Estrogen-induced proliferation of uterine epithelial cells is independent of estrogen receptor alpha binding to classical estrogen response elements
ABSTRACT Acting via the estrogen receptor (ER), estradiol exerts pleomorphic effects on the uterus, producing cyclical waves of cellular proliferation and differentiation in preparation for embryo implantation. In the classical pathway, the ER binds directly to an estrogen response element to activate or repress gene expression. However, emerging evidence supports the existence of nonclassical pathways in which the activated ER alters gene expression through protein-protein tethering with transcription factors such as c-Fos/c-Jun B (AP-1) and Sp1. In this report, we examined the relative roles of classical and nonclassical ER signaling in vivo by comparing the estrogen-dependent uterine response in mice that express wild-type ERalpha, a mutant ERalpha (E207A/G208A) that selectively lacks ERE binding, or ERalpha null. In the compound heterozygote (AA/-) female, the nonclassical allele (AA) was insufficient to mediate an acute uterotrophic response to 17beta-estradiol (E2). The uterine epithelial proliferative response to E2 and 4-hydroxytamoxifen was retained in the AA/-females, and uterine luminal epithelial height increased commensurate with the extent of ERalpha signaling. This proliferative response was confirmed by 5-bromo-2'-deoxyuridine incorporation. Microarray experiments identified cyclin-dependent kinase inhibitor 1A as a nonclassical pathway-responsive gene, and transient expression experiments using the cyclin-dependent kinase inhibitor 1A promoter confirmed transcriptional responses to the ERalpha (E207A/G208A) mutant. These results indicate that nonclassical ERalpha signaling is sufficient to restore luminal epithelial proliferation but not other estrogen-responsive events, such as fluid accumulation and hyperemia. We conclude that nonclassical pathway signaling via ERalpha plays a critical physiologic role in the uterine response to estrogen.
- SourceAvailable from: Hesam Mostafavi Toroghi
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- "One of the proliferative responses of the uterine epithelium is hyperplasia and stratification of the epithelial cells which affect the implantation phase. Therefore increasing the height of endometrial and fallopian epithelial cells can improve the proliferative indices (12,13). Previously it has been demonstrated that exposure to extremely low-frequency electromagnetic field (ELF-EMF) can increase height of fallopian tube epithelial cells. "
ABSTRACT: Background: Magnetized water has made many improvements in industry, agriculture and medicine. However its utilization in medicine still remains controversial. Objective: In this study we aimed to investigate the effects of magnetized water on height of epithelial cells in pre-implantation stage endometrium and fallopian tube and number of corpus lutea in female mice. Materials and Methods: Eighty female NRMI mice were recruited to this experimental study and randomly divided into two groups: the control group which drank normal water and the experimental (case) group which drank magnetized water for 2 weeks. Super-ovulation was induced in these mice and then they were mated with male mice as well. Samples of ovary, uterus and fallopian tube were obtained at the pre-implantation stage. Then, after preparation, the number of corpus lutea in each ovary was counted and the height of fallopian and endometrial epithelial cells was measured by light microscopy. Results: Data analysis showed a significant increase in the mean number of corpus lutea and the height of epithelial cells in fallopian tube comparing the case with the control group (p=0.01, p=0.002 respectively) whereas uterus epithelial cells of the case group showed insignificant increase in height, in compare with the control group (p=0.052). Conclusion: Our results suggest that magnetized water intake increases the number of corpus lutea and the height of fallopian tube epithelial cells. Further research is needed to determine whether this will increase in the success rate of fertility.Iranian Journal of Reproductive Medicine 04/2014; 12(4):243-248. · 0.19 Impact Factor
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- "est effect of our PPT replace - ment on uterine weight suggests that ERa was less active in these animals than in our E2 - replaced females . The small , Ovx - like uteri of the aERKO females observed in the present study resemble previous reports of reduced uterine sizes in these mice and indi - rectly confirms their lack of ERa signaling ( ( O ' Brien et al . , 2006 ) , reviewed in Couse and Korach ( 1999 ) ) . In contrast , the present and previous studies ( reviewed in Couse and Korach ( 1999 ) ) demon - strate that the uteri of bERKO mice are normally sized . Confirma - tion of ERb activity is difficult without a similar indirect measure . However , doses of DPN similar to or lower than the 8 mg"
