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Theca-Specific Estrogen Receptor- Knockout Mice Lose Fertility Prematurely

Division of Reproductive Sciences (S.L., D.-W.K., S.H.-S., C.K.), Department of Clinical Sciences, University of Kentucky, Lexington, Kentucky 40536; Department of Pathology (D.-W.K.), Eulgi University, 137-868 Seoul, Korea; Institut de Genetique et de Biologie Moleculaire et Cellulaire (A.K., P.C.) (Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, College de France), 67404 Illkirch-Strasbourg, France; Department of Pathology and Laboratory Medicine (E.-Y.L.), University of Kentucky, Lexington, Kentucky 40506; School of Biological Sciences (Y.K.), Inje University, Gimhae 621-749, Korea; Department of Biology (S.L., Y.C.), Sungshin Women’s University, Seoul 136-742, Korea; and Department of Life Science (M.C.G.), Hanyang University, Seoul 133-791, Korea

Address all correspondence and requests for reprints to: Dr. CheMyong (Jay) Ko, Department of Clinical Sciences, Division of Reproductive Sciences, University of Kentucky, 207 East College of Health Sciences, Lexington, Kentucky 40506. E-mail: cko2{at}uky.edu.

Estrogen receptor- (Esr1) mediates estrogen action in regulating at all levels of the hypothalamic-pituitary-ovarian axis. Whereas the importance of Esr1 in hypothalamus and pituitary has been demonstrated by loss of fertility in the neuron- and pituitary-specific Esr1 knockout mice, whether Esr1 plays a critical role in the ovary remains to be determined. In the ovary, Esr1 is mainly expressed in the theca/interstitial cells and germinal epithelium and thus is believed to mediate estrogen action in these cells. In this study, we assessed the importance of Esr1 in the ovarian theca cells in regulating female reproduction. The Cre-LoxP approach was used to selectively delete the Esr1 gene in the theca cells, and the reproductive consequence of the deletion was measured. Adolescent theca-specific Esr1 knockout (thEsr1KO) mice (<4 months of age) are fertile and cycling. However, they begin to display an erratic pattern of estrous cycles and become infertile before they reach the age of 6 months. The ovaries of thEsr1KOmice (4 months) have fewer corpora lutea but more antral follicles than the age-matching wild-type mice. The numbers of 17-hydroxylase-expressing cells are largely increased in the interstitium of the thEsr1KO mouse ovary. Interestingly, whereas basal levels of serum testosterone and FSH were mildly elevated, LH level was either markedly lower or undetectable in the thEsr1KO mice. When superstimulated by exogenous gonadotropins, thEsr1KO mice released significantly fewer oocytes that wild-type littermates and developed multiple hemorrhagic cysts. Taken together, this study demonstrates that theca Esr1 plays a critical role in regulating female reproduction.