Metabolic dysregulation in follicular fluid is associated with adverse reproductive outcomes in women with decreased ovarian reserve

BACKGROUND: This study aims to use non-targeted metabolomics to analyze the metabolic characteristics of follicular fluid in patients with decreased ovarian reserve (DOR) and explore the mediating role of these metabolites in DOR and assisted reproductive technology (ART) outcomes. METHODS: This study included 946 infertile women undergoing ART treatment, including 126 with DOR and 300 with normal ovarian reserve (NOR). Follicular fluid was collected during oocyte retrieval and analyzed by non-targeted metabolomics. Differential metabolites were identified using lasso regression, fold change analysis, t-tests, and OPLS-DA. Additionally, generalized linear models (GLMs) and mediation analysis were employed to investigate the relationship between follicular fluid metabolites and ART outcomes. RESULTS: The DOR group showed significantly lower antral follicle counts and anti-Müllerian hormone levels, but higher follicle-stimulating hormone levels compared with controls (P < 0.05). Additionally, reproductive outcomes were significantly poorer in DOR patients, with lower numbers of retrieved oocytes, clinical pregnancy rates, high-quality embryo rates, and live birth rates (P < 0.05). Metabolomics multivariate statistical analysis identified 17 key differential metabolites. KEGG pathway analysis showed that these metabolites were enriched in pathways such as steroid hormone biosynthesis, pentose phosphate pathway, lysine degradation, arachidonic and purine metabolism. Furthermore, GLMs showed that these 17 metabolites were significantly associated with ART outcomes. Further mediation analysis indicated that these metabolites partially mediated the adverse effects of DOR on oocyte yield and embryo quality. CONCLUSION: Follicular fluid from DOR patients exhibits significant metabolic disorders, and these abnormal metabolic characteristics may lead to adverse reproductive outcomes.