A non-hormonal male contraceptives using triptolide in developing

A non-hormonal male contraceptives using triptolide in developing.  Nearly 100% effective! Chinese and American scientists may be expected to use Tripterygium wilfordii extract (triptolide) to develop new non-hormonal male contraceptives!

Among all currently available contraceptive methods, oral contraceptives are still the most popular. However, contraceptives are only effective for women. After nearly half a century of research efforts, scientists have not successfully developed a contraceptive for men. Of non-hormonal contraceptives;

Part of the reason why scientists have not made significant progress in this field is that they do not fully understand the occurrence of male sperm and the biological characteristics of sperm; for example, many people believe that male contraceptives should suppress sperm count to a very low level Even zero, which can effectively prevent female conception;

However, the complete hindrance of sperm production requires the removal of spermatogenic cells, which often leads to testicular atrophy, which obviously brings certain side effects to men.

In addition, the removal of germ cells will also change the cell composition and microenvironment in the testis, which in turn will induce the hypothalamic-pituitary-testicular feedback system, leading to the body’s systemic side effects. Therefore, find a way to eliminate all Sperm compounds that do not produce toxic side effects are a huge challenge for scientists.

Figure 1: The proof-of-concept efficacy test of triptolide on contraceptive effects in mice

Image source: Chang, Z, et al. Nat Commun 12, 1253 (2021). doi: 10.1038/s41467-021-21517-5

Although women are responsible for most of the contraceptive tasks in the world, social surveys show that more and more men are willing to share this social obligation; the current male contraceptive methods are only limited to traditional in vitro ejaculation. , Sterilization, and condoms. The research and development of male contraceptives has been very limited in the past half a century. So far, there is no male contraceptive with clinical application potential. Recently, a research report entitled “Triptonide is a reversible non-hormonal male contraceptive agent in mice and non-human primates” was published in the international journal Nature Communications. Scientists have discovered through research that a natural compound purified from Chinese herbal medicine tripterygium wilfordii hook F—triptonide (triptonide) may be used in male rats and male cynomolgus monkeys. The body exhibits a reversible male contraceptive effect.

Daily oral administration of triptolide in a single dose may induce sperm deformity to make it only weak or even lose motility, and it can induce infertility in male rats and male cynomolgus monkeys at 3-4 weeks and 5-6 weeks, respectively. This method can achieve nearly 100% effectiveness.

The researchers said that when the intake of triptolide in male mice and male cynomolgus monkeys is stopped, the fertility of the body will recover in about 4-6 weeks; based on the histological examination of the important organs of the mice and the diet According to the hematology and serum biochemical analysis of cynomolgus monkeys, the researchers found that neither short-term nor long-term triptolide therapy would cause obvious systemic side effects in these two animals.

In the process of sperm formation in the body, triptolide seems to be able to target plakoglobin and interfere with its interaction with SPEM1, and targeting late spermatogenesis may be expected to help scientists develop new types of non-hormonal men Birth control pills.

The main results of this study include:

1) Oral triptolide can cause sperm deformity and reduced motility in male mice, leading to infertility; male adult mice oral triptolide 0.8 mg/kg (the lowest effective dose) daily for 4 weeks Later, the sperm of the body was severely deformed and lost vitality, and it was unable to conceive a fertile female mouse.

2) Oral triptolide can cause infertility in male cynomolgus monkeys; adult male cynomolgus monkeys (9-13 years old, 4.96-11.8kg) oral triptolide 0.1mg/kg daily (the lowest effective dose) After 5 weeks, the sperm began to deform, the vitality decreased, and the number decreased, and the fertile female cynomolgus monkey could not be pregnant.

