Rebalancing Reproductive Responsibility: Progress in Nonhormonal Male Contraception

Unplanned pregnancies account for nearly half of all pregnancies, which can leave a lasting impact emotionally, socially, and physically.^1,2 Throughout history, the sole responsibility of nonbarrier methods for pregnancy prevention has unequally been placed upon the shoulders of women. With an estimated 1.18 billion women using some form of birth control, both hormonal and nonhormonal, the risks associated with contraceptive use can often be overlooked.³ Although female contraceptives have advanced significantly, they still come with a wide range of adverse effects, such as ectopic pregnancies, breast swelling and pain, pancreatitis, and, in some cases, multiple forms of cancer.^4-6 The integration of male contraceptives, particularly nonhormonal pharmacologic approaches, allows for an opportunity to offset this responsibility, decrease the health risk placed upon women, and give individuals more flexible options for child planning.

Beyond the scope of just providing additional contraceptive options, male contraceptives represent a step toward equality in reproductive responsibility. Condoms and vasectomy are still the only methods of male contraception available, and both have drawbacks due to their complex process of reversibility or poor reliability.^7,8 Hormonal approaches have shown efficacy but are hindered by systemic adverse effects such as weight gain, mood changes, and decreased libido.^9,10 Nonhormonal pharmacologic male contraceptives look to bypass these challenges, acting on testis-specific pathways, sperm function without endocrine disruption, and generation of sperm.

A comprehensive search of PubMed, Embase, and ClinicalTrials.gov was performed for English-language studies published between January 2000 and August 2025. Search terms included “male contraception,” “nonhormonal,” “YCT-529,” “ADAM hydrogel,” “Triptonide,” “BRDT inhibitors,” and “retinoic acid receptor antagonists.” Preclinical animal studies, early-phase clinical trials, and review articles were included. Articles focusing exclusively on hormonal contraceptives were excluded.

Mechanistic Pathways and Therapeutic Agents

Retinoic Acid Receptor Antagonists

YCT-529, a selective retinoic acid receptor α (RAR-α) antagonist, disrupts spermatogenesis without altering systemic testosterone. The investigative contraceptive has demonstrated safety and full reversibility in murine models.¹¹ A phase 1a trial enrolled 16 vasectomized men who received single ascending doses of 10 mg, 30 mg, 90 mg, or 180 mg of YCT529 in the fasted state, with an additional 30-mg dose in the fed state to assess food effects. Single doses up to 180 mg were safe and well tolerated with no effects on heart rate, hormone levels, sex hormone-binding globulin, inflammatory biomarkers, sexual desire, or mood. There was no clear food effect on pharmacokinetics. Larger phase 1b/2 studies are ongoing to evaluate multiple-dose safety, tolerability, pharmacokinetics and pharmacodynamics, and sexual function and mood in healthy males.¹² The larger scaled upcoming trial will include healthy males who have made the decision to receive a vasectomy or not father children due to unknown adverse outcomes.

Vas-Occlusive Hydrogel: ADAM

ADAM is an injectable hydrogel that occludes the vas deferens to block sperm transport while maintaining ejaculation and sensation. A first-in-human dose-ranging trial enrolled 25 men seeking long-acting contraception as an alternative to vasectomy. The study showed mild adverse effects with preliminary azoospermia at 90 days; temporary scrotal enlargement and mild scrotal/inguinal pain were the most common adverse effects, resolving within 1 month without activity impairment.¹³ Durability up to 24 months was reported at the American Urological Association 2025 Annual Meeting.¹⁴ The sperm that is blocked will degrade and be absorbed, while the hydrogel, toward the end of its duration of action, will liquefy, thus removing the barrier blocking the sperm and reversing the process. It is estimated that the contraceptive can last up to 2 years, potentially providing prolonged reproductive control.

