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PubMed2005

Selective estrogen receptor modulator and selective progesterone receptor modulator: therapeutic efficacy in the treatment of uterine leiomyoma.

Recent advances in endocrinology open a door for clinical application of selective estrogen receptor modulator (SERM) and selective progesterone receptor modulator (SPRM) in the treatment of uterine leiomyoma. With regard to SERM, treatment with raloxifene is shown to reduce leiomyoma size in postmenopausal women. Although raloxifene causes shrinkage of leiomyomas in combination with gonadotropin-releasing hormone agonist in premenopausal women, the effects of monotherapy with raloxifene on leiomyoma growth in premenopausal women remain controversial. By contrast, tamoxifen may not be suitable for long-term treatment of leiomyomas due to an agonistic action on the endometrium. Treatment with progesterone antagonist (RU486) or SPRM (J867) has been demonstrated to inhibit leiomyoma growth and improve clinical symptoms in premenopausal women. No serious adverse effects associated with SERM or SPRM have been reported. In light of therapeutic efficacy and few adverse effects, SERM and SPRM may hold promise as novel treatment modalities for leiomyoma. Further studies are warranted to determine the optimal strategy for the treatment of leiomyoma with SERM and SPRM.

Female↗
PubMed2001

The past, present, and future of selective estrogen receptor modulation.

The recognition of selective estrogen receptor modulation in the mid-1980s provided a unique opportunity to develop multifunctional drugs. Tamoxifen, the first selective estrogen receptor modulator (SERM), is the first antiestrogen to be tested successfully for the prevention of breast cancer in high-risk women. However, the recognition that SERMs maintain bone density and lower circulating cholesterol suggested that the prevention of osteoporosis and coronary heart disease would be beneficial side effects of tamoxifen treatment. This hypothesis has not been pursued in clinical trial, but an alternate hypothesis, that SERMs could be developed to prevent osteoporosis and potentially reduce the risk of breast cancer, has been pursued with raloxifene. Current molecule modeling of the SERM-ER complex has identified the reason for the promiscuous estrogen-like actions of tamoxifen compared with raloxifene. Future studies of the signal transduction pathways of the ER alpha (alpha)- and beta (beta)-SERM complexes hold the promise of new drug discoveries and a menu of preventive medicine in clinical practice.

Animals↗
PubMed1999

Selective estrogen receptor modulators: a look ahead.

Selective estrogen receptor modulators (SERMs) are structurally diverse compounds that bind to estrogen receptors (ER) and elicit agonist or antagonist responses depending on the target tissue and hormonal milieu. They are being evaluated primarily for conditions associated with aging, including hormone-responsive cancer, osteoporosis and cardiovascular disease. Several SERMs are marketed or are in clinical development, including triphenylethylenes (tamoxifen and its derivatives: toremifene, droloxifene and idoxifene), chromans (levormeloxifene), benzothiophenes (raloxifene, LY353381) and naphthalenes (CP336,156). Tamoxifen and toremifene, both used to treat advanced breast cancer, also have beneficial effects on bone mineral density and serum lipids in postmenopausal women. Tamoxifen was recently shown to decrease the risk of invasive breast cancer in women at high risk. Unfortunately, both drugs also have stimulatory effects on the endometrium. Raloxifene, used for prevention of postmenopausal osteoporosis and fragility fractures, also has favourable effects on bone mineral density, serum lipids and the incidence of invasive breast cancer in postmenopausal women but does not stimulate the endometrium. Like replacement estrogens, SERMs increase the risk of venous thromboembolism. SERMs offer post-menopausal women many of the advantages of estrogen replacement while mitigating some of the disadvantages, particularly the concern over breast cancer. Newer SERMs, exemplified by raloxifene, also eliminate the concerns over endometrial stimulation that were not addressed by first generation SERMs. The clinical success of SERMs has set the stage for a variety of drug therapies based on selective modulation of nuclear receptor activity.

Estrogen Antagonists↗
PubMed2004

Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator.

PURPOSE: Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer. EXPERIMENTAL DESIGN: In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers. RESULTS: In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry. CONCLUSION: Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.

Anticarcinogenic Agents↗
PubMed2000

[Clinical results of selective estrogen receptor modulators (SERM)].

