Does antagonist administration on the day of HCG in ICSI/IVF cycles with premature progesterone rise (PPR)-using long agonist protocol- improves pregnancy outcome?

Abstract

OBJECTIVE: Previous studies have identified single nucleotide polymorphisms that impact hormones involved in the hypothalamic-pituitary-ovarian (HPO) axis. However, these genetic variants may present concurrently, the significance of which is not well understood. This study aimed to identify combinations of genetic variants that affect clinically relevant hormones, such as AMH, in ways that singularly occurring variants do not. DESIGN: Retrospective. MATERIALS AND METHODS: AMH levels and genotypes for 18 variants were recorded for 413 women; informed consent was obtained. To investigate joint effects of mutations on AMH, we ran a conditional association analysis as follows. For all pairs of mutations, we conditioned on the first mutation and tested for association on the second. For example, from our original 413 women, 95 women are wildtype (Ser/Ser) for the FSHR p.Ser680Asn mutation. We considered only the subset of 95 wildtype women, and ran association tests between AMH levels and genotype for each of the remaining 17 mutations. We repeated this process 54 times, conditioning on all 3 different genotypes for each of the 18 mutations. To account for multiple testing, we adjusted the p-value using a randomized permutation procedure.RESULTS: We found a few significant genotype combinations associated with AMH levels. For example, we identified the TP53 p.Pro72Arg mutation within the subset of patients that have Ser/Ser for the FSHR p.Ser680Asn mutation. The Ser/Ser/Pro/Pro group has significantly higher AMH levels (mean ¼ 5.88) than the Ser/Ser/Pro/Arg group and the Ser/Ser/Arg/Arg group combined (mean ¼ 2.85). No significant difference in age between the two groups was observed.CONCLUSIONS: The FSHR Ser allele and the TP53 Pro allele are associated with less active forms of their respective proteins. FSHR is responsible for promoting follicle growth and TP53 is associated with cell cycle control, including apoptosis. Individually, these mutations may not sufficiently disrupt folliculogenesis to alter AMH levels, but jointly this threshold may be reached, highlighting the importance of focusing analysis on genotyping combinations. Further investigation of such combinations may clarify the complex biological processes influencing AMH levels, as their significance is not well understood. Ultimately, a greater understanding may help to refine predictions of ovarian response.