Dehydroepiandrosterone supplementation and the impact of follicular fluid metabolome and cytokinome profiles in poor ovarian responders

• Published in: Journal of ovarian research 2023-06, Vol.16 (1), p.107-16, Article 107
• Main Authors: Viardot-Foucault, Veronique, Zhou, Jieliang, Bi, Dexi, Takinami, Yoshihiko, Chan, Jerry K Y, Lee, Yie Hou
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Amino acids; Analysis; Androgens; Chemokines; Chromatography; Chromatography, Liquid; Corticosteroids; Cytokines; Cytokines - metabolism; Dehydroepiandrosterone; DHEA; Dietary Supplements - analysis; Embryos; Endothelial growth factors; Estradiol; Fatty acids; Female; Fertilization; Fertilization in Vitro - methods; Follicles; Follicular fluid; Follicular Fluid - metabolism; Glucocorticoids; Growth factors; Hormones; Humans; In vitro fertilization; Insulin-like growth factor I; Insulin-Like Growth Factor I - analysis; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Ions; Linoleic acid; Linoleic Acids; Lipids; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Mathematical models; Metabolites; Metabolome; Metabolomics; Oocytes; Ovaries; Ovulation Induction - methods; Physiological aspects; Poor ovarian responder; Pregnancy; Progesterone; Progesterone - metabolism; Quality control; Reproductive status; Scientific imaging; Tandem Mass Spectrometry; Testosterone; Ultrasonic imaging; Unsaturated fatty acids; Vagina; Valine - analysis; Valine - metabolism; Vascular endothelial growth factor; Womens health; γ-Interferon
• ISSN: 1757-2215; 1757-2215
• DOI: 10.1186/s13048-023-01166-6

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 through tightly controlled metabolism and cell signaling. Androgens such as dehydroepiandrosterone (DHEA) have been proposed to alter the POR follicular microenvironment, but the impact DHEA imposes on the FF metabolome and cytokine profiles is unknown. Therefore, the objective of this study is to profile and identify metabolomic changes in the FF with DHEA supplementation in POR patients. FF samples collected from 52 POR patients who underwent IVF with DHEA supplementation (DHEA +) and without (DHEA-; controls) were analyzed using untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics and a large-scale multiplex suspension immunoassay covering 65 cytokines, chemokines and growth factors. Multivariate statistical modelling by partial least squares-discriminant regression (PLSR) analysis was performed for revealing metabolome-scale differences. Further, differential metabolite analysis between the two groups was performed by PLSR β-coefficient regression analysis and Student's t-test. Untargeted metabolomics identified 118 FF metabolites of diverse chemistries and concentrations which spanned three orders of magnitude. They include metabolic products highly associated with ovarian function - amino acids for regulating pH and osmolarity, lipids such fatty acids and cholesterols for oocyte maturation, and glucocorticoids for ovarian steroidogenesis. Four metabolites, namely, glycerophosphocholine, linoleic acid, progesterone, and valine were significantly lower in DHEA + relative to DHEA- (p