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Results for “Selective Estrogen Receptor Modulators”

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PubMed1996

Inhibition of estrogen-stimulated growth of uterine leiomyomas by selective estrogen receptor modulators.

Uterine leiomyoma is the most frequent gynecologic neoplasm in women. By using a panel of cell lines derived from spontaneous Eker rat leiomyomas, we examined the estrogen-responsive phenotype of these tumor cells. Leiomyoma-derived ELT cell lines proliferated in response to estrogen, and estrogen-induced cell proliferation could be inhibited by the estrogen antagonist ICI 182780 and the selective estrogen-receptor modulators (SERMs) raloxifene and tamoxifen. In addition to inhibiting cell growth, these antagonists also inhibited estrogen-induced increases in progesterone-receptor expression. These data indicate that SERMs such as raloxifene and tamoxifen act as estrogen antagonists in uterine myometrial cells and suggest that this class of compounds may be effective for treatment of this important gynecologic neoplasm.

Animals↗
PubMed2006

Administration of estrogen receptor beta-specific selective estrogen receptor modulators to the hippocampus decrease anxiety and depressive behavior of ovariectomized rats.

Estradiol (E(2)) may influence some of the sex differences in neuropsychiatric disorders that emerge post-puberty. Studies in our laboratory, and others, have shown that actions at the beta isoform of estrogen receptor (ER) are important for E(2)'s effects for anxiety and/or depressive behavior. Whether ERbeta in the hippocampus is a target for these effects was investigated in the present study. We hypothesized that if actions at ERbeta in the hippocampus are important for the anti-anxiety and anti-depressive effects, then administration of selective ER modulator (SERMs) with greater affinity for ERbeta than ERalpha to the hippocampus, but not a control region/missed sites (i.e. the ventral tegmental area), should decrease anxiety and depressive behavior, compared to vehicle and that ERalpha-specific SERMs should not have the same effect. To investigate this, ovariectomized (ovx) rats were surgically-implanted with guide cannulae aimed at the hippocampus (target site) or ventral tegmental area (control site). Rats were administered vehicle, or 17beta-E(2) (equal affinity for ERalpha and ERbeta), SERMs with greater affinity for ERalpha vs. ERbeta (17alpha-E(2) or propyl pyrazole triol), or SERMs with greater affinity for ERbeta vs. ERalpha (coumestrol or diarylpropionitrile) to these sites (2 microg/microl/side) before testing in anxiety (open field, elevated plus maze) or depression (forced swim) tasks. ERbeta-selective SERMs to the hippocampus, but not the ventral tegmental area, decreased anxiety and depressive behavior. Rats administered 17beta-E(2) or ERbeta SERMs entered more central squares in an open field, spent more time on the open arms of the plus maze, and spent less time immobile compared to rats administered vehicle. Administration of ERalpha-specific SERMs produced similar effects as vehicle administration. Thus, E(2)'s anti-anxiety and anti-depressive effects may involve ERbeta in the hippocampus.

Animals↗
PubMed2002

Solid-phase synthesis and investigation of benzofurans as selective estrogen receptor modulators.

A library of benzofurans was prepared by solid-phase synthesis methods, and several analogues were identified as potent ligands for the estrogen receptors ER-alpha and ER-beta, with some compounds having selectivity for ER-alpha. Analogues designed to more closely mimic Raloxifene were less effective. Certain benzofurans were effective in a bone pit assay, but were characterized as agonists in a MCF-7 breast tumor cell proliferation assay.

Benzofurans↗
PubMed2004

Selective estrogen receptor modulators 4-hydroxytamoxifen and raloxifene impact the stability and function of SRC-1 and SRC-3 coactivator proteins.

