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PubMed2003

Antiestrogens and selective estrogen receptor modulators reduce prostate cancer risk.

The development of chemoprevention strategies against prostate cancer would have the greatest overall impact both medically and economically against prostate cancer. Estrogens are required for prostate carcinogenesis. Estrogenic stimulation through estrogen receptor alpha in a milieu of decreasing androgens contributes significantly to the genesis of benign prostatic hyperplasia, prostate dysplasia, and prostate cancer. The ability of antiestrogens and selective estrogen receptor modulators (SERMs) to delay and to suppress prostate carcinogenesis is supported by preclinical, clinical, and epidemiological studies. SERMs have many features that make them attractive candidates for prostate cancer chemoprevention including their favorable safety profile and efficacy in preclinical prostate cancer models. The true clinical benefits of SERMs for chemoprevention to prevent prostate cancer, however, should continue to be investigated through human clinical trials. A phase IIb/III human clinical trial is currently evaluating safety and efficacy of toremifene, a SERM, in men who have high-grade prostatic intraepithelial neoplasia.

Clinical Trials, Phase II as Topic↗
PubMedDate not supplied

Selective estrogen receptor modulators: from bench to bedside and back.

OBJECTIVE: To provide a brief review of the history of the development of selective estrogen receptor modulators (SERMs), the current data assessing the effect of SERMs at the organ level, and the mechanism of action of these agents. METHODS: All the pertinent medical literature was reviewed, and the effects of SERMs on various end-organs were summarized. RESULTS: SERMs have been available for clinical use since the late 1960s. By the late 1980s, several SERMs had become available that influenced clinical practice. Multiorgan effects of these compounds include variable clinical efficacy for treatment of menopausal symptoms involving the central nervous system, variable effects on the genitourinary tract, and, in general, positive effects on serum lipid levels. SERMs seem to affect bone density positively, albeit to variable degrees, depending on the agent being used. The greatest effect of SERMs has been on the breast, and current SERMs seem to have efficacy for prevention of breast cancer as opposed to the controversial effect of estrogen on the breast. Disadvantages of SERMs include exacerbation of menopausal symptoms and, as with estrogen, an increased incidence of venous thrombosis and pulmonary emboli. SERMs act by modifying the configuration of the estrogen receptor. Effects at the gene transcription level seem to be tissue specific, a factor that likely accounts for the variability of clinical action seen. CONCLUSION: SERMs are a viable option for treatment of various problems associated with menopause.

Bone Density↗
PubMed2004

Embryo/fetal toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in rats and rabbits.

BACKGROUND: The purpose of this study was to evaluate the effects of lasofoxifene, a selective estrogen receptor modulator (SERM), on rat and rabbit fetal development. METHODS: Lasofoxifene was administered orally to rats (1, 10, 100 mg/kg) between gestation days (GD) 6-17, and in rabbits (0.1, 1, 3 mg/kg) between GD 6-18. Maternal body weight and food consumption were monitored throughout pregnancy. Fetuses were delivered by Cesarean section on GD 21 in rats, and GD 28 in rabbits, to evaluate fetal viability, weight, and morphology. Drug concentrations in maternal plasma were measured in a separate cohort of animals at several time points commencing on GD 17 (rats) and 18 (rabbits). On GD 18 (rat) and GD 19 (rabbit) drug concentrations were measured in maternal plasma and in fetal tissue 2 hr post dosing to determine the fetal to maternal drug ratio. RESULTS: In rats, there were dose-related declines in maternal weight gain and food consumption. Post implantation loss was significantly increased at dosages of 10 and 100 mg/kg, and the number of viable fetuses was decreased at 100 mg/kg. The placental weights increased, whereas fetal weights decreased in a dose-dependent manner. Lasofoxifene-related teratologic findings were noted at 10 and 100 mg/kg and included imperforate anus with hypoplastic tails, dilatation of the ureters and renal pelvis, misaligned sternebrae, hypoflexion of hindpaw, wavy ribs, and absent ossification of sternebrae. In rabbits, neither maternal weight gain nor food consumption were affected during treatment. Between GD 26-28, there was a dose-dependent increased incidence of red discharge beneath the cages. At 1 and 3 mg/kg, resorptions and post-implantation loss increased. There were no significant external or visceral effects, but 3 mg/kg there was an increased incidence of supernumerary ribs. Although the maternal plasma Cmax and AUC(0-24) were dose-dependent, the exposures in the rat were many orders of magnitude greater than in the rabbit even for the same 1 mg/kg dose. The single time point fetal/maternal drug ratio was higher in the rat (1.3-0.78) than in the rabbit (0.21-0.16). CONCLUSION: In general, both maternal and fetal effects of lasofoxifene were similar to those reported with other SERMs. Although the incidence or severity of these effects was, in some instances, greater in the rat than in the rabbit, the doses and the resultant maternal and fetal exposures were many orders of magnitude higher in the rat, suggesting the rabbit to be more sensitive to the toxicological effects of lasofoxifene.

Animals↗
PubMed2005

The selective estrogen receptor modulator acolbifene reduces cholesterolemia independently of its anorectic action in control and cholesterol-fed rats.

The cancer-preventing selective estrogen receptor modulator (SERM) acolbifene (ACOL) exerts a potent and pure antiestrogenic action in the mammary gland and uterus, yet it displays beneficial, estrogen-like actions on energy and lipid metabolism in rodents. The compound reduces food intake and strongly decreases cholesterolemia in rats fed a cholesterol-free diet. This study was designed to establish whether the anorectic effect of ACOL is involved in its cholesterol-lowering action, and whether the compound retains its ability to lower cholesterol concentrations in rats with diet-induced hypercholesterolemia. Female rats were fed a purified diet devoid of cholesterol (reference diet) or containing 2% cholesterol (C-diet); they were either not treated or treated daily with ACOL or not treated and pair-fed to the ACOL-treated rats. The C-diet did not affect food intake or weight and fat gains. ACOL reduced food intake (16%) and weight gain (45%, mainly fat) similarly in both dietary cohorts. ACOL, but not pair feeding, reduced cholesterolemia by 33% in rats fed the reference diet. As expected, the C-diet raised serum total cholesterol almost 3-fold and this increase was largely prevented by ACOL but not by pair feeding. Cholesterol was reduced by ACOL, mainly in the HDL fraction, in rats fed the reference diet, but only in the non-HDL fraction in those fed the C-diet. In livers of rats fed the reference diet, ACOL, but not pair feeding, increased protein abundance of the scavenger receptor, class B, type 1, and the LDL receptor, thought to be involved in ACOL-mediated cholesterol lowering. These findings demonstrate that the potent hypocholesterolemic action of ACOL is independent of the concomitant reduction in food intake and fat accretion, and that such action occurs in rats with overt diet-induced hypercholesterolemia.

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

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↗