The SERMs (selective estrogen receptor modulators) are a new class of molecules that bind to the estrogen receptor, resulting in an estradiol agonist or antagonist response according to the target tissue. Raloxifene, a new SERM, has been shown to prevent postmenopausal bone loss, to reduce the risk of vertebral fractures in osteoporotic women, to decrease serum cholesterol and its LDL fraction, and to reduce significantly the risk of breat cancer. Raloxifene is available in France for the prevention of post-menopausal osteoporosis.

Bone and Bones↗
PubMed2005

Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity.

We assessed the preclinical characteristics of a novel, stringently screened selective estrogen receptor modulator, bazedoxifene acetate, including its ability to bind to and activate estrogen receptors and promote increased bone mineral density and bone strength in rats, and the effects impacting the uterine endometrium, breast cancer cell proliferation, and central nervous system-associated vasomotor responses in an animal model. Bazedoxifene bound to estrogen receptor-alpha with an IC50 of 26 nm, an affinity similar to that of raloxifene. Bazedoxifene did not stimulate proliferation of MCF-7 cells but did inhibit 17beta-estradiol-induced proliferation with an IC50 of 0.19 nm. In an immature rat uterine model, bazedoxifene (0.5 and 5.0 mg/kg) was associated with less increase in uterine wet weight than either ethinyl estradiol (10 microg/kg) or raloxifene (0.5 and 5.0 mg/kg). Histological analysis revealed that coadministration of bazedoxifene also appeared to reduce raloxifene-stimulated endometrial luminal epithelial cell and myometrial cell hypertrophy. In ovariectomized rats, bazedoxifene was associated with significant increases in bone mineral density at 6 wk, compared with control, and better compressive strength of bone samples from the L4 vertebrae, compared with samples from ovariectomized animals. In the morphine-addicted rat model of vasomotor activity, bone-sparing doses of bazedoxifene alone were not associated with 17beta-estradiol inhibition of increased vasomotor activity. Bazedoxifene acetate represents a promising new treatment for osteoporosis, with a potential for less uterine and vasomotor effects than selective estrogen receptor modulators currently used in clinical practice. Controlled clinical trial data will be needed to confirm these effects.

Animals↗
PubMed2002

Inhibition of intimal hyperplasia using the selective estrogen receptor modulator raloxifene.

HYPOTHESIS: The selective estrogen receptor modulator raloxifene hydrochloride inhibits intimal hyperplasia. DESIGN: Controlled laboratory experiment. SETTING: Experimental animal model. INTERVENTION AND MAIN OUTCOME MEASURES: Forty-three senile female sheep were randomized to sham operation, ovariectomy, or ovariectomy followed by treatment with 17beta-estradiol or raloxifene. Six months after initial operation, we performed necropsy with histological assessment of the aortic bifurcation and bone mineral densitometry and assayed serum lipids. RESULTS: After 6 months, serum triglyceride and total and high-density lipoprotein cholesterol levels were similar among groups and within the reference range. Ovarian ablation alone resulted in intimal hyperplasia, which was attenuated with estradiol and raloxifene therapy. Furthermore, estradiol and raloxifene therapy reversed ovariectomy-induced decreases in bone mineral density measured using spine morphometry. CONCLUSIONS: Raloxifene attenuates ovariectomy-induced aortic intimal hyperplasia independent of serum lipid levels. These data suggest that raloxifene, in addition to its beneficial influence on bone density, has direct, beneficial cardiovascular effects.

Animals↗
PubMed2003

Review on raloxifene: profile of a selective estrogen receptor modulator.

Raloxifene is a selective estrogen receptor modulator approved for prevention and treatment of osteoporosis in postmenopausal women. Raloxifene has an estrogen-agonistic effect on bone, although it is unclear how this effect comes about. It has been proven that raloxifene decreases levels of both bone formation markers and bone resorption markers in postmenopausal women. Moreover, it preserves the bone mineral density at most skeletal sites in these women. Raloxifene decreases the serum levels of low-density lipoprotein cholesterol and total cholesterol. In breast tissue, raloxifene is an estrogen antagonist. It decreases the risk of breast cancer in postmenopausal women. In contrast to estrogen and tamoxifen, raloxifene does not increase the risk of uterine cancer and it does not cause endometrial proliferation. Raloxifene is rapidly absorbed after oral administration, but its bioavailability is only 2% because of an extensive first-past effect. The maximum plasma concentration of 0.5 ng/ml is reached after 6 hours. Raloxifene is more than 95% bound to plasma proteins and the apparent volume of distribution is 2,348 l/kg. The clearance is 40 - 60 l/kg x h and the half-life of raloxifene after multiple dosing is 32.5 h. Less than 0.2% of an oral dose is excreted unchanged in the urine and less than 6% is excreted in urine as glucuronide conjugates. Serious adverse event caused by raloxifene is a 3-fold increase in the risk of thromboembolic events.

