The polygenic score for age at menopause is independently associated with the response of controlled ovarian hyperstimulation in women undergoing IVF

BACKGROUND: While Anti-Müllerian hormone (AMH) helps personalise In Vitro Fertilization (IVF) stimulation protocols, a significant number of women still do not achieve an optimal ovarian response. To address this, we explore the utility of a polygenic score for age at natural menopause (ANM) as a predictor for ovarian response during IVF. METHODS: This cohort study included 435 women who underwent standardised IVF stimulation, and they were genotyped to calculate a polygenic score (PGS) for ANM. Linear regression and ANCOVA models were used to assess the associations between the PGS and ovarian response, oocyte and embryo quality and pregnancy rates, adjusting for genomic components and age. FINDINGS: A one standard deviation increase in the PGS for ANM was associated with 0.950 (p < 0.001) additional follicles two days before ovum pick-up. While the PGS did not significantly associate with the overall diminished ovarian response (DOR), a mean difference of -0.33 (p < 0.01) in PGS was observed when comparing individuals with fewer than 8 follicles retrieved to those with an optimal ovarian response. No association was found between the PGS and ongoing pregnancy. Causal mediation revealed that the effect of the PGS onto the number of follicles was partly mediated by AMH levels (proportion mediated = 31%, p = 0.002). INTERPRETATION: A lower PGS for ANM, indicative for earlier menopause, is independently associated with a reduced ovarian response during IVF stimulation, specifically fewer follicles retrieved and mostly independent of AMH levels. This highlights the potential of ANM-related genetic variants to inform personalised IVF protocols by predicting ovarian responsiveness. FUNDING: This study was supported by Ferring Pharmaceuticals.