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PubMed2000

Raloxifene: a review of its use in postmenopausal osteoporosis.

UNLABELLED: Raloxifene is a selective estrogen receptor modulator that partially mimics the effects of estrogens in bone and the cardiovascular system, while functioning as an antiestrogen in endometrial and breast tissue. In randomised placebo-controlled studies involving postmenopausal women or patients with osteoporosis, raloxifene 60 to 150 mg/day was effective in increasing bone mineral density (BMD) over 12- to 36-month periods. At the 60 mg/day recommended dosage, increases of 1.6 to 3.4%, 0.9 to 2.3% and 1.0 to 1.6% were reported in lumbar spine, femoral neck and total hip, respectively, versus < or =0.5% with placebo. Raloxifene 60 or 120 mg/day decreased the risk of vertebral fractures over a 36-month period in postmenopausal patients with osteoporosis. Significant reductions in radiographic fracture risk versus placebo (30 and 50%) occurred regardless of whether patients had existing fractures at baseline. Although raloxifene did not affect the overall incidence of nonvertebral fractures, a reduction in the incidence of ankle fracture was reported in comparison with placebo. In postmenopausal women, raloxifene 60 mg/day significantly reduced serum levels of total and low density lipoprotein cholesterol from baseline, compared with placebo. High density lipoprotein cholesterol and triglyceride levels were unaffected. Raloxifene 60 or 120 mg/day reduced the risk of invasive breast cancer by 76% during a median of 40 months' follow-up in postmenopausal patients with osteoporosis and no history of breast cancer. A relative risk reduction of 90% was reported for estrogen-receptor positive invasive breast cancers; estrogen-receptor negative cancer risk was unaffected by raloxifene. Raloxifene was generally well tolerated in clinical trials at dosages up to 150 mg/day. Adverse events thought to be related to raloxifene treatment were hot flushes and leg cramps. Venous thromboembolism was the only serious adverse event thought to be related to raloxifene treatment and a relative risk of 3.1 compared with placebo treatment was reported in patients with osteoporosis. Vaginal bleeding occurred in < or =6.4% of raloxifene-treated women but was reported by 50 to 88% of those receiving estrogens or hormone replacement therapy (HRT). Raloxifene treatment was not associated with stimulatory effects on the endometrium. CONCLUSIONS: Raloxifene significantly increases BMD in postmenopausal women and reduces vertebral fracture risk in patients with osteoporosis. In clinical trials, raloxifene was generally well tolerated compared with placebo and HRT, although its propensity to cause hot flushes precludes use in women with vasomotor symptoms. In particular, the lack of stimulatory effects on the endometrium and the reduction in invasive breast cancer incidence indicate raloxifene as an attractive alternative to HRT for the management of postmenopausal osteonorosis.

Bone Remodeling↗
PubMed2001

Estrogen response elements alter coactivator recruitment through allosteric modulation of estrogen receptor beta conformation.

Estrogen receptor beta (ERbeta) activates transcription by binding to estrogen response elements (EREs) and coactivator proteins that act as bridging proteins between the receptor and the basal transcription machinery. Although the imperfect vitellogenin B1, pS2, and oxytocin (OT) EREs each differ from the consensus vitellogenin A2 ERE sequence by a single base pair, ERbeta activates transcription of reporter plasmids containing A2, pS2, B1, and OT EREs to different extents. To explain how these differences in transactivation might occur, we have examined the interaction of ERbeta with these EREs and monitored recruitment of the coactivators amplified in breast cancer (AIB1) and transcription intermediary factor 2 (TIF2). Protease sensitivity, antibody interaction, and DNA pull-down assays demonstrated that ERbeta undergoes ERE-dependent changes in conformation resulting in differential recruitment of AIB1 and TIF2 to the DNA-bound receptor. Overexpression of TIF2 or AIB1 in transient transfection assays differentially enhanced ERbeta-mediated transcription of reporter plasmids containing the A2, pS2, B1, and OT EREs. Our studies demonstrate that individual ERE sequences induce changes in conformation of the DNA-bound receptor and influence coactivator recruitment. DNA-induced modulation of receptor conformation may contribute to the ability of ERbeta to differentially activate transcription of genes containing divergent ERE sequences.

