Role of estrogen in treatment of female depression

Abstract

Depression is a neurological disorder that profoundly affects human physical and mental health, resulting in various changes in the central nervous system. Despite several prominent hypotheses, such as the monoaminergic theory, hypothalamic-pituitary-adrenal (HPA) axis theory, neuroinflammation, and neuroplasticity, the current understanding of depression's pathogenesis remains incomplete. Importantly, depression is a gender-dimorphic disorder, with women exhibiting higher incidence rates than men. Given estrogen's pivotal role in the menstrual cycle, it is reasonable to postulate that its fluctuating levels could contribute to the pathogenesis of depression. Estrogen acts by binding to a diversity of receptors, which are widely distributed in the central nervous system. An abundance of research has established that estrogen and its receptors play a crucial role in depression, spanning pathogenesis and treatment. In this comprehensive review, we provide an in-depth analysis of the fundamental role of estrogen and its receptors in depression, with a focus on neuroinflammation, neuroendocrinology, and neuroplasticity. Furthermore, we discuss potential mechanisms underlying the therapeutic effects of estrogen in the treatment of depression, which may pave the way for new antidepressant drug development and alternative treatment options.

Keywords: HPA axis; depression; estrogen; inflammation; synaptic plasticity.

Figure 1

Estrogen-related signaling pathways. Abbreviations: E2: estradiol; AC: adenylate cyclase 1; ER: estrogen receptor; mGluR1a: metabotropic glutamate receptor subtype 1a; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; MEK: mitogen-activated protein kinase; ERK1/2: extracellular signal-regulated kinase 1/2; Gs: guanine nucleotide-binding proteins; GPER: G protein-coupled estrogen receptor; PKCδ: protein kinase C delta; DAG: diacylglycerol; PLC: Portland Limestone Cement; IP3: inositol 1,4,5-trisphosphate; IP3R: IP3 receptor; CAM: crassulacean acid metabolism; PI3K: phosphoinositide 3-kinase; eNOS: endothelial nitric oxide synthase; c-Src: cellular Src; pCREB: phosphorylated cyclic AMP response element binding; CoA: nuclear receptor coactivator.

Figure 2

Distribution of estrogen receptors in the brain. The color represents the projection of the corresponding brain region in the sagittal plane of the brain, where red indicates that the region mainly expresses ERα, blue indicates that the region mainly expresses ERβ, and green indicates that the region expresses both ERα and ERβ.

Figure 3

Relationship between estrogen and neuroinflammation in depression. Abbreviations: GPER: G protein-coupled estrogen receptor; ER: estrogen receptor; ERK: extracellular signal-regulated kinase; NF-κB P65: nuclear factor kappa-B P65; TLR4: toll-like receptor 4; MyD88.