Estrogen actions in the nervous system

Estrogens, primarily 17β-estradiol (E2), exert important modulatory functions in the CNS via both genomic and nongenomic (membrane-related) mechanisms. The sources of E2 for the brain include circulating E2 or testosterone secreted from peripheral tissue and rapidly gaining access to the CNS and E2 synthesized in neurons and glial cells. The effects of E2 are mediated by 2 types of estrogen receptors (ERs): ERα and ERβ. These receptors act as transcription factors mediating the genomic effects of E2 and as membrane-associated proteins that trigger rapid, nongenomic effects. Some of these rapid effects are also mediated by guanine-nucleotide binding (G)-protein-coupled receptors, including the G-protein-coupled ER-1 (GPER1, also known as GPR30). There is a cross-talk between the genomic and nongenomic effects of E2 via multiple phosphorylation cascades that also allow integration of E2 signaling with that of neurotransmitters and trophic factors. Many influences of E2 on neuronal development, dendritogenesis, synaptic plasticity, neuronal excitability, and neuroprotection involve these rapid, nongenomic membrane-related mechanisms. Via these effects, E2 may have a contributory role in epilepsy, migraine, and neurodegenerative disorders such as Alzheimer disease (AD) and Parkinson disease (PD). These subjects have been reviewed extensively.^1–14