ABSTRACT: Psychostimulant effects are enhanced by ovarian hormones in women and female rodents. Estradiol increases behavioral responses to psychostimulants in women and female rats, although the underlying mechanism is unknown. This study utilized mice to investigate the time frame and receptor mediation of estradiol's enhancement of cocaine-induced behavior as mice enable parallel use of genetic, surgical and pharmacological methods. The spontaneous behavior of Sham and Ovariectomized (Ovx) female wildtype (WT) mice was determined during habituation to a novel environment and after cocaine administration. Ovx mice were replaced with vehicle (sesame oil) or 17β-estradiol (E2) for 2 days or 30 minutes prior to a cocaine challenge to investigate the time course of E2's effects. To examine receptor mediation of estradiol effects, Ovx mice replaced for 2 days with either the ERα-selective agonist PPT or the ERβ-selective agonist DPN were compared to Sham mice, and mice lacking either ERα (αERKO) or ERβ (βERKO) were compared to WT littermates. Ovx mice exhibited fewer ambulations during habituation than Sham females. Cocaine-induced increases in behavioral ratings were greater in Sham than in Ovx mice. Two days but not 30 minutes of E2 replacement in Ovx mice increased cocaine responses to Sham levels. PPT replacement also increased the cocaine response relative to vehicle- or DPN- treated Ovx mice. αERKO mice displayed modestly attenuated behavioral responses to novelty and cocaine compared to αWT littermates, but no behavioral differences were found between βERKO and βWT mice. These results suggest that E2 enhances cocaine-stimulated locomotion in mice predominantly through ERα.Neuropharmacology 04/2013; 72. DOI:10.1016/j.neuropharm.2013.04.015 · 5.11 Impact Factor
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- "Although ERα is a nuclear receptor mediating most of its pleiotrophic effects as a DNA-binding transcription factor, several reports have suggested that estrogen receptors are also capable of associating with the cell membrane to conduct rapid responses independent of gene expression , . Alternatively ERα was reported to suppress gene transcription by interfering with DNA-bound transcription factors such as AP-1 . In this regard it is important to state that we have previously reported that glucocorticoid-induced bone loss still occurs in mice carrying a glucocorticoid receptor incapable of DNA-binding . "
ABSTRACT: Postmenopausal osteoporosis is characterized by declining estrogen levels, and estrogen replacement therapy has been proven beneficial for preventing bone loss in affected women. While the physiological functions of estrogen in bone, primarily the inhibition of bone resorption, have been studied extensively, the effects of pharmacological estrogen administration are still poorly characterized. Since elevated levels of follicle-stimulating hormone (FSH) have been suggested to be involved in postmenopausal bone loss, we investigated whether the skeletal response to pharmacological estrogen administration is mediated in a FSH-dependent manner. Therefore, we treated wildtype and FSHβ-deficicent (Fshb(-/-)) mice with estrogen for 4 weeks and subsequently analyzed their skeletal phenotype. Here we observed that estrogen treatment resulted in a significant increase of trabecular and cortical bone mass in both, wildtype and Fshb(-/-) mice. Unexpectedly, this FSH-independent pharmacological effect of estrogen was not caused by influencing bone resorption, but primarily by increasing bone formation. To understand the cellular and molecular nature of this osteo-anabolic effect we next administered estrogen to mouse models carrying cell specific mutant alleles of the estrogen receptor alpha (ERα). Here we found that the response to pharmacological estrogen administration was not affected by ERα inactivation in osteoclasts, while it was blunted in mice lacking the ERα in osteoblasts or in mice carrying a mutant ERα incapable of DNA binding. Taken together, our findings reveal a previously unknown osteo-anabolic effect of pharmacological estrogen administration, which is independent of FSH and requires DNA-binding of ERα in osteoblasts.PLoS ONE 11/2012; 7(11):e50301. DOI:10.1371/journal.pone.0050301 · 3.23 Impact Factor