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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.

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