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Gonadotropin-Releasing Hormone Neurons Express Estrogen Receptor-ß

Laboratory of Endocrine Neurobiology (E.H., I.K., Z.L.), Institute of Experimental Medicine, Hungarian Academy of Sciences; Department of Forensic Medicine (N.S., E.K.), Semmelweis University; and Department of Neuroscience (Z.L.), Faculty of Information Technology, Pázmány Péter Catholic University, Budapest, 1083 Hungary; and Departments of Epidemiology and Preventive Medicine and Anatomy and Neurobiology (I.M.), University of Maryland, Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Erik Hrabovszky, M.D., Ph.D., Department of Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, 1083 Hungary. E-mail: hrabovszky{at}koki.hu.

Context: Recent identification of the second estrogen receptor (ER) isoform (ER-ß) within GnRH neurons of the rodent brain has generated much enthusiasm in the field of neuroendocrine research by questioning the dogma that GnRH cells do not directly sense changes in circulating estrogens.

Objective: To address the issue of whether GnRH neurons of the human hypothalamus also contain ER-ß, we have performed dual-label immunocytochemical studies.

Design: Tissue sections were prepared from autopsy samples of male human individuals (n = 8; age < 50 yr), with sudden causes of death. Technical efforts were made to minimize postmortem interval (<24 h), optimize tissue fixation (use of a mixture of 2% paraformaldehyde and 4% acrolein for four tissue samples), and sensitize the immunocytochemical detection of ER-ß (application of silver-intensified nickel-diaminobenzidine chromogen).

Main Outcome Measure: Distribution and percent ratio of GnRH neurons that also contained ER-ß immunoreactivity were analyzed under the light microscope.

Results: With acrolein in tissue fixative, nuclear ER-ß immunoreactivity was observed in 10.8–28.0% of GnRH neurons of the four different individuals. ER-ß-containing GnRH neurons were widely distributed in the hypothalamus, without showing a noticeable preference in regional location.

Conclusions: The demonstration of ER-ß and the previous lack of detection of ER- in human GnRH cells indicate that estrogens may exert direct actions upon GnRH neurons exclusively through ER-ß. In the light of differing ligand-binding characteristics of ER-ß from those of ER-, this discovery offers a potential new approach to influence estrogen feedback to GnRH neurons through ER-ß-selective receptor ligands.

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