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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 19-nor derivatives of progesterone are referred to as "pure" progestational molecules as they bind almost exclusively to the progesterone receptor (PR) without interfering with receptors of other steroids. In this category is Nestorone, which has strong progestational activity and antiovulatory potency with no androgenic or estrogenic activity in vivo. These properties make it highly suitable for use in contraception and hormonal therapy (HT). Due to its high potency, very low doses of Nestorone may be delivered via long-term sustained-release delivery systems. Nestorone, 75 or 100 microg per day, released by vaginal ring has suppressed ovulation in women, with inhibition of follicular maturation. A vaginal ring releasing both 150 microg of Nestorone and 15 microg of ethinyl estradiol per day has effectively suppressed ovulation for 13 consecutive cycles. Nestorone has also been used effectively in a single implant for contraception in breastfeeding women and shows promise for use in transdermal systems as a contraceptive or for HT when combined with estrogen.
Steroids 2003 Nov
PMID:Nestorone: clinical applications for contraception and HRT. 1466 82

Demyelinating diseases are high impact neurological disorders. Steroids are regarded as protective molecules in the susceptibility to these diseases. Here, we studied the interactions between tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent proapoptotic molecule toxic to oligodendrocytes, and 17-beta-estradiol (E-17-beta), in human oligodendrocytic MO3.13 cells. Exposure of cells to TRAIL resulted in the upregulation of both death receptors DR4 and DR5 and apoptosis, as well as the activation of caspase-8 and -3, increased phosphorylation of Jun-N-terminal kinase and p38 kinase, and the reduction of bcl-2 and bcl-xL proteins. TRAIL-mediated MO3.13 cell apoptosis was abrogated by the dominant-negative form of the adaptor protein FADD and by caspase inhibitors. Preincubation with E-17-beta completely prevented both TRAIL-induced DR4 and DR5 upregulation and apoptosis. Estrogen-induced cytoprotection was time and concentration dependent and reverted by antiestrogens. Estrogen treatment per se reduced kinase phosphorylation, and upregulated bcl-2 and bcl-xL proteins. In conclusion, our data show that the detrimental role of TRAIL on oligodendrocytes can be effectively counteracted by estrogens, thus suggesting that the underlying molecular interactions can be of potential relevance in characterizing novel targets for therapy of demyelinating disorders.
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PMID:Protective effects of estradiol on TRAIL-induced apoptosis in a human oligodendrocytic cell line: evidence for multiple sites of interactions. 1473 40

Ethynylestradiol (EE2) is one of the most potent endocrine disrupting compounds capable to induce estrogenic effects even at trace level concentrations in the aquatic environment. Methods for detecting EE2 in such concentrations are generally based on GC or HPLC coupled to at least one mass spectrometer. Another approach are immunoassays and sensor systems but for most designs, derivatives of EE2 are required (e.g. for coupling to carrier proteins, enzyme or fluorescent labels, etc.). Here we present the straightforward synthesis and complete characterization of a new long-chain biotinylated EE2 derivative. The new EE2 derivative is used as tracer in a direct competitive enzyme-linked immunosorbent assay (ELISA) for the determination of EE2. With pure water, the limit of detection (LOD, signal-to-noise ratio, S/N = 3) and the test midpoint were found to be 14 and 136 ng l(-1), respectively. Cross reactivity (CR) was tested for 10 endogenous steroids and the BSA-conjugate used for immunization, as well as a synthetic precursor of the conjugate. Among the naturally occurring compounds, CR was determined to be maximum for metabolites of EE2 conjugated at ring-position 3 (17% and 37% for 3-glucuronide and 3-sulphate, respectively). Assay stability was tested against humic substances and organic solvents. Increasing amounts of organic solvents in the sample caused a clear decrease in sensitivity, presence of humic substances lead to an overestimation of EE2.
Steroids 2004 Apr
PMID:A novel enzyme-linked immunosorbent assay for ethynylestradiol using a long-chain biotinylated EE2 derivative. 1518 90

Breast cancer is one of the most common malignancies in the United States. Seventy percent of breast cancers are hormone-responsive due to the presence of estrogen receptors ERalpha and ERbeta, which are important diagnostic and therapeutic targets in cancer treatment. Estrogen acts through its receptors, which reside on the cell membrane as demonstrated recently and in the nucleus, leading to cancer cell proliferation and protection from cell death. The membrane ERalpha has been reported in MCF-7 human breast cancer cells and is believed to mediate estrogen effects to activate mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3-kinase). Activation of many growth factor receptors require adapter proteins to delivery the upstream signals to downstream kinases, such as MAP kinase. Both Shc and the p85alpha subunit of PI3-kinase are adapter proteins. In addition to their roles in transducing signals from membrane growth factor receptors, they have been demonstrated to interact with ERalpha in an estrogen dependent manner. In this review, the role of Shc in mediating estrogen effects on MAP Kinase regulation, cell growth and anti-apoptosis will be discussed. The possible role of PI3-kinase in estrogen rapid action is also reviewed in brief.
Steroids 2004 Aug
PMID:The role of adapter protein Shc in estrogen non-genomic action. 1528 64

