Dysregulated Acetate Metabolism and Cholesterol Biosynthesis in Cumulus Cells of Women with Polycystic Ovary Syndrome.

Abstract

Objective: Polycystic ovary syndrome (PCOS) is associated with metabolic disturbances within the follicular microenvironment that may impair oocyte competence. Although elevated acetate levels have been reported in the follicular fluid (FF) of PCOS patients, its metabolic fate and transcriptional impact in cumulus cells (CCs) remain unclear. This study investigated acetate-related metabolic reprogramming in CCs of women with PCOS.

Materials and methods: In this experimental study, FF acetate, glucose, and cholesterol levels were measured in 25 PCOS and 15 control women. Transcriptomic analysis of CCs was performed using RNA-seq dataset GSE155489 (discovery cohort with n=2 PCOS; n=2 controls) and independently validated in microarray dataset GSE10946. Differentially expressed genes (DEGs) were identified using platform-specific pipelines. Functional enrichment and protein-protein interaction (PPI) analyses were conducted to identify key metabolic pathways and hub genes. Selected genes were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in CCs obtained from 30 PCOS and 20 control subjects.

Results: FF from PCOS women exhibited significantly increased acetate and cholesterol levels and decreased glucose levels compared with the controls (P<0.001). Transcriptomic analysis identified 665 DEGs in PCOS CCs. Enrichment analyses revealed significant dysregulation of acetate metabolism, tricarboxylic acid (TCA) cycle, and cholesterol biosynthesis pathways. ACSS1 and ACSS2 were upregulated in PCOS CCs. Hub gene analysis identified PDHA1 and IDH1 (TCA cycle), and ACLY, HMGCS1, and MVD (cholesterol biosynthesis). RT-qPCR confirmed upregulation of ACSS1, ACSS2, ACLY, HMGCS1, and MVD, and downregulation of IDH1, while PDHA1 showed increased expression in the clinical cohort. Correlation analyses demonstrated modest associations between acetate-related genes and certain assisted reproductive technologies (ART) parameters.

Conclusion: Congenital hypothyroidism disrupts hormonal balance, increases oxidative stress, and induces ovarian histological alterations. Treadmill training exerts protective effects, highlighting its potential as a non-pharmacological strategy that could mitigate reproductive complications associated with hypothyroidism.