Follicular fluid metabolome and cytokinome profiles in poor ovarian responders and the impact of dehydroepiandrosterone supplementation

Poor ovarian responders (POR) are women undergoing in-vitro fertilization who respond poorly to ovarian stimulation, resulting in the retrieval of lower number of oocytes, and subsequently lower pregnancy rates. The follicular fluid (FF) provides a crucial microenvironment for the proper development of follicles and oocytes. Conversely, dysregulated FF metabolome and cytokinome could have detrimental effects on oocytes in POR. Androgens such as dehydroepiandrosterone (DHEA) have been proposed to alter the POR follicular microenvironment but its effects on the FF metabolome and cytokine profiles is unknown. In this study, untargeted LC-MS/MS metabolomics was performed on FF of POR patients with DHEA supplementation (DHEA+) and without (DHEA-) in a randomized clinical trial (N=52). Untargeted metabolomics identified 118 FF metabolites of diverse chemistries, which included lipids, steroids, amino acids, hormones, among others. FF metabolomes were different between DHEA+ and DHEA- groups. Specifically, glycerophosphocholine, linoleic acid, progesterone, and valine were significantly lower in DHEA+ relative to DHEA-. Among cytokines, MCP1, IFNγ, LIF and VEGF-D were significantly lower in DHEA+ relative to DHEA. Collectively, our data suggest a role of DHEA on these metabolic and cytokines pathways, and these FF metabolites could be used to guide future studies in DHEA supplementation regimen.