title: 17alpha-estradiol: a brain-active estrogen?
abstract: The estrogen 17beta-estradiol has profound effects on the brain throughout life, whereas 17alpha-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 17alpha-estradiol elicits rapid and sustained activation of the MAPK/ERK and phosphatidylinositol 3-kinase-Akt signaling pathways; is neuroprotective, after an ischemic stroke and oxidative stress, and in transgenic mice with Alzheimer's disease; and influences spatial memory and hippocampal-dependent synaptic plasticity. The present study measured the endogenous content of 17alpha-estradiol in the brain and further clarified its actions and kinetics. Here we report that: 1) endogenous levels of 17alpha-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; 2) 17alpha-estradiol and 17beta-estradiol bind estrogen receptors with similar binding affinities; 3) 17alpha-estradiol transactivates an estrogen-responsive reporter gene; and 4) unlike 17beta-estradiol, 17alpha-estradiol does not bind alpha-fetoprotein or SHBG, the estrogen-binding plasma proteins of the developing rodent and primate, respectively. 17alpha-Estradiol was also found in the brains of gonadectomized or gonadectomized/adrenalectomized mice, supporting the hypothesis that 17alpha-estradiol is locally synthesized in the brain. These findings challenge the view that 17alpha-estradiol is without biological significance and suggest that 17alpha-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. 17alpha-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.
authors.affiliation: Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, 650 West 168th Street, Black Building, Room 1615, New York, New York 10032, USA. cdt2@columbia.edu
authors.forename: C Dominique
authors.initials: CD
authors.lastname: Toran-Allerand
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Tinnikov
authors.forename: Ravinder J
authors.initials: RJ
authors.lastname: Singh
authors.forename: Imam S
authors.initials: IS
authors.lastname: Nethrapalli
mesh_terms: D000315:Adrenalectomy; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology; D019556:COS Cells; D002369:Castration; D002522:Chlorocebus aethiops; D002853:Chromatography, Liquid; D004958:Estradiol / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D007536:Isomerism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013237:Stereoisomerism; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D011960:Receptors, Estrogen; D012738:Sex Hormone-Binding Globulin; D000509:alpha-Fetoproteins; D004958:Estradiol