Adult↗
PubMed2005

Androgen dependent mammary gland virilism in rats given the selective estrogen receptor modulator LY2066948 hydrochloride.

A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with tissue specific estrogen receptor (ER) agonist or antagonist activities. In animals, SERMs may produce morphologic changes in hormonally-sensitive tissues like the mammary gland. Mammary glands from female rats given the SERM LY2066948 hydrochloride (LY2066948) for 1 month at >or= 175 mg/kg had intralobular ducts and alveoli lined by multiple layers of vacuolated, hypertrophied epithelial cells, resembling in part the morphology of the normal male rat mammary gland. We hypothesized that these SERM-mediated changes represented an androgen-dependent virilism of the female rat mammary gland. To test this hypothesis, the androgen receptor antagonist flutamide was co-administered with LY2066948 (175 mg/kg) to female rats for 1 month. Female rats given SERM alone had hyperandrogenemia and the duct and alveolar changes described here. Flutamide cotreatment did not affect serum androgen levels but completely blocked the SERM-mediated mammary gland change. In the mouse, a species that does not have the sex-specific differences in the mammary gland observed in the rat, SERM treatment resulted in hyperandrogenemia but did not alter mammary gland morphology. These studies demonstrate that LY2066948 produces species-specific, androgen-dependent mammary gland virilism in the female rat.

Androgen Antagonists↗
PubMed2001

Future use of selective estrogen receptor modulators and aromatase inhibitors.

Selective estrogen receptor modulators (SERMs) may act as estrogens or antiestrogens depending on the cell and tissue targets. The triphenylethylene SERMs are represented by tamoxifen and toremifene and a new agent with a novel carboxylic acid side chain (GW5638). Because of isomerization in the triphenylethylene molecule, "fixed ring" SERMs were introduced. The major one in development is the benzothiophene arzoxiphene (LY353381), which is now in Phase III clinical trial versus tamoxifen. A fourth group of SERMs is based on the estrogen molecule and comprises the so-called "pure" antiestrogen ICI 182,780 (fulvestrant, Faslodex) and a new oral analogue just entering trials, SR16234. The steroidal aromatase inhibitors [AIs (40H androstenedione 'and exemestane)] inactivate aromatase, whereas the triazole AIs (anastrozole and letrozole) inhibit the enzyme via the heme prosthetic group. Thus, there are two groups of AIs that show relative non-cross-resistance in advanced breast cancer and four groups of SERMs that also show a high degree of non-cross-resistance. With six different treatments and six or more clinical situations (prevention, neoadjuvant, adjuvant, and first- and second-line treatments for advanced disease) in which they may be used, the possible combinations of treatment are enormous. At present, we have few clinical pointers to optimal sequence of treatments. Now that most of the appropriate comparative trials have been performed, it may be the time to initiate novel approaches. These include alternating and sequential treatments, preferably with treatments changed before overt progression occurs.

Aromatase Inhibitors↗
PubMed1999

Raloxifene: a selective estrogen receptor modulator.

Raloxifene is a selective estrogen receptor modulator that produces both estrogen-agonistic effects on bone and lipid metabolism and estrogen-antagonistic effects on uterine endometrium and breast tissue. Because of its tissue selectivity, raloxifene may have fewer side effects than are typically observed with estrogen therapy. The most common adverse effects of raloxifene are hot flushes and leg cramps. The drug is also associated with an increased risk of thromboembolic events. The beneficial estrogenic activities of raloxifene include a lowering of total and low-density lipoprotein cholesterol levels and an augmentation of bone mineral density. Raloxifene has been labeled by the U.S. Food and Drug Administration for the prevention of osteoporosis. However, its effects on fracture risk and its ability to protect against cardiovascular disease have yet to be determined. Studies are also being conducted to determine its impact on breast and endometrial cancer reduction.

Bone and Bones↗
PubMed2004

[Selective estrogen receptor modulators: mechanisms of action and their tissue selectivity].

