Science.gov

Sample records for estrogens

  1. Estrogen

    MedlinePlus

    Estrogen is used to treat hot flushes ('hot flashes'; sudden strong feelings of heat and sweating) in ... and cause problems with the skin or nervous system), very high or very low levels of calcium ...

  2. Estrogen

    MedlinePlus

    ... estrogen tablets. If you will be taking Estrace® brand tablets, tell your doctor and pharmacist if you are allergic to aspirin or tartrazine (a food color additive). Ask your pharmacist or check the manufacturer's ...

  3. Estrogen overdose

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/002584.htm Estrogen overdose To use the sharing features on this page, please enable JavaScript. Estrogen is a female hormone. Estrogen overdose occurs when ...

  4. Estrogen Injection

    MedlinePlus

    ... forms of estrogen injection are used to treat hot flushes (hot flashes; sudden strong feelings of heat and sweating) ... If you are using estrogen injection to treat hot flushes, your symptoms should improve within 1 to ...

  5. Estrogen and Osteoporosis.

    ERIC Educational Resources Information Center

    Lindsay, Robert

    1987-01-01

    This article reviews the use of estrogen in the prevention and treatment of osteoporosis. Dosage levels, interactions with other factors, side effects, and the mechanism of estrogen action are discussed. (Author/MT)

  6. Estrogen and Bazedoxifene

    MedlinePlus

    Estrogen and bazedoxifene tablets are used to treat hot flashes (sudden feelings of warmth, especially in the ... women may experience other symptoms and body changes). Estrogen and bazedoxifene tablets are also used to prevent ...

  7. Estrogen and cancer.

    PubMed

    Liang, Jing; Shang, Yongfeng

    2013-01-01

    Estrogen exhibits a broad spectrum of physiological functions ranging from regulation of the menstrual cycle and reproduction to modulation of bone density, brain function, and cholesterol mobilization. Despite the beneficial actions of endogenous estrogen, sustained exposure to exogenous estrogen is a well-established risk factor for various cancers. We summarize our current understanding of the molecular mechanisms of estrogen signaling in normal and cancer cells and discuss the major challenges to existing antiestrogen therapies. PMID:23043248

  8. [Estrogens and pharmacological modulation of estrogen receptors].

    PubMed

    Sanidize, T V; Ratiani, L R; Gabuniia, L Iu; Tortladze, M L; Kuridze, N N

    2009-02-01

    Estrogens belong to more or less frequently prescribed preparations. Main fields of application of these preparations (as in monotherapy as well as in combination) are contraception and hormone replacement therapy during menopause. More uncommon indications of estrogens are growth inhibition and hypogonadism (in this case they are prescribed along with gonadotropic hormones). Synthesis and metabolism of estrogens, as well as their intracellular receptors are well studied these days, which allow us to understand physiology and pharmacology of these hormones. In pharmacology the main stage is detection of estrogen receptors inside of cells of targets. There are two types of estrogen receptors alpha- and beta- coded by different genes. A number of steroid and non-steroid compounds have characteristics of estrogens. Likely in the future their popularity will increase, as by the aging of population number of those women, who receive replacement therapy, will increase. Investigations to find an ideal elective modulator of estrogen receptors, that will possess anti-estrogenic activity in connection with mammal gland and develop indifference in connection with endometrium and at the same time will display ability to reduce hot flushes, bone resorption, atrophy of mucous membranes of vagina and urinary bladder, as well as it will favorably effect on metabolism of lipoproteins are carried out. PMID:19276483

  9. Estrogens, inflammation and cognition.

    PubMed

    Au, April; Feher, Anita; McPhee, Lucy; Jessa, Ailya; Oh, Soojin; Einstein, Gillian

    2016-01-01

    The effects of estrogens are pleiotropic, affecting multiple bodily systems. Changes from the body's natural fluctuating levels of estrogens, through surgical removal of the ovaries, natural menopause, or the administration of exogenous estrogens to menopausal women have been independently linked to an altered immune profile, and changes to cognitive processes. Here, we propose that inflammation may mediate the relationship between low levels of estrogens and cognitive decline. In order to determine what is known about this connection, we review the literature on the cognitive effects of decreased estrogens due to oophorectomy or natural menopause, decreased estrogens' role on inflammation - both peripherally and in the brain - and the relationship between inflammation and cognition. While this review demonstrates that much is unknown about the intersection between estrogens, cognition, inflammation, we propose that there is an important interaction between these literatures. PMID:26774208

  10. Estrogens, cartilage, and osteoarthritis.

    PubMed

    Richette, Pascal; Corvol, Maïté; Bardin, Thomas

    2003-08-01

    A role for estrogens in osteoarthritis is consistent with the larger increases in women than in men in the incidence and prevalence of hip, knee, and finger osteoarthritis after 50 years of age. Furthermore, hormone replacement therapy for the menopause seems to be associated with a decrease in the prevalence of symptoms and radiological alterations related to hip and knee osteoarthritis. The two estrogen receptors alpha and beta (ERalpha and Erbeta) have been identified in normal and osteoarthritic cartilage, indicating that cartilage can respond to estrogens. Finally, in vivo experiments in animals and in vitro studies have shed light on the mechanisms by which estrogens may influence chondrocyte metabolism. PMID:12951307

  11. The Measurement of Estrogens

    NASA Astrophysics Data System (ADS)

    Holder, Geoff; Makin, Hugh L. J.; Bradlow, H. Leon

    Biologists use the word ‘estrogen' when referring to molecules which have the ability to induce uterine growth or vaginal cornification in the immature or ovariectomized rodent. The word estrogen was derived from two Greek words - oistros meaning frenzy and gennein - to beget. Chemists and biochemists, however, often restrict their use of this term to molecules that contain a characteristic 18-carbon steroid nucleus with an aromatic (phenolic) A-ring, both those that are biologically active estrogens and those without biologic activity but which are of intrinsic interest, such as the estrogen conjugates. This chapter is concerned only with these steroid compounds. The structure and inter-relationship of some common estrogens are given in Fig. 8.1. In addition to the biological estrogens, there are a wide variety of both natural and synthetic compounds which have estrogenic activity when measured by one or another parameter. While many of the assay procedures described in this review are applicable to these compounds, their application to non C18-steroids will not be discussed here. Methodology for these non-steroidal compounds can be found in reviews by Wang et al. (2002), Wu et al. (2004), Muir (2006), and Delmonte and Rader (2006). While not wishing to downgrade the importance of previous work in the estrogen field, the authors have taken a deliberate decision to exclude most publications prior to 1975, not because these do not have value but simply because space is not unlimited and readers of the present chapter might be expected to be seeking information about methodology which is less than 30 years old. Readers seeking pre-1975 information in this area can find it in Oakey and Holder (1995).

  12. Removal of estrogens and estrogenicity through drinking water treatment.

    PubMed

    Schenck, Kathleen; Rosenblum, Laura; Wiese, Thomas E; Wymer, Larry; Dugan, Nicholas; Williams, Daniel; Mash, Heath; Merriman, Betty; Speth, Thomas

    2012-03-01

    Estrogenic compounds have been shown to be present in surface waters, leading to concerns over their possible presence in finished drinking waters. In this work, two in vitro human cell line bioassays for estrogenicity were used to evaluate the removal of estrogens through conventional drinking water treatment using a natural water. Bench-scale studies utilizing chlorine, alum coagulation, ferric chloride coagulation, and powdered activated carbon (PAC) were conducted using Ohio River water spiked with three estrogens, 17β-estradiol, 17α-ethynylestradiol, and estriol. Treatment of the estrogens with chlorine, either alone or with coagulant, resulted in approximately 98% reductions in the concentrations of the parent estrogens, accompanied by formation of by-products. The MVLN reporter gene and MCF-7 cell proliferation assays were used to characterize the estrogenic activity of the water before and after treatment. The observed estrogenic activities of the chlorinated samples showed that estrogenicity of the water was reduced commensurate with removal of the parent estrogen. Therefore, the estrogen chlorination by-products did not contribute appreciably to the estrogenic activity of the water. Coagulation alone did not result in significant removals of the estrogens. However, addition of PAC, at a typical drinking water plant dose, resulted in removals ranging from approximately 20 to 80%. PMID:22361701

  13. Removal of Estrogens and Estrogenicity through Drinking Water Treatment

    EPA Science Inventory

    Estrogenic compounds have been shown to be present in surface waters, leading to concerns over their possible presence in finished drining waters. In this work, two in vitro human cell line bioassays for estrogenicity were used to evaluate the removal of estrogens through conven...

  14. Estrogen receptors and endothelium.

    PubMed

    Arnal, Jean-François; Fontaine, Coralie; Billon-Galés, Audrey; Favre, Julie; Laurell, Henrik; Lenfant, Françoise; Gourdy, Pierre

    2010-08-01

    Estrogens, and in particular 17beta-estradiol (E2), play a pivotal role in sexual development and reproduction and are also implicated in a large number of physiological processes, including the cardiovascular system. Both acetylcholine-induced and flow-dependent vasodilation are preserved or potentiated by estrogen treatment in both animal models and humans. Indeed, E2 increases the endothelial production of nitric oxide and prostacyclin and prevents early atheroma through endothelial-mediated mechanisms. Furthermore, whereas it prevents endothelial activation, E2 potentiates the ability of several subpopulations of the circulating or resident immune cells to produce proinflammatory cytokines. The balance between these 2 actions could determine the final effect in a given pathophysiological process. E2 also promotes endothelial healing, as well as angiogenesis. Estrogen actions are essentially mediated by 2 molecular targets: estrogen receptor-alpha (ERalpha) and ERbeta. The analysis of mouse models targeted for ERalpha or ERbeta demonstrated a prominent role of ERalpha in vascular biology. ERalpha directly modulates transcription of target genes through 2 activation functions (AFs), AF-1 and AF-2. Interestingly, an AF-1-deficient ERalpha isoform can be physiologically expressed in the endothelium and appears sufficient to mediate most of the vasculoprotective actions of E2. In contrast, AF-1 is necessary for the E2 actions in reproductive targets. Thus, it appears conceivable to uncouple the vasculoprotective and sexual actions with appropriate selective ER modulators. PMID:20631350

  15. Estrogens and autoimmune diseases.

    PubMed

    Cutolo, Maurizio; Capellino, Silvia; Sulli, Alberto; Serioli, Bruno; Secchi, Maria Elena; Villaggio, Barbara; Straub, Rainer H

    2006-11-01

    Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune-suppressors . Several physiological, pathological, and therapeutic conditions may change the serum estrogen milieu and/or peripheral conversion rate, including the menstrual cycle, pregnancy, postpartum period, menopause, being elderly, chronic stress, altered circadian rhythms, inflammatory cytokines, and use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. In particular, cortisol and melatonin circadian rhythms are altered, at least in rheumatoid arthritis (RA), and partially involve sex hormone circadian synthesis and levels as well. Abnormal regulation of aromatase activity (i.e., increased activity) by inflammatory cytokine production (i.e., TNF-alpha, IL-1, and IL-6) may partially explain the abnormalities of peripheral estrogen synthesis in RA (i.e., increased availability of 17-beta estradiol and possible metabolites in synovial fluids) and in systemic lupus erythematosus, as well as the altered serum sex-hormone levels and ratio (i.e., decreased androgens and DHEAS). In the synovial fluids of RA patients, the increased estrogen concentration is observed in both sexes and is more specifically characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, which is a mitogenic and cell proliferative endogenous hormone. Local effects of sex hormones in autoimmune rheumatic diseases seems to consist mainly in modulation of cell proliferation and cytokine production (i.e., TNF-alpha, Il-1, IL-12). In this respect, it is interesting that male patients with RA seem to profit more from anti-TNFalpha strategies than do female patients. PMID:17261796

  16. Estrogens and endometrial carcinoma.

    PubMed

    Gray, L A; Christopherson, W M; Hoover, R N

    1977-04-01

    A group of 205 women with endometrial carcinoma was matched for age, parity, and year of operation with a group of 205 women who had had hysterectomies for benign disease. In the former group, 32 patients had used conjugated estrogens, while in the latter group 12 had used this hormone, yielding a relative risk of 3.1 (P = 0.0008). Users of other forms of systemic estrogens showed similar elevations in relative risk. Relative risk was related to duration of use, progressing from no evidence of risk among those using the hormone for less than 5 years to an 11.5-fold greater risk for those using it for 10 years or more. Risk was also related to the strength of the medication. The relative risk for users of the 1.25-mg tablets was 12.7 as compared to a two- to fourfold greater risk among users of lesser strength tablets. PMID:193072

  17. Estrogen Metabolism and Breast Cancer

    PubMed Central

    Samavat, Hamed; Kurzer, Mindy S

    2015-01-01

    There is currently accumulating evidence that endogenous estrogens play a critical role in the development of breast cancer. Estrogens and their metabolites have been studied in both pre- and postmenopausal women with more consistent results shown in the latter population, in part because of large hormonal variations during the menstrual cycle and far fewer studies having been performed in premenopausal women. In this review we describe in detail estrogen metabolism and associated genetic variations, and provide a critical review of the current literature regarding the role of estrogens and their metabolites in breast cancer risk. PMID:24784887

  18. Exercise, Eating, Estrogen, and Osteoporosis.

    ERIC Educational Resources Information Center

    Brown, Jim

    1986-01-01

    Osteoporosis affects millions of people, especially women. Three methods for preventing or managing osteoporosis are recommended: (1) exercise; (2) increased calcium intake; and (3) estrogen replacement therapy. (CB)

  19. Estrogen receptor scintigraphy.

    PubMed

    Scheidhauer, K; Scharl, A; Schicha, H

    1998-03-01

    Radio-labeled estrogen receptor ligands are tracers that can be used for functional receptor diagnosis. Their specificity towards receptors, together with the fact that only 50-70% of mammary carcinomas are receptor positive, renders them unsuitable for detection of primary tumors or metastases, and this means that estrogen receptor scintigraphy can be used neither for tumor screening nor for staging. However, both 18F-labeled and 123I-labeled estradiol derivatives are suitable for in vivo imaging of estrogen receptors. Their high specificity, established in animal experiments and in vitro studies has been reproduced in in vivo applications in humans. Tracers with positron radiation emitters are, however, hardly suitable for broad application owing to the short half-life of 18F, which would mean that users would need to be situated close to a cyclotron and a correspondingly equipped radiochemical laboratory. The number of available PET scanners, on the other hand, has increased over the last few years, especially in Germany, so that this, at least, does not present a limiting factor. All the same, 123I-labeled estradiol derivatives will find more widespread application, since the number of gamma-cameras incorporating modern multi-head systems is several times greater. The results of studies with 123I-E2-scintigraphy published to date are very promising, even given the initial technical problems mentioned above. As a method of examination, it could be optimised by using improved tracers with a higher tumor contrast and less disturbance from overlapping in diagnostically relevant locations, for instance, by selecting tracers with higher activities whose excretion is more renal than hepatobiliary. The use of modern multi-head camera systems can also be expected to improve the photon yield. PMID:9646642

  20. Selective Estrogen Receptor Modulators

    PubMed Central

    2016-01-01

    Selective estrogen receptor modulators (SERMs) are now being used as a treatment for breast cancer, osteoporosis and postmenopausal symptoms, as these drugs have features that can act as an estrogen agonist and an antagonist, depending on the target tissue. After tamoxifen, raloxifene, lasofoxifene and bazedoxifene SERMs have been developed and used for treatment. The clinically decisive difference among these drugs (i.e., the key difference) is their endometrial safety. Compared to bisphosphonate drug formulations for osteoporosis, SERMs are to be used primarily in postmenopausal women of younger age and are particularly recommended if there is a family history of invasive breast cancer, as their use greatly reduces the incidence of this type of cancer in women. Among the above mentioned SERMs, raloxifene has been widely used in prevention and treatment of postmenopausal osteoporosis and vertebral compression fractures, and clinical studies are now underway to test the comparative advantages of raloxifene with those of bazedoxifene, a more recently developed SERM. Research on a number of adverse side effects of SERM agents is being performed to determine the long-term safety of this class of compouds for treatment of osteoporosis. PMID:27559463

  1. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    PubMed

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter. PMID:26585147

  2. Estrogen receptor signaling during vertebrate development

    PubMed Central

    Bondesson, Maria; Hao, Ruixin; Lin, Chin-Yo; Williams, Cecilia; Gustafsson, Jan-Åke

    2014-01-01

    Estrogen receptors are expressed and their cognate ligands produced in all vertebrates, indicative of important and conserved functions. Through evolution estrogen has been involved in controlling reproduction, affecting both the development of reproductive organs and reproductive behavior. This review broadly describes the synthesis of estrogens and the expression patterns of aromatase and the estrogen receptors, in relation to estrogen functions in the developing fetus and child. We focus on the role of estrogens for development of reproductive tissues, as well as non-reproductive effects on the developing brain. We collate data from human, rodent, bird and fish studies and highlight common and species-specific effects of estrogen signaling on fetal development. Morphological malformations originating from perturbed estrogen signaling in estrogen receptor and aromatase knockout mice are discussed, as well as the clinical manifestations of rare estrogen receptor alpha and aromatase gene mutations in humans. PMID:24954179

  3. Estrogen Signaling in Metabolic Inflammation

    PubMed Central

    Monteiro, Rosário; Teixeira, Diana; Calhau, Conceição

    2014-01-01

    There is extensive evidence supporting the interference of inflammatory activation with metabolism. Obesity, mainly visceral obesity, is associated with a low-grade inflammatory state, triggered by metabolic surplus where specialized metabolic cells such as adipocytes activate cellular stress initiating and sustaining the inflammatory program. The increasing prevalence of obesity, resulting in increased cardiometabolic risk and precipitating illness such as cardiovascular disease, type 2 diabetes, fatty liver, cirrhosis, and certain types of cancer, constitutes a good example of this association. The metabolic actions of estrogens have been studied extensively and there is also accumulating evidence that estrogens influence immune processes. However, the connection between these two fields of estrogen actions has been underacknowledged since little attention has been drawn towards the possible action of estrogens on the modulation of metabolism through their anti-inflammatory properties. In the present paper, we summarize knowledge on the modification inflammatory processes by estrogens with impact on metabolism and highlight major research questions on the field. Understanding the regulation of metabolic inflammation by estrogens may provide the basis for the development of therapeutic strategies to the management of metabolic dysfunctions. PMID:25400333

  4. Estrogens, breast cancer, and intestinal flora.

    PubMed

    Gorbach, S L

    1984-01-01

    Epidemiologic evidence has linked diet to breast cancer, with the highest cancer rates observed in women who eat a high fat-low fiber diet. There is also substantial information, both clinical and experimental, that implicates estrogens in the etiology of breast cancer. A recent study from our laboratory has shown that diet influences levels of estrogens, and the main mechanism is metabolism of estrogens in the intestine. The intestinal microflora plays a key role in the enterohepatic circulation of estrogens by deconjugating bound estrogens that appear in the bile, thereby permitting the free hormones to be reabsorbed. By suppressing the microflora with antibiotic therapy, fecal estrogens increase and urinary estrogens decrease, changes indicating diminished intestinal reabsorption. A low fat-high fiber diet is associated with similar findings-high fecal estrogens and low urinary estrogens. It appears that the microflora plays a key role in the metabolism of female sex hormones. PMID:6326245

  5. Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids.

    PubMed

    Han, Dal-Ho; Denison, Michael S; Tachibana, Hirofumi; Yamada, Koji

    2002-07-01

    In this study, we investigated the estrogenic activity of environmental estrogens by a competition binding assay using a human recombinant estrogens receptor (hERbeta) and by a proliferation assay using MCF-7 cells and a sulforhodamine-B assay. In the binding assay, pharmaceuticals had a stronger binding activity to hERbeta than that of some phytoestrogens (coumestrol, daidzein, genistein, luteolin, chrysin, flavone, and naringenin) or industrial chemicals, but phytoestrogens such as coumestrol had a binding activity as strong as pharmaceuticals such as 17alpha-ethynylestradiol (EE), tamoxifen (Tam), and mestranol. In the proliferation assay, pharmaceuticals such as diethylstilbestrol, EE, Tam, and clomiphene, and industrial chemicals such as 4-nonylphenol, bisphenol A, and 4-dihydroxybiphenyl had a proliferation-stimulating activity as strong as 17beta-estradiol (ES). In addition, we found that phytoestrogens such as coumestrol, daidzein, luteolin, and quercetin exerted a proliferation stimulating activity as strong as ES. Furthermore, we examined the suppression of proliferation-stimulating activity, induced by environmental estrogen, by flavonoids, such as daidzein, genistein, quercetin, and luteolin, and found that these flavonoids suppressed the induction of the proliferation-stimulating activity of environmental estrogens. The suppressive effect of flavonoids suggests that these compounds have anti-estrogenic and anti-cancer activities. PMID:12224631

  6. Estrogenic profile on a water-soluble estrogen, estrazinol hydrobromide.

    PubMed

    Rassaert, C L; DiPasquale, G; Giannina, T; Manning, J P; Meli, A

    1973-01-01

    The estrogenic properties of estrazinol hydrobromide (EZ), a water-soluble estrogen, were compared with those of Premarin (PR), another water-soluble estrogen preparation consisting of conjugated equine estrogens. Estradiol-17beta, estra-1,3,5(10)-triene-3,17beta-diol (E), and ethinyl estradiol, 17alpha-ethinyl-1,3,5 (10)-estratriene-3,17beta-diol (EE) were used as reference standards. Subcutaneous progesterone (400 mcg) given to rabbits primed with comparable subcutaneous doses of either E or EE produced full secretory changes of the endometrium, while such a transformation could not be elicited in orally primed animals regardless of the estrogen used. The biological profile or orally administered EZ was very similar to that of oral EE and different from oral PR. Howerver, the oral EZ-induced morphological changes of the rabbit endometrium appeared somewhat different from those produced by oral EE. The findings indicated that following oral administration, EZ-induced endometrial transformation is more "normal" and/or adequate than the changes produced by either EE or PR. PMID:4368700

  7. VASCULAR ACTIONS OF ESTROGENS: FUNCTIONAL IMPLICATIONS

    PubMed Central

    Miller, Virginia M.; Duckles, Sue P.

    2009-01-01

    The impact of estrogen exposure in preventing or treating cardiovascular disease is controversial. But it is clear that estrogen has important effects on vascular physiology and pathophysiology, with potential therapeutic implications. Therefore, it is the goal of this review to summarize, using an integrated approach, current knowledge of the vascular effects of estrogen, both in humans and in experimental animals. Aspects of estrogen synthesis and receptors, as well as general mechanisms of estrogenic action are reviewed with an emphasis on issues particularly relevant to the vascular system. Recent understanding of the impact of estrogen on mitochondrial function suggests that the longer lifespan of women compared to men may depend in part on the ability of estrogen to decrease production of reactive oxygen species in mitochondria. Mechanisms by which estrogen increases endothelial vasodilator function, promotes angiogenesis and modulates autonomic function are summarized. Key aspects of the relevant pathophysiology of inflammation, atherosclerosis, stroke, migraine and thrombosis are reviewed concerning current knowledge of estrogenic effects. A number of emerging concepts are addressed throughout. These include the importance of estrogenic formulation and route of administration and the impact of genetic polymorphisms, either in estrogen receptors or in enzymes responsible for estrogen metabolism, on responsiveness to hormone treatment. The importance of local metabolism of estrogenic precursors and the impact of timing for initiation of treatment and its duration are also considered. While consensus opinions are emphasized, controversial views are presented in order to stimulate future research. PMID:18579753

  8. Effects of pinostrobin on estrogen metabolism and estrogen receptor transactivation.

    PubMed

    Le Bail, J C; Aubourg, L; Habrioux, G

    2000-08-01

    The interaction between the estrogen receptor and 5-hydroxy-7-methoxyflavanone (pinostrobin) was studied in the presence or absence of estradiol or dehydroepiandrosterone sulfate (DHEAS), respectively, using a stably transfected human breast cancer cell line (MVLN). We also evaluated its action on the proliferation in estrogen-dependent (MCF-7) human breast cancer cells in the same conditions than the estrogen receptor assay. On the other hand pinostrobin was evaluated for their effects on the human placental aromatase, 3beta-hydroxysteroid dehydrogenase Delta(4)/Delta(5) isomerase and 17beta-hydroxysteroid dehydrogenase activities. Pinostrobin did not possess antiestrogenic activity but presented anti-aromatase activity and decreased the growth of MCF-7 cells induced by DHEAS and E(2). This study provides particularly evidence of the potential biological interest of pinostrobin among the flavonoids. PMID:10840157

  9. ERGDB: Estrogen Responsive Genes Database.

    PubMed

    Tang, Suisheng; Han, Hao; Bajic, Vladimir B

    2004-01-01

    ERGDB is an integrated knowledge database dedicated to genes responsive to estrogen. Genes included in ERGDB are those whose expression levels are experimentally proven to be either up-regulated or down-regulated by estrogen. Genes included are identified based on publications from the PubMed database and each record has been manually examined, evaluated and selected for inclusion by biologists. ERGDB aims to be a unified gateway to store, search, retrieve and update information about estrogen responsive genes. Each record contains links to relevant databases, such as GenBank, LocusLink, Refseq, PubMed and ATCC. The unique feature of ERGDB is that it contains information on the dependence of gene reactions on experimental conditions. In addition to basic information about the genes, information for each record includes gene functional description, experimental methods used, tissue or cell type, gene reaction, estrogen exposure time and the summary of putative estrogen response elements if the gene's promoter sequence was available. Through a web interface at http://sdmc.i2r.a-star.edu.sg/ergdb/ cgi-bin/explore.pl users can either browse or query ERGDB. Access is free for academic and non-profit users. PMID:14681475

  10. Mixture interactions of xenoestrogens with endogenous estrogens.

    EPA Science Inventory

    There is growing concern of exposure to fish, wildlife, and humans to water sources contaminated with estrogens and the potential impact on reproductive health. These environmental estrogens originate from various sources including concentrated animal feedlot operations (CAFO), m...

  11. Estrogen Treatment in Multiple Sclerosis

    PubMed Central

    Gold, Stefan M; Voskuhl, Rhonda R

    2009-01-01

    Currently available treatments for multiple sclerosis reduce inflammatory lesions on MRI and decrease clinical relapses but have limited effects on disability. Novel treatment options that target both the inflammatory as well as the neurodegenerative component of the disease are therefore needed. A growing body of evidence from basic science and clinical studies supports the therapeutic potential of estrogens in MS. Mechanisms of action include both immunomodulatory and directly neuroprotective pathways. A first pilot trial of oral estriol treatment showed encouraging results. There are now several phase II trials underway to further determine the efficacy of estrogen treatment in MS. PMID:19539954

  12. Estrogens and Male Lower Urinary Tract Dysfunction

    PubMed Central

    Wynder, Jalissa L.; Nicholson, Tristan M.; DeFranco, Donald B.

    2016-01-01

    Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology and affect the majority of men at some time during their lives. The development of BPH/LUTS is associated with an increased ratio of estrogen to androgen levels, and this ratio, when mimicked in a variety of animals, induces BPH and lower urinary tract dysfunction (LUTD). While the precise molecular etiology remains unclear, estrogens have been implicated in the development and maintenance of BPH. Numerous endogenous and exogenous estrogens exist in humans. These estrogens act via multiple estrogen receptors to promote or inhibit prostatic hyperplasia and other BPH-associated processes. The prostate is an estrogen target tissue, and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of estrogen action directly affecting prostate growth and differentiation in the context of BPH is an understudied area and remains to be elucidated. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation illustrating their potential roles in the development of BPH as therapy. More work will be required to identify estrogen signaling pathways associated with LUTD in order to develop more efficacious drugs for BPH treatment and prevention. PMID:26156791

  13. Estrogen mediation of hormone responses to exercise.

    PubMed

    Kraemer, Robert R; Francois, Michelle; Castracane, V Daniel

    2012-10-01

    The roles of estrogens extend from the regulation of reproduction to other functions involved in control of metabolism, fluid balance, as well as gastrointestinal, lung, and brain function, with a strong effect on other hormones that subsequently alter the physiology of multiple tissues. As such, alteration of endogenous estrogens across the menstrual cycle, or from oral contraception and estrogen replacement therapy, can affect these tissues. Due to the important effects that estrogens have on different tissues, there are many investigations concerning the effects of a human estrogenic environment on endocrine responses to exercise. The following review will describe the consequences of varying estrogen levels on pituitary, adrenal, gonadal, and endocrine function, followed by discussion of the outcomes of different estrogen levels on endocrine tissues in response to exercise, problems encountered for interpretation of findings, and recommended direction for future research. PMID:22512823

  14. Targeted Radiotherapy of Estrogen Receptor Positive Tumors

    SciTech Connect

    Raghavan Rajagopalan

    2006-08-31

    The overall objectives of the proposal were to develop estrogen receptor (ER) binding small molecule radiopharmaceuticals for targeted radiotherapy of ER positive (ER+) tumors. In particular, this proposal focused on embedding a {sup 186,188}Re or a {sup 32}P radionuclide into an estrogen steroidal framework by isosteric substitution such that the resulting structure is topologically similar to the estrogen (estrogen mimic). The estrogen mimic molecules expected to bind to the ER and exhibit biodistribution akin to that of native estrogen due to structural mimicry. It is anticipated that the {sup 186,188}Re- or a {sup 32}P-containing estrogen mimics will be useful for targeted molecular radiotherapy of ER+ tumors. It is well established that the in vivo target tissue uptake of estrogen like steroidal molecules is related to the binding of the steroids to sex hormone binding globulin (SHBG). SHBG is important in the uptake of estrogens and testosterone in target tissues by SHBG receptors on the cell surface. However, hitherto the design of estrogen like small molecule radiopharmaceuticals was focused on optimizing ER binding characteristics without emphasis on SHBG binding properties. Consequently, even the molecules with good ER affinity in vitro, performed poorly in biodistribution studies. Based on molecular modeling studies the proposal focused on developing estrogen mimics 1-3 which were topologically similar to native estrogens, and form hydrogen bonds in ER and SHBG in the same manner as those of native estrogens. To this end the technical objectives of the proposal focused on synthesizing the rhenium-estrone and estradiol mimics 1 and 2 respectively, and phosphorous estradiol mimic 3 and to assess their stability and in vitro binding characteristics to ER and SHBG.

  15. [Carcinogenesis theory based on estrogen deficiency].

    PubMed

    Suba, Zsuzsanna

    2009-06-21

    Earlier, estrogens were considered simply the most important hormones involved in female physiology and reproduction. Nowadays it has become familiar that they have pivotal roles in gene regulation of cell differentiation and proliferation. There are many contradictions concerning the associations of female sexual steroids and cancer. Cancers of the highly estrogen dependent organs are in the forefront of tumors as they are regarded as hormone associated ones. However, re-evaluation of earlier results supporting the carcinogenic capacity of estrogen exhibited many shortcomings and controversies. Recently, the clinical studies on hormone replacement therapy in postmenopausal women justified beneficial anticancer effects in several organs even in the female breast. The newly revealed association between estrogen deficiency and oral cancer risk also means a contradiction of the traditional concept of estrogen-induced cancer. Distinction between cancers of moderately and highly estrogen dependent tumors can be based on their different epidemiological features. The vast majority of the so-called smoking associated malignancies of the moderately estrogen dependent organs occur typically in the late postmenopausal life of women when the ovarian estrogen production is fairly decreased. However cancers of the highly estrogen dependent organs such as breast, endometrium and ovary exhibit both premenopausal and postmenopausal occurrence. In spite of the different epidemiological data of these two groups of cancers the mechanism of gene regulation disorder in the background of tumor initiation cannot act through quite opposite pathways. This suggests that in moderately estrogen sensitive organs a serious, in the highly estrogen dependent sites even a mild estrogen deficiency is enough to provoke gene regulation disorders. The new findings both on smoking associated and hormone related cancers might lead to the same conversion; not estrogen but rather its deficiency may provoke

  16. The Estrogen Hypothesis of Obesity

    PubMed Central

    Grantham, James P.; Henneberg, Maciej

    2014-01-01

    The explanation of obesity as a simple result of positive energy balance fails to account for the scope of variable responses to diets and lifestyles. It is postulated that individual physiological and anatomical variation may be responsible for developing obesity. Girls in poor families develop greater adiposity than their male siblings, a trend not present in richer environments. This indicates strong influence of estrogen on fat accumulation irrespective of poor socioeconomic conditions. Obesity rates in males and females of developed nations are similar, while in poorer nations obesity is much more prevalent in females. Female to male ratio of obesity correlates inversely with gross domestic product. Therefore, the parity of male and female obesity in developed countries may result from male exposure to environmental estrogen-like substances associated with affluence. These hormonally driven mechanisms may be equally active within both sexes in more developed areas, thereby increasing overall obesity. PMID:24915457

  17. [Transdermal estrogenic therapy in menopause].

    PubMed

    Nencioni, T; Polvani, F; Penotti, M; Porcaro, E; Barbieri Carones, M

    1989-01-01

    The availability of percutaneous estrogenic preparations capable of directly entering the bloodstream, avoiding the liver, has opened new prospects in the treatment of the climacteric syndrome. The purpose of our work has been to compare the effectiveness and tolerability of a percutaneous 17-beta-estradiol-oral progestin association with an all oral association of conjugated estrogens and progestins and to evaluate the ability to control menopausal symptoms and biohumoral characteristics. 42 (1 to 7 years postmenopausal) heavily symptomatic patients were selected at the "Centro per lo studio e la terapia del climaterio" in Milan and divided in two equally sized groups. One group was treated using the percutaneous therapy, the other with the all-oral one. The results show that percutaneous administration leads to a quicker control of vasomotor symptomatology and metabolic effects similar to oral administration. PMID:2543896

  18. Estrogen receptor transcription and transactivation: Estrogen receptor knockout mice: what their phenotypes reveal about mechanisms of estrogen action.

    PubMed

    Curtis Hewitt, S; Couse, J F; Korach, K S

    2000-01-01

    Natural, synthetic and environmental estrogens have numerous effects on the development and physiology of mammals. Estrogen is primarily known for its role in the development and functioning of the female reproductive system. However, roles for estrogen in male fertility, bone, the circulatory system and immune system have been established by clinical observations regarding sex differences in pathologies, as well as observations following menopause or castration. The primary mechanism of estrogen action is via binding and modulation of activity of the estrogen receptors (ERs), which are ligand-dependent nuclear transcription factors. ERs are found in highest levels in female tissues critical to reproduction, including the ovaries, uterus, cervix, mammary glands and pituitary gland. Since other affected tissues have extremely low levels of ER, indirect effects of estrogen, for example induction of pituitary hormones that affect the bone, have been proposed. The development of transgenic mouse models that lack either estrogen or ER have proven to be valuable tools in defining the mechanisms by which estrogen exerts its effects in various systems. The aim of this article is to review the mouse models with disrupted estrogen signaling and describe the associated phenotypes. PMID:11250727

  19. ANALYSIS OF LAGOON SAMPLES FROM DIFFERENT CONCENTRATED ANIMAL FEEDING OPERATIONS FOR ESTROGENS AND ESTROGEN CONJUGATES

    EPA Science Inventory

    Although Concentrated Animal Feeding Operations CAFOs) have been identified as potentially important sources for the release of estrogens into the environment, information is lacking on the concentrations of estrogens in whole lagoon effluents (including suspended solids)which ar...

  20. The pesticides endosulfan, toxaphene, and dieldrin have estrogenic effects on human estrogen-sensitive cells.

    PubMed Central

    Soto, A M; Chung, K L; Sonnenschein, C

    1994-01-01

    Estrogenic pesticides such as DDT and chlordecone generate deleterious reproductive effects. An "in culture" bioassay was used to assess the estrogenicity of several pesticides. The E-screen test uses human breast estrogen-sensitive MCF7 cells and compares the cell yield achieved after 6 days of culture in medium supplemented with 5% charcoal-dextran stripped human serum in the presence (positive control) or absence (negative control) of estradiol and with diverse concentrations of xenobiotics suspected of being estrogenic. Among the organochlorine pesticides tested, toxaphene, dieldrin, and endosulfan had estrogenic properties comparable to those of DDT and chlordecone; the latter are known to be estrogenic in rodent models. The E-screen test also revealed that estrogenic chemicals may act cumulatively; when mixed together they induce estrogenic responses at concentrations lower than those required when each compound is administered alone. Images Figure 1. Figure 2. Figure 3. PMID:7925178

  1. Nongenomic Signaling Pathways of Estrogen Toxicity

    PubMed Central

    Watson, Cheryl S.; Jeng, Yow-Jiun; Kochukov, Mikhail Y.

    2010-01-01

    Xenoestrogens can affect the healthy functioning of a variety of tissues by acting as potent estrogens via nongenomic signaling pathways or by interfering with those actions of multiple physiological estrogens. Collectively, our and other studies have compared a wide range of estrogenic compounds, including some closely structurally related subgroups. The estrogens that have been studied include environmental contaminants of different subclasses, dietary estrogens, and several prominent physiological metabolites. By comparing the nongenomic signaling and functional responses to these compounds, we have begun to address the structural requirements for their actions through membrane estrogen receptors in the pituitary, in comparison to other tissues, and to gain insights into their typical non-monotonic dose-response behavior. Their multiple inputs into cellular signaling begin processes that eventually integrate at the level of mitogen-activated protein kinase activities to coordinately regulate broad cellular destinies, such as proliferation, apoptosis, or differentiation. PMID:19955490

  2. Distinct Effects of Estrogen on Mouse Maternal Behavior: The Contribution of Estrogen Synthesis in the Brain

    PubMed Central

    Murakami, Gen

    2016-01-01

    Estrogen surge following progesterone withdrawal at parturition plays an important role in initiating maternal behavior in various rodent species. Systemic estrogen treatment shortens the latency to onset of maternal behavior in nulliparous female rats that have not experienced parturition. In contrast, nulliparous laboratory mice show rapid onset of maternal behavior without estrogen treatment, and the role of estrogen still remains unclear. Here the effect of systemic estrogen treatment (for 2 h, 1 day, 3 days, and 7 days) after progesterone withdrawal was examined on maternal behavior of C57BL/6 mice. This estrogen regimen led to different effects on nursing, pup retrieval, and nest building behaviors. Latency to nursing was shortened by estrogen treatment within 2 h. Moreover, pup retrieval and nest building were decreased. mRNA expression was also investigated for estrogen receptor α (ERα) and for genes involved in regulating maternal behavior, specifically, the oxytocin receptor (OTR) and vasopressin receptor in the medial amygdala (MeA) and medial preoptic area (MPOA). Estrogen treatment led to decreased ERα mRNA in both regions. Although OTR mRNA was increased in the MeA, OTR and vasopressin receptor mRNA were reduced in the MPOA, showing region-dependent transcription regulation. To determine the mechanisms for the actions of estrogen treatment, the contribution of estrogen synthesis in the brain was examined. Blockade of estrogen synthesis in the brain by systemic letrozole treatment in ovariectomized mice interfered with pup retrieval and nest building but not nursing behavior, indicating different contributions of estrogen synthesis to maternal behavior. Furthermore, letrozole treatment led to an increase in ERα mRNA in the MeA but not in the MPOA, suggesting that involvement of estrogen synthesis is brain region dependent. Altogether, these results suggest that region-dependent estrogen synthesis leads to differential transcriptional activation due

  3. Distinct Effects of Estrogen on Mouse Maternal Behavior: The Contribution of Estrogen Synthesis in the Brain.

    PubMed

    Murakami, Gen

    2016-01-01

    Estrogen surge following progesterone withdrawal at parturition plays an important role in initiating maternal behavior in various rodent species. Systemic estrogen treatment shortens the latency to onset of maternal behavior in nulliparous female rats that have not experienced parturition. In contrast, nulliparous laboratory mice show rapid onset of maternal behavior without estrogen treatment, and the role of estrogen still remains unclear. Here the effect of systemic estrogen treatment (for 2 h, 1 day, 3 days, and 7 days) after progesterone withdrawal was examined on maternal behavior of C57BL/6 mice. This estrogen regimen led to different effects on nursing, pup retrieval, and nest building behaviors. Latency to nursing was shortened by estrogen treatment within 2 h. Moreover, pup retrieval and nest building were decreased. mRNA expression was also investigated for estrogen receptor α (ERα) and for genes involved in regulating maternal behavior, specifically, the oxytocin receptor (OTR) and vasopressin receptor in the medial amygdala (MeA) and medial preoptic area (MPOA). Estrogen treatment led to decreased ERα mRNA in both regions. Although OTR mRNA was increased in the MeA, OTR and vasopressin receptor mRNA were reduced in the MPOA, showing region-dependent transcription regulation. To determine the mechanisms for the actions of estrogen treatment, the contribution of estrogen synthesis in the brain was examined. Blockade of estrogen synthesis in the brain by systemic letrozole treatment in ovariectomized mice interfered with pup retrieval and nest building but not nursing behavior, indicating different contributions of estrogen synthesis to maternal behavior. Furthermore, letrozole treatment led to an increase in ERα mRNA in the MeA but not in the MPOA, suggesting that involvement of estrogen synthesis is brain region dependent. Altogether, these results suggest that region-dependent estrogen synthesis leads to differential transcriptional activation due

  4. Unbalanced estrogen metabolism in ovarian cancer.

    PubMed

    Zahid, Muhammad; Beseler, Cheryl L; Hall, James B; LeVan, Tricia; Cavalieri, Ercole L; Rogan, Eleanor G

    2014-05-15

    Greater exposure to estrogens is a risk factor for ovarian cancer. To investigate the role of estrogens in ovarian cancer, a spot urine sample and a saliva sample were obtained from 33 women with ovarian cancer and 34 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed in the urine samples using ultraperformance liquid chromatography/tandem mass spectrometry, and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates was significantly higher in cases compared to controls (p < 0.0001), demonstrating high specificity and sensitivity. DNA was purified from the saliva samples and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes. Women with two low-activity alleles of catechol-O-methyltransferase plus one or two high-activity alleles of cytochrome P450 1B1 had higher levels of estrogen-DNA adducts and were more likely to have ovarian cancer. These findings indicate that estrogen metabolism is unbalanced in ovarian cancer and suggest that formation of estrogen-DNA adducts plays a critical role in the initiation of ovarian cancer. PMID:24170413

  5. Estrogens and Cognition: Friends or Foes?

    PubMed Central

    Korol, Donna L.; Pisani, Samantha L.

    2015-01-01

    Estrogens are becoming well known for their robust enhancement on cognition particularly for learning and memory that relies upon functioning of the hippocampus and related neural systems. What is also emerging is that estrogen modulation of cognition is not uniform, at times enhancing yet at other times impairing learning. This review explores the bidirectional effects of estrogens on learning from a multiple memory systems view, focusing on the hippocampus and striatum, whereby modulation by estrogens sorts according to task attributes and neural systems engaged during cognition. We highlight our findings that show the ability to solve hippocampus-sensitive tasks typically improves under relatively high estrogen status while the ability to solve striatum-sensitive tasks degrades with estrogen exposures. Though constrained by dose and timing of exposure, these opposing enhancements and impairments of cognition can be observed following treatments with different estrogenic compounds including the hormone estradiol, the isoflavone genistein found in soybeans, and agonists that are selective for specific estrogen receptors, suggesting that activation of a single receptor type is sufficient to produce the observed shifts in learning strategies. Using this multi-dimensional framework will allow us to extend our thinking of the relationship between estrogens and cognition to other brain regions and cognitive functions. PMID:26149525

  6. Analysis of lagoon samples from different concentrated animal feeding operations for estrogens and estrogen conjugates.

    PubMed

    Hutchins, Stephen R; White, Mark V; Hudson, Felisa M; Fine, Dennis D

    2007-02-01

    Although Concentrated Animal Feeding Operations (CAFOs) have been identified as potentially important sources for the release of estrogens into the environment, information is lacking on the concentrations of estrogens in whole lagoon effluents (including suspended solids) which are used for land application. Lagoons associated with swine, poultry, and cattle operations were sampled at three locations each for direct analysis for estrogens by GC/ MS/MS and estrogen conjugates by LC/MS/MS. Estrogen conjugates were also analyzed indirectly by first subjecting the same samples to enzyme hydrolysis. Solids from centrifuged samples were extracted for free estrogens to estimate total estrogen load. Total free estrogen levels (estrone, 17alpha-estradiol, 17beta-estradiol, estriol) were generally higher in swine primary (1000-21000 ng/L), followed by poultry primary (1800-4000 ng/L), dairy secondary (370-550 ng/L), and beef secondary (22-24 ng/L) whole lagoon samples. Swine and poultry lagoons contained levels of 17(alpha-estradiol comparable to those of 17beta-estradiol. Confirmed estrogen conjugates included estrone-3-sulfate (2-91 ng/L), 17beta-estradiol-3-sulfate (8-44 ng/L), 17alpha-estradiol-3-sulfate (141-182 ng/L), and 17beta-estradiol-17-sulfate (72-84 ng/L) in some lagoons. Enzymatic hydrolysis indicated the presence of additional unidentified estrogen conjugates not detected bythe LC/MS/MS method. In most cases estrogen conjugates accounted for at least a third of the total estrogen equivalents. Collectively, these methods can be used to better determine estrogen loads from CAFO operations, and this research shows that estrogen conjugates contribute significantly to the overall estrogen load, even in different types of CAFO lagoons. PMID:17328177

  7. Role of estrogen in avian osteoporosis.

    PubMed

    Beck, M M; Hansen, K K

    2004-02-01

    One of the difficulties associated with commercial layer production is the development of osteoporosis in hens late in the production cycle. In light of this fact and because of hens' unique requirements for Ca, many studies have focused on the regulation of Ca and the role of estrogen in this process. The time course of estrogen synthesis over the productive life of hens has been well documented; increased circulating estrogen accompanies the onset of sexual maturity while decreases signal a decline in egg production prior to a molt. Numbers of estrogen receptors decrease with age in numerous tissues. The parallel changes in calcium-regulating proteins, primarily Calbindin D28K, and in the ability of duodenal cells to transport Ca, are thought to occur as a result of the changes in estrogen, and are also reversible by the molt process. In addition to the traditional model of estrogen action, evidence now exists for a possible nongenomic action of estrogen via membrane-bound receptors, demonstrated by extremely rapid surges of ionized Ca in chicken granulosa cells in response to 17beta-estradiol. Estrogen receptors have also been discovered in duodenal tissue, and tamoxifen, which binds to the estrogen receptor, has been shown to cause a rapid increase in Ca transport in the duodenum. In addition, recent evidence also suggests that mineralization of bone per se may not explain entirely the etiology of osteoporosis in the hen but that changes in the collagen matrix may contribute through decreases in bone elasticity. Taken together, these studies suggest that changes in estrogen synthesis and estrogen receptor populations may underlie the age-related changes in avian bone. As with postmenopausal women, dietary Ca and vitamin D are of limited benefit as remedies for osteoporosis in the hen. PMID:14979570

  8. Quantum chemical studies of estrogenic compounds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Quantum chemical methods are potent tools to provide information on the chemical structure and electronic properties of organic molecules. Modern computational chemistry methods have provided a great deal of insight into the binding of estrogenic compounds to estrogenic receptors (ER), an important ...

  9. Vascular Effects of Estrogenic Menopausal Hormone Therapy

    PubMed Central

    Reslan, Ossama M.; Khalil, Raouf A.

    2011-01-01

    Cardiovascular disease (CVD) is more common in men and postmenopausal women (Post-MW) than premenopausal women (Pre-MW). Despite recent advances in preventive measures, the incidence of CVD in women has shown a rise that matched the increase in the Post-MW population. The increased incidence of CVD in Post-MW has been related to the decline in estrogen levels, and hence suggested vascular benefits of endogenous estrogen. Experimental studies have identified estrogen receptor ERα, ERβ and a novel estrogen binding membrane protein GPR30 (GPER) in blood vessels of humans and experimental animals. The interaction of estrogen with vascular ERs mediates both genomic and non-genomic effects. Estrogen promotes endothelium-dependent relaxation by increasing nitric oxide, prostacyclin, and hyperpolarizing factor. Estrogen also inhibits the mechanisms of vascular smooth muscle (VSM) contraction including [Ca2+]i, protein kinase C and Rho-kinase. Additional effects of estrogen on the vascular cytoskeleton, extracellular matrix, lipid profile and the vascular inflammatory response have been reported. In addition to the experimental evidence in animal models and vascular cells, initial observational studies in women using menopausal hormonal therapy (MHT) have suggested that estrogen may protect against CVD. However, randomized clinical trials (RCTs) such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI), which examined the effects of conjugated equine estrogens (CEE) in older women with established CVD (HERS) or without overt CVD (WHI), failed to demonstrate protective vascular effects of estrogen treatment. Despite the initial set-back from the results of MHT RCTs, growing evidence now supports the ‘timing hypothesis’, which suggests that MHT could increase the risk of CVD if started late after menopause, but may produce beneficial cardiovascular effects in younger women during the perimenopausal period. The choice of

  10. Differential estrogen receptor binding of estrogenic substances: a species comparison.

    PubMed

    Matthews, J; Celius, T; Halgren, R; Zacharewski, T

    2000-11-15

    The study investigated the ability of 34 natural and synthetic chemicals to compete with [3H]17beta-estradiol (E2) for binding to bacterially expressed glutathione-S-transferase (GST)-estrogen receptors (ER) fusion proteins from five different species. Fusion proteins consisted of the ER D, E and F domains of human alpha (GST-hERalphadef), mouse alpha (GST-mERalphadef), chicken (GST-cERdef), green anole (GST-aERdef) and rainbow trout ERs (GST-rtERdef). All five fusion proteins displayed high affinity for E2 with dissociation constants (K(d)) ranging from 0.3 to 0.9 nM. Although, the fusion proteins exhibited similar binding preferences and binding affinities for many of the chemicals, several differences were observed. For example, alpha-zearalenol bound with greater affinity to GST-rtERdef than E2, which was in contrast to other GST-ERdef fusion proteins examined. Coumestrol, genistein and naringenin bound with higher affinity to the GST-aERdef, than to the other GST-ERdef fusion proteins. Many of the industrial chemicals examined preferentially bound to GST-rtERdef. Bisphenol A, 4-t-octylphenol and o,p' DDT bound with approximately a ten-fold greater affinity to GST-rtERdef than to other GST-ERdefs. Methoxychlor, p,p'-DDT, o,p'-DDE, p,p'-DDE, alpha-endosulfan and dieldrin weakly bound to the ERs from the human, mouse, chicken and green anole. In contrast, these compounds completely displaced [3H]E2 from GST-rtERdef. These results demonstrate that ERs from different species exhibit differential ligand preferences and relative binding affinities for estrogenic compounds and that these differences may be due to the variability in the amino acid sequence within their respective ER ligand binding domains. PMID:11162928

  11. Estrogens from sewage in coastal marine environments.

    PubMed

    Atkinson, Shannon; Atkinson, Marlin J; Tarrant, Ann M

    2003-04-01

    Estrogens are ancient molecules that act as hormones in vertebrates and are biologically active in diverse animal phyla. Sewage contains natural and synthetic estrogens that are detectable in streams, rivers, and lakes. There are no studies reporting the distribution of steroidal estrogens in marine environments. We measured estrogens in sewage, injection-well water, and coastal tropical and offshore tropical water in the Pacific Ocean, western Atlantic Ocean, and Caribbean Sea. Concentrations of unconjugated estrone ranged from undetectable (< 40 pg/L) in the open ocean to nearly 2,000 pg/L in Key West, Florida, and Rehoboth Bay, Delaware (USA); estrone concentrations were highest near sources of sewage. Enzymatic hydrolysis of steroid conjugates in seawater samples indicated that polar conjugates comprise one-half to two-thirds of "total estrone" (unconjugated plus conjugated) in Hawaiian coastal samples. Adsorption to basalt gravel and carbonate sand was less than 20% per week and indicates that estrogens can easily leach into the marine environment from septic fields and high-estrogen groundwater. Of 20 sites (n = 129 samples), the mean values from 12 sites were above the threshold concentration for uptake into coral, indicating that there is a net uptake of anthropogenic steroidal estrogen into these environments, with unknown impacts. PMID:12676611

  12. Estrogens from sewage in coastal marine environments.

    PubMed Central

    Atkinson, Shannon; Atkinson, Marlin J; Tarrant, Ann M

    2003-01-01

    Estrogens are ancient molecules that act as hormones in vertebrates and are biologically active in diverse animal phyla. Sewage contains natural and synthetic estrogens that are detectable in streams, rivers, and lakes. There are no studies reporting the distribution of steroidal estrogens in marine environments. We measured estrogens in sewage, injection-well water, and coastal tropical and offshore tropical water in the Pacific Ocean, western Atlantic Ocean, and Caribbean Sea. Concentrations of unconjugated estrone ranged from undetectable (< 40 pg/L) in the open ocean to nearly 2,000 pg/L in Key West, Florida, and Rehoboth Bay, Delaware (USA); estrone concentrations were highest near sources of sewage. Enzymatic hydrolysis of steroid conjugates in seawater samples indicated that polar conjugates comprise one-half to two-thirds of "total estrone" (unconjugated plus conjugated) in Hawaiian coastal samples. Adsorption to basalt gravel and carbonate sand was less than 20% per week and indicates that estrogens can easily leach into the marine environment from septic fields and high-estrogen groundwater. Of 20 sites (n = 129 samples), the mean values from 12 sites were above the threshold concentration for uptake into coral, indicating that there is a net uptake of anthropogenic steroidal estrogen into these environments, with unknown impacts. PMID:12676611

  13. Role of estrogen in diastolic dysfunction.

    PubMed

    Zhao, Zhuo; Wang, Hao; Jessup, Jewell A; Lindsey, Sarah H; Chappell, Mark C; Groban, Leanne

    2014-03-01

    The prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after menopause and may lead to heart failure. While evidence suggests that estrogens protect the premenopausal heart from hypertension and ventricular remodeling, the specific mechanisms involved remain elusive. Moreover, whether there is a protective role of estrogens against cardiovascular disease, and specifically LVDD, continues to be controversial. Clinical and basic science have implicated activation of the renin-angiotensin-aldosterone system (RAAS), linked to the loss of ovarian estrogens, in the pathogenesis of postmenopausal diastolic dysfunction. As a consequence of increased tissue ANG II and low estrogen, a maladaptive nitric oxide synthase (NOS) system produces ROS that contribute to female sex-specific hypertensive heart disease. Recent insights from rodent models that mimic the cardiac phenotype of an estrogen-insufficient or -deficient woman (e.g., premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2.Lewis female rat, provide evidence showing that estrogen modulates the tissue RAAS and NOS system and related intracellular signaling pathways, in part via the membrane G protein-coupled receptor 30 (GPR30; also called G protein-coupled estrogen receptor 1). Complementing the cardiovascular research in this field, the echocardiographic correlates of LVDD as well as inherent limitations to its use in preclinical rodent studies will be briefly presented. Understanding the roles of estrogen and GPR30, their interactions with the local RAAS and NOS system, and the relationship of each of these to LVDD is necessary to identify new therapeutic targets and alternative treatments for diastolic heart failure that achieve the cardiovascular benefits of estrogen replacement without its side effects and contraindications. PMID:24414072

  14. Aging, Estrogens, and Episodic Memory in Women

    PubMed Central

    Henderson, Victor W.

    2009-01-01

    Objective To review the relation in midlife and beyond between estrogen exposures and episodic memory in women. Background Episodic memory performance declines with usual aging, and impairments in episodic memory often portend the development of Alzheimer's disease. In the laboratory, estradiol influences hippocampal function and animal learning. However, it is controversial whether estrogens affect memory after a woman's reproductive years. Method Focused literature review, including a summary of a systematic search of clinical trials of estrogens in which outcomes included an objective measure of episodic memory. Results The natural menopause transition is not associated with objective changes in episodic memory. Strong clinical trial evidence indicates that initiating estrogen-containing hormone therapy after about age 60 years does not benefit episodic memory. Clinical trial findings in middle-age women before age 60 are limited by smaller sample sizes and shorter treatment durations, but these also do not indicate substantial memory effects. Limited short-term evidence, however, suggests that estrogens may improve verbal memory after surgical menopause. Although hormone therapy initiation in old age increases dementia risk, observational studies raise the question of an early critical window during which midlife estrogen therapy reduces late-life Alzheimer's disease. However, almost no data address whether midlife estrogen therapy affects episodic memory in old age. Conclusions Episodic memory is not substantially impacted by the natural menopause transition or improved by use of estrogen-containing hormone therapy after age 60. Further research is needed to determine whether outcomes differ after surgical menopause or whether episodic memory later in life is modified by midlife estrogenic exposures. PMID:19996872

  15. Role of estrogen in diastolic dysfunction

    PubMed Central

    Zhao, Zhuo; Wang, Hao; Jessup, Jewell A.; Lindsey, Sarah H.; Chappell, Mark C.

    2014-01-01

    The prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after menopause and may lead to heart failure. While evidence suggests that estrogens protect the premenopausal heart from hypertension and ventricular remodeling, the specific mechanisms involved remain elusive. Moreover, whether there is a protective role of estrogens against cardiovascular disease, and specifically LVDD, continues to be controversial. Clinical and basic science have implicated activation of the renin-angiotensin-aldosterone system (RAAS), linked to the loss of ovarian estrogens, in the pathogenesis of postmenopausal diastolic dysfunction. As a consequence of increased tissue ANG II and low estrogen, a maladaptive nitric oxide synthase (NOS) system produces ROS that contribute to female sex-specific hypertensive heart disease. Recent insights from rodent models that mimic the cardiac phenotype of an estrogen-insufficient or -deficient woman (e.g., premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2.Lewis female rat, provide evidence showing that estrogen modulates the tissue RAAS and NOS system and related intracellular signaling pathways, in part via the membrane G protein-coupled receptor 30 (GPR30; also called G protein-coupled estrogen receptor 1). Complementing the cardiovascular research in this field, the echocardiographic correlates of LVDD as well as inherent limitations to its use in preclinical rodent studies will be briefly presented. Understanding the roles of estrogen and GPR30, their interactions with the local RAAS and NOS system, and the relationship of each of these to LVDD is necessary to identify new therapeutic targets and alternative treatments for diastolic heart failure that achieve the cardiovascular benefits of estrogen replacement without its side effects and contraindications. PMID:24414072

  16. Vaginal Estrogen for Genitourinary Syndrome of Menopause

    PubMed Central

    Rahn, David D.; Carberry, Cassandra; Sanses, Tatiana V.; Mamik, Mamta M.; Ward, Renée M.; Meriwether, Kate V.; Olivera, Cedric K.; Abed, Husam; Balk, Ethan M.; Murphy, Miles

    2016-01-01

    OBJECTIVE To comprehensively review and critically assess the literature on vaginal estrogen and its alternatives for women with genitourinary syndrome of menopause and to provide clinical practice guidelines. DATA SOURCES MEDLINE and Cochrane databases were searched from inception to April 2013. We included randomized controlled trials and prospective comparative studies. Interventions and comparators included all commercially available vaginal estrogen products. Placebo, no treatment, systemic estrogen (all routes), and nonhormonal moisturizers and lubricants were included as comparators. METHODS OF STUDY SELECTION We double-screened 1,805 abstracts, identifying 44 eligible studies. Discrepancies were adjudicated by a third reviewer. Studies were individually and collectively assessed for methodologic quality and strength of evidence. TABULATION, INTEGRATION, AND RESULTS Studies were extracted for participant, intervention, comparator, and outcomes data, including patient-reported atrophy symptoms (eg, vaginal dryness, dyspareunia, dysuria, urgency, frequency, recurrent urinary tract infection (UTI), and urinary incontinence), objective signs of atrophy, urodynamic measures, endometrial effects, serum estradiol changes, and adverse events. Compared with placebo, vaginal estrogens improved dryness, dyspareunia, urinary urgency, frequency, and stress urinary incontinence (SUI) and urgency urinary incontinence (UUI). Urinary tract infection rates decreased. The various estrogen preparations had similar efficacy and safety; serum estradiol levels remained within postmenopausal norms for all except high-dose conjugated equine estrogen cream. Endometrial hyperplasia and adenocarcinoma were extremely rare among those receiving vaginal estrogen. Comparing vaginal estrogen with nonhormonal moisturizers, patients with two or more symptoms of vulvovaginal atrophy were substantially more improved using vaginal estrogens, but those with one or minor complaints had similar

  17. Fennel and anise as estrogenic agents.

    PubMed

    Albert-Puleo, M

    1980-12-01

    Fennel, Foeniculum vulgare, and anise, Pimpinella anisum, are plants which have been used as estrogenic agents for millennia. Specifically, they have been reputed to increase milk secretion, promote menstruation, facilitate birth, alleviate the symptoms of the male climacteric, and increase libido. In the 1930s, some interest was shown in these plants in the development of synthetic estrogens. The main constituent of the essential oils of fennel and anise, anethole, has been considered to be the active estrogenic agent. However, further research suggests that the actual pharmacologically active agents are polymers of anethole, such as dianethole and photoanethole. PMID:6999244

  18. Purified estrogen receptor enhances in vitro transcription.

    PubMed

    Nigro, V; Molinari, A M; Armetta, I; de Falco, A; Abbondanza, C; Medici, N; Puca, G A

    1992-07-31

    An in vitro transcription system was developed to investigate the mechanisms of gene regulation by the estrogen receptor (ER). ER purified from calf uterus was highly active in enhancing RNA transcription from a template DNA containing estrogen response elements (EREs) upstream from a minimal promoter. Under the conditions employed, no addition of tissue specific factors was required and both estrogen or antiestrogens were ineffective. The stimulation of transcription correlated with the copy number of EREs in the template. The addition of competitor ERE oligonucleotides specifically inhibited the ER-induced transcription. We suggest that the ER may be involved in the formation of the stable initiation complex. PMID:1497666

  19. Breast Cancer and Estrogen-Alone Update

    MedlinePlus

    ... Current Issue Past Issues Research News From NIH Breast Cancer and Estrogen-Alone Update Past Issues / Summer 2006 ... hormone therapy does not increase the risk of breast cancer in postmenopausal women, according to an updated analysis ...

  20. Bioinformatics Analysis of Estrogen-Responsive Genes.

    PubMed

    Handel, Adam E

    2016-01-01

    Estrogen is a steroid hormone that plays critical roles in a myriad of intracellular pathways. The expression of many genes is regulated through the steroid hormone receptors ESR1 and ESR2. These bind to DNA and modulate the expression of target genes. Identification of estrogen target genes is greatly facilitated by the use of transcriptomic methods, such as RNA-seq and expression microarrays, and chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq). Combining transcriptomic and ChIP-seq data enables a distinction to be drawn between direct and indirect estrogen target genes. This chapter discusses some methods of identifying estrogen target genes that do not require any expertise in programming languages or complex bioinformatics. PMID:26585125

  1. Pyrolysis of wastewater biosolids significantly reduces estrogenicity.

    PubMed

    Hoffman, T C; Zitomer, D H; McNamara, P J

    2016-11-01

    Most wastewater treatment processes are not specifically designed to remove micropollutants. Many micropollutants are hydrophobic so they remain in the biosolids and are discharged to the environment through land-application of biosolids. Micropollutants encompass a broad range of organic chemicals, including estrogenic compounds (natural and synthetic) that reside in the environment, a.k.a. environmental estrogens. Public concern over land application of biosolids stemming from the occurrence of micropollutants hampers the value of biosolids which are important to wastewater treatment plants as a valuable by-product. This research evaluated pyrolysis, the partial decomposition of organic material in an oxygen-deprived system under high temperatures, as a biosolids treatment process that could remove estrogenic compounds from solids while producing a less hormonally active biochar for soil amendment. The estrogenicity, measured in estradiol equivalents (EEQ) by the yeast estrogen screen (YES) assay, of pyrolyzed biosolids was compared to primary and anaerobically digested biosolids. The estrogenic responses from primary solids and anaerobically digested solids were not statistically significantly different, but pyrolysis of anaerobically digested solids resulted in a significant reduction in EEQ; increasing pyrolysis temperature from 100°C to 500°C increased the removal of EEQ with greater than 95% removal occurring at or above 400°C. This research demonstrates that biosolids treatment with pyrolysis would substantially decrease (removal>95%) the estrogens associated with this biosolids product. Thus, pyrolysis of biosolids can be used to produce a valuable soil amendment product, biochar, that minimizes discharge of estrogens to the environment. PMID:27344259

  2. Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among premenopausal women.

