Multi-omics approach to reveal follicular metabolic changes and their effects on oocyte competence in PCOS patients

Background: Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder linked with endocrine and metabolic disturbances. The underlying mechanism of PCOS, especially its effect on oocyte competence, remains unclear. The study aimed to identify abnormal follicular metabolic changes using a multi-omics approach in follicular fluid from PCOS patients and to determine their effects on oocyte competence. Methods: A total of 36 women with PCOS and 35 women without PCOS who underwent in vitro fertilization and embryo transfer were included in the study. Cumulus cells and follicular fluid samples were collected. Follicular fluid samples underwent metabolomic analysis, while cumulus cell clusters from the same patients were assessed using transcriptomic analysis. Clinical information of patients and assisted reproductive technology (ART) results were recorded. Transcriptomics and metabolomics were integrated to identify disrupted pathways, and receiver operation characteristics (ROC) analysis was conducted to identify potential diagnostic biomarkers for PCOS. Pearson correlation analysis was conducted to assess the relationship between metabolites in follicular fluid and oocyte competence (fertilization and early embryo development potential). Results: Through multi-omics analysis, we identified aberrantly expressed pathways at both transcriptional and metabolic levels, such as the citrate cycle (TCA cycle), oxidative phosphorylation, the cAMP signaling pathway, the mTOR signaling pathway, and steroid hormone biosynthesis. Ten candidate metabolites were identified based on metabolic profiling data from these altered pathways. Phytic acid, succinic acid, 2’-deoxyinosine triphosphate, and 4-trimethylammoniobutanoic acid in the follicular fluid exhibited high specificity and sensitivity in distinguishing PCOS. Among these metabolites, L-arginine showed a negative correlation with the 2PN fertilization rate and cleavage rate, while estrone sulfate showed a negative correlation with the high-quality embryo rate in the in-vitro fertilization (IVF) cycle. Conclusions: We have conducted a preliminary study of a novel metabolic signature in women with PCOS using a multi-omics approach. The alterations in key metabolic pathways may enhance our understanding of the pathogenesis of PCOS.