Theca-Specific Estrogen Receptor-α Knockout Mice Lose Fertility Prematurely

Abstract

Estrogen receptor-alpha (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 (>or=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.

Steroid Receptors in the Uterus and Ovary

“…362 In response to exogenous gonadotropins the thEsr1KO animals release similar numbers of oocytes to WT at 2 months of age ( thEsr1KO) and the ovaries show an increase in the number of cystic/hemorrhagic follicles. 362 Additionally, the oocytes collected from the thEsr1KO ampulla appeared to be more degenerated than WT oocytes, however, further studies are required to examine the viability of oocytes collected from thEsr1KO mice. The age-related reduction in fertility coincides with an increase in the length of estrous cycle these animals have at 6 months of age, 362 demonstrating that ERα is important for maintenance of fertility, but its expression in thecal cells is dispensable for normal ovarian response in younger mice.…”

“…361 Further characterization of this mouse and ovarian function in the absence of ERα demonstrated that these mice prematurely lose fertility. 362 Theca cell-specific ERα knockout (thEsr1KO) mice did not have an altered estrous cycle, fertility as measured by the number of offspring born, or ovarian response to exogenous gonadotropins (superovulation) in animals aged 2 months; however, these measures were significantly reduced in thEsr1KO females at 6 months of age (Table 25.7). 362 In response to exogenous gonadotropins the thEsr1KO animals release similar numbers of oocytes to WT at 2 months of age ( thEsr1KO) and the ovaries show an increase in the number of cystic/hemorrhagic follicles.…”

“…362 Theca cell-specific ERα knockout (thEsr1KO) mice did not have an altered estrous cycle, fertility as measured by the number of offspring born, or ovarian response to exogenous gonadotropins (superovulation) in animals aged 2 months; however, these measures were significantly reduced in thEsr1KO females at 6 months of age (Table 25.7). 362 In response to exogenous gonadotropins the thEsr1KO animals release similar numbers of oocytes to WT at 2 months of age ( thEsr1KO) and the ovaries show an increase in the number of cystic/hemorrhagic follicles. 362 Additionally, the oocytes collected from the thEsr1KO ampulla appeared to be more degenerated than WT oocytes, however, further studies are required to examine the viability of oocytes collected from thEsr1KO mice.…”

Malignant tumors of the uterine corpus: molecular background of their origin

“…The MiB1 gene is also overexpressed in sarcomas [48] besides leiomyoma. Other strongly expressed genes are ESR1 [49], Ki-67, TWIST1 [1], PGR1, and ER (progesterone and estrogen receptors) [50]. On the other hand, BCl-2 is underexpressed [51].…”

“…For example, carcinosarcomas, as mixed tumors and most common sarcoma types, overexpress the p53 gene in nearly 70 % of cases but also express or overexpress different genes such as TGF-β, HER-2 [49], VEGF, COX-2, and EGFR [62]. Previous studies of Atkins et al [63] found out that the CTAG1B gene appeared to be overexpressed in certain carcinomas and sarcomas.…”