Research advances on estrogen deficiency leading to depression.

Depression is a debilitating mental disorder with a significantly higher prevalence in women, particularly during periods of hormonal fluctuation such as perimenopause, postpartum, and postmenopause. Estrogen, especially 17β-estradiol (E2), serves as a crucial neuroactive steroid that regulates mood, cognition, and neural homeostasis through nuclear and membrane-associated receptors. Accumulating evidence suggests that estrogen deficiency contributes to the pathogenesis of depression via multiple interconnected mechanisms, including dysregulation of monoamine neurotransmission, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, decreased brain-derived neurotrophic factor (BDNF) expression, impaired mitochondrial function and bioenergetics, neuroinflammation mediated by glial cells, and disruption of gut-brain axis communication. These alterations collectively lead to synaptic dysfunction, reduced neuroplasticity, and increased neuronal vulnerability. Therapeutic strategies such as estrogen replacement therapy (ERT), selective estrogen receptor modulators (SERMs), and receptor-specific agonists show promising antidepressant effects, particularly when administered during critical windows of hypoestrogenism. This review systematically elaborates the pathophysiological mechanisms underlying estrogen deficiency-induced depression and discusses recent advances in estrogen-based therapeutics, highlighting future directions for targeted and personalized treatment approaches.