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Myometrial effects of selective estrogen receptor modulators on estradiol-responsive gene expression are gene and
1Department of Animal Science, Faculties of Genetics and Reproductive Biology, Texas A&M University, College Station, TX 77843-2471, USA.
Abstract:
We examined in vivo effects of selective estrogen receptor modulators (SERMs) 4-OH-tamoxifen (Tam), GW 5638 (GW) and EM-800 (EM) on myometrial gene expression. The uteri of ovariectomized ewes were infused with 10(-7)M of one SERM via indwelling catheters for 24h preceding hysterectomy. Half of the ewes in each SERM group received an intramuscular injection of 50 microg 17beta-estradiol (E2) 18 h prior to hysterectomy. Northern blot analysis and in situ hybridization demonstrated that E2 increased estrogen receptor (ER), progesterone receptor (PR) and cyclophilin (CYC) gene expression in the cells of both inner layer of myometrium (IM) and outer layer of myometrium (OM) as well as glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene expression in OM. Tam also increased ER mRNA levels in OM. EM appeared to increase ER gene expression, but antagonized E2's up-regulation of PR and CYC gene expression in both IM and OM. Tam and GW also antagonized E2 up-regulation of PR gene expression in OM but not IM. No SERM affected GAPDH gene expression with or without E2. Immunohistochemistry indicated that E2 increased nuclear ER and PR protein levels in both IM and OM. EM was unique in up-regulating ER protein levels, opposite to its effects in endometrial cells. All SERMs tested antagonized this increase in PR immunostaining preferentially in OM compared to the IM layer. These results illustrate gene and cell layer-specific effects of SERMs in sheep myometrium.
Insights
Selective estrogen receptor modulators (SERMs) show varied effects on sheep myometrial gene expression. Different SERMs impact estrogen and progesterone receptor levels differently in distinct uterine layers.
Area of Science:
- Reproductive Biology
- Endocrinology
- Pharmacology
Background:
- Estrogen receptors (ER) play a crucial role in uterine function.
- Selective estrogen receptor modulators (SERMs) are drugs that interact with ERs.
- Understanding SERM effects on myometrium is vital for reproductive health.
Purpose of the Study:
- To investigate the in vivo effects of specific SERMs on myometrial gene expression in ewes.
- To determine if SERM actions differ between inner (IM) and outer (OM) myometrial layers.
- To compare the effects of 4-OH-tamoxifen (Tam), GW 5638 (GW), and EM-800 (EM) on ER and progesterone receptor (PR) expression.
Main Methods:
- Ovariectomized ewes received SERMs (Tam, GW, EM) or vehicle.
- Some ewes received 17beta-estradiol (E2) treatment.
- Gene expression analyzed via Northern blot and in situ hybridization.
- Protein levels assessed using immunohistochemistry.
Main Results:
- E2 increased ER, PR, and cyclophilin (CYC) gene expression in both IM and OM.
- Tam increased ER mRNA in OM; EM also appeared to increase ER gene expression.
- EM, Tam, and GW antagonized E2-induced PR gene expression, with varying layer specificity.
- All SERMs antagonized E2-induced PR protein levels, particularly in the OM.
- EM uniquely increased ER protein in myometrium, contrasting with endometrial effects.
Conclusions:
- SERMs exhibit distinct, gene, and cell layer-specific effects on sheep myometrium.
- SERM-ER interactions in the myometrium are complex and context-dependent.
- These findings highlight differential SERM activity within uterine layers, impacting reproductive physiology.
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