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PubMed2006

Cyclooxygenases regulation by estradiol on endothelium.

Estrogen and hormone replacement therapies are being tested to prevent the incidence of cardiovascular disease in postmenopausal women. In spite of the evidence from several epidemiological studies suggesting that estrogens protect against atherosclerosis and associated diseases, controversy exists. Moreover, it is important to develop synthetic compounds that achieve the beneficial effects of estrogens on the cardiovascular system while minimizing such undesirable effects on other tissues as the increased risk of endometrial and breast cancer. Some drugs that modulate estrogen function in a tissue-specific manner (Selective Estrogen Receptor Modulators; SERMs) have been discovered and are currently being used in clinical practice. An example of these is raloxifene. Clinical and experimental data support the consideration of endothelium as a target for estradiol and other sexual hormones. Among other actions, estradiol has been implicated in the control of prostacyclin production through cyclooxygenases (COX) regulation in endothelial cells. Prostacyclins are powerful vasodilators and potent inhibitors of platelet aggregation which are produced from free arachidonic acid through the catalytic activity of two COX: COX-1 and COX-2. Together, these COX represent the main control mechanism for prostacyclin production. Although several non-specific COX inhibitors have been available for decades (aspirin, indomethacin, ibuprofen), COX-2 selective inhibitors have been commercialized only within the last few years, thus making it possible to increase the study and treatment of different disorders. This review will discuss clinical and experimental data that document the endothelial effects of estradiol and SERMs on prostacyclin production and COX regulation, their vascular consequences, and their possible interactions with COX inhibitors.

Animals↗
PubMed2002

[Estrogen receptor subtypes and the regulatory effect of receptor ligand binding on gene transcription].

This review introduces the structure, functions, tissue distribution, physiologic roles of estrogen receptor subtypes (ER alpha and ER beta) along with transcriptional activities of estrogen receptor ligands and the mechanism of the modulatory pathway and tissue specific property of selective estrogen receptor modulators (SERMs), and phytoestrogens. This article is to provide a systemic approach for increasing the selectivity of estrogenic drug and optimizing the clinically based strategy of drug design. Differences exist between ER alpha and ER beta in structure, function, tissue distribution, physiologic roles and response to ligands, as well as the regulating effect on gene transcription, which are mainly determined by different co-regulators they recruit respectively.

Animals↗
PubMed2003

Effects of estrogen and raloxifene on neuroglia number and morphology in the hippocampus of aged female mice.

Hormone replacement therapy with the gonadal steroid estrogen or synthetic agents such as raloxifene, a selective estrogen receptor modulator, may affect cellular function in brains of postmenopausal women. In vitro studies suggest that 17beta estradiol and raloxifene can alter the microglial and astrocyte expression of immuno-neuronal modulators, such as cytokines, complement factors, chemokines, and other molecules involved in neuroinflammation and neurodegeneration. To directly test whether exogenous 17beta estradiol and raloxifene affect the number of glial cells in brain, C57BL/6NIA female mice aged 20-24 months received bilateral ovariectomy followed by s.c. placement of a 60-day release pellet containing 17beta estradiol (1.7 mg), raloxifene (10 mg), or placebo (cholesterol). After 60 days, numbers of microglia and astrocytes were quantified in dentate gyrus and CA1 regions of the hippocampal formation using immunocytochemistry and design-based stereology. The results show that long-term 17beta estradiol treatment in aged female mice significantly lowered the numbers of astrocytes and microglial cells in dentate gyrus and CA1 regions compared with placebo. After long-term treatment with raloxifene, a similar reduction was observed in numbers of astrocytes and microglial cells in the hippocampal formation. These findings indicate that estrogen and selective estrogen receptor modulators can influence glial-mediated inflammatory pathways and possibly protect against age- and disease-related neuropathology.

Aging↗
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↗
PubMedDate not supplied

Controversy about uterine effects and safety of SERMs: the saga continues.