The SERMs (Selective Estrogen Receptor Modulators) exert selective agonistic or antagonistic effects on various estrogen target tissues. Conformational change of SERM-bound Estrogen Receptor (ER) and tissue specific expression patterns of transcription co-factors have been well investigated as the underlying factors of tissue selectivity of the SERMs. Nongenomic action, modulation of protein levels of ER and co-factors, and activation of other nuclear receptors, have been also reported as mechanisms of tissue selectivity by SERMs.

Animals↗
PubMed2001

Clinical use of selective estrogen receptor modulators.

The concept of selective estrogen receptor modulators (SERMs) is derived from the observation that tamoxifen, an effective adjuvant therapy of breast cancer that has an antiestrogenic effect on breast tissue, has estrogen-like effects on the skeleton and on plasma lipoproteins. Raloxifene is a SERM that has undergone extensive clinical investigation in the prevention and treatment of postmenopausal osteoporosis. It prevents bone loss at all skeletal sites, and in a large trial in osteoporotic women, the incidence of vertebral fractures was significantly decreased (relative risk 0.64) after up to 4 years of treatment with raloxifene 60 mg. The decrease of nonvertebral fractures did not reach the level of significance. Raloxifene decreased significantly the incidence of breast cancer (relative risk 0.28) and has no effect on the risk of endometrial cancer. SERMs are likely to play an important role in the management of postmenopausal women.

Bone Density↗
PubMed2005

Estrogen receptor alpha-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene.

OBJECTIVE: The selective estrogen receptor (ER) modulator (SERM) acolbifene (ACOL), a potent and pure antiestrogen in the mammary gland and uterus, exerts beneficial pro-estrogenic actions on energy balance, insulin sensitivity and lipid metabolism. ACOL binds ERs alpha and beta, both of which have been involved in the metabolic actions of estrogen. This study aimed at determining the identity of the ER involved in the beneficial metabolic actions of ACOL. DESIGN AND MEASUREMENTS: ACOL was administered for 4 weeks to male and female wild-type and ERalpha knockout (KO) mice, and indices of energy balance as well as plasma and liver lipid concentrations were determined. RESULTS: ERalpha KO mice were heavier, gained more fat mass and had larger adipose depots than their wild-type counterparts. In both genders, ACOL decreased fat gain (50%) and white adipose tissue mass in male and female wild-type, but not in ERalpha KO mice. ACOL reduced plasma cholesterol in female wild-type mice (-27%), whereas the compound remained ineffective in their ERalpha KO counterparts. Plasma triglycerides were unaffected by ACOL. Finally, ACOL decreased liver cholesterol and triglyceride concentrations only in wild-type female animals. CONCLUSION: The beneficial metabolic actions of the SERM ACOL on adiposity and on plasma and liver lipids are entirely due to its interaction with the ERalpha.

Adiposity↗
PubMed2002

[Selective estrogen receptor modulators (SERMs) in the practice].

Selective estrogen receptor modulators (SERMs) represent a growing class of compounds that act as either estrogen receptor gonists or ntagonists in tissue-selective manner. SERMs with the appropriate selectivity profile offer the opportunity to dissociate the favorable bone and cardio-vascular effects of estrogen from its unfavorable stimulatory effects on the breast and uterus. The triphenylethylene drug tamoxifen proved to be invaluable to treat and protect against breast cancer and bone loss, probably reduces cardiovascular risk, but had side effects on uterus similar to natural estrogens. The tamoxifen derivate toremifene is also used to treat breast cancer, but has less effect on bone. The non-steroidal benzothiophene derivate, raloxifene, is the best SERM available thus far. It has the potential to prevent breast cancer (like tamoxifen), but has better profile in its actions on bone and cardiovascular system (produces a rapid reduction of serum cholesterol, decreases fibrinogen and lipoprotein, improves the vascular epithelial function, attenuates vascular intimal thickening, etc.). It does not increase the incidence of endometrial cancer. Compounds of this class are the first step in developing the perfect hormone replacement and other multitargeted therapy. This review summarizes the recent important knowledge about SERMs.

