Distribution of estrogen receptor alpha and progesterone receptor, and leukocyte infiltration in the cervix of cyclic bitches and those with pyometra

The objectives were to localize estrogen receptor alpha (ERα) and progesterone receptor (PR), and enumerate leukocyte infiltration in cervical tissue of normal bitches during various stages of the estrous cycle (n = 35), as well as in those developing open (n = 22) or closed-cervix pyometra (n = 19). Each pyometra group was subdivided into anestrus and diestrus. Cervical tissues were collected after ovariohysterectomy. Receptor expressions were determined by immunohistochemistry and leukocyte infiltration was evaluated in histological sections stained with haematoxylin-eosin. The assessment was performed in two parts of cervical sections: the uterine part in four tissue layers (surface epithelium (SE), lamina propria (LP), glandular epithelium (GE), and tunica muscularis (M)), and the vaginal part in three layers (SE, LP and M). An immunohistochemical total score consisted of the addition of both the intensity and proportional scores. The ERα and PR scores differed between groups (P < 0.05) and between layers (P < 0.05), but were not significantly different between uterine and vaginal parts. The ERα score was lowest in the open-cervix pyometra bitches at anestrus and in closed-cervix pyometra bitches at diestrus. For all types of immune cells, there were no significant differences among stages of the estrous cycle in normal bitches, whereas neutrophils were lower in both sub-groups of closed-cervix versus open-cervix pyometra (P < 0.05). In conclusion, distributions of ERα and PR were similar along the longitudinal axis of the canine cervix. We inferred that cervical dilation in normal bitches and bitches with uterine pathology was likely controlled by different mechanisms. Receptor expressions were influenced by stage of the estrous cycle in normal bitches, whereas neutrophil infiltration in cervical tissue appeared to be involved in cervical dilation in bitches with pyometra, regardless of estrous stages.     

Serum estradiol-17 beta, progesterone and respective uterine cytosol receptor concentrations in bitches with spontaneous pyometra

The role of serum estradiol-17 beta (E(2)) and progesterone (P(4)) in relation to uterine estrogen (ER) and progesterone receptors (PR) was investigated in canine cystic endometrial hyperplasia-pyometra (CEH-P). Blood and uterine samples were collected pre- and post-ovariohysterectomy, respectively, from 54 bitches presenting spontaneous CEH-P and 25 healthy control bitches. Competitive enzyme immunoassays (EIA) and enzyme ligand immunoassays (ELIA) were applied to estimate serum hormones and uterine cytosol active receptors, respectively. Animals were classified in the stages of first half of diestrus, second half of diestrus and early anestrus on the basis of reproductive history, clinical signs, uterine and ovarian macro- and microscopic inspection and serum P(4) concentration. Bitches with CEH-P, compared to their respective stage controls, exhibited (a) similar P(4) fluctuations, (b) higher E(2) concentrations, (c) lower PR concentrations during diestrus first and second half and (d) lower ER concentrations during diestrus first half and early anestrus. Negative correlation was detected between P(4) and ER within both CEH-P and control groups. It was concluded that P(4) was the main uterine receptor regulator for both PR and ER during diestrus and early anestrus in healthy and affected uteri. However, in CEH-P bitches, high P(4) levels in diestrus appeared to over-activate uterine PRs, leading to stronger PR self-down regulation and ER suppression. These findings indicate an increased sensitivity of CEH-P uterus to P(4) action. During early anestrus, a complementary role of endogenous E(2) was considered, since reduction of P(4) action appeared to permit uterine ER replenishment and activation by relatively high E(2) levels.     

The effects of endometrial scarification on uterine steroid receptors, bacterial flora and histological structure in the bitch.

