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A series of estrogen receptor ligands based on benzothieno[3,2-b]indole were synthesized and their binding affinity for estrogen receptor subtypes (ERalpha and ERbeta) and effects on mouse uterus and bone were evaluated. Some of these compounds showed strong binding affinity to ER and significantly increased the bone mineral density of ovariectomized mice.
Estrogen, the traditional treatment of both short- and long-term consequences of the menopause, has fallen into disfavor. Thus, selective estrogen receptor modulators (SERMs) have been used as an alternative approach to activate estrogen signaling pathways in a tissue-specific manner. In addition, recent findings indicate that some compounds might activate specific estrogen signaling pathways that are beneficial without affecting other pathways that might lead to the harmful side-effects associated with estrogen. These so-called mechanism-specific ligands of estrogen or androgen receptors hold considerable promise as novel approaches to treat (or at least ameliorate) the consequences of estrogen deficiency.
We have shown previously that estrogen-stimulated transcription from the human lactoferrin gene in RL95-2 endometrium carcinoma cells is mediated through an imperfect estrogen response element (ERE) at the 5 -flanking region of the gene. Upstream from the ERE, a DNA sequence (-418 to -378, FP1) was selectively protected from DNase I digestion by nuclear extracts from endometrial and mammary gland cell lines. In this report, using the electrophoresis mobility shift assay, site-directed mutagenesis, and DNA methylation interference analyses, we show that three different nuclear proteins bind to the FP1 region (C1, C2, and C3 sites). The nuclear receptor, COUP-TF, binds to the C2 site. Mutations in the C1 binding region abolish C1 complex formation and reduce estrogen-dependent transcription from the lactoferrin ERE. When the imperfect ERE of the lactoferrin gene is converted to a perfect palindromic structure, the enhancing effect of the C1 binding element for estrogen responsiveness was abolished. We isolated a complementary DNA (cDNA) clone from an RL95-2 expression library that encodes the C1 site-binding protein. The encoded polypeptide maintains 99% amino acid identity with the previously described orphan nuclear receptor hERR1. A 2.2-kilobase mRNA was detected in RL95-2 cells by the newly isolated cDNA but not by the first 180 base pair of the published hERR1 sequence. By Western analysis, a major 42-kDa protein is detected in the RL95-2 nuclear extract with antibody generated against GST-hERR1 fusion protein. Finally, we show that the hERR1 interacts with the human estrogen receptor through protein-protein contacts.
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.
Estrogen receptor modulators (SERMs) are "designer drugs" that exert estrogen-like actions in some cells but not in others. We examined the effects of the SERMs LY-117018 (an analog of raloxifene) and tamoxifen on mesangial cells synthesis of type I and type IV collagen. We found that LY-117018 and tamoxifen suppressed mesangial cell type IV collagen gene transcription and type IV collagen protein synthesis in a dose-dependent manner, with a potency identical to that of estradiol. Type I collagen synthesis was also suppressed by LY-117018 in a dose-dependent manner with a potency identical to that of estradiol but greater than that of tamoxifen. Genistein, which selectively binds to estrogen receptor-beta in nanomolar concentrations, suppressed type I and type IV collagen synthesis, suggesting that estrogen receptor-beta mediates the effects of estrogen on collagen synthesis. Because matrix accumulation is central to the development of glomerulosclerosis, second-generation SERMs may prove clinically useful in ameliorating progressive renal disease without the adverse effects of estrogen on reproductive tissues.
OBJECTIVE: To review the study of estrogen receptor modulator and correlative Chinese herbs. METHOD: Based on to the documents in the world, the estrogen receptor modulator and correlative Chinese herbs summarized. RESULT AND CONCLUSION: Estrogen receptor modulator is biological compounds in botany. It can exert faint estrogen-like effects by low affinity with estrogen receptor. Some of the Chinese herbs have the estrogen-like activity, but further and more systemic research work are to be done.
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.