From the perspective of endometrial safety, there has been great controversy about what special management, if any, tamoxifen-treated patients should undergo. Periodic blind endometrial sampling or transvaginal ultrasound has been advocated by some. Because of the problems associated with either of these techniques alone, we recommended an approach that used transvaginal ultrasound and then proceeded to sonohysterography when the endometrial echo on transvaginal ultrasound was not reliably thin and distinct. The American College of Obstetricians and Gynecologists (ACOG), in its committee opinion, stated that patients receiving tamoxifen therapy should only have an annual pelvic exam with pap smear if they remain asymptomatic. Newer data suggest, however, that there are high- and low-risk groups that can be identified by pretreatment screening. Before tamoxifen therapy, 17% of patients have polyps. These patients have 17 times the incidence of atypical hyperplasia than those whose uterus was negative before tamoxifen therapy. Such findings call into question the validity of the only study of raloxifene where uterine safety was the primary endpoint. In that study, any woman with baseline endometrial findings other than pristinely negative (i.e., low risk) was excluded. However, other raloxifene studies without pretreatment screening show relative risk (RR) = 0.8 (95% CI = 0.2, 2.7) for endometrial carcinoma. This compares with the women over 50 years of age in the Breast Cancer Prevention Trial (National Surgical Adjuvant Breast and Bowel Project P-1) with tamoxifen when the RR = 4.01 (95% CI= 1.70, 10.90). The existence of potentially high- and low-risk groups should be taken into account in any future clinical trials looking at the endometrial safety of selective estrogen receptor modulators (SERMs).

Endometrial Neoplasms↗
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↗
PubMed2001

Chemoprevention with aromatase inhibitors--trial strategies.

Estrogen and its catechol metabolites from both the circulation and synthesized within the breast are important in the pathogenesis of breast cancer. Blocking estrogen's effects on the breast with selective estrogen receptor modulators (SERMS) is an ongoing strategy. Thus, tamoxifen and raloxifene reduce risk as monotherapy. Aromatase (estrogen synthetase) inhibitors are a logical alternative to SERMS. To date, SERMS have demonstrated reduction only in estrogen-progesterone receptor positive cancers without reduction in receptor negative tumors. By inhibiting the parent estrogens and their catechol metabolites, true prevention of cancer initiation might occur and reduction not only in the receptor positive but also negative tumors might result. Ongoing adjuvant breast cancer trials are exploring aromatase inhibitors as alternatives to tamoxifen, or in sequence or in combination with tamoxifen. Relative efficacies including reduction in contralateral breast cancer, toxicities and end-organ effects and impact on quality of life, are being explored. Data from these trials will help to guide future chemoprevention strategies. Proof of principal trials in 'high risk' cohorts such as premalignant breast lesions, dense screening mammograms, high plasma estradiol levels or increased bone density are already ongoing. Issues such as dose, schedule, therapeutic index and mono versus combination therapy are important to define.

Animals↗
PubMed2000

Progress in the prevention of breast cancer: concept to reality.

In 1936, Professor Antoine Lacassagne suggested that breast cancer could be prevented by developing drugs to block estrogen action in the breast. Jensen discovered the physiologic target, the estrogen receptor, that regulates estrogen action in its target tissues and Lerner discovered the first nonsteroidal antiestrogen MER25. However, the success of tamoxifen as a treatment of breast cancer opened the door for the testing of the worth of tamoxifen to reduce breast cancer incidence in high-risk women. In 1998, Fisher showed that tamoxifen could reduce breast cancer incidence by 50%. Nevertheless, only half the women who develop breast cancer have risk factors other than age, so what can be done for women without risk factors? The recognition that nonsteroidal antiestrogens have the ability to modulate estrogen action selectively has advanced the design and development of new drug for multiple diseases. Tamoxifen and raloxifene maintain bone density and raloxifene is now used to prevent osteoporosis and is being tested as a preventive for coronary heart disease and breast cancer. The drug group is now known as selective estrogen receptor modulators (SERMs) and the challenge is to design new agents for multiple applications. If the 20th century was the era of chemotherapy, the 21st century will be the era of chemoprevention.

Bone Density↗
PubMed2000

Symposium overview: estrogens and antiestrogens in managing the patient with breast cancer.

