The central role of hyperandrogenism in driving metabolic dysfunction in polycystic ovary syndrome: from pathophysiological mechanisms to targeted therapies
Abstract
Polycystic ovary syndrome is a prevalent endocrine disorder wherein hyperandrogenism plays a central pathogenic role that extends beyond its reproductive manifestations. This review systematically elucidates the pathophysiological mechanisms through which hyperandrogenism, acting in a vicious cycle with insulin resistance, drives systemic metabolic dysfunction. We synthesize evidence demonstrating that hyperandrogenism promotes organ-specific lipotoxicity and insulin resistance. This contributes to visceral adiposity, hepatic steatosis (and its progression to metabolic dysfunction-associated steatotic liver disease), and skeletal muscle dysfunction. Furthermore, we explore the detrimental effects of hyperandrogenism on cardiovascular integrity and gut microbial homeostasis. Based on this mechanistic framework, we evaluate current therapeutic strategies, drawing a key distinction between metabolic-focused interventions (e.g., lifestyle modifications, insulin-sensitizing agents) that disrupt the hyperandrogenism-insulin resistance cycle, and androgen-lowering therapies (e.g., combined oral contraceptives) that primarily alleviate symptoms with limited metabolic benefits. We conclude that redefining hyperandrogenism as a primary metabolic driver is crucial for developing targeted strategies that mitigate the long-term metabolic risks associated with polycystic ovary syndrome.
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