Fatty acid metabolism of granulose cells and follicular fluid and their associations with embryo quality in normal-weight women with PCOS

Polycystic ovary syndrome (PCOS) is the most common reproductive-endocrine disorder in women of reproductive age. The granulosa cell metabolism correlated with oocyte competence. However, the alteration of fatty acid in granulosa cell of PCOS patients is unclear. Besides, obesity per se is related to dysfunction of oocyte quality. Hence, this study was aimed to comprehensively investigate the fatty acid alteration of oocyte environment and their associations with embryo quality in normal weight women with PCOS. Two independent prospective cohorts included women with PCOS and age-BMI-matched controls that underwent IVF treatment were recruited. DIA-mass spectrometry-based proteomics analysis and absolute quantification of fatty acids were conducted in granulosa cells and follicular fluid from women with PCOS and controls, and then the relationship between fatty acid level and embryo quality in PCOS patients was analysed. Proteomic analysis in cohort 1 revealed 205 differentially expressed proteins in the granulosa cells of normal-weight PCOS patients compared with those of controls. Functional enrichment analysis and metabolism score calculation revealed that fatty acid metabolism pathways, especially the biosynthesis of unsaturated fatty acids, were downregulated. The hallmark fatty acid metabolism score was negatively correlated with the total testosterone level and the AMH level (R=-0.52, P = 0.004; R=-0.64, P = 0.00017, respectively).Compared with those in the control group, the levels of the SFAs myristic acid (C14:0) and MUFAs nervonic acid (C24:1) in the follicular fluid of PCOS patients in cohort 1 were greater, whereas the ratio of PUFAs LA: ALA was lower, which were validated by cohort 2. C14:0 was moderately positively correlated with the basal LH level and LH/FSH ratio, even after correction for multiple comparisons. Receiver operating characteristic (ROC) analysis combining the C24:1, C14:0, and LA: ALA ratios with the seven fatty acid metabolic-related proteins revealed that the predictive accuracy for PCOS was 0.86. In normal-weight women with PCOS, fatty acid disturbance occurs in granulosa cells and follicular fluid, and also suggesting a role for C14:0, C24:1 and LA: ALA in PCOS patients, independent of obesity.