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Molecular Endocrinology, doi:10.1210/me.2002-0398
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Molecular Endocrinology 17 (6): 1039-1053
Copyright © 2003 by The Endocrine Society

Characterization of the Hypothalamic-Pituitary-Gonadal Axis in Estrogen Receptor (ER) Null Mice Reveals Hypergonadism and Endocrine Sex Reversal in Females Lacking ER{alpha} But Not ERß

John F. Couse, Mariana M. Yates, Vickie R. Walker and Kenneth S. Korach

Receptor Biology Section (J.F.C., M.M.Y., V.R.W., K.S.K.), Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; and Department of Environmental and Molecular Toxicology (J.F.C.), North Carolina State University, Raleigh, North Carolina 27695

Address all correspondence and requests for reprints to: Dr. Kenneth S. Korach, Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, MD B3-02, P.O. Box 12233, Research Triangle Park, North Carolina 27709. E-mail: korach{at}niehs.nih.gov.

To determine the role of each estrogen receptor (ER) form (ER{alpha}, ERß) in mediating the estrogen actions necessary to maintain proper function of the hypothalamic-pituitary-gonadal axis, we have characterized the hypothalamic-pituitary-gonadal axis in female ER knockout (ERKO) mice. Evaluation of pituitary function included gene expression assays for Gnrhr, Cga, Lhb, Fshb, and Prl. Evaluation of ovarian steroidogenic capacity included gene expression assays for the components necessary for estradiol synthesis: i.e. Star, Cyp11a, Cyp17, Cyp19, Hsd3b1, and Hsd17b1. These data were corroborated by assessing plasma levels of the respective peptide and steroid hormones. {alpha}ERKO and {alpha}ßERKO females exhibited increased pituitary Cga and Lhb expression and increased plasma LH levels, whereas both were normal in ßERKO. Pituitary Fshb expression and plasma FSH were normal in all three ERKOs. In the ovary, all three ERKOs exhibited normal expression of Star, Cyp11a, and Hsd3b1. In contrast, Cyp17 and Cyp19 expression were elevated in {alpha}ERKO but normal in ßERKO and {alpha}ßERKO. Plasma steroid levels in each ERKO mirrored the steroidogenic enzyme expression, with only the {alpha}ERKO exhibiting elevated androstenedione and estradiol. Elevated plasma testosterone in {alpha}ERKO and {alpha}ßERKO females was attributable to aberrant expression of Hsd17b3 in the ovary, representing a form of endocrine sex reversal, as this enzyme is unique to the testes. Enhanced steroidogenic capacity in {alpha}ERKO ovaries was erased by treatment with a GnRH antagonist, indicating these phenotypes to be the indirect result of excess LH stimulation that follows the loss of ER{alpha} in the hypothalamic-pituitary axis. Overall, these findings indicate that ER{alpha}, but not ERß, is indispensable to the negative-feedback effects of estradiol that maintain proper LH secretion from the pituitary. The subsequent hypergonadism is illustrated as increased Cyp17, Cyp19, Hsd17b1, and ectopic Hsd17b3 expression in the ovary.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ
Ligands:   17β-Estradiol



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