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Results for “Selective Estrogen Receptor Modulators”

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PubMed1999

Clinical pharmacology of selective estrogen receptor modulators.

Observations of the pharmacology of tamoxifen and related compounds have lead to the concept of selective estrogen receptor modulators (SERMs). This new class of drug displays estrogen agonist or antagonist effects in a tissue-dependent manner and appears to offer an alternative to hormone replacement therapy for the prevention and treatment of osteoporosis and cardiovascular disease in postmenopausal women. Moreover, the estrogen antagonist actions of SERMs on breast tissue may also provide a protective effect against breast cancer. Although tamoxifen therapy reduces plasma cholesterol levels and maintains bone density, it is also associated with an increased risk of endometrial cancer, pulmonary embolism and deep vein thrombosis. This has lead to the development of newer SERMs which will hopefully lack these adverse effects of tamoxifen. These compounds promise a new era of disease prevention in the aging woman and their therapeutic potential is currently being evaluated in large-scale clinical trials.

Animals↗

PubMed2004

Effects of the selective estrogen receptor modulator LY117018 on growth hormone secretion: In vitro studies.

Sex steroids play an important role in modulating pulsatile growth hormone (GH) release, acting at both hypothalamic and pituitary level in both humans and experimental animals. Selective estrogen receptor modulators (SERMs) act as either estrogen receptor agonists or antagonists in a tissue-selective manner. In postmenopausal women, serum GH levels correlate positively with endogenous estradiol levels and insulin-like grwoth factor-I (IGF-I) is positively related to bone mineral density (BMD) at the spine and hip. The aim of the present study was to evaluate, for the first time, the direct effect of LY117018, an analog of raloxifene, on GH secretion from both human and rodent pituitary cells in vitro. Our results demonstrated that pharmacological concentrations of the raloxifene analog LY117018 can stimulate GH secretion through a direct action on the pituitary. LY117018 also showed an estrogen-like activity, inducing the proliferation of rat pituitary GH-secreting adenomatous cells (GH1).

Adenoma↗

PubMedDate not supplied

Effects of raloxifene, one of the selective estrogen receptor modulators, on pituitary-ovary axis and prolactin in postmenopausal women.

To investigate the clinical effects of raloxifene, one of the selective estrogen receptor modulators (SERMs), on the pituitary-ovary axis and prolactin, a prospective, randomized, double-blinded study on 59 healthy postmenopausal women was performed. Forty-eight women received raloxifene 60 mg daily. The other 11 received combined conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 5 mg daily (CCEP) as active controls. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and pro-lactin were measured at baseline and 1 yr after treatment. The mean levels of FSH and LH were significantly decreased in the raloxifene group (FSH: -10.7%; p < 0.01, LH: -10.3%; p < 0.05) and CCEP group (FSH: -53.7%, p < 0.001; LH: -46.8%, p < 0.001). The prolactin level decreased in the raloxifene group but not in the CCEP group (-17.0%; p < 0.001 vs +13.3%, p = no significance; NS). Consequently, long-term administration of raloxifene up to 1 yr decreases serum prolactin level significantly and may be a therapeutic alternative for postmenopausal osteoporotic women with hyperprolactinemia.

Administration, Oral↗

PubMed2001

Selective estrogen receptor modulator effects on serum lipoproteins and vascular function in postmenopausal women and in hypercholesterolemic men.

Epidemiological observations, clinical mechanistic studies, and basic laboratory research suggest that estrogen therapy is associated with beneficial cardiovascular effects in postmenopausal women. Estrogen has a multitude of biological effects that may account for this apparent benefit (which remains to be proved in randomized clinical trials), including favorable effects on the lipid profile, increased endothelial nitric oxide bioactivity, and enhanced fibrinolysis. However, long-term estrogen therapy increases the risk of breast and endometrial cancers. Raloxifene, a benzothiophene derivative that binds to the estrogen receptor, is a selective estrogen receptor modulator, producing estrogen-agonist effects in some tissues (liver, bone) and estrogen-antagonistic effects in others (breast, uterus), and may prove to be an option for women with atherosclerosis or its risk factors. This review updates the current knowledge of the biological effects of selective estrogen receptor modulators of potential cardiovascular importance in postmenopausal women.

Animals↗

PubMedDate not supplied

Selective estrogen receptor modulators (SERMs) in clinical practice.

