Estrogen and progesterone receptor signaling as candidate neuroendocrine modulators in Huntington’s disease

Huntington's disease (HD) is a genetically driven neurodegenerative disorder marked by progressive corticostriatal dysfunction, excitotoxicity, mitochondrial impairment, and neuroinflammation. Disease-modifying therapies remain limited, and the receptor-specific relevance of neuroendocrine signaling is poorly defined.This review evaluates estrogen receptor beta (ERβ), G-protein-coupled estrogen receptor 1 (GPER1), and progesterone-derived neurosteroids, particularly allopregnanolone, as candidate modulators of HD vulnerability. A structured search of PubMed, Web of Science, and Scopus covered studies published from January 1, 1990, through October 1, 2025, supplemented by manual reference screening. Evidence from patients and HD models is prioritized; mechanistic findings from other neurodegenerative and excitotoxic models are interpreted cautiously.We examine receptor-specific effects on glutamatergic signaling, mitochondrial bioenergetics, microglial activation, oxidative stress, and transcription, including potential disruption of estrogen-responsive pathways by mutant huntingtin. Sex differences, hypothalamic-pituitary-gonadal axis disturbances, and neurosteroid fluctuations are also considered.Finally, we assess SERMs, ERβ-selective agonists, and progesterone-based strategies as hypothesis-driven adjuncts-not established treatments-while addressing thromboembolic risk, endocrine contraindications, CNS penetration, receptor selectivity, and drug interactions. This synthesis identifies evidence gaps and proposes testable questions for early-phase translational research.