Allosteric Site↗
PubMed2002

[Tamoxifen and breast cancer].

Tamoxifen is a selective estrogen receptor modulator (SERM) with pro- and anti-estrogenic properties. Currently it is the most widely used agent for first line treatment against hormone sensitive metastatic breast cancer and the only approved hormonal agent for adjuvant treatment of organ confined breast cancer. Furthermore, its uses have been extended for the treatment of intraductal breast carcinoma patients. In such settings the most worrisome side effect of tamoxifen is its ability to increase the rates of uterine cancers. It has been claimed that most of these cancers are found at an early stage because of vaginal bleeding. Moreover, it has been shown that for most women transvaginal ultrasound is an ineffective screening method for the early detection of uterine carcinomas. It is important, however, to notice that long term tamoxifen treatment can cause metastatic uterine cancer--not only carcinomas but also sarcomas (mainly malignant mixed mesodermal tumors. It should be noted that, at least for the special population of BRCA mutation carriers, transvaginal ultrasound can increase our ability for the earlier discovery of ovarian cancer. Thus, we believe that there is still a place for the use of transvaginal ultrasound in special populations. This is specifically for long term tamoxifen users (more than the usually recommended five years), women with a higher chance of having uterine carcinomas (namely very high body weight, strong family history) and women with a high index of suspicion as carriers of a BRCA mutation. Until new second generation SERMs and aromatase inhibitors are shown to possess better anti-cancer abilities than tamoxifen, this drug will remain in wide use, however, we must not overlook its possible rare side effects.

Antineoplastic Agents, Hormonal↗
PubMed2001

Allosteric modulation of estrogen receptor conformation by different estrogen response elements.

Estrogen-regulated gene expression is dependent on interaction of the estrogen receptor (ER) with the estrogen response element (ERE). We assessed the ability of the ER to activate transcription of reporter plasmids containing either the consensus vitellogenin A2 ERE or the imperfect pS2, vitellogenin B1, or oxytocin (OT) ERE. The A2 ERE was the most potent activator of transcription. The OT ERE was significantly more effective in activating transcription than either the pS2 or B1 ERE. In deoxyribonuclease I (DNase I) footprinting experiments, MCF-7 proteins protected A2 and OT EREs more effectively than the pS2 and B1 EREs. Limited protease digestion of the A2, pS2, B1, or OT ERE-bound receptor with V8 protease or proteinase K produced distinct cleavage products demonstrating that individual ERE sequences induce specific changes in ER conformation. Receptor interaction domains of glucocorticoid receptor interacting protein 1 and steroid receptor coactivator 1 bound effectively to the A2, pS2, B1, and OT ERE-bound receptor and significantly stabilized the receptor-DNA interaction. Similar levels of the full-length p160 protein amplified in breast cancer 1 were recruited from HeLa nuclear extracts by the A2, pS2, B1, and OT ERE-bound receptors. In contrast, significantly less transcriptional intermediary factor 2 was recruited by the B1 ERE-bound receptor than by the A2 ERE-bound receptor. These studies suggest that allosteric modulation of ER conformation by individual ERE sequences influences the recruitment of specific coactivator proteins and leads to differential expression of genes containing divergent ERE sequences.

Allosteric Regulation↗
PubMed2003

Effect of estrogen and antiestrogens on the estrogen receptor content in the cochlea of ovariectomized rats.

Older women in the normal population tend to develop less severe hearing loss as compared to males in the same age. In Turner syndrome (45,X), estrogen deficiency is one of the predominant problems. Ear and hearing problems are common among these patients. Does estrogen have an impact on the hearing organ? Twenty-four rats were ovariectomized and treated with vehicle (controls), estradiol or selective estrogen receptor modulators such as tamoxifen and ICI182780, in order to study the effects on the estrogen receptor levels and distribution in the inner ear. The cochleas were stained immunohistochemically using antibodies against estrogen receptor alpha and beta. No major difference in estrogen receptor content in the cochleas was observed among groups. There was however a potential down regulation of estrogen receptor alpha in the marginal cells of stria vascularis in the rats that were substituted with ICI182780 (pure antiestrogen) as compared to those given estradiol or tamoxifen. When investigating the tissues with light microscopy no change in inner ear anatomy could be observed.

