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: 2.36). 04/2008; 63(3):163-81. DOI: 10.1097/OGX.0b013e31816400d7
Source: PubMed

ABSTRACT 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: 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. 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. 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. Ormeloxifene can be used asa effective drug in the treatment of Dysfunctional uterine bleeding.
    01/2013; 7(1):132-4. DOI:10.7860/JCDR/2012/4794.2687
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    • "First, selective estrogen receptor modulators are compounds that act as agonists on one ER and antagonists at the other ER (Zandi et al., 2002). This strategy has attempted to enhance ERβ agonist activity while antagonizing ERα (Brinton, 2004; Shelly et al., 2008). The rationale for this approach is that chronic activation of ERα, which is highly expressed in breast, uterus and liver, may account for the now known side effects of chronic estrogen administration to post-menopausal women. "
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    ABSTRACT: Menopause is associated with a precipitous decline in circulating estrogens and a resulting loss of the neuroprotective actions of this steroid hormone. In view of the results of the Women's Health Initiative and the preceding knowledge that orally administered estrogens has a variety of adverse side effects, likely through actions on peripheral estrogen receptor alpha (ERα), we initiated a program of research to synthesis and assess a group of non-feminizing estrogens that lack ability to interact with ERs but retain much of the neuroprotective action of feminizing estrogens. This program of research is aimed at the identification of compounds which do not stimulate ERs but are potentially neuroprotective in vitro and in animal models of neuronal cell death. We discovered that the most effective non-feminizing estrogens were those with large bulky groups in the 2 and/or 4 carbon of the phenolic A ring of the steroid. These compounds were 8- to 114-fold more potent than 17 β-estradiol (βE2), but lacked ER binding capacity in vitro and feminizing effects in vivo. The success of this program of research suggests that strategies to optimize non-feminizing estrogens for use in postmenopausal women can be successful.
    Brain research 11/2010; 1379:61-70. DOI:10.1016/j.brainres.2010.11.058 · 2.83 Impact Factor
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    • "Estrogen receptors are a target for therapeutic approaches to prevent cognition decline with aging or the development of affective and cognitive disorders after menopause. New selective modulators for estrogen receptors, such as arzoxifene, bazedoxifene, lasofoxifene, and ospemifene, among others, are being tested in clinical trials (Shelly et al., 2008). Before the therapeutic use of these drugs as neuroprotectants is considered, it is essential to learn much more about the expression and regulation of estrogen receptors and transcriptional cofactors in the aging brain and also about the impact of aging on the convergence of estrogen receptor signaling with other signaling pathways. "
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    ABSTRACT: Decreasing levels of sex hormones with aging may have a negative impact on brain function, since this decrease is associated with the progression of neurodegenerative disorders, increased depressive symptoms and other psychological disturbances. Extensive evidence from animal studies indicates that sex steroids, in particular estradiol, are neuroprotective. However, the potential benefits of estradiol therapy for the brain are counterbalanced by negative, life-threatening risks in the periphery. A potential therapeutic alternative to promote neuroprotection is the use of selective estrogen receptor modulators (SERMs), which may be designed to act with tissue selectivity as estrogen receptor agonists in the brain and not in other organs. Currently available SERMs act not only with tissue selectivity, but also with cellular selectivity within the brain and differentially modulate the activation of microglia, astroglia and neurons. Finally, SERMs may promote the interaction of estrogen receptors with the neuroprotective signaling of growth factors, such as the phosphatidylinositol 3-kinase/glycogen synthase kinase 3 pathway.
    Psychoneuroendocrinology 06/2009; 34 Suppl 1:S113-22. DOI:10.1016/j.psyneuen.2009.04.012 · 5.59 Impact Factor
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