Natural Products

Triptonide

Triptonide, derived from the Chinese herb Tripterygium wilfordii, disrupts sperm morphology and motility with a single daily oral dose. Triptonide affects only late spermiogenesis, possibly due to its protein-targeting capabilities. No human clinical trials have been conducted; all published data are from preclinical studies in mice and cynomolgus monkeys. In mice, single daily oral doses induced deformed sperm with minimal forward motility (close to 100% penetrance) and male infertility within 3 to 4 weeks. In cynomolgus monkeys, infertility occurred within 5 to 6 weeks, with fertility returning 4 to 6 weeks after cessation. Short- and long-term treatment showed no discernible systemic toxic adverse effects based on histological examination of vital organs in mice and hematological/serum biochemical analyses in monkeys. The compound appears to target junction plakoglobin and disrupts its interactions with SPEM1 during late spermiogenesis.¹⁵ Evidence of safety and pharmacokinetics in humans needs further testing before clinical trials can proceed.

Epigenetic and Chromatin Remodeling Inhibitors

JQ1 Bromodomain Testis-specific protein inhibitor (BRDT inhibitor) is a small molecule inhibitor blocking chromatin remodeling during spermatogenesis. No human clinical trials have been conducted; all data are from preclinical mouse studies. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. JQ1-treated males mated normally, but inhibitory effects at the spermatocyte and round spermatid stages caused a complete and reversible contraceptive effect. The compound crosses the blood-testis barrier and prevents BRDT recognition of acetylated histone H4. A major limitation is JQ1's short half-life, with metabolism studies identifying CYP3A4 as the main contributor to rapid drug clearance.¹⁶ Researchers believe that due to human and murine bromodomain pockets being nearly identical, the effects shown in mice can be translated to men for providing a contraceptive option. Other targets include testis-specific kinases and enzymes within retinoic acid pathways, now in preclinical discovery.¹⁷

Ejaculation Blockers and Polymer-Based Alternatives

RISUG and Vasalgel are 2 injectable vasal polymers undergoing long-term development, with RISUG trials ongoing in India and Vasalgel trials in the US. Both drugs’ mechanism of action is to inject the polymer into the vas deferens to block sperm from being ejaculated with the semen. RISUG has undergone the most extensive human testing. A multicentric, limited-phase 3 trial in India enrolled 139 young males, each with at least 2 children and living with their partners. Participants received 120 μl of RISUG as bilateral vas intraluminal injection. Temporary scrotal enlargement and mild scrotal/inguinal pain occurred in most individuals, resolving within 1 month. Six individuals (4.3%) had injection procedure failure and did not achieve azoospermia. Of the remaining 133 individuals, 82.7% had continued azoospermia from the first month onwards, while 17.3% achieved azoospermia within 3 to 6 months. During 6-month follow-up, no pregnancies occurred in participants’ partners, and no significant adverse effects were observed.¹⁹ The effects from this therapy could last up to 10 to 15 years. In theory, the trial aims to provide an alternative to vasectomy. Vasalgel is undergoing early-stage research in the US but has not reached human trials.¹⁷

Discussion

Nonhormonal methods avoid systemic hormonal adverse effects and may improve user acceptability. Early clinical data demonstrate promising safety and reversibility.^11-15 Despite the many challenges with the implementation of nonhormonal male contraceptives, these options are progressing from concept to clinic. YCT-529 represents the most advanced oral small-molecule, while ADAM offers a long- and locally acting alternative. Triptonide and JQ1 showcase mechanistic diversity in preclinical testing. With continued investment and supportive regulatory pathways, these innovations may soon offer men safe, reversible, and acceptable contraceptive options.

Drug delivery across the blood-testis barrier remains complex.¹⁷ Robust phase 2/3 efficacy trials are needed to confirm contraceptive effectiveness and reversibility in humans.^12,13 Sociocultural perceptions of male contraception and willingness to adopt new modalities are uncertain, and funding and regulatory pathways remain limited, compared with female contraceptive development.¹⁷ If successfully developed, nonhormonal pharmacologic contraceptives could expand reproductive autonomy, reduce unintended pregnancies, and balance contraceptive responsibility across genders.

About the Authors

William Freeman, PharmD, is a pharmacy resident at AdventHealth Celebration in Florida.

Jessica Russo, PharmD, MBA, BCACP, is a clinical ambulatory care pharmacist at AdventHealth Celebration in Florida.

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