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Formation of Cystic Ovarian Follicles Associated with Elevated Luteinizing Hormone Requires Estrogen Receptor-ß

Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology (J.F.C., M.M.Y., R.S., K.S.K.), and Laboratory of Experimental Pathology (A.N.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Environmental and Molecular Toxicology, North Carolina State University (J.F.C.), Raleigh, North Carolina 27695; and School of Molecular Biosciences, Washington State University (J.H.N.), Pullman, Washington 99164

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, P.O. Box 12233, MD B3-02, Research Triangle Park, North Carolina 27709. E-mail: korach{at}niehs.nih.gov.

Stringent regulation of LH secretion from the pituitary is vital to ovarian function in mammals. Two rodent models of LH hypersecretion are the transgenic LHß-C-terminal peptide (LHßCTP) and estrogen receptor- (ER)-null (ERKO) mice. Both exhibit ovarian phenotypes of chronic anovulation, cystic and hemorrhagic follicles, lack of corpora lutea, interstitial/stromal hyperplasia, and elevated plasma estradiol and testosterone. Because ERß is highly expressed in granulosa cells of the ovary, we hypothesized the intraovarian actions of ERß may be necessary for full manifestation of phenotypes associated with LH hyperstimulation. To address this question, we generated female mice that possess elevated LH, but lack ERß, by breeding the LHßCTP and ERß-null (ßERKO) mice. A comparison of LHßCTP, ERKO, and ßERKO^LHCTP females has allowed us to elucidate the contribution of each ER form to the pathologies and endocrinopathies that occur during chronic LH stimulation of the ovary. ERKO ovaries respond to elevated LH by exhibiting an amplified steroidogenic pathway characteristic of the follicular stage of the ovarian cycle, whereas wild-type^LHCTP and ßERKO^LHCTP females exhibit a steroidogenic profile more characteristic of the luteal stage. In addition, the hemorrhagic and cystic follicles of the LHßCTP and ERKO ovaries require the intraovarian actions of ERß for manifestation, because they were lacking in the ßERKO^LHCTP ovary. In turn, ectopic expression of the Leydig cell-specific enzyme, Hsd17b3, and male-like testosterone synthesis in the ERKO ovary are unique to this genotype and are therefore the culmination of elevated LH and the loss of functional ER within the ovary.

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