Proteasome-mediated protein degradation has been implicated in playing a role in nuclear receptor-mediated gene expression; inhibition of the proteasome impairs the transcriptional activity of estrogen receptor alpha (ERalpha) and most other nuclear receptors. This coincides with blockage of agonist-dependent degradation of the receptor and elevation of the steady-state levels of SRC family coactivators and CBP. Here, we examined the effects that different ERalpha ligands have on coactivator protein steady-state levels and demonstrate that the selective ER modulators (SERMs) 4-hydroxytamoxifen (4HT) and raloxifene are able to elevate SRC-1 and SRC-3 protein levels. Using the HeLa cell line, we show that this effect is ERalpha dependent. Consistent with the observed increase in coactivator protein levels, we were also able to observe an increase in the transcriptional activity of other nuclear receptors in SERM-treated cells. Information presented here demonstrates an unexpected consequence of SERM treatment, which could help further define the complex tissue responses to 4HT and raloxifene, and suggests that these ligands can have a broad biological action, stimulating the transcriptional activity of other nuclear receptors.

Acetyltransferases↗
PubMed2001

The effect of selective estrogen receptor modulators on parameters of the hypothalamic-pituitary-gonadal axis.

The SERMs currently in clinical practice or in late stages of clinical development have been studied primarily for their effects on the breast, cardiovascular, bone, and reproductive systems. The effect of SERMs on the hypothalamic-pituitary-gonadal (HPG) axis has not been the primary focus of the studies conducted thus far. However the effect of SERMs on the HPG axis and the associated regulation of endocrine parameters may play an important role in their overall clinical profile. In this review the effects of selected SERMs on the HPG axis in premenopausal women, postmenopausal women, and men are summarized.

Female↗
PubMed2005

Selective estrogen receptor modulators (SERMs) for the brain: current status and remaining challenges for developing NeuroSERMs.

Multiple issues regarding the efficacy of estrogen action in the brain remain unresolved. These include the timing, formulation and duration of the therapy intervention. Moreover, issues of thrombotic and neoplastic risks must be factored into the design of estrogen alternatives developed to prevent age-associated neurodegenerative disorders, as well as other climacteric symptoms such as hot flush and sleep dysfunction. One strategy to address these issues is to develop molecules that selectively target and activate estrogen mechanisms of action in the brain while avoiding activation of estrogen receptors peripheral to the brain, particularly in reproductive organs. An overview of recent advances in our understanding of the molecular mechanisms of estrogen action is discussed in the context of designing an efficacious NeuroSERM that will activate cellular, biochemical and genomic events required for the promotion of memory function and neuronal survival. Pharmacological analyses of estrogen receptor subtypes and the case for a membrane-associated estrogen receptor splice variant in mediating these mechanisms are provided along with a summary of the activation profiles of existing clinically relevant estrogen alternatives or SERMs in neurons. Results of these endeavors have yielded insights into strategies for developing novel molecules with NeuroSERM potential in order to prevent brain related climacteric symptoms and neurodegenerative diseases.

Brain↗
PubMed2005

Anti-inflammatory effect of selective estrogen receptor modulators (SERMs) in microglial cells.

OBJECTIVE: Our aim was to study how different SERMs modulate the inflammatory responses induced by lipopolysaccharide (LPS) or unmethylated CpG-oligonucleotides in mouse and rat microglial cells. MATERIALS AND METHODS: Inflammatory responses of mouse N9 microglial cells and rat primary hippocampal microglia to lipopolysaccharide (LPS) exposure were recorded by the secretion of nitric oxide (NO) and cytokine IL-6 in two models where SERM was added either 24 h before LPS addition or simultaneously or even after the LPS exposure. The responses of 17beta-estradiol, tamoxifen, raloxifene and ICI 182.780 were compared. Responses were recorded by ELISA, Northern and EMSA assays. RESULTS: SERMs but not 17beta-estradiol induced a significant, concentration-dependent anti-inflammatory response both in rat primary microglial cells and in mouse N9 microglial cells. The response was observed both in NO and IL-6 secretion as well as in total IL-6 mRNA expression. We have recently observed that histone deacetylase (HDAC) inhibitors can potentiate the LPS-induced inflammatory response. Raloxifene and tamoxifen inhibited the potentiation of LPS response induced by trichostatin A, an HDAC inhibitor, in N9 microglia. A SERM-induced anti-inflammatory response was observed in acute models where SERM was added simultaneously or even up to 6 h later than LPS exposure. In contrast, the pretreatment of N9 microglia with tamoxifen or raloxifene for 30 h before LPS exposure did not provide any protection against the LPS response. We also observed that the raloxifene-induced protection in N9 microglia was connected to a decline of LPS-induced DNA binding activity of AP-1 but not that of NF-kappaB transcription factors. CONCLUSIONS: Our results show that tamoxifen, raloxifene and ICI 182.780 induce an anti-inflammatory response in acute models of mouse and rat microglial cells. It seems that this response is not estrogen receptor-mediated but, probably, is attributable to some SERM-induced modulation of LPS-activated pro-inflammatory signalling cascades.