Estrogen receptors act via the regulation of transcriptional processes, involving nuclear translocation and binding on specific response elements, thus leading to regulation of target gene expression. However, novel non-transcriptional mechanisms of signal transduction through steroid hormone receptors have been identified. These so-called "non-genomic" effects are independent by gene transcription or protein synthesis and involve steroid-induced modulation of cytoplasmic or of cell membrane-bound regulatory proteins. Relevant biological actions of steroids have been associated with this signaling in different tissues. Ubiquitary regulatory cascades such as mitogen-activated protein kinases (MAPK), the phosphatidylinositol 3-OH kinase (PI3K) and tyrosine kinases are modulated through non-transcriptional mechanisms by steroid hormones. Furthermore, steroid hormone receptors modulation of cell membrane-associated molecules such as ion channels and G-protein-coupled receptors has been shown in diverse tissues. The vascular wall is a site where non-genomic steroid hormones actions are particularly prominent. For instance, estrogens and glucocorticoids trigger rapid vasodilatation due to rapid induction of nitric oxide synthesis in endothelial cells via the estrogen receptor-dependent activation of MAPK and PI3K, leading to relevant pathophysiological consequences, in vitro and in vivo. The growing amount of evidence collected in the last years claims that non-transcriptional signaling mechanisms play a primary role in the generation of the effects of steroids on endothelial cells, which may turn out to be of relevance for clinical purposes.
Steroids 2004 Aug
PMID:Genomic and non-genomic effects of estrogens on endothelial cells. 1528 66

Estrogen results in the suppression of experimental allergic encephalomyelitis (EAE), a frequently used experimental animal model of multiple sclerosis (MS). The mechanism by which estrogen acts in diseases with an autoimmune background is less clear. Here, we used splenic dendritic cells (DC) from the Lewis rats EAE model as target cells, and explored the pathway of estrogen in immune modulation. Estrogen did not affect the expression of MHC class II, CD80 and CD86 by DC, but inhibited the ability of DC to stimulate T cell proliferation and production of both Th1 and Th2 cytokines. This was accompanied by increased T cell apoptosis. Estrogen up-regulated DC to express indoleamine 2,3-dioxygenase (IDO) which can limit T cell responses. The effects of estrogen-exposed DC on T cell proliferation and apoptosis were partly abolished by addition of an IDO inhibitor (1-methyl-dl-tryptophan, 1-MT), indicating that estrogen-exposed DC induced IDO-dependent T cell suppression. Our data support the hypothesis that the estrogen-induced suppression of EAE, as well as the reduction in number of MS relapses observed during pregnancy, may be related to the estrogen-DC-IDO axis. This observation could open up a novel therapeutic target for influencing the course of MS and other diseases with an autoimmune diseases background.
Steroids 2004 Sep
PMID:Antigen-specific T cell functions are suppressed over the estrogen-dendritic cell-indoleamine 2,3-dioxygenase axis. 1546 10

Extranuclear estrogen receptors may mediate rapid effects of estradiol that communicate with nuclear receptors and contribute to proliferation of human cancers bearing these signaling proteins. To assess these growth-promoting pathways, we undertook controlled homogenization and fractionation of NIH-H23 non-small cell lung cancer cells. As many breast tumors, NIH-H23 cells express estrogen receptors (ER), with the bulk of specific estradiol binding in nuclear fractions. However, as in breast cells, a significant portion of specific, high-affinity estradiol-17beta binding-sites are also enriched in plasma membranes of lung tumor cells. These estrogen binding-sites co-purify with plasma membrane-marker enzymes and are not significantly contaminated by cytosol or nuclei. On further purification of membrane caveolae from lung tumor cells, proteins recognized by monoclonal antibodies to nuclear ER-alpha and to ER-beta were identified in close association with EGF receptor in caveolae. In parallel studies, ER-alpha and ER-beta are also detected in nuclear and extranuclear sites in archival human breast and lung tumor samples and are noted to occur in clusters at the cell membrane by using confocal microscopy to visualize fluorescent-labeled monoclonal antibodies to ER-alpha. Data on site-directed mutagenesis of cysteine-447 in ER-alpha suggest that association of ER forms with membrane sites may depend on acylation of cysteine by palmitate. Estrogen-induced growth of MCF-7 breast cancer and NIH-H23 lung cancer cells in vitro correlated closely with acute hormonal activation of mitogen-activated protein kinase signaling and was significantly reduced by treatment with Faslodex, a pure anti-estrogen. Further, combination of Faslodex with selected growth factor receptor inhibitors elicited a more pronounced inhibiton of tumor cell growth. Thus, extranuclear forms of ER play a role in promoting downstream signaling for hormone-mediated proliferation and survival of breast, as well as lung, cancers and offer a new target for anti-tumor therapy.
Steroids
PMID:Estrogen and growth factor receptor interactions in human breast and non-small cell lung cancer cells. 1586 20

