Shelly W, Draper MW, Krishnan V, Wong M, Jaffe RB. Selective estrogen receptor modulators: an update on recent clinical findings

Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California, USA.
Obstetrical and Gynecological Survey (Impact Factor: 1.86). 04/2008; 63(3):163-81. DOI: 10.1097/OGX.0b013e31816400d7
Source: PubMed


Recent clinical data on selective estrogen receptor modulators (SERMs) have provided the basis for reassessment of the SERM concept. The molecular basis of SERM activity involves binding of the ligand SERM to the estrogen receptor (ER), causing conformational changes which facilitate interactions with coactivator or corepressor proteins, and subsequently initiate or suppress transcription of target genes. SERM activity is intrinsic to each ER ligand, which accomplishes its unique profile by specific interactions in the target cell, leading to tissue selective actions. We discuss the estrogenic and anti-estrogenic effects of early SERMs, such as clomiphene citrate, used for treatment of ovulation induction, and the triphenylethylene, tamoxifen, which has ER antagonist activity in the breast, and is used for prevention and treatment of ER-positive breast cancer. Since the development of tamoxifen, other triphenylethylene SERMs have been studied for breast cancer prevention, including droloxifene, idoxifene, toremifene, and ospemifene. Other SERMs have entered clinical development more recently, including benzothiophenes (raloxifene and arzoxifene), benzopyrans (ormeloxifene, levormeloxifene, and EM-800), lasofoxifene, pipendoxifene, bazedoxifene, HMR-3339, and fulvestrant, an anti-estrogen which is approved for breast cancer treatment. SERMs have effects on tissues containing ER, such as the breast, bone, uterine and genitourinary tissues, and brain, and on markers of cardiovascular risk. Current evidence indicates that each SERM has a unique array of clinical activities. Differences in the patterns of action of SERMs suggest that each clinical end point must be evaluated individually, and conclusions about any particular SERM can only be established through appropriate clinical trials.

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    • "The current evidence indicates that each SERM has a unique array of clinical activities. The differences in the patterns of action of the SERMs suggest that each clinical end point must be evaluated individually , and the conclusions about any particular SERM can only be established through the appropriate clinical trials [12]. limitations of this study: The number of the study group was less. "
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    ABSTRACT: Objective: The complaints of excessive menstrual bleeding (menorrhagia) have a substantial impact on the gynaecological services and in most of the cases, no organic pathology is identified. Nonsteroidal anti-inflammatory drugs and tranexamic acid offer a simple therapy which has to be taken during menses, with reductions of 25-35% and 50% respectively in the Menstrual Blood Loss (MBL). Danazol and the gonadatrophin-releasing hormone analogues are highly effective, but their side-effects make them suitable only for a short-term use. In the present study, the role of ormeloxifene was studied in patients of DUB. Materials & methods: The subjects were diagnosed cases of DUB. After ruling out the possible causes of the abnormal uterine bleeding, a diagnosis of DUB was made and the treatment with ormiloxifene was started. The number of cases were 35 cases. The treatment with ormeloxifene was evaluated by measuring the Hb g/dl and the endometrial thickness before and after 3 months of treatment with sevista. Ormeloxifene was given in the dosage of a 60 mg tablet twice a week for 3 months, followed by once a week for another 3 months. Observation & results: There was a statistically significant increase in the Hb g/dl (p < 0.001) and a statistically significant decrease in the endometrial thickness (p< 0.001) after the treatment with ormeloxifene. Conclusion: Ormeloxifene can be used asa effective drug in the treatment of Dysfunctional uterine bleeding.
    Preview · Article · Apr 2013
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    • "Arzoxifene comes from a new generation of benzothiophene SERMs5, and both arzoxifene and its active metabolite desmethylarzoxifene (DMA) have a higher antiestrogenic potency than tamoxifen and better bioavailability than raloxifene6. Due to the absence of agonist activity in the endometrium, the presence of antiestrogenicity in the breast and estrogenicity in bones1, it is believed that benzothiophene SERMs are safer for long-term treatment compared to tamoxifen. Currently, there are no reports suggesting that raloxifene and arzoxifene could cause DNA damage and carcinogenesis. "
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    ABSTRACT: Aim: Benzothiophene compounds are selective estrogen receptor modulators (SERMs), which are recently found to activate antioxidant signaling. In this study the molecular mechanisms of antioxidant signaling activation by benzothiophene compound BC-1 were investigated. Methods: HepG2 cells were stably transfected with antioxidant response element (ARE)-luciferase reporter (HepG2-ARE cells). The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in HepG2-ARE cells was suppressed using siRNA. The metabolites of BC-1 in rat liver microsome incubation were analyzed using LC-UV and LC-MS. Results: Addition of BC-1 (5 μmol/L) in HepG2-ARE cells resulted in a 17-fold increase of ARE-luciferase activity. Pretreatment with the estrogen receptor agonist E2 (5 μmol/L) or antagonist ICI 182,780 (5 μmol/L) did not affect BC-1-induced ARE-luciferase activity. However, transfection of the cells with anti-Nrf2 siRNA suppressed this effect by 79%. Addition of BC-1 in rat microsome incubation resulted in formation of di-quinone methides and o-quinones, followed by formation of GSH conjugates. BC-1 analogues with hydrogen (BC-2) or fluorine (BC-3) at the 4′ position did not form the di-quinone methides. Both BC-2 and BC-3 showed comparable estrogenic activity with BC-1, but did not induce ARE-luciferase activity in HepG2-ARE cells. Conclusion: Benzothiophene compound BC-1 activates ARE signaling via reactive metabolite formation that is independent of estrogen receptors.
    Preview · Article · Jan 2013 · Acta Pharmacologica Sinica
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    • "Clomiphene citrate is a triphenylethylene compound, belonging to a family of synthetic nonsteroidal estrogens/antiestrogens and selective estrogen receptor modulators (SERMs). These compounds, when compared to the natural estrogens, have both agonistic and antagonistic properties and mimic estrogen in shape, see (Figure 1) [10]. It binds with a high affinity to estrogen-receptor systems of target cells and to antiestrogen-specific binding sites that have been identified in the cytosols of estrogen-receptor positive tissues, for example, the mammary gland and uterus [11]. "
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    ABSTRACT: The aim of this work was to develop a novel (99m)Tc-labelled derivative based on triphenylethylene for breast cancer imaging. (99m)Tc-Clomiphene was obtained with a radiochemical yield of 94.4% by adding (99m)Tc to 1.5 mg Clomiphene citrate in the presence of 10 μg SnCl(2) at pH 7. The optimization of the labeling yield of Clomiphene citrate, with (99m)Tc, is described. The reaction parameters that affect the labeling yield were studied to optimize the labeling conditions. Radiochemical purity of the final product has been verified by means of paper chromatography and paper electrophoresis. Ehrlich Ascites Carcinoma (EAC) as a model of breast cancer cells was injected intraperitoneally (IP) to produce ascites and intramuscularly (IM) to produce solid tumor. Biodistribution study was carried out by the injecting solution of (99m)Tc-Clomiphene in normal and tumor bearing mice. The uptake in ascites was over 12.5 % injected dose per gram tissue body weight, at 1hr after injection and above 12% in solid tumor. The T/NT value for (99m)Tc-Clomiphene complex was found to be 5.5 ± 0.4 which was higher than that of the commercially available (99m)Tc-MIBI. This data revealed the localization of tracer in tumor tissue with high percent sufficient to use (99m)Tc-Clomiphene as a promising tool for the diagnosis of breast cancer.
    Preview · Article · Nov 2012
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