GnRH-receptor antagonism as a targeted approach to reproductive dysfunction in polycystic ovary syndrome

BACKGROUND: Polycystic ovary syndrome (PCOS), recently renamed polyendocrine metabolic ovarian syndrome (PMOS), is characterised by neuroendocrine dysfunction with accelerated gonadotrophin-releasing hormone (GnRH)/luteinising hormone (LH) pulsatility driving hyperandrogenism and anovulatory infertility. METHODS: We used the prenatal anti-Müllerian hormone (AMH)-exposed PMOS-like mouse model (PAMH) and a phase I clinical trial in women with PMOS without obesity. PAMH and control mice received acute or intermittent low-dose Ganirelix, and oestrous cyclicity, ovulation, gonadotrophins, and steroids were assessed. In women, two subtherapeutic Ganirelix doses (0.025 mg, n = 8; 0.0625 mg, n = 10) were administered once in early follicular phase, with 10-min blood sampling over 8 h to quantify LH pulsatility and reproductive hormones. FINDINGS: In PMOS-like mice, a single Ganirelix injection normalised exaggerated LH pulsatility, and six-week intermittent treatment restored oestrous cyclicity, ovulation, and testosterone levels without affecting controls. In women with PMOS both Ganirelix doses reduced LH pulse frequency, basal, mean and total LH, and decreased the LH/FSH ratio. D4-androstenedione fell by 25-30% at both doses, AMH declined modestly at 0.0625 mg, while oestradiol remained unchanged. INTERPRETATION: Low-dose GnRH-receptor antagonism with Ganirelix can recalibrate, rather than suppress, GnRH/LH signalling, attenuating hyperandrogenism and, in mice, restoring ovulatory function. These data identify partial GnRHR blockade as a promising neuroendocrine-centred strategy in PMOS and provide a rationale for phase II trials evaluating repeated low-dose regimens, ovulatory restoration, and fertility outcomes. FUNDING: This work was supported by the European Research Council (ERC) Horizon-ERC-POC grant (ERC-2022-POC2, n° 101111874) and the French National Research Agency (ANR-24-CHBS-0002, France 2030).