The prevalence of breast cancer (a hormonally driven neoplasm) in the United States, the potential health benefits of estrogen replacement therapy for postmenopausal women, and the burgeoning research focusing on selective estrogen receptor modulators (SERMs) have resulted in additional complexity in managing breast cancer. In an attempt to clarify existing data, the Society of Surgical Oncology sponsored a symposium entitled "Estrogens and Antiestrogens in Managing the Patient with Breast Cancer" at its 52nd Annual Cancer Symposium. This conference was held in March 1999 and was chaired by Dr. S. Eva Singletary, Professor of Surgery and Chief of the Surgical Breast Section at The University of Texas M. D. Anderson Cancer Center in Houston, Texas. The following is a review of the material presented by the symposium participants.

Age Factors↗
PubMed1999

Antiestrogens--tamoxifen, SERMs and beyond.

Estrogens play a central role in reproductive physiology. The cellular effects of estrogens are mediated by binding to nuclear receptors (ER) which activate transcription of genes involved in cellular growth control. At least two such receptors, designated ERalpha and ERbeta, mediate these effects in conjunction with a number of coactivators. These receptors can directly interact with other members of the steroid receptor superfamily. A complex cross-talk exists between the estrogen-signaling pathways and the downstream signaling events initiated by growth factors, such as epidermal growth factor and insulin-like growth factors. Estrogens are also a causative factor in the pathogenesis of a variety of neoplastic and non-neoplastic diseases, including breast cancer, endometrial cancer, endometriosis, and uterine fibroids, among others. Antiestrogens, such as tamoxifen, are widely used for the treatment of breast cancer. Tamoxifen produces objective tumor shrinkage in advanced breast cancer, reduces the risk of relapse in women treated for invasive breast cancer, and prevents breast cancer in high-risk women. Although, initially developed as an antiestrogen, tamoxifen can also prevent postmenopausal osteoporosis as well as reduce cholesterol, due to its estrogen-agonist effects. Its estrogen-agonist activity, however, can lead to significant side-effects such as endometrial cancer and thromboembolic phenomena. This has led to the concept of "ideal" selective estrogen receptor modulators (SERMs), drugs that would have the desired, tissue selective, estrogen-agonist or -antagonist effects. Raloxifene is a SERM which has the desirable mixed agonist/antagonist effects of tamoxifen but does not cause uterine stimulation. "Pure" antiestrogens may provide very potent estrogen-antagonist drugs, but are likely to be devoid of beneficial effects on bone and lipids. Future drug development efforts should focus on developing superior SERMs that have a greater efficacy against ER-positive tumors and do not cause hot flashes or thromboembolism, and explore combination strategies to simultaneously target hormone-dependent as well as hormone-independent breast cancer.

Animals↗
PubMed2006

Chronic exposure to estrogen and tamoxifen regulates synaptophysin and phosphorylated cAMP response element-binding (CREB) protein expression in CA1 of ovariectomized rat hippocampus.

We report here the in vivo effects of estrogen (E2) on modulation of synaptic plasticity and the agonistic (estrogen-like) role of selective estrogen receptor modulator (SERM), tamoxifen (TAM) in the CA1 of the rat hippocampus. Effects on synaptophysin (SYP), a presynaptic vesicular protein, and phosphorylated cyclic AMP responsive element-binding (p-CREB) protein, a signal transduction pathway molecule, were studied using the ovariectomized (OVX) experimental rat model. Bilateral ovariectomy was performed on 40 rats and these were divided into 4 groups based on the treatment they received (at 2 weeks post-ovariectomy, a subcutaneous injection daily for 4 weeks) viz., OVX+E2 (0.1 mg/kg body weight), OVX+TAM (0.05 mg/kg body weight), OVX+vehicle and one group served as OVX control. An additional 10 animals served as the ovary intact control group. At the end of the treatment schedule, five animals/group were used for immunohistochemical staining of SYP and p-CREB using specific antibodies with peroxidase anti-peroxidase technique on paraformaldehyde-fixed cryostat sections. Protein estimation and Western blot analysis coupled with densitometric analysis (using gel-documentation system and image analysis software) were performed on unfixed hippocampus collected from rest of the five animals/group. Serum estradiol levels were estimated with radioimmunoassay prior to sacrifice. The results revealed that ovariectomy reduced SYP and p-CREB expression whereas E2 or TAM administration resulted in their upregulation. Serum estradiol levels of E2 administered animals were comparable with the ovary intact group whereas those of TAM administered group persisted in the range of OVX controls. To conclude, long-term estrogen therapy modulates the synaptic plasticity of hippocampal neurons and presumably, the agonist biocharacter of TAM as observed in the present investigations, may in the long run have a potential in the treatment and prevention of various estrogen-related disorders.