Animals↗
PubMed2001

Differential SERM activation of the estrogen receptors (ERalpha and ERbeta) at AP-1 sites.

BACKGROUND: The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are triphenylethylene derivatives that affect transcriptional regulation by the estrogen receptors (ERalpha and ERbeta) but show different effects in different tissues. A third triphenylethylene derivative, GW-5638, displays tissue selectivity in rats identical to that of raloxifene, suggesting that GW-5638 and raloxifene share a mechanism of action that is different from that of tamoxifen. RESULTS: Both GW-5638 and its hydroxylated analog GW-7604 were tested for their ability to bind to ERalpha and ERbeta and their ability to affect transcription of ERalpha and ERbeta at a consensus estrogen response element and an ER/AP-1 response element. The drugs were found to have the same affinity for ERalpha and ERbeta, although they were also found to activate transcription from an AP-1 promoter element more potently with ERbeta than with ERalpha. Derivatives of GW-5638 with alterations at the carboxylic acid still showed increased ERbeta potency compared to ERalpha, but the magnitude of the activation with ERalpha was much higher than with ERbeta. CONCLUSIONS: Despite similar binding affinities to isolated ERalpha and ERbeta, GW-5638 and GW-7604 show markedly lower EC(50) values with ERbeta at an AP-1-driven promoter as compared to ERalpha. This suggests that the two compounds produce a more active ER/AP-1 conformation of the ER/AP-1 transcription factor complex when bound to ERbeta than when bound to ERalpha.

Cinnamates↗
PubMed2006

Aromatase inhibitors and bone loss.

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < -2.5) and considered on an individual basis for those with osteopenia (T score < -1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.

Aromatase Inhibitors↗
PubMed2005

[Hormone resistance and its modulation in breast cancer].

Acquired hormone resistance is a reversible adaptative change of hormone-sensitive breast tumors promoting survival by changes in the balance and communication between estrogen receptor and growth factor signaling. The mechanisms of hormone resistance induced by various hormone therapies are different, however, their common feature is the dominance of growth factor signaling with the consequences of enhanced proliferation and decreased apoptosis. In case of tamoxifen or selective estrogen receptor modulator resistance, the agents' enhanced agonistic activity occurs. The increased expression of certain estrogen receptor coactivators may play an important role. The essential of hormone resistance after estrogen deprivation is estrogen hypersensitivity, which is a consequence of the enhanced activity of the membrane-associated estrogen receptor and its influence on the growth factor signaling. The integration of cell surface growth factor receptor or growth factor signal transduction blocking agents like tyrosine kinase, MAPK, mTOR, PI3K or farnesyl transferase inhibitors into hormone therapies may prevent or treat hormone resistance. The other possibility is to use the hormone therapies sequentially. A new promising agent is the pure antiestrogen fulvestrant which targets the estrogen receptor located in both the membrane or the nucleus. Also, estrogen therapy may revert hormone resistance. The use of predictive markers may promote treatment choice and indicate application of targeted therapies.

Breast Neoplasms↗
PubMed2004

Effects of raloxifene hydrochloride on endometrial cancer cells in vitro.