The objective of this literature review is to familiarize the reader with the clinical data on selective estrogen receptor modulators (SERMs) and antiestrogens currently in use in the US, excluding data on breast effects. Four compounds in the SERM and antiestrogen families are presently in clinical use in the US: clomiphene (CC), tamoxifen (TAM), toremifene (TOR), and raloxifene (RLX). The clinical database on these compounds is among the largest available. Each compound demonstrates a specific profile for its target tissue effects, and this may differ between premenopausal and postmenopausal women. CC is the most widely used agent for ovulation induction. TAM is indicated in the management of breast cancer and for prevention in women at high risk. TAM may have additional effects on the cardiovascular and skeletal systems. TOR also is used for its effects on breast tissue and may have positive cardiovascular effects. RLX is approved in the management of osteoporosis with data supporting favorable effects on the cardiovascular system and breast tissue. TAM and TOR appear to have stimulatory effects on the uterus and endometrium, whereas RLX is neutral. Few adverse events have been attributed to these agents, with hot flashes being the most common one. There appears to be an increased risk of thromboembolic events with continuous use of TAM, TOR, and RLX. SERMs and antiestrogens continue to be studied extensively. Their evolving profiles support key roles for these agents in modern day medicine, particularly in the management of postmenopausal women's health.

Breast Neoplasms↗

PubMed2003

Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: comparison with estradiol-17beta.

OBJECTIVE: Some phytoestrogens are believed to have selective estrogen receptor modulator (SERM) activity with no action in the uterus but beneficial effects in the hypothalamo/pituitary unit and in the bone and are presently the focus of clinical interest. In the present experiments, the effects of the clinically used Cimicifuga racemosa (CR) extract BNO 1055 in the uterus, in the bone and on serum luteinizing hormone (LH) were compared with the effects of estradiol-17beta (E(2)) under acute and chronic conditions in ovariectomized rats. METHODS: Ovariectomized rats were treated either acutely (6 h) or chronically (3 Months) with E(2) or the CR extract. Gene expression of some estrogen-regulated genes in the metaphysis of the tibia and the uterus was determined. Furthermore, bone mineral density was measured by quantitative computer tomography. RESULTS: When given acutely, both E(2) and the CR extract inhibited LH secretion and slightly stimulated gene expression of IGF-I, collagen-1alpha1, osteoprotegerin and osteocalcin (all osteoblast products), and of tartrate-resistant acid phosphatase (TRAP, an osteoclast product) in the metaphysis of the femur. While E(2) stimulated uterine weight and expression of progesterone receptor (PR), the complement protein (C3) and IGF-I genes, and inhibited gene expression of the estrogen receptor beta (ERbeta) in the uterus, no such effect was observed under acute CR treatment. After chronic application with pelleted food over 3 Months E(2) had profound effects in the uterus on weight and gene expression (ERbeta, PR, C3 and IGF-I) which were not seen in the CR-treated animals. Within 3 Months after ovariectomy, control rats had lost more than 50% of the metaphyseal bone mass of the tibia, an effect prevented by E(2) and partially by CR supplementation. CONCLUSIONS: These data confirm the concept that the CR extract BNO 1055 contains as yet unidentified substances with SERM properties which act in the hypothalamo/pituitary unit and in the bone but not in the uterus.

Acid Phosphatase↗

PubMed2000

Selective estrogen receptor modulators in reproductive medicine and biology.

Estrogen replacement therapy has significant potential benefits for postmenopausal women, such as improvement of menopausal symptoms and protection from osteoporosis, but it may also increase a woman's risk of breast cancer. Also, some women do not take hormone replacement therapy because of such undesirable side effects as breast tenderness and uterine bleeding. Therefore, there is much interest in the development of compounds that provide the benefits of estrogen replacement therapy without the risks and side effects. The selective estrogen receptor modulators make up one class of compounds with both estrogen agonist and antagonist activity. This review discusses the clinical indications, risks, benefits, and mechanisms of action of selective estrogen receptor modulators and related compounds.

Estradiol↗

PubMed1999

Selective estrogen receptor modulators and phytoestrogens: new therapies for the postmenopausal women.

Estrogen deficiency in the postmenopausal woman results in numerous symptomatic and asymptomatic manifestations, including vasomotor symptoms, osteoporosis, heart disease, bladder and vaginal symptoms, and cardiovascular disease. Estrogen replacement therapy is associated with amelioration of these problems but has attendant risks. A newer class of drugs, the selective estrogen receptor modulators, provides both estrogen agonist and antagonist properties, depending on the target tissue. This article discusses the mechanism by which selective estrogen receptor modulators may vary in their end-organ effects and reviews the clinical studies associated with these compounds. Phytoestrogens are widely used in the United States, but little information is available regarding their potential long-term effects.

