First Hormone-Free Male Pill? YCT-529 Shows Early Promise

Medscape

20-05-2025

For decades, oral contraceptive options have been limited to women, while men have had only two choices: Condoms or vasectomy. That could change with the development of YCT-529, a nonhormonal male contraceptive currently in phase 2 clinical trials, which offers a novel mechanism for inhibiting the production of viable sperm.
Developed by YourChoice Therapeutics, a US-based biotech company, YCT-529 targets retinoic acid receptor alpha, a protein critical for sperm production. 'When this receptor is blocked, spermatogenesis is disrupted. In animal studies, infertility in rats was observed after 4 weeks of use, while in primates, a significant reduction in sperm production occurred within just 2 weeks,' explained Arie Carneiro, MD, PhD, urologist and researcher at Hospital Israelita Albert Einstein in Sao Paulo, Brazil, who is not involved in the study.
YCT-529 represents a significant shift from most previous male contraceptive strategies that have largely relied on hormonal suppression using testosterone or other hormone combinations. 'These hormone-based methods have been associated with unwanted side effects, including mood changes, erectile dysfunction, and muscle mass loss,' said Giuliano Aita, MD, urologist and member of the Brazilian Society of Urology. 'YCT-529 is innovative because it avoids disrupting male sex hormone pathways,' he added.
According to Alex Meller, MD, urologist, and professor at the Paulista School of Medicine of the Federal University of Sao Paulo, this nonhormonal approach may improve acceptance among men. 'Other male contraceptives tested previously were often combined with progesterone or testosterone blockers. Even when designed to act locally, these compounds tend to cause sexual side effects,' he noted.
Preclinical trials in animals have shown that YCT-529 has a favorable safety profile. 'In mice, the compound achieved 99% efficacy in preventing pregnancy, with minimal adverse effects,' said Aita. Additionally, no significant clinical toxicity or laboratory abnormalities have been reported. Testosterone levels remained unchanged, confirming the drug's nonhormonal mode of action, added Carneiro.
One of the major concerns with male contraceptives is reversibility, the ability to restore fertility after discontinuation. YCT-529 has shown promising results in animal studies. 'In rats, normal sperm levels returned about 6 weeks after stopping the drug. In primates, recovery was observed between 2 and 3 months,' said Carneiro.
'This timing is in line with the natural sperm production cycle, which takes about 12 weeks to be produced and become viable,' said Meller. 'Once the medication is stopped, this is the natural time for a new generation of sperm to be formed, and fertility restored.'
With phase 1 clinical trials completed — though no results have been publicly released — YCT-529 has entered phase 2 trials. An ongoing study based in New Zealand is currently recruiting male volunteers who are either awaiting vasectomy or do not wish to have children.
'For this drug to be used clinically, it must demonstrate safety and efficacy in humans at scale,' said Aita. 'Clinical trials will need to confirm that the drug reliably prevents conception, is reversible, and does not produce serious side effects. Researchers must also determine the optimal dosage and confirm that fertility restoration is predictable following discontinuation.'
Continued Innovation
While women have access to a wide range of contraceptive options, progress toward safe, reversible, and effective male contraceptives has been slow and fraught with challenges.
'Sperm production is continuous and high in volume, which requires a more robust mechanism of suppression compared to female contraceptives,' noted Carneiro. 'There is also heightened concern about preserving long-term fertility and avoiding hormonal side effects that could affect overall health and sexual function.'
Several male contraceptive methods are currently being developed alongside YCT-529. 'One example is the hormonal contraceptive gel of norethisterone + testosterone, which is applied to the skin daily and is already in phase 2 of clinical studies,' said Aita. 'Also in the preclinical phase, there is the nonhormonal contraceptive EPPIN [epididymal protease inhibitor], which blocks sperm function.'
According to the Aita, 'devices such as Vasalgel, a type of reversible 'plug' in the vas deferens, are also being developed as nonhormonal alternatives.'
However, Vasalgel may have encountered a stumbling block. 'The gel is applied inside the duct, which leads to this blockage, and this obstruction must be reversed by applying a specific substance to the same region. However, in some cases, it was difficult to reverse it. This is the point that is proving most difficult to resolve,' warned Meller.
Another male contraceptive currently being tested is dimethandrolone undecanoate, an oral medication that works by inhibiting sperm production through hormonal action. 'There is also another experimental nonhormonal method, based on compounds from cottonseed, but it is in a very early stage [of development],' said Meller.
Despite promising clinical progress, one key challenge remains: Male adherence to contraceptive methods. 'For a contraceptive to be widely accepted by men, it must be effective, easy to use, have minimal or no noticeable side effects, and offer reliable reversibility,' explained Aita. He also emphasized the importance of public awareness: 'Educational campaigns will be essential to shift societal attitudes and reinforce the idea that contraceptive responsibility can — and should — be shared between partners.'
If YCT-529 continues to demonstrate efficacy and safety in upcoming clinical trials, it could become a much-needed addition to reproductive medicine, offering men a viable and reversible option for fertility control, a gap that remains largely unaddressed in current contraceptive strategies.