Targeting estrogen receptors in PCOS: A receptor-specific framework for neuropsychiatric dysfunction and therapeutic modulation.

Polycystic ovary syndrome (PCOS) is a complex multisystem disorder traditionally managed via androgen suppression or ovulation induction. We propose that dysregulated estrogen receptor (ER) signaling-specifically reduced ER-β and GPER1 activity relative to ER-α dominance-represents a core mechanism linking reproductive, metabolic, and neuropsychiatric manifestations of PCOS. Synthesizing genomic, transcriptomic, and neuroendocrine data, we argue that ER-β underexpression impairs hypothalamic-pituitary-ovarian (HPO) feedback and disrupts neuroplasticity-related pathways, including BDNF/CREB and mGluR signaling. Concurrently, GPER1 hypoactivity contributes to inflammation and insulin resistance, compounding metabolic and affective symptoms. We evaluate receptor-specific estradiol-based interventions-including selective estrogen receptor modulators (SERMs), brain-selective estrogens, and epigenetic inducers of ESR2-as promising therapeutic strategies, provided they avoid ER-α-mediated proliferative risks. A receptor-informed treatment model is presented, supported by data on ER-related polymorphisms (e.g., rs1256049, rs4986938, rs3808351) that may stratify patients by symptom profile and treatment responsiveness. We also address translational barriers, including gender-exclusionary study designs, stigma around estradiol, and chronic underfunding of PCOS research. This framework recasts estradiol as a neuroendocrine modulator with system-wide relevance. Future clinical trials should incorporate genotypic and symptom-based stratification to validate ER-targeted approaches and expand applicability to other ER-dysregulated conditions.