3) The infertility induced by triptolide in male mice and male cynomolgus monkeys can be completely reversed; when male C57BL/6 mice take 0.8mg/kg triptolide orally for 4 weeks, the sperm becomes severely deformed After the drug was stopped, the sperm morphology and sperm motility of the mice returned to normal after 4 weeks of drug withdrawal, which enabled fertile female mice to become pregnant and give birth to healthy offspring (Figure 1B). Cynomolgus monkeys took 0.1mg/kg triptolide orally for 8 weeks and then stopped taking the drug. After 5-6 weeks of drug withdrawal, the cynomolgus monkey sperm morphology, sperm motility and sperm count returned to normal, which could make the female cynomolgus monkey pregnant and give birth Healthy monkey (Figure 1C).

4) EC50 analysis (50% effective concentration analysis) results show that triptolide is a potentially safe and effective male contraceptive; 5) triptolide does not induce DNA double-strand breaks; 6) melanoglobin/ γ-catenin (junction plakoglobin/gamma-catenin) may be a candidate target for triptolide.

Figure 2: Study on the reversibility of male sterility in adult mice and cynomolgus monkeys induced by triptolide

Image source: Chang, Z, et al. Nat Commun 12, 1253 (2021). doi: 10.1038/s41467-021-21517-5

Researchers believe that the evidence supporting the safety of triptolide is that its EC50 is 0.1? mg/kg, which is 1/8 of the lowest effective dose (0.8 mg/kg) in mice, and 1/3000 of the LD50 (median lethal dose, 300? mg/kg). In other words, triptolide is very effective in inhibiting the fertility of male mice, because even at 1/8 of the normal dose, it can make half of the treated mice have the greatest effect; therefore, achieve male contraception The effective dose of triptolide required may be much lower than the level that will cause harmful side effects in the body.

Since triptolide is the compound with the highest content in Tripterygium wilfordii, triptolide purified from this Chinese herbal medicine is sometimes contaminated with trace amounts of triptolide or other rich compounds. Therefore, in this article, the researchers will Two batches of purified triptolide and one batch of chemically synthesized triptolide used in the study were tested for purity. Using NMR and elemental analysis, the results showed that the purity of these three kinds of triptolide were all close to 100 %.

In addition, the use of synthetic triptolide to carry out a proof-of-concept (POC) effect test on mice has obtained the same reversible male contraceptive effect; related research results show that the male contraceptive effect produced by triptolide is indeed caused by this It is caused by the compound, not by other trace pollutants.

It is worth noting that the focus of this article is on the POC efficacy test, which lacks obvious side effects. This may be based on their observation of the behavior of the two animals, and the examination of the morphology and histology of important organs (only mice). As well as hematology and serum biochemical analysis (only cynomolgus monkeys); although research data shows that triptolide may be a very promising male contraceptive drug candidate, later researchers still need to conduct more comprehensive drugs To further evaluate its safety using kinetics and toxicology, the question arises, why does triptolide only have an effect on late spermatogenesis without affecting the functions of other major organs of the body?

One explanation is that triptolide can target proteins that are only expressed in elongating sperm cells; the results of drug target recognition experiments conducted by researchers indicate that plaque globin/γ-catenin may be the most likely SPEM1, as an interactive partner of plaque globin/γ-catenin, is indeed expressed by elongated sperm cells during spermatogenesis. Therefore, the normal function of SPEM1 is very likely to be required The interaction with plagioglobin/γ-catenin, once the interaction between SPEM1 and plagioglobin/γ-catenin is destroyed in the presence of triptolide, the function of SPEM1 will be “abolished” “Although the interaction between the two may explain the special effects of triptolide on the testis, later researchers still need to use genetic models and in vitro tests to further study the effects.

In general, in this study, the researchers reported that triptolide may be used as a potentially safe non-hormonal male contraceptive in mice and non-human primates. This research result validates the development of males A more common idea of ​​contraceptives is that by targeting special proteins in the spermatogenesis process or other gene products that are important to the elongation step, all sperm can be rendered inactive, rather than killing or eliminating all sperm. ; Late-stage researchers need to further study the potential and safety of triptolide as a non-hormonal male contraceptive.

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