The Role of Physiological Androgen Receptor Signaling in Female Glucose Metabolism: Potential as a Protective Factor

The androgen receptor (AR), beyond its classical roles in male sexual function and muscle maintenance, has emerged as a pivotal regulator of metabolic health. In men, age- or hypogonadism-related androgen decline is strongly associated with an increased risk of type 2 diabetes and impaired glucose tolerance, underscoring the protective role of AR signaling in glucose homeostasis. Conversely, its physiological significance in women remains largely unexplored, as clinical and basic research has predominantly focused on pathological hyperandrogenism, such as polycystic ovary syndrome (PCOS). This review delineates the genomic and non-genomic molecular mechanisms of AR action and synthesizes evidence from male genetically modified mouse models and cellular studies to clarify its role across key metabolic tissues, including skeletal muscle, liver, pancreatic β-cells, adipose tissue, and the central nervous system. Based on these insights, we hypothesize that physiological AR signaling exerts beneficial metabolic effects in women, whereas adverse metabolic outcomes are primarily associated with supraphysiological AR activation. Finally, we highlight key knowledge gaps and propose future directions to validate this hypothesis, with the goal of establishing a novel conceptual framework for understanding female metabolic homeostasis and informing sex-specific therapeutic strategies.