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Endocrinology Vol. 140, No. 12 5855-5865
Copyright © 1999 by The Endocrine Society

ARTICLES

Prevention of the Polycystic Ovarian Phenotype and Characterization of Ovulatory Capacity in the Estrogen Receptor-{alpha} Knockout Mouse

John F. Couse, Donna O. Bunch, Jonathan Lindzey1, David W. Schomberg and Kenneth S. Korach

Receptor Biology Section (J.F.C., J.L., 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; Laboratory of Reproductive Biology (D.O.B.), Department of Cell Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; and Departments of Obstetrics and Gynecology and Cell Biology (D.W.S.), Duke University Medical Center, Durham, North Carolina 27710

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

Ovarian-derived estradiol plays a critical endocrine role in the regulation of gonadotropin synthesis and secretion from the hypothalamic-pituitary axis. In turn, several para/autocrine effects of estrogen within the ovary are known, including increased ovarian weight, stimulation of granulosa cell growth, augmentation of FSH action, and attenuation of apoptosis. The estrogen receptor-{alpha} (ER{alpha}) is present in all three components of the hypothalamic-pituitary-ovarian axis of the mouse. In contrast, estrogen receptor-ß (ERß) is easily detectable in ovarian granulosa cells but is low to absent in the pituitary of the adult mouse. This distinct expression pattern for the two ERs suggests the presence of separate roles for each in the regulation of ovarian function. Herein, we definitively show that a lack of ER{alpha} in the hypothalamic-pituitary axis of the ER{alpha}-knockout ({alpha}ERKO) mouse results in chronic elevation of serum LH and is the primary cause of the ovarian phenotype of polycystic follicles and anovulation. Prolonged treatment with a GnRH antagonist reduced serum LH levels and prevented the {alpha}ERKO cystic ovarian phenotype. To investigate a direct role for ER{alpha} within the ovary, immature {alpha}ERKO females were stimulated to ovulate with exogenous gonadotropins. Ovulatory capacity in the immature {alpha}ERKO female was reduced compared with age-matched wild-type (14.5 ± 2.9 vs. 40.6 ± 2.6 oocytes/animal, respectively); however, oocytes collected from the {alpha}ERKO were able to undergo successful in vitro fertilization. A similar discrepancy in oocyte yield was observed after superovulation of peripubertal (42 days) wild-type and {alpha}ERKO females. In addition, ovaries from immature superovulated {alpha}ERKO females possessed several ovulatory but unruptured follicles. Investigations of the possible reasons for the reduced number of ovulations in the {alpha}ERKO included ribonuclease protection assays to assess the mRNA levels of several markers of follicular maturation and ovulation, including ERß, LH-receptor, cyclin-D2, P450-side chain cleavage enzyme, prostaglandin synthase-2, and progesterone receptor. No marked differences in the expression pattern for these mRNAs during the superovulation regimen were observed in the immature {alpha}ERKO ovary compared with that of the wild-type. Serum progesterone levels just before ovulation were slightly lower in the {alpha}ERKO compared with wild-type. These studies indicate that treatment of {alpha}ERKO females with a GnRH antagonist decreased the serum LH levels to within the wild-type range and concurrently prevented development of the characteristic ovarian phenotype of cystic and hemorrhagic follicles. Furthermore, a lack of functional ER{alpha} within the ovary had no effect on the regulation of several genes required for follicular maturation and ovulation. However, the reduced numbers of ovulations following the administration of exogenous gonadotropins in the {alpha}ERKO suggests an intraovarian role for ER{alpha} in follicular development and ovulation.




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