Following laparotomy, the endometrium of six nulliparous Beagle bitches was scarified at the base of one uterine horn during early metoestrus, when the peripheral plasma P(4) concentration was >10 ng/ml; intrauterine swabs were taken at the same time for bacteriological culture. Twenty-one days later, a bilateral ovariohysterectomy was performed and segments of the scarified and non-scarified parts of the tubular genital tract removed; at the same time, swabs were taken from the uterine lumen. Tissue samples were collected and examined for histopathological structure, and the presence of nuclear oestrogen (ER) and progesterone (PR) receptors using an immunocytochemical method. The immunoreactivity was scored semiquantitatively, incorporating both the intensity and distribution of specific staining of the receptors using a simplified histoscore (H-score).All uterine swabs were sterile, and in three of the six bitches there were noticeable changes with distension of the uterine lumen with secretions and debris and distension of the endometrial gland ducts of the scarified uterine segment. There were no statistically significant differences in the H-scores of ER or PR between scarified and non-scarified segments, except for PR H-scores in the glandular epithelium where the values for the scarified were significantly higher than for the non-scarified endometrium (mean+/-S.E.M. is 129.9+/-22.8 versus 59.5+/-12.6; P<0.05). Thus, trauma can modify the structure of the endometrium and the characteristics of the PR. Whether changes in PR expression are involved in the pathogenesis of CEH/pyometra in the bitch could not be ascertained from this study.     

Estrogen and progestin receptors in human uterus: reference ranges of clinical conditions

Estrogen receptor (ER) and progestin receptor (PR) levels and their respective dissociation constants (Kd) were determined by titration assay and Scatchard analyses in 319 human uteri. Levels of receptors were neither age nor uterine weight dependent. ER was higher in postmenopausal patients while PR levels were lower in women under 25 years of age. ER ranged from undetectable to 560 fmol/mg cytosol protein (mcp) while PR levels were generally 10-fold greater with a mean of 791 fmol/mcp. The mean of the Kd of ER was 4.0 X 10(-10) M while that for the PR was 9.2 X 10(-10) M. Receptor levels were not correlated with their respective Kd values nor with the Kd of the other receptor; therefore ligand affinities were not receptor concentration dependent. A population of patients was identified (12.5% of the total) in which the ER levels were undetectable while their corresponding PR ranged from 38 to 2,100 fmol/mcp. This suggests the existence of a type of PR which may not require ER for its expression and is independent of the phase of the cycle. Both ER and PR content were significantly elevated in the proliferative phase of the cycle. Evaluation of results as a function of histopathological features showed no relationship between the ER and PR of patients with anovulatory bleeding versus pathology. Uteri with leiomyomas contained ER and PR at levels comparable to those of histologically normal uteri. Adenomyosis patients tended to have lower ER and higher PR levels than the normal uteri. Reference ranges have been established for these receptors in uteri as a corollary to studies of these proteins in endometrial cancer.     

Induction of abortion with aglepristone significantly changed the expression of progesterone and estrogen receptors in canine endometrial stromal cells

In the present study, resorption/abortion was induced between days 25 and 45 of gestation with aglepristone (group IRA, n=10). The aim was to observe the change in the distribution of progesterone (PR) and estrogen receptors (ER), in comparison to a group of spontaneous resorptions/abortions (group SRA, n=5), and a further group of normal healthy pregnant animals, ovariohysterectomized between days 25 and 45 of gestation (controls, n=7). The receptors were assessed by means of immunohistochemistry (IHC) and RT-PCR, at the placental and interplacental sites of the uterine horn as well as in the corpus uteri. Significant differences were observed between the controls on one side and the groups of resorption/abortion on the other side. The total scores of the progesterone receptors (TPR) in the placental and interplacental part of the uterine horn, was significantly lower in the endometrial stromal cells (ESC) of the control group than in those of the SRA- and IRA-group, respectively (placenta: 5.8 vs. 6.5 and 6.7, p<0.01; interplacental sites: 5.6 vs. 6.6 and 6.6, p<0.05). In contrary, the total scores of the estrogen receptors (TER) at interplacental sites and the corpus uteri, respectively, was significantly higher in the myometrial smooth muscle cells (MSMC) and the ESC (p<0.05) of the controls. We therefore conclude, that the here observed differences between groups point to an up-regulation of TPR- and a down-regulation of TER-scores in endometrial stromal cells at different uterine sites during resorption/abortion, which indicates a special role of these cells.     

