Metabolic profiling of human follicular fluid to unravel the pathways involved in polycystic ovary syndrome – a systematic review

Abstract

Polycystic ovary syndrome (PCOS), an endocrine-metabolic disorder, affects women of reproductive age. Follicular fluid (FF) reflects the biochemical microenvironment surrounding the oocyte, providing valuable insight into molecular mechanisms associated with PCOS. Metabolomics enables comprehensive profiling of small-molecule metabolites allowing the identification of disease-specific metabolic signatures, dysregulated pathways, and potential diagnostic/therapeutic targets. This systematic review summarizes available evidence on the FF metabolomic profile of women with PCOS compared to normo-ovulatory controls, aiming to identify PCOS-specific metabolic signatures and dysregulated metabolic pathways. PubMed, Web of Science, and Scopus were searched up to September 2025. Eligible studies were conducted in humans, included at least one group of women with PCOS and a control group with normal ovarian function and normal-weight. Thirty-one studies were included. FF from women with PCOS exhibited consistent metabolomic signatures across analytical platforms and cohorts. The most robust differences involved extensive lipidome alterations, along with amino acid and energy metabolism disturbances. Steroidogenic profiles showed higher testosterone and androsterone sulfate levels, while progesterone, 17-hydroxyprogesterone, and pregnenolone were decreased, suggesting impaired steroidogenesis. Fatty acid alterations included increased saturated, monounsaturated, and polyunsaturated fatty acids. Phosphatidylethanolamine species, triglycerides, and prostaglandin E2 were elevated, whereas phosphatidylcholine and lysophosphatidic acid species were reduced. Among water-soluble metabolites, isoleucine, succinate, malate, glycerol, hypoxanthine, and uracil were increased, while threonine, glutamine, arginine, citrulline, and 4PY were decreased. FF metabolomics reveals a PCOS signature characterized by lipid, amino acid, and energy metabolism dysregulation, potentially contributing to follicular dysfunction. Future studies should consider PCOS phenotypic heterogeneity.