OBJECTIVE: Determine effects of raloxifene hydrochloride, a selective estrogen receptor modulator (SERM), on growth and proliferation of an estrogen-responsive endometrial cancer cell line in vitro. MATERIALS AND METHODS: Studies were performed with Ishikawa endometrial adenocarcinoma cells, a well-differentiated cancer that expresses estrogen receptors and progesterone receptors. Raloxifene was purified as the hydrochloride salt. The four arms of the study were cells grown (1) without any further addition (control), (2) with estradiol only, (3) with raloxifene only, or (4) with estradiol and raloxifene. Three concentrations of estradiol (10, 100, 1000 pg/ml) and raloxifene (1, 10, 100 ng/ml) were used. After 1 week of culturing, the number of living cells for each experimental group was determined and expressed as a percentage of the control group. RESULTS: Cells treated with raloxifene 10 or 100 ng/ml alone grew significantly faster than control cells: 10 ng/ml [115.25%; SD, 11.05; 95% confidence interval (CI), 107.35-123.16; P = 0.002] and 100 ng/ml (111.14%; SD, 14.19; 95% CI, 100.98-121.29; P = 0.03). Estradiol 10 or 100 pg/ml did not stimulate cell growth, whereas cells treated with 1000 pg/ml grew significantly faster than control cells (114.69%; SD, 16.84; 95% CI, 102.65-126.74; P = 0.02). Raloxifene and estradiol together in any concentration did not affect cell growth. CONCLUSIONS: Raloxifene did not inhibit the growth of endometrial cancer cells in vitro. High concentrations even promoted cell growth. Estradiol in physiologic concentrations did not stimulate the growth of endometrial cancer cells in vitro.

Adenocarcinoma↗
PubMed2006

Osteoporosis management in a Medicaid population after the Women's Health Initiative study.

OBJECTIVE: Publication of the Women's Health Initiative (WHI) study has changed our understanding on the effects of hormone replacement therapy. This study was designed to evaluate patterns of antiosteoporosis medication (AOM) use in a Medicaid population before and after the release of the WHI study results. METHODS: A descriptive time series analysis was conducted among women 50 years of age and older who were enrolled in the Pennsylvania Medicaid program from December 1, 2001, through December 31, 2002. All AOMs were identified, including estrogens, bisphosphonates, selective estrogen receptor modulators (SERMs), and calcitonin. The monthly prevalence of each AOM and drug class was estimated. Comparisons between pre-WHI (December 1, 2001-July 30, 2002) and post-WHI (August 1, 2002-December 31, 2002) study periods were made for overall AOM use by AOM drug class as well as by recipient characteristics. RESULTS: The overall prevalence of AOM did not change between pre-WHI and post-WHI study publication. However, there were significant changes in the prevalence of certain AOM drug classes. Estrogen use decreased significantly after the WHI study release for all age and racial groups. The prevalence for bisphosphonates and SERM increased significantly in the post-WHI period. CONCLUSIONS: The WHI study influenced patterns of use of all types of AOM, decreasing estrogen and increasing nonestrogen use among postmenopausal women in a Medicaid program. These results suggest that the WHI study affected patterns of use of bone protective pharmacotherapy, with a shift in bone protection therapy use from estrogen to nonestrogen AOMs.

Aged↗
PubMed2002

Effects of SP500263, a novel, potent antiestrogen, on breast cancer cells and in xenograft models.

We have compared the antitumor activities of SP500263, a novel next-generation selective estrogen receptor modulator (SERM), tamoxifen, and raloxifene side-by-side in in vitro and in vivo MCF-7 breast cancer models. In vitro, SP500263 acted as an antiestrogen and potently inhibited estrogen-dependent MCF-7 proliferation with IC(50) values in the nanomolar range. SP500263 also strongly inhibited MCF-7 proliferation in the absence of estrogen at all of the concentrations tested. To investigate the antitumor activity of SP500263 in animals, athymic nude mice were implanted with MCF-7 tumor in the presence of a tumor growth-supporting sustained release estrogen pellet. Treatment was initiated after tumors were established. SP500263, administered for 28 days through daily i.p. dosing, effectively reduced estrogen-stimulated tumor growth at 3 and 30 mg/kg. SP500263 was as efficacious as tamoxifen and superior to raloxifene at the corresponding doses. Maximum efficacy was reached with the 30 mg/kg dose. The observed effects were highly significant. SP500263 represents a member of a novel series of SERMs that is structurally unrelated to SERMs currently on the market or in clinical development. The experiments described herein demonstrate that SP500263 is efficacious in the MCF-7 proliferation assay and in a murine model of breast cancer.