Animals↗
PubMed2002

Pros and cons of existing treatment modalities in osteoporosis: a comparison between tibolone, SERMs and estrogen (+/-progestogen) treatments.

Tibolone, selective estrogen receptor modulators (SERMs) like tamoxifen and raloxifene, and estrogen (+/-progestogen) treatments prevent bone loss in postmenopausal women. They exert their effects on bone via the estrogen receptor (ER) and the increase in bone mass is due to resorption inhibition. The effect of SERMs on bone mineral density is less than that with the other treatments, but the SERM raloxifene still has a positive effect on vertebral fractures. In contrast to tibolone and estrogens (+/-progestogen), SERMs do not treat climacteric complaints, whilst estrogen plus progestogen treatments cause a high incidence of bleeding. Estrogen plus progestogen combinations have compromising effects on the breast. Tibolone and SERMs do not stimulate the breast or endometrium. Unlike SERMs, tibolone does not possess antagonistic biological effects via the ER in these tissues. Estrogenic stimulation in these tissues is prevented by local metabolism and inhibition of steroid metabolizing enzymes by tibolone and its metabolites. SERMs and estrogen (+/-progestogen) treatments increase the risk of venous thromboembolism (VTE), whilst estrogen (+/-progestogen) combinations have unwanted effects on cardiovascular events. So far, no detrimental effects of tibolone have been observed with respect to VTE or cardiovascular events. The clinical profile of tibolone therefore has advantages over those of other treatment modalities. It is also clear that tibolone is a unique compound with a specific mode of action and that it belongs to a separate class of compounds that can best be described as selective, tissue estrogenic activity regulators (STEARs).

Bone and Bones↗
PubMed2000

[Drug treatment for the treatment of primary osteoporosis].

The goal of drug treatment of osteoporosis is to prevent fractures. Increase of bone density during therapy is not consistently associated with a clinical benefit. The purpose of this paper is to review the evidence of fracture prevention from published randomized controlled trials. Vitamin D, the bisphosphonate alendronate and the selective estrogen receptor modulator raloxifene have been evaluated in large randomized trials with clinical endpoints.

Alendronate↗
PubMed2001

Natural killer cells express estrogen receptor-alpha and estrogen receptor-beta and can respond to estrogen via a non-estrogen receptor-alpha-mediated pathway.

Natural killer (NK) cells play a crucial role in host defense against pathogens and immune surveillance against cancer. Given that estrogens have been reported to suppress NK cell activity, we sought to elucidate the mechanisms by which estrogen mediates this effect. We demonstrate by immunocytochemical staining with estrogen receptor-alpha (ERalpha)- and estrogen receptor-beta (ERbeta)-specific antibodies that both ERalpha and ERbeta are expressed in murine NK cells. We also compared the ability of high doses of 17beta-estradiol ( approximately 800 pg/ml) to regulate NK cell activity in wild-type and estrogen receptor-alpha-deficient (ERalphaKO) mice. 17beta-estradiol elicited a significant decrease in NK cell activity in both wild-type and ERalphaKO mice (P < 0.001). These data suggest that ERbeta or possibly a novel receptor is involved in mediating estrogen action on NK cell activity and raise the potential for therapeutic modulation of NK cell activity with selective estrogen receptor modulators (SERMS).

Animals↗
PubMed2003

Effect of chronic estradiol, tamoxifen or raloxifene treatment on serotonin 5-HT1A receptor.

