SAT-191 - Spatial and molecular characterization of the ovarian lipidome reveals widespread lipid dysregulation in a large-animal model of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) affects >10% of reproductive-age women and is the leading cause of anovulatory infertility worldwide. Systemic lipid dysregulation is a recognized feature of PCOS, but it is unknown whether the ovary also harbors a distinct, tissue-specific lipid profile. We hypothesized that the ovary in PCOS exhibits a distinct lipid signature reflecting systemic lipid dysregulation. Using the prenatal testosterone sheep model, which recapitulates both reproductive and metabolic features of PCOS, female offspring born to sheep treated with testosterone propionate (T; gestational days 30–90; n=6) or vehicle (corn oil; controls; n=8) were studied at 2 years of age. Ovarian lipidomes were characterized using complementary untargeted platforms, UHPLC-MS/MS and spatial lipidomics by MALDI-MSI at a 20 µm resolution. UHPLC-MS/MS identified ~400 lipid species; principal component analysis revealed clear separation between control and PCOS ovaries (PC1: 39.1%, PC2: 20.6%). The ovarian lipidome was dominated by membrane phospholipids. PCOS ovaries exhibited a marked redistribution of lipids, including depletion of phosphatidylserines (PS) and enrichment of neutral storage lipids, such as triacylglycerols (TG) and cholesteryl esters (CE). At the molecular level, 73 lipid species were significantly altered (p < 0.05), with PS species representing the most consistently reduced abundance in PCOS. Lipid pathway analysis revealed suppression of the PS→PE→PC interconversion and activation of glycerolipid pathways driving diacylglycerol (DG)→TG conversion, alongside impaired fatty acid elongation and desaturation. Spatial lipidomics in a subset (n=5/group), revealed strong compartmental enrichment with individual lipid ions mapping to specific ovarian regions, including stroma, follicular compartments (granulosa and theca cell layers), cortex, and vascular-associated structures, enabling the identification of region-associated lipid signatures. Notably, variation in lipid enrichment across differing follicle sizes suggests stage-dependent lipid compositional changes accompanying follicle maturation. Collectively, these findings provide the first spatially resolved map of ovarian lipid dysregulation in PCOS, identifying a marked shift from structural and signaling lipids toward storage lipids, consistent with a metabolically reprogrammed ovarian microenvironment underlying impaired folliculogenesis. NIH R01HD099096.

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