17α-Estradiol: A brain active estrogen?

C. Dominique Toran-Allerand, Alexander A. Tinnikov, Ravinder J. Singh, Imam S. Nethrapalli

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3843-3850
Number of pages8
JournalEndocrinology
Volume146
Issue number9
DOIs
StatePublished - Sep 1 2005

Keywords

  • "ER-X"
  • 17α-estradiol
  • 17β-estradiol
  • Brain
  • Estrone
  • Liquid chromatographytandem mass spectrometry

ASJC Scopus subject areas

  • Endocrinology

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  • Cite this

    Toran-Allerand, C. D., Tinnikov, A. A., Singh, R. J., & Nethrapalli, I. S. (2005). 17α-Estradiol: A brain active estrogen? Endocrinology, 146(9), 3843-3850. https://doi.org/10.1210/en.2004-1616