Neuroactive Steroid Regulation in Premenstrual Dysphoric Disorder: Cross-Integration of Metabolism, Dysfunction,...

Premenstrual Dysphoric Disorder (PMDD) is a cyclical mood disorder that affects approximately 3%-8% of menstruating individuals and leads to significant impairment in social functioning and quality of life. The disorder is characterized by increased sensitivity to neuroactive steroids (NASs) fluctuations, particularly allopregnanolone (ALLO), which disrupts the neuroendocrine-immune network. Emerging evidence highlights NASs-mediated mechanisms as core to PMDD pathology, underscoring the need for targeted treatments such as progesterone receptor modulators. This review synthesizes findings from studies analyzing NASs metabolic pathways, neuroimaging data, animal models, and clinical trials. We focus on three interconnected dimensions: dysregulation of NASs metabolism, aberrant Hypothalamic-pituitary-adrenal (HPA) axis interactions and Gamma-aminobutyric acidergic (GABAergic) system induced by NASs, and impaired neural circuit plasticity. The therapeutic mechanisms of pharmacological and traditional Chinese medicine (TCM) interventions are also evaluated. NASs imbalance critically impairs GABAergic signaling and HPA axis function, precipitating profound structural and functional abnormalities within critical emotion-regulation circuits, notably the prefrontal-limbic system. Neuroimaging evidence confirms heightened amygdala reactivity to NASs in PMDD patients, alongside significantly altered functional connectivity across the cortical-mesolimbic system network. SSRI antidepressants exert bidirectional modulation of ALLO levels, effectively alleviating PMDD symptoms. NAS-targeted therapies, such as Brexanolone and Sepranolone, along with oral contraceptives, also demonstrate therapeutic efficacy. Furthermore, active components such as peony glycoside and chaihu peony extract, as well as compound preparations such as Shuyu Capsule, can specifically regulate the neuro-endocrine-immune network through the ALLO-GABAA receptor mechanism and achieve good therapeutic effects for PMDD. The integration of multidisciplinary evidence supports NASs imbalance as a key pathological feature of PMDD. Targeting NAS-related pathways offers promising therapeutic strategies, as exemplified by recent advances in targeted drug development and individualized medicine. This review provides a foundation for precision medicine in PMDD and related psycho-neuroendocrine disorders, promoting future research into mechanism-based diagnostics and treatments.