mice pregnant. However, male adult cynomolgus monkeys (9- 13 years old, 4.96- 1 1.8kg) took triptolide 0. 1mg/kg (the lowest effective dose) orally for 5 weeks, and their sperm began to deform, their vitality decreased, their number decreased, and they failed to make them fertile. Long-term drug use in mice for 6 months and cynomolgus monkeys for 126 weeks (2.4 years) can maintain long-term infertility without obvious side effects.
Then, the researchers discussed the contraceptive reversibility of triptolide to male mice and cynomolgus monkeys. Male C57BL/6 mice took 0.8mg/kg triptolide orally for 4 weeks, and then stopped taking it. After 4 weeks, the sperm morphology and sperm motility of the mice returned to normal, which enabled the fertile female mice to get pregnant and give birth to healthy offspring (figure 1B). After oral administration of 0. 1mg/kg triptolide for 8 weeks and 5-6 weeks, the sperm morphology, sperm motility and sperm number of cynomolgus monkeys returned to normal, enabling female cynomolgus monkeys to get pregnant and give birth to healthy monkeys (Figure 1C).
Unlike other drugs, contraceptives are given to normal adults, so their safety is very important. In this study, the researchers systematically discussed the safety of triptolide. During the oral administration of triptolide to adult male cynomolgus monkeys, there was no obvious abnormality in appetite, sleep, mental state, blood routine, liver and kidney function and hormone level. In male mice, the EC50 of triptolide is 0. 1mg/kg, which is far lower than its minimum effective dose of 0.8mg/kg and LD50 300mg/kg.
Researchers screened and identified the target of triptolide as JUP by DARTS technology, glycolic acid magnetic bead affinity purification technology and mass spectrometry technology, and put forward a new mechanism of triptolide contraception: triptolide combined with JUP interfered with the combination of JUP and SPEM 1, resulting in severe sperm deformation, decreased sperm motility, loss of fertilization ability and contraceptive effect.
Chinese herbal medicine is the treasure of Chinese civilization and embodies the great wisdom of the Chinese nation. This study once again shows the infinite treasure contained in Chinese herbal medicine. Triptolide, like artemisinin, is expected to become a model for tapping the effective components of traditional Chinese medicine for drug research and development and human health care.
Dr. Zhang Zongliang from the Medical College of the University of Nevada, Dr. Qin from the Guangdong Institute of Family Planning Science and Technology, Dr. Kathleen Scheig from the University of Nevada Medical College are the first authors, and Professor Tang from the Guangdong Institute of Family Planning Science and Technology and Professor from the University of California, Los Angeles are the same authors.
References:
1. Dr. Mansour, Yinji, P.&The effectiveness of contraceptive methods: a literature review. European journal of contraception. Reproductive Health Care: Official Journal of European Contraceptive Society, 20 10,15Suppl2: s19-31.
2. Male infertility caused by spermatogenic defects: lessons from gene knockout. Molecular and cellular endocrinology, 2009,306: 24-32.
3. Bao, J.&The mechanism, efficacy and safety of tripterygium wilfordii in the treatment of rheumatoid arthritis. International Rheumatology, 20 1 1, 31:1123-1/29.
4. Tao, X. & Lipski, Pei. Anti-inflammatory and immune effects of tripterygium wilfordii hook. Clinical rheumatism in North America, 2000, 26: 29-50.
5. Contraception with male antifertility compound in Tripterygium wilfordii, 1993, 47: 387-400.
6. A new method for converting triptolide from tripterygium wilfordii to triptolide. Phytochemical analysis: PCA, 2006,17:129-133.
7. Micellar electrokinetic capillary chromatography was used to monitor the conversion of triptolide from tripterygium wilfordii to triptolide. Journal of chromatography, 2005, A 1097: 199-202.
8. Wang, Zhou Ping, et al. Effects of triptolide on epididymis and testis in rats. Asian Journal of Andrology, 1999,1:121-125.
9. The research progress of Zhen Qingsheng, Ye Xie&the male antifertility plant Tripterygium wilfordii. Contraception,1995,51:121-129.
10. Male reproductive toxicity and toxicokinetics of triptolide in rats. Arzneimittel-Forschung, 2008, 58: 673-680.
1 1.Hikim, A.P., et al. Antifertility effect of triptolide after testis in male rats: evidence of serious damage to the ultrastructure of sperm in epididymis. Journal of Andrology, 2000,21:431-437.
12. triptolide: a potential male contraceptive. J Androl， 1998， 19: 479-486。
13. Exploration of herbal contraceptives. Indian National Journal of Medicine,1993,6:199-201.
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