    PubMed

    Eliassen, A Heather; Spiegelman, Donna; Xu, Xia; Keefer, Larry K; Veenstra, Timothy D; Barbieri, Robert L; Willett, Walter C; Hankinson, Susan E; Ziegler, Regina G

    2012-02-01

    Endogenous estrogens and estrogen metabolism are hypothesized to be associated with premenopausal breast cancer risk but evidence is limited. We examined 15 urinary estrogens/estrogen metabolites and breast cancer risk among premenopausal women in a case-control study nested within the Nurses' Health Study II (NHSII). From 1996 to 1999, urine was collected from 18,521 women during the mid-luteal menstrual phase. Breast cancer cases (N = 247) diagnosed between collection and June 2005 were matched to two controls each (N = 485). Urinary estrogen metabolites were measured by liquid chromatography-tandem mass spectrometry and adjusted for creatinine level. Relative risks (RR) and 95% confidence intervals (CI) were estimated by multivariate conditional logistic regression. Higher urinary estrone and estradiol levels were strongly significantly associated with lower risk (top vs. bottom quartile RR: estrone = 0.52; 95% CI, 0.30-0.88; estradiol = 0.51; 95% CI, 0.30-0.86). Generally inverse, although nonsignificant, patterns also were observed with 2- and 4-hydroxylation pathway estrogen metabolites. Inverse associations generally were not observed with 16-pathway estrogen metabolites and a significant positive association was observed with 17-epiestriol (top vs. bottom quartile RR = 1.74; 95% CI, 1.08-2.81; P(trend) = 0.01). In addition, there was a significant increased risk with higher 16-pathway/parent estrogen metabolite ratio (comparable RR = 1.61; 95% CI, 0.99-2.62; P(trend) = 0.04). Other pathway ratios were not significantly associated with risk except parent estrogen metabolites/non-parent estrogen metabolites (comparable RR = 0.58; 95% CI, 0.35-0.96; P(trend) = 0.03). These data suggest that most mid-luteal urinary estrogen metabolite concentrations are not positively associated with breast cancer risk among premenopausal women. The inverse associations with parent estrogen metabolites and the parent estrogen metabolite/non-parent estrogen metabolite ratio

  3. Estrogen effects in allergy and asthma

    PubMed Central

    Bonds, Rana S.; Midoro-Horiuti, Terumi

    2012-01-01

    Purpose of review Asthma prevalence and severity are greater in women than in men, and mounting evidence suggests this is in part related to female steroid sex hormones. Of these, estrogen has been the subject of much study. This review highlights recent research exploring the effects of estrogen in allergic disease. Recent findings Estrogen receptors are found on numerous immunoregulatory cells and estrogen’s actions skew immune responses toward allergy. It may act directly to create deleterious effects in asthma, or indirectly via modulation of various pathways including secretory leukoprotease inhibitor, transient receptor potential vanilloid type 1 ion channel and nitric oxide production to exert effects on lung mechanics and inflammation. Not only do endogenous estrogens appear to play a role, but environmental estrogens have also been implicated. Environmental estrogens (xenoestrogens) including bisphenol A and phthalates enhance allergic sensitization in animal models and may enhance development of atopic disorders like asthma in humans. Summary Estrogen’s role in allergic disease remains complex. As allergic diseases continue to increase in prevalence and affect women disproportionately, gaining a fuller understanding of its effects in these disorders will be essential. Of particular importance may be effects of xenoestrogens on allergic disease. PMID:23090385

  4. Estrogen Regulation of MicroRNA Expression

    PubMed Central

    Klinge, Carolyn M

    2009-01-01

    Women outlive men, but life expectancy is not influenced by hormone replacement (estrogen + progestin) therapy. Estrogens appear to protect brain, cardiovascular tissues, and bone from aging. Estrogens regulate genes directly through binding to estrogen receptors alpha and beta (ERα and ERβ) that are ligand-activated transcription factors and indirectly by activating plasma membrane-associated ER which, in turns, activates intracellular signaling cascades leading to altered gene expression. MicroRNAs (miRNAs) are short (19-25 nucleotides), naturally-occurring, non-coding RNA molecules that base-pair with the 3’ untranslated region of target mRNAs. This interaction either blocks translation of the mRNA or targets the mRNA transcript to be degraded. The human genome contains ~ 700-1,200 miRNAs. Aberrant patterns of miRNA expression are implicated in human diseases including breast cancer. Recent studies have identified miRNAs regulated by estrogens in human breast cancer cells, human endometrial stromal and myometrial smooth muscle cells, rat mammary gland, and mouse uterus. The decline of estradiol levels in postmenopausal women has been implicated in various age-associated disorders. The role of estrogen-regulated miRNA expression, the target genes of these miRNAs, and the role of miRNAs in aging has yet to be explored. PMID:19881910

  5. Estrogen Protects against Radiation-Induced Cataractogenesis

    PubMed Central

    Dynlacht, Joseph R.; Valluri, Shailaja; Lopez, Jennifer; Greer, Falon; DesRosiers, Colleen; Caperell-Grant, Andrea; Mendonca, Marc S.; Bigsby, Robert M.

    2008-01-01

    Cataractogenesis is a complication of radiotherapy when the eye is included in the treatment field. Low doses of densely ionizing space radiation may also result in an increased risk of cataracts in astronauts. We previously reported that estrogen (17-β-estradiol), when administered to ovariectomized rats commencing 1 week before γ irradiation of the eye and continuously thereafter, results in a significant increase in the rate and incidence of cataract formation and a decreased latent period compared to an ovariectomized control group. We therefore concluded that estrogen accelerates progression of radiation-induced opacification. We now show that estrogen, if administered continuously, but commencing after irradiation, protects against radiation cataractogenesis. Both the rate of progression and incidence of cataracts were greatly reduced in ovariectomized rats that received estrogen treatment after irradiation compared to ovariectomized rats. As in our previous study, estradiol administered 1 week prior to irradiation at the time of ovariectomy and throughout the period of observation produced an enhanced rate of cataract progression. Estrogen administered for only 1 week prior to irradiation had no effect on the rate of progression but resulted in a slight reduction in the incidence. We conclude that estrogen may enhance or protect against radiation cataractogenesis, depending on when it is administered relative to the time of irradiation, and may differentially modulate the initiation and progression phases of cataractogenesis. These data have important implications for astronauts and radiotherapy patients. PMID:19138041

  6. Evidence of a correlation of estrogen receptor level and avian osteoclast estrogen responsiveness.

    PubMed

    Pederson, L; Kremer, M; Foged, N T; Winding, B; Ritchie, C; Fitzpatrick, L A; Oursler, M J

    1997-05-01

    Isolated osteoclasts from 5-week-old chickens respond to estradiol treatment in vitro with decreased resorption activity, increased nuclear proto-oncogene expression, and decreased lysosomal enzyme secretion. This study examines osteoclasts from embryonic chickens and egg-laying hens for evidence of estrogen responsiveness. Although osteoclasts from both of these sources express estrogen receptor mRNA and protein, estradiol treatment had no effect on resorption activity. In contrast to the lack of effect on resorption, estradiol treatment for 30 minutes resulted in steady-state mRNA levels of c-fos and c-jun increasing in osteoclasts from embryonic chickens and decreasing in osteoclasts from egg-laying hens. These data suggest that a nuclear proto-oncogene response may not be involved in estradiol-mediated decreased osteoclast resorption activity. To examine the influence of circulating estrogen on osteoclast estrogen responsiveness, 5-week-old chickens were injected with estrogen for 4 days prior to sacrifice. Estradiol treatment of osteoclasts from these chickens did not decrease resorption activity in vitro. Transfection of an estrogen receptor expression vector into osteoclasts from the estradiol-injected chickens and egg-laying hens restored estrogen responsiveness. Osteoclasts from 5-week-old chickens and estradiol treated 5-week-old chickens transfected with the estrogen receptor expression vector contained significantly higher levels of estrogen receptor protein and responded to estradiol treatment by decreasing secretion of cathepsins B and L and tartrate-resistant acid phosphatase. In contrast, osteoclasts from embryonic chickens, egg-laying hens, and estradiol-treated 5-week-old chickens either untransfected or transfected with an empty expression vector did not respond similarly. These data suggest that modulation of osteoclast estrogen responsiveness may be controlled by changes in the osteoclast estrogen receptor levels. PMID:9144340

  7. Estrogenic activity of natural and synthetic estrogens in human breast cancer cells in culture.

    PubMed

    Zava, D T; Blen, M; Duwe, G

    1997-04-01

    We investigated the estrogenic activity of various environmental pollutants (xenobiotics), in particular the xenoestrogen o,p-DDT, and compared their effects with those of endogenous estrogens, phytoestrogens, and mycoestrogens on estrogen receptor binding capacity, induction of estrogen end products, and activation of cell proliferation in estrogen-sensitive human breast cancer cells in monolayer culture. We also quantified the levels of phytoestrogens in extracts of some common foods, herbs, and spices and in human saliva following consumption of a high phytoestrogen food source (soy milk) to compare phytoestrogen abundance and bioavailability relative to the reported xenoestrogen burden in humans. Results show that natural endogenous estrogens, phytoestrogens, mycoestrogens, and xenoestrogens bind estrogen receptor (ER) in intact cells, but demonstrate marked differences in their ability to induce end products of estrogen action and to regulate cell proliferation. All of the different classes of estrogens stimulated cell proliferation at concentrations that half-saturated ER, but only some classes were able to induce estrogen-regulated end products. Genistein, a common phytoestrogen found in soy foods, differed from the xenoestrogen DDT in its effects on cell proliferation and ability to induce estrogen-regulated end products. Moreover, we found that many of the foods, herbs, and spices commonly consumed by humans contain significant amounts of phytoestrogens, and consumption of soy milk, a phytoestrogen-rich food, markedly increases the levels of phytoestrogens in saliva. In conclusion, our in vitro results predict that a diet high in phytoestrogens would significantly reduce the binding of weak xenoestrogens to ER in target tissues in vivo. PMID:9168008

  8. Estrogenic activity assessment of environmental chemicals using in vitro assays: identification of two new estrogenic compounds.

    PubMed Central

    Lascombe, I; Beffa, D; Rüegg, U; Tarradellas, J; Wahli, W

    2000-01-01

    Environmental chemicals with estrogenic activities have been suggested to be associated with deleterious effects in animals and humans. To characterize estrogenic chemicals and their mechanisms of action, we established in vitro and cell culture assays that detect human estrogen receptor [alpha] (hER[alpha])-mediated estrogenicity. First, we assayed chemicals to determine their ability to modulate direct interaction between the hER[alpha] and the steroid receptor coactivator-1 (SRC-1) and in a competition binding assay to displace 17ss-estradiol (E(2)). Second, we tested the chemicals for estrogen-associated transcriptional activity in the yeast estrogen screen and in the estrogen-responsive MCF-7 human breast cancer cell line. The chemicals investigated in this study were o,p'-DDT (racemic mixture and enantiomers), nonylphenol mixture (NPm), and two poorly analyzed compounds in the environment, namely, tris-4-(chlorophenyl)methane (Tris-H) and tris-4-(chlorophenyl)methanol (Tris-OH). In both yeast and MCF-7 cells, we determined estrogenic activity via the estrogen receptor (ER) for o,p'-DDT, NPm, and for the very first time, Tris-H and Tris-OH. However, unlike estrogens, none of these xenobiotics seemed to be able to induce ER/SRC-1 interactions, most likely because the conformation of the activated receptor would not allow direct contacts with this coactivator. However, these compounds were able to inhibit [(3)H]-E(2) binding to hER, which reveals a direct interaction with the receptor. In conclusion, the test compounds are estrogen mimics, but their molecular mechanism of action appears to be different from that of the natural hormone as revealed by the receptor/coactivator interaction analysis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:10903615

  9. Effects of Estrogens and Estrogenic Disrupting Compounds on Fish Mineralized Tissues

    PubMed Central

    Pinto, Patricia I. S.; Estêvão, Maria D.; Power, Deborah M.

    2014-01-01

    Estrogens play well-recognized roles in reproduction across vertebrates, but also intervene in a wide range of other physiological processes, including mineral homeostasis. Classical actions are triggered when estrogens bind and activate intracellular estrogen receptors (ERs), regulating the transcription of responsive genes, but rapid non-genomic actions initiated by binding to plasma membrane receptors were recently described. A wide range of structurally diverse compounds from natural and anthropogenic sources have been shown to interact with and disrupt the normal functions of the estrogen system, and fish are particularly vulnerable to endocrine disruption, as these compounds are frequently discharged or run-off into waterways. The effect of estrogen disruptors in fish has mainly been assessed in relation to reproductive endpoints, and relatively little attention has been given to other disruptive actions. This review will overview the actions of estrogens in fish, including ER isoforms, their expression, structure and mechanisms of action. The estrogen functions will be considered in relation to mineral homeostasis and actions on mineralized tissues. The impact of estrogenic endocrine disrupting compounds on fish mineralized tissues will be reviewed, and the potential adverse outcomes of exposure to such compounds will be discussed. Current lacunae in knowledge are highlighted along with future research priorities. PMID:25196834

  10. Binding of Estrogenic Compounds to Recombinant Estrogen Receptor-α: Application to Environmental Analysis

    PubMed Central

    Pillon, Arnaud; Boussioux, Anne-Marie; Escande, Aurélie; Aït-Aïssa, Sélim; Gomez, Elena; Fenet, Hélène; Ruff, Marc; Moras, Dino; Vignon, Françoise; Duchesne, Marie-Josèphe; Casellas, Claude; Nicolas, Jean-Claude; Balaguer, Patrick

    2005-01-01

    Estrogenic activity in environmental samples could be mediated through a wide variety of compounds and by various mechanisms. High-affinity compounds for estrogen receptors (ERs), such as natural or synthetic estrogens, as well as low-affinity compounds such as alkylphenols, phthalates, and polychlorinated biphenyls are present in water and sediment samples. Furthermore, compounds such as polycyclic aromatic hydrocarbons, which do not bind ERs, modulate estrogen activity by means of the aryl hydrocarbon receptor (AhR). In order to characterize compounds that mediate estrogenic activity in river water and sediment samples, we developed a tool based on the ER-αligand-binding domain, which permitted us to estimate contaminating estrogenic compound affinities. We designed a simple transactivation assay in which compounds of high affinity were captured by limited amounts of recombinant ER-αand whose capture led to a selective inhibition of transactivation. This approach allowed us to bring to light that water samples contain estrogenic compounds that display a high affinity for ERs but are present at low concentrations. In sediment samples, on the contrary, we showed that estrogenic compounds possess a low affinity and are present at high concentration. Finally, we used immobilized recombinant ER-αto separate ligands for ER and AhR that are present in river sediments. Immobilized ER-α, which does not retain dioxin-like compounds, enabled us to isolate and concentrate ER ligands to facilitate their further analysis. PMID:15743715

  11. Estrogen-related receptor γ modulates cell proliferation and estrogen signaling in breast cancer.

    PubMed

    Ijichi, Nobuhiro; Shigekawa, Takashi; Ikeda, Kazuhiro; Horie-Inoue, Kuniko; Fujimura, Tetsuya; Tsuda, Hitoshi; Osaki, Akihiko; Saeki, Toshiaki; Inoue, Satoshi

    2011-01-01

    Breast cancer is primarily a hormone-dependent tumor that can be regulated by status of steroid hormones including estrogen and progesterone. Estrogen-related receptors (ERRs) are orphan nuclear receptors most closely related to estrogen receptor (ER) and much attention has been recently paid to the functions of ERRs in breast cancer in terms of the interactions with ER. In the present study, we investigated the expression of ERRγ in human invasive breast cancers by immunohistochemical analysis (n=110) obtained by radical mastectomy. Nuclear immunoreactivity of ERRγ was detected in 87 cases (79%) and tended to correlate with the lymph node status. No significant associations were observed with other clinicopathological characteristics, including the expression levels of both estrogen and progesterone receptors. In MCF-7 breast cancer cells, we demonstrated that ERRγ mRNA was up-regulated dose-dependently by estrogen, and that this up-regulation of ERRγ mRNA by estrogen was abolished by ICI 182,780 treatment. We also demonstrated that exogenously transfected ERRγ increased MCF-7 cell proliferation. Furthermore, ERRγ enhanced estrogen response element (ERE)-driven transcription in MCF-7 cells. In 293T cells, ERRγ could also stimulate ERE-mediated transcription with or without ERα. These results suggest that ERRγ plays an important role as a modulator of estrogen signaling in breast cancer cells. PMID:20883782

  12. MODELING THE EFFECTS OF FLEXIBILITY ON THE BINDING OF ENVIRONMENTAL ESTROGENS TO THE ESTROGEN RECEPTOR

    EPA Science Inventory

    Modeling the effects of flexibility on the binding of environmental estrogens to the estrogen receptor
    There are many reports of environmental endocrine disruption in the literature, yet it has been difficult to identify the specific chemicals responsible for these effects. ...

  13. Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetics

    SciTech Connect

    Meeuwen, J.A. van Son, O. van; Piersma, A.H.; Jong, P.C. de; Berg, M. van den

    2008-08-01

    There is concern widely on the increase in human exposure to exogenous (anti)estrogenic compounds. Typical are certain ingredients in cosmetic consumer products such as musks, phthalates and parabens. Monitoring a variety of human samples revealed that these ingredients, including the ones that generally are considered to undergo rapid metabolism, are present at low levels. In this in vitro research individual compounds and combinations of parabens and endogenous estradiol (E{sub 2}) were investigated in the MCF-7 cell proliferation assay. The experimental design applied a concentration addition model (CA). Data were analyzed with the estrogen equivalency (EEQ) and method of isoboles approach. In addition, the catalytic inhibitory properties of parabens on an enzyme involved in a rate limiting step in steroid genesis (aromatase) were studied in human placental microsomes. Our results point to an additive estrogenic effect in a CA model for parabens. In addition, it was found that parabens inhibit aromatase. Noticeably, the effective levels in both our in vitro systems were far higher than the levels detected in human samples. However, estrogenic compounds may contribute in a cumulative way to the circulating estrogen burden. Our calculation for the extra estrogen burden due to exposure to parabens, phthalates and polycyclic musks indicates an insignificant estrogenic load relative to the endogenous or therapeutic estrogen burden.

  14. Estrogen and progesterone receptors in primary cutaneous melanoma.

    PubMed

    Ellis, D L; Wheeland, R G; Solomon, H

    1985-01-01

    Using a variety of techniques, estrogen and progesterone receptors have previously been identified in variable percentages of malignant melanomas. We examined 10 primary superficial spreading melanomas (SSM) with a fluorescent hormone-binding technique for estrogen and progesterone cytoplasmic receptors. Of these 6 SSM were markedly positive for estrogen and progesterone binding. Patients with dysplastic nevus syndrome (DNS) or a family history of DNS were markedly positive for estrogen and progesterone binding. A single patient with lentigo maligna and another patient with lentigo maligna melanoma were negative for estrogen and progesterone binding. None of the 21 control intradermal nevi examined for estrogen and progesterone binding exhibited marked positivity. PMID:3965520

  15. Effects of treadmill exercise training on cerebellar estrogen and estrogen receptors, serum estrogen, and motor coordination performance of ovariectomized rats

    PubMed Central

    Rauf, Saidah; Soejono, Sri Kadarsih; Partadiredja, Ginus

    2015-01-01

    Objective(s): The present study aims at examining the motor coordination performance, serum and cerebellar estrogen, as well as ERβ levels, of ovariectomized rats (as menopausal model) following regular exercise. Materials and Methods: Ten female Sprague Dawley rats aged 12 weeks old were randomly divided into two groups; all of which underwent ovariectomy. The first group was treated with regular exercise of moderate intensity, in which the rats were trained to run on a treadmill for 60 min per day for 12 weeks. The second group served as control. Rotarod test was carried out before and after exercise treatment. All rats were euthanized thereafter, and blood and cerebellums of the rats were collected. The serum and cerebellar estrogen as well as cerebellar ERβ levels were measured using ELISA assays. Results: The number of falls in the rotarod task of the exercise group was significantly lower than that of control group. The cerebellar estrogen level of the exercise group was significantly higher than that of control group. Accordingly, there was a significantly negative correlation between the number of falls and cerebellar estrogen level in the exercise group. Conclusion: The present study shows that a lengthy period of regular exercise improves the cerebellar estrogen level and motor coordination performance in ovariectomized rats. PMID:26221482

  16. Estrogenic Compounds, Estrogen Receptors and Vascular Cell Signaling in the Aging Blood Vessels

    PubMed Central

    Smiley, Dia A.; Khalil, Raouf A.

    2010-01-01

    The cardiovascular benefits of menopausal hormone therapy (MHT) remain controversial. The earlier clinical observations that cardiovascular disease (CVD) was less common in MHT users compared to non-users suggested cardiovascular benefits of MHT. Also, experimental studies have identified estrogen receptors ERα, ERβ and GPR30, which mediate genomic or non-genomic effects in vascular endothelium, smooth muscle, and extracellular matrix (ECM). However, data from randomized clinical trials (RCTs), most notably the Women's Health Initiative (WHI) study, have challenged the cardiovascular benefits and highlighted adverse cardiovascular events with MHT. The discrepancies have been attributed to the design of RCTs, the subjects' advanced age and preexisting CVD, and the form of estrogen used. The discrepancies may also stem from age-related changes in vascular ER amount, distribution, integrity, and post-receptor signaling pathways as well as structural changes in the vasculature. Age-related changes in other sex hormones such as testosterone may also alter the hormonal environment and influence the cardiovascular effects of estrogen. Investigating the chemical properties, structure-activity relationship and pharmacology of natural and synthetic estrogens should improve the effectiveness of conventional MHT. Further characterization of phytoestrogens, selective estrogen-receptor modulators (SERMs), and specific ER agonists may provide substitutes to conventional MHT. Conditions with excess or low estrogen levels such as polycystic ovary syndrome (PCOS) and Turner syndrome may provide insight into the development and regulation of ER and the mechanisms of aberrant estrogen-ER interactions. The lessons learned from previous RCTs have led to more directed studies such as the Kronos Early Estrogen Prevention Study (KEEPS). Careful design of experimental models and RCTs, coupled with the development of specific ER modulators, hold the promise of improving the actions of

  17. Noncontraceptive estrogen use and epithelial ovarian cancer.

    PubMed

    Kaufman, D W; Kelly, J P; Welch, W R; Rosenberg, L; Stolley, P D; Warshauer, M E; Lewis, J; Woodruff, J; Shapiro, S

    1989-12-01

    The relation of noncontraceptive estrogen use to epithelial ovarian cancer was evaluated in a case-control study conducted in hospitals mainly in the northeastern United States. There were 377 cases diagnosed within the year before hospital admission and 2,030 hospital controls; data were collected by interview in the hospital. Compared with women who never took noncontraceptive estrogens, the overall relative risk estimate for women whose estrogen use lasted at least one year and was not combined with progestogens or testosterone was 1.2 (95% confidence interval (CI) 0.8-1.9), after taking into account risk factors for ovarian cancer. There were 55 cases of the endometrioid, clear cell, or malignant mixed mesodermal cell type; the corresponding relative risk estimate was 0.9 (95% CI 0.3-3.0). There were 26 cases of undifferentiated cell type, with a relative risk estimate of 3.6 (95% CI 1.2-11). Relative risk estimates were similar in a subset of the cases (57%) for which pathology slides were reviewed. For estrogen use of long duration, use of high-dose preparations, or use in the distant past, the relative risk estimates were not significantly different from 1.0. The estimates were elevated for some categories of use, but not consistently--for example, for an interval of 5-9 years since estrogen use began (relative risk (RR) = 2.7), but not after shorter or longer intervals, and for use of conjugated estrogens with a dose of 0.3 mg (RR = 3.2) or 1.25 mg (RR = 2.4), but not for doses of 0.625 mg or 2.5 mg. The relative risk estimate was also elevated for use by nulliparous women (RR = 2.4). The results suggest that, overall, noncontraceptive estrogen use is not associated with the risk of epithelial ovarian cancer. Furthermore, our data do not support the hypothesis that estrogens increase the risk of endometrioid ovarian cancer. The elevated estimates could be due to multiple stratification of the data, but they should be explored in further studies, given the

  18. Is Estrogen a Therapeutic Target for Glaucoma?

    PubMed

    Dewundara, Samantha S; Wiggs, Janey L; Sullivan, David A; Pasquale, Louis R

    2016-01-01

    This article's objective is to provide an overview of the association between estrogen and glaucoma. A literature synthesis was conducted of articles published in peer-reviewed journals screened through May 5, 2015, using the PubMed database. Keywords used were "estrogen and glaucoma," "reproductive factors and glaucoma," and "estrogen, nitric oxide and eye." Forty-three journal articles were included. Results indicated that markers for lifetime estrogen exposure have been measured by several studies and show that the age of menarche onset, oral contraceptive (OC) use, bilateral oophorectomy, age of menopause onset and duration between menarche to menopause are associated with primary open-angle glaucoma (POAG) risk. The Blue Mountain Eye Study found a significantly increased POAG risk with later (>13 years) compared with earlier (≤12 years) age of menarche. Nurses' Health Study (NHS) investigators found that OC use of greater than 5 years was associated with a 25% increased risk of POAG. The Mayo Clinic Cohort Study of Oophorectomy and Aging found that women who underwent bilateral oophorectomy before age 43 years had an increased risk of glaucoma. The Rotterdam Study found that women who went through menopause before reaching the age of 45 years had a higher risk of open-angle glaucoma (2.6-fold increased risk), while the NHS showed a reduced risk of POAG among women older than 65 who entered menopause after age ≥ 54 years. Increased estrogen states may confer a reduced risk of glaucoma or glaucoma-related traits such as reduced intraocular pressure (IOP). Pregnancy, a hyperestrogenemic state, is associated with decreased IOP during the third trimester. Though the role of postmenopausal hormone (PMH) use in the reduction of IOP is not fully conclusive, PMH use may reduce the risk of POAG. From a genetic epidemiologic perspective, estrogen metabolic pathway single nucleotide polymorphisms (SNPs) were associated with POAG in women and polymorphisms in

  19. Using a customized DNA microarray for expression profiling of the estrogen-responsive genes to evaluate estrogen activity among natural estrogens and industrial chemicals.

    PubMed Central

    Terasaka, Shunichi; Aita, Yukie; Inoue, Akio; Hayashi, Shinichi; Nishigaki, Michiko; Aoyagi, Kazuhiko; Sasaki, Hiroki; Wada-Kiyama, Yuko; Sakuma, Yasuo; Akaba, Shuichi; Tanaka, Junko; Sone, Hideko; Yonemoto, Junzo; Tanji, Masao; Kiyama, Ryoiti

    2004-01-01

    We developed a DNA microarray to evaluate the estrogen activity of natural estrogens and industrial chemicals. Using MCF-7 cells, we conducted a comprehensive analysis of estrogen-responsive genes among approximately 20,000 human genes. On the basis of reproducible and reliable responses of the genes to estrogen, we selected 172 genes to be used for developing a customized DNA microarray. Using this DNA microarray, we examined estrogen activity among natural estrogens (17beta-estradiol, estriol, estrone, genistein), industrial chemicals (diethylstilbestrol, bisphenol A, nonylphenol, methoxychlor), and dioxin. We obtained results identical to those for other bioassays that are used for detecting estrogen activity. On the basis of statistical correlations analysis, these bioassays have shown more sensitivity for dioxin and methoxychlor. PMID:15159206

  20. Estrogen sulfotransferase ablation sensitizes mice to sepsis

    PubMed Central

    Chai, Xiaojuan; Guo, Yan; Jiang, Mengxi; Hu, Bingfang; Li, Zhigang; Fan, Jie; Deng, Meihong; Billiar, Timothy R.; Kucera, Heidi; Gaikwad, Nilesh W.; Xu, Meishu; Lu, Peipei; Yan, Jiong; Fu, Haiyan; Liu, Youhua; Yu, Lushan; Huang, Min; Zeng, Su; Xie, Wen

    2015-01-01

    Sepsis is the host's deleterious systemic inflammatory response to microbial infections. Here we report an essential role for the estrogen sulfotransferase (EST or SULT1E1), a conjugating enzyme that sulfonates and deactivates estrogens, in sepsis response. Both the cecal ligation and puncture (CLP) and lipopolysacharide (LPS) models of sepsis induce the expression of EST and compromise the activity of estrogen, an anti-inflammatory hormone. Surprisingly, EST ablation sensitizes mice to sepsis-induced death. Mechanistically, EST ablation attenuates sepsis-induced inflammatory responses due to compromised estrogen deactivation, leading to increased sepsis lethality. In contrast, transgenic overexpression of EST promotes estrogen deactivation and sensitizes mice to CLP-induced inflammatory response. The induction of EST by sepsis is NF-κB dependent and EST is a NF-κB target gene. The reciprocal regulation of inflammation and EST may represent a yet to be explored mechanism of endocrine regulation of inflammation, which has an impact on the clinical outcome of sepsis. PMID:26259151

  1. Estrogen receptors and human disease: an update

    PubMed Central

    Burns, Katherine A.

    2016-01-01

    A myriad of physiological processes in mammals are influenced by estrogens and the estrogen receptors (ERs), ERα and ERβ. As we reviewed previously, given the widespread role for estrogen in normal human physiology, it is not surprising that estrogen is implicated in the development or progression of a number of diseases. In this review, we are giving a 5-year update of the literature regarding the influence of estrogens on a number of human cancers (breast, ovarian, colorectal, prostate, and endometrial), endometriosis, fibroids, and cardiovascular disease. A large number of sophisticated experimental studies have provided insights into human disease, but for this review, the literature citations were limited to articles published after our previous review (Deroo and Korach in J Clin Invest 116(3):561–570, 2006) and will focus in most cases on human data and clinical trials. We will describe the influence in which estrogen’s action, through one of or both of the ERs, mediates the aforementioned human disease states. PMID:22648069

  2. Estrogenicity of Glabridin in Ishikawa Cells

    PubMed Central

    Su Wei Poh, Melissa; Viseswaran, Navaratnam

    2015-01-01

    Glabridin is an isoflavan from licorice root, which is a common component of herbal remedies used for treatment of menopausal symptoms. Past studies have shown that glabridin resulted in favorable outcome similar to 17β-estradiol (17β-E2), suggesting a possible role as an estrogen replacement therapy (ERT). This study aims to evaluate the estrogenic effect of glabridin in an in-vitro endometrial cell line -Ishikawa cells via alkaline phosphatase (ALP) assay and ER-α-SRC-1-co-activator assay. Its effect on cell proliferation was also evaluated using Thiazoyl blue tetrazolium bromide (MTT) assay. The results showed that glabridin activated the ER-α-SRC-1-co-activator complex and displayed a dose-dependent increase in estrogenic activity supporting its use as an ERT. However, glabridin also induced an increase in cell proliferation. When glabridin was treated together with 17β-E2, synergistic estrogenic effect was observed with a slight decrease in cell proliferation as compared to treatment by 17β-E2 alone. This suggest that the combination might be better suited for providing high estrogenic effects with lower incidences of endometrial cancer that is associated with 17β-E2. PMID:25816349

  3. Modulation of thymosin beta 4 by estrogen.

    PubMed

    Suh, B Y; Naylor, P H; Goldstein, A L; Rebar, R W

    1985-02-15

    The endocrine thymus produces several hormone-like peptides (generically termed thymosins) which control development of the thymic-dependent lymphoid system and participate in the process of immune regulation. In addition, recent literature supports the hypothesis that gonadal steroids in general and estrogens in particular affect the immune system. To determine whether steroid hormones modulate secretion of thymic peptides, basal concentrations of thymosins alpha 1 and beta 4 were determined by radioimmunoassay in morning blood samples from 87 women in various clinical states. Basal concentrations of thymosin alpha 1 were similar in all women sampled. Basal levels of thymosin beta 4 were similar in normal women during the early follicular phase, women with premature ovarian failure, postmenopausal women not receiving estrogen, and individuals with gonadal dysgenesis. However, the marked variability of basal levels in premature ovarian failure and in postmenopausal women suggests that these groups are quite heterogeneous. Thymosin beta 4 concentrations were reduced in castrated women not receiving estrogen and were decreased more in both postmenopausal women and castrated women who were on chronic estrogen therapy. These data suggest that estrogens can modulate the circulating levels of thymosin beta 4 but not of thymosin alpha 1. We do not yet know whether sex steroids modulate secretion of other thymic peptides. PMID:2983555

  4. Estrogenicity of glabridin in Ishikawa cells.

    PubMed

    Su Wei Poh, Melissa; Voon Chen Yong, Phelim; Viseswaran, Navaratnam; Chia, Yoke Yin

    2015-01-01

    Glabridin is an isoflavan from licorice root, which is a common component of herbal remedies used for treatment of menopausal symptoms. Past studies have shown that glabridin resulted in favorable outcome similar to 17β-estradiol (17β-E2), suggesting a possible role as an estrogen replacement therapy (ERT). This study aims to evaluate the estrogenic effect of glabridin in an in-vitro endometrial cell line -Ishikawa cells via alkaline phosphatase (ALP) assay and ER-α-SRC-1-co-activator assay. Its effect on cell proliferation was also evaluated using Thiazoyl blue tetrazolium bromide (MTT) assay. The results showed that glabridin activated the ER-α-SRC-1-co-activator complex and displayed a dose-dependent increase in estrogenic activity supporting its use as an ERT. However, glabridin also induced an increase in cell proliferation. When glabridin was treated together with 17β-E2, synergistic estrogenic effect was observed with a slight decrease in cell proliferation as compared to treatment by 17β-E2 alone. This suggest that the combination might be better suited for providing high estrogenic effects with lower incidences of endometrial cancer that is associated with 17β-E2. PMID:25816349

  5. ANALYSIS OF SWINE LAGOONS AND GROUND WATER FOR ENVIRONMENTAL ESTROGENS

    EPA Science Inventory

    A method was developed for analysis of low levels of natural (estradiol, estrone, estriol) and synthetic (ethinyl estradiol) estrogens in ground water and swine waste lagoon effluent. The method includes solid phase extraction of the estrogens, preparation of pentafluorobenzyl de...

  6. ANALYSIS OF SWINE LAGOONS AND GROUND WATER FOR ENVIRONMENTAL ESTROGENS

    EPA Science Inventory

    A method was developed for analysis of low levels of natural (estradiol, estrone, estriol) and synthetic (ethynylestradiol) estrogens in ground water and swine waste lagoon effluent. The method includes solid phase extraction of the estrogens, preparation of pentafluorobenzyl der...

  7. Novel Promising Estrogenic Receptor Modulators: Cytotoxic and Estrogenic Activity of Benzanilides and Dithiobenzanilides

    PubMed Central

    Kucinska, Malgorzata; Giron, Maria-Dolores; Piotrowska, Hanna; Lisiak, Natalia; Granig, Walter H.; Lopez-Jaramillo, Francisco-Javier; Salto, Rafael; Murias, Marek; Erker, Thomas

    2016-01-01

    The cytotoxicity of 27 benzanilides and dithiobenzanilides built on a stilbene scaffold and possessing various functional groups in aromatic rings previously described for their spasmolytic properties was assayed on three human cancer cell lines (A549 –lung adenocarcinoma, MCF-7 estrogen dependent breast adenocarcinoma and MDA-MB-231 estrogen independent breast adenocarcinoma) and 2 non-tumorigenic cell lines (CCD39Lu–lung fibroblasts, MCF-12A - breast epithelial). Three compounds (6, 15 and 18) showed selective antiproliferative activity against estrogen dependent MCF-7 cancer cells and their estrogenic activity was further confirmed in MCF-7 transfected with an estrogen receptor reporter plasmid and in HEK239 cells over-expressing the estrogen receptor alpha (ERα). Compound 18 is especially interesting as a potential candidate for therapy since it is highly toxic and selective towards estrogen dependent MCF7 cell lines (IC50 = 5.07 μM versus more than 100 μM for MDA-MB-231) and almost innocuous for normal breast cells (IC50 = 91.46 μM for MCF-12A). Docking studies have shown that compound 18 interacts with the receptor in the same cavity as estradiol although the extra aromatic ring is involved in additional binding interactions with residue W383. The role of W383 and the extended binding mode were confirmed by site-directed mutagenesis. PMID:26730945

  8. Estrophilin immunoreactivity versus estrogen receptor binding activity in meningiomas: evidence for multiple estrogen binding sites

    SciTech Connect

    Lesch, K.P.; Schott, W.; Gross, S.

    1987-09-01

    The existence of estrogen receptors in human meningiomas has long been a controversial issue. This may be explained, in part, by apparent heterogeneity of estrogen binding sites in meningioma tissue. In this study, estrogen receptors were determined in 58 meningiomas with an enzyme immunoassay using monoclonal antibodies against human estrogen receptor protein (estrophilin) and with a sensitive radioligand binding assay using /sup 125/I-labeled estradiol (/sup 125/I-estradiol) as radioligand. Low levels of estrophilin immunoreactivity were found in tumors from 62% of patients, whereas radioligand binding activity was demonstrated in about 46% of the meningiomas examined. In eight (14%) tissue samples multiple binding sites for estradiol were observed. The immunoreactive binding sites correspond to the classical, high affinity estrogen receptors: the Kd for /sup 125/I-estradiol binding to the receptor was approximately 0.2 nM and the binding was specific for estrogens. The second, low affinity class of binding sites considerably influenced measurement of the classical receptor even at low ligand concentrations. The epidemiological and clinical data from patients with meningiomas, and the existence of specific estrogen receptors confirmed by immunochemical detection, may be important factors in a theory of oncogenesis.

  9. Multicolor Imaging of Bifacial Activities of Estrogens.

    PubMed

    Kim, Sung-Bae; Umezawa, Yoshio

    2016-01-01

    The present protocol introduces multicolor imaging of bifacial activities of an estrogen. For the multicolor imaging, the authors fabricated two single-chain probes emitting green or red bioluminescence (named Simer-G and -R, respectively) from click beetle luciferase (CBLuc) green and red: Simer-R consists of the ligand binding domain of estrogen receptor (ER LBD) and the Src homology-2 (SH2) domain of Src, which are sandwiched between split-CBLuc red (CBLuc-R). On the other hand, Simer-G emitting red light consists of the ER LBD and a common consensus sequence of coactivators (LXXLL motif), which are inserted between split-CBLuc green (CBLuc-G). This probe set creates fingerprinting spectra from the characteristic green and red bioluminescence in response to agonistic and antagonistic activities of a ligand of interest. The present protocol further provides a unique methodology to calculate characteristic estrogenicity scores of various ligands from the spectra. PMID:27424902

  10. ANALYSIS OF LAGOON SAMPLES FROM DIFFERENT CONCENTRATED ANIMAL FEEDING OPERATIONS (CAFOS) FOR ESTROGENS AND ESTROGEN CONJUGATES (PRESENTATION)

    EPA Science Inventory

    Although Concentrated Animal Feeding Operations (CAFOs) have been identified as potentially important sources for the release of estrogens into the environment, information is lacking on the concentrations of estrogens in whole lagoon effluents (including suspended solids) which ...

  11. Exploration of Dimensions of Estrogen Potency

    PubMed Central

    Jeyakumar, M.; Carlson, Kathryn E.; Gunther, Jillian R.; Katzenellenbogen, John A.

    2011-01-01

    The estrogen receptors, ERα and ERβ, are ligand-regulated transcription factors that control gene expression programs in target tissues. The molecular events underlying estrogen action involve minimally two steps, hormone binding to the ER ligand-binding domain followed by coactivator recruitment to the ER·ligand complex; this ligand·receptor·coactivator triple complex then alters gene expression. Conceptually, the potency of an estrogen in activating a cellular response should reflect the affinities that characterize both steps involved in the assembly of the active ligand·receptor·coactivator complex. Thus, to better understand the molecular basis of estrogen potency, we developed a completely in vitro system (using radiometric and time-resolved FRET assays) to quantify independently three parameters: (a) the affinity of ligand binding to ER, (b) the affinity of coactivator binding to the ER·ligand complex, and (c) the potency of ligand recruitment of coactivator. We used this system to characterize the binding and potency of 12 estrogens with both ERα and ERβ. Some ligands showed good correlations between ligand binding affinity, coactivator binding affinity, and coactivator recruitment potency with both ERs, whereas others showed correlations with only one ER subtype or displayed discordant coactivator recruitment potencies. When ligands with low receptor binding affinity but high coactivator recruitment potencies to ERβ were evaluated in cell-based assays, elevation of cellular coactivator levels significantly and selectively improved their potency. Collectively, our results indicate that some low affinity estrogens may elicit greater cellular responses in those target cells that express higher levels of specific coactivators capable of binding to their ER complexes with high affinity. PMID:21321128

  12. 21 CFR 310.515 - Patient package inserts for estrogens.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Patient package inserts for estrogens. 310.515... package inserts for estrogens. (a) Requirement for a patient package insert. FDA concludes that the safe and effective use of drug products containing estrogens requires that patients be fully informed...

  13. 21 CFR 310.515 - Patient package inserts for estrogens.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Patient package inserts for estrogens. 310.515... package inserts for estrogens. (a) Requirement for a patient package insert. FDA concludes that the safe and effective use of drug products containing estrogens requires that patients be fully informed...

  14. 21 CFR 310.515 - Patient package inserts for estrogens.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Patient package inserts for estrogens. 310.515... package inserts for estrogens. (a) Requirement for a patient package insert. FDA concludes that the safe and effective use of drug products containing estrogens requires that patients be fully informed...

  15. 21 CFR 310.515 - Patient package inserts for estrogens.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Patient package inserts for estrogens. 310.515... package inserts for estrogens. (a) Requirement for a patient package insert. FDA concludes that the safe and effective use of drug products containing estrogens requires that patients be fully informed...

  16. Cumulative Estrogen Exposure and Prospective Memory in Older Women

    ERIC Educational Resources Information Center

    Hesson, Jacqueline

    2012-01-01

    This study looked at cumulative lifetime estrogen exposure, as estimated with a mathematical index (Index of Cumulative Estrogen Exposure (ICEE)) that included variables (length of time on estrogen therapy, age at menarche and menopause, postmenopausal body mass index, time since menopause, nulliparity and duration of breastfeeding) known to…

  17. 21 CFR 310.515 - Patient package inserts for estrogens.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Patient package inserts for estrogens. 310.515... package inserts for estrogens. (a) Requirement for a patient package insert. FDA concludes that the safe and effective use of drug products containing estrogens requires that patients be fully informed...

  18. Estrogen Abolishes Latent Inhibition in Ovariectomized Female Rats

    ERIC Educational Resources Information Center

    Nofrey, Barbara S.; Ben-Shahar, Osnat M.; Brake, Wayne G.

    2008-01-01

    Estrogen is frequently prescribed as a method of birth control and as hormone replacement therapy for post-menopausal women with varied effects on cognition. Here the effects of estrogen on attention were examined using the latent inhibition (LI) behavioral paradigm. Ovariectomized (OVX) female rats were given either estrogen benzoate (EB, 10 or…

  19. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.

    PubMed

    Khalil, Raouf A

    2013-12-15

    Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. PMID:24099797

  20. Estrogen, Vascular Estrogen Receptor and Hormone Therapy in Postmenopausal Vascular Disease

    PubMed Central

    Khalil, Raouf A.

    2013-01-01

    Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women’s Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject’s age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. PMID:24099797

  1. Histopathologic Effects of Estrogens on Marine Fishes

    EPA Science Inventory

    Endocrine-disrupting chemicals (EDCs), such as estrogens estradiol (E2) and ethinylestradiol (EE2) have been reported to affect fish reproduction. This study histologically compared and evaluated effects of EDCs in two species of treated fish. Juvenile male summer flounder (Paral...

  2. HUMAN HEALTH IMPACT OF ENVIRONMENTAL ESTROGENIC CHEMICALS

    EPA Science Inventory

    HUMAN HEALTH IMPACT OF ENVIRONMENTAL ESTROGENIC CHEMICALS.

    Robert J. Kavlock, Reproductive Toxicology Division, NHEERL, ORD, US Environmental Protection Agency, Research Triangle Park, NC USA.

    Over the past several decades a hypothesis has been put forth that a numb...

  3. Women's Skills Linked to Estrogen Levels.

    ERIC Educational Resources Information Center

    Weiss, R.

    1988-01-01

    Summarizes the result of research which considers the effect of women's hormone level on specific skills. Reports that low estrogen levels allow women to excel at spatial skills, but perform poorly at complex motor tasks and speech articulation. Discusses some implications and further research ideas. (YP)

  4. Targeted estrogen delivery reverses the metabolic syndrome

    PubMed Central

    Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Müller, Timo D; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C; García-Cáceres, Cristina; Kabra, Dhiraj G; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrabě; Tiano, Joseph P; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D; Tschöp, Matthias H

    2013-01-01

    We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases. PMID:23142820

  5. Melatonin and estrogen in breast cyst fluids.

    PubMed

    Burch, James B; Walling, Margie; Rush, Adam; Hennesey, Maxine; Craven, Winfield; Finlayson, Christina; Anderson, Benjamin O; Cosma, Greg; Wells, Robert L

    2007-07-01

    Increased breast cancer risks have been reported among women with gross cystic breast disease (GCBD), although the mechanism for this increase remains unexplained. Relationships between GCBD characteristics, breast cancer risk factors, and the biochemical composition and growth properties of 142 breast cyst fluid (BCF) samples were studied among 93 women with GCBD. Concentrations of melatonin, estrogen (17-beta-estradiol), dehydroepiandrosterone-sulfate (DHEA-S), epidermal growth factor (EGF), transforming growth factor beta (TGF-B1 and TGF-B2), sodium (Na), and potassium (K) were quantified in BCF samples, and human breast cancer cells (MCF-7) were treated with BCF in vitro. Patients were grouped according to BCF Na:K ratios previously linked with increased breast cancer risks (Na:K 3, Type 2) and mixed cyst groups. Women with larger and more frequently occurring cysts had higher BCF estrogen and DHEA-S, and lower TGF-B1 levels. Women with Type 1 cysts had elevated BCF melatonin, estrogen, DHEA-S, and EGF, and lower concentrations of TGF-B2 compared to women with Type 2 cysts. BCF generally inhibited cell growth relative to serum-treated controls, consistent with previous studies. Melatonin and estrogen in BCF independently predicted growth inhibition and stimulation, respectively. Biological monitoring of BCF may help identify women with GCBD at greatest risk for breast cancer development. PMID:17061046

  6. Estrogen receptor expert system overview and examples

    EPA Science Inventory

    The estrogen receptor expert system (ERES) is a rule-based system developed to prioritize chemicals based upon their potential for binding to the ER. The ERES was initially developed to predict ER affinity of chemicals from two specific EPA chemical inventories, antimicrobial pe...

  7. [Pharmacodynamics of synthetic estrogens. A review].

    PubMed

    Sojo-Aranda, I; Cortés-Gallegos, V

    1990-10-01

    Some details about the function of natural and synthetical hormonas are reviewed, particularly estrogens as ethynyl estradiol and its 3, Methyl ether (mestranol); its peripheral concentration vs tissular hormonal contents, a relationship of biological importance as the first step in its hormonal action and the cumulative local effects that could explain some intra and extracellular phenomena. PMID:2101377

  8. [Pharmacodynamics of synthetic estrogens. Review article].

    PubMed

    Sojo-Aranda, I; Cortés-Gallegos, V

    1990-10-01

    Some details about the function of natural and synthetical hormonas are reviewed, particularly estrogens as ethynyl estradiol and its 3, Methyl ether (mestranol); its peripheral concentration vs tissular hormonal contents, a relationship of biological importance as the first step in its hormonal action and the cummulative local effects that could explain some intra and extracellular phenomena. PMID:2292429

  9. In vitro estrogenicity of polybrominated flame retardants.

    PubMed

    Nakari, Tarja; Pessala, Piia

    2005-09-10

    Estrogenicity of five brominated flame retardants (BFRs), namely BDE-47, BDE-99, BDE-205, PBB-153 and technical Firemaster BP-6, were assessed by in vitro assays developed to detect chemicals with estrogenic properties. Recombinant yeast cells containing a human estrogen receptor gene failed to give any response to the chemicals tested. However, the positive control compound, estradiol-17beta, showed that the yeast cell assays had worked properly. The freshly separated fish hepatocyte assay based on the synthesis and secretion of vitellogenin from the isolated liver cells produced a clear dose-response curve in the presence of all tested flame retardants except Firemaster BP-6. The toxicity of the BFRs was detected by determining the cell ethoxyresorufin-O-deethylase activity (EROD). The BFRs tested induced hepatic EROD activity at low test concentrations, but started to inhibit activity at higher concentrations. The decreased detoxification capacity of the hepatocytes resulted in a decrease in the vitellogenin production of the cells. The capability of in vitro assays to detect estrogenic properties of chemicals seems to vary. Thus, further work is needed to understand the mechanisms responsible for these reactions. PMID:16024102

  10. Breast cancer survivors who use estrogenic botanical supplements have lower serum estrogen levels than non users

    PubMed Central

    Wayne, Sharon J; Neuhouser, Marian L; Koprowski, Carol; Ulrich, Cornelia M; Wiggins, Charles; Gilliland, Frank; Baumgartner, Kathy B; Baumgartner, Richard N; McTiernan, Anne; Bernstein, Leslie; Ballard-Barbash, Rachel

    2014-01-01

    Objective To measure the association between use of estrogenic botanical supplements and serum sex hormones in postmenopausal breast cancer survivors. Methods 502 postmenopausal women were queried 2-3 years after breast cancer diagnosis about their use of botanical supplements, and supplements were categorized according to their estrogenic properties. Concurrently, a fasting blood sample was obtained for assay of estrone, estradiol, free estradiol, testosterone, free testosterone, dehydroepiandrosterone sulfate (DHEAS) and sex hormone-binding globulin. Adjusted means of the serum hormones were calculated by use of estrogenic supplements. Results Women reporting use of any estrogenic botanical supplement had significantly lower levels of estrone (20.8 v 23.6 pg/mL), estradiol (12.8 v 14.7 pg/mL), free estradiol (0.29 v 0.35 pg/mL), and DHEAS (47.7 v 56.2 ug/dL) compared to women reporting no use. Conclusion Data from this cross-sectional study suggest the use of estrogenic botanical supplements may be associated with sex hormone concentrations in breast cancer survivors. Considering the high use of these supplements among breast cancer patients, further research is needed to clarify the relative estrogenicity/antiestrogenicity of these compounds and their relation with prognosis. PMID:18931907

  11. The other estrogen receptor in the plasma membrane: implications for the actions of environmental estrogens.

    PubMed Central

    Watson, C S; Pappas, T C; Gametchu, B

    1995-01-01

    Environmental or nutritional estrogenic toxicants are thought to mediate developmental and carcinogenic pathologies. Estrogen receptor (ER) measurements are currently used to predict hormonal responsiveness; therefore all ER subpopulations should be considered. We have been involved in the immunoidentification and characterization of membrane steroid receptors in several systems and have recently shown that binding of estradiol (E2) to a subpopulation of ERs (mER) residing in the plasma membrane of GH3 pituitary tumor cells mediates the rapid release of prolactin (PRL). Here we review these findings and present other important characterizations of these receptors such as trypsin and serum susceptibility, movement in the membrane, confocal localization to the membrane, binding to and function of impeded ligands, and immunoseparation of cells bearing mER. We plan to use this system as a model for both the physiological and pathological nongenomic effects of estrogens and estrogenic xenobiotics. Specifically, it should be useful as an in vitro assay system for the ability of estrogenic xenobiotics to cause rapid PRL release as an example of nongenomic estrogen effects. Images Figure 4. A Figure 4. B Figure 4. C Figure 4. D Figure 4. E Figure 4. F Figure 5. A Figure 5. B Figure 6. A Figure 6. B Figure 6. C Figure 7. A Figure 7. B Figure 7. C Figure 7. D PMID:8593873

  12. Identification of an estrogenic hormone receptor in Caenorhabditis elegans

    SciTech Connect

    Mimoto, Ai; Fujii, Madoka; Usami, Makoto; Shimamura, Maki; Hirabayashi, Naoko; Kaneko, Takako; Sasagawa, Noboru; Ishiura, Shoichi

    2007-12-28

    Changes in both behavior and gene expression occur in Caenorhabditis elegans following exposure to sex hormones such as estrogen and progesterone, and to bisphenol A (BPA), an estrogenic endocrine-disrupting compound. However, only one steroid hormone receptor has been identified. Of the 284 known nuclear hormone receptors (NHRs) in C. elegans, we selected nhr-14, nhr-69, and nhr-121 for analysis as potential estrogenic hormone receptors, because they share sequence similarity with the human estrogen receptor. First, the genes were cloned and expressed in Escherichia coli, and then the affinity of each protein for estrogen was determined using a surface plasmon resonance (SPR) biosensor. All three NHRs bound estrogen in a dose-dependent fashion. To evaluate the specificity of the binding, we performed a solution competition assay using an SPR biosensor. According to our results, only NHR-14 was able to interact with estrogen. Therefore, we next examined whether nhr-14 regulates estrogen signaling in vivo. To investigate whether these interactions actually control the response of C. elegans to hormones, we investigated the expression of vitellogenin, an estrogen responsive gene, in an nhr-14 mutant. Semi-quantitative RT-PCR showed that vitellogenin expression was significantly reduced in the mutant. This suggests that NHR-14 is a C. elegans estrogenic hormone receptor and that it controls gene expression in response to estrogen.

  13. Concentrations of estrogens in patients with preeclampsia.

    PubMed

    Zeisler, Harald; Jirecek, Stefan; Hohlagschwandtner, Maria; Knöfler, Martin; Tempfer, Clemens; Livingston, Jeffrey C

    2002-06-28

    The role of estrogens in the pathophysiology of preeclampsia remains to be determined. The aim of our study was to compare serum concentrations of 17 beta-estradiol and estriol in women with preeclampsia to normotensive pregnant controls. Serum concentrations of estrogens were measured in women with mild (n = 24) and severe (n = 24) preeclampsia as well as is normotensive pregnant controls (n = 24). Patients were matched for gestational age. Pregnancies complicated by early onset severe preeclampsia are associated with increased rates of maternal and fetal morbidity. Subsequently, we created further subgroups before and after 34 weeks of gestation (34 + 0). Serum estrogen concentrations were determined by standard ELISA technique. Compared to normotensive controls, the differences between the overall median serum concentrations of 17 beta-estradiol in women with mild (3811 v. 3730 pg/ml, P = 0.9) and severe (3811 v. 3630 pg/ml, P = 0.1) preeclampsia were statistically not significant. The differences between the overall median serum concentrations of estroil in controls and in patients with mild (121 v. 76 ng/ml, P = 0.6) and severe (121 v. 79 ng/ml, P = 0.4) preeclampsia were similar. The differences between the median concentrations of 17 beta-estradiol in patient with early onset severe preeclampsia compared to patients with mild preeclampsia (3061 v. 3715 pg/ml, P = 0.004) and controls (3061 v. 3807 pg/ml, P = 0.006) were statistically significant. In addition, the differences between the median concentrations of estriol in women with early onset severe preeclampsia compared to controls were statistically significant (20 v. 92 ng/ml, P = 0.02). The differences between the median concentrations of estrogens in those with late onset severe preeclampsia compared to women with mild preeclampsia were not significant. We found significantly lower concentrations of estrogens in women with early onset severe preeclampsia. PMID:12422581

  14. Calmodulin enhances the stability of the estrogen receptor.

    PubMed

    Li, Z; Joyal, J L; Sacks, D B

    2001-05-18

    The estrogen receptor mediates breast cell proliferation and is the principal target for chemotherapy of breast carcinoma. Previous studies have demonstrated that the estrogen receptor binds to calmodulin-Sepharose in vitro. However, the association of endogenous calmodulin with endogenous estrogen receptors in intact cells has not been reported, and the function of the interaction is obscure. Here we demonstrate by co-immunoprecipitation from MCF-7 human breast epithelial cells that endogenous estrogen receptors bind to endogenous calmodulin. Estradiol treatment of the cells had no significant effect on the interaction. However, incubation of the cells with tamoxifen enhanced by 5-10-fold the association of calmodulin with the estrogen receptor and increased the total cellular content of estrogen receptors by 1.5-2-fold. In contrast, the structurally distinct calmodulin antagonists trifluoperazine and CGS9343B attenuated the interaction between calmodulin and the estrogen receptor and dramatically reduced the number of estrogen receptors in the cell. Neither of these agents altered the amount of estrogen receptor mRNA, suggesting that calmodulin stabilizes the protein. This hypothesis is supported by the observation that, in the presence of Ca2+, calmodulin protected estrogen receptors from in vitro proteolysis by trypsin. Furthermore, overexpression of wild type calmodulin, but not a mutant calmodulin incapable of binding Ca2+, increased the concentration of estrogen receptors in MCF-7 cells, whereas transient expression of a calmodulin inhibitor peptide reduced the estrogen receptor concentration. These data demonstrate that calmodulin binds to the estrogen receptor in intact cells in a Ca2+-dependent, but estradiol-independent, manner, thereby modulating the stability and the steady state level of estrogen receptors. PMID:11278648

  15. Bridging the Gap From Screening Assays to Estrogenic Effects in Fish: Potential Roles of Multiple Estrogen Receptor Subtypes

    PubMed Central

    2015-01-01

    This study seeks to delineate the ligand interactions that drive biomarker induction in fish exposed to estrogenic pollutants and provide a case study on the capacity of human (h) estrogen receptor (ER)-based in vitro screening assays to predict estrogenic effects in aquatic species. Adult male Japanese medaka (Oryzias latipes) were exposed to solutions of singular steroidal estrogens or to the estrogenic extract of an anaerobic swine waste lagoon. All exposure concentrations were calibrated to be equipotent based on the yeast estrogen screen (YES), which reports activation of hERα. These exposures elicited significantly different magnitudes of hepatic vitellogenin and choriogenin gene induction in the male medaka. Effects of the same YES-calibrated solutions in the T47D-KBluc assay, which reports activation of hERα and hERβ, generally recapitulated observations in medaka. Using competitive ligand binding assays, it was found that the magnitude of vitellogenin/choriogenin induction by different estrogenic ligands correlated positively with preferential binding affinity for medaka ERβ subtypes, which are highly expressed in male medaka liver prior to estrogen exposure. Results support emerging evidence that ERβ subtypes are critically involved in the teleost estrogenic response, with the ERα:ERβ ratio being of particular importance. Accordingly, incorporation of multiple ER subtypes into estrogen screening protocols may increase predictive value for the risk assessment of aquatic systems, including complex estrogenic mixtures. PMID:24422420

  16. Analysis of estrogenic activity in environmental waters in Rio de Janeiro state (Brazil) using the yeast estrogen screen.

    PubMed

    Dias, Amanda Cristina Vieira; Gomes, Frederico Wegenast; Bila, Daniele Maia; Sant'Anna, Geraldo Lippel; Dezotti, Marcia

    2015-10-01

    The estrogenicity of waters collected from an important hydrological system in Brazil (Paraiba do Sul and Guandu Rivers) was assessed using the yeast estrogen screen (YES) assay. Sampling was performed in rivers and at the outlets of conventional water treatment plants (WTP). The removal of estrogenic activity by ozonation and chlorination after conventional water treatment (clarification and sand filtration) was investigated employing samples of the Guandu River spiked with estrogens and bisphenol A (BPA). The results revealed a preoccupying incidence of estrogenic activity at levels higher than 1ngL(-1) along some points of the rivers. Another matter of concern was the number of samples from WTPs presenting estrogenicity surpassing 1ngL(-1). The oxidation techniques (ozonation and chlorination) were effective for the removal of estrogenic activity and the combination of both techniques led to good results using less amounts of oxidants. PMID:26024813

  17. Estrogen Deficiency and the Origin of Obesity during Menopause

    PubMed Central

    Lizcano, Fernando; Guzmán, Guillermo

    2014-01-01

    Sex hormones strongly influence body fat distribution and adipocyte differentiation. Estrogens and testosterone differentially affect adipocyte physiology, but the importance of estrogens in the development of metabolic diseases during menopause is disputed. Estrogens and estrogen receptors regulate various aspects of glucose and lipid metabolism. Disturbances of this metabolic signal lead to the development of metabolic syndrome and a higher cardiovascular risk in women. The absence of estrogens is a clue factor in the onset of cardiovascular disease during the menopausal period, which is characterized by lipid profile variations and predominant abdominal fat accumulation. However, influence of the absence of these hormones and its relationship to higher obesity in women during menopause are not clear. This systematic review discusses of the role of estrogens and estrogen receptors in adipocyte differentiation, and its control by the central nervous systemn and the possible role of estrogen-like compounds and endocrine disruptors chemicals are discussed. Finally, the interaction between the decrease in estrogen secretion and the prevalence of obesity in menopausal women is examined. We will consider if the absence of estrogens have a significant effect of obesity in menopausal women. PMID:24734243

  18. Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer

    PubMed Central

    Mishra, Sweta; Tai, Qin; Gu, Xiang; Schmitz, James; Poullard, Ashley; Fajardo, Roberto J.; Mahalingam, Devalingam; Chen, Xiaodong; Zhu, Xueqiong; Sun, Lu-Zhe

    2015-01-01

    The role of estrogen signaling in regulating prostate tumorigenesis is relatively underexplored. Although, an increasing body of evidence has linked estrogen receptor beta (ERβ) to prostate cancer, the function of estrogen receptor alpha (ERα) in prostate cancer is not very well studied. We have discovered a novel role of ERα in the pathogenesis of prostate tumors. Here, we show that prostate cancer cells express ERα and estrogen induces oncogenic properties in prostate cancer cells through ERα. Importantly, ERα knockdown in the human prostate cancer PacMetUT1 cells as well as pharmacological inhibition of ERα with ICI 182,780 inhibited osteoblastic lesion formation and lung metastasis in vivo. Co-culture of pre-osteoblasts with cancer cells showed a significant induction of osteogenic markers in the pre-osteoblasts, which was attenuated by knockdown of ERα in cancer cells suggesting that estrogen/ERα signaling promotes crosstalk between cancer and osteoblastic progenitors to stimulate osteoblastic tumorigenesis. These results suggest that ERα expression in prostate cancer cells is essential for osteoblastic lesion formation and lung metastasis. Thus, inhibition of ERα signaling in prostate cancer cells may be a novel therapeutic strategy to inhibit the osteoblastic lesion development as well as lung metastasis in patients with advanced prostate cancer. PMID:26575018

  19. Delay in post-ovariectomy estrogen replacement negates estrogen-induced augmentation of post-exercise muscle satellite cell proliferation.

    PubMed

    Mangan, Gary; Iqbal, Sobia; Hubbard, Andrew; Hamilton, Victoria; Bombardier, Eric; Tiidus, Peter M

    2015-11-01

    This study examined the effects of a delay in post-ovariectomy replacement of 17β-estradiol (estrogen) on the post-exercise proliferation of muscle satellite cells. Nine-week-old, ovariectomized, female Sprague-Dawley rats (n = 64) were distributed among 8 groups based on estrogen status (0.25 mg estrogen pellet or sham), exercise status (90 min run at 17 m·min(-1) and a grade of -13.5° or unexercised), and estrogen replacement ("proximal", estrogen replacement within 2 weeks; or "delayed", estrogen replacement at 11 weeks following ovariectomy). Significant increases in satellite cells were found in the soleus and white gastrocnemius muscle (immunofluorescent colocalization of nuclei with Pax7) 72 h following eccentric exercise (p < 0.05) in all exercised groups. Proximal E2 replacement resulted in a further augmentation of muscle satellite cells in exercised rats (p < 0.05) relative to the delayed estrogen replacement group. Expression of PI3K was unaltered and phosphorylation of Akt relative to total Akt increased following estrogen supplementation and exercise. Exercise alone did not alter the expression levels of Akt. An 11 week delay in post-ovariectomy estrogen replacement negated the augmenting influence seen with proximal (2 week delay) post-ovariectomy estrogen replacement on post-exercise muscle satellite cell proliferation. This effect appears to be independent of the PI3K-Akt signaling pathway. PMID:26406298

  20. Sinonasal Leiomyoma With Estrogen Receptor Expression.

    PubMed

    Kim, Jong Seung; Shin, Jin Yong; Kwon, Sam Hyun

    2015-09-01

    Leiomyoma is an extremely rare tumor in sinonasal area. The reason for this is due to minimal amount of the smooth muscle in the area. The origin of this tumor is not clear and its etiology has not been proven in the literature. A 58-year-old woman who experienced nasal obstruction and epiphora visited our clinic. A huge mass was noted in right nasal cavity originating from the lacrimal bone area. The authors conducted endoscopic sinus surgery and obtained the specimen. Immunochemistry showed leiomyoma in the nasal cavity, which expressed estrogen receptor. There was no progesterone receptor expressed. The authors describe a sinonasal leiomyoma with estrogen receptors, not ever reported in previous article. PMID:26355987

  1. The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants.

    PubMed Central

    Soto, A M; Sonnenschein, C; Chung, K L; Fernandez, M F; Olea, N; Serrano, F O

    1995-01-01

    Estrogens are defined by their ability to induce the proliferation of cells of the female genital tract. The wide chemical diversity of estrogenic compounds precludes an accurate prediction of estrogenic activity on the basis of chemical structure. Rodent bioassays are not suited for the large-scale screening of chemicals before their release into the environment because of their cost, complexity, and ethical concerns. The E-SCREEN assay was developed to assess the estrogenicity of environmental chemicals using the proliferative effect of estrogens on their target cells as an end point. This quantitative assay compares the cell number achieved by similar inocula of MCF-7 cells in the absence of estrogens (negative control) and in the presence of 17 beta-estradiol (positive control) and a range of concentrations of chemicals suspected to be estrogenic. Among the compounds tested, several "new" estrogens were found; alkylphenols, phthalates, some PCB congeners and hydroxylated PCBs, and the insecticides dieldrin, endosulfan, and toxaphene were estrogenic by the E-SCREEN assay. In addition, these compounds competed with estradiol for binding to the estrogen receptor and increased the levels of progesterone receptor and pS2 in MCF-7 cells, as expected from estrogen mimics. Recombinant human growth factors (bFGF, EGF, IGF-1) and insulin did not increase in cell yields. The aims of the work summarized in this paper were a) to validate the E-SCREEN assay; b) to screen a variety of chemicals present in the environment to identify those that may be causing reproductive effects in wildlife and humans; c) to assess whether environmental estrogens may act cumulatively; and finally d) to discuss the reliability of this and other assays to screen chemicals for their estrogenicity before they are released into the environment. PMID:8593856

  2. Comparison of immunocytochemical estrogen receptor assay, estrogen receptor enzyme immunoassay, and radioligand-labeled estrogen receptor assay in human breast cancer and uterine tissue

    SciTech Connect

    Heubner, A.; Beck, T.; Grill, H.J.; Pollow, K.

