Genotyping FSHR and LHCGR genes enhances prediction accuracy of unexpected poor ovarian response in normo-prognosis women undergoing IVF

Abstract Purpose The aim of the research was to study the association of FSHR rs6166 and LHCGR rs2293275 genetic variants, and their gene-gene interactions, with poor ovarian response in women with normal prognosis based on the POSEIDON criteria, to enable personalized prediction of treatment outcomes. Materials and methods We conducted a retrospective cohort study, including 146 relatively healthy women with normal ovulation who underwent their first IVF/ICSI cycle using a short GnRH‑antagonist protocol. All participants in the study, according to the POSEIDON criteria, had sufficient prestimulation ovarian reserve parameters (antral follicle count (AFC) ≥ 5, anti-Mullerian hormone (AMH) ≥ 1.2 ng/ml). Women with anovulation and polycystic ovary syndrome (PCOS) were excluded from the study. Results The study identified a combined genotype that represents the absence of both (rs6166 and rs2293275) protective homozygous (AA) genotypes and is associated with more than twofold increased risk of a poor ovarian response. The combined genotype FSHR rs6166 AG/GG + LHCGR rs2293275 AG/GG have been identified as risk factor for a poor ovarian response in women with normal prognosis based on the POSEIDON criteria. The study found that among women with a normal prognosis, 75% of unexpected poor responders carried the risk genotype. The number of metaphase II (MII) oocytes retrieved was statistically significantly lower in individuals carried the risk genotype, compared to other patients. Besides, the FSHR rs6166 GG genotype has been shown to be statistically significantly associated with elevated serum FSH and progesterone levels, compared to the A allele ( AA + AG genotypes) carriers. The LHCGR rs2293275 GG genotype carriers had lower number of antral follicles and MII oocytes, compared to the A allele ( AA + AG genotypes) carriers. Conclusion A combined assessment of POSEIDON criteria and FSHR / LHCGR genotyping can help reduce the risk of unexpected poor response in patients with a normal prognosis.