In Vitro Growth and Ovulation of Follicles from Ovaries of Estrogen Receptor (ER)α and ERβ Null Mice Indicate a Role for ERβ in Follicular Maturation

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, USA.
Endocrinology (Impact Factor: 4.5). 07/2005; 146(6):2817-26. DOI: 10.1210/en.2004-1108
Source: PubMed


Both estrogen receptor (ER) alpha and beta are expressed within the ovary and lack of either of these receptors affects ovarian function. In this study, the role of ERalpha and ERbeta in folliculogenesis and ovulation was further analyzed. Evaluation of ovarian follicle populations in wild-type and ERbeta knockout (betaERKO) ovaries revealed reduced late antral growth and ovulatory capacity of betaERKO follicles, indicated by reduced numbers of large antral follicles and corpora lutea and increased atresia of large antral follicles. An in vitro culture system was used to study growth, rupture, and luteinization of wild-type, ERalpha knockout (alphaERKO) and betaERKO ovarian follicles. alphaERKO follicles exhibited wild-type-like growth and ovulation rates but an increased capacity to synthesize estradiol. In contrast, betaERKO follicles showed a significant lack of progression from early antral to large antral stage, decreased estradiol production, and reduced ovulation. Expression patterns of several genes involved in follicle maturation and ovulation were analyzed in follicles grown in vitro. Ar, Pgr, and Has2 mRNA expression levels were the same among the three genotypes. However, betaERKO follicles showed reduced expression of Cyp19 mRNA during follicle maturation and reduced Lhcgr and Ptgs2 mRNA expression after human chorionic gonadotropin stimulus. Luteinization occurs normally in alphaERKO and betaERKO follicles, shown by increased progesterone secretion and increased cdkn1b mRNA expression after human chorionic gonadotropin. Collectively, these data indicate that ERbeta, but not ERalpha, plays a direct role in folliculogenesis. ERbeta appears to facilitate follicle maturation from the early antral to the preovulatory stage.

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Available from: Kenneth S Korach
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    • "In addition, studies of hypophysectomized rats and mutant mice lacking follicle-stimulating hormone (FSH) or its receptor have shown that E2 and FSH exert a synergistic stimulatory effect on granulosa cell proliferation in preantral follicles [17]. In estrogen receptor (ER) β knockout mice, progression of follicles from the early antral to large antral stage is impaired, E2 production is decreased, and ovulation is also reduced, indicating that signaling via ERβ is necessary for both folliculogenesis and ovulation [18]–[20]. On the other hand, it has been reported that E2 has a marked influence on meiotic spindle organization and promotes multipolar spindle formation [21]. In addition, exposure to estrogen valerate induces the formation of follicular cysts that have thin layers of granulosa cells and lack oocytes [22]. "
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    • "In mouse ovaries, ERβ promoted the proliferation of granulosa cells in early folliculogenesis [49] and also follicular maturation from the early antral to preovulatory stages [50]. In Igf1 null mouse ovaries, the proliferation of granulosa cells was decreased, and E2 stimulated the proliferation of granulosa cells, although the increase was less compared with that of wild-type mice [23]. "
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    • "In the rodent ovary, estrogen was primarily produced by preovulatory follicles under the influence of FSH [12]. The well-documented endocrine actions of estrogen in the ovary were critical to reproduction, and signaled via two nuclear estrogen receptors, ERa and ERb [13]. Androgen mediated their action primarily via AR, a member of the nuclear receptor superfamily encoded by an X chromosomal gene [14]. "
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