GnRH-receptor antagonism as a targeted approach to reproductive dysfunction in polycystic ovary syndrome.
Level 4 - case-series / case-control
Phase I single-arm dose-finding human trial combined with preclinical animal experiments.
PubMed 42468113 · doi:10.1016/j.ebiom.2026.106398
What was done
Researchers evaluated low-dose GnRH-receptor antagonism using ganirelix in a prenatal anti-Müllerian hormone (PAMH) mouse model of polycystic ovary syndrome (PCOS/PMOS) and in a phase I clinical trial in women with PMOS without obesity. Mice received acute or 6-week intermittent ganirelix to evaluate estrous cyclicity, ovulation, gonadotrophins, and steroids. In the human trial, women received a single subtherapeutic dose of ganirelix in the early follicular phase (0.025 mg, n = 8; 0.0625 mg, n = 10), with 10-minute blood sampling conducted over 8 hours to measure luteinising hormone (LH) pulsatility and circulating reproductive hormones.
What was found
In PMOS-like mice, a single ganirelix injection normalized elevated LH pulsatility, and 6 weeks of intermittent treatment restored estrous cyclicity, ovulation, and testosterone levels without affecting control mice. In women with PMOS, both ganirelix doses decreased LH pulse frequency, basal LH, mean LH, total LH, and the LH/FSH ratio. D4-androstenedione decreased by 25% to 30% at both doses, AMH declined modestly at the 0.0625 mg dose, and estradiol remained unchanged.
Why it matters
Subtherapeutic GnRH-receptor antagonism can partially recalibrate LH hyperpulsatility and reduce hyperandrogenism in PCOS without completely suppressing estradiol, establishing proof-of-concept for low-dose pulsatility modulation.
Limits
The human phase I study was small (n = 18 total) and non-randomized with no placebo control. Measurements in women were limited to an acute 8-hour window after a single dose, so long-term clinical efficacy, ovulatory restoration, and live-birth fertility outcomes in humans were not evaluated. The clinical cohort was restricted to women without obesity, limiting generalizability to the broader PCOS population.