    1986-08-01

    Determination of estrogen receptor content in 82 breast cancer specimens with immunocytochemical estrogen receptor assay (ER-EIA) (Abbott) was compared with our routinely used binding assay using /sup 125/I-estradiol as radioligand with Scatchard plot analysis of the binding data. Although the estrogen receptor content measured with the ER-EIA was approximately 2-fold higher compared with the binding assay, the immunochemical method proved to be a useful alternative for estrogen receptor determination. Furthermore, it is possible to detect estrogen receptors in FPLC Superose 12 (size exclusion column) eluates or in the fractions obtained after sucrose density centrifugation using the ER-EIA. Forty breast cancer samples were analyzed utilizing the immunocytochemical technique (ER-ICA) for visualization of the estrogen receptor content in frozen tumor tissues in relationship to the quantitative results obtained with the ER-EIA assay. Specific staining for estrogen receptor was confined only to the cell nucleus, was distributed irregularly among the tumor cells, and was variable in intensity. The staining intensity and the percentage of positively stained cells increased with increasing level of cytosolic estrogen receptor. In 27 of 40 cases the immunocytochemical results correlated well with the ER-EIA assay. Nine cases were ER-ICA negative with positive ER-EIA, and four were ER-ICA positive with negative ER-EIA.

  3. Exogenous pubertal induction by oral versus transdermal estrogen therapy.

    PubMed

    Kenigsberg, Lisa; Balachandar, Sadana; Prasad, Kris; Shah, Bina

    2013-04-01

    Hypogonadal adolescent girls need estrogen therapy for the induction of puberty. For years, oral conjugated estrogens have been used for this purpose, starting at a very low dose, with gradual increments over time, to allow for the maturation of the reproductive organs, in order to mimic physiologic conditions. Several concerns, mainly due to first pass through the liver, are manifest with oral estrogen therapy. With the advent of transdermal estrogens and its improved efficacy profile as well as reduced side effects, it seems reasonable to consider it for pubertal induction. The primary objective of this study was to compare and contrast oral versus transdermal estrogen with regard to metabolism and physiology and to review current available data on transdermal estrogens with respect to exogenous pubertal induction. PMID:22112543

  4. Estrogenic modulation of auditory processing: a vertebrate comparison

    PubMed Central

    Caras, Melissa L.

    2013-01-01

    Sex-steroid hormones are well-known regulators of vocal motor behavior in several organisms. A large body of evidence now indicates that these same hormones modulate processing at multiple levels of the ascending auditory pathway. The goal of this review is to provide a comparative analysis of the role of estrogens in vertebrate auditory function. Four major conclusions can be drawn from the literature: First, estrogens may influence the development of the mammalian auditory system. Second, estrogenic signaling protects the mammalian auditory system from noise- and age-related damage. Third, estrogens optimize auditory processing during periods of reproductive readiness in multiple vertebrate lineages. Finally, brain-derived estrogens can act locally to enhance auditory response properties in at least one avian species. This comparative examination may lead to a better appreciation of the role of estrogens in the processing of natural vocalizations and may provide useful insights toward alleviating auditory dysfunctions emanating from hormonal imbalances. PMID:23911849

  5. Estrogen treatment affects brain functioning after menopause.

    PubMed

    Bayer, Ulrike; Hausmann, Markus

    2011-12-01

    Sex hormones have powerful neuromodulatory effects on functional brain organization and cognitive functioning. This paper reviews findings from studies investigating the influence of sex hormones in postmenopausal women with and without hormone therapy (HT). Functional brain organization was investigated using different behavioural tasks in postmenopausal women using either estrogen therapy or combined estrogen plus gestagen therapy and age- and IQ-matched postmenopausal women not taking HT. The results revealed HT-related modulations in specific aspects of functional brain organization including functional cerebral asymmetries and interhemispheric interaction. In contrast to younger women during the menstrual cycle, however, it seems that HT, and especially estrogen therapy, after menopause affects intrahemispheric processing rather than interhemispheric interaction. This might be explained by a faster and more pronounced age-related decline in intrahemispheric relative to interhemispheric functioning, which might be associated with higher sensitivity to HT. Taken together, the findings suggest that the female brain retains its plasticity even after reproductive age and remains susceptible to the effects of sex hormones throughout the lifetime, which might help to discover new clinical approaches in the hormonal treatment of neurological and psychiatric disorders. PMID:22120942

  6. The role of estrogen in intrusive memories.

    PubMed

    Cheung, Jessica; Chervonsky, Liza; Felmingham, Kim L; Bryant, Richard A

    2013-11-01

    Intrusive memories are highly vivid, emotional and involuntary recollections which cause significant distress across psychological disorders including posttraumatic disorder (PTSD). Recent evidence has potentially extended our understanding of the development of intrusive memories by identifying biological factors which significantly impact on memories for emotionally arousing stimuli. This study investigated the role of stress on the development of intrusions for negative and neutral images, and indexed the potential contributions of sex (estrogen and progesterone) and stress (noradrenaline and cortisol) hormones. Whilst viewing the images, half the participants underwent a cold pressor stress (CPS) procedure to induce stress while the control participants immersed their hands in warm water. Saliva samples were collected to index estrogen, progesterone and noradrenergic and cortisol response. Participants (55 university students, 26 men, 29 women) viewed a series of negatively arousing and neutral images. Participants completed recall and intrusions measures 2 days later. Negative images resulted in greater recall and more intrusions than neutral images. In the cold water condition females recalled fewer neutral memories than males. Cortisol increase predicted decreased recall of negative memories in males, and estrogen predicted increased intrusions of negative images in women. These findings are consistent with evidence that circulating levels of ovarian hormones influence memory for emotionally arousing events, and provides the first evidence of the influence of sex hormones on intrusive memories. These results provide one possible explanation for the higher incidence of anxiety disorders in women. PMID:23891994

  7. Removal of estrogens by electrochemical oxidation process.

    PubMed

    Cong, Vo Huu; Iwaya, Sota; Sakakibara, Yutaka

    2014-06-01

    Treatments of estrogens such as Estrone (E1), Estradiol (E2) and Ethinylestradiol (EE2) were conducted using an electrolytic reactor equipped with multi-packed granular glassy carbon electrodes. Experimental results showed that E1, E2 and EE2 were oxidized in the range of 0.45-0.85 V and were removed through electro-polymerization. Observed data from continuous experiments were in good agreement with calculated results by a mathematical model constructed based on mass transfer limitation. In continuous treatment of trace estrogens (1 μg/L), 98% of E1, E2 and EE2 were stably removed. At high loading rate (100 μg/L), removal efficiency of E1 was kept around 74%-88% for 21 days, but removal efficiency reduced due to passivation of electrodes. However, removal efficiency was recovered after electrochemical regeneration of electrodes in presence of ozone. Electric energy consumption was observed in the range of 1-2 Wh/m(3). From these results, we concluded that the present electrochemical process would be an alternative removal of estrogens. PMID:25079848

  8. Estrogen sulfotransferases in breast and endometrial cancers.

    PubMed

    Pasqualini, Jorge Raul

    2009-02-01

    Estrogen sulfotransferase is significantly more active in the normal breast cell (e.g., Human 7) than in the cancer cell (e.g., MCF-7). The data suggest that in breast cancer sulfoconjugated activity is carried out by another enzyme, the SULT1A, which acts at high concentration of the substrates. In breast cancer cells sulfotransferase (SULT) activity can be stimulated by various progestins: medrogestone, promegestone, and nomegestrol acetate, as well as by tibolone and its metabolites. SULT activities can also be controlled by other substances including phytoestrogens, celecoxib, flavonoids (e.g., quercetin, resveratrol), and isoflavones. SULT expression was localized in breast cancer cells, which can be stimulated by promegestone and correlated with the increase of the enzyme activity. The estrogen sulfotransferase (SULT1E1), which acts at nanomolar concentration of estradiol, can inactivate most of this hormone present in the normal breast; however, in the breast cancer cells, the sulfotransferase denoted as SULT1A1 is mainly present, and this acts at micromolar concentrations of E(2). A correlation was postulated among breast cancer cell proliferation, the effect of various progestins, and sulfotransferase stimulation. In conclusion, it is suggested that factors involved in the stimulation of the estrogen sulfotransferases could provide new possibilities for the treatment of patients with hormone-dependent breast and endometrial cancers. PMID:19250196

  9. Estrogen and Xenoestrogens in Breast Cancer

    PubMed Central

    Fernandez, S.V.; Russo, J.

    2010-01-01

    There is growing concern that estrogenic environmental compounds that act as endocrine disrupting chemicals might potentially have adverse effects on hormone-sensitive organs such as the breast. This concern is further fueled by evidence indicating that natural estrogens, specifically 17 β-estradiol (E2), are important factors in the initiation and progression of breast cancer. We have developed an in vitro- in vivo model in which we have demonstrated the carcinogenicity of E2 in the human breast epithelial cells MCF-10F. Hypermethylation of NRG1, STXBP6, BMP6, CSS3, SPRY1 and SNIP were found at different progression stages in this model. The utilization of this powerful and unique model has provided a tool for exploring whether bisphenol A (BPA) and butyl benzyl phthalate (BBP) have relevance in the initiation of breast cancer. These studies provide first hand evidence that the natural estrogen 17 β-estradiol and xenoestrogenic substances like BPA are able to induce neoplastic transformation in human breast epithelial cells. PMID:19933552

  10. Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens

    PubMed Central

    Woolfrey, Kevin M.; Penzes, Peter

    2013-01-01

    Converging evidence from cellular, electrophysiological, anatomic, and behavioral studies suggests that the remodeling of synapse structure and function is a critical component of cognition. This modulation of neuroplasticity can be achieved through the actions of numerous extracellular signals. Moreover, it is thought that it is the integration of different extracellular signals regulation of neuroplasticity that greatly influences cognitive function. One group of signals that exerts powerful effects on multiple neurologic processes is estrogens. Classically, estrogens have been described to exert their effects over a period of hours to days. However, there is now increasing evidence that estrogens can rapidly influence multiple behaviors, including those that require forebrain neural circuitry. Moreover, these effects are found in both sexes. Critically, it is now emerging that the modulation of cognition by rapid estrogenic signaling is achieved by activation of specific signaling cascades and regulation of synapse structure and function, cumulating in the rewiring of neural circuits. The importance of understanding the rapid effects of estrogens on forebrain function and circuitry is further emphasized as investigations continue to consider the potential of estrogenic-based therapies for neuropathologies. This review focuses on how estrogens can rapidly influence cognition and the emerging mechanisms that underlie these effects. We discuss the potential sources and the biosynthesis of estrogens within the brain and the consequences of rapid estrogenic-signaling on the remodeling of neural circuits. Furthermore, we argue that estrogens act via distinct signaling pathways to modulate synapse structure and function in a manner that may vary with cell type, developmental stage, and sex. Finally, we present a model in which the coordination of rapid estrogenic-signaling and activity-dependent stimuli can result in long-lasting changes in neural circuits

  11. Estrogens and Prostate Cancer: Etiology, Mediators, Prevention, and Management

    PubMed Central

    Ho, Shuk-Mei; Lee, Ming-tsung; Lam, Hung-Ming; Leung, Yuet-Kin

    2011-01-01

    The relationship between hormones and the pathogenesis of prostate cancer (PCa) has been studied extensively. All the mainstay targets for hormonal PCa therapies are based on negating androgen action. Recent epidemiologic and experimental data have clearly pinpointed the key roles of estrogens in PCa development and progression. Racial and geographical differences, as well as age-associated changes, in estrogen synthesis and metabolism contribute significantly to the etiology by increasing the ratio of circulating estrogen to androgen, sex hormone binding globulin synthesis, and aromatase activity and reducing androgen glucuronidation and tissue bioactivation. Promotion of aberrant cell growth, evasion of apoptosis, increased oxidative stress and inflammation, and gains in adiposity and bioactivation to genotoxic carcinogens during adulthood are probable mechanisms of estrogen carcinogenicity, while “estrogen imprinting” via epigenetics in early-life also determines PCa risk. Although the effects of estrogens are known to be mediated by genomic actions of the two estrogen receptor (ER) subtypes (ERα and ERβ), other non-canonical mediators, including the different ERβ isoforms, membrane and mitochondrial ERs, and G protein-coupled receptor 30, may have major actions diverging from classical ER actions. These new discoveries have led to renewed interest among the public and the medicinal field in estrogens and antiestrogens as singular and adjuvant PCa treatment and prevention regimens. This review summarizes current knowledge on how different estrogens/antiestrogens/estrogen mimics contribute to prostate carcinogenesis, the roles of the different mediators of estrogen in the process, and the potentials of new estrogenic/antiestrogenic compounds as targeted therapies for prevention and treatment of PCa. PMID:21889723

  12. Zinc finger protein 131 inhibits estrogen signaling by suppressing estrogen receptor {alpha} homo-dimerization

    SciTech Connect

    Oh, Yohan; Chung, Kwang Chul

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer ZNF131 directly interacts with ER{alpha}. Black-Right-Pointing-Pointer The binding affinity of ZNF131 to ER{alpha} increases upon E2 stimulation. Black-Right-Pointing-Pointer ZNF131 inhibits ER{alpha}-mediated trans-activation by suppressing its homo-dimerization. Black-Right-Pointing-Pointer ZNF131 inhibits ER{alpha}-dimerization and E2-induced breast cancer cell proliferation. Black-Right-Pointing-Pointer ZNF131 inhibits estrogen signaling by acting as an ER{alpha}-co-repressor. -- Abstract: Steroid hormone estrogen elicits various physiological functions, many of which are mediated through two structurally and functionally distinct estrogen receptors, ER{alpha} and ER{beta}. The functional role of zinc finger protein 131 (ZNF131) is poorly understood, but it is assumed to possess transcriptional regulation activity due to the presence of a DNA binding motif. A few recent reports, including ours, revealed that ZNF131 acts as a negative regulator of ER{alpha} and that SUMO modification potentiates the negative effect of ZNF131 on estrogen signaling. However, its molecular mechanism for ER{alpha} inhibition has not been elucidated in detail. Here, we demonstrate that ZNF131 directly interacts with ER{alpha}, which consequently inhibits ER{alpha}-mediated trans-activation by suppressing its homo-dimerization. Moreover, we show that the C-terminal region of ZNF131 containing the SUMOylation site is necessary for its inhibition of estrogen signaling. Taken together, these data suggest that ZNF131 inhibits estrogen signaling by acting as an ER{alpha}-co-repressor.

  13. Computational estimation of rainbow trout estrogen receptor binding affinities for environmental estrogens

    SciTech Connect

    Shyu, Conrad; Cavileer, Timothy D.; Nagler, James J.; Ytreberg, F. Marty

    2011-02-01

    Environmental estrogens have been the subject of intense research due to their documented detrimental effects on the health of fish and wildlife and their potential to negatively impact humans. A complete understanding of how these compounds affect health is complicated because environmental estrogens are a structurally heterogeneous group of compounds. In this work, computational molecular dynamics simulations were utilized to predict the binding affinity of different compounds using rainbow trout (Oncorhynchus mykiss) estrogen receptors (ERs) as a model. Specifically, this study presents a comparison of the binding affinity of the natural ligand estradiol-17{beta} to the four rainbow trout ER isoforms with that of three known environmental estrogens 17{alpha}-ethinylestradiol, bisphenol A, and raloxifene. Two additional compounds, atrazine and testosterone, that are known to be very weak or non-binders to ERs were tested. The binding affinity of these compounds to the human ER{alpha} subtype is also included for comparison. The results of this study suggest that, when compared to estradiol-17{beta}, bisphenol A binds less strongly to all four receptors, 17{alpha}-ethinylestradiol binds more strongly, and raloxifene has a high affinity for the {alpha} subtype only. The results also show that atrazine and testosterone are weak or non-binders to the ERs. All of the results are in excellent qualitative agreement with the known in vivo estrogenicity of these compounds in the rainbow trout and other fishes. Computational estimation of binding affinities could be a valuable tool for predicting the impact of environmental estrogens in fish and other animals.

  14. Visualization of Estrogen Receptor Transcriptional Activation in Zebrafish

    PubMed Central

    Halpern, Marnie E.

    2011-01-01

    Estrogens regulate a diverse range of physiological processes and affect multiple tissues. Estrogen receptors (ERs) regulate transcription by binding to DNA at conserved estrogen response elements, and such elements have been used to report ER activity in cultured cells and in transgenic mice. We generated stable, transgenic zebrafish containing five consecutive elements upstream of a c-fos minimal promoter and green fluorescent protein (GFP) to visualize and quantify transcriptional activation in live larvae. Transgenic larvae show robust, dose-dependent estrogen-dependent fluorescent labeling in the liver, consistent with er gene expression, whereas ER antagonists inhibit GFP expression. The nonestrogenic steroids dexamethasone and progesterone fail to activate GFP, confirming ER selectivity. Natural and synthetic estrogens activated the transgene with varying potency, and two chemicals, genistein and bisphenol A, preferentially induce GFP expression in the heart. In adult fish, fluorescence was observed in estrogenic tissues such as the liver, ovary, pituitary gland, and brain. Individual estrogen-responsive neurons and their projections were visualized in the adult brain, and GFP-positive neurons increased in number after 17β-estradiol exposure. The transgenic estrogen-responsive zebrafish allow ER signaling to be monitored visually and serve as in vivo sentinels for detection of estrogenic compounds. PMID:21540282

  15. Insights from the Study of Animals Lacking Functional Estrogen Receptor

    NASA Astrophysics Data System (ADS)

    Korach, Kenneth S.

    1994-12-01

    Estrogen hormones produce physiological actions within a variety of target sites in the body and during development by activating a specific receptor protein. Hormone responsiveness for the estrogen receptor protein was investigated at different stages of development with the use of gene knockout techniques because no natural genetic mutants have been described. A mutant mouse line without a functional estrogen receptor was created and is being used to assess estrogen responsiveness. Both sexes of these mutant animals are infertile and show a variety of phenotypic changes, some of which are associated with the gonads, mammary glands, reproductive tracts, and skeletal tissues.

  16. Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors

    SciTech Connect

    Pinto, Caroline; Grimaldi, Marina; Boulahtouf, Abdelhay; Pakdel, Farzad; Brion, François; Aït-Aïssa, Sélim; Cavaillès, Vincent; Bourguet, William; Gustafsson, Jan-Ake; and others

    2014-10-01

    Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28 °C as compared to 37 °C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology. - Highlights: • Zebrafish is increasingly used to study the effects of estrogens. • We assessed the activity of pharmaceutical and environmental estrogens on zfERs. • Environmental estrogens displayed greater potency for zfERα compared to zfERβs. • hERβ selective agonists displayed greater potency for zf

  17. Rapid Signaling Actions of Environmental Estrogens in Developing Granule Cell Neurons Are Mediated by Estrogen Receptor β

    PubMed Central

    Le, Hoa H.; Belcher, Scott M.

    2010-01-01

    Estrogenic endocrine disrupting chemicals (EDCs) constitute a diverse group of man-made chemicals and natural compounds derived from plants and microbial metabolism. Estrogen-like actions are mediated via the nuclear hormone receptor activity of estrogen receptor (ER)α and ERβ and rapid regulation of intracellular signaling cascades. Previous study defined cerebellar granule cell neurons as estrogen responsive and that granule cell precursor viability was developmentally sensitive to estrogens. In this study experiments using Western blot analysis and pharmacological approaches have characterized the receptor and signaling modes of action of selective and nonselective estrogen ligands in developing cerebellar granule cells. Estrogen treatments were found to briefly increase ERK1/2-phosphorylation and then cause prolonged depression of ERK1/2 activity. The sensitivity of granule cell precursors to estrogen-induced cell death was found to require the integrated activation of membrane and intracellular ER signaling pathways. The sensitivity of granule cells to selective and nonselective ER agonists and a variety of estrogenic and nonestrogenic EDCs was also examined. The ERβ selective agonist DPN, but not the ERα selective agonist 4,4′,4′-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol or other ERα-specific ligands, stimulated cell death. Only EDCs with selective or nonselective ERβ activities like daidzein, equol, diethylstilbestrol, and bisphenol A were observed to induce E2-like neurotoxicity supporting the conclusion that estrogen sensitivity in granule cells is mediated via ERβ. The presented results also demonstrate the utility of estrogen sensitive developing granule cells as an in vitro assay for elucidating rapid estrogen-signaling mechanisms and to detect EDCs that act at ERβ to rapidly regulate intracellular signaling. PMID:20926581

  18. Comparative analysis of the interaction of various estrogens with the estrogen-receptor system of the uterus

    SciTech Connect

    Fanchenko, N.D.; Alekseeva, M.L.; Minina, L.S.; Novikov, E.A.; Khel'mun, D.K.

    1986-05-20

    The binding of various labeled estrogens under conditions of equilibrium in the cytosol of the uterus of sexually immature Wistar rats was studied. An analysis of the data obtained, as well as the kinetics of the dissociation of the complexes of the ligands used with specific high-affinity estrogen-binding sites of the cytosol, suggested that the population of estrogen receptors in the rat uterus is homogeneous. The possibility of intracellular regulation of the action of estrogens in the target cell in the presence of a homogeneous population of receptors, both at the receptor and at the post-receptor stages, is suggested.

  19. Environmental estrogens in an urban aquatic ecosystem: I. Spatial and temporal occurrence of estrogenic activity in effluent-dominated systems.

    PubMed

    Martinovic-Weigelt, Dalma; Minarik, Thomas A; Curran, Erin M; Marchuk, Jascha S; Pazderka, Matt J; Smith, Eric A; Goldenstein, Rachel L; Miresse, Christine L; Matlon, Thomas J; Schultz, Melissa M; Schoenfuss, Heiko L

    2013-11-01

    The present study investigated occurrence of environmental estrogens (EEs) in waterways managed by the Metropolitan Water Reclamation District of Greater Chicago ('District') - one of the largest and most complex water districts in the United States. The objectives of the study were: (i) to document spatial and temporal occurrence of EEs in the Chicago Area Waterways (CAWs); (ii) to determine whether water reclamation plant (WRP) effluents contribute to estrogenic pollution of the receiving streams; (iii) to determine whether the mandated water quality monitoring data could be used to predict estrogenic pollution in the receiving streams; and (iv) to determine whether snow melt, storm runoff and combined sewer overflows may also be contributors of estrogenic activity to these systems. The estrogenic potency of the waterways was assessed using a cell-based reporter gene assay. The water quality data was readily available as part of the District's regular monitoring program. Our findings indicate that EEs are commonly found in the CAWs, and that WRP effluents are one of, but not the only important contributor to estrogenic activity. Mean estrogenic activities in CAWs (11ng estradiol equivalents (EEQs/L)) are well within the values reported for other urban areas and WRP effluents. The estrogenic activity exhibited significant seasonal variation with highest values noted during the spring and summer months. When comparing the mean estrogenic activity of general use waters, secondary contact waters and WRP effluents, we found that general use waters had significantly lower estrogenic activity (ca 5ng EEQ/L) than the other two matrices (ca 15 and 17ng EEQ/L respectively). Our analyses indicate that estrogenic activity of the waterways was not reliably associated with mandated water quality parameters, and that such measurements may not be useful for predicting estrogenic activity, especially so in the complex urban systems. One of the prominent findings of this study is

  20. Manure-borne estrogens as potential environmental contaminants: a review.

    PubMed

    Hanselman, Travis A; Graetz, Donald A; Wilkie, Ann C

    2003-12-15

    Livestock wastes are potential sources of endocrine disrupting compounds to the environment. Steroidal estrogen hormones such as estradiol, estrone, and estriol are a particular concern because there is evidence that low nanogram per liter concentrations of estrogens in water can adversely affect the reproductive biology of fish and other aquatic vertebrate species. We performed a literature review to assess the current state of science regarding estrogen physicochemical properties, livestock excretion, and the fate of manure-borne estrogens in the environment. Unconjugated steroidal estrogens have low solubility in water (0.8-13.3 mg L(-1)) and are moderately hydrophobic (log Kow 2.6-4.0). Cattle excrete mostly 17alpha-estradiol, 17beta-estradiol, estrone, and respective sulfated and glucuronidated counterparts, whereas swine and poultry excrete mostly 17beta-estradiol, estrone, estriol, and respective sulfated and glucuronidated counterparts. The environmental fate of estrogens is not clearly known. Laboratory-based studies have found that the biological activity of these compounds is greatly reduced or eliminated within several hours to days due to degradation and sorption. On the other hand, field studies have demonstrated that estrogens are sufficiently mobile and persistent to impact surface and groundwater quality. Future research should use standardized methods for the analysis of manure, soil, and water. More information is needed about the types and amounts of estrogens that exist in livestock wastes and the fate of manure-borne estrogens applied to agricultural lands. Field and laboratory studies should work toward revealing the mechanisms of estrogen degradation, sorption, and transport so that the risk of estrogen contamination of waterways can be minimized. PMID:14717153

  1. Postmenopausal Estrogen Therapy and Depressive Symptoms in Older Women

    PubMed Central

    Whooley, Mary A; Grady, Deborah; Cauley, Jane A

    2000-01-01

    BACKGROUND Evidence regarding the effect of postmenopausal estrogen therapy on mood is limited. METHODS To determine whether postmenopausal estrogen therapy is associated with fewer depressive symptoms in elderly women, we conducted a cross-sectional study of 6,602 white women ages 71 years or older who were recruited from population-based listings in Baltimore, Md; Minneapolis, Minn; Portland, Ore; and the Monongahela Valley, Pa. Use of estrogen and progestin was determined by interview. Participants completed the Geriatric Depression Scale short form (GDS) and were considered depressed if they reported 6 or more of 15 possible symptoms of depression. RESULTS A total of 6.3% (72/1,150) of current estrogen users, 7.2% (142/1,964) of past estrogen users, and 9.0% (313/3,488) of never users reported 6 or more symptoms of depression (P = .004). Current estrogen users had a decreased risk of reporting 6 or more depressive symptoms, compared with not current (past or never) users of estrogen (odds ratio [OR], 0.7; 95% CI, 0.5 to 0.9; P = .01], adjusted for living alone, bilateral oophorectomy, current smoking, physical activity, social network, self-perceived health, cognitive function, functional status, and antidepressant use. However, excluding women who use estrogen or progestin alone, we were unable to find an association between current use of combined estrogen plus progestin therapy and depressive symptoms (adjusted OR, 0.8; 95% CI, 0.5 to 1.4; P = .5). CONCLUSIONS This cross-sectional study found that current use of unopposed estrogen was associated with a decreased risk of depressive symptoms in older women. Additional studies are needed to understand the effect of combined estrogen and progestin therapy on the prevalence of depressive symptoms in older women. PMID:10940144

  2. Is there a role for estrogen activity assays? Recombinant cell bioassay for estrogen: Development and applications.

    PubMed

    Klein, Karen Oerter

    2015-07-01

    There are many questions which cannot be answered without a very sensitive estradiol assay. A recombinant cell bioassay (RCBA) for estradiol was developed in 1994. The sensitivity of the bioassay is 0.02-0.2 pg/ml (0.07-0.7 pmol/L), more than 20 times more sensitive than commercial RIAs and 10 times more sensitive than newer mass spectrometry assays. The RCBA for estradiol opened the door to study low levels of estradiol equivalents (EE) across the physiological spectrum of life from prepubertal children through menopause and across the spectrum from normal physiology, in boys as well as girls, to pathology, including: premature thelarche; estradiol suppression in children treated with GnRH analogues for precocious puberty; aromatase inhibition in boys with growth hormone deficiency; the differences between oral and transdermal routes of estrogen administration in girls with Turner's syndrome; women with breast cancer treated with aromatase inhibitors; and women with urogenital atrophy treated with low dose vaginal estrogen. A bioassay also allows study of endocrine disruptors, like phytoestrogens and other environmental compounds, which are relevant to public health and alternative medicine options. This paper reviews the assay and the last 20 years of applications. A bioassay for estrogen has a role because measuring biological effect is theoretically useful, increasing the understanding of physiology in addition to biochemical levels, giving different information than other assays, and opening the door to measure very low levels of estrogen activity in both humans and the environment. PMID:25159103

  3. The in vivo estrogenic and in vitro anti-estrogenic activity of permethrin and bifenthrin

    PubMed Central

    Brander, Susanne M.; He, Guochun; Smalling, Kelly L.; Denison, Michael S.; Cherr, Gary N.

    2012-01-01

    Pyrethroids are highly toxic to fish at parts per billion or parts per trillion concentrations. Their intended mechanism is prolonged sodium channel opening, but recent studies reveal that pyrethroids such as permethrin and bifenthrin also have endocrine activity. Additionally, metabolites may have greater endocrine activity than parent compounds. We evaluated the in vivo concentration-dependent ability of bifenthrin and permethrin to induce choriogenin (an estrogen-responsive protein) in Menidia beryllina, a fish species known to reside in pyrethroid contaminated aquatic habitats. We then compared the in vivo response to an in vitro assay: CALUX (Chemical Activated Luciferase Gene Expression). Juvenile Menidia beryllina exposed to bifenthrin (1, 10, 100 ng/L), permethrin (0.1, 1, 10 µg/L), and ethinylestradiol (1, 10, 50 ng/L) had significantly higher ng/mL choriogenin (Chg) measured in whole body homogenate than controls. While Chg expression in fish exposed to ethinylestradiol (EE2) exhibited a traditional sigmoidal concentration-response, curves fit to Chg expressed in fish exposed to pyrethroids suggest a unimodal response, decreasing slightly as concentration increases. While the in vivo response indicated that bifenthrin and permethrin or their metabolites act as estrogen agonists, the CALUX assay demonstrated estrogen antagonism by the pyrethroids. Our results, supported by evidence from previous studies, suggest that bifenthrin and permethrin, and/or their metabolites, appear to act as estrogen receptor (ER) agonists in vivo, and that the unmetabolized pyrethroids, particularly bifenthrin, act as an ER antagonists in cultured mammalian cells. PMID:23007834

  4. Nonsteroidal Bivalent Estrogen Ligands - An Application of the Bivalent Concept to the Estrogen Receptor

    PubMed Central

    Shan, Min; Carlson, Kathryn E.; Bujotzek, Alexander; Wellner, Anja; Gust, Ronald; Weber, Marcus; Katzenellenbogen, John A.; Haag, Rainer

    2013-01-01

    The estrogen receptor (ER) is a hormone-regulated transcription factor that binds, as a dimer, to estrogens and to specific DNA sequences. To explore at a fundamental level the geometric and topological features of bivalent-ligand binding to the ER dimer, dimeric ER crystal structures were used to rationally design nonsteroidal bivalent estrogen ligands. Guided by this structure-based ligand design, we prepared two series of bivalent ligands (agonists and antagonists) tethered by flexible spacers of varying lengths (7–47Å) and evaluated their ER-binding affinities for the two ER subtypes and their biological activities in cell lines. Bivalent ligands based on the agonist diethylstilbestrol (DES) proved to be poor candidates, but bivalent ligands based on the antagonist hydroxytamoxifen (OHT) were well suited for intensive study. Binding affinities of the OHT-based bivalent ligands were related to spacer length in a distinctive fashion, reaching two maximum values at 14 and 29Å in both ER subtypes. These results demonstrate that the bivalent concept can operate in determining ER-ligand binding affinity and suggest that two distinct modes operate for the binding of bivalent estrogen ligands to the ER dimers, an intermolecular as well as an intramolecular mode. Our insights, particularly the possibility of intramolecular bivalent binding on a single ER monomer, may provide an alternative strategy to prepare more selective and active ER antagonists for endocrine therapy of breast cancer. PMID:23312071

  5. Estrogen receptors alpha mediates postischemic inflammation in chronically estrogen-deprived mice.

    PubMed

    Cordeau, Pierre; Lalancette-Hébert, Mélanie; Weng, Yuan Cheng; Kriz, Jasna

    2016-04-01

    Estrogens are known to exert neuroprotective and immuneomodulatory effects after stroke. However, at present, little is known about the role of estrogens and its receptors in postischemic inflammation after menopause. Here, we provide important in vivo evidence of a distinct shift in microglial phenotypes in the model of postmenopause brain. Using a model-system for live imaging of microglial activation in the context of chronic estrogen- and ERα-deficiency associated with aging, we observed a marked deregulation of the TLR2 signals and/or microglial activation in ovariectomized and/or ERα knockout mice. Further analysis revealed a 5.7-fold increase in IL-6, a 4.7-fold increase in phospho-Stat3 levels suggesting an overactivation of JAK/STAT3 pathway and significantly larger infarction in ERα knockouts chronically deprived of estrogen. Taken together, our results suggest that in the experimental model of menopause and/or aging, ERα mediates innate immune responses and/or microglial activation, and ischemia-induced production of IL-6. Based on our results, we propose that the loss of functional ERα may lead to deregulation of postischemic inflammatory responses and increased vulnerability to ischemic injury in aging female brains. PMID:26973103

  6. Is Soy Estrogenic? Hepatic Gene Expression in the Presence or Absence of Endogenous Estrogen

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to address the question of soy's estrogenicity by studying the hepatic gene expression (HGE) signature of diets made with soy protein isolate (SPI) fed in the presence or absence of estradiol (E2). Sprague-Dawley rats were ovariectomized (OVX) at PND50, infused with E...

  7. Estrogenic activity of UV filter mixtures.

    PubMed

    Kunz, Petra Y; Fent, Karl

    2006-11-15

    UV-absorbing chemicals (UV filters) are widely used for protection against UV radiation in sunscreens and in a variety of cosmetic products and materials. Depending on the breadth and factor of UV protection, they are added as single compounds or as a combination thereof. Some UV filters have estrogenic activity, but their activity and interactions in mixtures are largely unknown. In this work, we analyzed 8 commonly used UV filters, which are pure or partial hERalpha agonists, for their estrogenic activity in equieffective mixtures in a recombinant yeast assay carrying the human estrogen receptor alpha (hERalpha). Mixtures of two, four and eight UV filters alone, or in combination with 17 beta estradiol (E2), were assessed at different effect levels and no-observed-effect-concentrations (NOEC). Predictions of the joint effects of these mixtures were calculated by employing the concentration addition (CA) and independent action (IA) model. Most binary mixtures comprising of pure hERalpha agonists showed a synergistic activity at all mixture combinations. Only in combination with benzophenone-1, antagonistic activity was observed at some effect levels. All mixtures of four or eight, pure or pure and partial hERalpha agonists, alone or including E2, showed synergistic activity at concentrations giving an increase of 10% of basal activity (BC10). This occurred even at concentrations that were at the NOEC level of each single compound. Hence, there were substantial mixture effects even though each UV filter was present at its NOEC level. These results show that significant interactions occur in UV filter mixtures, which is important for the hazard and risk assessments of these personal care products. PMID:17027055

  8. Estrogenic activity of UV filter mixtures

    SciTech Connect

    Kunz, Petra Y. . E-mail: petra.kunz@fhnw.ch; Fent, Karl . E-mail: karl.fent@bluewin.ch

    2006-11-15

    UV-absorbing chemicals (UV filters) are widely used for protection against UV radiation in sunscreens and in a variety of cosmetic products and materials. Depending on the breadth and factor of UV protection, they are added as single compounds or as a combination thereof. Some UV filters have estrogenic activity, but their activity and interactions in mixtures are largely unknown. In this work, we analyzed 8 commonly used UV filters, which are pure or partial hER{alpha} agonists, for their estrogenic activity in equieffective mixtures in a recombinant yeast assay carrying the human estrogen receptor alpha (hER{alpha}). Mixtures of two, four and eight UV filters alone, or in combination with 17 {beta} estradiol (E2), were assessed at different effect levels and no-observed-effect-concentrations (NOEC). Predictions of the joint effects of these mixtures were calculated by employing the concentration addition (Canada) and independent action (IA) model. Most binary mixtures comprising of pure hER{alpha} agonists showed a synergistic activity at all mixture combinations. Only in combination with benzophenone-1, antagonistic activity was observed at some effect levels. All mixtures of four or eight, pure or pure and partial hER{alpha} agonists, alone or including E2, showed synergistic activity at concentrations giving an increase of 10% of basal activity (BC10). This occurred even at concentrations that were at the NOEC level of each single compound. Hence, there were substantial mixture effects even though each UV filter was present at its NOEC level. These results show that significant interactions occur in UV filter mixtures, which is important for the hazard and risk assessments of these personal care products.

  9. Isoflavones: estrogenic activity, biological effect and bioavailability.

    PubMed

    Vitale, Daniela Cristina; Piazza, Cateno; Melilli, Barbara; Drago, Filippo; Salomone, Salvatore

    2013-03-01

    Isoflavones are phytoestrogens with potent estrogenic activity; genistein, daidzein and glycitein are the most active isoflavones found in soy beans. Phytoestrogens have similarity in structure with the human female hormone 17-β-estradiol, which can bind to both alpha and beta estrogen receptors, and mimic the action of estrogens on target organs, thereby exerting many health benefits when used in some hormone-dependent diseases. Numerous clinical studies claim benefits of genistein and daidzein in chemoprevention of breast and prostate cancer, cardiovascular disease and osteoporosis as well as in relieving postmenopausal symptoms. The ability of isoflavones to prevent cancer and other chronic diseases largely depends on pharmacokinetic properties of these compounds, in particular absorption and distribution to the target tissue. The chemical form in which isoflavones occur is important because it influences their bioavailability and, therefore, their biological activity. Glucose-conjugated isoflavones are highly polar, water-soluble compounds. They are hardly absorbed by the intestinal epithelium and have weaker biological activities than the corresponding aglycone. Different microbial families of colon can transform glycosylated isoflavones into aglycones. Clinical studies show important differences between the aglycone and conjugated forms of genistein and daidzein. The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects. Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability. Complexation with cyclodextrin also represent a valid method to improve the physicochemical characteristics of these substances in order to be absorbed and distributed to target tissues. We review and discuss pharmacokinetic issues that critically influence the biological activity of isoflavones. PMID:23161396

  10. Effectiveness of estrogen replacement in restoration of cognitive function after long-term estrogen withdrawal in aging rats.

    PubMed

    Markowska, Alicja L; Savonenko, Alena V

    2002-12-15

    Recent studies suggest that some aspects of learning and memory may be altered by a midlife loss of estrogen, indicating a potential causal relationship between the deficiency of ovarian hormones and cognitive aging. In this study, the effects of estrogen withdrawal and replacement were tested in middle-aged Fischer-344 rats using different memory tasks. Estrogen withdrawal accelerated the rate of cognitive aging. A deficit first occurred 4 months after ovariectomy in working memory, which was tested in a delayed-nonmatching-to-position task, and progressed from long-delay to short-delay trials. Reference memory, which was tested in a place discrimination task and a split-stem T-maze, was not affected by aging or ovariectomy. The efficacy of estrogen in ameliorating the cognitive deficit in old rats depended on the type of treatment (acute vs chronic) and whether the aging-related decline in a particular cognitive process was aggravated by estrogen withdrawal. Chronic estrogen treatment (implants) was effective in improving working memory only when primed with repeated injections of estrogen, indicating that simulating the estrogen fluctuations of the estrous cycle may be more effective than the widely used mode of chronic pharmacological treatment. A challenge with scopolamine revealed that ovariectomy-induced cognitive deterioration coincided with a compromised cholinergic system. Importantly, the estrogen treatment that had restored effectively the cognitive abilities of old ovariectomized rats did not reduce their sensitivity to scopolamine. Taking into consideration that estrogen was highly effective against the amnestic action of scopolamine when tested in young-adult rats, these data emphasize that mechanisms of the protective effect of estrogen differ in young and old rats. PMID:12486194

  11. Comparing predicted estrogen concentrations with measurements in US waters.

    EPA Science Inventory

    The range of exposure rates to the steroidal estrogens estrone (E1), beta-estradiol (E2), estriol (E3), and ethinyl estradiol (EE2) in the aquatic environment was investigated by modeling estrogen introduction via municipal wastewater from sewage plants across the US. Model predi...

  12. Modulation of estrogenic effects by environmental temperature and food availability

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Endocrine-disrupting chemicals (EDCs), in combination with environmental influences, interfere with endocrine function in humans and wildlife. Estrogens are a type of EDC that may alter the hypothalamic-pituitary-gonadal axis in male fathead minnows, Pimephales promelas. The impact of estrogens on P...

  13. Estrogen receptor mutations in tamoxifen-resistant breast cancer.

    PubMed

    Karnik, P S; Kulkarni, S; Liu, X P; Budd, G T; Bukowski, R M

    1994-01-15

    Clinical resistance to antiestrogens like tamoxifen is a major problem in the treatment of hormone-dependent breast cancers. Since the estrogen receptor plays a central role in mediating the effects of estrogens and antiestrogens, we hypothesized that mutations in the estrogen receptor could be one mechanism by which breast tumors evolve from a hormone-dependent to a hormone-independent phenotype. The eight exons of the estrogen receptor complementary DNA from 20 tamoxifen-resistant and 20 tamoxifen-sensitive tumors were screened by Single Strand Conformation Polymorphism (SSCP), and the variant conformers were sequenced to identify the nucleotide changes. A 42-base pair replacement was found in exon 6 of a tamoxifen-resistant tumor. A single base pair deletion in exon 6 of a tamoxifen-resistant metastatic tumor but not in the primary tumor was detected in another case. If translated, both these mutations could generate truncated receptors with an intact DNA-binding domain and a defective hormone-binding domain that could constitutively activate transcription of previously estrogen-responsive genes. The remaining 18 of 20 tamoxifen-resistant tumors did not contain mutations in any of the 8 exons of the estrogen receptor complementary DNA. These results suggest that mutations in the estrogen receptor occur at a low frequency and do not account for most estrogen-independent, tamoxifen-resistant breast tumors. PMID:8275466

  14. Estrogen Actions on Mitochondria-Physiological and Pathological Implications

    PubMed Central

    Simpkins, James W.; Yang, ShaoHua; Sarkar, Saumyendra N.; Pearce, Virginia

    2009-01-01

    Estrogens are potent neuroprotective hormones and mitochondria are the site of cellular life-death decisions. As such, it is not surprising that we and other have shown that estrogens have remarkable effects on mitochondrial function. Herein we provide evidence for a primary effect of estrogens on mitochondrial function, achieved in part by the import of estrogen receptor β (ERβ) into the mitochondria where it mediates a number of estrogen actions on this vital organelle. ERβ is imported into the mitochondria, through tethering to cytosolic chaperone protein and/or through direct interaction with mitochondrial import proteins. In the mitochondria, ERβ can affect transcription of critical mitochondrial genes through the interaction with estrogen response elements (ERE) or through protein-protein interactions with mitochondrially imported transcription factors. The potent effects of estrogens on mitochondrial function, particularly during mitochondrial stress, argues for a role of estrogens in the treatment of mitochondrial defects in chronic neurodegenerative diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD) and more acute conditions of mitochondrial compromise, like cerebral ischemia and traumatic brain injury. PMID:18571833

  15. The Endocrine Role of Estrogens on Human Male Skeleton

    PubMed Central

    Rochira, Vincenzo; Kara, Elda; Carani, Cesare

    2015-01-01

    Before the characterization of human and animal models of estrogen deficiency, estrogen action was confined in the context of the female bone. These interesting models uncovered a wide spectrum of unexpected estrogen actions on bone in males, allowing the formulation of an estrogen-centric theory useful to explain how sex steroids act on bone in men. Most of the principal physiological events that take place in the developing and mature male bone are now considered to be under the control of estrogen. Estrogen determines the acceleration of bone elongation at puberty, epiphyseal closure, harmonic skeletal proportions, the achievement of peak bone mass, and the maintenance of bone mass. Furthermore, it seems to crosstalk with androgen even in the determination of bone size, a more androgen-dependent phenomenon. At puberty, epiphyseal closure and growth arrest occur when a critical number of estrogens is reached. The same mechanism based on a critical threshold of serum estradiol seems to operate in men during adulthood for bone mass maintenance via the modulation of bone formation and resorption in men. This threshold should be better identified in-between the ranges of 15 and 25 pg/mL. Future basic and clinical research will optimize strategies for the management of bone diseases related to estrogen deficiency in men. PMID:25873947

  16. Estrogens maintain skeletal muscle and satellite cell functions.

    PubMed

    Kitajima, Yuriko; Ono, Yusuke

    2016-06-01

    Estrogens have crucial roles in an extensive range of physiological functions regulating cellular proliferation and differentiation, development, homeostasis, and metabolism. Therefore, prolonged estrogen insufficiency influences various types of tissues expressing estrogen receptors (ERs). Although ERs are expressed in skeletal muscle and its stem cells, called satellite cells, how prolonged estrogen insufficiency affects their function remains unclear. In this study, we investigated the effect of estrogen reduction on muscle in young ovariectomized (OVX) female mice. We found that reduced estrogens resulted in muscle atrophy in a time-dependent manner. Muscle force generation was reduced in OVX mice. Interestingly, prolonged estrogen insufficiency shifted fiber types toward faster myosin heavy chain isoforms. The number of satellite cells per isolated myofiber was unchanged, while satellite cell expansion, differentiation, and self-renewal were all markedly impaired in OVX mice. Indeed, muscle regeneration was significantly compromised in OVX mice. Taken together, our results demonstrate that estrogens are essential for comprehensively maintaining muscle function with its insufficiency affecting muscle strength and regeneration in young female mice. PMID:27048232

  17. Bioluminescent bioreporter integrated circuit devices and methods for detecting estrogen

    DOEpatents

    Simpson, Michael L.; Paulus, Michael J.; Sayler, Gary S.; Applegate, Bruce M.; Ripp, Steven A.

    2006-08-15

    Bioelectronic devices for the detection of estrogen include a collection of eukaryotic cells which harbor a recombinant lux gene from a high temperature microorganism wherein the gene is operably linked with a heterologous promoter gene. A detectable light-emitting lux gene product is expressed in the presence of the estrogen and detected by the device.

  18. Bioassay- versus analytically-derived estrogen equivalents: Ramifications for monitoring

    EPA Science Inventory

    Due to concern for possible endocrine-related effects on aquatic vertebrates, environmental estrogens (EEs) are a growing focus of surface water contaminant monitoring programs. Some efforts utilize measurement of a targeted set of chemicals known to act as estrogen receptor (ER)...

  19. Breast-related effects of selective estrogen receptor modulators and tissue-selective estrogen complexes

    PubMed Central

    2014-01-01

    A number of available treatments provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis. However, as breast safety is a major concern, new options are needed, particularly agents with an improved mammary safety profile. Results from several large randomized and observational studies have shown an association between hormone therapy, particularly combined estrogen-progestin therapy, and a small increased risk of breast cancer and breast pain or tenderness. In addition, progestin-containing hormone therapy has been shown to increase mammographic breast density, which is an important risk factor for breast cancer. Selective estrogen receptor modulators (SERMs) provide bone protection, are generally well tolerated, and have demonstrated reductions in breast cancer risk, but do not relieve menopausal symptoms (that is, vasomotor symptoms). Tissue-selective estrogen complexes (TSECs) pair a SERM with one or more estrogens and aim to blend the positive effects of the components to provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis without stimulating the breast or endometrium. One TSEC combination pairing conjugated estrogens (CEs) with the SERM bazedoxifene (BZA) has completed clinical development and is now available as an alternative option for menopausal therapy. Preclinical evidence suggests that CE/BZA induces inhibitory effects on breast tissue, and phase 3 clinical studies suggest breast neutrality, with no increases seen in breast tenderness, breast density, or cancer. In non-hysterectomized postmenopausal women, CE/BZA was associated with increased bone mineral density and relief of menopausal symptoms, along with endometrial safety. Taken together, these results support the potential of CE/BZA for the relief of menopausal symptoms and prevention of postmenopausal osteoporosis combined with breast and endometrial safety. PMID:25928299

  20. Assaying estrogenicity by quantitating the expression levels of endogenous estrogen-regulated genes.

    PubMed Central

    Jørgensen, M; Vendelbo, B; Skakkebaek, N E; Leffers, H

    2000-01-01

    Scientific evidence suggests that humans and wildlife species may experience adverse health consequences from exposure to environmental chemicals that interact with the endocrine system. Reliable short-term assays are needed to identify hormone-disrupting chemicals. In this study we demonstrate that the estrogenic activity of a chemical can be evaluated by assaying induction or repression of endogenous estrogen-regulated "marker genes" in human breast cancer MCF-7 cells. We included four marker genes in the assay--pS2, transforming growth factor beta3 (TGFbeta3), monoamine oxidase A, and [alpha]1-antichymotrypsin--and we evaluated estrogenic activity for 17beta-estradiol (E(2)), diethylstilbestrol, [alpha]-zearalanol, nonylphenol, genistein, methoxychlor, endosulphan, o,p-DDE, bisphenol A, dibutylphthalate, 4-hydroxy tamoxifen, and ICI 182.780. All four marker genes responded strongly to the three high-potency estrogens (E(2), diethylstilbestrol, and [alpha]-zearalanol), whereas the potency of the other chemicals was 10(3)- to 10(6)-fold lower than that of E(2). There were some marker gene-dependent differences in the relative potencies of the tested chemicals. TGFbeta3 was equally sensitive to the three high-potency estrogens, whereas the sensitivity to [alpha]-zearalanol was approximately 10-fold lower than the sensitivity to E(2) and diethylstilbestrol when assayed with the other three marker genes. The potency of nonylphenol was equal to that of genistein when assayed with pS2 and TGFbeta3, but 10- to 100-fold higher/lower with monoamine oxidase A and [alpha]1-antichymotrypsin, respectively. The results are in agreement with results obtained by other methods and suggest that an assay based on endogenous gene expression may offer an attractive alternative to other E-SCREEN methods. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:10811566

  1. Caffeine, coffee and tea intake and urinary estrogens and estrogen metabolites in premenopausal women

    PubMed Central

    Sisti, Julia S.; Hankinson, Susan E.; Caporaso, Neil E.; Gu, Fangyi; Tamimi, Rulla M.; Rosner, Bernard; Xu, Xia; Ziegler, Regina; Eliassen, A. Heather

    2015-01-01

    Background Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. Methods High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses’ Health Study II with mid-luteal phase urine samples and caffeine, coffee and/or tea intakes from self-reported food frequency questionnaires. Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways and ratios by intake categories, and P-values for tests of linear trend. Results Compared to women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16α-hydroxyestrone (28% difference; P-trend=0.01) and 16-epiestriol (13% difference; P-trend=0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (P-trend=0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, ≥4 cups/day vs. ≤6 cups/week; P-trend=0.001) and 2-hydroxyestrone (52% difference; P-trend=0.001), and several ratio measures. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. lowest) category of intake (≥2 cups/day vs. ≤1–3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference; P-trend=0.01) and 17-epiestriol (48% difference; Ptrend=0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; Ptrend=0.01). Conclusion Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. Impact Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism. PMID:26063478

  2. Evolution of estrogen receptors in ray-finned fish and their comparative responses to estrogenic substances.

    PubMed

    Tohyama, Saki; Miyagawa, Shinichi; Lange, Anke; Ogino, Yukiko; Mizutani, Takeshi; Ihara, Masaru; Tanaka, Hiroaki; Tatarazako, Norihisa; Kobayashi, Tohru; Tyler, Charles R; Iguchi, Taisen

    2016-04-01

    In vertebrates, estrogens play fundamental roles in regulating reproductive activities through estrogen receptors (ESRs), and disruption of estrogen signaling is now of global concern for both wildlife and human health. To date, ESRs of only a limited number of species have been characterized. We investigated the functional diversity and molecular basis or ligand sensitivity of ESRs among ray-finned fish species (Actinopterygii), the most variable group within vertebrates. We cloned and characterized ESRs from several key species in the evolution of ray-finned fish including bichir (Polypteriformes, ESR1 and ESR2) at the basal lineage of ray-finned fish, and arowana (Osteoglossiformes, ESR1 and ESR2b) and eel (Anguilliformes, ESR1, ESR2a and ESR2b) both belonging to ancient early-branching lineages of teleosts, and suggest that ESR2a and ESR2b emerged through teleost-specific whole genome duplication, but an ESR1 paralogue has been lost in the early lineage of euteleost fish species. All cloned ESR isoforms showed similar responses to endogenous and synthetic steroidal estrogens, but they responded differently to non-steroidal estrogenic endocrine disrupting chemicals (EDCs) (e.g., ESR2a exhibits a weaker reporter activity compared with ESR2b). We show that variation in ligand sensitivity of ESRs can be attributed to phylogeny among species of different taxonomic groups in ray-finned fish. The molecular information provided contributes both to understanding of the comparative role of ESRs in the reproductive biology of fish and their comparative responses to EDCs. PMID:26707410

  3. Alcohol Consumption and Urinary Estrogens and Estrogen Metabolites in Premenopausal Women.

    PubMed

    Hartman, Terryl J; Sisti, Julia S; Hankinson, Susan E; Xu, Xia; Eliassen, A Heather; Ziegler, Regina

    2016-02-01

    In a cross-sectional analysis, we evaluated the associations of usual total alcohol and wine intake with a comprehensive profile of mid-luteal phase urinary estrogens and estrogen metabolites (referred to jointly as EM) in a sample of 603 premenopausal women participating in the Nurses' Health Study II (NHSII). A total of 15 individual EM (pmol/mg creatinine) were measured by a liquid chromatography/tandem mass spectrometry (LC-MS/MS) method with high accuracy and reproducibility. We used linear mixed models to calculate the adjusted geometric means of individual EM, EM grouped by metabolic pathways, and pathway ratios by category of alcohol intake with non-drinkers of alcohol as the referent. Total alcohol intake was not associated with total EM but was positively associated with estradiol (26% higher among women consuming >15 g/day vs. non-drinkers; P trend = 0.03). Wine consumption was positively associated with a number of EM measures including estradiol (22% higher among women consuming ≥ 5 drinks/week vs. non-drinkers, P trend < 0.0001). In conclusion, the total alcohol intake was positively and significantly associated with urinary estradiol levels. Some differences in urinary estrogen metabolites were observed with wine drinking, when compared with non-drinkers. This study strengthens the evidence that alcohol consumption might play a role in breast cancer and other estrogen-related conditions. Additional studies of premenopausal women are needed to further explore the association of alcohol, particularly the specific types of alcohol, on patterns of estrogen metabolism in blood, urine, and tissue. PMID:26728472

  4. Mouse monoclonal antibodies against estrogen receptor.

    PubMed

    De Rosa, Caterina; Rossi, Valentina; Abbondanza, Ciro

    2014-01-01

    The production of monoclonal antibodies, by cloning hybridoma derived from the fusion of myeloma cells and spleen lymphocytes, has allowed to obtain great advances in many fields of biological knowledge. The use of specific antibodies to the estrogen receptor, in fact, has been an invaluable method to bring out its mechanisms of action and its effects, both genomic and extra-genomic. Here we describe, step by step, the production of monoclonal antibodies, starting from protocol for antigen preparation to the selection of antibody-secreting hybridoma. PMID:25182770

  5. Multiple sclerosis at menopause: Potential neuroprotective effects of estrogen.

    PubMed

    Christianson, Mindy S; Mensah, Virginia A; Shen, Wen

    2015-02-01

    Multiple sclerosis (MS) is an autoimmune demyelinating and neurodegenerative condition of the central nervous system that preferentially afflicts women more than men. Low estrogen states such as menopause and the postpartum period favor exacerbations of multiple sclerosis in women with the disease. Existing and emerging evidence suggests a role for estrogen in the alleviation of symptoms and reversal of pathology associated with MS. While clinical evidence is sparse regarding the benefit of estrogen therapy for women at risk for MS exacerbations, scientific data demonstrates that estrogen potentiates numerous neuroprotective effects on the central nervous system (CNS). Estrogens play a wide range of roles involved in MS disease pathophysiology, including increasing antiinflammatory cytokines, decreasing demyelination, and enhancing oxidative and energy producing processes in CNS cells. PMID:25544310

  6. Estrogen therapy for severe persistent depressions in women.

    PubMed

    Klaiber, E L; Broverman, D M; Vogel, W; Kobayashi, Y

    1979-05-01

    Positive results are reported from a double-blind study of estrogen therapy administered to severely depressed, inpatient women who had failed to respond to various conventional treatments of depression. Large doses of oral conjugated estrogen were administered for a three-month period to 23 premenopausal and postmenopausal inpatient women. Placebos were administered for a comparable period to 17 similar patients. The posttreatment Hamilton ratings of depression were significantly reduced in the estrogen-treated group, but not in the placebo group. Possible physiological mechanisms are discussed. The risk-benefit ratio for estrogen therapy of depression in these patients was judged to be favorable. However, periodic endometrial biopsies are required to monitor the endometrial response of women receiving high doses of estrogens. PMID:219802

  7. Science Signaling podcast for 24 May 2016: Designer estrogens.

    PubMed

    Katzenellenbogen, Benita S; Katzenellenbogen, John A; Madak-Erdogan, Zeynep; VanHook, Annalisa M

    2016-01-01

    This Podcast features an interview with Zeynep Madak-Erdogan, Benita Katzenellenbogen, and John Katzenellenbogen, authors of a Research Article that appears in the 24 May 2016 issue of Science Signaling, about designer estrogens that have the therapeutic benefits of natural estrogens, but less cancer risk. In addition to controlling female reproduction and secondary sex characteristics, estrogen is also an important regulator of metabolism, the vasculature, and bone. Estrogen production decreases as women enter menopause, leading to changes in metabolism, a reduced ability to repair blood vessels, and decreased bone density. Although hormone replacement therapy can alleviate these symptoms, it can also promote the growth of uterine and breast cancers. Madak-Erdogan et al engineered synthetic forms of estrogen that activate the cytosolic signaling pathways that are associated with the beneficial effects of this hormone without also activating the nuclear signaling events associated with cancer growth.Listen to Podcast. PMID:27221709

  8. The Antidepressant-like Effects of Estrogen-mediated Ghrelin

    PubMed Central

    Wang, Pu; Liu, Changhong; Liu, Lei; Zhang, Xingyi; Ren, Bingzhong; Li, Bingjin

    2015-01-01

    Ghrelin, one of the brain-gut peptides, stimulates food-intake. Recently, ghrelin has also shown to play an important role in depression treatment. However, the mechanism of ghrelin’s antidepressant-like actions is unknown. On the other hand, sex differences in depression, and the fluctuation of estrogens secretion have been proved to play a key role in depression. It has been reported that women have higher level of ghrelin expression, and ghrelin can stimulate estrogen secretion while estrogen acts as a positive feedback mechanism to up-regulate ghrelin level. Ghrelin may be a potential regulator of reproductive function, and estrogen may have additional effect in ghrelin’s antidepressantlike actions. In this review, we summarize antidepressant-like effects of ghrelin and estrogen in basic and clinical studies, and provide new insight on ghrelin’s effect in depression. PMID:26412072

  9. Androgens and estrogens in skeletal sexual dimorphism.

    PubMed

    Laurent, Michaël; Antonio, Leen; Sinnesael, Mieke; Dubois, Vanessa; Gielen, Evelien; Classens, Frank; Vanderschueren, Dirk

    2014-01-01

    Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T) to estradiol (E2) by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution) peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refi ned our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen defi ciency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the fi eld of sex steroid actions in male bone homeostasis. PMID:24385015

  10. Contemporary Alternatives to Plant Estrogens for Menopause

    PubMed Central

    Geller, Stacie E.; Studee, Laura

    2006-01-01

    Objectives Every year, millions of women begin the peri-menopause and may experience a number of symptoms related to this transition. Many women are reluctant to use exogenous hormone therapy for treatment of menopausal symptoms and are turning to botanical and dietary supplements (BDS) for relief. This paper reviews the literature on alternatives to plant estrogens for relief of menopausal symptoms. Methods The MEDLINE database was searched for clinical trials of non-estrogenic plant extracts for menopausal symptoms. To be included, studies had to include peri- or postmenopausal women as subjects. All clinical trials (randomized-controlled trials, open trials, and comparison group studies) were included for this review. Results Black Cohosh appears to be one of the most effective botanicals for relief of vasomotor symptoms, while St. John’s wort can improve mood disorders related to the menopausal transition. Many other botanicals have limited evidence to demonstrate safety and efficacy for relief of symptoms related to menopause. Conclusions A growing body of evidence suggests that some botanicals and dietary supplements could result in improved clinical outcomes. Health care providers should discuss these issues with their patients so they can assist them in managing these alternative therapies through an evidence-based approach. PMID:16884867

  11. Licorice root components in dietary supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic activities.

    PubMed

    Boonmuen, Nittaya; Gong, Ping; Ali, Zulfiqar; Chittiboyina, Amar G; Khan, Ikhlas; Doerge, Daniel R; Helferich, William G; Carlson, Kathryn E; Martin, Teresa; Piyachaturawat, Pawinee; Katzenellenbogen, John A; Katzenellenbogen, Benita S

    2016-01-01

    Licorice root extracts are often consumed as botanical dietary supplements by menopausal women as a natural alternative to pharmaceutical hormone replacement therapy. In addition to their components liquiritigenin (Liq) and isoliquiritigenin (Iso-Liq), known to have estrogenic activity, licorice root extracts also contain a number of other flavonoids, isoflavonoids, and chalcones. We have investigated the estrogenic activity of 7 of these components, obtained from an extract of Glycyrrhiza glabra powder, namely Glabridin (L1), Calycosin (L2), Methoxychalcone (L3), Vestitol (L4), Glyasperin C (L5), Glycycoumarin (L6), and Glicoricone (L7), and compared them with Liq, Iso-Liq, and estradiol (E2). All components, including Liq and Iso-Liq, have low binding affinity for estrogen receptors (ERs). Their potency and efficacy in stimulating the expression of estrogen-regulated genes reveal that Liq and Iso-Liq and L2, L3, L4, and L6 are estrogen agonists. Interestingly, L3 and L4 have an efficacy nearly equivalent to E2 but with a potency ca. 10,000-fold less. The other components, L1, L5 and L7, acted as partial estrogen antagonists. All agonist activities were reversed by the antiestrogen, ICI 182,780, or by knockdown of ERα with siRNA, indicating that they are ER dependent. In HepG2 hepatoma cells stably expressing ERα, only Liq, Iso-Liq, and L3 stimulated estrogen-regulated gene expression, and in all cases gene stimulation did not occur in HepG2 cells lacking ERα. Collectively, these findings classify the components of licorice root extracts as low potency, mixed ER agonists and antagonists, having a character akin to that of selective estrogen receptor modulators or SERMs. PMID:26631549

  12. Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-{alpha} with BCAR1 and Traf6

    SciTech Connect

    Robinson, Lisa J.; Yaroslavskiy, Beatrice B.; Griswold, Reed D.; Zadorozny, Eva V.; Guo, Lida; Tourkova, Irina L.; Blair, Harry C.

    2009-04-15

    The effects of estrogen on osteoclast survival and differentiation were studied using CD14-selected mononuclear osteoclast precursors from peripheral blood. Estradiol at {approx} 1 nM reduced RANKL-dependent osteoclast differentiation by 40-50%. Osteoclast differentiation was suppressed 14 days after addition of RANKL even when estradiol was withdrawn after 18 h. In CD14+ cells apoptosis was rare and was not augmented by RANKL or by 17-{beta}-estradiol. Estrogen receptor-{alpha} (ER{alpha}) expression was strongly down-regulated by RANKL, whether or not estradiol was present. Mature human osteoclasts thus cannot respond to estrogen via ER{alpha}. However, ER{alpha} was present in CD14+ osteoclast progenitors, and a scaffolding protein, BCAR1, which binds ER{alpha} in the presence of estrogen, was abundant. Immunoprecipitation showed rapid ({approx} 5 min) estrogen-dependent formation of ER{alpha}-BCAR1 complexes, which were increased by RANKL co-treatment. The RANKL-signaling intermediate Traf6, which regulates NF-{kappa}B activity, precipitated with this complex. Reduction of NF-{kappa}B nuclear localization occurred within 30 min of RANKL stimulation, and estradiol inhibited the phosphorylation of I{kappa}B in response to RANKL. Inhibition by estradiol was abolished by siRNA knockdown of BCAR1. We conclude that estrogen directly, but only partially, curtails human osteoclast formation. This effect requires BCAR1 and involves a non-genomic interaction with ER{alpha}.