Aged↗

PubMed2000

Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer.

Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ERalpha and ERbeta, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents.

Animals↗

PubMed2004

Greek plant extracts exhibit selective estrogen receptor modulator (SERM)-like properties.

To prevent bone loss that occurs with increasing age, nutritional and pharmacological factors are needed. Traditional therapeutic agents (selective estrogen receptor modulators or SERMs, biphosphonates, calcitonin) may have serious side effects or contraindications. In an attempt to find food components potentially acting as SERMs, we submitted four plant aqueous extracts derived from Greek flora (Sideritis euboea, Sideritis clandestina, Marticaria chamomilla, and Pimpinella anisum) in a series of in vitro biological assays reflective of SERM profile. We examined their ability (a) to stimulate the differentiation and mineralization of osteoblastic cell culture by histochemical staining for alkaline phosphatase and Alizarin Red-S staining, (b) to induce, like antiestrogens, the insulin growth factor binding protein 3 (IGFBP3) in MCF-7 breast cancer cells, and (c) to proliferate cervical adenocarcinoma (HeLa) cells by use of MTT assay. Our data reveal that all the plant extracts studied at a concentration range 10-100 microg/mL stimulate osteoblastic cell differentiation and exhibit antiestrogenic effect on breast cancer cells without proliferative effects on cervical adenocarcinoma cells. The presence of estradiol inhibited the antiestrogenic effect induced by the extracts on MCF-7 cells, suggesting an estrogen receptor-related mechanism. In conclusion, the aqueous extracts derived from Sideritis euboea, Sideritis clandestina, Marticaria chamomilla, and Pimpinella anisum may form the basis to design "functional foods" for the prevention of osteoporosis.

Breast Neoplasms↗

PubMed2004

Crossover trial for lipid abnormality in postmenopausal breast cancer patients during selective estrogen receptor modulators (SERMs) administrations.

The objective of this study was to evaluate the different profiles of serum lipids resulting from the administration of selective estrogen receptor modulators (SERMs). Postmenopausal primary breast cancer patients (n = 197) with node-negative, hormone receptor-positive who were treated at our department or in other related medical institutions from April 1997 through March 2001 were given adjuvant therapy. The adjuvant therapy included 1 year's administration of tamoxifen (TAM) 20 mg or toremifene (TOR) 40 mg. The profiles of serum lipids such as total cholesterol (TC), high-density lipoprotein cholesterol (HDL) and triglyceride (TG) were observed. After 1 year administration TC had significantly decreased (p < 0.001) both in the TAM group and the TOR group, but no significant difference was found between these groups (p = 0.249). HDL had significantly decreased in the TAM group (p < 0.001), while it had significantly increased in the TOR group (p < 0.001), and a significant difference was found between the groups (p < 0.001). TG had significantly increased in the TAM group (p < 0.001) but significantly decreased in the TOR group (p < 0.001). The medication was switched in those who still had abnormal lipid metabolism and given to them for another year. After 1 year from the crossover TC and HDL had increased to the levels of before administration (p < 0.001) and TG had decreased in those (n = 57) whose medication was switched from TAM to TOR. While TC had decreased and TG had increased in those (n = 23) whose medication was switched from TOR to TAM (p < 0.001). The above findings have suggested that TOR provides better profiles of lipid metabolism than TAM.

Administration, Oral↗

PubMed2005

A selective estrogen receptor modulator designed for the treatment of uterine leiomyoma with unique tissue specificity for uterus and ovaries in rats.

The design of a novel selective estrogen receptor modulator (SERM) for the potential treatment of uterine leiomyoma is described. 16 (LY2066948-HCl) binds with high affinity to estrogen receptors alpha and beta (ERalpha and ERbeta, respectively) and is a potent uterine antagonist with minimal effects on the ovaries as determined by serum biomarkers and histologic evaluation.

Animals↗

PubMed2004

Belamcanda chinensis and the thereof purified tectorigenin have selective estrogen receptor modulator activities.

