Context: Recent identification of the second estrogen receptor isoform (ER-) within gonadotropin-releasing hormone (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-, 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 post mortem 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- (application of silver-intensified nickel-diaminobenzidine chromogen).

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

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

Conclusions: The demonstration of ER- 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-. In the light of differing ligand binding characteristics of ER- from those of ER-, this discovery offers a potential new approach to influence estrogen feed-back to GnRH neurons through ER--selective receptor ligands.