This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Toran-Allerand, C. D. Articles by Nethrapalli, I. S. Search for Related Content PubMed PubMed Citation Articles by Toran-Allerand, C. D. Articles by Nethrapalli, I. S.

17-Estradiol: A Brain-Active Estrogen?

Departments of Anatomy and Cell Biology, Obstetrics and Gynecology, (C.D.T.-A., A.A.T., I.S.N.), and Neurology (C.D.T.-A.) and the Centers for Neurobiology and Behavior and Reproductive Sciences (C.D.T.-A., A.A.T., I.S.N.), Columbia University College of Physicians and Surgeons, New York, New York 10032; and Department of Laboratory Medicine and Pathology (R.J.S.), Mayo Clinic and Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Dr. C. Dominique Toran-Allerand, 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. E-mail: cdt2{at}columbia.edu.

The estrogen 17ß-estradiol has profound effects on the brain throughout life, whereas 17-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 17-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 17-estradiol in the brain and further clarified its actions and kinetics. Here we report that: 1) endogenous levels of 17-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) 17-estradiol and 17ß-estradiol bind estrogen receptors with similar binding affinities; 3) 17-estradiol transactivates an estrogen-responsive reporter gene; and 4) unlike 17ß-estradiol, 17-estradiol does not bind -fetoprotein or SHBG, the estrogen-binding plasma proteins of the developing rodent and primate, respectively. 17-Estradiol was also found in the brains of gonadectomized or gonadectomized/adrenalectomized mice, supporting the hypothesis that 17-estradiol is locally synthesized in the brain. These findings challenge the view that 17-estradiol is without biological significance and suggest that 17-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. 17-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.

This article has been cited by other articles:

				Y. Hojo, S. Higo, H. Ishii, Y. Ooishi, H. Mukai, G. Murakami, T. Kominami, T. Kimoto, S. Honma, D. Poirier, et al. Comparison between Hippocampus-Synthesized and Circulation-Derived Sex Steroids in the Hippocampus Endocrinology, November 1, 2009; 150(11): 5106 - 5112. [Abstract] [Full Text] [PDF]

				Z. Chu, J. Andrade, M. A. Shupnik, and S. M. Moenter Differential Regulation of Gonadotropin-Releasing Hormone Neuron Activity and Membrane Properties by Acutely Applied Estradiol: Dependence on Dose and Estrogen Receptor Subtype J. Neurosci., April 29, 2009; 29(17): 5616 - 5627. [Abstract] [Full Text] [PDF]

				P. I. Mackenzie, A. Rogers, J. Treloar, B. R. Jorgensen, J. O. Miners, and R. Meech Identification of UDP Glycosyltransferase 3A1 as a UDP N-Acetylglucosaminyltransferase J. Biol. Chem., December 26, 2008; 283(52): 36205 - 36210. [Abstract] [Full Text] [PDF]

				M. M. McCARTHY Estradiol and the Developing Brain Physiol Rev, January 1, 2008; 88(1): 91 - 134. [Abstract] [Full Text] [PDF]

				J. M. Wang, L. Liu, and R. D. Brinton Estradiol-17 -Induced Human Neural Progenitor Cell Proliferation Is Mediated by an Estrogen Receptor -Phosphorylated Extracellularly Regulated Kinase Pathway Endocrinology, January 1, 2008; 149(1): 208 - 218. [Abstract] [Full Text] [PDF]

				S. Fournier, M. Allard, R. Gulemetova, V. Joseph, and R. Kinkead Chronic corticosterone elevation and sex-specific augmentation of the hypoxic ventilatory response in awake rats J. Physiol., November 1, 2007; 584(3): 951 - 962. [Abstract] [Full Text] [PDF]

				D. Meffre, A. Pianos, P. Liere, B. Eychenne, A. Cambourg, M. Schumacher, D. G. Stein, and R. Guennoun Steroid Profiling in Brain and Plasma of Male and Pseudopregnant Female Rats after Traumatic Brain Injury: Analysis by Gas Chromatography/Mass Spectrometry Endocrinology, May 1, 2007; 148(5): 2505 - 2517. [Abstract] [Full Text] [PDF]

				S. Musatov, W. Chen, D. W. Pfaff, C. V. Mobbs, X.-J. Yang, D. J. Clegg, M. G. Kaplitt, and S. Ogawa Silencing of estrogen receptor {alpha} in the ventromedial nucleus of hypothalamus leads to metabolic syndrome PNAS, February 13, 2007; 104(7): 2501 - 2506. [Abstract] [Full Text] [PDF]

				P. Mannella and R. D. Brinton Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. J. Neurosci., September 13, 2006; 26(37): 9439 - 9447. [Abstract] [Full Text] [PDF]