  13. 21 CFR 862.1270 - Estrogens (total, in pregnancy) test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Estrogens (total, in pregnancy) test system. 862... Test Systems § 862.1270 Estrogens (total, in pregnancy) test system. (a) Identification. As estrogens (total, in pregnancy) test system is a device intended to measure total estrogens in plasma, serum,...

  14. Estrogenic effects of marijuana smoke condensate and cannabinoid compounds

    SciTech Connect

    Lee, Soo Yeun; Oh, Seung Min; Chung, Kyu Hyuck . E-mail: khchung@skku.edu

    2006-08-01

    Chronic exposure to marijuana produces adverse effects on the endocrine and reproductive systems in humans; however, the experimental evidence for this presented thus far has not been without controversy. In this study, the estrogenic effect of marijuana smoke condensate (MSC) was evaluated using in vitro bioassays, viz., the cell proliferation assay, the reporter gene assay, and the ER competitive binding assay. The results of these assays were compared with those of three major cannabinoids, i.e., THC, CBD, and CBN. The estrogenic effect of MSC was further confirmed by the immature female rat uterotrophic assay. MSC stimulated the estrogenicity related to the ER-mediated pathway, while neither THC, CBD, nor CBN did. Moreover, treatment with 10 and 25 mg/kg MSC induced significant uterine response, and 10 mg/kg MSC resulted in an obvious change in the uterine epithelial cell appearance. MSC also enhanced the IGFBP-1 gene expression in a dose-dependent manner. To identify the constituents of MSC responsible for its estrogenicity, the MSC fractionated samples were examined using another cell proliferation assay, and the estrogenic active fraction was analyzed using GC-MS. In the organic acid fraction that showed the strongest estrogenic activity among the seven fractions of MSC, phenols were identified. Our results suggest that marijuana abuse is considered an endocrine-disrupting factor. Furthermore, these results suggest that the phenolic compounds contained in MSC play a role in its estrogenic effect.

  15. Estrogen deficiency heterogeneously affects tissue specific stem cells in mice

    PubMed Central

    Kitajima, Yuriko; Doi, Hanako; Ono, Yusuke; Urata, Yoshishige; Goto, Shinji; Kitajima, Michio; Miura, Kiyonori; Li, Tao-Sheng; Masuzaki, Hideaki

    2015-01-01

    Postmenopausal disorders are frequently observed in various organs, but their relationship with estrogen deficiency and mechanisms remain unclear. As tissue-specific stem cells have been found to express estrogen receptors, we examined the hypothesis that estrogen deficiency impairs stem cells, which consequently contributes to postmenopausal disorders. Six-week-old C57BL/6 female mice were ovariectomized, following which they received 17β-estradiol replacement or vehicle (control). Sham-operated mice were used as healthy controls. All mice were killed for evaluation 2 months after treatments. Compared with the healthy control, ovariectomy significantly decreased uterine weight, which was partially recovered by 17β-estradiol replacement. Ovariectomy significantly increased the numbers of c-kit-positive hematopoietic stem/progenitor cells in bone marrow, but impaired their capacity to grow mixed cell-type colonies in vitro. Estrogen replacement further increased the numbers of c-kit-positive hematopoietic stem/progenitor cells in bone marrow, without significantly affecting colony growth in vitro. The number of CD105-positive mesenchymal stem cells in bone marrow also significantly decreased after ovariectomy, but completely recovered following estrogen replacement. Otherwise, neither ovariectomy nor estrogen replacement changed the number of Pax7-positive satellite cells, which are a skeletal muscle-type stem cell. Estrogen deficiency heterogeneously affected tissue-specific stem cells, suggesting a likely and direct relationship with postmenopausal disorders. PMID:26245252

  16. Synthesis and Functional Analysis of Novel Bivalent Estrogens

    PubMed Central

    Wendlandt, Alison E.; Yelton, Sharon M.; Lou, Dingyuan; Watt, David S.; Noonan, Daniel J.

    2010-01-01

    The steroid hormone estrogen plays a critical role in female development and homeostasis. Estrogen mediates its effects through binding and activation of specific estrogen receptors alpha (ERα) and beta (ERβ), members of the steroid/nuclear receptor family of ligand-induced transcription factors. Due to their intimate roles in genomic and nongenomic signaling pathways, these hormones and their receptors have been also implicated in the pathologies of a variety of cancers and metabolic disorders, and have been the target of large therapeutic development efforts. The binding of estrogen to its respective receptors initiates a cascade of events that include receptor dimerization, nuclear localization, DNA binding and recruitment of co-regulatory protein complexes. In this manuscript, we investigate the potential for manipulating steroid receptor gene expression activity through the development of bivalent steroid hormones that are predicted to facilitate hormone receptor dimerization events. Data are presented for the development and testing of novel estrogen dimers, linked through their C-17 moiety, that can activate estrogen receptor alpha (ERα)-mediated transcription events with efficacy and potency equal to or greater than that of ERα’s cognate ligand, 17β-estradiol. These bivalent estrogen structures open the door to the development of a variety of steroid therapeutics that could dramatically impact future drug development in this area. PMID:20685325

  17. A human fetal prostate xenograft model of developmental estrogenization.

    PubMed

    Saffarini, Camelia M; McDonnell-Clark, Elizabeth V; Amin, Ali; Boekelheide, Kim

    2015-01-01

    Prostate cancer is a common disease in older men. Rodent models have demonstrated that an early and later-life exposure to estrogen can lead to cancerous lesions and implicated hormonal dysregulation as an avenue for developing future prostate neoplasia. This study utilizes a human fetal prostate xenograft model to study the role of estrogen in the progression of human disease. Histopathological lesions were assessed in 7-, 30-, 90-, 200-, and 400-day human prostate xenografts. Gene expression for cell cycle, tumor suppressors, and apoptosis-related genes (ie, CDKN1A, CASP9, ESR2, PTEN, and TP53) was performed for 200-day estrogen-treated xenografts. Glandular hyperplasia was observed in xenografts given both an initial and secondary exposure to estradiol in both 200- and 400-day xenografts. Persistent estrogenic effects were verified using immunohistochemical markers for cytokeratin 10, p63, and estrogen receptor α. This model provides data on the histopathological state of the human prostate following estrogenic treatment, which can be utilized in understanding the complicated pathology associated with prostatic disease and early and later-life estrogenic exposures. PMID:25633637

  18. Sexual maturation protects against development of lung inflammation through estrogen.

    PubMed

    Draijer, Christina; Hylkema, Machteld N; Boorsma, Carian E; Klok, Pieter A; Robbe, Patricia; Timens, Wim; Postma, Dirkje S; Greene, Catherine M; Melgert, Barbro N

    2016-01-15

    Increasing levels of estrogen and progesterone are suggested to play a role in the gender switch in asthma prevalence during puberty. We investigated whether the process of sexual maturation in mice affects the development of lung inflammation in adulthood and the contributing roles of estrogen and progesterone during this process. By inducing ovalbumin-induced lung inflammation in sexually mature and immature (ovariectomized before sexual maturation) adult mice, we showed that sexually immature adult mice developed more eosinophilic lung inflammation. This protective effect of "puberty" appears to be dependent on estrogen, as estrogen supplementation at the time of ovariectomy protected against development of lung inflammation in adulthood whereas progesterone supplementation did not. Investigating the underlying mechanism of estrogen-mediated protection, we found that estrogen-treated mice had higher expression of the anti-inflammatory mediator secretory leukoprotease inhibitor (SLPI) and lower expression of the proasthmatic cytokine IL-33 in parenchymal lung tissue and that their expressions colocalized with type II alveolar epithelial cells (AECII). Treating AECII directly with SLPI significantly inhibited IL-33 production upon stimulation with ATP. Our data suggest that estrogen during puberty has a protective effect on asthma development, which is accompanied by induction of anti-inflammatory SLPI production and inhibition of proinflammatory IL-33 production by AECII. PMID:26608529

  19. Estrogen Stimulates Homing of Endothelial Progenitor Cells to Endometriotic Lesions.

    PubMed

    Rudzitis-Auth, Jeannette; Nenicu, Anca; Nickels, Ruth M; Menger, Michael D; Laschke, Matthias W

    2016-08-01

    The incorporation of endothelial progenitor cells (EPCs) into microvessels contributes to the vascularization of endometriotic lesions. Herein, we analyzed whether this vasculogenic process is regulated by estrogen. Estrogen- and vehicle-treated human EPCs were analyzed for migration and tube formation. Endometriotic lesions were induced in irradiated FVB/N mice, which were reconstituted with bone marrow from FVB/N-TgN (Tie2/green fluorescent protein) 287 Sato mice. The animals were treated with 100 μg/kg β-estradiol 17-valerate or vehicle (control) over 7 and 28 days. Lesion growth, cyst formation, homing of green fluorescent protein(+)/Tie2(+) EPCs, vascularization, cell proliferation, and apoptosis were analyzed by high-resolution ultrasonography, caliper measurements, histology, and immunohistochemistry. Numbers of blood circulating EPCs were assessed by flow cytometry. In vitro, estrogen-treated EPCs exhibited a higher migratory and tube-forming capacity when compared with controls. In vivo, numbers of circulating EPCs were not affected by estrogen. However, estrogen significantly increased the number of EPCs incorporated into the lesions' microvasculature, resulting in an improved early vascularization. Estrogen further stimulated the growth of lesions, which exhibited massively dilated glands with a flattened layer of stroma. This was mainly because of an increased glandular secretory activity, whereas cell proliferation and apoptosis were not markedly affected. These findings indicate that vasculogenesis in endometriotic lesions is dependent on estrogen, which adds a novel hormonally regulated mechanism to the complex pathophysiology of endometriosis. PMID:27315780

  20. Selective binding of the estrogen receptor to one strand of the estrogen responsive element.

    PubMed Central

    Mukherjee, R

    1993-01-01

    The human estrogen receptor (hER) activates gene transcription by binding to cognate palindromic sequences called estrogen responsive elements (ERE). I used gel retardation assays and oligonucleotides containing the ERE from the Xenopus vitellogenin gene to study the interaction of the hER with the ERE. I observed that the hER bound to double-stranded ERE and to the single strand of the ERE that had T in the center with nearly equal affinity, but not to the strand which had A in the center. Interchanging the two central nucleotides changed the strand specificity. Binding of the hER to a single strand is extremely sensitive to temperature. Initial recognition of one of the two strands of the ERE may be involved in the binding of the hER to the ERE. Images PMID:8332462

  1. CERAPP: Collaborative Estrogen Receptor Activity Prediction Project

    PubMed Central

    Mansouri, Kamel; Abdelaziz, Ahmed; Rybacka, Aleksandra; Roncaglioni, Alessandra; Tropsha, Alexander; Varnek, Alexandre; Zakharov, Alexey; Worth, Andrew; Richard, Ann M.; Grulke, Christopher M.; Trisciuzzi, Daniela; Fourches, Denis; Horvath, Dragos; Benfenati, Emilio; Muratov, Eugene; Wedebye, Eva Bay; Grisoni, Francesca; Mangiatordi, Giuseppe F.; Incisivo, Giuseppina M.; Hong, Huixiao; Ng, Hui W.; Tetko, Igor V.; Balabin, Ilya; Kancherla, Jayaram; Shen, Jie; Burton, Julien; Nicklaus, Marc; Cassotti, Matteo; Nikolov, Nikolai G.; Nicolotti, Orazio; Andersson, Patrik L.; Zang, Qingda; Politi, Regina; Beger, Richard D.; Todeschini, Roberto; Huang, Ruili; Farag, Sherif; Rosenberg, Sine A.; Slavov, Svetoslav; Hu, Xin; Judson, Richard S.

    2016-01-01

    Background: Humans are exposed to thousands of man-made chemicals in the environment. Some chemicals mimic natural endocrine hormones and, thus, have the potential to be endocrine disruptors. Most of these chemicals have never been tested for their ability to interact with the estrogen receptor (ER). Risk assessors need tools to prioritize chemicals for evaluation in costly in vivo tests, for instance, within the U.S. EPA Endocrine Disruptor Screening Program. Objectives: We describe a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) and demonstrate the efficacy of using predictive computational models trained on high-throughput screening data to evaluate thousands of chemicals for ER-related activity and prioritize them for further testing. Methods: CERAPP combined multiple models developed in collaboration with 17 groups in the United States and Europe to predict ER activity of a common set of 32,464 chemical structures. Quantitative structure–activity relationship models and docking approaches were employed, mostly using a common training set of 1,677 chemical structures provided by the U.S. EPA, to build a total of 40 categorical and 8 continuous models for binding, agonist, and antagonist ER activity. All predictions were evaluated on a set of 7,522 chemicals curated from the literature. To overcome the limitations of single models, a consensus was built by weighting models on scores based on their evaluated accuracies. Results: Individual model scores ranged from 0.69 to 0.85, showing high prediction reliabilities. Out of the 32,464 chemicals, the consensus model predicted 4,001 chemicals (12.3%) as high priority actives and 6,742 potential actives (20.8%) to be considered for further testing. Conclusion: This project demonstrated the possibility to screen large libraries of chemicals using a consensus of different in silico approaches. This concept will be applied in future projects related to other

  2. Mixture Effects of Estrogenic Pesticides at the Human Estrogen Receptor α and β.

    PubMed

    Seeger, Bettina; Klawonn, Frank; Nguema Bekale, Boris; Steinberg, Pablo

    2016-01-01

    Consumers of fruits and vegetables are frequently exposed to small amounts of hormonally active pesticides, some of them sharing a common mode of action such as the activation of the human estrogen receptor α (hERα) or β (hERβ). Therefore, it is of particular importance to evaluate risks emanating from chemical mixtures, in which the individual pesticides are present at human-relevant concentrations, below their corresponding maximum residue levels. Binary and ternary iso-effective mixtures of estrogenic pesticides at effect concentrations eliciting a 1 or 10% effect in the presence or absence of 17β-estradiol were tested experimentally at the hERα in the yeast-based estrogen screen (YES) assay as well as in the human U2-OS cell-based ERα chemical-activated luciferase gene expression (ERα CALUX) assay and at the hERβ in the ERβ CALUX assay. The outcome was then compared to predictions calculated by means of concentration addition. In most cases, additive effects were observed with the tested combinations in all three test systems, an observation that supports the need to expand the risk assessment of pesticides and consider cumulative risk assessment. An additional testing of mixture effects at the hERβ showed that most test substances being active at the hERα could also elicit additive effects at the hERβ, but the hERβ was less sensitive. In conclusion, effects of the same ligands at the hERα and the hERβ could influence the estrogenic outcome under physiological conditions. PMID:26812056

  3. Dynamic Estrogen Receptor Interactomes Control Estrogen-Responsive Trefoil Factor (TFF) Locus Cell-Specific Activities

    PubMed Central

    Quintin, Justine; Le Péron, Christine; Palierne, Gaëlle; Bizot, Maud; Cunha, Stéphanie; Sérandour, Aurélien A.; Avner, Stéphane; Henry, Catherine; Percevault, Frédéric; Belaud-Rotureau, Marc-Antoine; Huet, Sébastien; Watrin, Erwan; Eeckhoute, Jérôme; Legagneux, Vincent; Salbert, Gilles

    2014-01-01

    Estradiol signaling is ideally suited for analyzing the molecular and functional linkages between the different layers of information directing transcriptional regulations: the DNA sequence, chromatin modifications, and the spatial organization of the genome. Hence, the estrogen receptor (ER) can bind at a distance from its target genes and engages timely and spatially coordinated processes to regulate their expression. In the context of the coordinated regulation of colinear genes, identifying which ER binding sites (ERBSs) regulate a given gene still remains a challenge. Here, we investigated the coordination of such regulatory events at a 2-Mb genomic locus containing the estrogen-sensitive trefoil factor (TFF) cluster of genes in breast cancer cells. We demonstrate that this locus exhibits a hormone- and cohesin-dependent reduction in the plasticity of its three-dimensional organization that allows multiple ERBSs to be dynamically brought to the vicinity of estrogen-sensitive genes. Additionally, by using triplex-forming oligonucleotides, we could precisely document the functional links between ER engagement at given ERBSs and the regulation of particular genes. Hence, our data provide evidence of a formerly suggested cooperation of enhancers toward gene regulation and also show that redundancy between ERBSs can occur. PMID:24752895

  4. Impaired estrogen sensitivity in bone by inhibiting both estrogen receptor alpha and beta pathways.

    PubMed

    Ogawa, S; Fujita, M; Ishii, Y; Tsurukami, H; Hirabayashi, M; Ikeda, K; Orimo, A; Hosoi, T; Ueda, M; Nakamura, T; Ouchi, Y; Muramatsu, M; Inoue, S

    2000-07-14

    Although it is well established that estrogen deficiency causes osteoporosis among the postmenopausal women, the involvement of estrogen receptor (ER) in its pathogenesis still remains uncertain. In the present study, we have generated rats harboring a dominant negative ERalpha, which inhibits the actions of not only ERalpha but also recently identified ERbeta. Contrary to our expectation, the bone mineral density (BMD) of the resulting transgenic female rats was maintained at the same level with that of the wild-type littermates when sham-operated. In addition, ovariectomy-induced bone loss was observed almost equally in both groups. Strikingly, however, the BMD of the transgenic female rats, after ovariectomized, remained decreased even if 17beta-estradiol (E(2)) was administrated, whereas, in contrast, the decrease of littermate BMD was completely prevented by E(2). Moreover, bone histomorphometrical analysis of ovariectomized transgenic rats revealed that the higher rates of bone turnover still remained after treatment with E(2). These results demonstrate that the prevention from the ovariectomy-induced bone loss by estrogen is mediated by ER pathways and that the maintenance of BMD before ovariectomy might be compensated by other mechanisms distinct from ERalpha and ERbeta pathways. PMID:10806217

  5. Estrogenic and anti-estrogenic activity of off-the-shelf hair and skin care products.

    PubMed

    Myers, Sharon L; Yang, Chun Z; Bittner, George D; Witt, Kristine L; Tice, Raymond R; Baird, Donna D

    2015-05-01

    Use of personal care products is widespread in the United States but tends to be greater among African Americans than whites. Of special concern is the possible hazard of absorption of chemicals with estrogenic activity (EA) or anti-EA (AEA) in these products. Such exposure may have adverse health effects, especially when it occurs during developmental windows (e.g., prepubertally) when estrogen levels are low. We assessed the ethanol extracts of eight commonly used hair and skin products popular among African Americans for EA and AEA using a cell proliferation assay with the estrogen sensitive MCF-7:WS8 cell line derived from a human breast cancer. Four of the eight personal care products tested (Oil Hair Lotion, Extra-dry Skin Lotion, Intensive Skin Lotion, Petroleum Jelly) demonstrated detectable EA, whereas three (Placenta Hair Conditioner, Tea-Tree Hair Conditioner, Cocoa Butter Skin Cream) exhibited AEA. Our data indicate that hair and skin care products can have EA or AEA, and suggest that laboratory studies are warranted to investigate the in vivo activity of such products under chronic exposure conditions as well as epidemiologic studies to investigate potential adverse health effects that might be associated with use of such products. PMID:24849798

  6. Estrogen Signalling and the Metabolic Syndrome: Targeting the Hepatic Estrogen Receptor Alpha Action

    PubMed Central

    Matic, Marko; Bryzgalova, Galyna; Gao, Hui; Antonson, Per; Humire, Patricia; Omoto, Yoko; Portwood, Neil; Pramfalk, Camilla; Efendic, Suad; Berggren, Per-Olof; Gustafsson, Jan-Åke; Dahlman-Wright, Karin

    2013-01-01

    An increasing body of evidence now links estrogenic signalling with the metabolic syndrome (MS). Despite the beneficial estrogenic effects in reversing some of the MS symptoms, the underlying mechanisms remain largely undiscovered. We have previously shown that total estrogen receptor alpha (ERα) knockout (KO) mice exhibit hepatic insulin resistance. To determine whether liver-selective ablation of ERα recapitulates metabolic phenotypes of ERKO mice we generated a liver-selective ERαKO mouse model, LERKO. We demonstrate that LERKO mice have efficient reduction of ERα selectively within the liver. However, LERKO and wild type control mice do not differ in body weight, and have a comparable hormone profile as well as insulin and glucose response, even when challenged with a high fat diet. Furthermore, LERKO mice display very minor changes in their hepatic transcript profile. Collectively, our findings indicate that hepatic ERα action may not be the responsible factor for the previously identified hepatic insulin resistance in ERαKO mice. PMID:23451233

  7. Estrogenic and anti-estrogenic activity of off-the-shelf hair and skin care products

    PubMed Central

    Myers, Sharon L.; Yang, Chun Z.; Bittner, George D.; Witt, Kristine L.; Tice, Raymond R.; Baird, Donna D.

    2014-01-01

    Use of personal care products is widespread in the United States but tends to be greater among African Americans than whites. Of special concern is the possible hazard of absorption of chemicals with estrogenic activity (EA) or anti-EA (AEA) in these products. Such exposure may have adverse health effects, especially when it occurs during developmental windows (e.g., prepubertally) when estrogen levels are low. We assessed the ethanol extracts of eight commonly used hair and skin products popular among African Americans for EA and AEA using a cell proliferation assay with the estrogen sensitive MCF-7:WS8 cell line derived from a human breast cancer. Four of the eight personal care products tested (Oil Hair Lotion, Extra-dry Skin Lotion, Intensive Skin Lotion, Petroleum Jelly) demonstrated detectable EA, whereas three (Placenta Hair Conditioner, Tea-Tree Hair Conditioner, Cocoa Butter Skin Cream) exhibited AEA. Our data indicate that hair and skin care products can have EA or AEA, and suggest that laboratory studies are warranted to investigate the in vivo activity of such products under chronic exposure conditions as well as epidemiologic studies to investigate potential adverse health effects that might be associated with use of such products. PMID:24849798

  8. Biomarker Genes for Detecting Estrogenic Activity of Endocrine Disruptors via Estrogen Receptors

    PubMed Central

    Jung, Eui-Man; An, Beum-Soo; Yang, Hyun; Choi, Kyung-Chul; Jeung, Eui-Bae

    2012-01-01

    Endocrine disruptors (EDs) are compounds used in various industrial products, drugs, and cosmetics. They can be found in the environment and disturb the endocrine and reproductive systems, resulting in adverse effects to humans and wildlife such as birth defects and developmental disorders. Since several EDs have a structure similar to that of endogenous steroid hormones such as estrogens, they intend to have an affinity for steroid hormone receptors and alter hormone-mediated metabolism by binding to these receptors. EDs are therefore a global concern and assays should be developed to efficiently determine whether these compounds are detrimental to biological systems. Diverse experimental methods may help determine the endocrine disrupting potential of EDs and evaluate the adverse effects of a single and/or combination of these reagents. Currently, biomarkers have been employed to objectively measure EDs potency and understand the underlying mechanisms. Further studies are required to develop ideal screening methods and biomarkers to determine EDs potency at environmentally relevant concentrations. In this review, we describe the biomarkers for estrogenicity of EDs identified both in vitro and in vivo, and introduce a biomarker, cabindin-D9k (CaBP-9k), that may be used to assess estrogenic activity of EDs. PMID:22690157

  9. The cerebellum as a target for estrogen action

    PubMed Central

    Hedges, Valerie L.; Ebner, Timothy J.; Meisel, Robert L.; Mermelstein, Paul G.

    2012-01-01

    This review focuses on the effects of estrogens upon the cerebellum, a brain region long ignored as a site of estrogen action. Highlighted are the diverse effects of estradiol within the cerebellum, emphasizing the importance of estradiol signaling in cerebellar development, modulation of synaptic neurotransmission in the adult, and the potential influence of estrogens on various health and disease states. We also provide new data, consistent with previous studies, in which locally synthesized estradiol modulates cerebellar glutamatergic neurotransmission, providing one underlying mechanism by which the actions of estradiol can affect this brain region. PMID:22975197

  10. [Local estrogen therapy--clinical implications--2012 update].

    PubMed

    Kokot-Kierepa, Marta; Bartuzi, Aleksandra; Kulik-Rechberger, Beata; Rechberger, Tomasz

    2012-10-01

    With increasing longevity in Poland, women can now expect to live around 40% of their lives after menopause, and there is a growing desire for older women to preserve their vitality sexual function and quality of life. The most common urogenital symptoms associated with menopause are dryness, followed by irritation or itching, and discharge, with a substantial number of post-menopausal women also being affected by dysuria. These symptoms are the result of vaginal atrophy which is in turn caused by reduced transudation through the vaginal epithelium and reduced cervical gland secretions resulting from post-menopausal estrogen depletion. Vaginal atrophy generally occurs 4-5 years after the last menstrual period and progressively increases in prevalence in the subsequent years. Importantly vaginal atrophy is strongly associated with sexual dysfunction, and lower urinary tract symptoms, such as frequency urgency nocturia and dysuria, as well as incontinence and recurrent infection are reported more frequently in the presence of vaginal atrophy Those symptoms, apart from being bothersome for the patients also negatively impact their quality of life. Consequently before irreversible changes occur, early detection and treatment of vaginal atrophy should be implemented. Estrogen therapy is the most commonly prescribed treatment. Estrogens restore the cytology pH and vascularity of the vagina, resulting in symptom resolution for the majority of treated women. Because vaginal atrophy symptoms tend to occur later than vasomotor symptoms, many women do not necessarily require or wish to take systemic estrogen treatment if their symptoms are restricted to the urogenital tract. Vaginal estrogen products deliver estrogen locally to vaginal tissues with little or no systemic absorption and provide an effective alternative to systemic estrogen therapy for these women. Various vaginal estrogen preparations such as conjugated equine estrogens, estradiol and estriol vaginal creams, a

  11. Channel catfish (Ictalurus punctatus) leukocytes express estrogen receptor isoforms ERα and ERβ2 and are functionally modulated by estrogens

    USGS Publications Warehouse

    Iwanowicz, Luke R.; Stafford, James L.; Patiño, Reynaldo; Bengten, Eva; Miller, Norman W.; Blazer, Vicki

    2014-01-01

    Estrogens are recognized as modulators of immune responses in mammals and teleosts. While it is known that the effects of estrogens are mediated via leukocyte-specific estrogen receptors (ERs) in humans and mice, leucocyte-specific estrogen receptor expression and the effects of estrogens on this cell population is less explored and poorly understood in teleosts. Here in, we verify that channel catfish (Ictalurus punctaus) leukocytes express ERα and ERβ2. Transcripts of these isoforms were detected in tissue-associated leukocyte populations by PCR, but ERβ2 was rarely detected in PBLs. Expression of these receptors was temporally regulated in PBLs following polyclonal activation by concanavalin A, lipopolysaccharide or alloantigen based on evaluation by quantitative and end-point PCR. Examination of long-term leukocyte cell lines demonstrated that these receptors are differentially expressed depending on leukocyte lineage and phenotype. Expression of ERs was also temporally dynamic in some leukocyte lineages and may reflect stage of cell maturity. Estrogens affect the responsiveness of channel catfish peripheral blood leukocytes (PBLs) to mitogens in vitro. Similarly, bactericidal activity and phorbol 12-myristate 13-acetate induced respiratory burst was modulated by 17β-estradiol. These actions were blocked by the pure ER antagonist ICI 182780 indicating that response is, in part, mediated via ERα. In summary, estrogen receptors are expressed in channel catfish leukocytes and participate in the regulation of the immune response. This is the first time leukocyte lineage expression has been reported in teleost cell lines.

  12. The removal of estrogenic activity with UV/chlorine technology and identification of novel estrogenic disinfection by-products.

    PubMed

    Li, Man; Xu, Bi; Liungai, Zhiqi; Hu, Hong-Ying; Chen, Chao; Qiao, Juan; Lu, Yun

    2016-04-15

    As a recently developed disinfection technology, ultraviolet (UV)/chlorine treatment has received much attention. Many studies have evaluated its effects on pathogen inactivation, contaminant removal, and formation of disinfection by-products (DBPs), but its potential for environmental estrogen removal and estrogenic DBP generation, which can also be a risk to both ecosystem and human health, have not been evaluated. In this study, UV/chlorine treatment resulted in a greater removal of estrogenic activity in synthetic effluent samples containing 17β-estradiol (E2) than did UV or chlorine treatment alone regardless of the water quality. For both the UV/chlorine and chlorine treatments, there was significant interference from NH3-N, although the UV/chlorine treatment was less affected. Estrogen receptor based affinity chromatography was used to isolate the specific estrogenic DBPs, and a novel product, with high estrogenic activity compared to E2, Δ9(11)-dehydro-estradiol, was identified. It was generated by all three treatments, and might be previously mistakenly recognized as estrone (E1). This study demonstrated that UV/chlorine is a better treatment for the removal of 17β-estradiol than chlorine and UV alone. The new identified estrogenic DBP, Δ9(11)-dehydro-estradiol, which can be isolated by affinity chromatography, could be an emerging concern in the future. PMID:26780699

  13. Molecular characterization of an estrogen receptor and estrogen-related receptor and their autoregulatory capabilities in two Mytilus species.

    PubMed

    Nagasawa, Kazue; Treen, Nicholas; Kondo, Reki; Otoki, Yurika; Itoh, Naoki; Rotchell, Jeanette M; Osada, Makoto

    2015-06-15

    Vertebrate-like sex steroid hormones have been widely detected in mollusks, and numerous experiments have shown the importance of steroids in gonad development. Nevertheless, their signaling pathways in invertebrates have not been uncovered yet. Steroid receptors are an ancient class of transcription factors with multiple roles in not only vertebrates but also invertebrates. Estrogen signaling is thought to have major roles in mollusk physiology, but the full repertoire of estrogen receptors is unknown. We presented the successful cloning of two novel forms of estrogen receptor-like genes. These receptors are present in two closely related species of Mytilus: Mytilus edulis and Mytilus galloprovincialis, commonly known and widely distributed sentinel species. Our phylogenetic analysis revealed that one of these receptors is an estrogen receptor (ER) and the other one is an estrogen-related receptor (ERR). Studies of expression analysis showed that both receptor mRNAs were localized in the oocytes and follicle cells in contact with developing oocytes in the ovary and Sertoli cells in the testis, and in the ciliated cells of the gill. In addition, we have evidence that one (ER) of these may have a capacity to autoregulate its own expression in the gonadal cells by estrogen (E2) and that this gene is responsive to estrogenic compounds. PMID:25862924

  14. The Immune System Is a Natural Target for Estrogen Action: Opposing Effects of Estrogen in Two Prototypical Autoimmune Diseases

    PubMed Central

    Khan, Deena; Ansar Ahmed, S.

    2016-01-01

    Analogous to other physiological systems, the immune system also demonstrates remarkable sex differences. Although the reasons for sex differences in immune responses are not precisely understood, it potentially involves differences in sex hormones (estrogens, androgens, and differential sex hormone receptor-mediated events), X-chromosomes, microbiome, epigenetics among others. Overall, females tend to have more responsive and robust immune system compared to their male counterparts. It is therefore not surprising that females respond more aggressively to self-antigens and are more susceptible to autoimmune diseases. Female hormone (estrogen or 17β-estradiol) can potentially act on all cellular subsets of the immune system through estrogen receptor-dependent and -independent mechanisms. This minireview highlights differential expression of estrogen receptors on immune cells, major estrogen-mediated signaling pathways, and their effect on immune cells. Since estrogen has varied effects in female-predominant autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus, we will mechanistically postulate the potential differential role of estrogen in these chronic debilitating diseases. PMID:26779182

  15. Estrogen receptor beta agonists in neurobehavioral investigations.

    PubMed

    Choleris, Elena; Clipperton, Amy E; Phan, Anna; Kavaliers, Martin

    2008-07-01

    Neurobehavioral investigations into the functions of estrogen receptor (ER)alpha and ERbeta have utilized 'knockout' mice, phytoestrogens and, more recently, ER-specific agonists. Feeding, sexual, aggressive and social behavior, anxiety, depression, drug abuse, pain perception, and learning (and associated synaptic plasticity) are affected by ERalpha and ERbeta in a manner that is dependent upon the specific behavior studied, gender and developmental stage. Overall, ERalpha and ERbeta appear to function together to foster sociosexual behavior while inhibiting behaviors that, if occurring at the time of behavioral estrous, may compete with reproduction (eg, feeding). Recently developed pharmacological tools have limited selectivity and availability to the research community at large, as they are not commercially available. The development of highly selective, commercially available ERbeta-specific antagonists would greatly benefit preclinical and applied research. PMID:18600582

  16. [Estrogen receptor alpha in obesity and diabetes].

    PubMed

    Cahua-Pablo, José Ángel; Flores-Alfaro, Eugenia; Cruz, Miguel

    2016-01-01

    Estradiol (E2) is an important hormone in reproductive physiology, cardiovascular, skeletal and in the central nervous system (CNS). In human and rodents, E2 and its receptors are involved in the control of energy and glucose metabolism in health and metabolic diseases. The estrogen receptor (ER) belongs to the superfamily of nuclear receptors (NR), which are transcription factors that regulate gene expression. Three ER, ER-alpha, ER-beta and the G protein-coupled ER (GPER; also called GPR30) in tissues are involved in glucose and lipid homeostasis. Also, it may have important implications for risk factors associated with metabolic syndrome (MS), insulin resistance (IR), obesity and type 2 diabetes (T2D). PMID:27197110

  17. Immunoresponsiveness in endometriosis: implications of estrogenic toxicants.

    PubMed Central

    Rier, S E; Martin, D C; Bowman, R E; Becker, J L

    1995-01-01

    Endometriosis is a reproductive disease characterized by the growth of endometrial cells at sites outside the uterus. This disease is a serious disorder associated with chronic pain and infertility, which may be present in 6 million women in this country. Traditional medical therapy has consisted of hormonal regimens that limit the action of endogenous estrogen. The etiology of endometriosis is unknown, but studies suggest that soluble factors known as cytokines play a role in disease pathogenesis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is an environmental toxicant that alters the action of estrogen in reproductive organs and adversely affects immunocompetence. The incidence of endometriosis was determined in rhesus monkeys that were chronically exposed to dioxin for a period of approximately 4 years. Ten years after termination of dioxin treatment, the presence and severity of endometriosis was assessed by surgical laparoscopy. The incidence of endometriosis correlated with dioxin exposure and disease severity was dependent upon the dose administered. Moderate to severe endometriosis was not found in control animals but was documented in three of seven animals exposed to 5 ppt dioxin (43%) and in five of seven animals exposed to 25 ppt dioxin (71%). The frequency of spontaneous disease in the control group was 33%, similar to an overall prevalence of 30% in 304 rhesus monkeys with no history of dioxin exposure. This study indicates that endometriosis may be associated with dioxin exposure in the rhesus. In view of overwhelming evidence that cytokines participate in the mediation of reproductive-endocrine phenomena and regulation of endometrial growth, future assessment of the effects of environmental toxicants on reproductive health may depend upon our understanding of the bidirectional cytokine network between the immune and endocrine systems. PMID:8593863

  18. Bioassay of estrogenicity and chemical analyses of estrogens in streams across the United States associated with livestock operations.

    PubMed

    Alvarez, D A; Shappell, N W; Billey, L O; Bermudez, D S; Wilson, V S; Kolpin, D W; Perkins, S D; Evans, N; Foreman, W T; Gray, J L; Shipitalo, M J; Meyer, M T

    2013-06-15

    Animal manures, used as a nitrogen source for crop production, are often associated with negative impacts on nutrient levels in surface water. The concentrations of estrogens in streams from these manures also are of concern due to potential endocrine disruption in aquatic species. Streams associated with livestock operations were sampled by discrete samples (n = 38) or by time-integrated polar organic chemical integrative samplers (POCIS, n = 19). Samples were analyzed for estrogens by gas chromatography-tandem mass spectrometry (GC-MS(2)) and estrogenic activity was assessed by three bioassays: Yeast Estrogen Screen (YES), T47D-KBluc Assay, MCF-7 Estrogenicity Screen (E-Screen). Samples were collected from 19 streams within small (≈ 1-30 km(2)) watersheds in 12 U.S. states representing a range of hydrogeologic conditions, dominated by: dairy (3), grazing beef (3), feedlot cattle (1); swine (5); poultry (3); and 4 areas where no livestock were raised or manure was applied. Water samples were consistently below the United Kingdom proposed Lowest Observable Effect Concentration for 17β-estradiol in fish (10 ng/L) in all watersheds, regardless of land use. Estrogenic activity was often higher in samples during runoff conditions following a period of manure application. Estrone was the most commonly detected estrogen (13 of 38 water samples, mean 1.9, maximum 8.3 ng/L). Because of the T47D-KBluc assay's sensitivity towards estrone (1.4 times 17β-estradiol) it was the most sensitive method for detecting estrogens, followed by the E-Screen, GC-MS(2), and YES. POCIS resulted in more frequent detections of estrogens than discrete water samples across all sites, even when applying the less-sensitive YES bioassay to the POCIS extracts. PMID:23623470

  19. Bioassay of estrogenicity and chemical analyses of estrogens in streams across the United States associated with livestock operations

    USGS Publications Warehouse

    Alvarez, David A.; Shappell, Nancy W.; Billey, L.O.; Bermudez, Dietrich S.; Wilson, Vickie S.; Kolpin, Dana W.; Perkins, Stephanie D.; Evans, Nicola; Foreman, William T.; Gray, James L.; Shipitalo, J.M.; Meyer, Michael T.

    2013-01-01

    Animal manures, used as a nitrogen source for crop production, are often associated with negative impacts on nutrient levels in surface water. The concentrations of estrogens in streams from these manures also are of concern due to potential endocrine disruption in aquatic species. Streams associated with livestock operations were sampled by discrete samples (n = 38) or by time-integrated polar organic chemical integrative samplers (POCIS,n = 19). Samples were analyzed for estrogens by gas chromatography-tandem mass spectrometry (GC-MSM2) and estrogenic activity was assessed by three bioassays: Yeast Estrogen Screen (YES), T47D-KBluc Assay, MCF-7 Estrogenicity Screen (E-Screen). Samples were collected from 19 streams within small (∼1-30 km2) watersheds in 12 U.S. states representing a range of hydrogeologic conditions, dominated by: dairy (3), grazing beef (3), feedlot cattle (1); swine (5); poultry (3); and 4 areas where no livestock were raised or manure was applied. Water samples were consistently below the United Kingdom proposed Lowest Observable Effect Concentration for 17b-estradiol in fish (10 ng/L) in all watersheds, regardless of land use. Estrogenic activity was often higher in samples during runoff conditions following a period of manure application. Estrone was the most commonly detected estrogen (13 of 38 water samples, mean 1.9, maximum 8.3 ng/L). Because of the T47D-KBluc assay’s sensitivity towards estrone (1.4 times 17β-estradiol) it was the most sensitive method for detecting estrogens, followed by the E-Screen, GC-MS2, and YES. POCIS resulted in more frequent detections of estrogens than discrete water samples across all sites, even when applying the less-sensitive YES bioassay to the POCIS extracts.

  20. BIOCHEMICAL AND ANALYTICAL CHARACTERIZATION OF ESTROGENICALLY ACTIVE WASTEWATER: COMPARISON OF FIELD EXTRAPOLATIONS TO THE MEASURED CONCENTRATION OF ESTROGENS IN SEWAGE EFFLUENT

    EPA Science Inventory

    Estrogenically active wastewater was observed at two municipal wastewater treatment plants (WWTPs) utilizing caged male channel catfish in a previous study. The focus of this investigation was to identify and characterize the compound(s) responsible for this estrogenic response. ...

  1. Modeling mixtures of environmental estrogens found in U.S. surface waters with an in vitro estrogen mediated transcriptionai activation assay (T47D-KBluc).

    EPA Science Inventory

    There is growing concern of exposure to fish, wildlife, and humans to water sources contaminated with estrogens and the potential impact on reproductive health. Environmental estrogens can come from various sources including concentrated animal feedlot operations (CAFO), municipa...

  2. Estrogen regulation of chicken riboflavin carrier protein gene is mediated by ERE half sites without direct binding of estrogen receptor.

    PubMed

    Bahadur, Urvashi; Ganjam, Goutham K; Vasudevan, Nandini; Kondaiah, Paturu

    2005-02-28

    Estrogen is an important steroid hormone that mediates most of its effects on regulation of gene expression by binding to intracellular receptors. The consensus estrogen response element (ERE) is a 13bp palindromic inverted repeat with a three nucleotide spacer. However, several reports suggest that many estrogen target genes are regulated by diverse elements, such as imperfect EREs and ERE half sites (ERE 1/2), which are either the proximal or the distal half of the palindrome. To gain more insight into ERE half site-mediated gene regulation, we used a region from the estrogen-regulated chicken riboflavin carrier protein (RCP) gene promoter that contains ERE half sites. Using moxestrol, an analogue of estrogen and transient transfection of deletion and mutation containing RCP promoter/reporter constructs in chicken hepatoma (LMH2A) cells, we identified an estrogen response unit (ERU) composed of two consensus ERE 1/2 sites and one non-consensus ERE 1/2 site. Mutation of any of these sites within this ERU abolishes moxestrol response. Further, the ERU is able to confer moxestrol responsiveness to a heterologous promoter. Interestingly, RCP promoter is regulated by moxestrol in estrogen responsive human MCF-7 cells, but not in other cell lines such as NIH3T3 and HepG2 despite estrogen receptor-alpha (ER-alpha) co transfection. Electrophoretic mobility shift assays (EMSAs) with promoter regions encompassing the half sites and nuclear extracts from LMH2A cells show the presence of a moxestrol-induced complex that is abolished by a polyclonal anti-ERalpha antibody. Surprisingly, estrogen receptor cannot bind to these promoter elements in isolation. Thus, there appears to be a definite requirement for some other factor(s) in addition to estrogen receptor, for the generation of a suitable response of this promoter to estrogen. Our studies therefore suggest a novel mechanism of gene regulation by estrogen, involving ERE half sites without direct binding of ER to the

  3. A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings.

    PubMed

    Gogos, Andrea; Sbisa, Alyssa M; Sun, Jeehae; Gibbons, Andrew; Udawela, Madhara; Dean, Brian

    2015-01-01

    Gender differences in schizophrenia have been extensively researched and it is being increasingly accepted that gonadal steroids are strongly attributed to this phenomenon. Of the various hormones implicated, the estrogen hypothesis has been the most widely researched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severity of the illness. In this review, we comprehensively analyse studies that have investigated the effects of estrogen, in particular 17β-estradiol, in clinical, animal, and molecular research with relevance to schizophrenia. Specifically, we discuss the current evidence on estrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment in schizophrenia patients. Preclinical research that has used animal models and molecular probes to investigate estradiol's underlying protective mechanisms is also substantially discussed, with particular focus on estradiol's impact on the major neurotransmitter systems implicated in schizophrenia, namely, the dopamine, serotonin, and glutamate systems. PMID:26491441

  4. Comparison of estrogen mixtures in vitro vs. in vivo

    EPA Science Inventory

    Numerous sources contribute to widespread contamination of drinking water sources with both natural and synthetic estrogens, which isa concern for potential ecological and human health effects. In vitro screening assays are valuable tools for identifying mechanisms of toxicity bu...

  5. ROLE OF ESTROGEN RECEPTOR-α ON FOOD DEMAND ELASTICITY

    PubMed Central

    Minervini, Vanessa; Rowland, Neil E.; Robertson, Kimberly L.; Foster, Thomas C.

    2016-01-01

    Estrogens have been shown to have an inhibitory effect on food intake under free-feeding conditions, yet the effects of estrogens on food-maintained operant responding have been studied to a much lesser extent and, thus, are not well understood. Therefore, the purpose of the present experiment was to use a behavioral economics paradigm to assess differences in demand elasticity between mice with knockout of the estrogen receptor subtype α, knockout of subtype β, and their wild type controls. The mice responded in a closed economy, and the price of food was increased by increasing the fixed-ratio response requirement every four sessions. Overall, we found that mice with the knockout of receptor subtype α had the most elastic demand functions. Therefore, under these conditions, estrogens increased food seeking via activation of the receptor subtype α. The results were inconsistent with those reported by previous studies that employed free-feeding conditions. PMID:25869426

  6. The Role and Use of Estrogens Following Trauma.

    PubMed

    Weniger, Maximilian; Angele, Martin K; Chaudry, Irshad H

    2016-09-01

    Several lines of evidence indicate that female sex is a protective factor in trauma and hemorrhage. In both clinical and experimental studies, proestrus females have been shown to have better chances of survival and reduced rates of posttraumatic sepsis. Estrogen receptors are expressed in a variety of tissues and exert genomic, as well as nongenomic effects. By improving cardiac, pulmonary, hepatic, and immune function, estrogens have been shown to prolong survival in animal models of hemorrhagic shock. Despite encouraging results from experimental studies, retrospective clinical studies have not clearly pointed to advantages of estrogens following trauma-hemorrhage, which may be due to insufficient study design. Therefore, this review aims to give an overview on the current evidence and emphasizes on the importance of further clinical investigation on estrogens following trauma. PMID:27380534

  7. Modeling environmental loading rates of municipal wastewater contaminants: steroidal estrogens

    EPA Science Inventory

    Estrogenic compounds in municipal wastewater are of substantial interest because of suspicion that they may cause reproductive disruption in aquatic invertebrates, and because of their potential to contaminate human drinking water sources. Previous work suggests the primary contr...

  8. Estrogen-induced myelotoxicity in dogs: A review

    PubMed Central

    Sontas, Hasan B.; Dokuzeylu, Banu; Turna, Ozge; Ekici, Hayri

    2009-01-01

    Exogenous estrogens used for therapeutic purposes or endogenous estrogen sources such as functional Sertoli cell or ovarian granulosa cell tumors may cause bone marrow toxicity in dogs. The condition is characterized by hematologic abnormalities including thrombocytopenia, anemia, and leukocytosis or leukopenia. Despite intensive therapy with blood or platelet-rich transfusions, broad-spectrum antibiotics, steroids, and bone marrow stimulants, prognosis is unfavorable. Due to the the risk of stimulating the development of uterine diseases and the potential for inducing aplastic anemia, estrogen use in dogs is best avoided where possible. This paper describes the causes of estrogen-induced myelotoxicity, the clinical presentation of the patients, the diagnosis, and the treatment options in the dog. PMID:20046604

  9. SPONTANEOUS AIRWAY HYPERRESPONSIVENESS IN ESTROGEN RECEPTOR-A DEFICIENT MICE

    EPA Science Inventory

    Rationale: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans. Objectives: To examine the role of estrogen receptors in modulat...

  10. ESTROGEN RECEPTORS AND THE REGULATION OF NEURAL STRESS RESPONSES

    PubMed Central

    Handa, Robert J.; Mani, Shaila K.; Uht, Rosalie M.

    2012-01-01

    It is now well established that estrogens can influence a panoply of physiological and behavioral functions. In many instances, the effects of estrogens are mediated by the ‘classical’ actions of two different estrogen receptors (ER), alpha or beta. Estrogen receptor alpha and beta appear to have opposing actions in the control of stress responses and modulate different neurotransmitter or neuropeptide systems. Studies elucidating the molecular mechanisms for such regulatory processes are currently in progress. Furthermore, the use of ERalpha and ERbeta knockout mouse lines has allowed the exploration of the importance of these receptors in behavioral responses such as anxiety-like and depressive-like behaviors. This review examines some of the recent advances in our knowledge of hormonal control of neuroendocrine and behavioral responses to stress and underscore the importance of these receptors as future therapeutic targets for control of stress-related signaling pathways. PMID:22538291

  11. A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings

    PubMed Central

    Gogos, Andrea; Sbisa, Alyssa M.; Sun, Jeehae; Gibbons, Andrew; Udawela, Madhara; Dean, Brian

    2015-01-01

    Gender differences in schizophrenia have been extensively researched and it is being increasingly accepted that gonadal steroids are strongly attributed to this phenomenon. Of the various hormones implicated, the estrogen hypothesis has been the most widely researched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severity of the illness. In this review, we comprehensively analyse studies that have investigated the effects of estrogen, in particular 17β-estradiol, in clinical, animal, and molecular research with relevance to schizophrenia. Specifically, we discuss the current evidence on estrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment in schizophrenia patients. Preclinical research that has used animal models and molecular probes to investigate estradiol's underlying protective mechanisms is also substantially discussed, with particular focus on estradiol's impact on the major neurotransmitter systems implicated in schizophrenia, namely, the dopamine, serotonin, and glutamate systems. PMID:26491441

  12. Role of estrogen receptor-α on food demand elasticity.

    PubMed

    Minervini, Vanessa; Rowland, Neil E; Robertson, Kimberly L; Foster, Thomas C

    2015-05-01

    Estrogens have been shown to have an inhibitory effect on food intake under free-feeding conditions, yet the effects of estrogens on food-maintained operant responding have been studied to a much lesser extent and, thus, are not well understood. Therefore, the purpose of the present experiment was to use a behavioral economics paradigm to assess differences in demand elasticity between mice with knockout of the estrogen receptor subtype α, knockout of subtype β, and their wild type controls. The mice responded in a closed economy, and the price of food was increased by increasing the fixed-ratio response requirement every four sessions. Overall, we found that mice with the knockout of receptor subtype α had the most elastic demand functions. Therefore, under these conditions, estrogens increased food seeking via activation of the receptor subtype α. The results were inconsistent with those reported by previous studies that employed free-feeding conditions. PMID:25869426

  13. The estrogenic activity of phthalate esters in vitro.

    PubMed Central

    Harris, C A; Henttu, P; Parker, M G; Sumpter, J P

    1997-01-01

    A large number of phthalate esters were screened for estrogenic activity using a recombinant yeast screen. a selection of these was also tested for mitogenic effect on estrogen-responsive human breast cancer cells. A small number of the commercially available phthalates tested showed extremely weak estrogenic activity. The relative potencies of these descended in the order butyl benzyl phthalate (BBP) > dibutyl phthalate (DBP) > diisobutyl phthalate (DIBP) > diethyl phthalate (DEP) > diisiononyl phthalate (DINP). Potencies ranged from approximately 1 x 10(6) to 5 x 10(7) times less than 17beta-estradiol. The phthalates that were estrogenic in the yeast screen were also mitogenic on the human breast cancer cells. Di(2-ethylhexyl) phthalate (DEHP) showed no estrogenic activity in these in vitro assays. A number of metabolites were tested, including mono-butyl phthalate, mono-benzyl phthalate, mono-ethylhexyl phthalate, mon-n-octyl phthalate; all were wound to be inactive. One of the phthalates, ditridecyl phthalate (DTDP), produced inconsistent results; one sample was weakly estrogenic, whereas another, obtained from a different source, was inactive. analysis by gel chromatography-mass spectometry showed that the preparation exhibiting estrogenic activity contained 0.5% of the ortho-isomer of bisphenol A. It is likely that the presence of this antioxidant in the phthalate standard was responsible for the generation of a dose-response curve--which was not observed with an alternative sample that had not been supplemented with o,p'-bisphenol A--in the yeast screen; hence, DTDP is probably not weakly estrogenic. The activities of simple mixtures of BBP, DBP, and 17beta-estradiol were assessed in the yeast screen. No synergism was observed, although the activities of the mixtures were approximately additive. In summary, a small number of phthalates are weakly estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vitro. No data has

  14. Sex-Dependent Influence of Endogenous Estrogen in Pulmonary Hypertension

    PubMed Central

    Mair, Kirsty M.; Wright, Audrey F.; Duggan, Nicholas; Rowlands, David J.; Hussey, Martin J.; Roberts, Sonia; Fullerton, Josephine; Nilsen, Margaret; Loughlin, Lynn; Thomas, Matthew

    2014-01-01

    Rationale: The incidence of pulmonary arterial hypertension is greater in women, suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males, exogenously administered estrogen can protect against pulmonary hypertension (PH). However, in models that display female susceptibility, estrogens may play a causative role. Objectives: To clarify the influence of endogenous estrogen and sex in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. Methods: We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH: the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of sex on pulmonary expression of aromatase in these models and in lungs from patients with pulmonary arterial hypertension. Measurements and Main Results: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was caused by reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor α also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased bone morphogenetic protein receptor 2 and Id1 expression compared with male. Anastrozole treatment reversed the impaired bone morphogenetic protein receptor 2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared with male. Conclusions: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential. PMID:24956156

  15. Human Colon Microbiota Transform Polycyclic Aromatic Hydrocarbons to Estrogenic Metabolites

    PubMed Central

    Van de Wiele, Tom; Vanhaecke, Lynn; Boeckaert, Charlotte; Peru, Kerry; Headley, John; Verstraete, Willy; Siciliano, Steven

    2005-01-01

    Ingestion is an important exposure route for polycyclic aromatic hydrocarbons (PAHs) to enter the human body. Although the formation of hazardous PAH metabolites by human biotransformation enzymes is well documented, nothing is known about the PAH transformation potency of human intestinal microbiota. Using a gastrointestinal simulator, we show that human intestinal microbiota can also bioactivate PAHs, more in particular to estrogenic metabolites. PAH compounds are not estrogenic, and indeed, stomach and small intestine digestions of 62.5 nmol naphthalene, phenanthrene, pyrene, and benzo(a)pyrene showed no estrogenic effects in the human estrogen receptor bioassay. In contrast, colon digests of these PAH compounds displayed estrogenicity, equivalent to 0.31, 2.14, 2.70, and 1.48 nmol 17α-ethynylestradiol (EE2), respectively. Inactivating the colon microbiota eliminated these estrogenic effects. Liquid chromatography–mass spectrometry analysis confirmed the microbial PAH transformation by the detection of PAH metabolites 1-hydroxypyrene and 7-hydroxybenzo(a)pyrene in colon digests of pyrene and benzo(a)pyrene. Furthermore, we show that colon digests of a PAH-contaminated soil (simulated ingestion dose of 5 g/day) displayed estrogenic activity equivalent to 0.58 nmol EE2, whereas stomach or small intestine digests did not. Although the matrix in which PAHs are ingested may result in lower exposure concentrations in the gut, our results imply that the PAH bioactivation potency of colon microbiota is not eliminated by the presence of soil. Moreover, because PAH toxicity is also linked to estrogenicity of the compounds, the PAH bioactivation potency of colon microbiota suggests that current risk assessment may underestimate the risk from ingested PAHs. PMID:15626640

  16. Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse

    PubMed Central

    Hara, Yuko; Waters, Elizabeth M.; McEwen, Bruce S.; Morrison, John H.

    2015-01-01

    Estrogen facilitates higher cognitive functions by exerting effects on brain regions such as the prefrontal cortex and hippocampus. Estrogen induces spinogenesis and synaptogenesis in these two brain regions and also initiates a complex set of signal transduction pathways via estrogen receptors (ERs). Along with the classical genomic effects mediated by activation of ER α and ER β, there are membrane-bound ER α, ER β, and G protein-coupled estrogen receptor 1 (GPER1) that can mediate rapid nongenomic effects. All key ERs present throughout the body are also present in synapses of the hippocampus and prefrontal cortex. This review summarizes estrogen actions in the brain from the standpoint of their effects on synapse structure and function, noting also the synergistic role of progesterone. We first begin with a review of ER subtypes in the brain and how their abundance and distributions are altered with aging and estrogen loss (e.g., ovariectomy or menopause) in the rodent, monkey, and human brain. As there is much evidence that estrogen loss induced by menopause can exacerbate the effects of aging on cognitive functions, we then review the clinical trials of hormone replacement therapies and their effectiveness on cognitive symptoms experienced by women. Finally, we summarize studies carried out in nonhuman primate models of age- and menopause-related cognitive decline that are highly relevant for developing effective interventions for menopausal women. Together, we highlight a new understanding of how estrogen affects higher cognitive functions and synaptic health that go well beyond its effects on reproduction. PMID:26109339

  17. Exercise (and Estrogen) Make Fat Cells “Fit”

    PubMed Central

    Vieira-Potter, Victoria J.; Zidon, Terese M.; Padilla, Jaume

    2016-01-01

    Adipose tissue inflammation links obesity and metabolic disease. Both exercise and estrogen improve metabolic health, enhance mitochondrial function, and have anti-inflammatory effects. We hypothesize that there is an inverse relationship between mitochondrial function and inflammation in adipose tissue and that exercise acts as an estrogen “mimetic”. Explicitly, exercise may improve adipose tissue “immunometabolism” by improving mitochondrial function and reducing inflammation. Summary Exercise improves adipose tissue metabolic health by reducing inflammation and improving mitochondrial function. PMID:25906425

  18. Determining estrogenic activity in serum from ovariectomized rats treated with environmental compounds using an in vitro estrogen-mediated transcriptional activation assay (T47D-KBluc).

    EPA Science Inventory

    The use of cell-based assays to quantify low levels of estrogen in human serum is an accepted method. These assays are more sensitive but less specific than radioimmunoassays (RIA). Thus, we hypothesized that estrogen responsive T47D-KBluc cells would detect estrogenic activity i...

  19. Estrogen replacement during hypoalbuminemia may enhance atherosclerotic risk.

    PubMed

    Joles, J A; Bijleveld, C; van Tol, A; Geelen, M J; Koomans, H A

    1997-12-01

    Estrogen replacement therapy is considered antiatherosclerotic because it reduces LDL cholesterol and fibrinogen and increases HDL cholesterol concentrations. However, exogenous estrogen is also known to increase hepatic triglyceride production. Hyperlipidemia in the nephrotic syndrome is probably due to increased lipoprotein secretion into plasma and decreased clearance of lipoprotein cholesterol and triglycerides. Previously, lipid-lowering effects of ovariectomy in analbuminemic rats were observed, suggesting that in the presence of hypoalbuminemia, estrogen replacement may have adverse effects on the lipid profile. To test this hypothesis, ovariectomized control rats and rats with Adriamycin-induced nephrotic syndrome were treated with estradiol. In ovariectomized controls, estradiol reduced plasma LDL cholesterol, apolipoprotein B, and fibrinogen and increased apolipoprotein A-I and triglycerides. Nephrotic rats were characterized by a marked decrease in plasma colloid osmotic pressure, hyperfibrinogenemia, hyperlipidemia, and stimulated hepatic fatty acid synthesis. The beneficial effects of estradiol on LDL cholesterol, apolipoprotein B, and fibrinogen found in ovariectomized controls were not present in estradiol-treated nephrotic rats. This suggests that in hypoalbuminemia, downregulation of the LDL receptor overrides putative estradiol-induced increases in LDL receptor activity. Moreover, estrogen replacement in the nephrotic syndrome doubled fatty acid synthesis and triglyceride secretion, and markedly exacerbated hypertriglyceridemia, suggesting saturation of triglyceride clearance. Thus, severe hypoalbuminemia in rats induces an atherosclerotic metabolic response that is aggravated by estrogen replacement. These findings suggest that estrogen replacement in hypoalbuminemic subjects could be contra-indicated. PMID:9402089

  20. Estrogen Biology: New Insights into GPER Function and Clinical Opportunities

    PubMed Central

    Prossnitz, Eric R.; Barton, Matthias

    2014-01-01

    Estrogens play an important role in the regulation of normal physiology, aging and many disease states. Although the nuclear estrogen receptors have classically been described to function as ligand-activated transcription factors mediating genomic effects in hormonally regulated tissues, more recent studies reveal that estrogens also mediate rapid signaling events traditionally associated with G protein-coupled receptors. The G protein-coupled estrogen receptor GPER (formerly GPR30) has now become recognized as a major mediator of estrogen’s rapid cellular effects throughout the body. With the discovery of selective synthetic ligands for GPER, both agonists and antagonists, as well as the use of GPER knockout mice, significant advances have been made in our understanding of GPER function at the cellular, tissue and organismal levels. In many instances, the protective/beneficial effects of estrogen are mimicked by selective GPER agonism and are absent or reduced in GPER knockout mice, suggesting an essential or at least parallel role for GPER in the actions of estrogen. In this review, we will discuss recent advances and our current understanding of the role of GPER and certain drugs such as SERMs and SERDs in physiology and disease. We will also highlight novel opportunities for clinical development towards GPER-targeted therapeutics, for molecular imaging, as well as for theranostic approaches and personalized medicine. PMID:24530924

  1. The in vitro estrogenic activities of triclosan and triclocarban.

    PubMed

    Huang, Hongyu; Du, Guizhen; Zhang, Wei; Hu, Jialei; Wu, Di; Song, Ling; Xia, Yankai; Wang, Xinru

    2014-09-01

    Triclosan (TCS) and triclocarban (TCC), as broad spectrum antibacterial agents, are distributed widely in the environment and humans. Most studies have focused on their distribution and biodegradation, but the endocrine-disrupting effects of these chemicals, especially their estrogenic effects, are still unclear. In the present study, we investigated the estrogenic effects of TCS and TCC using a series of in vitro assays, including the ER reporter gene assay in the CV-1 cells, E-screen assay and evaluation of estrogen-responsive genes in the MCF-7 cells. The tested concentrations of TCS and TCC were both from 1 × 10(-9) to 1 × 10(-6)  M. Results showed that TCS and TCC exerted estrogenic activities by inducing luciferase activities in an ER reporter gene assay, promoting the proliferation of the MCF-7 cells, up-regulating the expression of pS2 and down-regulating ERα expression at both the mRNA and protein levels in the MCF-7 cells. We further found that TCS and TCC could alter the expression of multiple microRNAs (mir-22, mir-206 and mir-193b) in the MCF-7 cells, which would help understand the mechanisms of their estrogenic effects on regulating the expression of ERα. In brief, our results demonstrated the potential estrogenic effects and profiled in vitro data for further risk assessment of TCS and TCC. PMID:24740835

  2. Estrogenic Impact on Cardiac Ischemic/Reperfusion Injury.

    PubMed

    Sivasinprasasn, Sivaporn; Shinlapawittayatorn, Krekwit; Chattipakorn, Siriporn C; Chattipakorn, Nipon

    2016-02-01

    The increase in cardiovascular disease and metabolic syndrome incidence following the onset of menopause has highlighted the role of estrogen as a cardiometabolic protective agent. Specifically regarding the heart, estrogen induced an improvement in cardiac function, preserved calcium homeostasis, and inhibited the mitochondrial apoptotic pathway. The beneficial effects of estrogen in relation to cardiac ischemia/reperfusion (I/R) injury, such as reduced infarction and ameliorated post-ischemic recovery, have also been shown. Nevertheless, controversial findings exist and estrogen therapy is reported to be related to a higher rate of thromboembolic events and atrial fibrillation in post-menopausal women. Therefore, greater clarification is needed to evaluate the exact potential of estrogen use in cases of cardiac I/R injury. This article reviews the effects of estrogen, in both acute and chronic treatment, and collates the studies with regard to their in vivo, in vitro, or clinical trial settings in cases of cardiac I/R injury and myocardial infarction. PMID:26786980

  3. Evaluation of the estrogenic effects of legume extracts containing phytoestrogens.

    PubMed

    Boué, Stephen M; Wiese, Thomas E; Nehls, Suzanne; Burow, Matthew E; Elliott, Steven; Carter-Wientjes, Carol H; Shih, Betty Y; McLachlan, John A; Cleveland, Thomas E

    2003-04-01

    Seven legume extracts containing phytoestrogens were analyzed for estrogenic activity. Methanol extracts were prepared from soybean (Glycine max L.), green bean (Phaseolus vulgaris L.), alfalfa sprout (Medicago sativa L.), mung bean sprout (Vigna radiata L.), kudzu root (Pueraria lobata L.), and red clover blossom and red clover sprout (Trifolium pratense L.). Extracts of kudzu root and red clover blossom showed significant competitive binding to estrogen receptor beta (ERbeta). Estrogenic activity was determined using an estrogen-dependent MCF-7 breast cancer cell proliferation assay. Kudzu root, red clover blossom and sprout, mung bean sprout, and alfalfa sprout extracts displayed increased cell proliferation above levels observed with estradiol. The pure estrogen antagonist, ICI 182,780, suppressed cell proliferation induced by the extracts, suggesting an ER-related signaling pathway was involved. The ER subtype-selective activities of legume extracts were examined using transiently transfected human embryonic kidney (HEK 293) cells. All seven of the extracts exhibited preferential agonist activity toward ERbeta. Using HPLC to collect fractions and MCF-7 cell proliferation, the active components in kudzu root extract were determined to be the isoflavones puerarin, daidzin, genistin, daidzein, and genistein. These results show that several legumes are a source of phytoestrogens with high levels of estrogenic activity. PMID:12670155

  4. Combined effects of estrogenic chemicals with the same mode of action using an estrogen receptor binding bioassay.

    PubMed

    Yang, Rong; Li, Na; Ma, Mei; Wang, Zijian

    2014-11-01

    The increasing amounts of various estrogenic chemicals coexisting in the aquatic environment may pose environmental risks. While the concept of estradiol equivalent (EEQ) has been frequently applied in studying estrogenic mixtures, few experiments have been done to prove its reliability. In this study, the reliability of EEQ and the related model concentration addition (CA) was verified based on the two-hybrid recombinant yeast bioassay when all mixture components had the same mode of action and target of action. Our results showed that the measured estrogenic effects could be well predicted by CA and EEQ for all laboratory-made mixtures using two designs, despite the varying estrogenic activity, concentration levels and ratios of the test chemicals. This suggests that when an appropriate endpoint and its relevant bioassay are chosen, CA should be valid and the application of EEQ in predicting the effect of non-equi-effect mixtures is feasible. PMID:25461542

  5. Assessment of in vivo estrogenic response and identification of environmental estrogens in influent and effluent from a sewage treatment plant.