Numerous reports demonstrate the potency of estrogens to modulate brain function and their implications in schizophrenia and depression. The 5-HT(1A) receptor has been suggested to be implicated in depression and anxiety. Selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene, have estrogenic and/or antiestrogenic activity depending on the target tissue. Hence, SERMs have beneficial effects in skeleton and cardiovascular systems but act as antagonists in breast and uterus. The aim of the present study was thus to investigate in ovariectomized rats the effects of 17beta-estradiol, tamoxifen and raloxifene treatments on 5-HT(1A) receptor binding sites (agonist and antagonist) and mRNA levels in the hippocampal formation, prefrontal and cingulate cortex, as well as dorsal raphea nucleus which are known to express estrogen receptors (ER). Two weeks ovariectomy of female rats led to a 60% decrease of uterine weight, which was prevented by a 2-week 17beta-estradiol treatment; tamoxifen and raloxifene increased uterine weights by 35% and 15%, respectively, but significantly less than estradiol treatment. Specific binding to 5-HT(1A) receptors was determined by autoradiography of brain sections using the selective ligands: [3H]8-OH-DPAT and [3H]MPPF. Ovariectomy and hormone replacement therapy did not significantly affect 5-HT(1A) receptor agonist and antagonist specific binding sites as well as mRNA levels in all subregions of the hippocampus, prefrontal and cingulate cortex as well as dorsal raphea nucleus. Although the present treatments had functional effects as assessed with uterine weights, ovariectomy and estrogen-receptor directed drugs had no effect on hippocampal 5-HT(1A) receptors as compared to 5-HT(2A) receptors previously reported.

Animals↗
PubMedDate not supplied

Current strategies for anticancer chemoprevention and chemoprotection.

Relatively new targets in drug design projects in cancer pharmacology include cytostatic agents, immune system modulators, and angiogenesis inhibitors. Preventive oncology applies pharmacological agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy. Prevention of cancer, however, can be accomplished through many strategies, including changes in diet and lifestyle. For example, the vast majority of lung cancers (80-90%) can be attributed to cigarette smoking and therefore, the most effective primary preventive strategy for lung cancer is to quit smoking. Chemoprevention through interruption of multistage careinogenesis include different molecular targets. Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists. Ligands for the peroxisome proliferator-activated receptor gamma (PPAR-gamma) suppress breast carcinogenesis in experimental models and induce differentiation of human liposarcoma cells. Selective PPAR modulators (SPARMs), by analogy to the SERM concept, are designed to have desired effects on specific genes relevant to carcinogenesis. Enzymatic approach in endocrine-related tumors involve inhibition of aromatase to prevent breast cancer and inhibition of 5-alpha-reductase to prevent prostate cancer. Down-regulation of inflammatory prostaglandin synthesis by inhibition of cyclooxygenase-2 (COX-2). inhibition of the inducible nitric oxide synthase (iNOS), and stimulation of phase II detoxication system, are currently examined in experimental models and clinical trials. Overall, potential targets in preventive strategies to reduce the risk of cancer involve agonists of endocrine receptors, factors down-regulating inflammation, factors inducing programmed cell death (PCD)/apoptosis, enzymatic inhibitors and gene therapy.

5-alpha Reductase Inhibitors↗
PubMed2001

Engineering of a mouse for the in vivo profiling of estrogen receptor activity.

In addition to their well known control of reproductive functions, estrogens modulate important physiological processes. The identification of compounds with tissue-selective activity will lead to new drugs mimicking the beneficial effects of estrogen on the prevention of osteoporosis and cardiovascular or neurodegenerative diseases, while avoiding its detrimental proliferative effects. As an innovative model for the in vivo identification of new selective estrogen receptor modulators (SERMs), we engineered a mouse genome to express a luciferase reporter gene ubiquitously. The constructs for transgenesis consist of the reporter gene driven by a dimerized estrogen-responsive element (ERE) and a minimal promoter. Insulator sequences, either matrix attachment region (MAR) or beta-globin hypersensitive site 4 (HS4), flank the construct to achieve a generalized, hormoneresponsive luciferase expression. In the mouse we generated, the reporter expression is detectable in all 26 tissues examined, but is induced by 17beta-estradiol (E2) only in 15 of them, all expressing estrogen receptors (ERs). Immunohistochemical studies show that in the mouse uterus, luciferase and ERs colocalize. In primary cultures of bone marrow cells explanted from the transgenic mice and in vivo, luciferase activity accumulates with increasing E(2) concentration. E2 activity is blocked by the ER full antagonist ICI 182,780. Tamoxifen shows partial agonist activity in liver and bone when administered to the animals. In the mouse system here illustrated, by biochemical, immunohistochemical, and pharmacological criteria, luciferase content reflects ER transcriptional activity and thus represents a novel system for the study of ER dynamics during physiological fluctuations of estrogen and for the identification of SERMs or endocrine disruptors.

Animals↗