Neuregulin-4 and Emerging Metabolic and Reproductive Biomarkers in Polycystic Ovary Syndrome: A Narrative Review

Abstract

Polycystic ovary syndrome (PCOS) is a common and heterogeneous endocrine–metabolic disorder characterized by reproductive dysfunction and increased cardiometabolic risk. Conventional diagnostic criteria do not fully capture disease heterogeneity or long-term metabolic vulnerability. In recent years, multiple emerging biomarkers reflecting adipose tissue dysfunction, insulin resistance, inflammation, neuroendocrine dysregulation, skeletal muscle signaling, and gut–metabolic interactions have been investigated in PCOS. This narrative review synthesizes human studies published over the past 15 years evaluating neuregulin-4 (NRG4) and other emerging biomarkers in women with PCOS. Literature was identified through structured searches of PubMed/MEDLINE and complementary databases, prioritizing observational and interventional studies using established diagnostic criteria. Evidence was critically appraised and synthesized across biomarker categories with emphasis on metabolic and reproductive relevance. NRG4, a brown adipose tissue–derived batokine, is consistently elevated in women with PCOS, particularly in those with obesity, insulin resistance, and metabolically severe phenotypes. It appears to function as a compensatory marker of metabolic stress and low-grade inflammation, with levels declining following lifestyle-induced metabolic improvement. Beyond NRG4, dysregulated adipokines, inflammatory mediators, myokines, reproductive hormones, and gut-derived metabolites demonstrate strong associations with PCOS phenotypes and cardiometabolic risk profiles. Emerging biomarkers highlight PCOS as a multisystem disorder involving coordinated metabolic and reproductive dysregulation. Integration of selected biomarkers into multimarker panels may improve phenotypic classification, risk stratification, and individualized management, although further validation and standardization are required before routine clinical use.