    PubMed

    Song, Wenting; Wang, Zhijun; Lian, Chuanjie

    2013-09-01

    The in vivo estrogenic response and estrogenic contents of the influent and effluent collected from a sewage treatment plant located in Jiaozuo were assessed. The bioassay showed significant serum vitellogenin (VTG) induction in all the treated male goldfish (Carassius auratus) and significant gonad atrophies were only observed in the fish induced the most VTG expressions. Six target estrogens (estrone, 17β-estradiol, 17α-ethynylestradiol, 4-n-octylphenol, 4-n-nonylphenol and bisphenol A) were detected in different polar fractions, with the exception of the 25 % and 50 % methanol fractions extracted from the influent and the 25 %, 50 %, 95 % and 100 % methanol fractions extracted from the effluent. For both the influent and effluent, natural and synthetic steroidal estrogens were detected in those extracted fractions induced the most abundant VTG expressions. PMID:23877625

  6. Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes

    PubMed Central

    Segars, James H.; Driggers, Paul H.

    2014-01-01

    Remarkable progress in recent years has suggested that estrogen action in vivo is complex and often involves activation of cytoplasmic signaling cascades in addition to genomic actions mediated directly through estrogen receptors α and β. Rather than a linear response mediated solely through estrogen-responsive DNA elements, in vivo estrogen might simultaneously activate distinct signaling cascades that function as networks to coordinate tissue responses to estrogen. This complex signaling system provides for exquisite control and plasticity of response to estrogen at the tissue level, and undoubtedly contributes to the remarkable tissue-specific responses to estrogens. In part I of this series, we summarize cytoplasmic signaling modules involving estrogen or estrogen receptors, with particular focus on recently described membrane-associated signaling complexes. PMID:12217492

  7. Acquisition of Estrogen Independence Induces TOB1-Related Mechanisms Supporting Breast Cancer Cell Proliferation

    PubMed Central

    Zhang, Yong-Wei; Nasto, Rochelle E.; Varghese, Rency; Jablonski, Sandra A.; Serebriiskii, Ilya G; Surana, Rishi; Calvert, Valerie S.; Bebu, Ionut; Murray, Joseph; Jin, Lu; Johnson, Michael; Riggins, Rebecca; Ressom, Habtom; Petricoin, Emmanuel; Clarke, Robert; Golemis, Erica A.; Weiner, Louis M.

    2015-01-01

    Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen-receptor positive breast cancer. To address this challenge, a systems biology approach was used. A library of siRNAs targeting an estrogen receptor- and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells, and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent estrogen receptor-positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mTOR inhibitors in estrogen-independent cells but not estrogen-dependent cells. Phosphoproteomic profiles from reverse phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with estrogen receptor-positive breast cancers. PMID:26165839

  8. Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals.

    PubMed Central

    Tsutsui, T; Barrett, J C

    1997-01-01

    Estrogens are clearly carcinogenic in humans and rodents but the mechanisms by which these hormones induce cancer are only partially understood. Stimulation of cell proliferation and gene expression by binding to the estrogen receptor is one important mechanism in hormonal carcinogenesis; however, estrogenicity is not sufficient to explain the carcinogenic activity of all estrogens because some estrogens are not carcinogenic. Estrogens are nonmutagenic in many assays but exhibit specific types of genotoxic activity under certain conditions. We have studied extensively the mechanisms by which estrogens induce neoplastic transformation in a model in vitro system and our findings are summarized in this review. 17beta-Estradiol (E2) and diethylstilbestrol (DES) and their metabolites induce morphological and neoplastic transformation of Syrian hamster embryo (SHE) cells that express no measurable levels of estrogen receptor. Treatment of the cells with E2 or DES fails to induce DNA damage, chromosome aberrations and gene mutations in SHE cells but results in numerical chromosome aberrations (aneuploidy) that could arise from microtubule disruption or disfunction of mitotic apparatus. Estrogen-induced genotoxicity is detected in cells following treatment with estrogen metabolites or following exogenous metabolic activation of estrogens. The estrogens induce DNA adduct formation that is detected by 32P-postlabeling. Both aneuploidy induction and DNA damage caused by DNA adduct formation correlate with the estrogen-induced cell transformation and may be important in hormonal carcinogenesis. We propose that multiple effects of estrogens acting together cause genetic alterations leading to cell transformation. PMID:9168005

  9. Occurrence of selected estrogenic compounds and estrogenic activity in surface water and sediment of Langat River (Malaysia).

    PubMed

    Praveena, Sarva Mangala; Lui, Tang Seok; Hamin, Nur'Aqilah; Razak, Siti Quistina Noorain Abdul; Aris, Ahmad Zaharin

    2016-07-01

    The occurrence and estrogenic activities of steroid estrogens, such as the natural estrone (E1), 17β estradiol (E2), and estriol (E3), as well as the synthetic 17α-ethynylestradiol (EE2), were investigated in eight sampling points along the Langat River (Malaysia). Surface water samples were collected at 0.5 m and surface sediment 0-5 cm from the river surface. Instrument analysis of steroid estrogens was determined by UPLC-ESI-MS with an ultra-performance liquid chromatograph (Perkin Elmer FX15) coupled to a Q Trap function mass spectrophotometer (model 3200: AB Sciex). Steroid estrogen concentrations were higher in the Langat River sediments than those in its surface water. In surface water, E1 was not detected in any sampling point, E2 was only detected in two midstream sampling points (range 0-0.004 ng/L), E3 in three sampling points (range 0-0.002 ng/L), and EE2 in four sampling points (range 0-0.02 ng/L). E1 and E2 were detected in sediments from all sampling points, E3 in five sampling points, while EE2 only in one midstream sample (3.29E-4 ng/g). Sewage treatment plants, farming waste, and agricultural activities particularly present midstream and downstream were identified as potential sources of estrogens. Estrogenic activity expressed as estradiol equivalents (EEQs) was below 1 ng/L in all samples for both surface water and sediment, indicating therefore a low potential estrogenic risk to the aquatic environment. Although the health risks are still uncertain for drinking water consumers exposed to low levels of steroid estrogen concentrations, Langat River water is unacceptable for direct drinking purposes without treatment. Further studies of endocrine disruptors in Malaysian waters are highly recommended. PMID:27353134

  10. Optimization of a yeast estrogen screen and its applicability to study the release of estrogenic isoflavones from a soygerm powder.

    PubMed Central

    De Boever, P; Demaré, W; Vanderperren, E; Cooreman, K; Bossier, P; Verstraete, W

    2001-01-01

    Here we describe a redesigned protocol of the yeast estrogen screen developed by Routledge and Sumpter. The redesigned test comprises two steps. First, a large amount of yeast with estrogenic compounds is incubated for 24 hr. Subsequently, a mixture of cycloheximide and the chromogenic substrate chlorophenol red-beta-d-galactopyranoside (CPRG) is added. The cycloheximide stops protein synthesis and allows for an end-point measurement of beta-galactosidase activity generated during the first 24 hr. CPRG is converted to chlorophenol red and reflects beta-galactosidase activity, which is indicative of the estrogenic activity. The modifications shorten the duration of the assay at least 1 day and avoid interference of the estrogenic CPRG or chlorophenol red. The redesigned and the original protocol were used to study the estrogenic activity of bisphenol A, methoxychlor, p,p'-DDT, and isoflavones (genistein, daidzein, and glycitein). Bisphenol A, methoxychlor, and genistein triggered higher levels of beta-galactosidase activity in the redesigned protocol. Estrogenic activity of p,p'-DDT could only be demonstrated with the redesigned protocol. Glycitein and daidzein failed to give a response with both protocols. We also studied deconjugation of beta-glycosidic isoflavones present in soygerm powder. Treatment of the soygerm powder with beta-glycosidase released isoflavones. The estrogenic response of the samples was confirmed with the redesigned protocol and correlated with the amount of genistein present. The release of isoflavones under conditions prevailing in the intestines was studied. Bacterial beta-glycosidase present in the large intestine released isoflavones, and moderate estrogenic activity could be demonstrated. PMID:11485867

  11. Estrogen withdrawal from osteoblasts and osteocytes causes increased mineralization and apoptosis.

    PubMed

    Brennan, M Á; Haugh, M G; O'Brien, F J; McNamara, L M

    2014-07-01

    Recent studies have demonstrated increased bone mineral heterogeneity following estrogen withdrawal in vivo. Such changes likely contribute to fracture risk during post-menopausal osteoporosis since tissue mineralization is correlated with bone strength and stiffness. However, the cellular mechanisms responsible for increased mineral variability have not yet been distinguished. The objective of this study is to elucidate how alterations in mineral distribution are initiated during estrogen depletion. Specifically, we tested two separate hypotheses; (1) estrogen deficiency directly alters osteoblast mineralization and (2) estrogen deficiency increases bone cell apoptosis. Osteoblast-like cells (MC3T3-E1) and osteocyte-like cells (MLO-Y4) were pretreated with or without estrogen (17β-estradiol) for 14 days. Estrogen deficiency was subsequently induced by either withdrawing estrogen from cells or blocking estrogen receptors using an estrogen antagonist, fulvestrant (ICI 182,780). Cell number (Hoechst DNA), alkaline phosphatase activity (p-NPP), mineralization (alizarin red) and apoptosis (Caspase 3/7) were evaluated. Whether estrogen withdrawal altered apoptosis rates in the presence of an apoptosis promoting agent (etoposide) was also determined. Interestingly, estrogen withdrawal from cells accustomed to estrogen exposure caused significantly increased osteoblast mineralization and osteocyte apoptosis compared with continued estrogen treatment. In contrast, blocking estrogen receptors with fulvestrant abrogated the mineralization induced by estrogen treatment. When apoptosis was induced using etoposide, cells undergoing estrogen withdrawal increased apoptosis compared to cells with continued estrogen treatment. Recognizing the underlying mechanisms regulating bone cell mineralization and apoptosis during estrogen deficiency and their consequences is necessary to further our knowledge of osteoporosis. PMID:24446157

  12. Estrogen, SNP-Dependent Chemokine Expression and Selective Estrogen Receptor Modulator Regulation.

    PubMed

    Ho, Ming-Fen; Bongartz, Tim; Liu, Mohan; Kalari, Krishna R; Goss, Paul E; Shepherd, Lois E; Goetz, Matthew P; Kubo, Michiaki; Ingle, James N; Wang, Liewei; Weinshilboum, Richard M

    2016-03-01

    We previously reported, on the basis of a genome-wide association study for aromatase inhibitor-induced musculoskeletal symptoms, that single-nucleotide polymorphisms (SNPs) near the T-cell leukemia/lymphoma 1A (TCL1A) gene were associated with aromatase inhibitor-induced musculoskeletal pain and with estradiol (E2)-induced TCL1A expression. Furthermore, variation in TCL1A expression influenced the downstream expression of proinflammatory cytokines and cytokine receptors. Specifically, the top hit genome-wide association study SNP, rs11849538, created a functional estrogen response element (ERE) that displayed estrogen receptor (ER) binding and increased E2 induction of TCL1A expression only for the variant SNP genotype. In the present study, we pursued mechanisms underlying the E2-SNP-dependent regulation of TCL1A expression and, in parallel, our subsequent observations that SNPs at a distance from EREs can regulate ERα binding and that ER antagonists can reverse phenotypes associated with those SNPs. Specifically, we performed a series of functional genomic studies using a large panel of lymphoblastoid cell lines with dense genomic data that demonstrated that TCL1A SNPs at a distance from EREs can modulate ERα binding and expression of TCL1A as well as the expression of downstream immune mediators. Furthermore, 4-hydroxytamoxifen or fulvestrant could reverse these SNP-genotype effects. Similar results were found for SNPs in the IL17A cytokine and CCR6 chemokine receptor genes. These observations greatly expand our previous results and support the existence of a novel molecular mechanism that contributes to the complex interplay between estrogens and immune systems. They also raise the possibility of the pharmacological manipulation of the expression of proinflammatory cytokines and chemokines in a SNP genotype-dependent fashion. PMID:26866883

  13. Gene Alterations of Ovarian Cancer Cells Expressing Estrogen Receptors by Estrogen and Bisphenol A Using Microarray Analysis

    PubMed Central

    Hwang, Kyung-A; Park, Se-Hyung; Yi, Bo-Rim

    2011-01-01

    Since endocrine disrupting chemicals (EDCs) may interfere with the endocrine system(s) of our body and have an estrogenicity, we evaluated the effect(s) of bisphenol A (BPA) on the transcriptional levels of altered genes in estrogen receptor (ER)-positive BG-1 ovarian cancer cells by microarray and real-time polymerase-chain reaction. In this study, treatment with 17β-estradiol (E2) or BPA increased mRNA levels of E2-responsive genes related to apoptosis, cancer and cell cycle, signal transduction and nucleic acid binding etc. In parallel with their microarray data, the mRNA levels of some altered genes including RAB31_MEMBER RAS ONCOGENE FAMILY (U59877), CYCLIN D1 (X59798), CYCLIN-DEPENDENT KINASE 4 (U37022), IGF-BINDING PROTEIN 4 (U20982), and ANTI-MULLERIAN HORMONE (NM_000479) were significantly induced by E2 or BPA in this cell model. These results indicate that BPA in parallel with E2 induced the transcriptional levels of E2-responsive genes in an estrogen receptor (ER)-positive BG-1 cells. In conclusion, these microarray and real-time polymerase-chain reaction results indicate that BPA, a potential weak estrogen, may have estrogenic effect by regulating E2-responsive genes in ER-positive BG-1 cells and BG-1 cells would be the best in vitro model to detect these estrogenic EDCs. PMID:21826169

  14. Effects of gamma irradiation on the DNA-protein complex between the estrogen response element and the estrogen receptor

    NASA Astrophysics Data System (ADS)

    Štísová, Viktorie; Goffinont, Stephane; Spotheim-Maurizot, Melanie; Davídková, Marie

    2010-08-01

    Signaling by estrogens, risk factors in breast cancer, is mediated through their binding to the estrogen receptor protein (ER), followed by the formation of a complex between ER and a DNA sequence, called estrogen response element (ERE). Anti-estrogens act as competitive inhibitors by blocking the signal transduction. We have studied in vitro the radiosensitivity of the complex between ERα, a subtype of this receptor, and a DNA fragment bearing ERE, as well as the influence of an estrogen (estradiol) or an anti-estrogen (tamoxifen) on this radiosensitivity. We observe that the complex is destabilized upon irradiation with γ rays in aerated aqueous solution. The analysis of the decrease of binding abilities of the two partners shows that destabilization is mainly due to the damage to the protein. The destabilization is reduced when irradiating in presence of tamoxifen and is increased in presence of estradiol. These effects are due to opposite influences of the ligands on the loss of binding ability of ER. The mechanism that can account for our results is: binding of estradiol or tamoxifen induces distinct structural changes of the ER ligand-binding domain that can trigger (by allostery) distinct structural changes of the ER DNA-binding domains and thus, can differently affect ER-ERE interaction.

  15. Corncob bedding alters the effects of estrogens on aggressive behavior and reduces estrogen receptor-α expression in the brain.

    PubMed

    Villalon Landeros, Rosalina; Morisseau, Christophe; Yoo, Hyun Ju; Fu, Samuel H; Hammock, Bruce D; Trainor, Brian C

    2012-02-01

    There is growing appreciation that estrogen signaling pathways can be modulated by naturally occurring environmental compounds such as phytoestrogens and the more recently discovered xenoestrogens. Many researchers studying the effects of estrogens on brain function or behavior in animal models choose to use phytoestrogen-free food for this reason. Corncob bedding is commonly used in animal facilities across the United States and has been shown to inhibit estrogen-dependent reproductive behavior in rats. The mechanism for this effect was unclear, because the components of corncob bedding mediating this effect did not bind estrogen receptors. Here, we show in the California mouse (Peromyscus californicus) that estrogens decrease aggression when cardboard-based bedding is used but that this effect is absent when corncob bedding is used. California mice housed on corncob bedding also had fewer estrogen receptor-α-positive cells in the bed nucleus of the stria terminalis and ventromedial hypothalamus compared with mice housed on cardboard-based bedding. In addition, corncob bedding suppressed the expression of phosphorylated ERK in these brain regions as well as in the medial amygdala and medial preoptic area. Previous reports of the effects of corncob bedding on reproductive behavior are not widely appreciated. Our observations on the effects of corncob bedding on behavior and brain function should draw attention to the importance that cage bedding can exert on neuroendocrine research. PMID:22186416

  16. Committee Opinion No. 659: The Use of Vaginal Estrogen in Women With a History of Estrogen-Dependent Breast Cancer.

    PubMed

    2016-03-01

    Cancer treatment should address female-specific survivorship issues, including the hypoestrogenic- related adverse effects of cancer therapies or of natural menopause in survivors. Systemic and vaginal estrogen are widely used for symptomatic relief of vasomotor symptoms, sexual dysfunction, and lower urinary tract infections in the general population. However, given that some types of cancer are hormone sensitive, there are safety concerns about the use of local hormone therapy in women who currently have breast cancer or have a history of breast cancer. Nonhormonal approaches are the first-line choices for managing urogenital symptoms or atrophy-related urinary symptoms experienced by women during or after treatment for breast cancer. Among women with a history of estrogen-dependent breast cancer who are experiencing urogenital symptoms, vaginal estrogen should be reserved for those patients who are unresponsive to nonhormonal remedies. The decision to use vaginal estrogen may be made in coordination with a woman's oncologist. Additionally, it should be preceded by an informed decision-making and consent process in which the woman has the information and resources to consider the benefits and potential risks of low-dose vaginal estrogen. Data do not show an increased risk of cancer recurrence among women currently undergoing treatment for breast cancer or those with a personal history of breast cancer who use vaginal estrogen to relieve urogenital symptoms. PMID:26901334

  17. Estrogenic and anti-estrogenic influences in cultured brown trout hepatocytes: Focus on the expression of some estrogen and peroxisomal related genes and linked phenotypic anchors.

    PubMed

    Madureira, Tânia Vieira; Malhão, Fernanda; Pinheiro, Ivone; Lopes, Célia; Ferreira, Nádia; Urbatzka, Ralph; Castro, L Filipe C; Rocha, Eduardo

    2015-12-01

    Estrogens, estrogenic mimics and anti-estrogenic compounds are known to target estrogen receptors (ER) that can modulate other nuclear receptor signaling pathways, such as those controlled by the peroxisome proliferator-activated receptor (PPAR), and alter organelle (inc. peroxisome) morphodynamics. By using primary isolated brown trout (Salmo trutta f. fario) hepatocytes after 72 and 96h of exposure we evaluated some effects in selected molecular targets and in peroxisomal morphological features caused by: (1) an ER agonist (ethinylestradiol-EE2) at 1, 10 and 50μM; (2) an ER antagonist (ICI 182,780) at 10 and 50μM; and (3) mixtures of both (Mix I-10μM EE2 and 50μM ICI; Mix II-1μM EE2 and 10μM ICI and Mix III-1μM EE2 and 50μM ICI). The mRNA levels of the estrogenic targets (ERα, ERβ-1 and vitellogenin A-VtgA) and the peroxisome structure/function related genes (catalase, urate oxidase-Uox, 17β-hydroxysteroid dehydrogenase 4-17β-HSD4, peroxin 11α-Pex11α and PPARα) were analyzed by real-time polymerase chain reaction (RT-PCR). Stereology combined with catalase immunofluorescence revealed a significant reduction in peroxisome volume densities at 50μM of EE2 exposure. Concomitantly, at the same concentration, electron microscopy showed smaller peroxisome profiles, exacerbated proliferation of rough endoplasmic reticulum, and a generalized cytoplasmic vacuolization of hepatocytes. Catalase and Uox mRNA levels decreased in all estrogenic stimuli conditions. VtgA and ERα mRNA increased after all EE2 treatments, while ERβ-1 had an inverse pattern. The EE2 action was reversed by ICI 182,780 in a concentration-dependent manner, for VtgA, ERα and Uox. Overall, our data show the great value of primary brown trout hepatocytes to study the effects of estrogenic/anti-estrogenic inputs in peroxisome kinetics and in ER and PPARα signaling, backing the still open hypothesis of crosstalk interactions between these pathways and calling for more mechanistic

  18. No substantial changes in estrogen receptor and estrogen-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals☆☆☆

    PubMed Central

    Bannister, Richard; Beresford, Nicola; Granger, David W.; Pounds, Nadine A.; Rand-Weaver, Mariann; White, Roger; Jobling, Susan; Routledge, Edwin J.

    2013-01-01

    Estrogen receptor orthologues in molluscs may be targets for endocrine disruptors, although mechanistic evidence is lacking. Molluscs are reported to be highly susceptible to effects caused by very low concentrations of environmental estrogens which, if substantiated, would have a major impact on the risk assessment of many chemicals. The present paper describes the most thorough evaluation to-date of the susceptibility of Marisa cornuarietis ER and ERR gene transcription to modulation by vertebrate estrogens in vivo and in vitro. We investigated the effects of estradiol-17β and 4-tert-Octylphenol exposure on in vivo estrogen receptor (ER) and estrogen-related receptor (ERR) gene transcription in the reproductive and neural tissues of the gastropod snail M. cornuarietis over a 12-week period. There was no significant effect (p > 0.05) of treatment on gene transcription levels between exposed and non-exposed snails. Absence of a direct interaction of estradiol-17β and 4-tert-Octylphenol with mollusc ER and ERR protein was also supported by in vitro studies in transfected HEK-293 cells. Additional in vitro studies with a selection of other potential ligands (including methyl-testosterone, 17α-ethinylestradiol, 4-hydroxytamoxifen, diethylstilbestrol, cyproterone acetate and ICI182780) showed no interaction when tested using this assay. In repeated in vitro tests, however, genistein (with mcER-like) and bisphenol-A (with mcERR) increased reporter gene expression at high concentrations only (>10−6 M for Gen and >10−5 M for BPA, respectively). Like vertebrate estrogen receptors, the mollusc ER protein bound to the consensus vertebrate estrogen-response element (ERE). Together, these data provide no substantial evidence that mcER-like and mcERR activation and transcript levels in tissues are modulated by the vertebrate estrogen estradiol-17β or 4-tert-Octylphenol in vivo, or that other ligands of vertebrate ERs and ERRs (with the possible exception of

  19. Cystic fibrosis and estrogens: a perfect storm

    PubMed Central

    Zeitlin, Pamela L.

    2008-01-01

    Irreversible destruction and widening of the airways due to acquired infections or genetic mutations as well as those of unknown cause are more severe in females. Differences between male and female anatomy, behavior, and hormonal state have been proposed to explain the increased incidence and severity in females with airway disease such as cystic fibrosis (CF); however, a mechanism to explain a sex-related difference has remained elusive. In this issue of the JCI, Coakley et al. report that elevations in the major estrogen hormone in humans — 17β-estradiol — reduce Ca2+-activated Cl– secretion by airway epithelial cells in culture, thereby disrupting ion and water balance (see the related article beginning on page 4025). They measure a similar diminution of nasal epithelial Ca2+-activated Cl– secretion in women with CF during the menstrual cycle phase at which 17β-estradiol level is at its highest. These data suggest that for about one week of a four-week menstrual cycle, women with CF will have a reduced ability to efficiently clear airway secretions, the buildup of which is a hallmark of CF. The authors suggest that these data warrant the testing of antiestrogen therapy in females with CF and propose an alternative avenue for CF therapeutic development. PMID:19033654

  20. Designer interface peptide grafts target estrogen receptor alpha dimerization.

    PubMed

    Chakraborty, S; Asare, B K; Biswas, P K; Rajnarayanan, R V

    2016-09-01

    The nuclear transcription factor estrogen receptor alpha (ERα), triggered by its cognate ligand estrogen, regulates a variety of cellular signaling events. ERα is expressed in 70% of breast cancers and is a widely validated target for anti-breast cancer drug discovery. Administration of anti-estrogen to block estrogen receptor activation is still a viable anti-breast cancer treatment option but anti-estrogen resistance has been a significant bottle-neck. Dimerization of estrogen receptor is required for ER activation. Blocking ERα dimerization is therefore a complementary and alternative strategy to combat anti-estrogen resistance. Dimer interface peptide "I-box" derived from ER residues 503-518 specifically blocks ER dimerization. Recently using a comprehensive molecular simulation we studied the interaction dynamics of ERα LBDs in a homo-dimer. Based on this study, we identified three interface recognition peptide motifs LDKITDT (ERα residues 479-485), LQQQHQRLAQ (residues 497-506), and LSHIRHMSNK (residues 511-520) and reported the suitability of using LQQQHQRLAQ (ER 497-506) as a template to design inhibitors of ERα dimerization. Stability and self-aggregation of peptide based therapeutics poses a significant bottle-neck to proceed further. In this study utilizing peptide grafted to preserve their pharmacophoric recognition motif and assessed their stability and potential to block ERα mediated activity in silico and in vitro. The Grafted peptides blocked ERα mediated cell proliferation and viability of breast cancer cells but did not alter their apoptotic fate. We believe the structural clues identified in this study can be used to identify novel peptidometics and small molecules that specifically target ER dimer interface generating a new breed of anti-cancer agents. PMID:27462021

  1. Quantitative comparisons of in vitro assays for estrogenic activities.

    PubMed Central

    Fang, H; Tong, W; Perkins, R; Soto, A M; Prechtl, N V; Sheehan, D M

    2000-01-01

    Substances that may act as estrogens show a broad chemical structural diversity. To thoroughly address the question of possible adverse estrogenic effects, reliable methods are needed to detect and identify the chemicals of these diverse structural classes. We compared three assays--in vitro estrogen receptor competitive binding assays (ER binding assays), yeast-based reporter gene assays (yeast assays), and the MCF-7 cell proliferation assay (E-SCREEN assay)--to determine their quantitative agreement in identifying structurally diverse estrogens. We examined assay performance for relative sensitivity, detection of active/inactive chemicals, and estrogen/antiestrogen activities. In this examination, we combined individual data sets in a specific, quantitative data mining exercise. Data sets for at least 29 chemicals from five laboratories were analyzed pair-wise by X-Y plots. The ER binding assay was a good predictor for the other two assay results when the antiestrogens were excluded (r(2) is 0.78 for the yeast assays and 0.85 for the E-SCREEN assays). Additionally, the examination strongly suggests that biologic information that is not apparent from any of the individual assays can be discovered by quantitative pair-wise comparisons among assays. Antiestrogens are identified as outliers in the ER binding/yeast assay, while complete antagonists are identified in the ER binding and E-SCREEN assays. Furthermore, the presence of outliers may be explained by different mechanisms that induce an endocrine response, different impurities in different batches of chemicals, different species sensitivity, or limitations of the assay techniques. Although these assays involve different levels of biologic complexity, the major conclusion is that they generally provided consistent information in quantitatively determining estrogenic activity for the five data sets examined. The results should provide guidance for expanded data mining examinations and the selection of appropriate

  2. Effects of pyridoxal 5'-phosphate on uterine estrogen receptor. II. Inhibition of estrogen . receptor transformation.

    PubMed

    Traish, A; Müller, R E; Wotiz, H H

    1980-05-10

    Previous observations suggested that pyridoxal 5'-phosphate was capable of inhibiting estrogen . receptor (R . E2) activation, or translocation to the nucleus, or both. The present study attempts to define more specifically the locus of this action. To this end we have examined the physicochemical alteration produced by interaction of pyridoxal 5'-phosphate with estrogen . receptor complex, using sucrose density gradient analysis and dissociation kinetics. Receptor transformation was inhibited when activation was performed in the presence of pyridoxal 5'-phosphate. This effect was protein- and pyridoxal 5'-phosphate concentration-dependent. When pyridoxal 5'-phosphate was introduced postactivation it did not have any effect on the activated receptor, but when similar treatment was followed by NABH4 reduction, the complex reverted to the monomeric entity. The dissociation behavior obtained with cytosol R . E2, warmed in the presence of pyridoxal 5'-phosphate, showed a biphasic curve suggesting that a significant portion of receptors remained nonactivated as demonstrated by the fast dissociating component. Due to the fact that Tris buffers cannot be used for pyridoxal 5'-phosphate experiments, we have used a borate buffer which resulted in a displacement of the sedimentation values from a 4S to 4.6 S for the unactivated receptor and 5S to 6 S for the activated form. The observations reported suggest that at least the initial effect of pyridoxal 5'-phosphate results in the inhibition of cytosolic receptor transformation from the nonactivated to the activated form. PMID:7372667

  3. Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1.

    PubMed

    Pelekanou, Vasiliki; Kampa, Marilena; Kiagiadaki, Foteini; Deli, Alexandra; Theodoropoulos, Panayiotis; Agrogiannis, George; Patsouris, Efstratios; Tsapis, Andreas; Castanas, Elias; Notas, George

    2016-02-01

    Estrogens are known modulators of monocyte/macrophage functions; however, the underlying mechanism has not been clearly defined. Recently, a number of estrogen receptor molecules and splice variants were identified that exert different and sometimes opposing actions. We assessed the expression of estrogen receptors and explored their role in mediating estrogenic anti-inflammatory effects on human primary monocytes. We report that the only estrogen receptors expressed are estrogen receptor-α 36-kDa splice variant and G-protein coupled receptor 30/G-protein estrogen receptor 1, in a sex-independent manner. 17-β-Estradiol inhibits the LPS-induced IL-6 inflammatory response, resulting in inhibition of NF-κB transcriptional activity. This is achieved via a direct physical interaction of ligand-activated estrogen receptor-α 36-kDa splice variant with the p65 component of NF-κB in the nucleus. G-protein coupled receptor 30/G-protein estrogen receptor 1, which also physically interacts with estrogen receptor-α 36-kDa splice variant, acts a coregulator in this process, because its inhibition blocks the effect of estrogens on IL-6 expression. However, its activation does not mimic the effect of estrogens, on neither IL-6 nor NF-κB activity. Finally, we show that the estrogen receptor profile observed in monocytes is not modified during their differentiation to macrophages or dendritic cells in vitro and is shared in vivo by macrophages present in atherosclerotic plaques. These results position estrogen receptor-α 36-kDa splice variant and G-protein coupled receptor 30 as important players and potential therapeutic targets in monocyte/macrophage-dependent inflammatory processes. PMID:26394816

  4. Temperature dependence of estrogen binding: importance of a subzone in the ligand binding domain of a novel piscine estrogen receptor.

    PubMed

    Tan, N S; Frecer, V; Lam, T J; Ding, J L

    1999-11-11

    The full length estrogen receptor from Oreochromis aureus (OaER) was cloned and expressed in vitro and in vivo as a functional transcription factor. Amino acid residues involved in the thermal stability of the receptor are located at/near subzones beta1 and beta3, which are highly conserved in other non-piscine species but not in OaER. Hormone binding studies, however, indicate that OaER is thermally stable but exhibited a approximately 3-fold reduced affinity for estrogen at elevated temperatures. Transfection of OaER into various cell lines cultured at different temperatures displayed a significant estrogen dose-response shift compared with that of chicken ER (cER). At 37 degrees C, OaER requires approximately 80-fold more estrogen to achieve half-maximal stimulation of CAT. Lowering of the incubation temperature from 37 degrees C to 25 degrees C or 20 degrees C resulted in a 4-fold increase in its affinity for estrogen. The thermally deficient transactivation of OaER at temperatures above 25 degrees C was fully prevented by high levels of estrogen. Thus, compared to cER, the OaER exhibits reduced affinity for estrogen at elevated temperature as reflected in its deficient transactivation capability. Amino acid replacements of OaER beta3 subzones with corresponding amino acids from cER could partially rescue this temperature sensitivity. The three-dimensional structure of the OaER ligand binding domain (LBD) was modelled based on conformational similarity and sequence homology with human RXRalpha apo, RARgamma holo and ERalpha LBDs. Unliganded and 17beta-estradiol-liganded OaER LBD retained the overall folding pattern of the nuclear receptor LBDs. The residues at/near the subzone beta3 of the LBD constitute the central core of OaER structure. Thus, amino acid alteration at this region potentially alters the structure and consequently its temperature-dependent ligand binding properties. PMID:10559464

  5. The estrogenic and androgenic potential of pyrethroids in vitro. Review.

    PubMed

    Saillenfait, Anne-Marie; Ndiaye, Dieynaba; Sabaté, Jean-Philippe

    2016-08-01

    Synthetic pyrethroids are used worldwide as insecticides. Their metabolites are regularly detected in the urine of adults and children from the general population. There is increasing concern that they may induce sex-hormone disrupting effects. The present work reviews available published information on the (anti)estrogenic and (anti)androgenic activity of pyrethroids in in vitro screening tests. In recent years, a large number of pyrethroids have been evaluated using various common testing methods. In tests using recombinant yeast or mammalian cells, the pyrethroids were found to be essentially negative or weakly estrogenic. More inconsistent results were found regarding their estrogenic action in proliferation tests. Conflicting findings were also reported across studies and/or assays which evaluated their anti-estrogenic or anti-androgenic potential. Some studies have suggested that certain pyrethroids may have potential antagonist activity. However, no strong interaction with the estrogenic or androgenic pathway was reported. The present review confirms the interest in performing a screening battery and in adopting an integrative approach for identifying the potential of different compounds from a chemical family to interfere with the endocrine system. PMID:26921664

  6. Structural and Functional Diversity of Estrogen Receptor Ligands

    PubMed Central

    Farooq, Amjad

    2015-01-01

    Estrogen receptors, comprised of ERα and ERβ isoforms in mammals, act as ligand-modulated transcription factors and orchestrate a plethora of cellular functions from sexual development and reproduction to metabolic homeostasis. Herein, I revisit the structural basis of the binding of ERα to DNA and estradiol in light of the recent discoveries and emerging trends in the field of nuclear receptors. A particular emphasis of this review is on the chemical and structural diversity of an ever-increasing repertoire of physiological, environmental and synthetic ligands of estrogen receptors that ultimately modulate their interactions with cognate DNA located within the promoters of estrogen-responsive genes. In particular, modulation of estrogen receptors by small molecule ligands represents an important therapeutic goal toward the treatment of a wide variety of human pathologies including breast cancer, cardiovascular disease, osteoporosis and obesity. Collectively, this article provides an overview of a wide array of small organic and inorganic molecules that can fine-tune the physiological function of estrogen receptors, thereby bearing a direct impact on human health and disease. PMID:25866274

  7. Inhibition of estrogen biosynthesis enhances lymphoma growth in mice

    PubMed Central

    Talaber, Gergely; Yakimchuk, Konstantin; Guan, Jiyu; Inzunza, Jose; Okret, Sam

    2016-01-01

    Most lymphomas show higher incidence and poorer prognosis in males compared to females. However, the endocrine contribution to this gender difference is not entirely known. Here we show that castration accelerates lymphoma growth in C57BL6 male mice grafted with murine EG7 T cell lymphoma cells. However, the androgen receptor antagonist Bicalutamide did not affect lymphoma growth, suggesting no impact of androgen receptor signaling on lymphoma progression. In contrast, inhibition of androgen-to-estrogen conversion by the aromatase inhibitor (AI) Letrozole induced faster lymphoma growth in mice, suggesting that androgens impact lymphoma growth through its conversion to estrogens. This was supported by the inability of dihydrotestosterone, which is not converted to estrogens by aromatase, to influence lymphoma growth in castrated male mice. Lymphoma growth was also stimulated in immunocompromised mice grafted with human B cell lymphoma (Granta-519) and treated with either reversible or irreversible AIs, showing that the blockage of estrogen synthesis caused enhanced growth of both murine T and human B cell lymphomas and with different AIs. Additionally, AI-treated EG7 lymphomas showed accelerated growth not only in male but also in intact female mice. Altogether, our results demonstrate that aromatase inhibition accelerates lymphoma growth but not androgens per se, highlighting a protective role of estrogens in lymphoma pathogenesis. These results also raise concern that the use of AIs in women with breast cancer might enhance lymphoma progression. PMID:26943574

  8. Estrogen-Dependent Gene Expression in the Mouse Ovary

    PubMed Central

    Liew, Seng H.; Sarraj, Mai A.; Drummond, Ann E.; Findlay, Jock K.

    2011-01-01

    Estrogen (E) plays a pivotal role in regulating the female reproductive system, particularly the ovary. However, the number and type of ovarian genes influenced by estrogen remain to be fully elucidated. In this study, we have utilized wild-type (WT) and aromatase knockout (ArKO; estrogen free) mouse ovaries as an in vivo model to profile estrogen dependent genes. RNA from each individual ovary (n = 3) was analyzed by a microarray-based screen using Illumina Sentrix Mouse WG-6 BeadChip (45,281 transcripts). Comparative analysis (GeneSpring) showed differential expression profiles of 450 genes influenced by E, with 291 genes up-regulated and 159 down-regulated by 2-fold or greater in the ArKO ovary compared to WT. Genes previously reported to be E regulated in ArKO ovaries were confirmed, in addition to novel genes not previously reported to be expressed or regulated by E in the ovary. Of genes involved in 5 diverse functional processes (hormonal processes, reproduction, sex differentiation and determination, apoptosis and cellular processes) 78 had estrogen-responsive elements (ERE). These analyses define the transcriptome regulated by E in the mouse ovary. Further analysis and investigation will increase our knowledge pertaining to how E influences follicular development and other ovarian functions. PMID:21347412

  9. Genetic Bases of Estrogen-Induced Pituitary Tumorigenesis

    PubMed Central

    Strecker, Tracy E.; Spady, Thomas J.; Schaffer, Beverly S.; Gould, Karen A.; Kaufman, Amy E.; Shen, Fangchen; McLaughlin, Mac T.; Pennington, Karen L.; Meza, Jane L.; Shull, James D.

    2005-01-01

    Estrogens stimulate proliferation and enhance survival of the prolactin (PRL)-producing lactotroph of the anterior pituitary gland and induce development of PRL-producing pituitary tumors in certain inbred rat strains but not others. The goal of this study was to elucidate the genetic bases of estrogen-induced pituitary tumorigenesis in reciprocal intercrosses between the genetically related ACI and Copenhagen (COP) rat strains. Following 12 weeks of treatment with the synthetic estrogen diethylstilbestrol (DES), pituitary mass, an accurate surrogate marker of absolute lactotroph number, was increased 10.6-fold in ACI rats and 4.5-fold in COP rats. Composite interval mapping analyses of the phenotypically defined F2 progeny from the reciprocal crosses identified six quantitative trait loci (QTL) that determine the pituitary growth response to DES. These loci reside on chromosome 6 [Estrogen-induced pituitary tumor (Ept)1], chromosome 3 (Ept2 and Ept6), chromosome 10 (Ept9), and chromosome 1 (Ept10 and Ept13). Together, these six Ept loci and one additional suggestive locus on chromosome 4 account for an estimated 40% of the phenotypic variance exhibited by the combined F2 population, while 34% of the phenotypic variance was estimated to result from environmental factors. These data indicate that DES-induced pituitary mass behaves as a quantitative trait and provide information that will facilitate identification of genes that determine the tumorigenic response of the pituitary gland to estrogens. PMID:15687265

  10. Function of G-Protein-Coupled Estrogen Receptor-1 in Reproductive System Tumors

    PubMed Central

    Qian, Hongyan; Xuan, Jingxiu; Liu, Yuan; Shi, Guixiu

    2016-01-01

    The G-protein-coupled estrogen receptor-1 (GPER-1), also known as GPR30, is a novel estrogen receptor mediating estrogen receptor signaling in multiple cell types. The progress of estrogen-related cancer is promoted by GPER-1 activation through mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), and phospholipase C (PLC) signaling pathways. However, this promoting effect of GPER-1 is nonclassic estrogen receptor (ER) dependent manner. In addition, clinical evidences revealed that GPER-1 is associated with estrogen resistance in estrogen-related cancer patients. These give a hint that GPER-1 may be a novel therapeutic target for the estrogen-related cancers. However, preclinical studies also found that GPER-1 activation of its special agonist G-1 inhibits cancer cell proliferation. This review aims to summarize the characteristics and complex functions of GPER-1 in cancers. PMID:27314054

  11. COMPARISON OF FATHEAD MINNOW AND HUMAN ESTROGEN RECEPTOR BINDING TO ENDOCRINE DISRUPTING COMPOUNDS

    EPA Science Inventory

    Environmental estrogens have the potential to disrupt endocrine function in a myriad of species. However, in vitro assays designed to detect and characterize endocrine disrupting chemicals (EDCs) typically utilize mammalian estrogen receptors. Our overall objective is to charac...

  12. Adaptive Significance of ERα Splice Variants in Killifish (Fundulus heteroclitus) Resident in an Estrogenic Environment

    EPA Science Inventory

    The possibility that chronic, multigenerational exposure to environmental estrogens selects for adaptive hormone response phenotypes is a critical unanswered question. Embryos/larvae of killifish from an estrogenic polluted environment (New Bedford Harbor, NBH), as compared to th...

  13. DEVELOPMENT OF AN ENVIRONMENTAL ESTROGEN SCREEN USING TRANSIENTLY TRANSFECTED RAINBOW TROUT CELL LINES

    EPA Science Inventory

    Rainbow troutp hepatoma (RTH-149) and gonad cells (RTG-2) were used to develop a screening protocol for estrogen disrupting chemicals. Transfection of an estrogen-responsive luciferase reporter plasmid into...

  14. COLLAPSE OF A FISH POPULATION FOLLOWING EXPOSURE TO A SYNTHETIC ESTROGEN

    EPA Science Inventory

    Municipal wastewaters are a complex mixture containing estrogens and estrogen mimics that are known to affect the reproductive health of wild fishes. Male fishes downstream of some wastewater outfalls produce vitellogenin (VTG) (a protein normally synthesized by females during oo...

  15. INDUCTION OF MAMMARY GLAND DEVELOPMENT IN ESTROGEN RECEPTOR-ALPHA KNOCKOUT MICE

    EPA Science Inventory

    Mammary glands from the estrogen receptor knockout ( ERKO) mouse do not undergo ductal morphogenesis or alveolar development. Disrupted Er signaling may result in reduced estrogen-responsive gene products in the mammary gland or reduced mammotropic hormones that contribute t...

  16. ESTROGEN INDUCED VITELLOGENIN MRNA AND PROTEIN IN SHEEPSHEAD MINNOW (CYPRINODON VARIEGATUS)

    EPA Science Inventory

    Many environmentally persistent xenobiotic chemicals appear to disrupt normal endocrine function by acting as ligands for endogenous steroid receptors, including the estrogen receptor. Xenobiotics that bind to the estrogen receptor may elicit several effects, one of which is acti...

  17. Tissue-Specific Effects of Loss of Estrogen during Menopause and Aging

    PubMed Central

    Wend, Korinna; Wend, Peter; Krum, Susan A.

    2012-01-01

    The roles of estrogens have been best studied in the breast, breast cancers, and in the female reproductive tract. However, estrogens have important functions in almost every tissue in the body. Recent clinical trials such as the Women’s Health Initiative have highlighted both the importance of estrogens and how little we know about the molecular mechanism of estrogens in these other tissues. In this review, we illustrate the diverse functions of estrogens in the bone, adipose tissue, skin, hair, brain, skeletal muscle and cardiovascular system, and how the loss of estrogens during aging affects these tissues. Early transcriptional targets of estrogen are reviewed in each tissue. We also describe the tissue-specific effects of selective estrogen receptor modulators (SERMs) used for the treatment of breast cancers and postmenopausal symptoms. PMID:22654856

  18. Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice☆

    PubMed Central

    Kim, Jun Ho; Meyers, Matthew S.; Khuder, Saja S.; Abdallah, Simon L.; Muturi, Harrison T.; Russo, Lucia; Tate, Chandra R.; Hevener, Andrea L.; Najjar, Sonia M.; Leloup, Corinne; Mauvais-Jarvis, Franck

    2014-01-01

    Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice. PMID:24634829

  19. Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention.

    PubMed

    Cavalieri, Ercole L; Rogan, Eleanor G

    2016-03-01

    Estrogens can initiate cancer by reacting with DNA. Specific metabolites of endogenous estrogens, the catechol estrogen-3,4-quinones, react with DNA to form depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating mutations that can lead to the initiation of cancer. A variety of endogenous and exogenous factors can disrupt estrogen homeostasis, which is the normal balance between estrogen activating and protective enzymes. In fact, if estrogen metabolism becomes unbalanced and generates excessive catechol estrogen 3,4-quinones, formation of depurinating estrogen-DNA adducts increases and the risk of initiating cancer is greater. The levels of depurinating estrogen-DNA adducts are high in women diagnosed with breast cancer and those at high risk for the disease. High levels of depurinating estrogen-DNA adducts before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Women with thyroid or ovarian cancer also have high levels of estrogen-DNA adducts, as do men with prostate cancer or non-Hodgkin lymphoma. Depurinating estrogen-DNA adducts are initiators of many prevalent types of human cancer. These findings and other discoveries led to the recognition that reducing the levels of estrogen-DNA adducts could prevent the initiation of human cancer. The dietary supplements N-acetylcysteine and resveratrol inhibit formation of estrogen-DNA adducts in cultured human breast cells and in women. These results suggest that the two supplements offer an approach to reducing the risk of developing various prevalent types of human cancer. Graphical abstract Major metabolic pathway in cancer initiation by estrogens. PMID:26979321

  20. Body Size in Relation to Urinary Estrogens and Estrogen Metabolites (EM) among Premenopausal Women during the Luteal Phase

    PubMed Central

    Xie, Jing; Eliassen, A. Heather; Xu, Xia; Matthews, Charles E.; Hankinson, Susan E.; Ziegler, Regina G.; Tworoger, Shelley S.

    2012-01-01

    Estrogen metabolism profiles may play an important role in the relationship between body size and breast carcinogenesis. Previously, we observed inverse associations between current body mass index (BMI) and plasma levels of parent estrogens (estrone and estradiol) among premenopausal women during both follicular and luteal phases. Using data from the Nurses’ Health Study II (NHS II), we assessed whether height, current BMI, and BMI at age 18 were associated with the urinary concentrations of 15 estrogens and estrogen metabolites (jointly referred to as EM) measured during the luteal phase among 603 premenopausal women. We observed inverse associations with total EM for height (Ptrend=0.01) and current BMI (Ptrend=0.01), but not BMI at age 18 (Ptrend=0.26). Six EMs were 18–27% lower in women with a height 68+ inches versus ≤62 inches, primarily in the methylated catechol pathway (Ptrend=0.04). Eight EMs were 18–50% lower in women with a BMI of 30+ versus <20, primarily in the 2-catechol and methylated catechol pathways (Ptrend<0.001 for both). Our results suggest that height and current BMI are associated with estrogen metabolism profiles in premenopausal women. Further studies with timed urine and blood collections are required to confirm and extend our findings. PMID:23011724

  1. Estrogen receptor profiling and activity in cardiac myocytes.

    PubMed

    Pugach, Emily K; Blenck, Christa L; Dragavon, Joseph M; Langer, Stephen J; Leinwand, Leslie A

    2016-08-15

    Estrogen signaling appears critical in the heart. However a mechanistic understanding of the role of estrogen in the cardiac myocyte is lacking. Moreover, there are multiple cell types in the heart and multiple estrogen receptor (ER) isoforms. Therefore, we studied expression, localization, transcriptional and signaling activity of ERs in isolated cardiac myocytes. We found only ERα RNA (but no ERβ RNA) in cardiac myocytes using two independent methods. The vast majority of full-length ERα protein (ERα66) localizes to cardiac myocyte nuclei where it is competent to activate transcription. Alternate isoforms of ERα encoded by the same genomic locus (ERα46 and ERα36) have differential transcriptional activity in cardiac myocytes but also primarily localize to nuclei. In contrast to other reports, no ERα isoform is competent to activate MAPK or PI3K signaling in cardiac myocytes. Together these data support a role for ERα at the level of transcription in cardiac myocytes. PMID:27164442

  2. Bisphenol A in dental sealants and its estrogen like effect

    PubMed Central

    Rathee, Manu; Malik, Poonam; Singh, Jyotirmay

    2012-01-01

    Bisphenol A or BPA-based epoxy resins are widely used in the manufacture of commercial products, including dental resins, polycarbonate plastics, and the inner coating of food cans. BPA is a precursor to the resin monomer Bis-GMA. During the manufacturing process of Bis-GMA dental sealants, Bisphenol A (BPA) might be present as an impurity or as a degradation product of Bis-DMA through esterases present in saliva. Leaching of these monomers from resins can occur during the initial setting period and in conjunction with fluid sorption and desorption over time and this chemical leach from dental sealants may be bioactive. Researchers found an estrogenic effect with BPA, Bis-DMA, and Bis-GMA because BPA lacks structural specificity as a natural ligand to the estrogen receptor. It generated considerable concern regarding the safety of dental resin materials. This review focuses on the BPA in dental sealants and its estrogen-like effect. PMID:22629496

  3. Synthesis of catechol estrogens by human uterus and leiomyoma

    SciTech Connect

    Reddy, V.V.; Hanjani, P.; Rajan, R.

    1981-02-01

    Homogenates of human endometrial, myometrial and leiomyoma tissues were incubated with (2,4,6,7-/sub 3/H)-estradiol and tritiated catechol estrogens were isolated and identified. Though 2- and 4-hydroxylations were about the same in endometrium, 4-hydroxylation was two to four fold higher than 2-hydroxylation in myometrium and leiomyoma. However, endometrium showed greater capacity to form both 2- and 4-hydroxyestrogens than the other two tissues. Both 2- and 4-hydroxylations were significantly less than in myometrium. In view of the reports indicating that inhibitors of catechol 0-methyl transferase (COMT) might act as antineoplastic agents due to their interference with t-RNA methylases and since catechol estrogens inhibit COMT, the present results suggest that endogenous synthesis of catechol estrogens may play an important role in the pathophysiology of uterine leiomyoma.

  4. Estrogen and neuroprotection: from clinical observations to molecular mechanisms

    PubMed Central

    Dubal, Dena B.; Wise, Phyllis M.

    2002-01-01

    We now appreciate that estrogen is a pleiotropic gonadal steroid that exerts profound effects on the plasticity and cell survival of the adult brain. Over the past century, the life span of women has increased, but the age of the menopause remains constant. This means that women may now live over one third of their lives in a hypoestrogenic, postmenopausal state. The impact of prolonged hypoestrogenicity on the brain is now a critical health concern as we realize that these women may suffer an increased risk of cognitive dysfunction and neurodegeneration due to a variety of diseases. Accumulating evidence from both clinical and basic science studies indicates that estrogen exerts critical protective actions against neurodegenerative conditions such as Alzheimer's disease and stroke. Here, we review the discoveries that comprise our current understanding of estrogen action against neurodegeneration. These findings carry far-reaching possibilities for improving the quality of life in our aging population. PMID:22034440

  5. Estrogen formulations and beauty care practices in Japanese women

    PubMed Central

    Takeda, Takashi; Wong, Tze Fang; Kitamura, Mari; Yaegashi, Nobuo

    2012-01-01

    Purpose Traditionally, oral estrogens have been used for hormone replacement therapy. However, in Japan, additional estrogen formulations have been used, including transdermal patches and transdermal gels. The latter have a unique commonality with cosmetics because both of them are applied to the skin. Beauty care is one of the most important lifestyle factors for women, and it has been reported that the amount of attention paid to beauty care has an effect in determining whether or not women will choose to undergo HRT during menopause. Therefore, our study focused on estrogen formulations and beauty care practices. Patients and methods Fifty women who use hormone replacement therapy were recruited from the outpatient clinic of Tohoku University Hospital. They were treated with oral conjugated estrogen (n = 11), transdermal 17β-estradiol patch (n = 11), and transdermal 17β-estradiol gel (n = 28). They completed a questionnaire to assess their lifestyle (beauty care practices and exercise habits) and their compliance. The transdermal gel users were further interviewed about their subjective impressions regarding “smell”, “sticky feeling”, “spreadability”, and “irritation” on the skin using a five-grade scale. Results There were no differences in the usability of medicines and patient compliance among the estrogen formulations. We observed a positive tendency between the level of beauty care and transdermal gel use (P = 0.0645, ordinary logistic regression analysis). The gel users placed top priority on a lack of “sticky feeling” but the subjective impression regarding “sticky feeling” was worst among the four factors (P < 0.01, Steel–Dwass test). Correspondence analysis showed that the subjective impressions of transdermal gel corresponding to usability in the range of “moderate” to “very good” and “sticky feeling” greatly affected the usability of the formulation. Conclusion These results suggest that the level of attention

  6. Neuro-estrogens rapidly regulate sexual motivation but not performance

    PubMed Central

    Seredynski, Aurore L.; Balthazart, Jacques; Christophe, Virginie J.; Ball, Gregory F.; Cornil, Charlotte A.

    2013-01-01

    Estrogens exert pleiotropic effects on reproductive traits, which include differentiation and activation of reproductive behaviors and the control of the secretion of gonadotropins. Estrogens also profoundly affect non-reproductive traits such as cognition and neuroprotection. These effects are usually attributed to nuclear receptor binding and subsequent regulation of target gene transcription. Estrogens also affect neuronal activity and cell-signaling pathways via faster, membrane-initiated events. How these two types of actions that operate in distinct time scales interact in the control of complex behavioral responses is poorly understood. Here, we show that the central administration of estradiol rapidly increases the expression of sexual motivation, as assessed by several measures of sexual motivation produced in response to the visual presentation of a female but not sexual performance in male Japanese quail. This effect is mimicked by membrane-impermeable analogs of estradiol, indicating that it is initiated at the cell membrane. Conversely, blocking the action of estrogens or their synthesis by a single intracereboventricular injection of estrogen receptor antagonists or aromatase inhibitors respectively decreases sexual motivation within minutes without affecting performance. The same steroid has thus evolved complementary mechanisms to regulate different behavioral components (motivation vs. performance) in distinct temporal domains (long- vs. short-term) so that diverse reproductive activities can be properly coordinated to improve reproductive fitness. Given the pleiotropic effects exerted by estrogens, other responses controlled by these steroids might also depend on a slow genomic regulation of neuronal plasticity underlying behavioral activation and an acute control of motivation to engage in behavior. PMID:23283331

  7. Deoxybenzoins are novel potent selective estrogen receptor modulators.

    PubMed

    Papoutsi, Zoi; Kassi, Eva; Fokialakis, Nikolas; Mitakou, Sofia; Lambrinidis, George; Mikros, Emmanuel; Moutsatsou, Paraskevi

    2007-09-01

    Deoxybenzoins are plant compounds with similar structure to isoflavones. In this study, we evaluated the ability of two synthesized deoxybenzoins (compound 1 and compound 2) (a) to influence the activity of the estrogen receptor subtypes ERalpha and ERbeta in HeLa cells co-transfected with an estrogen response element-driven luciferase reporter gene and ERalpha- or ERbeta-expression vectors, (b) to modulate the IGFBP-3 and pS2 protein in MCF-7 breast cancer cells, (c) to induce mineralization of KS483 osteoblasts and (d) to affect the cell viability of endometrial (Ishikawa) and breast (MCF-7, MDA-MB-231) cancer cells. Docking and binding energy calculations were performed using the mixed Monte Carlo/Low Mode search method (Macromodel 6.5). Compound 1 displayed significant estrogenic activity via ERbeta but no activity via ERalpha. Compound 2 was an estrogen-agonist via ERalpha and antagonist via ERbeta. Both compounds increased, like the pure antiestrogen ICI182780, the IGFBP-3 levels. Compound 2 induced, like 17beta-estradiol, significant mineralization in osteoblasts. The cell viability of Ishikawa cells was unchanged in the presence of either compound. Compound 1 increased MCF-7 cell viability consistently with an increase in pS2 levels, whereas compound 2 inhibited the cell viability. Molecular modeling confirmed the agonistic or antagonistic behaviour of compound 2 via ER subtypes. Compound 2, being an agonist in osteoblasts, an antagonist in breast cancer cells, with no estrogenic effects in endometrial cancer cells, makes it a potential selective estrogen receptor modulator and a choice for hormone replacement therapy. PMID:17659312

  8. Rapid Actions of Xenoestrogens Disrupt Normal Estrogenic Signaling

    PubMed Central

    Watson, Cheryl S.; Hu, Guangzhen; Paulucci-Holthauzen, Adriana A.

    2014-01-01

    Some chemicals used in consumer products or manufacturing (eg. plastics, surfactants, pesticides, resins) have estrogenic activities; these xenoestrogens (XEs) chemically resemble physiological estrogens and are one of the major categories of synthesized compounds that disrupt endocrine actions. Potent rapid actions of XEs via nongenomic mechanisms contribute significantly to their disruptive effects on functional endpoints (eg. cell proliferation/death, transport, peptide release). Membrane-initiated hormonal signaling in our pituitary cell model is predominantly driven by mERα with mERβ and GPR30 participation. We visualized ERα on plasma membranes using many techniques in the past (impeded ligands, antibodies to ERα ) and now add observations of epitope proximity with other membrane signaling proteins. We have demonstrated a range of rapid signals/protein activations by XEs including: calcium channels, cAMP/PKA, MAPKs, G proteins, caspases, and transcription factors. XEs can cause disruptions of the oscillating temporal patterns of nongenomic signaling elicited by endogenous estrogens. Concentration effects of XEs are nonmonotonic (a trait shared with natural hormones), making it difficult to design efficient (single concentration) toxicology tests to monitor their harmful effects. A plastics monomer, Bisphenol A, modified by waste treatment (chlorination) and other processes causes dephosphorylation of extracellular-regulated kinases, in contrast to having no effects as it does in genomic signaling. Mixtures of XEs, commonly found in contaminated environments, disrupt the signaling actions of physiological estrogens even more severely than do single XEs. Understanding the features of XEs that drive these disruptive mechanisms will allow us to redesign useful chemicals that exclude estrogenic or anti-estrogenic activities. PMID:24269739

  9. Estrogen-Cholinergic Interactions: Implications for Cognitive Aging

    PubMed Central

    Newhouse, Paul; Dumas, Julie

    2015-01-01

    While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects. PMID:26187712

  10. Estrogen-cholinergic interactions: Implications for cognitive aging.

    PubMed

    Newhouse, Paul; Dumas, Julie

    2015-08-01

    This article is part of a Special Issue "Estradiol and Cognition". While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects. PMID:26187712

  11. Progress in the molecular understanding of central regulation of body weight by estrogens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Estrogens can act in the brain to prevent body weight gain. Tremendous research efforts have been focused on estrogen physiology in the brain in the context of body weight control; estrogen receptors and the related signals have been attractive targets for development of new obesity therapies. The o...

  12. Fate and transformation of an estrogen conjugate and its metabolites in agricultural soils

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Estrogens are naturally produced steroid hormones that are constantly being eliminated by many life forms, including production animals. An important form of release of estrogens is as water-soluble conjugates, which are not toxic, but may readily be hydrolyzed back to parent estrogens, which are kn...

  13. [Focusing on tissue biomarkers. Estrogens as key players in the immune response and autoimmunity].

    PubMed

    Vásárhelyi, Barna; Mészáros, Katalin; Karvaly, Gellért; Patócs, Attila

    2015-12-20

    Estrogens modulate the immune response as well as the risk and progression of autoimmune disorders. Their effects are mediated by nuclear receptors (i.e. estrogen receptor alpha and beta), membrane receptors, and are influenced by their interactions with other hormones. Locally produced hormones and cytokines are the main factors in maintaining tissue homeostasis. The response of immune cells to estrogens is related to their developmental stage. The diverse effects of estrogens on various autoimmune disorders are the result of the versatility of their pathomechanism. In general, progression of B-cell mediated disorders is aggravated by estrogens. Their effects on T-cell mediated disorders, on the other hand, are driven by Th1 or Th2 dominance. As estrogens promote the escalation of the Th2 immune response, Th2-dominant disorders are aggravated, while Th1-dominant disorders are ameliorated upon high estrogen levels. Inflammation on its own also modulates the impact of estrogens. Inflammatory cytokines alter the expression of the alpha and beta estrogen receptors as well as the activity of estrogen metabolizing enzymes. Monitoring the local, tissue-wide interaction between hormones and immune cells would provide a better tool for identification and characterization of molecules involved in this system. To date, routinely used laboratory methods have a limited role in monitoring the local effects of estrogens. In this current paper the authors summarize the role of estrogens in immune system and overview those novel methods which are useful in the investigation of local endocrine milieu. PMID:26654543

  14. Evaluation of surface waters associated with animal feeding operations for estrogenic chemicals and activity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Estrogens and estrogenic activity (EA) were evaluated in surface waters associated with animal feeding operations. Water was sampled at 19 sites in 12 states using discrete (n=41) and POCIS (n=19) sampling methods. Estrogenic chemicals measured in unfiltered water by GC/MS2 included: estrone (E1),17...

  15. Bone marrow oxytocin mediates the anabolic action of estrogen on the skeleton

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Estrogen withdrawal in women due to natural or artificial menopause is followed by rapid bone loss, osteoporosis, and a high fracture risk. Replacement with estrogen prevents this bone loss and reduces the risk of fracture. Estrogen uses two mechanisms to exert this effect: it inhibits bone resorpti...

  16. DNA Repair, Redox Regulation and Modulation of Estrogen Receptor Alpha Mediated Transcription

    ERIC Educational Resources Information Center

    Curtis-Ducey, Carol Dianne

    2009-01-01

    Interaction of estrogen receptor [alpha] (ER[alpha]) with 17[beta]-estradiol (E[subscript 2]) facilitates binding of the receptor to estrogen response elements (EREs) in target genes, which in turn leads to recruitment of coregulatory proteins. To better understand how estrogen-responsive genes are regulated, our laboratory identified a number of…

  17. Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation.

    PubMed

    Zhang, Y-W; Nasto, R E; Varghese, R; Jablonski, S A; Serebriiskii, I G; Surana, R; Calvert, V S; Bebu, I; Murray, J; Jin, L; Johnson, M; Riggins, R; Ressom, H; Petricoin, E; Clarke, R; Golemis, E A; Weiner, L M

    2016-03-31

    Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)- and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers. PMID:26165839

  18. Estrogen-induced neurochemical and electrophysiological changes in the parabrachial nucleus of the male rat.

    PubMed

    Saleh, Tarek M; Connell, Barry J; McQuaid, Tim; Cribb, Alastair E

    2003-11-14

    Estrogen has previously been shown to significantly change sympathetic and parasympathetic system output via an action within the central nuclei responsible for regulating autonomic tone. These estrogen-induced changes were observed within 30 min of systemic administration and could be blocked by the direct microinjection of the estrogen receptor antagonist, ICI 182780, into the parabrachial nucleus (PBN) of the pons. In the present investigation, we sought to determine the possible mechanism(s) by which estrogen produced these rapid changes in autonomic tone by determining if estrogen modulates neuronal excitability within the PBN. Male Sprague-Dawley rats were anaesthetized with Inactin (sodium thiobutabarbitol, 100 mg/kg) and instrumented for the intravenous injection of estrogen and placed in a stereotaxic frame for the insertion of a microdialysis probe or glass recording electrode into the PBN. In the first experiment, we sought to determine the local concentration of estrogen in the cerebrospinal fluid in the PBN following systemic injection of estrogen. In the second experiment, we sought to determine the functional significance of systemic estrogen injection on neuronal activity and amino acid neurotransmitter levels in the PBN. Systemic estrogen injection resulted in a significant increase in local estrogen concentration in the PBN which corresponded to a decrease in neuronal excitability and extracellular glutamate levels while increasing GABA levels in the PBN. These results suggest that estrogen decreases neuronal excitability in the PBN by modulating synaptic transmission via an increased release of GABA and a decreased release of glutamate. PMID:14568330

  19. Measuring free, conjugated, and halogenated estrogens in secondary treated wastewater effluent.

    PubMed

    Griffith, David R; Kido Soule, Melissa C; Matsufuji, Hiroshi; Eglinton, Timothy I; Kujawinski, Elizabeth B; Gschwend, Philip M

    2014-01-01

    Steroidal estrogens are potent endocrine-disrupting chemicals that enter natural waters through the discharge of treated and raw sewage. Because estrogens are detrimental to aquatic organisms at sub-nanogram per liter concentrations, many studies have measured so-called "free" estrogen concentrations in wastewater effluents, rivers, and lakes. Other forms of estrogens are also of potential concern because conjugated estrogens can be easily converted to potent free estrogens by bacteria in wastewater treatment plants and receiving waters and halogenated estrogens are likely produced during wastewater disinfection. However, to the best of our knowledge, no studies have concurrently characterized free, conjugated, and halogenated estrogens. We have developed a method that is capable of simultaneously quantifying free, conjugated, and halogenated estrogens in treated wastewater effluent, in which detection limits were 0.13-1.3 ng L(-1) (free), 0.11-1.0 ng L(-1) (conjugated), and 0.18-18 ng L(-1) (halogenated). An aqueous phase additive, ammonium fluoride, was used to increase the electrospray (negative mode) ionization efficiency of free and halogenated estrogens by factors of 20 and 2.6, respectively. The method was validated using treated effluent from the greater Boston metropolitan area, where conjugated and halogenated estrogens made up 60-70% of the steroidal estrogen load on a molar basis. PMID:24476066

  20. Steroid receptor coactivator-1 mediates estrogenic actions to prevent body weight gain in female mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Estrogen receptor-alpha (ERalpha) expressed by hypothalamic proopiomelanocortin and steroidogenic factor-1 neurons largely mediates the antiobesity effects of estrogens in females. However, the critical molecular events that are coupled to ERalpha and mediate estrogenic effects on energy balance rem...