Animals↗
PubMed2002

Baseline characteristics of participants in the Raloxifene Use for The Heart (RUTH) trial.

The Raloxifene Use for The Heart (RUTH) trial is a randomized, placebo-controlled, double-blind trial designed to determine whether raloxifene 60 mg/day compared with placebo lowers the risk of coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI) and reduces the risk of invasive breast cancer in women at risk for a major coronary event. Raloxifene is a selective estrogen receptor modulator that improves cardiovascular risk factors, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. Between June 1998 and August 2000, 10,101 women were enrolled at 187 sites in 26 countries. Approximately half of the women had documented coronary heart disease (CHD) (n = 5,031); the remainder had multiple CHD risk factors that increased their risk for a CHD event (n = 5,070). The mean age of participants was 68 years (39% were >70 years old), and did not differ between those with documented CHD and those at increased CHD risk. Most women were Caucasian (84%); 60% had a body mass index >/=27 kg/m(2), 46% had diabetes mellitus, 78% had systemic hypertension, and 14% had low-density lipoprotein cholesterol >160 mg/dl. Compared with women at increased CHD risk, women with documented CHD had higher cardiovascular risk scores, a higher prevalence of abnormal electrocardiograms, greater use of cardiovascular medications, were more likely to have had cardiac rehabilitation, and were more likely to have previously used estrogen or oral contraceptives, but had a slightly lower prevalence of CHD risk factors such as smoking, obesity, diabetes mellitus, and systemic hypertension, and had lower serum levels of total and low-density lipoprotein cholesterol. The RUTH cohort is the largest group of postmenopausal women at increased risk of CHD events ever assembled in a clinical trial, and is the first trial designed to determine the effect of a selective estrogen receptor modulator on the risk of CHD events.

Aged↗
PubMed2002

Transcriptional activation of estrogen receptor ERalpha and ERbeta by polycyclic musks is cell type dependent.

In the past decade the list of chemicals in the environment that are able to mimic the natural hormone estrogen, thereby disrupting endocrine function, has grown rapidly. These chemicals are able to bind to estrogen receptors (ERs) and influence estrogen signaling pathways, although several of them have structures that differ substantially from the endogenous hormone 17beta-estradiol. Because of their polycyclic nature, the polycyclic musks AHTN (6-acetyl-1,1,2,4,4,7-hexamethyltetraline) and HHCB (1,2,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-gamma-2-benzopyran) were assessed for interaction with estrogen receptors. These compounds are ubiquitously present in surface waters and have been identified in human milk fat and blood. Using sensitive in vitro reporter gene assays, we found that AHTN and HHCB act as selective estrogen receptor modulators (SERMs), inducing both estrogenic and antiestrogenic activity dependent on the cell line and the ER subtype targeted. Weak estrogenic effects were observed only at relatively high concentrations (10 microM). Antiestrogenic effects were observed in various cell lines starting at concentrations of 0.1 microM. In comparison with the well-known SERM, 4-hydroxytamoxifen, AHTN and HHCB have a much lower potency in suppressing estradiol-induced transactivation. Results with various mutant ER receptor types suggest that binding sites of the musk compounds differ from 17beta-estradiol and 4-hydroxytamoxifen. The cell type dependency of ER transactivation shows that caution should be exerted when interpreting effects of estrogenic compounds using in vitro systems.

Benzopyrans↗
PubMed1997

Specific modulation of estrogen receptor mRNA isoforms in rat pituitary throughout the estrous cycle and in response to steroid hormones.

