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17alpha-estradiol: a brain-active estrogen?

C Dominique Toran-Allerand1, Alexander A Tinnikov, Ravinder J Singh

  • 1Department 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

Endocrinology
|June 11, 2005
PubMed
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17alpha-estradiol, previously thought inactive, is abundant in the brain and activates key signaling pathways. This isomer shows significant neuroprotective effects and may offer new therapeutic strategies for neurodegenerative diseases.

Area of Science:

  • Neuroendocrinology
  • Molecular Neuroscience

Background:

  • 17beta-estradiol significantly impacts brain function throughout life.
  • 17alpha-estradiol, its isomer, was considered less active due to lower estrogen receptor binding affinity.

Purpose of the Study:

  • To measure endogenous 17alpha-estradiol levels in the brain.
  • To elucidate the actions and kinetics of 17alpha-estradiol.
  • To challenge the notion of 17alpha-estradiol's limited biological significance.

Main Methods:

  • Liquid chromatography/tandem mass spectrometry to quantify 17alpha-estradiol and estrone.
  • Estrogen receptor binding affinity assays.
  • Estrogen-responsive reporter gene assays.
  • Analysis in gonadectomized and adrenalectomized mice.

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Main Results:

  • Significantly elevated endogenous levels of 17alpha-estradiol and estrone found in mouse brains and adrenal glands.
  • 17alpha-estradiol exhibits similar binding affinities to estrogen receptors as 17beta-estradiol.
  • 17alpha-estradiol activates estrogen-responsive genes and does not bind plasma proteins like alpha-fetoprotein or SHBG.
  • Evidence suggests local synthesis of 17alpha-estradiol within the brain.

Conclusions:

  • 17alpha-estradiol possesses significant biological activity in the brain, contrary to previous assumptions.
  • It functions via autocrine/paracrine pathways, potentially involving a selective receptor (ER-X).
  • Findings suggest therapeutic potential for 17alpha-estradiol in neurodegenerative diseases and hormone replacement therapy.