  1. Binding and transactivation of the largemouth bass estrogen receptors by model compounds

    EPA Science Inventory

    Environmental estrogens (EEs) are chemicals in the environment that can elicit adverse effects on estrogen (E2) signaling by binding with the estrogen receptors (ERs). In largemouth bass (LMB), the physiological actions of E2 are primarily mediated via three receptors (ERα, ERßb ...

  2. Reversal of fortune: estrogen receptor-β in endometriosis.

    PubMed

    Simmen, Rosalia C M; Kelley, Angela S

    2016-08-01

    Enhanced inflammation and reduced apoptosis sustain the growth of endometriotic lesions. Alterations in the expression of estrogen receptor-alpha (ERα) and estrogen receptor-beta (ERβ) accompany the conversion of resident endometrial cells within the normal uterine environment to ectopic lesions located in extrauterine sites. Recent studies highlighted in this focused review linked ERβ to dysregulation of apoptotic and inflammatory networks involving novel interacting partners in endometriosis. The elucidation of these nongenomic actions of ERβ using human cells and mouse models is an important step in understanding key regulatory pathways that are disrupted leading to disease establishment and progression. PMID:27272520

  3. Keto-enol tautomerism in estrogen hormone. A theoretical study

    NASA Astrophysics Data System (ADS)

    Jameh-Bozorghi, Saeed; Shirani, Hossein; Ghaempanah, Aram; Ghapanvari, Hamed

    2015-01-01

    The HF/6-311+G** calculation was used to investigate Keto-Enol tautomerism of Estrogen Hormone. Molecular geometries of keto, enol and transition state of this reaction were optimized and NBO calculations were performed. These calculation results showed that activation energy (Ea) of Keto-Enol tautomerization of Estrogen is 118.65 Kcal mol-1. Energetic study at B3LYP/6-311+G** level of theory revealed that keto tautomer is more stable structure. NBO analysis results have a good agreements with optimized geometries and experimental data.

  4. Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump.

    PubMed

    Chen, Yuan; Vasilenko, Alex; Song, Xiulong; Valanejad, Leila; Verma, Ruchi; You, Sangmin; Yan, Bingfang; Shiffka, Stephanie; Hargreaves, Leeza; Nadolny, Christina; Deng, Ruitang

    2015-04-01

    Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17β-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α and farnesoid X receptor (FXR) and transrepression of BSEP by E2/ERα is an etiological contributing factor to intrahepatic cholestasis of pregnancy. Currently the mechanistic insights into such transrepression are not fully understood. In this study, the dynamics of coregulator recruitment to BSEP promoter after FXR activation and E2 treatment were established with quantitative chromatin immunoprecipitation assays. Coactivator peroxisome proliferator-activated receptor-γ coactivator-1 was predominantly recruited to the BSEP promoter upon FXR activation, and its recruitment was decreased by E2 treatment. Meanwhile, recruitment of nuclear receptor corepressor was markedly increased upon E2 treatment. Functional evaluation of ERα and ERβ chimeras revealed that domains AC of ERα are the determinants for ERα-specific transrepression on BSEP. Further studies with various truncated ERα proteins identified the domains in ERα responsible for ligand-dependent and ligand-independent transrepression. Truncated ERα-AD exhibited potent ligand-independent transrepressive activity, whereas ERα-CF was fully capable of transrepressing BSEP ligand dependently in vitro in Huh 7 cells and in vivo in mice. Both ERα-AD and ERα-CF proteins were associated with FXR in the coimmunoprecipitation assays. In conclusion, E2 repressed BSEP expression through diminishing peroxisome proliferator-activated receptor-γ coactivator-1 recruitment with a concurrent increase in nuclear receptor corepressor recruitment to the BSEP promoter. Domains AD and CF in ERα mediated ligand-independent and ligand-dependent transrepression on BSEP, respectively, through interacting with FXR. PMID:25675114

  5. ERRF is essential for Estrogen-Estrogen Receptor alpha signaling pathway in ER positive breast cancer cells.

    PubMed

    Luo, Ang; Zhang, Xuan

    2016-05-27

    Estrogen-Estrogen Receptor alpha (ERα) belongs to one of the most important signaling pathways controlling breast tissue development and progression of breast cancer. ERRF was recently identified as a candidate breast cancer associated protein and showed positive association with ERα status in clinical samples and cell lines. To further explore the relationship between ERRF and ERα, we studied whether ERRF plays any roles in estrogen-ERα pathway. Knockdown of ERRF in ER positive breast cancer cells T-47D and BT-474 reduced the level of p-AKT, p-MAPK, and phosphorylation of ERα at Ser 118 and Ser 167, and the transcriptional activity of ERα was inhibited as well. Further mechanism study proved ERRF to be an interacting partner of ERα. In total, these data revealed that ERRF is essential for the activity of E2-ERα pathway. PMID:27125460

  6. Treatment of BG-1 Ovarian Cancer Cells Expressing Estrogen Receptors with Lambda-cyhalothrin and Cypermethrin Caused a Partial Estrogenicity Via an Estrogen Receptor-dependent Pathway

    PubMed Central

    Kim, Cho-Won; Go, Ryeo-Eun

    2015-01-01

    Synthetic pyrethroids (SPs) are the most common pesticides which are recently used for indoor pest control. The widespread use of SPs has resulted in the increased exposure to wild animals and humans. Recently, some SPs are suspected as endocrine disrupting chemicals (EDCs) and have been assessed for their potential estrogenicity by adopting various analyzing assays. In this study, we examined the estrogenic effects of lambda-cyhalothrin (LC) and cypermethrin (CP), the most commonly used pesticides in Korea, using BG-1 ovarian cancer cells expressing estrogen receptors (ERs). To evaluate the estrogenic activities of two SPs, LC and CP, we employed MTT assay and reverse-transcription polymerase chain reaction (RT-PCR) in LC or CP treated BG-1 ovarian cancer cells. In MTT assay, LC (10−6 M) and CP (10−5 M) significantly induced the growth of BG-1 cancer cells. LC or CP-induced cell growth was antagonized by addition of ICI 182,720 (10−8 M), an ER antagonist, suggesting that this effect appears to be mediated by an ER-dependent manner. Moreover, RT-PCR results showed that transcriptional level of cyclin D1, a cell cycle-regulating gene, was significantly up-regulated by LC and CP, while these effects were reversed by co-treatment of ICI 182,780. However, p21, a cyclin D-ckd-4 inhibitor gene, was not altered by LC or CP. Moreover, ERα expression was not significantly changed by LC and CP, while downregulated by E2. Finally, in xenografted mouse model transplanted with human BG-1 ovarian cancer cells, E2 significantly increased the tumor volume compare to a negative control, but LC did not. Taken together, these results suggest that LC and CP may possess estrogenic potentials by stimulating the growth of BG-1 ovarian cancer cells via partially ER signaling pathway associated with cell cycle as did E2, but this estrogenic effect was not found in in vivo mouse model. PMID:26877835

  7. Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen

    PubMed Central

    Wang, Li-jie; Li, Jian; Hao, Fang-ran; Yuan, Yin; Li, Jing-yun; Lu, Wei; Zhou, Tian-yan

    2016-01-01

    Aim: Dexamethasone (DEX) is a widely used synthetic glucocorticoid, which has shown anti-cancer efficacy and anti-estrogenic activity. In this study we explored the possibility that DEX might be used as an endocrine therapeutic agent to treat human non-small cell lung cancer (NSCLC). Methods: The viability and proliferation of human NSCLC cell lines A549 and H1299 were assessed in vitro. Anti-tumor action was also evaluated in A549 xenograft nude mice treated with DEX (2 or 4 mg·kg−1·d−1, ig) or the positive control tamoxifen (50 mg·kg−1·d−1, ig) for 32 d. The expression of estrogen sulfotransferase (EST) in tumor cells and tissues was examined. The intratumoral estrogen levels and uterine estrogen responses were measured. Results: DEX displayed mild cytotoxicity to the NSCLC cells (IC50 >500 μmol/L) compared to tamoxifen (IC50 <50 μmol/L), but it was able to inhibit the cell proliferation at low micromolar ranges. Furthermore, DEX (0.1–10 μmol/L) dose-dependently up-regulated EST expression in the cells, and inhibited the cell migration in vitro. Triclosan, a sulfation inhibitor, was able to diminish DEX-caused inhibition on the cell viability. In A549 xenograft nude mice, DEX or tamoxifen administration remarkably suppressed the tumor growth. Moreover, DEX administration dose-dependently increased EST expression in tumor tissues, and reduced intratumoral estrogen levels as well as the volumes and weights of uterine. Conclusion: DEX suppresses the growth of A549 xenograft tumors via inducing EST and decreasing estradiol levels in tumor tissues, suggesting that DEX may be used as anti-estrogenic agent for the treatment of NSCLC. PMID:27133297

  8. Estrogen increases the permeability of the cultured human cervical epithelium by modulating cell deformability.

    PubMed

    Gorodeski, G I

    1998-09-01

    Estrogens increase secretion of cervical mucus in females. The objective of this research was to study the mechanisms of estrogen action. The experimental models were human CaSki (endocervical) and hECE (ectocervical) epithelial cells cultured on filters. Incubation in steroid-free medium increased transepithelial electrical resistance (RTE) and decreased epithelial permeability to the cell-impermeant acid pyranine. Estrogen treatment reversed the effects, indicating estrogen decreases epithelial paracellular resistance. The estrogen effect was time and dose related (EC50 approximately 1 nM) and specific (estradiol = diethylstilbestrol > estrone, estriol; no effect by progesterone, testosterone, or cortisol) and was blocked by progesterone, tamoxifen, and ICI-182780 (an estrogen receptor antagonist). Estrogen treatment did not modulate dilution potential or changes in RTE in response to diC8 or to low extracellular Ca2+ (modulators of tight junctional resistance). In contrast, estrogen augmented decreases in RTE in response to hydrostatic and hypertonic gradients [modulators of resistance of lateral intercellular space (RLIS)], suggesting estrogen decreases RLIS. Estrogen decreased cervical cell size, shortened response time relative to changes in cell size after hypertonic challenge, and augmented the decrease in cell size in response to hypertonic and hydrostatic gradients. Lowering luminal NaCl had no significant effect on RTE, and the Cl- channel blocker diphenylamine-2-carboxylate attenuated the hypertonicity-induced decrease in cell size to the same degree in control and estrogen-treated cells, suggesting estrogen effects on permeability and cell size are not mediated by modulating Na+ or Cl- transport. In contrast, estrogen increased cellular G-actin levels, suggesting estrogens shift actin steady-state toward G-actin and the cervical cell cytoskeleton toward a more flexible structure. We suggest that the mechanism by which estrogens decrease RLIS and

  9. Estrogen receptor transcription and transactivation: Structure-function relationship in DNA- and ligand-binding domains of estrogen receptors

    PubMed Central

    Ruff, Marc; Gangloff, Monique; Marie Wurtz, Jean; Moras, Dino

    2000-01-01

    Estrogen receptors are members of the nuclear receptor steroid family that exhibit specific structural features, ligand-binding domain sequence identity and dimeric interactions, that single them out. The crystal structures of their DNA-binding domains give some insight into how nuclear receptors discriminate between DNA response elements. The various ligand-binding domain crystal structures of the two known estrogen receptor isotypes (α and β) allow one to interpret ligand specificity and reveal the interactions responsible for stabilizing the activation helix H12 in the agonist and antagonist positions. PMID:11250728

  10. Relationship between the expression of estrogen-regulated genes and estrogen-stimulated proliferation of MCF-7 mammary tumor cells.

    PubMed

    Aitken, S C; Lippman, M E; Kasid, A; Schoenberg, D R

    1985-06-01

    The growth of MCF-7 cells was arrested by 24 h of isoleucine deprivation. Following replenishment of the medium, the incorporation of uridine and thymidine into trichloroacetic acid-precipitable material began to increase slowly and gradually rose to the level of cycling cells. The addition of 5 X 10(-9) M estradiol to growth-arrested cells dramatically shortened the time of onset of macromolecular synthesis and increased the overall amount of precursor incorporation 2- to 4-fold over the level obtained by arrested control cells. The increase in uridine incorporation preceded the increase in thymidine incorporation by 6 h. Inhibition of protein synthesis with cycloheximide blocked the recovery of macromolecular synthesis in both control and estrogen-treated cells. Actinomycin D was ineffective in blocking the estrogen-stimulated recovery of macromolecular synthesis at concentrations known to inhibit pre-rRNA synthesis (10(-8) M). At higher concentrations, uridine and thymidine incorporation were inhibited in a dose-dependent manner. Inhibition of RNA polymerase II activity with alpha-amanitin similarly blocked both the recovery of the cells from isoleucine starvation and the potentiation of this by estradiol. Dihydrofolate reductase and thymidine kinase activities are both stimulated by estradiol in MCF-7 cells. In cycling cells, estrogen stimulates a 2-fold increase in their messenger RNAs (mRNAs) within 24 h. The level of dihydrofolate reductase mRNA is unaffected by isoleucine starvation, and estrogen caused no change in dihydrofolate reductase mRNA levels over a 24-h period following reversal of growth arrest. Similar results were observed for the 600-nucleotide pS2 mRNA that has been identified as an estrogen-induced RNA in MCF-7 cells. In contrast, thymidine kinase mRNA was found to be increased by estrogen at 24 h, but not at 12 h, following reversal of growth arrest. This increase correlates with increases in thymidine, but not uridine incorporation. These

  11. Farm-scale reconnaissance of estrogens in subsurface waters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    17ß-estradiol is a natural estrogenic hormone found in animal manure and urine. In its parent form it has the ability to affect the reproductive systems of aquatic organisms at very low concentrations (10-100 ngL-1). While it has been reported to dissipate rapidly in soil laboratory studies it is...

  12. METHOXYCHLOR REGULATES RAT UTERINE ESTROGEN-INDUCED PROTEIN

    EPA Science Inventory

    Methoxychlor (MXC), a pesticide, affects fertility and the uterus. o address the question of whether MXC acts like estradiol (E2) at the molecular level, we used immature rat uteri to compare the effects of MXC and E2 on the estrogen-induced protein (IP), also known as creatine k...

  13. Ontogeny of the estrogen receptor in the chick oviduct.

    PubMed

    Joensuu, T K; Tuohimaa, P J

    1989-01-01

    The distribution of estrogen receptor (ER) in the chick oviduct was studied immunohistochemically with monoclonal antibody H222, known to recognize chick ER [1]. The ontogeny of ER appeared to be very dependent on cellular differentiation. In the undifferentiated oviduct ER was located in the epithelial, mesothelial, stromal and smooth muscle cells. During differentiation ER disappeared from the surface epithelium, mesothelium, stromal and smooth muscle cells. At the onset of differentiation the protodifferentiated gland cells invaginated into the underlying stroma; these cells expressed ER. In the fully differentiated chick oviduct ER was located only in the tubular gland cells, which correlates with the known transcriptional activity of estrogen-induced ovalbumin-gene. However, we have reported estrogen dependency of PR also in ER-negative stromal cells, the mechanism being so far unknown. It is possible that there are mechanisms other than ER regulating the expression of PR. Estrogen-induced differentiation did not differ from normal maturation in regard to the distribution of ER. Since stromal, epithelial, mesothelial and smooth muscle cells were ER-negative in the mature oviduct, the concentration of ER, i.e. ER binding sites/cell is underestimated when whole tissue homogenates are used. PMID:2626020

  14. Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands

    SciTech Connect

    Fang, Jing; Akwabi-Ameyaw, Adwoa; Britton, Jonathan E.; Katamreddy, Subba R.; Navas III, Frank; Miller, Aaron B.; Williams, Shawn P.; Gray, David W.; Orband-Miller, Lisa A.; Shearin, Jean; Heyer, Dennis

    2009-06-24

    A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ER{alpha} and ER{beta} binding affinity ranging from micromolar to low nanomolar.

  15. DEVELOPMENTAL EVALUATION OF A POTENTIAL NON-STEROIDAL ESTROGEN: TRICLOSAN

    EPA Science Inventory

    Triclosan is an antibacterial agent commonly used in industry and often detected in wastewater effluent. The potential of triclosan to act as an endocrine disruptor was examined because its chemical structure closely resembles known non-steroidal estrogens (e.g. DES, bis-phenol A...

  16. Potential estrogenic effects of phosphorus-containing flame retardants.

    PubMed

    Zhang, Quan; Lu, Meiya; Dong, Xiaowu; Wang, Cui; Zhang, Chunlong; Liu, Weiping; Zhao, Meirong

    2014-06-17

    As the substitute of polybrominated diphenyl ethers (PBDEs), further assessments about the potential ecological safety and health risks of phosphorus-containing flame retardants (PFRs) are required because the worldwide demand for PFRs has been increasing every year. In this study, we examined the agonistic/antagonistic activity of a group of PFRs by three in vitro models (luciferase reporter gene assay, yeast two-hybrid assay, and E-screen assay). Molecule docking was used to further explain the interactions between ERα and PFRs. Data from luciferase reporter gene analysis showed three members of the nine tested PFRs significantly induced estrogenic effects, with the order of TPP > TCP > TDCPP, while TCEP and TEHP have remarkable antiestrogenic properties with calculated REC20 and RIC20 values of 10(-6) M or lower. Results from the luciferase reporter gene method are generally consistent with results obtained from the yeast two-hybrid assay and E-screen, except for the positive estrogenic activity of TBP in E-screen testing. Docking results showed that binding between ligands and ERα was stabilized by hydrophobic interactions. As a proposed alternative for brominated flame retardant, PFRs may have anti/estrogenic activity via ERα at the low dose typical of residue in environmental matrix or animals. PFRs with a short chain, halogen, and benzene ring in the substituent group tend to be estrogenic. Our research suggests that comprehensive evaluations, including health and ecological assessments, are required in determining whether PFRs are preferable as an emerging industrial substitute. PMID:24844797

  17. ASSAYS FOR ENDOCRINE DISRUPTING CHEMICALS: BEYOND ENVIRONMENTAL ESTROGENS

    EPA Science Inventory

    Recent popular and scientific articles have reported the presence of estrogenic and other hormone mimicking chemicals in the environment and their potential for causing reproductive dysfunction in humans and wildlife. The purpose of this session was to present the best available,...

  18. Sorption and degradation of estrogen conjugates in agricultural soils

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The natural estrogenic hormone, 17'-estradiol (E2), can disrupt the endocrine system of some aquatic species at ng/L concentrations. Laboratory studies have shown low potentials for E2 persistence and mobility in the environment due to high degradation and soil retention. However, field studies have...

  19. Biochar as potential adsorptive media for estrogenic compounds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Endocrine disrupting chemicals are an emerging problem in water pollution due to their toxic effects on humans and wildlife. Estrogenic compounds are a subset of endocrine disrupting chemicals that are particularly dangerous since they are very potent and can affect fish at concentrations as low as ...

  20. EFFECTS OF EXTROGENOUS ESTROGEN ON MATE SELECTION OF HOUSE FINCHES

    EPA Science Inventory

    Effects of exogenous estrogen on mate selection of house finches. Clark, J., Fairbrother, A*. Parametrix, Inc., Corvallis, OR; Brewer, L., EBA, Inc., Sisters, OR; Bennett, R.S., USEPA, Mid-Continent Ecology Division, Duluth, MN.

    Concern about the potential for endocrine...

  1. EFFECTS OF EXOGENOUS ESTROGEN ON MATE SELECTION OF HOUSE FINCHES

    EPA Science Inventory

    Concern about the potential for endocrine disrupting chemicals to interfere with normal breeding behaviors of wildlife has prompted this study of effects of exogenous estrogen on mate selection in songbirds. The house finch (Carpodacus mexicanus) was selected as a model as it is ...

  2. 21 CFR 862.1275 - Estrogens (total, nonpregnancy) test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Estrogens (total, nonpregnancy) test system. 862.1275 Section 862.1275 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  3. 21 CFR 862.1275 - Estrogens (total, nonpregnancy) test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Estrogens (total, nonpregnancy) test system. 862.1275 Section 862.1275 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  4. 21 CFR 862.1275 - Estrogens (total, nonpregnancy) test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Estrogens (total, nonpregnancy) test system. 862.1275 Section 862.1275 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  5. 21 CFR 862.1275 - Estrogens (total, nonpregnancy) test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Estrogens (total, nonpregnancy) test system. 862.1275 Section 862.1275 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  6. Examining triclosan-induced potentiation of the estrogen uterotrophic effect

    EPA Science Inventory

    Triclosan (TCS), a widely used antibacterial, has been shown to be an endocrine disruptor. We reported previously that TCS potentiated the estrogenic effect of ethinyl estradiol (EE) on uterine growth in rats orally administered 3 μg/kg EE and TCS (2 to 18 mg/kg) in the utero...

  7. Prenatal Estrogens and the Development of Homosexual Orientation.

    ERIC Educational Resources Information Center

    Meyer-Bahlburg, Heino F. L.; And Others

    1995-01-01

    Examines the hypothesis that prenatal estrogens contribute to the development of human sexual orientation. Several groups of women with a history of prenatal exposure to diethylstilbestrol (DES) were compared with several samples of control women. Findings showed that more DES-exposed women than controls were rated as bisexual or homosexual,…

  8. Novel Metal Ion Based Estrogen Mimics for Molecular Imaging

    SciTech Connect

    Rajagopalan, Raghavan

    2006-01-30

    The overall objective of the SBIR Phase I proposal is to prepare and evaluate a new class of {sup 99m}Tc or {sup 94m}Tc containing estrogen-like small molecules ('estrogen mimics') for SPECT or PET molecular imaging of estrogen receptor positive (ER+) tumors. In this approach, the metal ion is integrated into the estrone skeleton by isosteric substitution of a carbon atom in the steroidal structure to give new class of mimics that are topologically similar to the native estrogen (Fig. 1). Although both N{sub 2}S{sub 2} and N{sub 3}S mimics 1 and 2 were considered as target structures, molecular modeling study revealed that the presence of the acetyl group at position-15 in the N{sub 3}S mimic 2 causes steric hinderance toward binding of 2 to SHBG. Therefore, initial efforts were directed at the synthesis and evaluation of the N{sub 2}S{sub 2} mimic 1.

  9. EADB: An Estrogenic Activity Database for Assessing Potential Endocrine Activity

    EPA Science Inventory

    Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the body’s endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many ...

  10. 21 CFR 862.1275 - Estrogens (total, nonpregnancy) test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Estrogens (total, nonpregnancy) test system. 862.1275 Section 862.1275 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  11. Molecular cloning of estrogen receptor alpha of the Nile crocodile.

    PubMed

    Katsu, Yoshinao; Myburgh, Jan; Kohno, Satomi; Swan, Gerry E; Guillette, Louis J; Iguchi, Taisen

    2006-03-01

    Estrogens are essential for normal reproductive activity in female and male vertebrates. In female reptiles, they are essential for ovarian differentiation during a critical developmental stage. To understand the molecular mechanisms of estrogen action in the Nile crocodile (Crocodylus niloticus), we have isolated cDNA encoding the estrogen receptor alpha (ERalpha) from the ovary. Degenerate PCR primers specific to ER were designed and used to amplify Nile crocodile cDNA from the ovary. The full-length Nile crocodile ERalpha cDNA was obtained using 5' and 3' rapid amplification cDNA ends (RACE). The deduced amino acid sequence of the Nile crocodile ERalpha showed high identity to the American alligator ERalpha (98%), caiman ER (98%), lizard ER (82%) and chicken ERalpha (92%), although phylogenetic analysis suggested profound differences in the rate of sequence evolution for vertebrate ER sequences. Expression of ERalpha was observed in the ovary and testis of juvenile Nile crocodiles. These data provide a novel tool allowing future studies examining the regulation and ontogenic expression of ERalpha in crocodiles and expands our knowledge of estrogen receptor evolution. PMID:16455277

  12. Synchronous Multiple Lung Adenocarcinomas: Estrogen Concentration in Peripheral Lung

    PubMed Central

    Shinchi, Yusuke; Sanada, Mune; Motooka, Yamato; Fujino, Kosuke; Mori, Takeshi; Suzuki, Makoto

    2016-01-01

    Background The detection rate of synchronous multiple lung adenocarcinomas (SMLA), which display multiple ground glass opacity nodules in the peripheral lung, is increasing due to advances in high resolution computed tomography. The backgrounds of multicentric development of adenocarcinoma are unknown. In this study, we quantitated estrogen concentration in the peripheral lungs of postmenopausal female patients with SMLA. Methods The tissue concentration of estrogens (estrone [E1] and estdadiol [E2]) in the noncancerous peripheral lung were measured with liquid chromatography/electrospray tandem mass spectrometry in postmenopausal female patients with lung adenocarcinoma. The expression levels of CYP19A1 in the normal lung were also quantitated with real-time PCR. Thirty patients with SMLA and 79 cases of control patients with single lung adenocarcinoma were analyzed. Results The concentrations of E1 and E2 in the noncancerous tissue were significantly higher in SMLA cases than control cases (P = 0.004 and P = 0.02, respectively). The minor allele (A) of single nucleotide polymorphism rs3764221 were significantly associated with higher concentration of E1 and E2 (P = 0.002 and P = 0.01, respectively) and higher CYP19A1 mRNA expression (P = 0.03). Conclusion The tissue estrogen concentration of peripheral lung was significantly higher in SMLA than control cases. The high concentration of estrogen may be one of the causes of multicentric development of peripheral lung adenocarcinomas. PMID:27526096

  13. Removal and Transformation of Estrogens During the Coagulation Process

    EPA Science Inventory

    Estrogenic compounds have been shown to be present in surface waters, leading to concerns over the possible presence of endocrine disrupting compounds in finished drinking waters. Bench-scale studies (jar tests) simulating coagulation were conducted to evaluate the ability of tw...

  14. In vitro assessment of estrogenic bioactivity in complex environmental effluents**

    EPA Science Inventory

    Environmental effluents contain a diversity of chemicals, can originate from a variety of sources, and have been found to contain estrogenic and/or androgenic activity. In this study, samples were collected from targeted sites or as runoff from an agriculture field that was spray...

  15. In vitro assessment of estrogenic bioactivity in complex environmental effluents

    EPA Science Inventory

    Environmental effluents contain a diversity of chemicals, can originate from a variety of sources, and have been found to contain estrogenic and/or androgenic activity. In this study, samples were collected from targeted sites or as runoff from an agriculture field that was spray...

  16. Exercise and Estrogen in Women's Health: Getting a Clearer Picture.

    ERIC Educational Resources Information Center

    Munnings, Frances

    1988-01-01

    This article surveys recent research on how and when exercise or estrogen therapy should be used to treat or prevent athletic amenorrhea, osteoporosis, cancer, and heart disease. The suspected causes of each disease are discussed and the benefits and dangers of each form of treatment/prevention are weighed. (JL)

  17. Modulation by estrogen of synthesis of specific uterine proteins.

    PubMed

    Skipper, J K; Eakle, S D; Hamilton, T H

    1980-11-01

    The contemporary procedure for high resolution two dimensional gel electrophoresis was extended to include an initial nondenaturing dimension of electrophoresis. Use of the resulting three dimensional procedure revealed that the previously described single peak of estrogen-induced protein in the uterus of the rat contains at least three distinct proteins whose rates of synthesis are regulated by estrogen. These proteins were localized within partial protein maps, thereby providing definitive operational definitions for the detection and identification of each. It was unambiguously demonstrated that each of the three proteins is continuously synthesized in control uteri. These findings cast doubt on the simplistic hypothesis that estrogen induces a single key protein that triggers a "cascade" of sequential transcriptional events in the uterus. Our finding that the major uterine protein induced by estrogen is also synthesized in liver and muscle cells is significant in that it points to a more general cellular function for the protein, rather than a unique role within uterine cells. Finally, our procedure for three dimensional gel electrophoresis opens new avenues for the detection of minor proteins in heterogeneous protein mixtures, such as those from the tissues of higher animals. PMID:7428041

  18. Lack of activity of cadmium in in vitro estrogenicity assays

    SciTech Connect

    Silva, Elisabete . E-mail: elisabete.silva@pharmacy.ac.uk; Lopez-Espinosa, Maria Jose; Molina-Molina, Jose-Manuel; Fernandez, Marieta; Olea, Nicolas; Kortenkamp, Andreas

    2006-10-01

    Prompted by reports about strong estrogenic effects of cadmium, attempts were made to reproduce these observations using the yeast estrogen screen (YES) and the E-Screen assays. For the first time, possible activation of the Src/MAPK pathway was also investigated. In the YES, only a slight activation (10% of a maximal effect) of the estrogen receptor alpha (ER{alpha}) was observed at cadmium concentrations between 5 x 10{sup -7} M and 5 x 10{sup -6} M. In the E-Screen assay, carried out by two laboratories, the heavy metal was without observable cell proliferative effects when tested in the range between 6 x 10{sup -11} M and 1 x 10{sup -5} M. However, in both assays, cadmium led to a reduction of the effects of 17{beta}-estradiol (E2). Treatment of MCF-7 human breast cancer cells with 1 x 10{sup -7} M cadmium failed to induce phosphorylation of Src and the MAP kinases Erk1 and Erk2-effects shown to occur with E2 and epidermal growth factor (EGF). In summary, we were unable to confirm the strong estrogenicity of cadmium reported recently by a number of laboratories. This apparent absence of effects in our hands is not due to a lack of uptake of the metal or to effective protection against cadmium by high levels of glutathione or metallothionein, since toxicity and an antagonism of E2 responses were observed both in the YES and the E-Screen.

  19. EVALUATION OF THE REMOVAL OF ESTROGENS THROUGH THE COAGULATION PROCESS

    EPA Science Inventory

    A number of estrogenic compounds have been shown to be present in surface waters in the U.S. These compounds have the potential to act as potent endocrine disrupting chemicals (EDCs), leading to a growing concern over the possible presence of EDCs in finished drinking waters. Con...

  20. EVALUATION OF THE REMOVAL OF ESTROGENS THROUGH THE COAGULATION PROCESS

    EPA Science Inventory

    A number of estrogenic compounds have been shown to be present in surface waters in the U.S. These compounds have the potential to act as endocrine disrupting chemicals (EDCs), leading to concern over the possible presence of EDCs in finished drinking waters. Consequently, it is ...

  1. EVALUATION OF THE REMOVAL OF ESTROGENS THROUGH THE COAGULATION PROCESS

    EPA Science Inventory

    A number of estrogenic compounds have been shown to be present in surface waters in the U.S. These compounds have the potential to act as potent endocrine disrupting chemicals (EDCs), leading to a growing concern over the possible presence of EDCs in finished drinking waters. C...

  2. Steroidal estrogen sources in a sewage-impacted coastal ocean.

    PubMed

    Griffith, David R; Kido Soule, Melissa C; Eglinton, Timothy I; Kujawinski, Elizabeth B; Gschwend, Philip M

    2016-08-10

    Estrogens are known to be potent endocrine disrupting chemicals that are commonly found in wastewater effluents at ng L(-1) levels. Yet, we know very little about the distribution and fate of estrogens in coastal oceans that receive wastewater inputs. This study measured a wide range of steroidal estrogens in sewage-impacted seawater using ultra high performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) together with the method of standard addition. In Massachusetts Bay, we find conjugated, free, and halogenated estrogens at concentrations that are consistent with dilution at sites close to the sewage source. At a site 6 miles down current of the sewage source, we observe estrone (E1) concentrations (520 ± 180 pg L(-1)) that are nearly double the nearfield concentrations (320 ± 60 pg L(-1)) despite 9-fold dilution of carbamazepine, which was used as a conservative sewage tracer. Our results suggest that background E1 concentrations in Massachusetts Bay (∼270 ± 50 pg L(-1)) are derived largely from sources unrelated to wastewater effluent such as marine vertebrates. PMID:27465804

  3. EVALUATION OF THE REMOVAL OF ESTROGENS FOLLOWING CHLORINATION

    EPA Science Inventory

    A number of estrogenic compounds have been shown to be present in surface waters in the U.S. These compounds have the potential to act as potent endocrine disrupting chemicals (EDCs). Although there has not yet been a determination of risks posed by EDCs in finished drinking wat...

  4. RELATIVE BINDING AFFINITY OF ALKYLPHENOLS TO RAINBOW TROUT ESTROGEN RECEPTOR

    EPA Science Inventory

    RELATIVE BINDING AFFINITY OF ALKYLPHENOLS TO RAINBOW TROUT ESTROGEN RECEPTOR. T R Henry1, J S Denny2 and P K Schmieder2. USEPA, ORD, NHEERL, 1Experimental Toxicology Division and 2Mid-Continent Ecology Division, Duluth, MN, USA.
    The USEPA has been mandated to screen industria...

  5. Evaluation of the in vitro estrogenicity of emerging bisphenol analogs and their respective estrogenic contributions in municipal sewage sludge in China.

    PubMed

    Ruan, Ting; Liang, Dong; Song, Shanjun; Song, Maoyong; Wang, Hailin; Jiang, Guibin

    2015-04-01

    There is a potential risk to the environment from persistent estrogenic compounds in sewage sludge. In this study, eight bisphenols (BPs) were identified in sewage sludge collected from wastewater treatment plants in 15 cities in China. The estrogenic potencies of the eight BPs and the estrogenic activities of sludge samples were evaluated using a bioluminescence yeast estrogen screen (BLYES) assay. All sludge samples elicited considerable estrogenic activity at a range of 2.8-4.7 ng E2 g(-1) dry weight (dw). All BPs exhibited estrogenic activity in the BLYES assay, but there were significant differences between the potency of individual chemicals. Bisphenol AF had the highest activity, followed by tetrachlorobisphenol A, bisphenol F, bisphenol A, bisphenol E, bisphenol S and 2,4-dihydroxybenzophenone. Tetrabromobisphenol A showed weak estrogenic activity at 1×10(4)nM, but significant cytotoxicity above this concentration. The total estradiol equivalency quantities (EEQs) of BPs were in the range of 2.16-49.13 pg E2 g(-1) dw, accounting for 0.05-1.47% of the total EEQs in sewage sludge samples. The results indicate that BPs made a minor contribution to the estrogenic activity of the investigated sewage sludge. Nevertheless, our results suggest that considerable attention should be directed to the estrogenic potentials of emerging organic pollutants because of their widespread use and their potential to persist in the environment. PMID:25548037

  6. Biosensor Zebrafish Provide New Insights into Potential Health Effects of Environmental Estrogens

    PubMed Central

    Lee, Okhyun; Takesono, Aya; Tada, Masazumi; Kudoh, Tetsuhiro

    2012-01-01

    Background: Environmental estrogens alter hormone signaling in the body that can induce reproductive abnormalities in both humans and wildlife. Available testing systems for estrogens are focused on specific systems such as reproduction. Crucially, however, the potential for significant health impacts of environmental estrogen exposures on a variety of body systems may have been overlooked. Objective: Our aim was to develop and apply a sensitive transgenic zebrafish model to assess real-time effects of environmental estrogens on signaling mechanisms in a whole body system for use in integrated health assessments. Methods: We created a novel transgenic biosensor zebrafish containing an estrogen-inducible promoter derived with multiple tandem estrogen responsive elements (EREs) and a Gal4ff-UAS system for enhanced response sensitivity. Results: Using our novel estrogen-responsive transgenic (TG) zebrafish, we identified target tissues for environmental estrogens; these tissues have very high sensitivity even at environmentally relevant concentrations. Exposure of the TG fish to estrogenic endocrine-disrupting chemicals (EDCs) induced specific expression of green fluorescent protein (GFP) in a wide variety of tissues including the liver, heart, skeletal muscle, otic vesicle, forebrain, lateral line, and ganglions, most of which have not been established previously as targets for estrogens in fish. Furthermore, we found that different EDCs induced GFP expression with different tissue response patterns and time trajectories, suggesting different potential health effects. Conclusion: We have developed a powerful new model for understanding toxicological effects, mechanisms, and health impacts of environmental estrogens in vertebrates. PMID:22510978

  7. Electrochemical estrogen screen method based on the electrochemical behavior of MCF-7 cells.

    PubMed

    Li, Jinlian; Song, Jia; Bi, Sheng; Zhou, Shi; Cui, Jiwen; Liu, Jiguang; Wu, Dongmei

    2016-08-01

    It was an urgent task to develop quick, cheap and accurate estrogen screen method for evaluating the estrogen effect of the booming chemicals. In this study, the voltammetric behavior between the estrogen-free and normal fragmented MCF-7 cell suspensions were compared, and the electrochemical signal (about 0.68V attributed by xanthine and guanine) of the estrogen-free fragmented MCF-7 cell suspension was obviously lower than that of the normal one. The electrochemistry detection of ex-secretion purines showed that the ability of ex-secretion purines of cells sharp decreased due to the removing of endogenous estrogen. The results indicated that the electrochemical signal of MCF-7 cells was related to the level of intracellular estrogen. When the level of intracellular estrogen was down-regulated, the concentrations of the xanthine and hypoxanthine decreased, which led to the electrochemical signal of MCF-7 cells fall. Based on the electrochemical signal, the electrochemical estrogen screen method was established. The estrogen effect of estradiol, nonylphenol and bisphenol A was evaluated with the electrochemical method, and the result was accordant with that of MTT assay. The electrochemical estrogen screen method was simple, quickly, cheap, objective, and it exploits a new way for the evaluation of estrogenic effects of chemicals. PMID:27108272

  8. Detection of xenoestrogens in serum after immunoprecipitation of endogenous steroidal estrogens.

    PubMed Central

    Natarajan, Kala; Overstreet, James W; Rogers, Jane M; Denison, Michael S; Chen, Jiangang; Lohstroh, Peter N; McConnell, Daniel S; Lasley, Bill L

    2002-01-01

    In this article we report a simple and efficient method for detecting nonsteroidal estrogens in a biologic sample. This method uses polyclonal antibodies to estradiol (E2) to immunoprecipitate these major biologically active steroidal estrogens, leaving behind the nonsteroidal estrogens, which are then detected in a cell-based transcriptional activation bioassay for estrogen receptor agonist. The immunoprecipitation method efficiently removed 99% of radiolabeled E2 and estrone (E1) from human serum. In experiments in which supraphysiologic concentrations of E2 and E1 to human serum, all of the immunoreactive estrogens were still removed by the immunoprecipitation protocol. We carried out an in vivo validation study of this method in which we treated female macaques with the xenoestrogen nonylphenol (NP), during the late follicular phase of the menstrual cycle. We used blood samples collected before and after treatment to evaluate and characterize endogenous and exogenous serum estrogens. An immunoassay for E2 did not detect the NP in treated monkeys. The cell-based bioassay also did not detect the estrogenic activity of NP because of its saturation by the endogenous serum steroidal estrogens. However, when steroidal estrogens were removed by immunoprecipitation, we detected the estrogenic activity of NP in the bioassay. Thus, this approach is appropriate for detecting exogenous, nonsteroidal estrogens in serum samples. PMID:12153760

  9. Estrogen and cancers of the colorectum, breast, and lung in postmenopausal women.

    PubMed

    Honma, Naoko; Hosoi, Takayuki; Arai, Tomio; Takubo, Kaiyo

    2015-09-01

    As estrogens play an important role in maintaining physiological function in various organs, the estrogen decrease after menopause is thought to cause various diseases frequently observed in postmenopausal or elderly women. With the aging of society and a decrease in infectious or vascular diseases, neoplasms have now become the most frequent cause of death in Japan. Cancers of the colorectum, breast, and lung have been rapidly increasing both in incidence and death, especially among postmenopausal women. Interestingly, all three of these cancers are associated with estrogens. In premenopausal women, ovarian estrogens plays major roles in the female reproductive organs through the classic estrogen receptor, ER-α. In postmenopausal women, however, estrogens produced/activated by peripherally localized estrogen-metabolizing enzymes such as aromatase, which converts androgen into estrogens, are thought to play physiologically and pathobiologically important roles in various organs through second ER, namely ER-β, distributing systemically. In this article, the association of estrogens with these cancers in postmenopausal or elderly women are reviewed, especially focusing on the role of ER-β and peripheral estrogen metabolism. The possibility of prevention or treatment of these diseases through estrogenic control is also discussed. PMID:26126901

  10. Identification of Estrogen Response Element in Aquaporin-3 Gene that Mediates Estrogen-induced Cell Migration and Invasion in Estrogen Receptor-positive Breast Cancer

    PubMed Central

    Huang, Yi-Ting; Zhou, Jun; Shi, Shuai; Xu, Hai-Yan; Qu, Fan; Zhang, Dan; Chen, Yi-Ding; Yang, Jing; Huang, He-Feng; Sheng, Jian-Zhong

    2015-01-01

    Accumulating evidence suggests that aquaporins (AQPs) may facilitate tumor development. The molecular pathways connecting the pathological functions of AQPs are unclear and need to be better defined. This study aimed to investigate whether AQP3, one of the AQPs expressed highly in breast cancer, had any clinical implication in estrogen-receptor (ER) positive breast cancer, and explore the regulatory mechanisms of AQP3 in estrogen-related breast cancer progression. Here we show that AQP3 is an important enforcer of migration and invasion in breast cancer. We, for the first time, reported that ER-positive breast cancer tissues obtained from premenopausal patients had higher AQP3 expression when compared to those obtained from postmenopausal patients. Estrogen directly upregulates AQP3 by activating ERE in the promoter of the AQP3 gene. The upregulation of AQP3 can influence the expression of molecules related to epithelial-mesenchymal transition and the reorganization of actin-cytoskeleton, resulting in enhancement of cell migration and invasion in ER-positive breast cancer cells. PMID:26219409

  11. The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis

    PubMed Central

    Clegg, Deborah J.; Hevener, Andrea L.

    2013-01-01

    Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet β-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders. PMID:23460719

  12. Regulation of Baboon Fetal Pituitary Prolactin Expression by Estrogen1

    PubMed Central

    Pepe, Gerald J.; Lynch, Terrie J.; Davies, William A.; Albrecht, Eugene D.

    2009-01-01

    We previously showed that fetal adrenal fetal zone growth was increased and the number of follicles in the fetal ovary reduced in baboons in which estradiol was suppressed by treatment with the aromatase inhibitor letrozole between mid and late gestation periods. Because adrenal/ovarian development was restored in animals treated with letrozole and estradiol, and both tissues express estrogen receptor, we proposed that estrogen regulates fetal adrenal/ovary development via a direct action. However, because prolactin can modulate fetal adrenal and adult pituitary/ovarian function, the current study determined whether estrogen action involved estradiol-regulated changes in fetal prolactin/luteinizing hormone (LH) expression. Fetal prolactin levels and the number of prolactin-positive fetal pituitary cells (per 0.37 mm2) were increased (P < 0.01) between mid (6 ± 1 ng/ml; 15.8 ± 2.4) and late (257 ± 28 ng/ml; 57.3 ± 5.1) gestation, reduced (P < 0.01) in late-gestation fetuses in which estradiol was suppressed (>95%) by letrozole (61 ± 11 ng/ml; 19.3 ± 2.0), and minimally but not significantly increased by letrozole and estradiol (99 ± 11 ng/ml; 32.7 ± 5.2). In contrast, the number of LH-positive fetal pituitary cells decreased (P < 0.01) between mid (48.8 ± 9.5) and late (17.4 ± 3.2) gestation, remained elevated (P < 0.01) in estrogen-suppressed animals (56.6 ± 5.1), and was partially but not significantly decreased by letrozole-estradiol (28.8 ± 5.2). We conclude that estrogen regulates fetal pituitary prolactin and LH expression and fetal prolactin levels. However, because prolactin and LH expressions in estrogen-suppressed fetuses were inversely related to previously demonstrated changes in adrenal/ovarian development, we propose that estrogen regulates the fetal ovary and adrenal gland directly and not via action on the fetal pituitary gland. PMID:19176882

  13. Positive association of female overactive bladder symptoms and estrogen deprivation

    PubMed Central

    Cheng, Chen-Li; Li, Jian-Ri; Lin, Ching-Heng; de Groat, William C.

    2016-01-01

    Abstract Objective: Estrogen is considered to be a unique hormone in females that has an impact on voiding function. Animal models and clinical epidemiologic studies showed high correlation between estrogen deficiency and female overactive bladder (OAB) symptoms. We designed a population-based cohort study from a national health database to assess the association of estrogen deprivation therapy and female OAB. Materials and methods: This study examined the records of 16,128 patients ranging in age from 18 to 40 that were included in the Taiwan National Health Insurance Research Database (NHIRD) in the years between 2001 and 2010. Of these, 1008 had breast cancer with hormone therapy only and the other 15,120 controls did not have breast cancer or hormone therapy. All patients with neurologic diseases and those with pre-existing OAB identified by information in the NHIRD database were excluded. OAB was defined by medications prescribed for at least 1 month. Risk of new onset OAB in the breast cancer and nonbreast cancer groups was estimated. Fourteen patients (1.4%) experienced OAB in the breast cancer group. Overall, breast cancer with estrogen deprivation therapy increased the risk of OAB by 14.37-fold (adjusted hazard ratio, 95% confidence interval 7.06–29.27). Subgroup analysis showed that in the older age breast cancer group (36–40), a lower Charlson comorbidity index (CCI) score and antidepressant medication use for at least 30 days had an impact on the increase of OAB risk. After adjustment of variables, the higher CCI and the use of antipsychotic drugs increased risk of OAB 3.45-fold and 7.45-fold, respectively. The Kaplan–Meier analysis of OAB-free survival in the breast cancer group showed a significant time-dependent increase in incidence of OAB. Conclusion: Estrogen deprivation in young patients with breast cancer increased the risk of OAB. The OAB development rate was steady and fast in the beginning 3 years after estrogen deprivation. This result

  14. Fate of Estrogens in Soils and Detection by ELISA

    NASA Astrophysics Data System (ADS)

    Caron, Emmanuelle; Sheedy, Claudia; Farenhorst, Annemieke; Zvomuya, Francis; Gaultier, Jeanette; Goddard, Tom

    2010-05-01

    Land application of manure can contribute to the release of estrogenic compounds in the environment. Estrogens may move from soils to water by processes such as runoff and leaching. The objectives of the present study were to determine the fate of estrogens in soils and to develop a detection method for these compounds. The sorption (soil sorption coefficient (Kd) and sorption coefficient per unit organic carbon (Koc)) of 17β-estradiol, estrone, estriol and equol were studied, using batch equilibrium experiments, in 121 surface soils from Alberta, Canada. The mineralization of [4-14C] 17β-estradiol was determined in soil microcosms in a subset of 36 samples. Quantitative relationships at the regional level were explored using partial least squares regression (PLS) (between Kd or Koc values and soil properties) and by ordinary least squares regression (between Kd or Koc values of different estrogens). Soil properties (r2 0.51-0.87 for Kd and 0.32-0.44 for Koc) provided better prediction models than using the data of different estrogens (r2 0.38-0.71 for Kd and 0.18-0.40 for Koc). PLS regression models for mineralization parameters of 17ß-estradiol had lower predictive power (lower r2)than models developed for sorption parameters. In addition, it has become of primary importance to develop sensitive detection methods that are able to detect low estrogen concentrations (ng L-1) in a wide variety of environmental matrices in order to validate the prediction of their fate and to study their presence in affected ecosystems. Conjugates were synthesized using a mixed anhydride reaction and two Enzyme-Linked Immunosorbent Assays (ELISAs) were developed using polyclonal antibodies. One ELISA was highly specific for 17β-estradiol (with an IC50 of 243 ng mL-1) and the second allowed for the broader detection of 17β-estradiol, estrone and estriol (with an IC50 of 18 ng mL-1 for 17β-estradiol). The cross-reactivity of both ELISAs was studied against 13 compounds (natural

  15. Localization of estrogen receptor in the central lymphoid organs of chickens during the late stage of embryogenesis.

    PubMed

    Katayama, Masafumi; Fukuda, Tomokazu; Narabara, Kiyoaki; Abe, Asaki; Kondo, Yasuhiro

    2012-01-01

    Immunological function in chicks is greatly affected by estrogen treatment during embryogenesis, but the mechanism of the estrogen effect is not fully understood. To elucidate the effect of estrogen on immune function, we observed estrogen receptor expression in the thymus and bursa of chick embryos by immunohistochemistry. We compared the distribution of estrogen receptor-positive cells with that of keratin-positive epithelial cells. Intense expression of estrogen receptors was detected in thymic and bursal lymphocytes. In peripheral lymphocytes, ER mRNA was detected by RT-PCR analysis. The results of fluorescence-activated cell sorting analysis indicated that the estrogen receptor was expressed in the cytoplasm of the lymphocytes. Furthermore, intense expression of the estrogen receptor was also confirmed in thymic Hassall's corpuscles, bursal follicle-associated epithelial cells, and the bursal interfollicular epithelium. Our results indicate that estrogen affects the differentiation of thymic and bursal lymphocytes, suggesting that the underlying role for estrogen in immune function. PMID:23132558

  16. Estrogen-dependent visceral hypersensitivity following stress in rats

    PubMed Central

    Hubbard, Catherine S; Karpowicz, Jane M; Furman, Andrew J; da Silva, Joyce Teixeira; Traub, Richard J

    2016-01-01

    We used functional MRI and a longitudinal design to investigate the brain mechanisms in a previously reported estrogen-dependent visceral hypersensitivity model. We hypothesized that noxious visceral stimulation would be associated with activation of the insula, anterior cingulate cortex, and amygdala, and that estrogen-dependent, stress-induced visceral hypersensitivity would both enhance activation of these regions and recruit activation of other brain areas mediating affect and reward processing. Ovariectomized rats were treated with estrogen (17 β-estradiol, E2) or vehicle (n = 5 per group) and scanned in a 7T MRI at three different time points: pre-stress (baseline), 2 days post-stress, and 18 days post-stress. Stress was induced via a forced-swim paradigm. In a separate group of ovariectomized rats, E2 treatment induced visceral hypersensitivity at the 2 days post-stress time point, and this hypersensitivity returned to baseline at the 18 days post-stress time point. Vehicle-treated rats show no hypersensitivity following stress. During the MRI scans, rats were exposed to noxious colorectal distention. Across groups and time points, noxious visceral stimulation led to activations in the insula, anterior cingulate, and left amygdala, parabrachial nuclei, and cerebellum. A group-by-time interaction was seen in the right amygdala, ventral striatum-pallidum, cerebellum, hippocampus, mediodorsal thalamus, and pontine nuclei. Closer inspection of the data revealed that vehicle-treated rats showed consistent activations and deactivations across time, whereas estrogen-treated animals showed minimal deactivation with noxious visceral stimulation. This unexpected finding suggests that E2 may dramatically alter visceral nociceptive processing in the brain following an acute stressor. This study is the first to examine estrogen-stress dependent interactions in response to noxious visceral stimulation using functional MRI. Future studies that include other control

  17. Estrogen positive feedback on LH secretion in transsexuality.

    PubMed

    Gooren, L J; Rao, B R; van Kessel, H; Harmsen-Louman, W

    1984-01-01

    In order to test the hypothesis whether there is variation in hormonal levels or response to hormonal manipulation that could permit a distinction between heterosexuals and transsexuals, we designed the following protocol: Six male-to-female (m-to-f) transsexuals, six heterosexual control females and six female-to-male (f-to-m) transsexuals were given estradiol benzoate (E2B) (4.5 micrograms/kg/12 hr) for five days. In the female population, E2B treatment was initiated on day 5 of the menstrual cycle. In all the subjects blood luteinizing hormone (LH) and follicle stimulating hormone (FSH), estradiol-17 beta (E2) and testosterone (T) levels were measured twice daily. Additionally, LH and FSH responses to LHRH (100 micrograms iv) stimulation prior to and on day 5 of the E2B treatment were evaluated. In the m-to-f transsexuals, T levels decreased sharply and progressively during estrogen treatment, along with a fall in LH and FSH levels. The magnitude of the LH and FSH responses to LHRH stimulation also decreased following estrogen administration. In the heterosexual female controls and in the f-to-m transsexuals, estrogen administration increased LH levels to a minimum of 100% above initial values from day 3 onwards. Interestingly, the magnitude of the LH increase in the f-to-m transsexuals was greater than that of the heterosexual female controls. In both groups, LHRH stimulation resulted in a greater LH response compared to that prior to estrogen treatment. Our present observations, based on blood hormonal levels and responses to hormonal manipulations do not permit a distinction between heterosexual females and f-to-m transsexuals. There was no convincing evidence for the existence of a positive estrogen feedback on LH secretion in m-to-f transsexuals. These results contradict some of the reported hypotheses concerning hormonal alterations in these individuals. PMID:6436856

  18. Mammary gland development--It's not just about estrogen.

    PubMed

    Berryhill, Grace E; Trott, Josephine F; Hovey, Russell C

    2016-01-01

    The mammary gland (MG) is one of a few organs that undergoes most of its growth after birth. Much of this development occurs concurrently with specific reproductive states, such that the ultimate goal of milk synthesis and secretion is coordinated with the nutritional requirements of the neonate. Central to the reproductive-MG axis is its endocrine regulation, and pivotal to this regulation is the ovarian secretion of estrogen (E). Indeed, it is widely accepted that estrogens are essential for growth of the MG to occur, both for ductal elongation during puberty and for alveolar development during gestation. As the factors regulating MG development continually come to light from the fields of developmental biology, lactation physiology, and breast cancer research, a growing body of evidence serves as a reminder that the MG are not as exclusively dependent on estrogens as might have been thought. The objective of this review is to summarize the state of information regarding our understanding of how estrogen (E) has been implicated as the key regulator of MG development, and to highlight some of the alternative E-independent mechanisms that have been discovered. In particular, we review our findings that dietary trans-10,cis-12 conjugated linoleic acid promotes ductal elongation and that the combination of progesterone (P) and prolactin (PRL) can stimulate branching morphogenesis in the absence of E. Ultimately, these examples stand as a healthy challenge to the question of just how important estrogens are for MG development. Answers to this question, in turn, increase our understanding of MG development across all mammals and the ways in which it can affect milk production. PMID:26506542

  19. Estrogen Decrease in Tight Junctional Resistance Involves Matrix-Metalloproteinase-7-Mediated Remodeling of Occludin

    PubMed Central

    Gorodeski, George I.

    2008-01-01

    Estrogen modulates tight junctional resistance through estrogen receptor-α-mediated remodeling of occludin. The objective of the study was to understand the mechanisms involved. Experiments using human normal vaginal-cervical epithelial cells showed that human normal vaginal-cervical epithelial cells secrete constitutively matrix-metalloproteinase-7 (MMP-7) into the luminal solution and that MMP-7 is necessary and sufficient to produce estrogen decrease of tight junctional resistance and remodeling of occludin. Treatment with estrogen stimulated activation of the pro-MMP-7 intracellularly and augmented secretion of the activated MMP-7 form. Steady-state levels of MMP-7 mRNA and protein were not affected by estrogen. Estrogen modulated phosphorylation of the MMP-7, but the changes were most likely secondary to changes in cellular MMP-7 mass. Estrogen increased coimmunoreactivity of MMP-7 with the Golgi protein GPP130. Tunicamycin and brefeldin-A had no effect on cellular MMP-7 but monensin (inhibitor of Golgi traffic) blocked estrogen effects, suggesting estrogen site of action is at the Golgi system. Estrogen increased generalized secretory activity, including of luminal exocytosis of polycarbohydrates. However, estrogen increased coimmunoreactivity of MMP-7 with synaptosomal-associated protein of 25 kDa in apical membranes, suggesting soluble N-ethylmaleimide sensitive fusion factor attachment protein receptor-facilitated exocytosis of MMP-7. Treatment with the vesicular-ATPase inhibitor bafilomycin A1 inhibited activation of MMP-7. These data suggest that estrogen up-regulates activation of the MMP-7 intracellularly, at the level of Golgi, and augments secretion of activated MMP-7 through soluble N-ethylmaleimide sensitive fusion factor attachment protein receptor-dependent exocytosis. On the other hand, estrogen acidification of the luminal solution would tend to alkalinize exocytotic vesicles and may lead to decreased activation of the MMP-7. These mechanisms

  20. Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

    PubMed Central

    Osakabe, Asami; Waku, Tsuyoshi; Suzuki, Takashi; Akaogi, Kensuke; Fujimura, Tetsuya; Homma, Yukio; Inoue, Satoshi; Yanagisawa, Junn

    2015-01-01

    Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17β-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor β (ERβ) or Krüppel-like zinc finger transcription factor 5 (KLF5). Ιn addition, E2 suppressed KLF5-mediated transcription through ERβ, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ERβ-KLF5 pathway and regulated prostate tumor growth without ERβ transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ERβ and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation. PMID:26483416

  1. Bioassay of estrogenicity and chemical analyses of estrogens in streams across the United States associated with livestock operations

    EPA Science Inventory

    Animal manures, used as a nitrogen source for crop production, are often associated with negative impacts on nutrient levels in surface water. The concentration of estrogens in streams from these manures is of concern due to potential endocrine disruption in aquatic species. S...

  2. Bioassay of estrogenicity and chemical analysis of estrogens in streams across the United States associated with livestock operations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Animal manures, used as a nitrogen source for crop production, are often associated with negative impacts on nutrient levels in surface water. The concentration of estrogens in streams from these wastes is of concern due to potential endocrine disruption in aquatic species. Streams associated with...

  3. Extranuclear Estrogen Receptors Mediate the Neuroprotective Effects of Estrogen in the Rat Hippocampus

    PubMed Central

    Yang, Fang; Zhang, Yi-dong; Wang, Rui-min; Brann, Darrell W.

    2010-01-01

    Background 17β-estradiol (E2) has been implicated to exert neuroprotective effects in the brain following cerebral ischemia. Classically, E2 is thought to exert its effects via genomic signaling mediated by interaction with nuclear estrogen receptors. However, the role and contribution of extranuclear estrogen receptors (ER) is unclear and was the subject of the current study. Methodology/Principal Findings To accomplish this goal, we employed two E2 conjugates (E2 dendrimer, EDC, and E2-BSA) that can interact with extranuclear ER and exert rapid nongenomic signaling, but lack the ability to interact with nuclear ER due to their inability to enter the nucleus. EDC or E2-BSA (10 µM) was injected icv 60 min prior to global cerebral ischemia (GCI). FITC-tagged EDC or E2-BSA revealed high uptake in the hippocampal CA1 region after icv injection, with a membrane (extranuclear) localization pattern in cells. Both EDC and E2-BSA exerted robust neuroprotection in the CA1 against GCI, and the effect was blocked by the ER antagonist, ICI182,780. EDC and E2-BSA both rapidly enhanced activation of the prosurvival kinases, ERK and Akt, while attenuating activation of the proapoptotic kinase, JNK following GCI, effects that were blocked by ICI182,780. Administration of an MEK or PI3K inhibitor blocked the neuroprotective effects of EDC and E2-BSA. Further studies showed that EDC increased p-CREB and BDNF in the CA1 region in an ERK- and Akt-dependent manner, and that cognitive outcome after GCI was preserved by EDC in an ER-dependent manner. Conclusions/Significance In conclusion, the current study demonstrates that activation of extranuclear ER results in induction of ERK-Akt-CREB-BDNF signaling in the hippocampal CA1 region, which significantly reduces ischemic neuronal injury and preserves cognitive function following GCI. The study adds to a growing literature that suggests that extranuclear ER can have important actions in the brain. PMID:20479872

  4. Occurrence of free estrogens, conjugated estrogens, and bisphenol A in fresh livestock excreta and their removal by composting in North China.

    PubMed

    Zhang, Hui; Shi, Jianghong; Liu, Xiaowei; Zhan, Xinmin; Dang, Jinhua; Bo, Ting

    2014-01-01

    An efficient pretreatment and analytical method was developed to investigate the occurrence and fate of four free estrogens (estrone (E1), 17β-estradiol (17β-E2), estriol (E3), and 17α-ethinylestradiol (EE2)), four conjugated estrogens (estrone-3-sulfate sodium salt (E1-3S), 17β-estradiol-3-sulfate sodium salt (E2-3S), estrone-3-glucuronide sodium salt (E1-3G), and 17β-estradiol-3-glucuronide sodium salt (E2-3G)), and bisphenol A (BPA) in three livestock farms raising beef cattle, cows, sheep, swine, and chickens in Qi County, which is located in North China. The results demonstrated that one cow and one beef cattle excreted 956.25-1,270.41 and 244.38-319.99 μg/day of total (free and conjugated) estrogen, respectively, primarily through feces (greater than 91%), while swine excreted 260.09-289.99 μg/day of estrogens, primarily through urine (98-99%). The total estrogen excreted in sheep and broiler chicken feces was calculated to be 21.64-28.67 and 4.62-5.40 μg/day, respectively. It was determined that conjugated estrogens contributed to 21.1-21.9% of the total estrogen excreted in cow feces and more than 98% of the total estrogen excreted in swine urine. After composting, the concentration of total estrogen decreased by 18.7-59.6%; however, increased levels of BPA were measured. In treated compost samples, estrogens were detected at concentrations up to 74.0 ng/g, which indicates a potential risk of estrogens entering the surrounding environment. PMID:24828825

  5. Icariin exerts estrogen-like activity in ameliorating EAE via mediating estrogen receptor β, modulating HPA function and glucocorticoid receptor expression

    PubMed Central

    Wei, Zhisheng; Wang, Mengxia; Hong, Mingfan; Diao, Shengpeng; Liu, Aiqun; Huang, Yeqing; Yu, Qingyun; Peng, Zhongxing

    2016-01-01

    Background: Estrogen exerts neuroprotective and anti-inflammatory effects in EAE and multiple sclerosis (MS), but its clinical application is hindered due to side effects and risk of tumor. Phytoestrogen structurally or functionally mimics estrogen with fewer side effects than endogenous estrogen. Icariin (ICA), an active component of Epimedium extracts, demonstrates estrogen-like neuroprotective effects. However, it is unclear whether ICA is effective in EAE and what are the underlying mechanisms. Objective: To determine the therapeutic effects of ICA in EAE and explore the possible mechanisms. Methods: C57BL/6 EAE mice were treated with Diethylstilbestrol, different dose of ICA and mid-dose ICA combined with ICI 182780. The clinical scores and serum Interleukin-17 (IL-17), Corticosterone (CORT) concentrations were then analyzed. Western blot were performed to investigate the expressions of glucocorticoid receptor (GR), estrogen receptor alpha (ERα) and ERβ in the cerebral white matter of EAE mice. Results: High dose ICA is equally effective in ameliorating neurological signs of EAE as estrogen. Estrogen and ICA has no effects on serum concentrations of IL-17 in EAE. While the CORT levels were decreased by ICA at mid or high doses, the expressions of GR, ERα and ERβ were up-regulated by estrogen or different doses of ICA in a dosedependent manner. Estrogen induced the elevation of ERα more markedly than ICA. In contrast, ICA at mid and high doses promoted ERβ more significantly than estrogen. Conclusion: ICA exerts estrogen-like activity in ameliorating EAE via mediating ERβ, modulating HPA function and up-regulating the expression of GR in cerebral white matter. ICA may be a promising therapeutic option for MS. PMID:27186315

  6. Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass

    PubMed Central

    Farman, H. H.; Windahl, S. H.; Westberg, L.; Isaksson, H.; Egecioglu, E.; Schele, E.; Ryberg, H.; Jansson, J. O.; Tuukkanen, J.; Koskela, A.; Xie, S. K.; Hahner, L.; Zehr, J.; Clegg, D. J.; Lagerquist, M. K.

    2016-01-01

    Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα−/−). Female POMC-ERα−/− and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 μg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα−/− mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice. PMID:27254004

  7. Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass.