Belamcanda chinensis (BC) belongs to the family of iridaceae and the isoflavone tectorigenin has been isolated from the rhizome of this plant. Whether this isoflavone has estrogenic, possibly selective estrogen receptor modulator activities and if so, whether they are mediated via the estrogen receptor alpha or beta is unknown at present. Therefore, we performed binding studies with recombinant human ERalpha and ERbeta to show that tectorigenin binds to both receptor subtypes. In ERalpha-expressing MCF7 and ERbeta-expressing MDA-MB231 reporter gene transfected cells tectorigenin causes transactivation. When given intravenously to ovariectomized (ovx) rats, it inhibits pulsatile pituitary LH secretion. In postmenopausal women estrogen-unopposed LH pulses correlate with hot flushes. Therefore, suppression of pulsatile LH secretion may be beneficial in women suffering from hot flushes. Upon chronic application to ovx rats a BC extract containing 5% Belamcanda at a daily dose of 33 mg or 130 mg of the extract had no effect on uterine weight or on estrogen-regulated uterine gene expression while estrogenic effects in the bone, on bone mineral density of the metaphysis of the tibia could be established. Hence, tectorigenin may have antiosteoporotic effects also in postmenopausal women. Immunohistochemical staining of proliferating cell nuclear antigen--a proliferation marker--in the mammary gland did not indicate a mammotrophic effect of the tectorigenin-containing BC extract at both tested doses. In summary, tectorigenin or the B. chinensis extract containing tectorigenin had a strong hypothalamotropic and osteotropic effect but no effect in the uterus or the mammary gland. Therefore, tectorigenin may be in the future a clinically useful selective estrogen receptor modulator.

Animals↗

PubMed2002

Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor.

Selective Estrogen Receptor Modulators (SERMs) are a new class of drugsthat bind to estrogen receptor (ER) and elicit agonistic or antagonistic responses, depending on the target tissue. We have developed an in vitro system in which some SERMs (4-hydroxytamoxifen and resveratrol) demonstrate estrogenic response through wild-type (wt) ER, whereas others (raloxifene and GW7604) remain antiestrogenic. This system mimics the tamoxifen-resistant phenotype in clinic, when resistant tumors contain wtER. We used Atlas cDNA arrays to study gene expression profiles after ER activation by different SERMs in MDA-MB-231 human breast cancer cells stably transfected with wtER. Cells were treated with estradiol, four different SERMs, and the pure antiestrogen ICI 182,780. The obtained expression data were analyzed using GeneSpring software. Real-time reverse transcription-PCR was used to verify the array data. Our results showed that treatment with various compounds altered the expression of a diverse group of genes, revealing sets of overlapping genes that may represent a complex network of genes of interrelated signal transduction pathways. Sets of "agonistic" and "antagonistic" genes were identified on the basis of the known response to different SERMs. Further analysis of selected sets of genes revealed functionally related group of genes in each set, encoding proteins that were related to cell proliferation, survival, and apoptosis. Flow cytometry data indicated an antiapoptotic activity in cells treated with agonists versus apoptotic activity in cells treated with antagonists. A model for estradiol-like (survival) and antiestrogen-like (apoptosis) activities of SERMs on the basis of their gene expression profiles is suggested.

Breast Neoplasms↗

PubMed2001

Mechanism of action and preclinical profile of raloxifene, a selective estrogen receptor modulation.

Raloxifene possesses a complex pharmacology with tissue-selective estrogen agonist and antagonist effects. At the center of these effects resides the high affinity interaction of raloxifene with the ER. The ability of raloxifene to compete with estrogen for ER binding accounts for the estrogen antagonist effects of raloxifene in uterine and mammary tissue. Since the precise mechanism for the agonist effect of estrogen on the skeleton remains uncertain, it is difficult to unequivocally cite a single estrogen-like mechanism for raloxifene in bone. However, multiple lines of evidence clearly indicate that the estrogen agonist effect of raloxifene on bone is also mediated via an interaction with ER. The data showing non-additivity of raloxifene and estrogen effects in bone, and those showing the requirement for a pituitary hormone in the anti-estrogenic action of raloxifene and estrogen are particularly important. Thus, global evaluation of the similarities and parallel responses of raloxifene and estrogen in bone and the cardiovascular system, as summarized above, strongly support a similar mechanistic basis for the agonist effects of these agents on the skeleton.

Animals↗

PubMed2001

Sex hormones and the selective estrogen receptor modulator tamoxifen modulate weekly body weights and food intakes in adolescent and adult rats.

