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Polycystic ovary syndrome (PCOS) afflicts ∼15% of women in their reproductive years (1). PCOS women exhibit high circulating levels of testosterone (T), intermittent or absent menstrual cycles, and polycystic ovaries on ultrasound, or at least two of these three diagnostic criteria (2). Hyperandrogenism is at the core of PCOS, its ∼70% heritability, and likely its pathogenic origin (1). PCOS pathophysiology, however, extends well beyond hirsutism and infertility to encompass hypothalamic neuroendocrine dysfunction, and of particular concern, increased risks for metabolic disease and cancer associated with long-term morbidity and mortality (3). PCOS origins are currently considered polygenic (4) and prepubertal (5), with over 21 replicated candidate genes affecting gonadotropin secretion and action, extracellular matrix formation, and various common cellular functions. Such PCOS risk genes, however, account for <10% of patient presentation. A definitive etiology for PCOS remains elusive and delays progress toward a cure. In contrast, evidence from animal models has consistently indicted T in the pathogenic origins of PCOS-like traits (6). Naturally occurring hyperandrogenic female monkeys spontaneously exhibit PCOS-like traits (7), and early development T or dihydrotestosterone (DHT) exposure in female rodents, sheep, and monkeys reproduces a variety of PCOS-like traits (8), demonstrating potential genetic, epigenetic, and developmental contributions to PCOS pathogenesis mediated by androgen receptor (AR) signaling. Caldwell et al. (9) recently took this molecular understanding to a new level by blocking AR gene expression in female mice and preventing PCOS-like trait development after fetal DHT exposure, specifically implicating AR action in PCOS developmental pathogenesis. In PNAS, the same group (10) refine this molecular precision and convincingly demonstrate how neuronal AR genomic excision, alone, protects female mice from certain PCOS-like traits induced by prepubertal onset of DHT excess. AR-enabled conversion to a PCOS-like phenotype therefore occurs predominantly in neurons, as protection provided by neuron-specific AR deletion (NeuroARKO) and not …

Neuronal androgen receptor: Molecular gateway to polycystic ovary syndrome?