17α-Estradiol: A brain active estrogen?

The estrogen 17β-estradiol has profound effects on the brain throughout life, while 17α-estradiol, the natural optical isomer, is generally considered less active, because it binds less avidly to estrogen receptors. On the contrary, recent studies in the brain document that 17α-estradiol (a) elicits rapid and sustained activation of the MAP/ERK kinase and PI3K-Akt signalling pathways, (b) is neuroprotective, following an ischemic stroke and oxidative stress, and in transgenic mice with Alzheimer's disease, and (c) influences spatial memory and hippocampal-dependent synaptic plasticity. The present study measured the endogenous content of 17α-estradiol in the brain and further clarified its actions and kinetics. Here we report that (i) endogenous levels of 17α-estradiol and its precursor estrone are significantly elevated in the postnatal and adult mouse brain and adrenal gland of both sexes, as determined by liquid chromatography/tandem mass spectrometry (LC-MS/MS); (ii) 17α-estradiol and 17β-estradiol bind estrogen receptors with similar binding affinities; (iii) 17α-estradiol transactivates an estrogen-responsive reporter gene, and (iv) unlike 17β-estradiol, 17α-estradiol does not bind α-fetoprotein or sex hormone binding globulin, the estrogen-binding plasma proteins of the developing rodent and primate, respectively. 17α-estradiol was also found in the brains of gonadectomized or gonadectomized/adrenalectomized mice, supporting the hypothesis that 17α-estradiol is locally synthesized in the brain. These findings challenge the view that 17α-estradiol is without biological significance and suggest that 17α-estradiol and its selective receptor "ER-X" are not part of a classical hormone/receptor endocrine system, but of a system with important autocrine/paracrine functions in the developing and adult brain. 17α-estradiol may have enormous implications for hormone replacement strategies at the menopause and in the treatment of such neurodegenerative disorders as Alzheimer's disease and ischemic stroke.