Breast Neoplasms↗
PubMed2005

Urogenital effects of selective estrogen receptor modulators: a systematic review.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) include a relatively large number of compounds, each with different profiles of estrogenic/antiestrogenic actions on the genital tract. The aim of this review was to systematically evaluate all the available data from randomized, controlled studies on the effects of these compounds on pelvic organ prolapse and urinary incontinence. METHODS: Literature searches were performed using three computerized databases to identify the result of all randomized, controlled trials performed with SERMs having any effects on pelvic floor as an outcome. A manual search was performed on all related articles. RESULTS: We have identified only one randomized, placebo-controlled trial specifically designed to assess the effect of raloxifene and tamoxifen on the urogenital tract. Most of the data on genitourinary effects of various compounds derive from either questionnaires or adverse events reported during phase III clinical trials. Both tamoxifen and raloxifene appear to increase the incidence of pelvic floor prolapse in one trial, although this was not apparent from the licensing studies data for either of the drugs. Raloxifene does not appear to increase the incidence of urinary incontinence. Levormeloxifene and idoxifene, on the contrary, were noted to increase uterine prolapse and incontinence during phase III trials that prematurely terminated. No data are available on the genitourinary effect of toremifene and on the newer SERMs currently undergoing phase III trials: basedoxifene, lasofoxifene, and arzoxifene. CONCLUSION: Contrary to their effects in bone, SERMs do not have a class-specific effect on the genitourinary tract. In fact, compounds that are more estrogenic on the uterus such as levormeloxifene and idoxifene also increase the risk of prolapse and incontinence. SERMs can adversely affect the pelvic floor and incontinence but data from urodynamic studies are not yet available. Data on prolapse are contradictory. Given the increased incidence of prolapse and incontinence observed in several licensing trials, more focused research on the effect of these molecules on pelvic floor function is needed.

Clinical Trials as Topic↗
PubMed2000

Cardiovascular effects of droloxifene, a new selective estrogen receptor modulator, in healthy postmenopausal women.

Selective estrogen receptor modulators, like tamoxifen and related compounds, have mixed estrogen agonistic/antagonistic effects. Tamoxifen may confer significant cardiovascular benefits without the estrogen-associated risks of endometrial and breast cancer. Droloxifene, a structural analogue of tamoxifen, has estrogen agonistic effects on bone and antagonistic effects on endometrial and breast tissue. Its cardiovascular effects in women are unknown. We enrolled 24 healthy postmenopausal women in a randomized, double-blind, 2-period crossover trial comparing the effects of droloxifene (60 mg/d) with conjugated estrogen (0.625 mg/d). Plasma lipids, coagulation and fibrinolytic factors, and brachial flow-mediated vasodilator responses were measured at the beginning and end of each treatment period. Droloxifene and estrogen resulted in 16.6% and 12.0% reductions, respectively, in low density lipoprotein cholesterol (P<0.001) and 13.2% and 9.5% reductions, respectively, in lipoprotein(a) (P<0.05). In contrast, estrogen, but not droloxifene, increased high density lipoprotein (18.5%, P<0.001). Droloxifene also reduced fibrinogen by 17.8% versus a 7.3% reduction with estrogen (P=0.004) but produced no estrogen-like changes in plasminogen, plasminogen activator inhibitor-1, or tissue plasminogen activator. Droloxifene and estrogen produced 36.4% and 27.3% increases, respectively, in flow-mediated vasodilation (percent change from baseline, P<0.05 for both). Droloxifene has estrogen agonistic properties regarding low density lipoprotein and lipoprotein(a) metabolism, certain coagulation factors, and endothelium-dependent vasodilation but, unlike estrogen, has no effect on high density lipoprotein/triglyceride metabolism and the fibrinolytic cascade. It remains unknown whether droloxifene can confer a true cardiovascular benefit.

Aged↗
PubMed2002

A review of selective estrogen receptor modulators in the treatment of breast and endometrial cancer.

The understanding of how estrogen affects different body tissues by selective actions on the two subtypes of estrogen receptors (alpha and beta) has created the possibility of targeted therapy by the manufacturing of a group of compounds known as selective estrogen receptor modulators. The goal of an ideal selective estrogen receptor modulator that has all the beneficial effects of estrogen receptor modulation without adverse side effects seems increasingly achievable with improving drug design. The clinical findings for the new selective estrogen receptor modulator, arzoxifene, which has been shown to be highly active in the treatment of advanced breast cancer as well as advanced endometrial cancer, has confirmed the value of selective targeting of the estrogen receptors, and may herald a new era in endocrine therapy in clinical oncology.

Antineoplastic Agents, Hormonal↗