We have identified several estrogen receptor (ER) mRNA isoforms in rat pituitary and characterized their regulation by gonadal steroids. The ER mRNAs correspond to splice variants in which either exon 4, exons 3 and 4, or exons 5 and 6 are deleted. A previously isolated pituitary-specific truncated mRNA, TERP-1, containing a unique 5'-end and exons 5 through 8 of the full-length ER, was also studied. The exon deletion variants were expressed in males and females, in pituitary, uterus, testes, heart, hypothalamus, and liver. An antibody to the ER C-terminus bound to full-length (64 kDa) and smaller (50 55 kDa and 40-45 kDa) ER proteins in uterus and pituitary and a pituitary-specific ER of 20-24 kDa corresponding to TERP-1. Estrogen (E) treatment in vivo stimulated full-length ER 2-3-fold, and TERP-1 7-10-fold, but had no effect on any exon deletion variant. Progesterone treatment, alone or with E, had no consistent effect on any ER mRNA form. TERP-1 mRNA was also dramatically and specifically modulated during the estrous cycle, increasing approximately 500-fold between the morning of diestrous and the afternoon of proestrus. Thus, ER mRNA variants exist in estrogen-responsive tissues; the pituitary contains at least one tissue-specific ER which is regulated by steroids and which may contribute to changes in regulated biological activity.

Animals↗
PubMed2006

Differential modulation of estrogen receptors (ERs) in ischemic brain injury: a role for ERalpha in estradiol-mediated protection against delayed cell death.

Estradiol enhances plasticity and survival of the injured brain. Our previous work demonstrates that physiological levels of estradiol protect against cerebral ischemia in the young and aging brain through actions involving estrogen receptors (ERs) and alterations in gene expression. The major goal of this study was to establish mechanisms of neuroprotective actions induced by low levels of estradiol. We first examined effects of estradiol on the time-dependent evolution of ischemic brain injury. Because estradiol is known to influence apoptosis, we hypothesized that it acts to decrease the delayed phase of cell death observed after middle cerebral artery occlusion (MCAO). Furthermore, because ERs are pivotal to neuroprotection, we examined the temporal expression profiles of both ER subtypes, ERalpha and ERbeta, after MCAO and delineated potential roles for each receptor in estradiol-mediated neuroprotection. We quantified cell death in brains at various times after MCAO and analyzed ER expression by RT-PCR, in situ hybridization, and immunohistochemistry. We found that during the first 24 h, the mechanisms of estradiol-induced neuroprotection after MCAO are limited to attenuation of delayed cell death and do not influence immediate cell death. Furthermore, we discovered that ERs exhibit distinctly divergent profiles of expression over the evolution of injury, with ERalpha induction occurring early and ERbeta modulation occurring later. Finally, we provide evidence for a new and functional role for ERalpha in estradiol-mediated protection of the injured brain. These findings indicate that physiological levels of estradiol protect against delayed cell death after stroke-like injury through mechanisms requiring ERalpha.

Animals↗
PubMed2003

Response-specific and ligand dose-dependent modulation of estrogen receptor (ER) alpha activity by ERbeta in the uterus.

Estrogen is of great importance in the regulation of uterine function. The aim of this study was to examine the individual physiological roles of each of the two receptors for estradiol, estrogen receptor (ER) alpha and ERbeta, and their potential comodulatory effects on gene expression and uterine growth using recently developed ER subtype-selective agonist ligands. The use of ER subtype-selective ligands provides an alternative, complementary approach to the use of receptor knockout mice. Administration of the ERalpha-selective ligand propyl pyrazole triol (PPT) to immature mice resulted in a significant increase in uterine weight, as well as bromodeoxyuridine incorporation and proliferating cell nuclear antigen expression in luminal epithelial cells. PPT also increased complement component 3, lactoferrin, and glucose-6-phosphate dehydrogenase (G6PDH), and decreased androgen receptor (AR) and progesterone receptor (PR) mRNA levels in uterine tissue, as did estradiol (E(2)). However, when compared with E(2), PPT was less effective in stimulating uterine weight, complement component 3, and G6PDH expression but was as effective as E(2) in regulating lactoferrin, AR, and PR expression. In contrast to the action of the ERalpha agonist PPT, the ERbeta agonist diarylpropionitrile (DPN) did not increase uterine weight or luminal epithelial cell proliferation at a dose that reduced G6PDH and elicited a decrease in PR and AR mRNA and protein expression. Interestingly, DPN reduced the uterine weight stimulation by PPT, and enhanced the effect of PPT in decreasing uterine PR and AR mRNA. These findings with ER subtype-selective ligands indicate that ERalpha is the major regulator of estrogen function in the uterus, but that ERbeta does exert effects on some uterine markers of estrogen action. In addition, ERbeta can modulate ERalpha activity in a response-specific and dose-dependent manner.