This study documented the effect of changes in male and female sex hormones and the selective estrogen receptor modulator (SERM) tamoxifen on weight gain and food consumption of rats from puberty to adulthood, and assessed whether age at onset of treatment affected outcome. In Study 1, male and female WKY rats were either neutered or sham-operated before puberty, and a subgroup of neutered females underwent estrogen replacement (ERT) at the age of puberty. In Study 2, subgroups of neutered females received either ERT or tamoxifen beginning well into the postpuberty period. Weekly body weight and food consumption were assessed, and food consumption was normalized to metabolic weight (body weight(0.67)). Neutering reduced the rate of weight gain in males (P < 0.05), but significantly increased it in females (P < 0.0001). ERT immediately reduced weight gain and prevented any further increase, resulting in weights below that of sham-operated females (P < 0.05). Tamoxifen prevented further weight gain and returned profiles to that of sham-operated females. Food consumption, normalized to metabolic weight, was similar in females and males, and both sexes showed a decrease through maturation to adulthood. Neutering decreased food consumption below that of sham-operated animals in both males and females (P < 0.05), and ERT returned it to sham levels. Despite the fact that tamoxifen had an effect on body weight similar to that of ERT, females receiving tamoxifen treatment consumed less food than both sham-operated and ERT females (P < 0.05). Weight gain is modulated by sex hormones in male and female rats, with both estrogen and tamoxifen exerting immediate effects in females, irrespective of the age at which treatment is initiated. Differences in food consumption do not appear to account for the effects of hormones and tamoxifen on body weight, suggesting that they exert a direct effect on overall body metabolism.

Aging↗

PubMed2000

Nitric oxide stimulatory and endothelial protective effects of idoxifene, a selective estrogen receptor modulator, in the splanchnic artery of the ovariectomized rat.

Estrogen is known to stimulate endothelial nitric oxide production and attenuate endothelial dysfunction after ischemia and reperfusion. However, estrogen therapy increases the risk of breast and endometrial cancer. The present study was designed to determine whether idoxifene, a selective estrogen receptor modulator without adverse effects on reproductive organs, may stimulate nitric oxide release and protect endothelial function. In U-46619 precontracted superior mesenteric arterial (SMA) segments isolated from ovariectomized rats, idoxifene and 17 beta-estradiol resulted in a comparable dose-dependent vasorelaxation (maximal relaxation: 75.3 +/- 4.9 and 71 +/- 4.7%, respectively). Treatment of the rings with N(omega)-nitro-L-arginine methyl ester completely blocked idoxifene- and 17 beta-estradiol-induced vasorelaxation. In vitro incubation of SMA rings with TNF alpha significantly reduced vasorelaxation to an endothelium-dependent vasodilator, acetylcholine (maximal relaxation: 73 +/- 3.7 versus 95 +/- 2.9% pre-TNF alpha, P <.01). Idoxifene, but surprisingly not 17 beta-estradiol, prevented TNF alpha-induced endothelial dysfunction (maximal relaxation: 86 +/- 2.6% in idoxifene-treated rings and 77 +/- 5.1% in 17beta-estrogen-treated rings). In vivo ischemia and reperfusion resulted in significant endothelial dysfunction as evidenced by decreased vasorelaxation to acetylcholine (maximal relaxation: 48 +/- 5.5 versus 92 +/- 3.9% in normal SMA rings), but a normal relaxation response to an endothelium-independent vasodilator, acidified NaNO(2) (95 +/- 3.2%). Treatment with idoxifene at either 1 or 2 mg/kg/day, or 17beta-estrogen at 1 mg/kg/day for 4 days significantly preserved endothelial function (P <.01 versus vehicle). Taken together, these results demonstrate that idoxifene is an endothelium-dependent vasodilator and exerts significant endothelial protective effects against TNF alpha- and ischemia-reperfusion-induced endothelial injury. These results suggest that selective estrogen receptor modulators have therapeutic potential in diseases where endothelial dysfunction plays an important role.

Animals↗

PubMed2006

Extracellular matrix integrity: a possible mechanism for differential clinical effects among selective estrogen receptor modulators and estrogens?

Recent gene microarray studies have illustrated heterogeneity in gene expression changes not only between estrogens and selective estrogen receptor modulators (SERMs), but also across different SERM molecules. In ovariectomized rats, this phenomenon was observed with respect to a number of genes involved in collagen turnover and extracellular matrix (ECM) integrity in the uterus and vaginal tissues. Preliminary mechanistic data suggest that these effects on ECM integrity may have relevance in the context of the effect of estrogens and some SERMs to increase the risk of pelvic organ prolapse and the incidence of urinary incontinence in postmenopausal women. Given the pivotal role of ECM integrity and collagen turnover in other tissues and disease states, these processes may provide a fruitful target for future research into the mechanisms for the heterogeneous pharmacology of estrogens and SERMs across different cell types and target tissues.

Animals↗