GnRH-receptor antagonism as a targeted approach to reproductive dysfunction in polycystic ovary syndrome.
Low-dose Ganirelix may help reduce LH levels and improve hormonal balance in women with PCOS, but further research is needed to confirm these effects.
Where it sits
this study against the rest of the leuprorelin corpusSummary and findings
This study investigated the effects of low-dose Ganirelix on reproductive dysfunction in women with polycystic ovary syndrome (PCOS) and in a mouse model. Two subtherapeutic doses of Ganirelix were administered to women, with assessments of LH pulsatility and reproductive hormones. Results indicated reductions in LH pulse frequency and D4-androstenedione levels.
Abstract
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).
Background
This paper addresses reproductive dysfunction in polycystic ovary syndrome (PCOS), a condition characterized by neuroendocrine dysfunction and hyperandrogenism. Prior research has indicated that gonadotrophin-releasing hormone (GnRH) signaling plays a critical role in this condition. The study aims to explore the potential of GnRH-receptor antagonism as a targeted therapeutic approach to restore reproductive function.
Methods
The study utilized a prenatal anti-Müllerian hormone (AMH)-exposed PMOS-like mouse model and a phase I clinical trial involving women with PMOS without obesity. In the mouse model, acute or intermittent low-dose Ganirelix was administered, and various reproductive parameters were assessed. In the clinical trial, two subtherapeutic doses of Ganirelix (0.025 mg, n=8; 0.0625 mg, n=10) were given once in the early follicular phase, with blood sampling conducted over 8 hours to measure LH pulsatility and reproductive hormones.
Results
The primary endpoint observed was a reduction in LH pulse frequency, with both doses of Ganirelix leading to decreased basal, mean, and total LH levels. Additionally, the LH/FSH ratio decreased, and D4-androstenedione levels fell by 25-30%. In the mouse model, a single injection of Ganirelix normalized exaggerated LH pulsatility, while six weeks of intermittent treatment restored oestrous cyclicity and ovulation.
Interpretation
The findings suggest that low-dose GnRH-receptor antagonism may recalibrate GnRH/LH signaling rather than suppress it, which could be beneficial in managing hyperandrogenism in PCOS. However, the clinical significance of the observed reductions in hormone levels needs further investigation, as the sample size in the human trial was small. The study's limitations, including potential biases from funding sources and the small n, warrant caution in applying these findings to clinical practice.
Key findings
- D4-androstenedione fell by 25-30% at both doses in women.
- LH pulse frequency, basal, mean, and total LH decreased with both doses.
- The LH/FSH ratio decreased in women with PMOS.
- AMH declined modestly at 0.0625 mg in women.
- In PMOS-like mice, a single Ganirelix injection normalized exaggerated LH pulsatility.
- Six-week intermittent treatment in mice restored oestrous cyclicity and ovulation.
Limitations
- small n=8 for 0.025 mg and n=10 for 0.0625 mg in human trial
- industry-funded research grants may introduce bias
- short duration of human study with only a single dose administered
- results based on a PMOS-like mouse model may not fully translate to humans