Estrogen and Progesterone Receptors in the Uterus of the Vervet Monkey

Abstract

Experimental conditions for the optimal measurement of estrogen (ER) and progesterone (PR) receptors in normal vervet monkey (Cercopithecus aethiops pygerythrus) uteri are described. The uteri of this primate were found to contain relatively high concentrations of both ER and PR. Levels of ER ranged from 151 to 822 femtomoles per mg protein (mean for group assayed is 327±165 femtomoles per mg protein). PR assays were performed on the same cytosols and the levels ranged from 444 to 2267 femtomoles per mg protein (mean of 1285±511 femtomoles per mg protein). Mean K_d values for the ER- and PR-ligand complexes were found to be 3.15±1.4x10^-10 M and 2.38±0.2x10^-9 M respectively, within the group analysed (n=21). The ratio of PR to ER varied between 1.1 and 13.1 with a mean of 4.5±2.4. Ligand specificity studies revealed that [³H]-17β-estradiol binding to the ER could only be inhibited by estrogens or estrogen analogues. The PR however exhibited an affinity for a wider range of ligand types. In low ionic strength buffers both ER and PR sedimented as ±8S type molecules in the presence or absence of 10mM sodium molybdate. Both receptors dissociated into smaller components, following a short exposure to 0.4 M KCl and subsequent centrifugation in a gradient containing 0.4 M KCl.     

Estrogen and progesterone receptors in carpal tunnel syndrome

Carpal tunnel syndrome (CTS) is a compression median nerve neuropathy common in women at menopausal age. The aim of this work was to study immunohistochemically the expression of estrogen (ER) and progesterone (PR) receptors in CTS and control specimens. Biopsies of transverse carpal ligament (TCL) and flexor tendon synovitis were collected from 23 women and from 7 men undergoing surgery for median nerve decompression at the wrist for CTS. In TCL and synovial tissue, cells expressed ER and PR with statistically significant differences related to the age and sex of patients. Immunoreactivity was observed in fibroblasts of TCL, and in lining cells and fibroblasts of synovial tissue. In women, the number of ER-positive cells in the TCL and synovial tissue increased with the age, peaking at 55-70 years, and then decreasing. PR-immunoreactivity was observed only in fibroblasts of TCL and its expression decreased with age, while no immunolabeling was found in the synovial tissue. In TCL samples, the number of ER- and PR-positive cells in non-CTS patients was significantly lower than in CTS patients. These results demonstrate that ER and PR are present in TCL and flexor tendon synovitis, suggesting a role for sex steroid hormones in the pathogenesis of CTS disease.     

Changes in equine endometrial oestrogen receptor alpha and progesterone receptor mRNAs during the oestrous cycle, early pregnancy and after treatment with exogenous steroids

Two experiments were performed to determine changes in the abundance of oestrogen and progesterone receptor (ER alpha and PR) mRNAs in equine endometrium during the oestrous cycle and early pregnancy, and under the influence of exogenous steroids. In Expt 1, endometrial biopsies were obtained from non-mated mares during oestrus and at days 5, 10 and 15 after ovulation, and from pregnant mares at days 10, 15 and 20 after ovulation. There were overall effects of day on the abundance of ER alpha (P = 0.0001) and PR (P = 0.0014) mRNAs. The amount of ER alpha mRNA decreased at day 10 of pregnancy, and PR mRNA was reduced at day 5 in non-mated mares and at day 15 of pregnancy, compared with oestrous values. Experiment 2 was conducted to determine the effects of exogenous steroids on endometrial ER alpha and PR mRNAs. Endometrial biopsies were obtained from 19 anoestrous mares that had been treated with vehicle, oestradiol, progesterone, or oestradiol followed by progesterone for either a short or a long duration. The steroid treatment affected the abundance of ER alpha mRNA (P = 0.0420), which was higher (P < 0.05) in the oestradiol group than in the group treated with oestradiol followed by long duration progesterone. The steroid treatment did not affect the abundance of PR mRNA. These results demonstrate that the amount of steroid receptor mRNA changes with the fluctuating steroid environment in the uterine endometrium of cyclic and early pregnant mares, and that the duration of progesterone dominance may affect ER alpha gene expression. In addition, factors other than steroids may regulate ER alpha and PR gene expression in equine uterine endometrium.     