Withdrawal of estrogen represents the primary factor determining post menopausal bone loss and has been associated with negative indicators of bone quality including the apoptotic death of osteocytes in vivo. While hormone replacement therapy in the form of Estrogen or Selective Estrogen Receptor Modulators (SERMs) demonstrates clear estrogen receptor (ER)-mediated benefits to bone mass, less is known regarding the mechanism of action of these compounds in the maintenance of bone cell populations. We have investigated the potential antioxidant effects of estrogen, estrogen derivatives and the SERMs Raloxifene and LY117018 in the prevention of oxidative stress induced apoptosis in the osteocyte like cell line MLO-Y4. Treatment of MLO-Y4 with 0.3 mM H(2)O(2) induced apoptosis that was significantly inhibited (p< or =0.002) when the cells were pre-treated for 1 h with either 17beta-estradiol, Raloxifene or LY117018 (10 nM). The stereoisomer 17alpha-estradiol also prevented H(2)O(2) induced apoptosis in MLO-Y4. Importantly, pre-treatment of ER-negative HEK293 cells with either 1 microM, 100 nM or 10 nM 17beta-estradiol, Raloxifene or LY117018 significantly inhibited H(2)O(2) induced apoptosis in these cells (p< or =4.2x10(-5)) indicating an estrogen receptor-independent effect of these compounds. Comparisons of 17beta-estradiol and similar molecules containing the putative free radical scavenger C3-OH moiety on the steroid A-ring (17alpha-estradiol, 17alpha-ethinylestradiol; 10 nM) with structurally related molecules lacking the C3-OH grouping (Mestranol and Quinestrol; 10 nM) demonstrated that only compounds containing the C3-OH moiety showed anti-apoptotic behavior in these studies (p< or =0.0033). Similarly the identification of the presence of reactive oxygen species (ROS) in cells as evidenced by the free radical indicator 2'7'-dichlorodihydrofluorescein diacetate demonstrated that 17beta-estradiol, SERMs and related molecules with C3-OH moiety were capable of blocking ROS generated in cells by H(2)O(2) (p< or =0.002) while Mestranol and Quinestrol showed no such blockade. It is possible that the loss of osteocytes during estrogen insufficiency may occur through a failure to suppress the activity of naturally occurring or disease associated oxidant molecules. These data suggest that the osteocyte protective effects of estrogen and SERMs may operate through a common receptor-independent mechanism which may be related to the antioxidant activity of these molecules.
Breast cancer is a classic hormone-dependent malignant disease that is influenced by estrogen. However, the molecular links between estrogen and cell proliferation in healthy and malignant breast tissue are complex and as yet not well understood. The selective estrogen receptor modulators (SERMs), which are competitive inhibitors of estrogen binding at estrogen receptors alpha and beta, have become important weapons in the prevention and treatment of breast cancer. These agents also offer opportunities for the elucidation of the multiple molecular mechanisms by which estrogen affects cell proliferation. Each SERM-estrogen receptor complex has a unique structure that influences its activity in different body tissues. Unraveling the links between SERM structure and function not only may shed light on the signaling pathways that connect estrogen to cell proliferation but also may allow the design of new agents specifically targeted to affect certain events along these pathways.
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.
Raloxifene, a selective estrogen receptor modulator, favorably alters several markers of cardiovascular risk in healthy postmenopausal women. While many of its effects are similar to those of conventional hormone replacement therapy (HRT), there are also important differences. Raloxifene lowered low-density lipoprotein cholesterol levels similarly to estrogen. However, raloxifene lacked the potentially beneficial effects of HRT on high-density lipoprotein cholesterol levels and plasminogen activation inhibitor-1, as well as the potentially adverse effects of HRT on triglycerides and C-reactive protein. Raloxifene also had a potentially beneficial fibrinogen-lowering effect not seen with conventional HRT. The net effect of these differences is unclear. Proof that raloxifene or HRT reduces the risk of heart disease must await the results of ongoing clinical trials with cardiovascular event end points.
OBJECTIVE: Selective estrogen receptor modulators are novel compounds that bind to the estrogen receptor and have mixed agonistic and antagonistic activities. Recently, an increase in urinary incontinence has been reported with hormone replacement therapy use. A decrease in surgical procedures for pelvic floor relaxation has been recently reported with raloxifene, a selective estrogen receptor modulator that is not uterotropic. Levormeloxifene is a selective estrogen receptor modulator that was developed for the purpose of the treatment and prevention of postmenopausal osteoporosis. STUDY DESIGN: This was a multicentered prospective study of healthy women aged >or=65 years with osteoporosis who were randomized to blindly receive placebo or levormeloxifene 0.5 mg or 1.25 mg daily as part of a planned 3-year osteoporosis treatment study. Multiple medical and gynecologic evaluations were performed. Adverse events were reported to investigators and coded with the use of World Health Organization terminology. This study was halted after 10 months because of the large number of gynecologic and other adverse events. RESULTS: Among 2924 women who were studied, those women who were treated with levormeloxifene had a marked increase compared with placebo in leukorrhea (30% vs 3%), increased endometrial thickness on ultrasound scan (19% vs 1%), enlarged uterus (17% vs 3%), uterovaginal prolapse (7% vs 2%), urinary incontinence (17% vs 4%), increased micturition frequency (9% vs 4%), lower abdominal pain (17% vs 6%), hot flushes (10% vs 3%), and leg cramps (6% vs 0.8%). All of these differences were highly statistically significant with a probability value of.0001 for each. CONCLUSION: Levormeloxifene results in multiple adverse gynecologic and other events in postmenopausal women with osteoporosis.
Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen agonists and antagonists. Thus far SERMs have proven to be a highly versatile group and are being evaluated primarily for conditions associated with aging, including hormone-responsive cancer and osteoporosis. Tamoxifen and toremifene are currently used to treat advanced breast cancer and also have beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene is the only SERM compound actually approved worldwide for the prevention and treatment of postmenopausal osteoporosis and fragility fractures. Unfortunately, although these SERMs possess many benefits, they are also responsible for some very serious side effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These contraindications represent a major concern for the type of long-term, chronic therapy that is required to prevent osteoporosis. Moreover, both preclinical and clinical reports suggest that these SERMs are considerably less potent than estrogen, probably due to their reduced bioavailability. Lasofoxifene (CP 336,156) is a naphthalene-derivative, third-generation SERM, structurally distinct from the first- and second-generation SERMs. This compound selectively binds to both estrogen receptor subtypes (estrogen receptor-alpha or -beta) with high affinity. It has a half-inhibition concentration similar to that seen with estradiol and thus at least 10-fold higher than those reported for raloxifene and tamoxifen. Moreover, due to increased resistance to intestinal wall glucuronidation, lasofoxifene has a remarkably improved oral bioavailability with respect to other SERMs. In both preclinical and short-term clinical studies lasofoxifene has shown a proven efficacy in preventing bone loss and lowering cholesterol levels. Dose modeling from phase II studies allowed the selection of lasofoxifene 0.25 mg/day as the lowest fully effective dose. The compound shows a favorable safety profile and is currently in phase III development for the prevention and treatment of osteoporosis in 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.
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.
Selective estrogen receptor modulators are a new category of therapeutic agents that bind with high affinity to estrogen receptors and mimic the effect of estrogens in some tissues but act as estrogen antagonists in others. Tamoxifen, a triphenylethylene derivative, was the first clinically available selective estrogen receptor modulator. It is a potent antiestrogen in the breast, and its use in breast cancer patients has made it the most prescribed antineoplastic drug worldwide. It has estrogen-like activity on bone metabolism, and it also reduces cholesterol. However, its ability to produce proliferation, polyp formation, and even carcinomas in the endometrium is well known. A new selective estrogen receptor modulator, raloxifene, a benzothiopene derivative, has a clinical profile similar to that of tamoxifen. However, both preclinical and clinical studies reveal that, unlike tamoxifen, it is a pure antiestrogen in the uterus. It has recently been approved by the Food and Drug Administration for prevention of osteoporosis in postmenopausal women. This report reviews pertinent preclinical and currently available clinical studies about this new selective estrogen receptor modulator and discusses clinical applicability.
Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed.
BACKGROUND: Nontranscriptional signaling through estrogen receptors (ERs) is important in the cardiovascular system. In particular, estrogen stimulates endothelial NO synthase (eNOS) via the phosphatidylinositol 3-kinase (PI3K) pathway. The selective estrogen receptor modulator (SERM) raloxifene is effective for the treatment of postmenopausal osteoporosis, but its ability to activate eNOS via PI3K is unknown. METHODS AND RESULTS: Human umbilical vein endothelial cells were cultured in estrogen-deprived, phenol red-free medium. Raloxifene stimulated eNOS in a concentration- and time-dependent manner. Activation of eNOS by raloxifene was blocked by the PI3K inhibitor wortmannin and by the ER antagonist ICI 182,780 but not by transcriptional or translational inhibitors. Coimmunoprecipitation studies demonstrated that, in a ligand-dependent manner, raloxifene increased ERalpha-associated p85alpha, p110alpha, and PI3K activity. This correlated temporally with increases in the serine and threonine phosphorylation and activation of protein kinase Akt. CONCLUSIONS: Our findings indicate that nongenomic ER signaling triggered by a SERM leads to a rapid activation of NO synthesis in human endothelial cells. The ability of raloxifene to facilitate ERalpha-PI3K interaction may provide additional insight into the structure-function relationship of specific SERMs, which promote the nontranscriptional effects of ER.