Inflammation and polyendocrine metabolic ovarian syndrome: utilizing proteomics to unravel this link in adolescents

Abstract

Abstract Purpose and Methods Polyendocrine metabolic ovarian syndrome (PMOS) affects 10% to 26% of adolescent females. Yet, its pathogenesis is poorly understood. Proteomics is a valuable tool to explore biological pathways underpinning PMOS and identify novel diagnostic/monitoring biomarkers. We undertook deep-phenotyping discovery proteomic profiling (nanoflow 2-dimensional liquid chromatography–quadrupole time-of-flight mass spectrometry with alternating low- and elevated-energy acquisition) on urine samples from a subset of a longitudinal adolescent PMOS cohort (n = 40). We compared the urinary proteome of adolescents (12-19 years, ≥1-year postmenarche) recruited from adolescent endocrinology/gynecology clinics with PMOS or insulin resistance (IR), and community-recruited age-, sex-, and puberty-matched controls. PMOS was defined by adolescent-specific criteria (irregular menstrual cycles and hyperandrogenism). Exclusion criteria included the combined oral contraceptive pill. Results were validated in the whole cohort with a multiplexed targeted proteomic panel. Results Discovery proteomic analysis identified 3793 proteins, of which 66 were differentially expressed in the PMOS cohort vs IR and controls (candidate PMOS biomarkers). Bioinformatic analysis revealed that almost half of the PMOS-associated biological pathways were related to inflammatory/immunological responses. The inflammatory response was the most significant biological process (P < .001). Targeted proteomic analysis of 89 known inflammatory-associated proteins validated this association. Multivariate analysis demonstrated a distinct inflammatory proteome in adolescent PMOS. Twenty inflammatory-associated proteins were differentially expressed in the PMOS cohort vs IR and control groups, with notable roles in oxidative stress and neuroinflammation. Six proteins were significantly different in PMOS compared with both IR and control cohorts. Conclusion These analyses provide insight into the pathophysiology of PMOS, highlighting inflammatory processes as a prominent feature of adolescent PMOS and identifying several candidate novel noninvasive biomarkers and drug targets that need further validation.