    PubMed

    Farman, H H; Windahl, S H; Westberg, L; Isaksson, H; Egecioglu, E; Schele, E; Ryberg, H; Jansson, J O; Tuukkanen, J; Koskela, A; Xie, S K; Hahner, L; Zehr, J; Clegg, D J; Lagerquist, M K; Ohlsson, C

    2016-08-01

    Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα(-/-)). Female POMC-ERα(-/-) and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 μg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα(-/-) mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice. PMID:27254004

  8. Binding of type II nuclear receptors and estrogen receptor to full and half-site estrogen response elements in vitro.

    PubMed Central

    Klinge, C M; Bodenner, D L; Desai, D; Niles, R M; Traish, A M

    1997-01-01

    The mechanism by which retinoids, thyroid hormone (T3) and estrogens modulate the growth of breast cancer cells is unclear. Since nuclear type II nuclear receptors, including retinoic acid receptor (RAR), retinoid X receptor (RXR) and thyroid hormone receptor (TR), bind direct repeats (DR) of the estrogen response elements (ERE) half-site (5'-AGGTCA-3'), we examined the ability of estrogen receptor (ER) versus type II nuclear receptors, i.e. RARalpha, beta and gamma, RXRbeta, TRalpha and TRbeta, to bind various EREs in vitro . ER bound a consensus ERE, containing a perfectly palindromic 17 bp inverted repeat (IR), as a homodimer. In contrast, ER did not bind to a single ERE half-site. Likewise, ER did not bind two tandem (38 bp apart) half-sites, but low ER binding was detected to three tandem copies of the same half-site. RARalpha,beta or gamma bound both ERE and half-site constructs as a homodimer. RXRbeta did not bind full or half-site EREs, nor did RXRbeta enhance RARalpha binding to a full ERE. However, RARalpha and RXRbeta bound a half-site ERE cooperatively forming a dimeric complex. The RARalpha-RXRbeta heterodimer bound the Xenopus vitellogenin B1 estrogen responsive unit, with two non-consensus EREs, with higher affinity than one or two copies of the full or half-site ERE. Both TRalpha and TRbeta bound the full and the half-site ERE as monomers and homodimers and cooperatively as heterodimers with RXRbeta. We suggest that the cellular concentrations of nuclear receptors and their ligands, and the nature of the ERE or half-site sequence and those of its flanking sequences determine the occupation of EREs in estrogen-regulated genes in vivo . PMID:9115356

  9. Δ9-Tetrahydrocannabinol Disrupts Estrogen-Signaling through Up-Regulation of Estrogen Receptor β (ERβ)

    PubMed Central

    Takeda, Shuso; Yoshida, Kazutaka; Nishimura, Hajime; Harada, Mari; Okajima, Shunsuke; Miyoshi, Hiroko; Okamoto, Yoshiko; Amamoto, Toshiaki; Watanabe, Kazuhito; Omiecinski, Curtis J.; Aramaki, Hironori

    2014-01-01

    Δ9-Tetrahydrocannabinol (Δ9-THC) has been reported as possessing antiestrogenic activity, although the mechanisms underlying these effects are poorly delineated. In this study, we used the estrogen receptor α (ERα)-positive human breast cancer cell line, MCF-7, as an experimental model and showed that Δ9-THC exposures markedly suppresses 17β-estradiol (E2)- induced MCF-7 cell proliferation. We demonstrate that these effects result from Δ9-THC’s ability to inhibit E2-liganded ERα activation. Mechanistically, the data obtained from biochemical analyses revealed that (i) Δ9-THC up-regulates ERβ, a repressor of ERα, inhibiting the expression of E2/ERα-regulated genes that promote cell growth and that (ii) Δ9-THC induction of ERβ modulates E2/ERα signaling in the absence of direct interaction with the E2 ligand binding site. Therefore, the data presented support the concept that Δ9-THC’s antiestrogenic activities are mediated by the ERβ disruption of E2/ERα signaling. PMID:23718638

  10. Biliary excretion and intestinal metabolism of progesterone and estrogens in man.

    PubMed

    Adlercreutz, H; Martin, F

    1980-02-01

    The biliary excretion and intestinal metabolism (including intestinal mucosa and small intestine and bowel) of progesterone and estrogens in humans are reviewed here along with presentation of experimental results from other mammalian systems. In general, the biliary excretion of estrogens and the enterohepatic circulation of estrogen metabolites are more extensive than for progesterone. These processes may be of greater physiological importance because of the possible reformation of biologically active estrogens in the intestine, which occurs 2 ways: 1) by hydrolysis of biliary estrogen conjugates and absorption of the unconjugated estrogens which may partly reach general circulation, and 2) by production of biologically active estrogens from neutral steroids or less active estrogens in the intestinal tract, followed by absorption. Here, the kidneys also play a significant role in estrogen metabolism and conjugation. The quantitative contribution of liver, kidneys, and intestine to estrogen metabolism cannot be accurately assessed at present, but the liver and intestines probably play the most significant role, followed by the kidneys. Progesterone (from orally administered doses) and its metabolites are extensively metabolized in the intestine to compounds with less progestational activity; hence, synthetic progestins may alter the intestinal flora which in turn may influence the plasma levels of these compounds. On these subjects more research in indicated. PMID:6991820

  11. Bioaugmentation Mitigates the Impact of Estrogen on Coliform-Grazing Protozoa in Slow Sand Filters.

    PubMed

    Haig, Sarah-Jane; Gauchotte-Lindsay, Caroline; Collins, Gavin; Quince, Christopher

    2016-03-15

    Exposure to endocrine-disrupting chemicals (EDCs), such as estrogens, is a growing issue for human and animal health as they have been shown to cause reproductive and developmental abnormalities in wildlife and plants and have been linked to male infertility disorders in humans. Intensive farming and weather events, such as storms, flash flooding, and landslides, contribute estrogen to waterways used to supply drinking water. This paper explores the impact of estrogen exposure on the performance of slow sand filters (SSFs) used for water treatment. The feasibility and efficacy of SSF bioaugmentation with estrogen-degrading bacteria was also investigated, to determine whether removal of natural estrogens (estrone, estradiol, and estriol) and overall SSF performance for drinking water treatment could be improved. Strains for SSF augmentation were isolated from full-scale, municipal SSFs so as to optimize survival in the laboratory-scale SSFs used. Concentrations of the natural estrogens, determined by gas chromatography coupled with mass spectrometry (GC-MS), revealed augmented SSFs reduced the overall estrogenic potency of the supplied water by 25% on average and removed significantly more estrone and estradiol than nonaugmented filters. A negative correlation was found between coliform removal and estrogen concentration in nonaugmented filters. This was due to the toxic inhibition of protozoa, indicating that high estrogen concentrations can have functional implications for SSFs (such as impairing coliform removal). Consequently, we suggest that high estrogen concentrations could impact significantly on water quality production and, in particular, on pathogen removal in biological water filters. PMID:26895622

  12. Removal of natural estrogens and their conjugates in municipal wastewater treatment plants: a critical review.

    PubMed

    Liu, Ze-hua; Lu, Gui-ning; Yin, Hua; Dang, Zhi; Rittmann, Bruce

    2015-05-01

    This article reviews studies focusing on the removal performance of natural estrogens in municipal wastewater treatment plants (WWTPs). Key factors influencing removal include: sludge retention time (SRT), aeration, temperature, mixed liquor suspended solids (MLSS), and substrate concentration. Batch studies show that natural estrogens should biodegrade well; however, batch observations do not always agree with observations from full-scale municipal WWTPs. To explain this discrepancy, deconjugation kinetics of estrogen conjugates in lab-scale studies were examined and compared. Most estrogen conjugates with slow deconjugation rates are unlikely to be easily removed; others could be cleaved in WWTP settings. Nevertheless, some estrogens cleaved from their conjugates may be found in treated effluent, because deconjugation requires several hours or longer, and there is insufficient rest time for the biodegradation of the cleaved natural estrogens in the WWTP. Therefore, WWTP removals of natural estrogens are likely to be underestimated when estrogen conjugates are present in raw wastewater. This review suggests that biodeconjugation of estrogen conjugates should be enhanced to more effectively remove natural estrogens in WWTPs. PMID:25844648

  13. Ecological risk of estrogenic endocrine disrupting chemicals in sewage plant effluent and reclaimed water.

    PubMed

    Sun, Yan; Huang, Huang; Sun, Ying; Wang, Chao; Shi, Xiao-Lei; Hu, Hong-Ying; Kameya, Takashi; Fujie, Koichi

    2013-09-01

    The long-term ecological risk of micropollutants, especially endocrine disrupting chemicals (EDCs) has threatened reclaimed water quality. In this study, estrogenic activity and ecological risk of eight typical estrogenic EDCs in effluents from sewage plants were evaluated. The estrogenic activity analysis showed that steroidal estrogens had the highest estrogenic activity (ranged from 10(-1) to 10(3) ng-E2/L), phenolic compounds showed weaker estrogenic activity (mainly ranged from 10(-3) to 10 ng-E2/L), and phthalate esters were negligible. The ecological risk of the estrogenic EDCs which was characterized by risk quotient ranged from 10(-4) to 10(3), with an order in descending: steroids estrogens, phenolic compounds and phthalate esters. The eight estrogenic EDCs were scored and sorted based on the comparison of the estrogenic activity and the ecological risk, suggesting that 17α-ethynylestradiol (EE2), estrone (E1) and estradiol (E2) should be the priority EDCs to control in municipal sewage plants. PMID:23735815

  14. ERα Mediates Estrogen-Induced Expression of the Breast Cancer Metastasis Suppressor Gene BRMS1

    PubMed Central

    Ma, Hongtao; Gollahon, Lauren S.

    2016-01-01

    Recently, estrogen has been reported as putatively inhibiting cancer cell invasion and motility. This information is in direct contrast to the paradigm of estrogen as a tumor promoter. However, data suggests that the effects of estrogen are modulated by the receptor isoform with which it interacts. In order to gain a clearer understanding of the role of estrogen in potentially suppressing breast cancer metastasis, we investigated the regulation of estrogen and its receptor on the downstream target gene, breast cancer metastasis suppressor 1 (BRMS1) in MCF-7, SKBR3, TTU-1 and MDA-MB-231 breast cancer cells. Our results showed that estrogen increased the transcription and expression of BRMS1 in the ERα positive breast cancer cell line, MCF-7. Additionally, the ERα specific agonist PPT also induced the transcription and expression of BRMS1. However, the two remaining estrogen receptor (ER) subtype agonists had no effect on BRMS1 expression. In order to further examine the influence of ERα on BRMS1 expression, ERα expression was knocked down using siRNA (siERα). Western blot analysis showed that siERα reduced estrogen-induced and PPT-induced BRMS1 expression. In summary, this study demonstrates estrogen, via its α receptor, positively regulates the expression of BRMS1, providing new insight into a potential inhibitory effect of estrogen on metastasis suppression. PMID:26821020

  15. Estrogenic activity and identification of potential xenoestrogens in a coking wastewater treatment plant.

    PubMed

    Zhao, Jian-Liang; Chen, Xiao-Wen; Yan, Bo; Wei, Chaohai; Jiang, Yu-Xia; Ying, Guang-Guo

    2015-02-01

    In this study, the estrogenic activities in influent and effluents of coking wastewater from different treatment stages were studied using Yeast Estrogen Screen (YES) bioassays. Raw extracts were further fractioned to identify the potential xenoestrogens combined with YES bioassays and gas chromatography-mass spectrometry analysis. Influent, primary effluent, and anaerobic effluent showed high estrogenic activities, with potencies of 1136±269, 1417±320, and 959±69 ng/L of 17β-estradiol (E2) equivalent (EEQ), respectively. The potency of estrogenic activity was gradually removed through the treatment processes. In the final effluent, the estrogenic activity was reduced to 0.87 ng EEQ/L with a total removal efficiency of more than 99%, suggesting that the estrogenic activity was almost completely removed in the coking wastewater. For the fractions of raw extracts, bioassay results showed that the estrogenic activities were mostly present in the polar fractions. Correlation analysis between estrogenic activities and responses of identified chemicals indicated that potential xenoestrogens were the derivatives of indenol, naphthalenol, indol, acridinone, fluorenone, and carbazole. The estrogenic activity in the final effluent was higher than the predicted no effect concentration (PNEC) for E2, implying that the discharged effluent would probably exert estrogenic activity risk to the aquatic ecosystem in "the worst-case scenario." PMID:25463876

  16. Reduction of estrogen-induced transformation of mouse mammary epithelial cells by N-acetylcysteine

    PubMed Central

    Venugopal, Divya; Zahid, Muhammad; Mailander, Paula C; Meza, Jane L.; Rogan, Eleanor G.; Cavalieri, Ercole L.; Chakravarti, Dhrubajyoti

    2009-01-01

    A growing number of studies indicate that breast cancer initiation is related to abnormal estrogen oxidation to form an excess of estrogen-3,4-quinones, which react with DNA to form depurinating adducts and induce mutations. This mechanism is often called estrogen genotoxicity. 4-catechol estrogens, precursors of the estrogen-3,4-quinones, were previously shown to account for most of the transforming and tumorigenic activity. We examined whether estrogen-induced transformation can be reduced by inhibiting the oxidation of a 4-catechol estrogen to its quinone. We demonstrate that E6 cells (a normal mouse epithelial cell line) can be transformed by a single treatment with a catechol estrogen or its quinone. The transforming activities of 4-hydroxyestradiol and estradiol-3,4-quinone were comparable. N-acetylcysteine, a common antioxidant, inhibited the oxidation of 4-hydroxyestradiol to the quinone and consequent formation of DNA adducts. It also drastically reduced estrogen-induced transformation of E6 cells. These results strongly implicate estrogen genotoxicity in mammary cell transformation. Since N-acetylcysteine is well-tolerated in clinical studies, it may be a promising candidate for breast cancer prevention. PMID:18226522

  17. Prenylation has a compound specific effect on the estrogenicity of naringenin and genistein.

    PubMed

    Kretzschmar, Georg; Zierau, Oliver; Wober, Jannette; Tischer, Sandra; Metz, Peter; Vollmer, Günter

    2010-01-01

    A variety of plant derived substances, so-called phytoestrogens (PEs), although structurally not related to steroids, produce effects similar to the mammalian estradiol. However, little is known so far about the structural requirements which determine PE activities. Taking into consideration that prenylation reactions are relatively common in plant secondary metabolism, the activity of a set of three PE derivatives of genistein and naringenin, namely genistein, 8-prenylgenistein (8PG), 6-(1,1-dimethylallyl)genistein (6DMAG), naringenin, 8-prenylnaringenin (8PN) and 6-(1,1-dimethylallyl)naringenin (6DMAN) was compared regarding structure-estrogenicity relationships in three functionally different estrogen receptor assays. Strong estrogenic activities were recorded for 6DMAN and 8PN in all assays used, while the parent compound naringenin showed only very weak estrogenicity. In contrast, in the case of genistein derivatives, only genistein itself exhibited estrogenic activity in a yeast based assay. In MVLN breast cancer cells, a bioluminescent MCF-7-derived cell line, the estrogenic activity of all three genistein derivatives was similar. Studying alkaline phosphatase activity in Ishikawa endometrial cancer cells as an estrogenic response marker revealed a similar pattern of estrogenicity of the genistein derivatives compared to the yeast based assay although a slight estrogenic effect of 6DMAG and 8PG was apparent. In summary, this study demonstrates that prenylation often found in plant secondary metabolism differentially modifies estrogenic properties of PEs depending on the basic structure of the respective PE. PMID:19733663

  18. Bioaugmentation Mitigates the Impact of Estrogen on Coliform-Grazing Protozoa in Slow Sand Filters

    PubMed Central

    2016-01-01

    Exposure to endocrine-disrupting chemicals (EDCs), such as estrogens, is a growing issue for human and animal health as they have been shown to cause reproductive and developmental abnormalities in wildlife and plants and have been linked to male infertility disorders in humans. Intensive farming and weather events, such as storms, flash flooding, and landslides, contribute estrogen to waterways used to supply drinking water. This paper explores the impact of estrogen exposure on the performance of slow sand filters (SSFs) used for water treatment. The feasibility and efficacy of SSF bioaugmentation with estrogen-degrading bacteria was also investigated, to determine whether removal of natural estrogens (estrone, estradiol, and estriol) and overall SSF performance for drinking water treatment could be improved. Strains for SSF augmentation were isolated from full-scale, municipal SSFs so as to optimize survival in the laboratory-scale SSFs used. Concentrations of the natural estrogens, determined by gas chromatography coupled with mass spectrometry (GC-MS), revealed augmented SSFs reduced the overall estrogenic potency of the supplied water by 25% on average and removed significantly more estrone and estradiol than nonaugmented filters. A negative correlation was found between coliform removal and estrogen concentration in nonaugmented filters. This was due to the toxic inhibition of protozoa, indicating that high estrogen concentrations can have functional implications for SSFs (such as impairing coliform removal). Consequently, we suggest that high estrogen concentrations could impact significantly on water quality production and, in particular, on pathogen removal in biological water filters. PMID:26895622

  19. ESTROGEN RELATED MECHANISMS OF HYPERTENSION IN MENOPAUSAL WOMEN.

    PubMed

    Buleishvili, M; Lobjanidze, N; Ormotsadze, G; Enukidze, M; Machavariani, M; Sanikidze, T

    2016-06-01

    The aim of our investigation was to establish the role of estrogens in the pathogenesis of hypertension during menopause. Menopausal women (40-55 years) with hypertension who had been admitted to "The N. Kipshidze Central University Clinic" (Tbilisi, Georgia) during 2011-2015 and without hypertension were investigated. Essential hypertension was defined as elevated blood pressure while in a sitting position, exceeding 160±10/90±10 mm Hg 60/95 mm Hg, for three consecutive measurements over a period of at least 4 weeks. Determination and verification of menopause was provided based on the criteria of at least 12 months of amenorrhea. All the patients had given their informed consent before any procedure. Study protocol was approved by Local Ethical Committee of Davit Agmashenebeli University. In each group blood content of estradiol, free nitric oxide (NO) and nitrosilated hemoglobin (HbNO), endothelin-1 and angiotensin II (ANG) were investigated. Decrease free nitric oxide (NO) (by 10%) and increase in endothelin-1 (by 14%) and Angiotensin II (ANG) (by 12%) content in the blood of menopausal women with hypertension were identified. In some patients with hypertension it was detected low intensity of NOHb EPR signal in blood (~1,5±0,07 mm/mg). In blood of hypertensive postmenopausal women there was revealed statistically significant correlation between estrogen level and NO content (r=-0,7935, p=0,0061), estrogen level and ANG II content (r=-0,7080, p=0,0328), statistically nonsignificant dependence between NOHb EPR signal intensity and estradiol content (r=-0,29, p=0,12). In normotensive postmenopausal women correlation between blood estrogen and NO level, blood estrogen and ANGII level was not statistically significant (r=-0,4342, p=0,2429; r=-0,2676, p=0,4547). These data indicate that in postmenopausal women in the regulation of arterial pressure in addition to the estrogens involve other factors, like as was shown in our previous investigation, oxidative

  20. Expression of Estrogen Receptor Alpha and Beta is Decreased in Hypospadias

    PubMed Central

    Qiao, Liang; Rodriguez, Esequiel; Weiss, Dana A.; Ferretti, Max; Risbridger, Gail; Cunha, Gerald R.; Baskin, Laurence S.

    2012-01-01

    Purpose Estrogenic endocrine disruptors acting via estrogen receptors α and β have been implicated in the etiology of hypospadias. However, the expression and distribution of estrogen receptors α and β in normal and hypospadiac human foreskins is unknown. We characterized the location and expression of estrogen receptors α and β in normal and hypospadiac foreskins. Materials and Methods We prospectively collected excess foreskin from 35 patients undergoing hypospadias repair and 15 patients undergoing elective circumcision. Hypospadias was classified as severe in 18 patients and mild in 17 based on the ectopic position of the meatus. mRNA expression levels in estrogen receptors α and β were quantified using reverse transcriptase polymerase chain reaction. Receptor location was characterized by immunohistochemical analysis. Additionally immunohistochemical analysis was performed in 4 archived human fetal penises. Results Mean ± SD ages were similar for the circumcision (9.5 ± 3 months) and hypospadias repair groups (9 ± 3 months, p = 0.75). mRNA expression levels in estrogen receptors α and β were significantly decreased in hypospadiac foreskin cases compared to controls (p <0.001), while no statistically significant differences were seen between foreskins with severe and mild hypospadias. Estrogen receptor β immunostaining was strong in normal foreskin but weak in hypospadiac foreskin. Estrogen receptor β immunoreactivity was most intense in the stratum basale and stratum spinosum. Estrogen receptor α immunostaining was weak in normal and mild hypospadias foreskin, and undetectable in severe hypospadias. Fetal penises expressed strong estrogen receptor β immunopositivity in the urethral plate epithelium, corpus spongiosum, corpora cavernosa and penile skin, while estrogen receptor α immunostaining was not detected. Conclusions These data demonstrate a difference in estrogen receptor α and β expression and location in the foreskin of patients

  1. Impact of secondary treatment types and sludge handling processes on estrogen concentration in wastewater sludge.

    PubMed

    Marti, Erica J; Batista, Jacimaria R

    2014-02-01

    Endocrine-disrupting compounds (EDCs), such as estrogen, are known to be present in the aquatic environment at concentrations that negatively affect fish and other wildlife. Wastewater treatment plants (WWTPs) are major contributors of EDCs into the environment. EDCs are released via effluent discharge and land application of biosolids. Estrogen removal in WWTPs has been studied in the aqueous phase; however, few researchers have determined estrogen concentration in sludge. This study focuses on estrogen concentration in wastewater sludge as a result of secondary treatment types and sludge handling processes. Grab samples were collected before and after multiple treatment steps at two WWTPs receiving wastewater from the same city. The samples were centrifuged into aqueous and solid phases and then processed using solid phase extraction. Combined natural estrogens (estrone, estradiol and estriol) were measured using an enzyme-linked immunosorbent assay (ELISA) purchased from a manufacturer. Results confirmed that activated sludge treatments demonstrate greater estrogen removal compared to trickling filters and mass concentration of estrogen was measured for the first time on trickling filter solids. Physical and mechanical sludge treatment processes, such as gravity thickeners and centrifuges, did not significantly affect estrogen removal based on mass balance calculations. Dissolved air flotation thickening demonstrated a slight decrease in estrogen concentration, while anaerobic digestion resulted in increased mass concentration of estrogen on the sludge and a high estrogen concentration in the supernatant. Although there are no state or federally mandated discharge effluent standards or sludge application standards for estrogen, implications from this study are that trickling filters would need to be exchanged for activated sludge treatment or followed by an aeration basin in order to improve estrogen removal. Also, anaerobic digestion may need to be replaced

  2. Interaction of putative estrogens and the estrogen receptor system in Leydig cells in the BALB/c mouse testis resulting in the initiation of DNA synthesis

    SciTech Connect

    Juriansz, R.L.

    1986-01-01

    Continuous administration of estrogens for 7-9 months, both steroidal and nonsteroidal, to male BALB/c mice, leads to the formation of testicular Leydig cell tumors. Three days following the subcutaneous implantation of a pellet of estrogen in cholesterol, there is a peak in the incorporation of /sup 3/H-thymidine into the DNA of the interstitial cells. These effects are hypothesized to be mediated by the estrogen receptor system in the Leydig cell. Common experimental techniques for the measurement of hormone binding, such as dextran coated charcoal treatment, proved to be impossible to employ in this system, therefore a procedure was developed using hydroxyapatite to obtain binding data. The cytosolic estrogen receptor was found to have a dissociation constant for estradiol-17..beta.. of 6.5 x 10/sup -8/ M, while that of the nuclear estrogen receptor was 1.25 x 10/sup -8/ M. Competition assays were utilized to determine the cytosolic estrogen receptor's affinity for nonsteroidal estrogens, steroidal estrogens, and triphenylethylene.

  3. Estrogen-mediated Regulation of Igf1 Transcription and Uterine Growth Involves Direct Binding of Estrogen Receptor α to Estrogen-responsive Elements*

    PubMed Central

    Hewitt, Sylvia C.; Li, Yin; Li, Leping; Korach, Kenneth S.

    2010-01-01

    Estrogen enables uterine proliferation, which depends on synthesis of the IGF1 growth factor. This proliferation and IGF1 synthesis requires the estrogen receptor (ER), which binds directly to target DNA sequences (estrogen-responsive elements or EREs), or interacts with other transcription factors, such as AP1, to impact transcription. We observe neither uterine growth nor an increase in Igf1 transcript in a mouse with a DNA-binding mutated ERα (KIKO), indicating that both Igf1 regulation and uterine proliferation require the DNA binding function of the ER. We identified several potential EREs in the Igf1 gene, and chromatin immunoprecipitation analysis revealed ERα binding to these EREs in wild type but not KIKO chromatin. STAT5 is also reported to regulate Igf1; uterine Stat5a transcript is increased by estradiol (E2), but not in KIKO or αERKO uteri, indicating ERα- and ERE-dependent regulation. ERα binds to a potential Stat5a ERE. We hypothesize that E2 increases Stat5a transcript through ERE binding; that ERα, either alone or together with STAT5, then acts to increase Igf1 transcription; and that the resulting lack of IGF1 impairs KIKO uterine growth. Treatment with exogenous IGF1, alone or in combination with E2, induces proliferation in wild type but not KIKO uteri, indicating that IGF1 replacement does not rescue the KIKO proliferative response. Together, these observations suggest in contrast to previous in vitro studies of IGF-1 regulation involving AP1 motifs that direct ERα-DNA interaction is required to increase Igf1 transcription. Additionally, full ERα function is needed to mediate other cellular signals of the growth factor for uterine growth. PMID:19920132

  4. Bromine-80m-labeled estrogens: Auger-electron emitting, estrogen receptor-directed ligands with potential for therapy of estrogen receptor positive cancers

    SciTech Connect

    DeSombre, E.R.; Mease, R.C.; Hughes, A.; Harper, P.V.; DeJesus, O.T.; Friedman, A.M.

    1988-01-01

    A triphenylbromoethylene, 1,1-bis(p-hydroxyphenyl)-2-bromo-2-phenylethylene, Br-BHPE, and a bromosteroidal estrogen, 17..cap alpha..- bromovinylestradiol, BrVE/sub 2/, were labeled with the Auger electron emitting nuclide bromine-80m, prepared by the (p,n) reaction with /sup 80/Se. To assess their potential as estrogen receptor (ER) directed therapeutic substrates the bromine-80m labeled estrogens were injected into immature female rats and the tissue distribution studied at 0.5 and 2 hours. Both radiobromoestrogens showed substantial diethylstilbesterol (DES)-inhibitable localization in the ER rich tissues, uterus, pituitary, ovary and vagina at both time points. While the percent dose per gram tissue was higher for the Br-BHPE, the BrVE/sub 2/ showed higher tissue to blood ratios, especially at 2 hr, reflecting the lower blood concentrations of radiobromine following administration of the steroidal bromoestrogen. Comparing intraperitoneal, intravenous and subcutaneous routes of administration for the radiobromine labeled Br-BHPE, the intraperitoneal route was particularly advantageous to provide maximum, DES-inhibitable concentrations in the peritoneal, ER-rich target organs, the uterus, ovary and vagina. While uterine concentrations after BrBHPE were from 10--48% dose/g and after BrVE/sub 2/ were 15--25% dose/g, similar treatment with /sup 80m/Br as sodium bromide showed uniform low concentrations in all tissues at about the levels seen in blood. The effective specific activity of (/sup 80m/Br)BrBHPE, assayed by specific binding to ER in rat uterine cytosol, was 8700 Ci/mmole. 23 refs., 9 figs., 2 tabs.

  5. Relationship of serum estrogens and estrogen metabolites to postmenopausal breast cancer risk: a nested case-control study

    PubMed Central

    2013-01-01

    Introduction Elevated levels of circulating estrogens are linked to breast cancer risk among postmenopausal women but little is known about the importance of estrogen metabolism. A recently developed liquid chromatography tandem mass spectrometry-based method (LC-MS/MS) measuring a panel of 15 estrogen metabolites (EM) has been evaluated in one study, linking high levels of 2-pathway metabolites relative to the parent estrogens to reduced breast cancer risk. We analyzed this panel of EM in a nested case-control study of postmenopausal breast cancer. Methods Between 1977 and 1987, 6,915 women provided blood samples to the Columbia Missouri Serum Bank and were followed for incident breast cancer through December 2002. We studied 215 postmenopausal breast cancer cases and 215 matched controls who were postmenopausal and not using exogenous hormones at the time of blood draw. EM were examined individually, grouped by pathway (hydroxylation at the C-2, C-4 or C-16 positions of the steroid ring) and by ratios of the groupings. Logistic regression models controlling for matching and breast cancer risk factors were used to calculate quartile-specific odds ratios (ORs) and 95% CIs. Results Significant elevated risks were not observed for individual EM, except for quartiles of 16-epiestriol (P trend = 0.07). The OR for total EM, the parent estrogens estrone and estradiol, and 2-pathway catechol EM (2-hydroxyestrone and 2-hydroxyestradiol) were elevated but the trends were not statistically significant. Among 2-pathway metabolites, risks for the highest levels of 2-hydroxyestrone-3-methyl ether and 2-methoxyestradiol were reduced; ORs for women in the highest versus lowest quartiles were 0.57 (95% CI = 0.33 to 0.99) and 0.53 (95% CI = 0.30 to 0.96), respectively. Overall, women with higher levels of 2-pathway EM had a reduced risk of breast cancer, which remained after accounting for levels of parent EM, 4-pathway EM and 16-pathway EM (all trends, P <0.11). Conclusions Women

  6. Selective estrogen receptor modulators: tissue specificity and clinical utility

    PubMed Central

    Martinkovich, Stephen; Shah, Darshan; Planey, Sonia Lobo; Arnott, John A

    2014-01-01

    Selective estrogen receptor modulators (SERMs) are a diverse group of nonsteroidal compounds that function as agonists or antagonists for estrogen receptors (ERs) in a target gene-specific and tissue-specific fashion. SERM specificity involves tissue-specific expression of ER subtypes, differential expression of co-regulatory proteins in various tissues, and varying ER conformational changes induced by ligand binding. To date, the major clinical applications of SERMs are their use in the prevention and treatment of breast cancer, the prevention of osteoporosis, and the maintenance of beneficial serum lipid profiles in postmenopausal women. However, SERMs have also been found to promote adverse effects, including thromboembolic events and, in some cases, carcinogenesis, that have proven to be obstacles in their clinical utility. In this review, we discuss the mechanisms of SERM tissue specificity and highlight the therapeutic application of well-known and emergent SERMs. PMID:25210448

  7. THE ESTROGENIC ENDOCRINE DISRUPTING CHEMICAL BISPHENOL A (BPA) AND OBESITY

    PubMed Central

    vom Saal, Frederick S.; Nagel, Susan C.; Coe, Benjamin L.; Angle, Brittany M.; Taylor, Julia A.

    2012-01-01

    There is increasing experimental and epidemiological evidence that fetal programming of genetic systems is a contributing factor in the recent increase in adult obesity and other components of metabolic syndrome. In particular, there is evidence that epigenetic changes associated with the use of manmade chemicals may interact with other factors that influence fetal and postnatal growth in contributing to the current obesity epidemic. The focus of this review is on the developmental effects of estrogenic endocrine disrupting chemicals (EDCs), and more specifically on effects of exposure to the estrogenic EDC bisphenol A (BPA), on adipocytes and their function, and the ultimate impact on adult obesity; BPA exposure also results in impaired reproductive capacity. We discuss the interaction of EDCs with other factors that impact growth during fetal and neonatal life, such as placental blood flow and nutrient transport to fetuses, and how these influence fetal growth and abnormalities in homeostatic control systems required to maintain normal body weight throughout life. PMID:22249005

  8. Relationship between Postmenopausal Estrogen Deficiency and Aneurysmal Subarachnoid Hemorrhage

    PubMed Central

    Tabuchi, Sadaharu

    2015-01-01

    Aneurysmal subarachnoid hemorrhage (SAH) is one of the most severe forms of stroke, which results from the rupture of a cerebral aneurysm. SAH is the only type of stroke with a female predominance, suggesting that reproductive factors may play a significant role in the etiology. Estrogen has important effects on vascular physiology and pathophysiology of cerebral aneurysm and SAH and, thus, potential therapeutic implications. There have been growing bodies of epidemiological and experimental studies which support the hypothesis of a significant relationship between estrogen deficiency and cerebral aneurysm formation with subsequent SAH. This hypothesis is the focus of this review as well as possible pathology-based therapeutics with regard to aspects of molecular pathophysiology, especially related to women's health. PMID:26538819

  9. Expression of Estrogen Receptor α in the Mouse Cerebral Cortex

    PubMed Central

    Dietrich, Alicia K.; Humphreys, Gwendolyn I.; Nardulli, Ann M.

    2015-01-01

    Although estrogen receptor alpha (ERα) and 17β-estradiol play critical roles in protecting the cerebral cortex from ischemia-induced damage, there has been some controversy about the expression of ERα in this region of the brain. We have examined ERα mRNA and protein levels in the cerebral cortices of female mice at postnatal days 5 and 17 and at 4, 13, and 18 months of age. We found that although ERα transcript levels declined from postnatal day 5 through 18 months of age, ERα protein levels remained stable. Importantly, expression of the E2-regulated progesterone receptor gene was sustained in younger and in older females suggesting that age-related changes in estrogen responsiveness in the cerebral cortex are not due to the absence of ERα protein. PMID:25700604

  10. COLORECTAL CANCER IN RELATION TO POSTMENOPAUSAL ESTROGEN AND ESTROGEN PLUS PROGESTIN IN THE WOMEN'S HEALTH INITIATIVE CLINICAL TRIAL AND OBSERVATIONAL STUDY

    PubMed Central

    Prentice, Ross L.; Pettinger, Mary; Beresford, Shirley A. A.; Wactawski-Wende, Jean; Hubbell, F. Allan; Stefanick, Marcia L.; Chlebowski, Rowan T.

    2009-01-01

    Background Colorectal cancer incidence was reduced among women assigned to active treatment in the Women's Health Initiative (WHI) estrogen plus progestin randomized trial, but the interpretation was obscured by an associated later stage of diagnosis. In contrast the estrogen-alone trial showed no incidence reduction or differential stage at diagnosis. Here, data from the WHI observational study are considered, in conjunction with colorectal cancer mortality data from the hormone therapy trials, in an attempt to clarify postmenopausal hormone therapy effects. Participants and Methods Postmenopausal women aged 50−79 at WHI enrollment. Estrogen-alone analyses include 21,552 and 10,739 women who were post-hysterectomy from the observational study and clinical trial respectively. Estrogen plus progestin analyses include 32,084 and 16,608 observational study and clinical trial women with uterus. Colorectal cancers were verified by central medical and pathology report review. Results Hazard ratios (95% confidence intervals) from the WHI observational study were 0.80 (0.53 to 1.20) for estrogen and 1.15 (0.74 to 1.79) for estrogen plus progestin, with respectively 168 and 175 women diagnosed with colorectal cancer. Delayed diagnosis with estrogen plus progestin is not evident in the observational study. No protective effect on colorectal cancer mortality in the estrogen plus progestin trial is seen over an 8-year intervention and follow-up period. Conclusion Hazard ratio patterns in the WHI clinical trial and observational study do not provide strong evidence of a clinically important colorectal cancer benefit with either estrogen-alone or estrogen plus progestin over 7−8 years of treatment and follow-up. PMID:19423530

  11. Estrogens and memory in physiological and neuropathological conditions.

    PubMed

    Pompili, Assunta; Arnone, Benedetto; Gasbarri, Antonella

    2012-09-01

    Ovarian hormones can influence brain regions crucial to higher cognitive functions, such as learning and memory, acting at structural, cellular and functional levels, and modulating neurotransmitter systems. Among the main effects of estrogens, the protective role that they may play against the deterioration of cognitive functions occurring with normal aging is of essential importance. In fact, during the last century, there has been a 30 years increase in female life expectancy, from 50 to 83 years; however, the mean age of spontaneous menopause remains stable, 50-51 years, with variability related to race and ethnicity. Therefore, women are now spending a greater fraction of their lives in a hypoestrogenic state. Although many cognitive functions seem to be unaffected by normal aging, age-related impairments are particularly evident in tasks involving working memory (WM), whose deficits are a recognized feature of Alzheimer's disease (AD). Many studies conducted over the past two decades showed that the female gonadal hormone estradiol can influence performance of learning and memory tasks, both in animal and humans. There is a great deal of evidence, mostly from animal models, that estrogens can facilitate or enhance performance on WM tasks; therefore, it is very important to clarify their role on this type of memory. To this aim, in this review we briefly describe the most relevant neurobiological bases of estrogens, that can explain their effects on cognitive functioning, and then we summarize the results of works conducted in our laboratory, both on animals and humans, utilizing the menstrual/estrous cycle as a useful noninvasive model. Finally, we review the possible role of estrogens in neuropathological conditions, such as AD and schizophrenia. PMID:22309827

  12. Effects of estroprogestins containing natural estrogen on vaginal flora.

    PubMed

    De Seta, Francesco; Restaino, Stefano; Banco, Rubina; Conversano, Ester; De Leo, Rossella; Tonon, Maddalena; Maso, Gianpaolo; Barbati, Giulia; Lello, Stefano

    2014-11-01

    Estroprogestins with "natural oestrogen" has represented a new option in terms of combined hormonal contraception. So, the aim of this study is to investigate how estroprogestins with natural estrogen may modify the vaginal niche. In literature, very few studies focused on the interaction between hormonal contraception and vaginal milieu. This is a prospective comparative study. We enrolled 60 women from January 2013 to September 2013, 30 of them were administered estradiol valerate dienogest (E2V+DNG - Klaira®) in a quadriphasic regimen, while the other 30 women were administered 17-β estradiol with nomestrol acetate (EV+NOMAC - Zoely®) in a monophasic regimen. After a baseline study of vaginal milieu at recruitment of patients (Gram stain with Nugent score, vaginal pH, vaginal wet mount for the quantification of leukocytes, Lactobacilli and/or presence of Candida), we performed the same follow-up after six months of estroprogestin therapy. Our results showed that the women treated with E2V+DNG had a trend of an improvement of vaginal health in terms of increase of lactobacillar flora and reduction of vaginal pH in place of women treated with EV+NOMAC that showed a reduction of cervical mucus. Finally, our data about the effects on vaginal flora exerted by two estroprogestin pills (EPs) containing a natural estrogen suggest slight, but interesting differences in terms of vaginal ecology. These differences could be related to the type of estrogen, type of progestin, regimen of administration and, after all, to the net balance between estrogenic and progestin component of the EPs. PMID:24993504

  13. Non-estrogenic approaches for the treatment of climacteric symptoms.

    PubMed

    Albertazzi, P

    2007-10-01

    Non-estrogenic alternatives for the treatment of climacteric symptoms have their origin lost in history. Recent clinical trial data have shown that lifestyle and diet adjustment have some effect in improving both hot flushes and mood. Over-the-counter phytotherapeutic extracts are very popular and women often try a variety of products before resorting to traditional medicine. Preparations containing isoflavones in variable doses, such as soy extract and red clover, or extracts from evening primrose, Cimifuga racemosa, ginseng and black cohosh are often used for treating the climacteric syndrome. The scientific support for their efficacy certainly does not equal their popularity. The most tested pharmacological alternatives to estrogens are serotonin reuptake inhibitors (SSRIs). All available SSRIs have undergone trials for the relief of hot flushes. In spite of the difference between the compounds in both half-life and engagement of serotonin receptors, they appear to have very similar effectiveness in reducing hot flushes. At their best, SSRIs reduce hot flushes by 50-60%, compared with 80% for estrogen, and their effect appears only in the short term. SSRIs have mood-improving effects that appear to be independent of the effect on hot flushes. When used for the treatment of the climacteric syndrome, SSRIs do not adversely affect libido. Dependence is a major concern in women when offered this type of treatment, but does not appear to be a problem with this class of drugs. Withdrawal symptoms have never been reported in trials for hot flushes but are known to occur when SSRIs are used in the long term. In order to avoid these symptoms, the dose should be tapered slowly. Gabapentin, a drug used for the treatment of neuropathic pain and epilepsy, has shown that, in high doses, it has an efficacy similar to that of estrogen; however, this needs further confirmation. PMID:17882686

  14. Hepatosteatosis and estrogen increase apolipoprotein O production in the chicken.

    PubMed

    Schmidinger, Barbara; Weijler, Anna M; Schneider, Wolfgang J; Hermann, Marcela

    2016-08-01

    Apolipoprotein O (ApoO) is a recently discovered plasma apolipoprotein that may also play a role in the mitochondrial inner membrane. Possibly due to this complexity, its physiological functions have not been elucidated yet. To gain insight from a non-mammalian experimental system, we have investigated the regulation of ApoO levels in an alternative, well-suited model for studies on lipid metabolism, the chicken. qPCR using specific primer pairs and Western blot analysis with our rabbit anti-chicken ApoO antiserum demonstrated ApoO in the liver of chickens fed a control or a fat-enriched diet, as well as in 2 chicken hepatoma cell lines, LMH cells and the estrogen-responsive LMH-2A cells, under conditions of lipid loading by incubation with BSA-complexed oleic acid. Induced triglyceride accumulation in both the liver and the hepatic cells was associated with significantly increased levels of ApoO mRNA and protein. Furthermore, upon treatment for 24 h with estrogen of the estrogen receptor-expressing LMH-2A cells, quantitative analysis of ApoO transcripts and Western blotting revealed increases of ApoO expression. Finally, upon a single administration of estrogen to roosters that leads to hyperlipidemia, higher hepatic levels of both ApoO transcript and protein were observed within 24 h. Based on these data, we propose that hepatic expression of ApoO is tightly linked not only to diet-induced hepatosteatosis, but also to increased lipoprotein-production induced by, e.g., hormones. The findings support a role of ApoO as an effector of compromised mitochondrial function that likely accompanies the onset of non-alcoholic fatty liver disease. PMID:27126072

  15. Assays for endocrine-disrupting chemicals: Beyond environmental estrogens

    SciTech Connect

    Folmar, L.C.

    1999-07-01

    Recent popular and scientific articles have reported the presence of estrogenic and other hormone mimicking chemicals in the environment and their potential for causing reproductive dysfunction in humans and wildlife. The purpose of this session was to present the best available, if not standard, analytical methods to assay for the effects of xenobiotic chemicals on a broad range of endocrine-mediated events, including reproduction, growth, development and stress responses in aquatic vertebrate and invertebrate animals.

  16. [Estrogenic activity of ultraviolet absorbers and the related compounds].

    PubMed

    Matsumoto, Hisashi; Adachi, Shinichi; Suzuki, Yasuhiko

    2005-08-01

    The estrogenic activities of ultraviolet absorbers and their related compounds were investigated using MCF-7 cell proliferation assay. Nine of 33 chemicals (benzophenone, 2,4-dihydroxybenzophenone, 2,2',4,4'-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 4-hydroxybenzophenone, 3-(4-methylbenzylidene) camphor, ethyl 2-cyano-3,3-diphenylacrylate (etocrylene) and 2-ethylhexyl-2-cyano-3,3-diphenylacrylate (octocrylene)) were positive compared with the vehicle control. Benzhydrol, ethyl cinnamate and 2,2'-dihydroxy-4-methoxybenzophenone were weakly active. When each xenoestrogen was added to the cells along with ICI 182780, an estrogen receptor (ER) antagonist, the cell growth was reduced according to its doses. Therefore, the cell proliferation was suggested to generate through ER. Most of these chemicals were also positive using CHOOSER assay, a new method of testing estrogenic activity of xenoestrogen. Each xenoestrogen was also confirmed to bind to ERalpha and ERbeta using a human ER competitive binding assay against 17beta-estradiol. The concentration order of the strength of its inhibitory effect using both ERalpha and ERbeta was similar to that of MCF-7 cell proliferation assay, except for benzyl 4-hydroxybenzoate (B4HB). B4HB showed a stronger activity on CHOOSER assay and the competitive binding assay using both ERalpha and ERbeta, although there was no activity observed on MCF-7 cell proliferation assay. Our findings were to detect the estrogenic activity of etocrylene and octocrylene in vitro, in addition to confirming the activities of some ultraviolet absorbers as previously reported. PMID:16079615

  17. Estrogen maintains myometrial tumors in a lymphangioleiomyomatosis model.

    PubMed

    Prizant, Hen; Taya, Manisha; Lerman, Irina; Light, Allison; Sen, Aritro; Mitra, Soumya; Foster, Thomas H; Hammes, Stephen R

    2016-04-01

    Lymphangioleiomyomatosis (LAM) is a rare disease in women. Patients with LAM develop metastatic smooth-muscle cell adenomas within the lungs, resulting in reduced pulmonary function. LAM cells contain mutations in tuberous sclerosis genes (TSC1 or TSC2), leading to up-regulation of mTORC1 activity and elevated proliferation. The origin of LAM cells remains unknown; however, inactivation of Tsc2 gene in the mouse uterus resulted in myometrial tumors exhibiting LAM features, and approximately 50% of animals developed metastatic myometrial lung tumors. This suggests that LAM tumors might originate from the uterine myometrium, possibly explaining the overwhelming prevalence of LAM in female. Here, we demonstrate that mouse Tsc2-null myometrial tumors exhibit nearly all the features of LAM, including mTORC1/S6K activation, as well as expression of melanocytic markers and matrix metalloproteinases (MMPs). Estrogen ablation reduces S6K signaling and results in Tsc2-null myometrial tumor regression. Thus, even without TSC2, estradiol is required to maintain tumors and mTORC1/S6K signaling. Additionally, we find that MMP-2 and -9, as well as neutrophil elastase (NE), are overexpressed in Tsc2-null myometrial tumors in an estrogen-dependent fashion. In vivo fluorescent imaging using MMP- or NE-sensitive optical biomarkers confirms that protease activity is specific to myometrial tumors. Similar to LAM cells, uterine Tsc2-null myometrial cells also overexpress melanocytic markers in an estrogen-dependent fashion. Finally, we identify glycoprotein NMB (GPNMB) as a melanocytic marker up-regulated in Tsc2-null mouse uteri and human LAM samples. Our data highlight the potential importance of estradiol in LAM cells, suggesting that anti-estrogen therapy may be a treatment modality. Furthermore, proteases and GPNMB might be useful LAM biomarkers. PMID:26880751

  18. Estrogen receptor independent neurotoxic mechanism of bisphenol A, an environmental estrogen

    PubMed Central

    Lee, Yoot Mo; Seong, Min Jae; Lee, Jae Woong; Lee, Yong Kyung; Kim, Tae Myoung; Nam, Sang-Yoon; Kim, Dae Joong; Yun, Young Won; Kim, Tae Seong; Han, Soon Young

    2007-01-01

    Bisphenol A (BPA), a ubiquitous environmental contaminant, has been shown to cause developmental toxicity and carcinogenic effects. BPA may have physiological activity through estrogen receptor (ER) -α and -β, which are expressed in the central nervous system. We previously found that exposure of BPA to immature mice resulted in behavioral alternation, suggesting that overexposure of BPA could be neurotoxic. In this study, we further investigated the molecular neurotoxic mechanisms of BPA. BPA increased vulnerability (decrease of cell viability and differentiation, and increase of apoptotic cell death) of undifferentiated PC12 cells and cortical neuronal cells isolated from gestation 18 day rat embryos in a concentration-dependent manner (more than 50 µM). The ER antagonists, ICI 182,780, and tamoxifen, did not block these effects. The cell vulnerability against BPA was not significantly different in the PC12 cells overexpressing ER-α and ER-β compared with PC12 cells expressing vector alone. In addition, there was no difference observed between BPA and 17-β estradiol, a well-known agonist of ER receptor in the induction of neurotoxic responses. Further study of the mechanism showed that BPA significantly activated extracellular signal-regulated kinase (ERK) but inhibited anti-apoptotic nuclear factor kappa B (NF-κB) activation. In addition, ERK-specific inhibitor, PD 98,059, reversed BPA-induced cell death and restored NF-κB activity. This study demonstrated that exposure to BPA can cause neuronal cell death which may eventually be related with behavioral alternation in vivo. However, this neurotoxic effect may not be directly mediated through an ER receptor, as an ERK/NF-κB pathway may be more closely involved in BPA-induced neuronal toxicity. PMID:17322771

  19. Estrogen: A master regulator of bioenergetic systems in the brain and body

    PubMed Central

    Rettberg, Jamaica R; Yao, Jia; Brinton, Roberta Diaz

    2014-01-01

    Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer’s disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral metabolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as indicators of efficacy of hormone therapy or other preventative interventions. PMID:23994581

  20. Inducibility of the avidin gene by progesterone is suppressed during estrogen-induced cytodifferentiation.

    PubMed

    Joensuu, T; Niemelä, A; Kunnas, T; Salomaa, S; Alho, H; Vilja, P; Ylikomi, T; Kulomaa, M; Tuohimaa, P

    1992-12-01

    We have studied epithelial differentiation of the chick oviduct as induced by diethylstilbestrol (DES) and 17 beta-estradiol (E2). The proportion of goblet cells in the oviduct was slightly higher after E2 than after DES treatment. Also avidin induction by progesterone was stronger following DES than E2 priming. In the estrogen pretreated oviduct epithelium, avidin expression was induced by progesterone in the surface epithelial cells, protodifferentiated gland cells and tubular gland cells, but not in goblet cells. During prolonged estrogen treatment, however, the inducibility of avidin by progesterone ceased in tubular gland cells but not in surface epithelial cells. The estrogen action on the expression of avidin could be explained by estrogen-induced terminal differentiation of the epithelial gland cells or by a direct effect of estrogen on the progesterone action, for instance interaction of estrogen receptor and progesterone receptor in the regulation of transcription. PMID:1472452

  1. Expression of estrogen and progesterone receptors in astrocytomas: a literature review.

    PubMed

    Tavares, Cléciton Braga; Gomes-Braga, Francisca das Chagas Sheyla Almeida; Costa-Silva, Danylo Rafhael; Escórcio-Dourado, Carla Solange; Borges, Umbelina Soares; Conde-Junior, Airton Mendes; Barros-Oliveira, Maria da Conceição; Sousa, Emerson Brandão; Barros, Lorena da Rocha; Martins, Luana Mota; Facina, Gil; da-Silva, Benedito Borges

    2016-08-01

    Gliomas are the most common type of primary central nervous system neoplasm. Astrocytomas are the most prevalent type of glioma and these tumors may be influenced by sex steroid hormones. A literature review for the presence of estrogen and progesterone receptors in astrocytomas was conducted in the PubMed database using the following MeSH terms: "estrogen receptor beta" OR "estrogen receptor alpha" OR "estrogen receptor antagonists" OR "progesterone receptors" OR "astrocytoma" OR "glioma" OR "glioblastoma". Among the 111 articles identified, 13 studies met our inclusion criteria. The majority of reports showed the presence of estrogen and progesterone receptors in astrocytomas. Overall, higher tumor grades were associated with decreased estrogen receptor expression and increased progesterone receptor expression. PMID:27626480

  2. Expression of estrogen-related receptor gamma (ERRgamma) in human skin.

    PubMed

    Krahn-Bertil, Elodie; Bolzinger, Marie-Alexandrine; Andre, Valérie; Orly, Isabelle; Kanitakis, Jean; Rousselle, Patricia; Damour, Odile

    2008-01-01

    Skin is a non-classical target for estrogens. Despite evidence showing that estrogen receptors (ER) are expressed in skin, there are still extensive gaps in our understanding of how estrogens exert their action in non-reproductive tissues. Estrogen-related receptor gamma (ERRgamma), an orphan member of the nuclear receptor superfamily, shows a strong sequence homology with estrogen receptor alpha but it does not bind estradiol. Here, for the first time, we demonstrate the expression of ERRgamma in adult human skin. ERRgamma mRNA was detected in the keratinocytes and fibroblasts of 8 female donor skins using RT-PCR. The presence of the protein was confirmed using immunohistochemistry on 11 adult human skins and Western Blotting on monolayer-cultures of fibroblasts and keratinocytes from respectively 4 and 2 donors. This study shows that ERRgamma is expressed in human skin and could intervene in a potentially new estrogen signaling pathway in the skin. PMID:18573717

  3. Colocalization of Estrogen Receptors with the Fluorescent Tamoxifen Derivative, FLTX1, Analyzed by Confocal Microscopy.

    PubMed

    Morales, Araceli; Marín, Raquel; Marrero-Alonso, Jorge; Boto, Alicia; Díaz, Mario

    2016-01-01

    Tamoxifen is a selective estrogen receptor modulator that competitively binds the ligand-binding domain of estrogen receptors. Binding of tamoxifen displaces its cognate ligand, 17β-estradiol, thereby hampering the activation of estrogen receptors. Cellular labeling of ER is typically carried out using specific antibodies which require permeabilization of cells, incubation with secondary antibodies, and are expensive and time consuming. In this article, we describe the usefulness of FLTX1, a novel fluorescent tamoxifen derivative, which allows the labeling of estrogen receptors in immunocytochemistry and immunohistochemistry studies, both under permeabilized and non-permeabilized conditions. Further, besides labeling canonical estrogen receptors, this novel fluorescent probe is also suitable for the identification of unconventional targets such membrane estrogen receptors as well as other noncanonical targets, some of which are likely responsible for the number of undesired side effects reported during long-term tamoxifen treatments. PMID:26585134

  4. Expression of estrogen and progesterone receptors in astrocytomas: a literature review

    PubMed Central

    Tavares, Cléciton Braga; Gomes-Braga, Francisca das Chagas Sheyla Almeida; Costa-Silva, Danylo Rafhael; Escórcio-Dourado, Carla Solange; Borges, Umbelina Soares; Conde, Airton Mendes; da Conceição Barros-Oliveira, Maria; Sousa, Emerson Brandão; da Rocha Barros, Lorena; Martins, Luana Mota; Facina, Gil; da-Silva, Benedito Borges

    2016-01-01

    Gliomas are the most common type of primary central nervous system neoplasm. Astrocytomas are the most prevalent type of glioma and these tumors may be influenced by sex steroid hormones. A literature review for the presence of estrogen and progesterone receptors in astrocytomas was conducted in the PubMed database using the following MeSH terms: “estrogen receptor beta” OR “estrogen receptor alpha” OR “estrogen receptor antagonists” OR “progesterone receptors” OR “astrocytoma” OR “glioma” OR “glioblastoma”. Among the 111 articles identified, 13 studies met our inclusion criteria. The majority of reports showed the presence of estrogen and progesterone receptors in astrocytomas. Overall, higher tumor grades were associated with decreased estrogen receptor expression and increased progesterone receptor expression.

  5. Selective chromatographic fractionation of catechol estrogens on anion exchangers in borate form.

    PubMed

    Fotsis, T; Heikkinen, R

    1983-03-01

    The borate form of anion exchangers has been investigated for its utility in the field of estrogen analysis. The borate form of a weak (DEAE-Sephadex A-25) and a strong (QAE-Sephadex A-25) anion exchanger was easily prepared by appropriate washing of the gels, without the need of time consuming immobilization techniques. Estrogens with vicinal cis-hydroxyls were strongly retained in both gels through formation of borate complexes and readily separated from estrogens not possessing such groups. Moreover, borate complex formation with the labile o-dihydroxyphenyl moiety of catechol estrogens fully protected them from decomposition during chromatography. Quantitative recovery of catechol estrogens was thereby obtained without use of antioxidants. The borate form of QAE-Sephadex A-25 was capable, in addition, of separating estrogens not possessing vicinal cis-hydroxyls from the corresponding neutral steroids. PMID:6298506

  6. Modulation of Estrogen Chemical Carcinogenesis by Botanical Supplements used for Postmenopausal Women’s Health

    PubMed Central

    Snelten, Courtney S.; Dietz, Birgit; Bolton, Judy L.

    2012-01-01

    Breast cancer risk has been associated with long-term estrogen exposure including traditional hormone therapy (HT, formally hormone replacement therapy). To avoid traditional HT and associated risks, women have been turning to botanical supplements such as black cohosh, red clover, licorice, hops, dong gui, and ginger to relieve menopausal symptoms despite a lack of efficacy evidence. The mechanisms of estrogen carcinogenesis involve both hormonal and chemical pathways. Botanical supplements could protect women from estrogen carcinogenesis by modulating key enzymatic steps [aromatase, P4501B1, P4501A1, catechol-O-methyltransferase (COMT), NAD(P)H quinone oxidoreductase 1 (NQO1), and reactive oxygen species (ROS) scavenging] in estradiol metabolism leading to estrogen carcinogenesis as outlined in Figure 1. This review summarizes the influence of popular botanical supplements used for women’s health on these key steps in the estrogen chemical carcinogenesis pathway, and suggests that botanical supplements may have added chemopreventive benefits by modulating estrogen metabolism. PMID:24223609

  7. Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription.

    PubMed

    Halachmi, S; Marden, E; Martin, G; MacKay, H; Abbondanza, C; Brown, M

    1994-06-01

    The estrogen receptor is a transcription factor which, when bound to estradiol, binds DNA and regulates expression of estrogen-responsive genes. A 160-kilodalton estrogen receptor-associated protein, ERAP160, was identified that exhibits estradiol-dependent binding to the receptor. Mutational analysis of the receptor shows that its ability to activate transcription parallels its ability to bind ERAP160. Antiestrogens are unable to promote ERAP160 binding and can block the estrogen-dependent interaction of the receptor and ERAP160 in a dose-dependent manner. This evidence suggests that ERAP160 may mediate estradiol-dependent transcriptional activation by the estrogen receptor. Furthermore, the ability of antiestrogens to block estrogen receptor-ERAP160 complex formation could account for their therapeutic effects in breast cancer. PMID:8197458

  8. Occurrence and removal of estrogens in Brazilian wastewater treatment plants.

    PubMed

    Pessoa, Germana P; de Souza, Neyliane C; Vidal, Carla B; Alves, Joana A C; Firmino, Paulo Igor M; Nascimento, Ronaldo F; dos Santos, André B

    2014-08-15

    This paper evaluated the occurrence and removal efficiency of four estrogenic hormones in five biological wastewater treatment plants (WWTPs), located in the State of Ceará, Brazil. The five WWTPs comprised: two systems consisted of one facultative pond followed by two maturation ponds, one facultative pond, one activated sludge (AS) system followed by a chlorination step, and one upflow anaerobic sludge blanket (UASB) reactor followed by a chlorination step. Estrogen occurrence showed a wide variation among the analyzed influent and effluent samples. Estrone (E1) showed the highest occurrence in the influent (76%), whereas both 17β-estradiol (E2) and 17α-ethynylestradiol (EE2) presented a 52% occurrence, and the compound 17β-estradiol 17-acetate (E2-17A), a 32% one. The occurrence in the effluent samples was 48% for E1, 28% for E2, 12% for E2-17A, and 40% for EE2. The highest concentrations of E1 and EE2 hormones in the influent were 3050 and 3180 ng L(-1), respectively, whereas E2 and E2-17A had maximum concentrations of 776 and 2300 ng L(-1), respectively. The lowest efficiencies for the removal of estrogenic hormones were found in WWTP consisted of waste stabilization ponds, ranging from 54 to 79.9%. The high-rate systems (AS and UASB), which have chlorination as post-treatment, presented removal efficiencies of approximately 95%. PMID:24858226

  9. Molecular Background of Estrogen Receptor Gene Expression in Endometriotic Cells.

    PubMed

    Izawa, Masao; Taniguchi, Fuminori; Harada, Tasuku

    2016-07-01

    The molecular background of estrogen receptor (ER) expression is important to understand the pathophysiology of the high estrogen environment in endometriosis. However, the molecular details have not been fully understood. The objective of this study is to evaluate the molecular background of ERα and ERβ messenger RNA (mRNA) expression in endometriotic cells. The following summarizes our observations: (1) ERα mRNA expression in endometriotic cells was estimated to be approximately one-tenth of that in endometrial cells. (2) Three mRNAs, which include 3 different 5'-untranslated exons tagged to an open reading frame of wild-type ERα, were detected. (3) Expression of ERβ mRNA depends mostly on 0N promoter and includes 2 open reading frames: one for a wild-type ERβ1 and another for a splice variant ERβ2. (4) Expression of ERβ1 mRNA was approximately 40-fold higher than that in endometrial cells. (5) Expression of ERβ2 mRNA was almost at a comparable level of the ERβ1. 9 (6) ERα and ERβ mRNAs are equivalently expressed in endometriotic cells. These observations show the molecular background of ER mRNA expression in endometriotic cells and provide a clue to further understanding the estrogen-dependent pathophysiology leading to clinical application in endometriosis. PMID:26704524

  10. Estrogen replacement therapy (ERT) in high-risk cancer patients.

    PubMed Central

    Hutchinson-Williams, K. A.; Gutmann, J. N.

    1991-01-01

    Menopausal estrogens are now being prescribed not only for symptom relief, but also to prevent the long-term sequelae of estrogen deficiency, namely osteoporosis and atherosclerotic disease. The well-established association between endometrial cancer and estrogen replacement therapy (ERT) has become less of a clinical concern due to the recognition of the protective effect of progestogens in this setting. A small literature has emerged suggesting that extending ERT to the woman with a history of endometrial carcinoma imposes no increased risk of recurrence and may improve survival. Candidates for ERT should be women with a better prognostic profile with reference to their cancer. The relationship between ERT and breast cancer remains a topic of intense debate and investigation. Overall, the current literature finds no significant increase in risk among healthy women without a family history of breast cancer. There are no guidelines with reference to the woman with a history of breast cancer and the use of ERT. The most prudent approach with this population is to consider alternative treatments until more is known. PMID:1810102

  11. The ventromedial hypothalamus oxytocin induces locomotor behavior regulated by estrogen.

    PubMed

    Narita, Kazumi; Murata, Takuya; Matsuoka, Satoshi

    2016-10-01

    Our previous studies demonstrated that excitation of neurons in the rat ventromedial hypothalamus (VMH) induced locomotor activity. An oxytocin receptor (Oxtr) exists in the VMH and plays a role in regulating sexual behavior. However, the role of Oxtr in the VMH in locomotor activity is not clear. In this study we examined the roles of oxytocin in the VMH in running behavior, and also investigated the involvement of estrogen in this behavioral change. Microinjection of oxytocin into the VMH induced a dose-dependent increase in the running behavior in male rats. The oxytocin-induced running activity was inhibited by simultaneous injection of Oxtr-antagonist, (d(CH2)5(1), Try(Me)(2), Orn(8))-oxytocin. Oxytocin injection also induced running behavior in ovariectomized (OVX) female rats. Pretreatment of the OVX rats with estrogen augmented the oxytocin-induced running activity twofold, and increased the Oxtr mRNA in the VMH threefold. During the estrus cycle locomotor activity spontaneously increased in the dark period of proestrus. The Oxtr mRNA was up-regulated in the proestrus afternoon. Blockade of oxytocin neurotransmission by its antagonist before the onset of the dark period of proestrus decreased the following nocturnal locomotor activity. These findings demonstrate that Oxtr in the VMH is involved in the induction of running behavior and that estrogen facilitates this effect by means of Oxtr up-regulation, suggesting the involvement of oxytocin in the locomotor activity of proestrus female rats. PMID:27237044

  12. Circulating Hepcidin-25 Is Reduced by Endogenous Estrogen in Humans

    PubMed Central

    Lehtihet, Mikael; Bonde, Ylva; Beckman, Lena; Berinder, Katarina; Hoybye, Charlotte; Rudling, Mats; Sloan, John H.; Konrad, Robert J.; Angelin, Bo

    2016-01-01

    Objective Hepcidin reduces iron absorption by binding to the intestinal iron transporter ferroportin, thereby causing its degradation. Although short-term administration of testosterone or growth hormone (GH) has been reported to decrease circulating hepcidin levels, little is known about how hepcidin is influenced in human endocrine conditions associated with anemia. Research design and methods We used a sensitive and specific dual–monoclonal antibody sandwich immunoassay to measure hepcidin-25 in patients (a) during initiation of in vitro fertilization when endogenous estrogens were elevated vs. suppressed, (b) with GH deficiency before and after 12 months substitution treatment, (c) with hyperthyroidism before and after normalization, and (d) with hyperprolactinemia before and after six months of treatment with a dopamine agonist. Results In response to a marked stimulation of endogenous estrogen production, median hepcidin levels decreased from 4.85 to 1.43 ng/mL (p < 0.01). Hyperthyroidism, hyperprolactinemia, or GH substitution to GH-deficient patients did not influence serum hepcidin-25 levels. Conclusions In humans, gonadotropin-stimulated endogenous estrogen markedly decreases circulating hepcidin-25 levels. No clear and stable correlation between iron biomarkers and hepcidin-25 was seen before or after treatment of hyperthyroidism, hyperprolactinemia or growth hormone deficiency. PMID:26866603

  13. New thoughts about estrogen therapy from the Women's Health Initiative.

    PubMed

    Ko, Marcia Gene

    2008-09-01

    Since the introduction of hormone replacement therapy (HRT) in 1942, the availability of scientific information regarding the physiologic action of estrogen alone and in combination with progesterone has grown substantially. The specific physiology of changes in endogenous estrogen as a causal factor in bone loss that occurs as the result of menopause is now better understood. Accumulating evidence regarding the benefit of estrogen in protecting against bone loss at the time of menopause made it the first choice for prevention and treatment of osteoporosis, until the findings of the Women's Health Initiative (WHI) were announced in 2002. Fortunately, the availability of multiple alternative agents for prevention and treatment of osteoporosis in menopausal women has provided clinicians with other options. There remain a small number of patients who cannot tolerate or afford these alternative therapies. Recent publications resulting from the WHI should be understood by practicing physicians who are faced with this dilemma and may need to consider HRT in treating patients with osteoporosis. PMID:18752772

  14. Suburbanization, estrogen contamination, and sex ratio in wild amphibian populations.

    PubMed

    Lambert, Max R; Giller, Geoffrey S J; Barber, Larry B; Fitzgerald, Kevin C; Skelly, David K

    2015-09-22

    Research on endocrine disruption in frog populations, such as shifts in sex ratios and feminization of males, has predominantly focused on agricultural pesticides. Recent evidence suggests that suburban landscapes harbor amphibian populations exhibiting similar levels of endocrine disruption; however the endocrine disrupting chemical (EDC) sources are unknown. Here, we show that sex ratios of metamorphosing frogs become increasingly female-dominated along a suburbanization gradient. We further show that suburban ponds are frequently contaminated by the classical estrogen estrone and a variety of EDCs produced by plants (phytoestrogens), and that the diversity of organic EDCs is correlated with the extent of developed land use and cultivated lawn and gardens around a pond. Our work also raises the possibility that trace-element contamination associated with human land use around suburban ponds may be contributing to the estrogenic load within suburban freshwaters and constitutes another source of estrogenic exposure for wildlife. These data suggest novel, unexplored pathways of EDC contamination in human-altered environments. In particular, we propose that vegetation changes associated with suburban neighborhoods (e.g., from forests to lawns and ornamental plants) increase the distribution of phytoestrogens in surface waters. The result of frog sex ratios varying as a function of human land use implicates a role for environmental modulation of sexual differentiation in amphibians, which are assumed to only have genetic sex determination. Overall, we show that endocrine disruption is widespread in suburban frog populations and that the causes are likely diverse. PMID:26372955

  15. Anti-Estrogen Withdrawal Effect With Raloxifene? A Case Report.

    PubMed

    Lemmo, Walter

    2016-09-01

    A 66-year-old patient presented with acute recurrent metastatic estrogen and progesterone receptor-positive, Her-2/neu-negative breast cancer, bone lesions (lumbar spine, pelvis), pulmonary nodules, hepatic metastasis, elevated cancer antigen 15 and liver enzymes, dyspepsia, and diarrhea. The patient had been taking raloxifene for approximately 8 years. After discontinuation, clinical parameters and symptoms improved rapidly without oncological therapy or other forms of treatment. Three months after raloxifene discontinuation, capecitabine was initiated by the treating oncologist who deemed an anti-estrogen withdrawal effect (AEWE) implausible. However, the lasting regression was more indicative of a raloxifene rebound effect than chemotherapy or other interventions. Today, the patient is asymptomatic with a good performance status. Hepatic metastatic regression has been confirmed, without any oncological treatment administered in the past 16 months and approximately 23 months following the withdrawal of raloxifene. This case highlights the need to screen breast cancer patients for the possibility of an AEWE if they are using raloxifene and possibly similar selective estrogen receptor modulators (SERMs) which includes tamoxifen, when diagnosed with advanced breast cancer, especially in the recurrent disease setting. PMID:27411856

  16. Splice isoform estrogen receptors as integral transmembrane proteins

    PubMed Central

    Kim, Kyung Hee; Toomre, Derek; Bender, Jeffrey R.

