99% Protection and No Hormones: Male Contraceptive Enters Final Testing Phase

A new male contraceptive called YCT-529 can temporarily block sperm production without causing side effects. The drug works by blocking a receptor essential for male fertility, but its effects are reversible: sperm production returns to normal after stopping use. Tests in mice and non-human primates have shown the compound to be 99% effective and safe. These results pave the way for future human trials, bringing hope for a new option for male contraception.

With nearly half of all pregnancies in the U.S. and worldwide being unintended, there is a critical need for additional contraceptive options that can be used throughout the reproductive lifespan of both women and men. Currently, men have few options for contraception. Women, on the other hand, have several alternatives, including pills, intrauterine devices (IUDs), and injections.

Male contraception has been a challenge in reproductive medicine because, unlike the many options available to women, methods for men are limited to condoms and vasectomy. While vasectomy is usually an irreversible procedure, condoms, while effective, require consistent and correct use.

This creates a gap in contraception, leaving the responsibility largely on women. In recent years, researchers have been exploring new approaches to a safe, effective, and reversible male contraceptive.

One of the most promising strategies involves inhibiting retinoic acid, a vitamin A derivative that is essential for sperm production. Retinoic acid is essential for the development of male germ cells.

It activates specific receptors called RARs (retinoic acid receptors), which regulate spermatogenesis. Previous studies have shown that genetically engineered mice lacking the RARα receptor become infertile, but without other health problems.

This led researchers to investigate whether temporarily chemically blocking this receptor could be a viable strategy for male contraception.

They knew that blocking a specific receptor for retinoic acid, called RARα, could disrupt spermatogenesis (the process of sperm production), leading to temporary infertility.

So the study tested whether YCT-529, a highly selective inhibitor of this receptor, could be used as a safe and reversible male contraceptive.

The researchers conducted experiments on mice and non-human primates to test the efficacy and safety of YCT-529.

Chemical and pharmacological tests: First, they analyzed the properties of YCT-529 to ensure that it was safe, well absorbed by the body, and effective in blocking RARα.

Tests on mice: The animals were given daily doses of YCT-529 orally. After four weeks, their sperm counts dropped dramatically, making them 99% infertile.

Mice treated with different doses and periods of time. Histological (microscopic) sections were imaged to observe changes in sperm formation. Mice treated with 10 mg/kg for 2 weeks showed changes in germ cell structure, including failures in sperm translocation and release into the seminiferous tubules (sites where sperm production occurs). These changes were identified by different stages of cell maturation and marked with numbers and symbols in the tests. In addition, there was a reduction in the number of sperm in the epididymis and detachment of germ cells, indicating that the treatment affected normal sperm production. When the dose was increased to 20 mg/kg for 2 weeks, the effects were even more evident, including abnormal cells with multiple nuclei and changes in the condensation of genetic material. However, when the treatment was stopped, the mice fully recovered their fertility, suggesting that the contraceptive effect is reversible.

Six weeks after the end of treatment, fertility returned to normal. A rapid recovery of spermatogenesis in testes of males treated with a longer dosing period and examined 4 weeks after the drug.

a–d Testicular and epididymal histological sections of male mice treated with 10 mg/kg/day YCT-529 for 4 weeks and terminated 4 weeks after CDT. Recovery of spermatogenesis was observed in most tubules with some characteristic residual abnormalities remaining, in particular failure of sperm release. Other characteristic residual abnormalities included tubules with pachytene spermatocytes or round spermatids as the most advanced germ cells and reduced numbers of epididymal spermatozoa, and some tubules almost completely lacking entire layers of specific germ cells were observed.

Primate testing: Next, experiments were performed in non-human primates, animals biologically closest to humans. After only two weeks of treatment, sperm counts dropped significantly, with no apparent side effects. Approximately 10–15 weeks after stopping the drug, the animals recovered full fertility.

The results indicate that YCT-529 may be a promising method of non-hormonal, safe, and reversible male contraception.

The next step will be to test the drug in humans to assess its efficacy and safety. If the trials are successful, we may have a reliable male contraceptive in the future, providing more options for both men and couples who want to plan their families.

These findings pave the way for clinical trials in humans, which will be essential to confirm the safety and efficacy of YCT-529. If the results are positive, we may soon have a non-hormonal, safe and reversible male contraceptive, increasing the options for men and couples in reproductive planning.

READ MORE:

Targeting the retinoid signaling pathway with YCT-529 for effective and reversible oral contraception in mice and primates

Nadja Mannowetz, Sanny S. W. Chung, Soma Maitra, Md Abdullah Al Noman, Henry L. Wong, Narsihmulu Cheryala, Akash Bakshi, Debra J. Wolgemuth and Gunda I. Georg, Communications Medicine. 5, Article number: 68 (2025) 

DOI: 10.1038/s43856-025-00752-7

Abstract: 

The retinoic acid receptor alpha (Rarα) has been validated as a male contraceptive target by genetic knockouts resulting in male sterility. The effects on spermatogenesis in the absence of RARα resemble the loss of RAR signaling in vitamin A deficiency, and the mice are otherwise normal. The effects on spermatogenesis in animals treated orally with the dual RARα/RARγ antagonist BMS-189453 closely phenocopies the absence of RARα function. Notably, the resulting male sterility is reversible. We, therefore, wished to identify RARα−selective inhibitors for potential male non-hormonal contraception. YCT-529 was investigated for RARα selective inhibition, physicochemical characteristics, oral bioavailability, and pharmacokinetic properties in mice and non-human primates. It was assessed in mouse mating trials to determine the most effective dosing regimen to induce infertility in male mice and in male non-human primates to reduce sperm levels. Characterization of YCT-529 shows suitable biochemical, physicochemical, and pharmacokinetic properties for in vivo testing. YCT-529 inhibits mouse fertility of male mice within 4 weeks of oral administration, correlating with disrupted spermatogenesis demonstrating specific inhibition of the RARα pathway. Within 6 weeks after cessation of dosing, mouse fertility reverses. Furthermore, YCT-529 inhibits sperm production in a non-human primate model within 2 weeks of oral dosing without adverse side effects. Within 10–15 weeks after cessation of dosing, non-human primates’ sperm counts fully reverses. These results lay the groundwork for evaluating YCT-529 in human clinical trials.