Changes in sex hormone receptors during administration of progesterone to prevent estrus in the bitch

The development of lesions and the changes in sex hormone receptors were studied in the uteri of bitches under progesterone treatment. Twelve weeks after the onset of treatment, there was atrophy of the endometrium and increased thickness of the myometrium, without cystic dilatation of endometrial glands. This was accompanied by a dramatic reduction in estrogen-alpha and progesterone receptors in all cell types of the uterine wall. By 24 weeks after the onset of treatment, however, the endometrium was thickened due to the development of cysts of endometrial glands, while the myometrium thickness had returned to normal. The estrogen-alpha and progesterone receptors in most cell types of the uterine wall were again within the normal range. These results clarify and reconcile some apparent contradictions in the literature. They show that sex hormone receptors in most cell types of the uterine wall, especially endometrial gland cells and stromal cells, escape progestin (down) regulation after prolonged exogenous administration of progesterone.     

The influence of exogenous steroid hormones on steroid receptors, uterine histological structure and the bacterial flora of the normal bitch.

Oestrogen (ER) and progesterone (PR) receptors have been shown to vary in both concentration and distribution during the oestrous cycle of the bitch, influenced by the normal changes in endogenous reproductive hormones. The influence of exogenous steroid hormones on steroid receptors and the histological structure of the uterus was studied in two groups of parous Beagle bitches. Group A (n = 6) were treated with progesterone (P4) in oil i.m. (3 mg/kg) in late metoestrus on the day that peripheral plasma P4 concentrations were first identified as <10 ng/ml, and subsequently once weekly on three other occasions. Group B (n = 6) were treated with a single i.m. injection of MPA (50 mg, 4.2-5.6 mg/kg) following the same protocol. Full-thickness uterine wall biopsies were obtained from the mid part of one horn 2-7 days after the last (fourth) injection of P4 or MPA. During the subsequent oestrus, when peripheral plasma P4 concentrations were between 8 and 10 ng/ml, each bitch in both groups (n = 12) received a single injection of oestradiol benzoate (ODB) in oil i.m. (7.5 mg, 0.63-0.84 mg/kg). All bitches had an ovariohysterectomy 7 days later. Full-thickness uterine wall samples were obtained from the mid part of the intact horn and other parts of the uterus. Swabs were taken from the uterine lumen for bacteriological examination; all were sterile. Tissue samples were sectioned and examined for evidence of lesions, and stained for ER and PR receptors using an immunocytochemical method. The immunoreactivity was scored semiquantitatively, incorporating both the intensity and distribution of specific staining of the receptors using a simplified histoscore (H-score). At the time of ovariohysterectomy, fluid had accumulated in the isolated section of the uterine horn distal to the point of biopsy; the volume was greater in the MPA-treated bitches. There was also evidence in some sections of histological changes in the endometrium. Variations in the expression of both ER and PR were seen between bitches, which may have been due to some not being in mid-metoestrus at the time of treatment. In general, ER scores were low after P4 and MPA treatment, but following ODB there was a significant (P<0.05) increase in ER expression in all parts of the endometrium. PR scores were zero in the glandular epithelium of all 12 bitches after P4, MPA and ODB treatment, whereas in the other parts of the endometrium they were generally moderate to high. Following treatment with ODB, PR generally increased in the three regions of the endometrium where PR were present. The study shows that ER and PR distribution and expression in the endometrium of bitches can be modified by P4, MPA and ODB, with evidence of individual variation.     