Animals↗
PubMed2000

[Physiopathology of bone loss and pharmacologic approach of selective estrogen receptor modulators].

Osteoclastic resorption increases at menopause and remains high during aging. The complex mechanism responsible for this increase involves cytokines and growth factors secreted by stromal cells and/or by osteoblasts and cells in the hematopoietic microenvironment. Although estrogen receptors have been found mainly on osteoblasts and their precursors, the stromal cells, they have also been demonstrated on osteoclast precursors. Raloxifene is a selective estrogen receptor modifier (SERM) that has the beneficial effects of estrogens on bone tissue but no estrogen agonist effects on the breast and uterus. Although recent data have established that the mechanism of action of estrogens and SERMs is far more complex than was previously thought, the reason for the tissue selectivity of these molecules remains unknown.

Animals↗
PubMed2000

Selective estrogen receptor modulators suppress mesangial cell collagen synthesis.

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.

Angiotensin II↗
PubMed2003

Adaptive hypersensitivity to estrogen: mechanism for superiority of aromatase inhibitors over selective estrogen receptor modulators for breast cancer treatment and prevention.

Clinical observations suggest that human breast tumors can adapt to endocrine therapy by developing hypersensitivity to estradiol (E(2)). To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term E(2) deprivation (LTED) causes "adaptive hypersensitivity". The enhanced responses to E(2) do not involve mechanisms acting at the level of transcription of estrogen-regulated genes. We found no evidence of hypersensitivity when examining the effects of E(2) on regulation of c-myc, pS2, progesterone receptor, several estrogen receptor (ER) reporter genes, or c-myb in hypersensitive cells. Estrogen deprivation of breast cells long-term does up-regulate both the MAP kinase and phosphatidyl-inositol 3-kinase pathways. As a potential explanation for up-regulation of these signaling pathways, we found that ERalpha is 4- to 10-fold up-regulated and co-opts a classic growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. E(2) binds to cell membrane-associated ERalpha, physically associates with the adapter protein SHC, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which results in the rapid activation of MAP kinase. These non-genomic effects of E(2) produce biological effects as evidenced by Elk activation and by morphological changes in cell membranes. Further proof of the non-genomic effects of E(2) involved use of cells which selectively expressed ERalpha in the nucleus, cytosol and cell membrane. We created these COS-1 "designer cells" by transfecting ERalpha lacking a nuclear localization signal and containing a membrane localizing signal. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. Adaptive hypersensitivity would explain the superiority of aromatase inhibitors over the selective ER modulators (SERMs) for treatment of breast cancer. The development of highly potent third-generation aromatase inhibitors allows reduction of breast tissue E2 to very low levels and circumvents the enhanced sensitivity of these cells to the proliferative effects of E(2). Clinical trials in the adjuvant, neoadjuvant and advanced disease settings demonstrate the greater clinical efficacy of the aromatase inhibitors over the SERMs. More recent observations indicate that the aromatase inhibitors are superior for the prevention of breast cancer as well. These observations may be explained by the hypothesis that estrogens induce breast cancer both by stimulating cell proliferation and by their metabolism to genotoxic products. The SERMs block ER-mediated proliferation only, whereas the aromatase inhibitors exert dual effects on proliferation and genotoxic metabolite formation.

Adaptation, Physiological↗