Estrogen mimetics in the environment and in foods can have important consequences for endocrine functions. When previously examined for action via genomic steroid signaling mechanisms, most of these compounds were found to be very weak agonists. We have instead tested their actions via several membrane-initiated signaling mechanisms in GH3/B6 pituitary tumor cells extensively selected for high (responsive) or low (nonresponsive) expression of the membrane version of estrogen receptor-alpha (mERalpha). We found many estrogen mimetic compounds to be potently active in our quantitative extracellular-regulated kinase (ERK) activation assays, to increase cellular Ca++ levels, and to cause rapid prolactin release. However, these compounds may activate one or both mechanisms with different potencies. For instance, some compounds activate ERKs in both pM and nM concentration ranges, while others are only active at nM and higher concentrations. Compounds also show great differences in their temporal activation patterns. While estradiol causes a bimodal time-dependent ERK activation (peaking at both 3 and 30 min), most estrogen mimetics cause either an early phase activation, a late phase activation, or an early sustained activation. One xenoestrogen known to be a relatively potent activator of estrogen response element-mediated actions (bisphenol A) is inactive as an ERK activator, and only a modest inducer of Ca++ levels and prolactin release. Many different signaling machineries culminate in ERK activation, and xenoestrogens differentially affect various pathways. Clearly individual xenoestrogens must be individually investigated for their differing abilities to activate distinct membrane-initiated signal cascades that lead to a variety of cellular functions.
Steroids
PMID:Signaling from the membrane via membrane estrogen receptor-alpha: estrogens, xenoestrogens, and phytoestrogens. 1586 19

Estrogen is a ligand for the estrogen receptor (ER), which on binding 17beta-estradiol, functions as a ligand-activated transcription factor and regulates the transcription of target genes. This is the slow genomic mode of action. However, rapid non-genomic actions of estrogen also exist at the cell membrane. Using a novel two-pulse paradigm in which the first pulse rapidly initiates non-genomic actions using a membrane-limited estrogen conjugate (E-BSA), while the second pulse promotes genomic transcription from a consensus estrogen response element (ERE), we have demonstrated that rapid actions of estrogen potentiate the slower transcriptional response from an ERE-reporter in neuroblastoma cells. Since rapid actions of estrogen activate kinases, we used selective inhibitors in the two-pulse paradigm to determine the intracellular signaling cascades important in such potentiation. Inhibition of protein kinase A (PKA), PKC, mitogen activated protein kinase (MAPK) or phosphatidylinositol 3-OH kinase (PI-3K) in the first pulse decreases potentiation of transcription. Also, our data with both dominant negative and constitutive mutants of Galpha subunits show that Galpha(q) initiates the rapid signaling cascade at the membrane in SK-N-BE(2)C neuroblastoma cells. We discuss two models of multiple kinase activation at the membrane Pulses of estrogen induce lordosis behavior in female rats. Infusion of E-BSA into the ventromedial hypothalamus followed by 17beta-estradiol in the second pulse could induce lordosis behavior, demonstrating the applicability of this paradigm in vivo. A model where non-genomic actions of estrogen couple to genomic actions unites both aspects of hormone action.
Steroids
PMID:Integration of steroid hormone initiated membrane action to genomic function in the brain. 1586 22

It is clear that estradiol has profound, rapid effects on the conformation of the estrogen receptors (ERs), ERalpha and ERbeta, which mediate the transcriptional effects of estradiol. Estrogen can elicit many other rapid changes in cells including changes in ion fluxes across membranes and stimulation of kinases and phosphatases. The proteins which are the targets of these actions are the subject of intense investigation. One of the issues that have not been satisfactorily resolved is whether ERalpha or ERbeta can reside in the plasma membrane and participate in the rapid effects of estrogen. In the present commentary, we take a careful look at some of the published data in an attempt to understand why it is so difficult to obtain a definitive answer to this question.
Steroids 2006 Feb
PMID:Nongenomic effects of estrogen: why all the uncertainty? 1625 1


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