Progesterone receptor repression by estrogens in rat uterine epithelial cells

Measurements performed using cell lines or animal tissues have shown that the progesterone receptor (PR) can be induced by estrogens. By use of immunohistochemistry we studied the effects of estrogens on the PR levels in the individual cell types of the target organs uterus and breast. In the uteri of rats, ovariectomy induced a decrease in PR immunoreactivity within the myometrium and outer stromal cell layers. In contrast, in the uterine luminal and glandular epithelium and surrounding stromal cell layers the PR immunoreactivity was significantly enhanced. The same picture emerged when intact rats were treated with the pure estrogen receptor antagonist, ZM 182780 (10 mg/kg/d). Treatment of ovariectomized rats with estradiol resulted in high PR levels in the myometrium and stroma cells but low PR immunoreactivity in the epithelial cells. The ER-mediated repression of the PR immunoreactivity was evidently restricted to the uterine epithelium, as we found that in the epithelial cells of the mammary gland and in cells of N-nitrosomethylurea-induced mammary carcinomas the PR expression was induced by estrogens and was blocked by the pure antiestrogen ZM 182780. These results clearly show that in the rat the activated ER induces diverging effects on PR expression in different cell types even within the same organ.     

Endometrial effects of selective estrogen receptor modulators (SERMs) on estradiol-responsive gene expression are gene and cell-specific

Three selective estrogen receptor modulator (SERM) drugs which included 4-OH-tamoxifen (Tam), EM-800 (EM) and GW 5638 (GW) were investigated to determine their ability to inhibit estradiol-responsive gene expression in sheep endometrium. The uteri of ovariectomized ewes (10 ewes per SERM group) were infused with 10⁻⁷ M SERMs for 24 h prior to hysterectomy. Five ewes from each group received 50 μg 17β-estradiol (E2) and the remaining five ewes received vehicle 18 h prior to hysterectomy. Northern blot analyses and in situ hybridization demonstrated that E2 treatment increased estrogen receptor (ER), progesterone receptor (PR), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and cyclophilin (CYC) mRNA levels in most endometrial cells examined. Tam and GW exhibited characteristics similar to E2 by increasing ER gene expression, but they antagonized the E2-induced increases in PR and CYC mRNA levels. EM acted as an E2-agonist of GAPDH gene expression, but antagonized the E2 up-regulation of ER, PR and CYC gene expression in most endometrial cells. Immunohistochemistry determined that EM decreased ER protein levels in the glandular epithelium, and the SERMs investigated antagonized increases in PR protein levels in endometrium. In conclusion, GW and EM exhibit fewer agonist effects than Tam on endometrial gene expression. EM demonstrated the greatest antagonism of E2-enhanced levels of ER, PR and CYC, likely due to the inhibition of ER gene expression at both mRNA and protein levels.     

Tissue- and hormone- dependent progesterone receptor distribution in the rat uterus

Background  

Estradiol (E2) and progesterone (P) are well known regulators of progesterone receptor (PR) expression in the rat uterus. However, it is not known which receptor subtypes are involved. Little knowledge exist about possible differences in PR regulation through ERalpha or ERbeta, and whether the PR subtypes are differently regulated depending on ER type bound. Thus, in the present study PR immunostaining has been examined in uteri of ovariectomized (ovx) rats after different treatments of estrogen and P, in comparison with that in immature, cycling, and pregnant animals.     

Steroid hormone receptors in the uterus and ovary of immature rats treated with gonadotropins

We administered either saline (group A) or 10 IU of pregnant mare serum gonadotropin (PMS; groups B and C) to female immature rats. Fifty-three hours later, the rats were injected with saline (groups A and B) or 30 IU of human chorionic gonadotropin (hCG; group C). The rats were decapitated 17 h after the last treatment, and the serum levels of progesterone (P4) and estradiol (E2) were measured by specific radioimmunoassays (RIA). The receptor levels of progesterone (PR) and estrogen (ER) in the uterus and ovaries were measured and the dissociation constant (Kd) of PR was obtained. The highest serum level of P4 was found in group C and that of E2 in group B. Cytosol levels of PR and ER in the uterus and ovary of the group B were the highest. It was indicated that the PMS treated-group (B), which had developing follicles in the ovary and the high serum level of E2, showed the highest concentration of ER and PR in both the ovary and the uterus. In the PMS and hCG-treated group (C), the uterine and ovarian steroid receptors decreased probably because of the luteinization and the high serum level of P4. The Kd uterine PR value was less than that of ovarian PR.     