Animals↗
PubMed2001

Induction of endothelial nitric-oxide synthase phosphorylation by the raloxifene analog LY117018 is differentially mediated by Akt and extracellular signal-regulated protein kinase in vascular endothelial cells.

Raloxifene is a tissue-selective estrogen receptor modulator. The effect of estrogen on cardiovascular disease is mainly dependent on direct actions on the vascular wall involving activation of endothelial nitric oxide synthase (eNOS) via Akt and extracellular signal-regulated protein kinase (ERK) cascades. Although raloxifene is also known to activate eNOS in the vascular endothelium, the molecular mechanism responsible for this effect remains to be elucidated. In studies of both human umbilical vein endothelial cells and simian virus 40-transformed rat lung vascular endothelial cells (TRLECs), the raloxifene analog LY117018 caused acute phosphorylation of eNOS that was unaffected by actinomycin D and was blocked by the pure estrogen receptor antagonist ICI182,780. Activation of Akt by raloxifene reached a plateau at 15-30 min and declined thereafter, a similar time frame to that of Akt activation by 17beta-estradiol. On the other hand, both activation and phosphorylation of ERK by raloxifene showed a biphasic pattern (peaks at 5 min and 1 h), whereas ERK activation and phosphorylation by 17beta-estradiol reached a plateau at 5 min and declined thereafter. A MEK inhibitor, PD98059, had no effect on the raloxifene-induced Akt activity, suggesting an absence of cross-talk between the ERK and Akt cascades. Either exogenous expression of a dominant-negative Akt or pretreatment of TRLECs with PD98059 decreased the raloxifene-induced eNOS phosphorylation. Moreover, raloxifene stimulated the activation of Akt, ERK, and eNOS in Chinese hamster ovary cells expressing estrogen receptor alpha but not Chinese hamster ovary cells expressing estrogen receptor beta. Our findings suggest that raloxifene-induced eNOS phosphorylation is mediated by estrogen receptor alpha via a nongenomic mechanism and is differentially mediated by Akt- and ERK-dependent cascades.

Animals↗
PubMed2003

Exposure to the environmental estrogen bisphenol A differentially modulated estrogen receptor-alpha and -beta immunoreactivity and mRNA in male mouse testis.

We examined the effects of bisphenol A (0.5 microg/ml or 50 microg/ml) in the drinking water on estrogen receptor (ER) alpha and beta proteins and mRNA in the testis of young mice following 8-weeks of oral administration of bisphenol A utilizing immunohistochemistry and semiquantitative reverse transcription polymerase chain reaction amplification (RT-PCR). ER beta was clearly localized in the nuclei of spermatogonia and/or spermatocytes. ER beta immunopositive cell numbers per testis section were significantly decreased in the 50 microg/ml bisphenol A-treated group compared with control and the 0.5 microg/ml bisphenol A-treated group. The number of ER alpha positive cells in the testis was significantly lower than ER beta positive cells in control group. ER alpha immunopositive cell numbers per testis section were markedly increased in the 50 microg/ml bisphenol A-treated group compared with the control and the 0.5 microg/ml bisphenol A-treated group. ER beta mRNA expression was significantly decreased in the 50 microg/ml bisphenol A-treated group compared with the control and the 0.5 microg/ml bisphenol A-treated group. In contrast, ER alpha mRNA expression was markedly increased in the 50 microg/ml bisphenol A-treated group compared with the control and the 0.5 microg/ml bisphenol A-treated group. The existence of ER alpha and beta in the testis suggests that estrogens directly affect germ cells during testicular development and spermatogenesis, and differential modulation of ER alpha and beta in the testis could be involved in the effects of bisphenol A.

Animals↗