In vivo analysis of progesterone receptor action in the uterus during embryo implantation

In order for a successful pregnancy to occur, the embryo must attach to the luminal epithelial cells and invade into the stroma. Then, the surrounding stromal cells need to undergo decidualization in order to establish the vasculature necessary for survival of the embryo. These events in early pregnancy are tightly regulated by the steroid hormones, estrogen (E2) and progesterone (P4), through their cognate receptors, the estrogen receptor (ER) and the progesterone receptor (PR), respectively. Using a mouse model in which the PR has been ablated, it was demonstrated that the PR is necessary for embryo implantation and decidualization. Therefore, understanding the mechanism of PR action in the adult uterus is necessary in order to understand the events of early pregnancy. Insights from both mouse models and human samples have been integral in elucidating uterine PR action. These studies have shown that not only PR target genes, but also mediators of PR action are important for correct PR action in early pregnancy. Many of the genes involved in PR action in early pregnancy have also been shown to have roles in uterine diseases such as endometriosis and endometrial cancer. Therefore, the integration of mouse and human studies on PR action in the uterus will be important for the future understanding of uterine diseases and in the development of treatment for these diseases.     

蛹虫草菌丝体多糖对乳腺增生患者ER 和PR 表达的影响

目的:探究蛹虫草菌丝体多糖对良性乳腺增生患者增生乳腺组织中雌激素受体(ER)、孕激素受体(PR)表达的影响。方法:选取我院收治的良性乳腺增生患者50例,行随机数字表法随机分为两组,其中对照组行乳癖消临床常规治疗;实验组在乳癖消治疗基础上加用蛹虫草菌丝体多糖联合治疗,检测和比较两组患者治疗前后增生乳腺组织中ER和PR表达的变化情况。结果:治疗后,两组患者增生乳腺组织中ER和PR表达均明显低于对照组,且实验组显著低于对照组,差异均有统计学意义(P0.05)。结论:蛹虫草菌丝体多糖能有效抑制良性乳腺增生症患者增生乳腺组织中ER、PR是表达,为临床治疗良性乳腺增生症提供了新的思路和方法,值得临床应用和推广。     

Progesterone and 17β-estradiol increase differentiation of mouse embryonic stem cells to motor neurons

Embryonic stem (ES) cells have the capacity to differentiate into endodermal, mesodermal, and ectodermal lineages. Motor neuron (MN) differentiation of mouse ES cells involves embryoid bodies formation with addition of Sonic hedgehog and retinoic acid. In this work, using immunocytochemistry, flow cytometry, and quantitative RT-PCR, we investigated whether progesterone or 17β-estradiol have inductive effects on ES cell-derived MN, as it has been demonstrated that these hormones modify proliferation and neural differentiation of pluripotent cells. When 100 nM progesterone was added during differentiation, we found higher proportions of MN, compared to the control condition; coincubation of progesterone with the progesterone receptor (PR) antagonist RU-486 caused a decrease in the number of MN to a percentage even lower than controls. The addition of nanomolar concentrations of 17β-estradiol also significantly induced MN differentiation. This effect of estradiol was completely antagonized by addition of the general estrogen receptor (ER) antagonist ICI 182,780. To identify the ER subtype mediating the increase on MN differentiation, we incubated estradiol with the ER-α antagonist MPP or with the ER-β blocker PHTPP. When we coincubated 17β-estradiol with MPP, we found a significant decrease in the percentage of MN. In contrast, the coincubation of 17β-estradiol with PHTPP had no effect on the induction of MN differentiation. All these effects on cell number were confirmed by significant changes in the expression of the MN markers Islet-1 and Choline acetyl transferase, assessed by real-time RT-PCR. Cell proliferation in embryoid bodies was significantly enhanced by progesterone treatment. No changes in apoptotic cell death were found in differentiating cells after progesterone or 17β-estradiol addition. Our findings indicate that progesterone and 17β-estradiol induce a higher proportion of MN derived from mouse ES cells through intracellular PR and ER, respectively. Furthermore, the effect of estradiol was mediated by specific activation of ER-α.     

Myometrial effects of selective estrogen receptor modulators on estradiol-responsive gene expression are gene and cell-specific

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 24 h preceding hysterectomy. Half of the ewes in each SERM group received an intramuscular injection of 50 μg 17β-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.