    2011-01-01

    In addition to enhancing or repressing transcription, steroid hormone receptors rapidly transduce kinase activation signals. On ligand engagement, an N-terminus–truncated splice isoform of estrogen receptor (ER) α, ER46, triggers membrane-initiated signals, resulting in endothelial nitric oxide synthase (eNOS) activation and endothelial NO production. The orientation of ER46 at the plasma membrane is incompletely defined. With the use of ecliptic pHluorin-fused ER46, total internal reflection fluorescence microscopy in live human endothelial cells illustrates that ER46 can topologically conform to a type I transmembrane protein structure. Mutation of isoleucine-386 at the center of ER46's transmembrane hydrophobic core prevents membrane spanning, obscures the N-terminal ectodomain, and effects a marked reduction in membrane-impermeant estrogen binding with diminished rapid eNOS activation and NO production, despite maintained genomic induction of an estrogen response element–luciferase reporter. Thus there exist pools of transmembrane steroid hormone receptors that are efficient signaling molecules and potential novel therapeutic targets. PMID:21937726

  17. Multiple estrogen receptor subtypes influence ingestive behavior in female rodents.

    PubMed

    Santollo, Jessica; Daniels, Derek

    2015-12-01

    Postmenopausal women are at an increased risk of obesity and cardiovascular-related diseases. This is attributable, at least in part, to loss of the ovarian hormone estradiol, which inhibits food and fluid intake in humans and laboratory animal models. Although the hypophagic and anti-dipsogenic effects of estradiol have been well documented for decades, the precise mechanisms underlying these effects are not fully understood. An obvious step toward addressing this open question is identifying which estrogen receptor subtypes are involved and what intracellular processes are involved. This question, however, is complicated not only by the variety of estrogen receptor subtypes that exist, but also because many subtypes have multiple locations of action (i.e. in the nucleus or in the plasma membrane). This review will highlight our current understanding of the roles that specific estrogen receptor subtypes play in mediating estradiol's anorexigenic and anti-dipsogenic effects along with highlighting the many open questions that remain. This review will also describe recent work being performed by our laboratory aimed at answering these open questions. PMID:26037634

  18. The SEEM: selective estrogen enzyme modulators in breast cancer.

    PubMed

    Pasqualini, J R; Ebert, C; Chetrite, G S

    1999-12-01

    Human breast cancer tissue contains all the enzymes (estrone sulfatase, 17 beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol biosynthesis. This tissue also contains sulfotransferase for the formation of the biologically inactive estrogen sulfates. In the past years, it has been demonstrated that various progestins (promegestone, nomegestrol acetate, medrogestone) as well as tibolone and its metabolites are potent inhibitors of sulfatase and 17 beta-hydroxysteroid dehydrogenase activities. It was also shown that medrogestone, nomegestrol acetate, promegestone or tibolone can stimulate the sulfotransferase activity for the local production of estrogen sulfates. All these data, in addition to numerous agents which can block the aromatase action, lead to the new concept of Selective Estrogen Enzyme Modulators (SEEM) which can largely apply to breast cancer tissue. The exploration of various progestins and other active agents in trials with breast cancer patients, showing an inhibitory effect on sulfatase and 17 beta-hydroxysteroid dehydrogenase, or a stimulatory effect on sulfotransferase, will provide a new option in the treatment of this disease. PMID:10862262

  19. The selective estrogen enzyme modulator (SEEM) in breast cancer.

    PubMed

    Chetrite, G S; Pasqualini, J R

    2001-01-01

    Human breast cancer tissue contains all the enzymes (estrone sulfatase, 17beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol biosynthesis. This tissue also contains sulfotransferase for the formation of the biologically inactive estrogen sulfates. In the last years, it was demonstrated that various progestins (promegestone, nomegestrol acetate, medrogestone), as well as tibolone and its metabolites are potent inhibitors of sulfatase and 17beta-hydroxysteroid dehydrogenase activities. It was also shown that medrogestone, nomegestrol acetate, promegestone or tibolone can stimulate the sulfotransferase activity for the local production of estrogen sulfates. All these data, in addition to numerous agents, which can block the aromatase action, lead to the new concept of selective estrogen enzyme modulators (SEEM), which can largely apply to breast cancer tissue. The exploration of various progestins and other active agents in trials with breast cancer patients, showing an inhibitory effect on sulfatase and 17beta-hydroxysteroid dehydrogenase, or a stimulatory effect on sulfotransferase, will provide a new possibility in the treatment of this disease. PMID:11384867

  20. Intravenous estrogens increase insulin clearance and action in postmenopausal women

    PubMed Central

    Van Pelt, R. E.; Gozansky, W. S.; Schwartz, R. S.; Kohrt, W. M.

    2010-01-01

    To test the hypothesis that estrogens alter insulin action, we evaluated the effects of intravenous conjugated estrogens (CE) on insulin-stimulated steady-state glucose infusion rate (SSGIR) and suppression of plasma glycerol in postmenopausal women (mean ± SD; 56 ± 4 yr; n = 12) not using hormone replacement. SSGIR and glycerol were measured during a two-stage (8 and 40 mU · m−2· min−1) hyperinsulinemic euglycemic clamp on 2 days, with or without a 2.5-mg intravenous CE bolus. Serum estradiol concentrations were increased ~200% on the estrogen (EST) compared with the control (CON) days. Serum insulin was reduced (P < 0.01) during stage 2 of the clamp for EST (63.3 ± 12.8 μU/ml) vs. CON (78.2 ± 15.8 μU/ml). Mean SSGIR and plasma glycerol did not differ between CON and EST days. With adjustment for differences in insulin concentration between conditions, stage 2 glucose disposals were significantly higher (8.63 vs. 7.20 mg · kg−1 · min−1) and plasma glycerol concentrations were significantly lower (29.4 vs. 35.0 μmol/l) for EST vs. CON. Our findings suggest that acute CE administration increases insulin clearance and action in postmenopausal women. PMID:12684221

  1. G Protein-coupled Estrogen Receptor Protects from Atherosclerosis

    PubMed Central

    Meyer, Matthias R.; Fredette, Natalie C.; Howard, Tamara A.; Hu, Chelin; Ramesh, Chinnasamy; Daniel, Christoph; Amann, Kerstin; Arterburn, Jeffrey B.; Barton, Matthias; Prossnitz, Eric R.

    2014-01-01

    Coronary atherosclerosis and myocardial infarction in postmenopausal women have been linked to inflammation and reduced nitric oxide (NO) formation. Natural estrogen exerts protective effects on both processes, yet also displays uterotrophic activity. Here, we used genetic and pharmacologic approaches to investigate the role of the G protein-coupled estrogen receptor (GPER) in atherosclerosis. In ovary-intact mice, deletion of gper increased atherosclerosis progression, total and LDL cholesterol levels and inflammation while reducing vascular NO bioactivity, effects that were in some cases aggravated by surgical menopause. In human endothelial cells, GPER was expressed on intracellular membranes and mediated eNOS activation and NO formation, partially accounting for estrogen-mediated effects. Chronic treatment with G-1, a synthetic, highly selective small molecule agonist of GPER, reduced postmenopausal atherosclerosis and inflammation without uterotrophic effects. In summary, this study reveals an atheroprotective function of GPER and introduces selective GPER activation as a novel therapeutic approach to inhibit postmenopausal atherosclerosis and inflammation in the absence of uterotrophic activity. PMID:25532911

  2. Estrogen Modulates Expression of Tight Junction Proteins in Rat Vagina

    PubMed Central

    Oh, Kyung-Jin; Ahn, Kyuyoun

    2016-01-01

    Background. The objectives of this study were to investigate the localization of tight junctions and the modulation of zonula occludens- (ZO-) 1, occludin and claudin-1 expression by estrogen in castrated female rat vagina. Female Sprague-Dawley rats (230–240 g, n = 45) were divided into three groups and subjected to a sham operation (control group, n = 15), bilateral ovariectomy (Ovx group, n = 15), or bilateral ovariectomy followed by daily subcutaneous injection of 17β-estradiol (50 μg/kg/day, Ovx + Est group, n = 15). The cellular localization and expression of ZO-1, occludin, and claudin-1 were determined in each group by immunohistochemistry and western blot. Results. Expression of ZO-1 was diffuse in all groups, with the highest intensity in the superficial epithelium in the control group. Occludin was localized in the intermediate and basal epithelium. Claudin-1 was most intense in the superficial layer of the vaginal epithelium in the control group. Expression of ZO-1, occludin, and claudin-1 was significantly decreased after ovariectomy and was restored to the level of the control after estrogen replacement. Conclusions. Tight junctions are distinctly localized in rat vagina, and estrogen modulates the expression of tight junctions. Further researches are needed to clarify the functional role of tight junctions in vaginal lubrication. PMID:27127786

  3. Suburbanization, estrogen contamination, and sex ratio in wild amphibian populations

    PubMed Central

    Lambert, Max R.; Giller, Geoffrey S. J.; Barber, Larry B.; Fitzgerald, Kevin C.; Skelly, David K.

    2015-01-01

    Research on endocrine disruption in frog populations, such as shifts in sex ratios and feminization of males, has predominantly focused on agricultural pesticides. Recent evidence suggests that suburban landscapes harbor amphibian populations exhibiting similar levels of endocrine disruption; however the endocrine disrupting chemical (EDC) sources are unknown. Here, we show that sex ratios of metamorphosing frogs become increasingly female-dominated along a suburbanization gradient. We further show that suburban ponds are frequently contaminated by the classical estrogen estrone and a variety of EDCs produced by plants (phytoestrogens), and that the diversity of organic EDCs is correlated with the extent of developed land use and cultivated lawn and gardens around a pond. Our work also raises the possibility that trace-element contamination associated with human land use around suburban ponds may be contributing to the estrogenic load within suburban freshwaters and constitutes another source of estrogenic exposure for wildlife. These data suggest novel, unexplored pathways of EDC contamination in human-altered environments. In particular, we propose that vegetation changes associated with suburban neighborhoods (e.g., from forests to lawns and ornamental plants) increase the distribution of phytoestrogens in surface waters. The result of frog sex ratios varying as a function of human land use implicates a role for environmental modulation of sexual differentiation in amphibians, which are assumed to only have genetic sex determination. Overall, we show that endocrine disruption is widespread in suburban frog populations and that the causes are likely diverse. PMID:26372955

  4. Evaluation of the estrogenic effects of dietary perinatal Trifolium pratense

    PubMed Central

    Daglioglu, Suzan

    2011-01-01

    This study was designed to investigate the potential estrogenic effects of perinatal dietary phytoestrogens on the rat uterus. Pregnant rats were divided to three groups provided the following diets: (1) rat chow, (2) rat chow with 7.5% Trifolium (T.) pratense, or (3) rat chow supplemented with 17β-estradiol (0.5 mg/kg). The dams in each group were kept on the same diet during pregnancy and lactation. Female offspring were euthanized on day 21 at which time body and organ weights were recorded and tissue samples were taken for histology. Immunohistochemistry was performed to detect estrogen receptor alpha (ERα) and progesterone receptor (PR) levels. Our results revealed estrogen-like biological effects of perinatal T. pratense exposure. Relative uterus and ovary weights in the experimental groups were increased compared to control. The number of uterine glands and luminal epithelium heights were also increased. However, there were no statistically significant changes detected in the immunostaining intensity of ERα and PR between the groups. PMID:21586870

  5. Social memory associated with estrogen receptor polymorphisms in women.

    PubMed

    Karlsson, Sara; Henningsson, Susanne; Hovey, Daniel; Zettergren, Anna; Jonsson, Lina; Cortes, Diana S; Melke, Jonas; Laukka, Petri; Fischer, Håkan; Westberg, Lars

    2016-06-01

    The ability to recognize the identity of faces and voices is essential for social relationships. Although the heritability of social memory is high, knowledge about the contributing genes is sparse. Since sex differences and rodent studies support an influence of estrogens and androgens on social memory, polymorphisms in the estrogen and androgen receptor genes (ESR1, ESR2, AR) are candidates for this trait. Recognition of faces and vocal sounds, separately and combined, was investigated in 490 subjects, genotyped for 10 single nucleotide polymorphisms (SNPs) in ESR1, four in ESR2 and one in the AR Four of the associations survived correction for multiple testing: women carrying rare alleles of the three ESR2 SNPs, rs928554, rs1271572 and rs1256030, in linkage disequilibrium with each other, displayed superior face recognition compared with non-carriers. Furthermore, the uncommon genotype of the ESR1 SNP rs2504063 was associated with better recognition of identity through vocal sounds, also specifically in women. This study demonstrates evidence for associations in women between face recognition and variation in ESR2, and recognition of identity through vocal sounds and variation in ESR1. These results suggest that estrogen receptors may regulate social memory function in humans, in line with what has previously been established in mice. PMID:26955855

  6. DHEA metabolites activate estrogen receptors alpha and beta

    PubMed Central

    Michael Miller, Kristy K.; Al-Rayyan, Numan; Ivanova, Margarita M.; Mattingly, Kathleen A.; Ripp, Sharon L.; Klinge, Carolyn M.; Prough, Russell A.

    2012-01-01

    Dehydroepiandrosterone (DHEA) levels were reported to associate with increased breast cancer risk in postmenopausal women, but some carcinogen-induced rat mammary tumor studies question this claim. The purpose of this study was to determine how DHEA and its metabolites affect estrogen receptors α or β (ERα or ERβ) -regulated gene transcription and cell proliferation. In transiently transfected HEK-293 cells, androstenediol, DHEA, and DHEA-S activated ERα. In ERβ transfected HepG2 cells, androstenedione, DHEA, androstenediol, and 7-oxo DHEA stimulated reporter activity. ER antagonists ICI 182,780 (fulvestrant) and 4-hydroxytamoxifen, general P450 inhibitor miconazole, and aromatase inhibitor exemestane inhibited activation by DHEA or metabolites in transfected cells. ERβ-selective antagonist R,R-THC (R,R-cis-diethyl tetrahydrochrysene) inhibited DHEA and DHEA metabolite transcriptional activity in ERβ-transfected cells. Expression of endogenous estrogen-regulated genes: pS2, progesterone receptor, cathepsin D1, and nuclear respiratory factor-1 was increased by DHEA and its metabolites in an ER-subtype, gene, and cell-specific manner. DHEA metabolites, but not DHEA, competed with 17β-estradiol for ERα and ERβ binding and stimulated MCF-7 cell proliferation, demonstrating that DHEA metabolites interact directly with ERα and ERβ in vitro, modulating estrogen target genes in vivo. PMID:23123738

  7. Pancreatic Insulin Content Regulation by the Estrogen Receptor ERα

    PubMed Central

    Alonso-Magdalena, Paloma; Ropero, Ana B.; Carrera, M. Pilar; Cederroth, Christopher R.; Baquié, Mathurin; Gauthier, Benoit R.; Nef, Serge; Stefani, Enrico; Nadal, Angel

    2008-01-01

    The function of pancreatic β-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ERα and ERβ, are important molecules involved in glucose metabolism, yet their role in pancreatic β-cell physiology is still greatly unknown. In this report we show that both ERα and ERβ are present in pancreatic β-cells. Long term exposure to physiological concentrations of 17β-estradiol (E2) increased β-cell insulin content, insulin gene expression and insulin release, yet pancreatic β-cell mass was unaltered. The up-regulation of pancreatic β-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA). The use of ERα and ERβ agonists as well as ERαKO and ERβKO mice suggests that the estrogen receptor involved is ERα. The up-regulation of pancreatic insulin content by ERα activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis. PMID:18446233

  8. The Spectroscopic Study of Estrogen and its Hydrated Clusters in a Super Sonic Jet

    NASA Astrophysics Data System (ADS)

    Morishima, Fumiya; Inokuchi, Yoshiya; Ebata, Takayuki

    2012-06-01

    Structures of estrogen and its hydrated clusters have been studied by several laser spectroscopies in supersonic jet. The electronic spectrum of estrogen shows several origin bands. By observing UV-UV hole-burning and IR-UV spectra, it is concluded they are due to different conformers originating from difference of orientation of OH group(s). We also observed electronic and IR spectra of estrogen-H_2O. By aids of DFT calculations, the conformations and hydrated structures are determined.

  9. [Effects and side effects of estrogens and gestagens in pediatric and adolescent gynecology].

    PubMed

    Lauritzen, C

    1990-10-01

    An overview is given on the indications and possibilities of estrogen-progestagen medication in girls during childhood and adolescence. The physiological effects of estrogen and progestagen treatment are described, and practical advice is given for the management with estrogens-progestagens of labial adhesions, lichen sclerosus, vulvovaginitis, breast anomalies, the different forms of amenorrhoeas, pubertas tarda, anorexia-bulimia, bleeding anomalies and high stature. PMID:2079940

  10. Combinations of Physiologic Estrogens with Xenoestrogens Alter ERK Phosphorylation Profiles in Rat Pituitary Cells

    PubMed Central

    Jeng, Yow-Jiun; Watson, Cheryl S.

    2011-01-01

    Background Estrogens are potent nongenomic phospho-activators of extracellular-signal–regulated kinases (ERKs). A major concern about the toxicity of xenoestrogens (XEs) is potential alteration of responses to physiologic estrogens when XEs are present simultaneously. Objectives We examined estrogen-induced ERK activation, comparing the abilities of structurally related XEs (alkylphenols and bisphenol A) to alter ERK responses induced by physiologic concentrations (1 nM) of estradiol (E2), estrone (E1), and estriol (E3). Methods We quantified hormone/mimetic-induced ERK phosphorylations in the GH3/B6/F10 rat pituitary cell line using a plate immunoassay, comparing effects with those on cell proliferation and by estrogen receptor subtype-selective ligands. Results Alone, these structurally related XEs activate ERKs in an oscillating temporal pattern similar (but not identical) to that with physiologic estrogens. The potency of all estrogens was similar (active between femtomolar and nanomolar concentrations). XEs potently disrupted physiologic estrogen signaling at low, environmentally relevant concentrations. Generally, XEs potentiated (at the lowest, subpicomolar concentrations) and attenuated (at the highest, picomolar to 100 nM concentrations) the actions of the physiologic estrogens. Some XEs showed pronounced nonmonotonic responses/inhibitions. The phosphorylated ERK and proliferative responses to receptor-selective ligands were only partially correlated. Conclusions XEs are both imperfect potent estrogens and endocrine disruptors; the more efficacious an XE, the more it disrupts actions of physiologic estrogens. This ability to disrupt physiologic estrogen signaling suggests that XEs may disturb normal functioning at life stages where actions of particular estrogens are important (e.g., development, reproductive cycling, pregnancy, menopause). PMID:20870566

  11. Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer.

    PubMed

    Stein, Rebecca A; Chang, Ching-Yi; Kazmin, Dmitri A; Way, James; Schroeder, Thies; Wergin, Melanie; Dewhirst, Mark W; McDonnell, Donald P

    2008-11-01

    Expression of estrogen-related receptor alpha (ERRalpha) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERalpha) and ERRalpha initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ERalpha-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERalpha-ERRalpha cross-talk using an unbiased microarray approach. In addition to generating a host of novel ERRalpha target genes, this study yielded the surprising result that most ERRalpha-regulated genes are unrelated to estrogen signaling. The relatively small number of genes regulated by both ERalpha and ERRalpha led us to expand our study to the more aggressive and less clinically treatable ERalpha-negative class of breast cancers. In this setting, we found that ERRalpha expression is required for the basal level of expression of many known and novel ERRalpha target genes. Introduction of a small interfering RNA directed to ERRalpha into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERRalpha expression in MDA-MB-231 cells had no effect on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERRalpha in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor-negative breast cancer. PMID:18974123

  12. Estrogen-Like Activity of Perfluoroalkyl Acids In Vivo and Interaction with Human and Rainbow Trout Estrogen Receptors In Vitro

    PubMed Central

    Benninghoff, Abby D.; Bisson, William H.; Koch, Daniel C.; Ehresman, David J.; Kolluri, Siva K.; Williams, David E.

    2011-01-01

    The objectives of this study were to determine the structural characteristics of perfluoroalkyl acids (PFAAs) that confer estrogen-like activity in vivo using juvenile rainbow trout (Oncorhynchus mykiss) as an animal model and to determine whether these chemicals interact directly with the estrogen receptor (ER) using in vitro and in silico species comparison approaches. Perfluorooctanoic (PFOA), perfluorononanoic (PFNA), perfluorodecanoic (PFDA), and perfluoroundecanoic (PFUnDA) acids were all potent inducers of the estrogen-responsive biomarker protein vitellogenin (Vtg) in vivo, although at fairly high dietary exposures. A structure-activity relationship for PFAAs was observed, where eight to ten fluorinated carbons and a carboxylic acid end group were optimal for maximal Vtg induction. These in vivo findings were corroborated by in vitro mechanistic assays for trout and human ER. All PFAAs tested weakly bound to trout liver ER with half maximal inhibitory concentration (IC50) values of 15.2–289μM. Additionally, PFOA, PFNA, PFDA, PFUnDA, and perlfuorooctane sulfonate (PFOS) significantly enhanced human ERα-dependent transcriptional activation at concentrations ranging from 10–1000nM. Finally, we employed an in silico computational model based upon the crystal structure for the human ERα ligand-binding domain complexed with E2 to structurally investigate binding of these putative ligands to human, mouse, and trout ERα. PFOA, PFNA, PFDA, and PFOS all efficiently docked with ERα from different species and formed a hydrogen bond at residue Arg394/398/407 (human/mouse/trout) in a manner similar to the environmental estrogens bisphenol A and nonylphenol. Overall, these data support the contention that several PFAAs are weak environmental xenoestrogens of potential concern. PMID:21163906

  13. Regulation of the intronic promoter of rat estrogen receptor alpha gene, responsible for truncated estrogen receptor product-1 expression.

    PubMed

    Schausi, Diane; Tiffoche, Christophe; Thieulant, Marie-Lise

    2003-07-01

    We have characterized the intronic promoter of the rat estrogen receptor (ER) alpha gene, responsible for the lactotrope-specific truncated ER product (TERP)-1 isoform expression. Transcriptional regulation was investigated by transient transfections using 5'-deletion constructs. TERP promoter constructs were highly active in MMQ cells, a pure lactotrope cell line, whereas a low basal activity was detected in alphaT3-1 gonadotrope cells or in COS-7 monkey kidney cells. Serial deletion analysis revealed that 1) a minimal -693-bp region encompassing the TATA box is sufficient to allow lactotrope-specific expression; 2) the promoter contains strong positive cis-acting elements both in the distal and proximal regions, and 3) the region spanning the -1698/-1194 region includes repressor elements. Transient transfection studies, EMSAs, and gel shifts demonstrated that estrogen activates the TERP promoter via an estrogen-responsive element (ERE1) located within the proximal region. Mutation of ERE1 site completely abolishes the estradiol-dependent transcription, indicating that ERE1 site is sufficient to confer estrogen responsiveness to TERP promoter. In addition, ERalpha action was synergized by transfection of the pituitary-specific factor Pit-1. EMSAs showed that a single Pit-1 DNA binding element in the vicinity of the TATA box is sufficient to confer response by the TERP promoter. In conclusion, we demonstrated, for the first time, that TERP promoter regulation involves ERE and Pit-1 cis-elements and corresponding trans-acting factors, which could play a role in the physiological changes that occur in TERP-1 transcription in lactotrope cells. PMID:12810539

  14. Estrogen Receptor beta binds Sp1 and recruits a Corepressor Complex to the Estrogen Receptor alpha Gene Promoter

    PubMed Central

    Bartella, V; Rizza, P; Barone, I; Zito, D; Giordano, F; Giordano, C; Catalano, S; Mauro, L; Sisci, D; Panno, ML; Fuqua, SA; Andò, Sebastiano

    2015-01-01

    Human estrogen receptors (ERs) alpha and beta are crucially involved in the regulation of mammary growth and development. Normal breast tissues display a prevalently expression of ER beta than ER alpha, which drastically increases during breast tumorogenesis. So, it is reasonable to assume how a dysregulation of the two estrogen receptor subtypes may induce breast cancer development. However, the molecular mechanism underlying the opposite role played by the two estrogen receptors on tumor cell growth remains to be elucidated. In the present study, we have demonstrated that ER beta overexpression in breast cancer cells decreases cell proliferation and down-regulates ER alpha mRNA and protein content along with a concomitant repression of estrogen-regulated genes. Transient transfection experiments, using a vector containing the human ER alpha promoter region, showed that elevated levels of the ER beta down-regulated basal ER alpha promoter activity. Furthermore, side-directed mutagenesis and deletion analysis have revealed that the proximal GC-rich motifs at −223 and −214 is crucial for the ER beta-induced ER alpha down-regulation in breast cancer cells. This occurred through ER beta-Sp1 protein-protein interaction within the ER alpha promoter region and the recruitment of a corepressor complex containing NCoR/SMRT (nuclear receptor corepressor/silencing mediator of retinoic acid and thyroid hormone receptor), accompanied by hypoacetylation of histone H4 and displacement of RNA polymerase II. Silencing of NCoR gene expression by RNA interference reversed the down-regulatory effect of ER beta on ER alpha gene expression and cell proliferation. Our results provide evidence for a novel mechanism by which overexpression of ER beta through NCoR is able to down regulate ER alpha gene expression, thus inhibiting ER alpha’s driving role on breast cancer cell growth. PMID:22622808

  15. Amphipathic Benzenes Are Designed Inhibitors of the Estrogen Receptor α/Steroid Receptor Coactivator Interaction

    PubMed Central

    Gunther, Jillian R.; Moore, Terry W.; Collins, Margaret L.; Katzenellenbogen, John A.

    2008-01-01

    We report here on the design, synthesis and evaluation of small molecule inhibitors of the interaction between a steroid receptor coactivator and estrogen receptor α. These inhibitors are based upon an amphipathic benzene scaffold whose hydrophobic face mimics the leucine-rich α-helical consensus sequence on the steroid receptor coactivators that interacts with a shallow groove on estrogen receptor α. Several of these molecules are among the most potent inhibitors of this interaction described to date, and they are active at low micromolar concentrations in both in vitro models of estrogen receptor action and in cell-based assays of estrogen receptor-mediated coactivator interaction and transcription. PMID:18484708

  16. Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice.

    PubMed

    Cao, Xuehong; Xu, Pingwen; Oyola, Mario G; Xia, Yan; Yan, Xiaofeng; Saito, Kenji; Zou, Fang; Wang, Chunmei; Yang, Yongjie; Hinton, Antentor; Yan, Chunling; Ding, Hongfang; Zhu, Liangru; Yu, Likai; Yang, Bin; Feng, Yuxin; Clegg, Deborah J; Khan, Sohaib; DiMarchi, Richard; Mani, Shaila K; Tong, Qingchun; Xu, Yong

    2014-10-01

    Binge eating afflicts approximately 5% of US adults, though effective treatments are limited. Here, we showed that estrogen replacement substantially suppresses binge-like eating behavior in ovariectomized female mice. Estrogen-dependent inhibition of binge-like eating was blocked in female mice specifically lacking estrogen receptor-α (ERα) in serotonin (5-HT) neurons in the dorsal raphe nuclei (DRN). Administration of a recently developed glucagon-like peptide-1-estrogen (GLP-1-estrogen) conjugate designed to deliver estrogen to GLP1 receptor-enhanced regions effectively targeted bioactive estrogens to the DRN and substantially suppressed binge-like eating in ovariectomized female mice. Administration of GLP-1 alone reduced binge-like eating, but not to the same extent as the GLP-1-estrogen conjugate. Administration of ERα-selective agonist propylpyrazole triol (PPT) to murine DRN 5-HT neurons activated these neurons in an ERα-dependent manner. PPT also inhibited a small conductance Ca2+-activated K+ (SK) current; blockade of the SK current prevented PPT-induced activation of DRN 5-HT neurons. Furthermore, local inhibition of the SK current in the DRN markedly suppressed binge-like eating in female mice. Together, our data indicate that estrogens act upon ERα to inhibit the SK current in DRN 5-HT neurons, thereby activating these neurons to suppress binge-like eating behavior and suggest ERα and/or SK current in DRN 5-HT neurons as potential targets for anti-binge therapies. PMID:25157819

  17. Kaempferol is an estrogen-related receptor alpha and gamma inverse agonist.

    PubMed

    Wang, Junjian; Fang, Fang; Huang, Zhiyan; Wang, Yanfei; Wong, Chiwai

    2009-02-18

    Kaempferol is a dietary flavonoid that is thought to function as a selective estrogen receptor modulator. In this study, we established that kaempferol also functions as an inverse agonist for estrogen-related receptors alpha and gamma (ERRalpha and ERRgamma). We demonstrated that kaempferol binds to ERRalpha and ERRgamma and blocks their interaction with coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). Kaempferol also suppressed the expressions of ERR-target genes pyruvate dehydrogenase kinase 2 and 4 (PDK2 and PDK4). This evidence suggests that kaempferol may exert some of its biological effect through both estrogen receptors and estrogen-related receptors. PMID:19171140

  18. Assessing the Effects of Estrogen on the Dynamics of Breast Cancer

    PubMed Central

    Mufudza, Chipo; Sorofa, Walter; Chiyaka, Edward T.

    2012-01-01

    Worldwide, breast cancer has become the second most common cancer in women. The disease has currently been named the most deadly cancer in women but little is known on what causes the disease. We present the effects of estrogen as a risk factor on the dynamics of breast cancer. We develop a deterministic mathematical model showing general dynamics of breast cancer with immune response. This is a four-population model that includes tumor cells, host cells, immune cells, and estrogen. The effects of estrogen are then incorporated in the model. The results show that the presence of extra estrogen increases the risk of developing breast cancer. PMID:23365616

  19. Rapid estrogen actions on ion channels: A survey in search for mechanisms.

    PubMed

    Kow, Lee-Ming; Pfaff, Donald W

    2016-07-01

    A survey of nearly two hundred reports shows that rapid estrogenic actions can be detected across a range of kinds of estrogens, a range of doses, on a wide range of tissue, cell and ion channel types. Striking is the fact that preparations of estrogenic agents that do not permeate the cell membrane almost always mimic the actions of the estrogenic agents that do permeate the membrane. All kinds of estrogens, ranging from natural ones, through receptor modulators, endocrine disruptors, phytoestrogens, agonists, and antagonists to novel G-1 and STX, have been reported to be effective. For actions on specific types of ion channels, the possibility of opposing actions, in different cases, is the rule, not the exception. With this variety there is no single, specific action mechanism for estrogens per se, although in some cases estrogens can act directly or via some signaling pathways to affect ion channels. We infer that estrogens can bind a large number of substrates/receptors at the membrane surface. As against the variety of subsequent routes of action, this initial step of the estrogen's binding action is the key. PMID:26939826

  20. Effect of source-separated urine storage on estrogenic activity detected using bioluminescent yeast Saccharomyces cerevisiae.

    PubMed

    Jaatinen, Sanna; Kivistö, Anniina; Palmroth, Marja R T; Karp, Matti

    2016-09-01

    The objective was to demonstrate that a microbial whole cell biosensor, bioluminescent yeast, Saccharomyces cerevisiae (BMAEREluc/ERα) can be applied to detect overall estrogenic activity from fresh and stored human urine. The use of source-separated urine in agriculture removes a human originated estrogen source from wastewater influents, subsequently enabling nutrient recycling. Estrogenic activity in urine should be diminished prior to urine usage in agriculture in order to prevent its migration to soil. A storage period of 6 months is required for hygienic reasons; therefore, estrogenic activity monitoring is of interest. The method measured cumulative female hormone-like activity. Calibration curves were prepared for estrone, 17β-estradiol, 17α- ethinylestradiol and estriol. Estrogen concentrations of 0.29-29,640 μg L(-1) were detectable while limit of detection corresponded to 0.28-35 μg L(-1) of estrogens. The yeast sensor responded well to fresh and stored urine and gave high signals corresponding to 0.38-3,804 μg L(-1) of estrogens in different urine samples. Estrogenic activity decreased during storage, but was still higher than in fresh urine implying insufficient storage length. The biosensor was suitable for monitoring hormonal activity in urine and can be used in screening anthropogenic estrogen-like compounds interacting with the receptor. PMID:26804108

  1. Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways

    PubMed Central

    Watson, Cheryl S.; Jeng, Yow-Juin; Guptarak, Jutatip

    2011-01-01

    When inappropriate (non-physiologic) estrogens affect organisms at critical times of estrogen sensitivity, disruption of normal endocrine functions can result. Non-physiologic estrogen mimetics (environmental, dietary, pharmaceutical) can signal rapidly and potently via the membrane versions of estrogen receptors, as can physiologic estrogens. Both physiologic and non-physiologic estrogens activate multiple signaling pathways, leading to altered cellular functions (eg. peptide release, cell proliferation or death, transport). Xenoestrogens’ mimicry of physiologic estrogens is imperfect. When superimposed, xenoestrogens can alter endogenous estrogens’ signaling and thereby disrupt normal signaling pathways, leading to malfunctions in many tissue types. Though these xenoestrogen actions occur rapidly via nongenomic signaling pathways, they can be sustained with continuing ligand stimulation, combinations of ligands, and signaling that perpetuates downstream, eventually also impinging on genomic regulation by controlling the activation state of transcription factors. Because via these pathways estrogens and xenoestrogens cause nonmonotonic stimulation patterns, they must be carefully tested for activity and toxicity over wide dose ranges. Nongenomic actions of xenoestrogens in combination with each other, and with physiologic estrogens, are still largely unexplored from these mechanistic perspectives. PMID:21300151

  2. Evaluation of estrogenic activity and measurement of EDCs in wastewater treatment plants

    NASA Astrophysics Data System (ADS)

    Lee, B. C.; Jung, J. Y.; Kim, H. K.

    2006-10-01

    Correlations between estrogenic activity and DOC/UV260 ratio in wastewater treatment processes were investigated to propose a simple, reliable and comprehensive indicator for the presence of estrogenic substances. Contrary to this, when short-term bioassays such as the E-SCREEN, receptor binding and reporter gene expression assays are used for detecting estrogenic activity in the wastewater sample, they require a long time, at least a few days. The major factors contributing to the estrogenic activity were found to be 17β-estradiol (E2) and estrone (El). A good relationship between the DOC/ UV260 ratio and the concentration of estrogens (El and E2) in the effluent of the activated sludge process was found: the E2 concentration increased as the DOC/UV260 ratio increased while the El concentration decreased. The relative estrogenic activity and DOC/UV260 ratio showed a good correlation (R2=0.84) for all sewage samples except the ozonized samples in the sewage treatment plants. This study shows that the estrogenic compounds are hard to be mineralized by the conventional biological processes. Advanced oxidation processes are required to further remove estrogenic substances in the secondary effluent. By analysis of DOC and UV260, the estrogenic activity in the wastewater can be rapidly estimated.

  3. Effects of sex and estrogen on chicken ductus arteriosus reactivity.

    PubMed

    Flinsenberg, Thijs W H; van der Sterren, Saskia; van Cleef, Anne N H; Schuurman, Marijn J; Agren, Pia; Villamor, Eduardo

    2010-05-01

    Sex hormones have an important influence on cardiovascular physiology and pathophysiology and sex differences in vascular reactivity have been widely demonstrated. In the present study we hypothesized 1) the presence of sexual dimorphism in chicken ductus arteriosus (DA) responsiveness to contractile and relaxant stimuli and 2) that estrogens are vasoactive in the chicken DA. In vitro contractions (assessed with a wire myograph) induced by normoxia, KCl, 4-aminopyridine, norepinephrine, phenylephrine, U46619, or endothelin-1, as well as relaxations induced by ACh, sodium nitroprusside, BAY 41-2272, PGE(2), isoproterenol, forskolin,Y-27632, and hydroxyfasudil were not significantly different between males and females. The estrogen 17beta-estradiol elicited concentration-dependent relaxation of KCl-, phenylephrine-, and oxygen-induced active tone in male and female chicken DA. The stereoisomer 17alpha-estradiol showed lesser relaxant effects, and the selective estrogen receptor (ER) agonists 4,4',4''-(4-propyl-[(1)H]pyrazole-1,3,5-triyl)tris-phenol (ERalpha) and 2,3-bis(4-hydroxyphenyl)-propionitrile (ERbeta) did not show any effect. There were no sex differences in the responses to estrogen. Endothelium removal or the presence of the soluble guanylate cyclase inhibitor ODQ, the K(+) channel blockers tetraethylammonium, glibenclamide, and charybdotoxin, or the ER antagonist fulvestrant did not modify 17beta-estradiol-induced relaxation. CaCl(2) (30 muM-10 mM) induced concentration-dependent contraction in DA rings depolarized by 62.5 mM KCl or stimulated with 21% O(2) in Ca(2+)-free medium. Preincubation with 17beta-estradiol or the L-type Ca(2+) channel blocker nifedipine produced an inhibition of CaCl(2)-induced contractions. In conclusion, there are no sex-related differences in chicken DA reactivity. The estrogen 17beta-estradiol induces an endothelium-independent relaxation of chicken DA that is not mediated by ER activation. This relaxant effect is, at least

  4. Analgesic use and patterns of estrogen metabolism in premenopausal women.

    PubMed

    Fortner, Renée T; Oh, Hannah; Daugherty, Sarah E; Xu, Xia; Hankinson, Susan E; Ziegler, Regina G; Eliassen, A Heather

    2014-04-01

    Analgesic use has been hypothesized to reduce the risk of some cancers, with inverse associations between analgesics and colon cancer, and suggestive inverse associations for breast cancer. Estrogen metabolites (EM) have genotoxic and estrogenic potential; genotoxicity may differ by hydroxylation pathway. Analgesic use may impact patterns of estrogen metabolism; effects of analgesics on disease risk could be mediated through these patterns. We conducted a cross-sectional study among 603 premenopausal women in the Nurses' Health Study II. Frequency of aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen use was reported via questionnaire; average frequency in 1997 and 1999 was calculated. Women provided urine samples between 1996 and 1999, collected during the mid-luteal phase of the menstrual cycle. Urinary EM were quantified using high-performance liquid chromatography-tandem mass spectrometry. We observed no association between analgesic use and estradiol, estrone, or specific pathways of estrogen metabolism. Women reporting more frequent aspirin use had lower methylated 2-catechols (e.g., 2-hydroxyestrone-3-methyl ether, 2+ days/week vs. non-use: 0.95 vs. 1.21 pmol/mg creatinine; p difference = 0.01, p trend = 0.07). Non-aspirin NSAID use was positively associated with 17-epiestriol (4+ days/week vs. non-use: 2.48 vs. 1.52 pmol/mg creatinine; p difference = 0.01, p trend = 0.11). Acetaminophen use was positively associated with total EM (2+ days/week vs. non-use: 236 vs. 198 pmol/mg creatinine; p difference = 0.02, p trend = 0.11), 2-hydroxyestrone-3-methyl ether (1.6 vs. 1.1 pmol/mg creatinine; p difference < 0.01, p trend = 0.02), and 16α-hydroxyestrone (17 vs. 12 pmol/mg creatinine; p difference = 0.01, p trend = 0.05). This study provides the first assessment of analgesic use and patterns of estrogen metabolism in women. While we observed some associations between analgesics and

  5. The New Biology of Estrogen-induced Apoptosis Applied to Treat and Prevent Breast Cancer

    PubMed Central

    Jordan, V Craig

    2014-01-01

    The successful use of high dose synthetic estrogens to treat post-menopausal metastatic breast cancer, is the first effective “chemical therapy” proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) for postmenopausal hysterectomized women which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long term estrogen deprivation. However, through trial and error estrogen independent growth occurs. At the cellular level, estrogen induced apoptosis is dependent upon the presence of the estrogen receptor (ER) which can be blocked by non-steroidal or steroidal anti-estrogens. The shape of an estrogenic ligand programs the conformation of the ER complex which in turn can modulate estrogen induced apoptosis: class I planar estrogens (eg: estradiol) trigger apoptosis after 24 hours whereas class II angular estrogens (eg: bisphenol triphenylethylene) delay the process until after 72 hours. This contrasts with paclitaxel that causes G2 blockade with immediate apoptosis. The process is complete within 24 hours. Estrogen induced apoptosis is modulated by glucocorticoids and cSrc inhibitors but the target mechanism for estrogen action is genomic and not through a non-genomic pathway. The process is step wise through the creation of endoplasmic reticulum stress and, inflammatory responses that then initiate an unfolded protein response. This in turn initiates apoptosis through the intrinsic pathway (mitochondrial) with subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of

  6. Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha

    SciTech Connect

    Jang, Eun Hyang; Jang, Soon Young; Cho, In-Hye; Hong, Darong; Jung, Bom; Park, Min-Ju; Kim, Jong-Ho

    2015-08-07

    Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. - Highlights: • Hispolon decreased ERα expression at both mRNA and protein levels. • Hispolon decreased ERα transcriptional activity. • Hispolon treatment inhibited expression of ERα target gene pS2. • Shikonin is a candidate chemotherapeutic target in the treatment of human breast cancer.

  7. Estrogen receptor α and G-protein coupled estrogen receptor 1 are localized to GABAergic neurons in the dorsal striatum.

    PubMed

    Almey, Anne; Milner, Teresa A; Brake, Wayne G

    2016-05-27

    Estrogens affect dopamine transmission in the striatum, increasing dopamine availability, maintaining D2 receptor density, and reducing the availability of the dopamine transporter. Some of these effects of estrogens are rapid, suggesting that they are mediated by membrane associated receptors. Recently our group demonstrated that there is extra-nuclear labeling for ERα, ERβ, and GPER1 in the striatum, but that ERα and GPER1 are not localized to dopaminergic neurons in this region. GABAergic neurons are the most common type of neuron in the striatum, and changes in GABA transmission affect dopamine transmission. Thus, to determine whether ERα or GPER1 are localized to GABAergic neurons, we double labeled the striatum with antibodies for ERα or GPER1 and GABA and examined them using electron microscopy. Ultrastructural analysis revealed that ERα and GPER1 are localized exclusively to extranuclear sites in the striatum, and ∼35% of the dendrites and axon terminals labeled for these receptors contain GABA immunoreactivity. Binding at membrane-associated ERα and GPER1 could account for rapid estrogen-induced decreases in GABA transmission in the striatum, which, in turn, could affect dopamine transmission in this region. PMID:27080432

  8. Developmental regulation of the estrogen receptor and the estrogen responsiveness of five yolk protein genes in the avian liver.

    PubMed Central

    Evans, M I; O'Malley, P J; Krust, A; Burch, J B

    1987-01-01

    The magnitude of the expression of five yolk protein genes in the avian liver in response to exogenous estradiol is shown to be developmentally regulated. Though each of these yolk protein genes gains the capacity to respond to estradiol during embryonic development, we demonstrate that maximal responses for the different genes are achieved at distinct ages between 1 and 6 weeks after hatching. This observation prompted us to look for possible correlations between yolk protein gene expression and changes in the expression of estrogen receptors that might also occur after hatching. We discovered that indeed the maximal level of nuclear estrogen receptors (assayed following the administration of estradiol) increases progressively over this same period of development from approximately 1000 receptors per cell at 1 week after hatching to approximately 3500 receptors per cell at 6 weeks after hatching. The latter number represents the fully mature state, as comparable levels of receptors are present in the livers of egg-laying hens. Thus, though increases in the expression of estrogen receptors during embryonic liver development have previously been reported, our results indicate that the changes that occur after hatching are quantitatively far more significant to the developmental program for this transcription factor. PMID:3479803

  9. Regulation of Mitochondrial Respiratory Chain Biogenesis by Estrogens/Estrogen Receptors and Physiological, Pathological and Pharmacological Implications

    PubMed Central

    Chen, Jin-Qiang; Cammarata, Patrick R.; Baines, Christopher P.; Yager, James D.

    2009-01-01

    There has been increasing evidence pointing to the mitochondrial respiratory chain (MRC) as a novel and important target for the actions of 17β-estradiol(E2) and estrogen receptors (ER) in a number of cell types and tissues that have high demands for mitochondrial energy metabolism. This novel E2-mediated mitochondrial pathway involves the cooperation of both nuclear and mitochondrial ERα and ERβ and their co-activators on the coordinate regulation of both nuclear DNA- and mitochondrial DNA-encoded genes for MRC proteins. In this paper, we have: 1) comprehensively reviewed studies that reveal a novel role of estrogens and ERs in the regulation of MRC biogenesis; 2) discussed their physiological, pathological and pharmacological implications in the control of cell proliferation and apoptosis in relation to estrogen-mediated carcinogenesis, anticancer drug resistance in human breast cancer cells, neuro-protection for Alzheimer’s disease and Parkinson’s disease in brain, cardiovascular protection in human heart and their beneficial effects in lens physiology related to cataract in the eye; and 3) pointed out new research directions to address the key questions in this important and newly emerging area. We also suggest a novel conceptual approach that will contribute to innovative regimines for the prevention or treatment of a wide variety of medical complications based on E2/ER-mediated MRC biogenesis pathway. PMID:19559056

  10. Estrogen protects against amyloid-β toxicity by estrogen receptor α-mediated inhibition of Daxx translocation.

    PubMed

    Mateos, Laura; Persson, Torbjörn; Katoozi, Shirin; Kathozi, Shirin; Gil-Bea, Francisco Javier; Cedazo-Minguez, Angel

    2012-01-11

    Estrogen was shown to promote neuronal survival against several neurotoxic insults including β-amyloid (Aβ). The proposed mechanism includes the activation of the mitogen activated protein kinase/extracellular signal-regulated kinase (Mapk/Erk), phosphatidylinositol 3-kinase/Akt pathways and the upregulation of antiapoptotic proteins. On the other hand, Aβ neurotoxicity depends on the activation of apoptosis signal-regulating kinase 1 (Ask1), and both Ask1 activity and Aβ toxicity are inhibited by thioredoxin-1 (Trx1). Here, we explored the possibility that estrogen could protect cells against Aβ(1-42) toxicity by inhibiting the Ask1 cascade or by modulating Trx1. Cytosolic translocation of death-associated protein Daxx was used as indicator of Ask1 activity. Using human SH-SY5Y neuroblastoma cells, 17β-estradiol (E2) and specific agonists for estrogen receptor (ER) α or β we demonstrated that nM concentrations of E2 protected against Aβ(1-42) by a mechanism depending upon ERα stimulation, Akt activation and Ask1 inhibition. Moreover, this protection would occur independently of ERβ and the induction of Trx1 expression. Our results emphasize the importance of Ask1 cascade in Aβ toxicity, and of ERα and Ask1 as targets for developing new neuroprotective drugs. PMID:22119000

  11. Pomegranate extract demonstrate a selective estrogen receptor modulator profile in human tumor cell lines and in vivo models of estrogen deprivation.

    PubMed

    Sreeja, Sreekumar; Santhosh Kumar, Thankayyan R; Lakshmi, Baddireddi S; Sreeja, Sreeharshan

    2012-07-01

    Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) ligands exhibiting tissue-specific agonistic or antagonistic biocharacter and are used in the hormonal therapy for estrogen-dependent breast cancers. Pomegranate fruit has been shown to exert antiproliferative effects on human breast cancer cells in vitro. In this study, we investigated the tissue-specific estrogenic/antiestrogenic activity of methanol extract of pericarp of pomegranate (PME). PME was evaluated for antiproliferative activity at 20-320 μg/ml on human breast (MCF-7, MDA MB-231) endometrial (HEC-1A), cervical (SiHa, HeLa), ovarian (SKOV3) carcinoma and normal breast fibroblast (MCF-10A) cells. Competitive radioactive binding studies were carried out to ascertain whether PME interacts with ER. The reporter gene assay measured the estrogenic/antiestrogenic activity of PME in MCF-7 and MDA MB-231 cells transiently transfected with plasmids coding estrogen response elements with a reporter gene (pG5-ERE-luc) and wild-type ERα (hEG0-ER). PME inhibited the binding of [³H] estradiol to ER and suppressed the growth and proliferation of ER-positive breast cancer cells. PME binds ER and down-regulated the transcription of estrogen-responsive reporter gene transfected into breast cancer cells. The expressions of selected estrogen-responsive genes were down-regulated by PME. Unlike 17β-estradiol [1 mg/kg body weight (BW)] and tamoxifen (10 mg/kg BW), PME (50 and 100 mg/kg BW) did not increase the uterine weight and proliferation in ovariectomized mice and its cardioprotective effects were comparable to that of 17β-estradiol. In conclusion, our findings suggest that PME displays a SERM profile and may have the potential for prevention of estrogen-dependent breast cancers with beneficial effects in other hormone-dependent tissues. PMID:21839626

  12. Estrogen response element and the promoter context of the human and mouse lactoferrin genes influence estrogen receptor alpha-mediated transactivation activity in mammary gland cells.

    PubMed

    Stokes, Kenya; Alston-Mills, Brenda; Teng, Christina

    2004-10-01

    A critical step in estrogen action is the recognition of estrogen responsive elements (EREs) by liganded estrogen receptor. Our current studies were designed to determine whether an extended estrogen response element half-site (ERRE) contributes to the differential estrogen responses of the human and mouse lactoferrin overlapping chicken ovalbumin upstream promoter/ERE sequences (estrogen response modules, ERMs) in the context of their natural promoters. Transient transfections of MCF-7 cells show that liganded estrogen receptor alpha (ERalpha) activates transcription of the human lactoferrin ERM fourfold higher than the mouse lactoferrin ERM in the context of their natural promoters. Since the ERRE of the human lactoferrin gene naturally occurs 18 bp upstream from the ERM and is absent in the mouse lactoferrin gene promoter, we created a chimeric mouse lactoferrin CAT reporter, which now encodes the ERRE in the identical location as in the human lactoferrin gene. The addition of the ERRE in the mouse lactoferrin gene rendered this reporter extremely responsive to estrogen stimulation. Using limited protease digestions and electrophoretic mobility shift assays, we showed that the binding and protease sensitivity of ERalpha bound to the mouse ERM with or without the ERRE, differed. Importantly, occupancy of additional nuclear receptors at the ERRE may contribute to ERalpha binding and activation. Furthermore, the presence of ERRE influences the selectivity of coactivators in liganded ERalpha-mediated transcriptional activity. When the receptor is bound to human and mouse plus genes, which contain the ERRE, steroid receptor coactivator (SRC)-2 was preferred, while SRC-1 and SRC-3 coactivators selectively enhanced the mouse lactoferrin gene activity. Moreover, peroxisome proliferator activated receptor-gamma coactivator-1 (PGC-1alpha) and PGC-1-related estrogen receptor coactivator (PERC) robustly increase the transcriptional function of ERalpha in the presence of the

  13. Klotho/fibroblast growth factor 23- and PTH-independent estrogen receptor-α-mediated direct downregulation of NaPi-IIa by estrogen in the mouse kidney.

    PubMed

    Webster, Rose; Sheriff, Sulaiman; Faroqui, Rashma; Siddiqui, Faraaz; Hawse, John R; Amlal, Hassane

    2016-08-01

    Estrogen treatment causes renal phosphate (Pi) wasting and hypophosphatemia in rats and humans; however, the signaling mechanisms mediating this effect are still poorly understood. To determine the specific roles of estrogen receptor isoforms (ERα and ERβ) and the Klotho pathway in mediating these effects, we studied the effects of estrogen on renal Pi handling in female mice with null mutations of ERα or ERβ or Klotho and their wild type (WT) using balance studies in metabolic cages. Estrogen treatment of WT and ERβ knockout (KO) mice caused a significant reduction in food intake along with increased renal phosphate wasting. The latter resulted from a significant downregulation of NaPi-IIa and NaPi-IIc protein abundance. The mRNA expression levels of both transporters were unchanged in estrogen-treated mice. These effects on both food intake and renal Pi handling were absent in ERα KO mice. Estrogen treatment of Klotho KO mice or parathyroid hormone (PTH)-depleted thyroparathyroidectomized mice exhibited a significant downregulation of NaPi-IIa with no change in the abundance of NaPi-IIc. Estrogen treatment of a cell line (U20S) stably coexpressing both ERα and ERβ caused a significant downregulation of NaPi-IIa protein when transiently transfected with a plasmid containing full-length or open-reading frame (ORF) 3'-untranslated region (UTR) but not 5'-UTR ORF of mouse NaPi-IIa transcript. In conclusion, estrogen causes phosphaturia and hypophosphatemia in mice. These effects result from downregulation of NaPi-IIa and NaPi-IIc proteins in the proximal tubule through the activation of ERα. The downregulation of NaPi-IIa by estrogen involves 3'-UTR of its mRNA and is independent of Klotho/fibroblast growth factor 23 and PTH signaling pathways. PMID:27194721

  14. Hops (Humulus lupulus) inhibits Oxidative Estrogen Metabolism and Estrogen-Induced Malignant Transformation in Human Mammary Epithelial cells (MCF-10A)

    PubMed Central

    Madhubhani, L.P.; Hemachandra, P.; Esala, R.; Chandrasena, P.; Chen, Shao-Nong; Main, Matthew; Lankin, David C.; Scism, Robert A.; Dietz, Birgit M.; Pauli, Guido F.; Thatcher, Gregory R. J.; Bolton, Judy L.

    2011-01-01

    Long-term exposure to estrogens including those in traditional hormone replacement therapy (HRT) increases the risk of developing hormone-dependent cancers. As a result, women are turning to over-the-counter (OTC) botanical dietary supplements such as black cohosh (Cimicifuga racemosa) and hops (Humulus lupulus) as natural alternatives to HRT. The two major mechanisms which likely contribute to estrogen and/or HRT cancer risk are: the estrogen receptor (ER) mediated hormonal pathway; and, the chemical carcinogenesis pathway involving formation of estrogen quinones that damage DNA and proteins, hence initiating and promoting carcinogenesis. Since OTC botanical HRT alternatives are in widespread use they may have the potential for chemopreventive effects on estrogen carcinogenic pathways in vivo. Therefore the effect of OTC botanicals on estrogen-induced malignant transformation of MCF-10A cells was studied. Cytochrome P450 catalyzed hydroxylation of estradiol at the 4-position leads to an o-quinone believed to act as the proximal carcinogen. LC-MS/MS analysis of estradiol metabolites showed that 4-hydroxylation was inhibited by hops, whereas black cohosh was without effect. Estrogen-induced expression of CYP450 1B1 and CYP450 1A1 was attenuated by the hops extract. Two phenolic constituents of hops (xanthohumol, XH; and 8-prenylnaringenin, 8-PN) were tested: 8-PN was a potent inhibitor whereas XH had no effect. Finally, estrogen-induced malignant transformation of MCF-10A cells was observed to be significantly inhibited by hops (5 μg/mL) and 8-PN (50 nM). These data suggest that hops extracts possess cancer chemopreventive activity through attenuation of estrogen metabolism mediated by 8-PN. PMID:21997247

  15. Hops (Humulus lupulus) inhibits oxidative estrogen metabolism and estrogen-induced malignant transformation in human mammary epithelial cells (MCF-10A).

    PubMed

    Hemachandra, L P; Madhubhani, P; Chandrasena, R; Esala, P; Chen, Shao-Nong; Main, Matthew; Lankin, David C; Scism, Robert A; Dietz, Birgit M; Pauli, Guido F; Thatcher, Gregory R J; Bolton, Judy L

    2012-01-01

    Long-term exposure to estrogens including those in traditional hormone replacement therapy (HRT) increases the risk of developing hormone-dependent cancers. As a result, women are turning to over-the-counter (OTC) botanical dietary supplements, such as black cohosh (Cimicifuga racemosa) and hops (Humulus lupulus), as natural alternatives to HRT. The two major mechanisms which likely contribute to estrogen and/or HRT cancer risk are: the estrogen receptor-mediated hormonal pathway; and the chemical carcinogenesis pathway involving formation of estrogen quinones that damage DNA and proteins, hence initiating and promoting carcinogenesis. Because, OTC botanical HRT alternatives are in widespread use, they may have the potential for chemopreventive effects on estrogen carcinogenic pathways in vivo. Therefore, the effect of OTC botanicals on estrogen-induced malignant transformation of MCF-10A cells was studied. Cytochrome P450 catalyzed hydroxylation of estradiol at the 4-position leads to an o-quinone believed to act as the proximal carcinogen. Liquid chromatography/tandem mass spectrometry analysis of estradiol metabolites showed that 4-hydroxylation was inhibited by hops, whereas black cohosh was without effect. Estrogen-induced expression of CYP450 1B1 and CYP450 1A1 was attenuated by the hops extract. Two phenolic constituents of hops (xanthohumol, XH; 8-prenylnaringenin, 8-PN) were tested: 8-PN was a potent inhibitor, whereas XH had no effect. Finally, estrogen-induced malignant transformation of MCF-10A cells was observed to be significantly inhibited by hops (5 μg/mL) and 8-PN (50 nmol/L). These data suggest that hops extracts possess cancer chemopreventive activity through attenuation of estrogen metabolism mediated by 8-PN. PMID:21997247

  16. Estrogen-induced DNA synthesis in vascular endothelial cells is mediated by ROS signaling

    PubMed Central

    Felty, Quentin

    2006-01-01

    Background Since estrogen is known to increase vascular endothelial cell growth, elevated estrogen exposure from hormone replacement therapy or oral contraceptives has the potential to contribute in the development of abnormal proliferative vascular lesions and subsequent thickening of the vasculature. How estrogen may support or promote vascular lesions is not clear. We have examined in this study whether estrogen exposure to vascular endothelial cells increase the formation of reactive oxygen species (ROS), and estrogen-induced ROS is involved in the growth of endothelial cells. Methods The effect of estrogen on the production of intracellular oxidants and the role of estrogen-induced ROS on cell growth was studied in human umbilical vein endothelial cells. ROS were measured by monitoring the oxidation of 2'7'-dichlorofluorescin by spectrofluorometry. Endothelial cell growth was measured by a colorimetric immunoassay based on BrdU incorporation into DNA. Results Physiological concentrations of estrogen (367 fmol and 3.67 pmol) triggered a rapid 2-fold increase in intracellular oxidants in endothelial cells. E2-induced ROS formation was inhibited to basal levels by cotreatment with the mitochondrial inhibitor rotenone (2 μM) and xanthine oxidase inhibitor allopurinol (50 μM). Inhibitors of NAD(P)H oxidase, apocynin and DPI, did not block E2-induced ROS formation. Furthermore, the NOS inhibitor, L-NAME, did not prevent the increase in E2-induced ROS. These findings indicate both mitochondria and xanthine oxidase are the source of ROS in estrogen treated vascular endothelial cells. E2 treated cells showed a 2-fold induction of BrdU incorporation at 18 h which was not observed in cells exposed to vehicle alone. Cotreatment with ebselen (20 μM) and NAC (1 mM) inhibited E2-induced BrdU incorporation without affecting the basal levels of DNA synthesis. The observed inhibitory effect of NAC and ebselen on E2-induced DNA synthesis was also shown to be dose dependent

  17. DNA and chromosome breaks induced by {sup 123}I-estrogen in CHO cells

    SciTech Connect

    Schwartz, J.L. |; Mustafi, R.; Hughes, A.; DeSombre, E.R.

    1997-07-01

    The effects of the Auger electron-emitting isotope I-123, covalently bound to estrogen, on DNA single- and double-strand breakage and on chromosome breakage was determined in estrogen positive Chinese hamster ovary (CHO-ER) cells. Exposure to the {sup 123}I-estrogen induced both single- and double-strand breaks with a ratio of single- to double-strand breaks of 2.2. The corresponding ratio with {sup 60}Co gamma rays was 15.6. The dose-response was biphasic suggesting that either receptor sites are saturated at high does, or that there is a nonrandom distribution of breaks induced by the {sup 123}I-estrogen. The {sup 123}I-estrogen treatment induced chromosome aberrations with an efficiency of about 1 aberration for each 1,000 disintegrations per cell. This corresponds to the mean lethal dose of {sup 123}I-estrogen for these cells suggesting that the lethal event induced by the Auger electron emitter bound to estrogen is a chromosome aberration. Most of the chromosome-type aberrations were dicentrics and rings, suggesting that {sup 123}I-estrogen-induced chromosome breaks are rejoined. The F-ratio, the ratio of dicentrics to centric rings, was 5.8 {plus_minus} 1.7, which is similar to that seen with high LET radiations. Their results suggest that I-123 bound to estrogen is an efficient clastogenic agent, that the cytotoxic damage produced by I-123 bound to estrogen is very like high LET-induced damage, and the I-123 in the estrogen-receptor-DNA complex is probably in close proximity to the sugar-phosphate backbone of the DNA.

  18. DNA and chromosome breaks induced by iodine-123-labeled estrogen in Chinese hamster ovary cells

    SciTech Connect

    Schwartz, J.L. |; Mustafi, R.; Hughes, A.; DeSombre, E.R.

    1996-08-01

    The effects of the Auger electron-emitting isotope {sup 123}I, covalently bound to estrogen, on DNA single- and double-strand breakage and on chromosome breakage was determined in estrogen receptor-positive Chinese hamster ovary (CHO-ER) cells. Exposure to the {sup 123}I-labeled estrogen induced both single- and double-strand breaks with a ratio of single- to double-strand breaks of 2.8. The corresponding ratio with {sup 60}Co {gamma} rays was 15.6. The dose response was biphasic, suggesting either that receptor sites are saturated at high doses, or that there is a nonrandom distribution of breaks induced by the {sup 123}I-labeled estrogen. The {sup 123}I-labeled estrogen treatment induced chromosome aberrations with an efficiency of about 1 aberration for each 1000 disintegrations per cell. This corresponds to the mean lethal dose of {sup 123}I-labeled estrogen for these cells, suggesting that the lethal event induced by the Auger electron emitter bound to estrogen is a chromosome aberration. Most of the chromosome-type aberrations were dicentrics and rings, suggesting that {sup 123}I-labeled estrogen-induced chromosome breaks are rejoined. The F ratio, the ratio of dicentrics to centric rings, was 5.8 {+-} 1.7, which is similar to that seen with high-LET radiations. Our results suggest that {sup 123}I bound to estrogen is an efficient clastogenic agent, the cytotoxic damage produced by {sup 123}I bound to estrogen is very like damage induced by high-LET radiation, and the {sup 123}I in the estrogen receptor-DNA complex is probably in proximity to the sugar-phosphate backbone of the DNA. 40 refs., 7 figs.

  19. Detection of estrogenic activity in sediment-associated compounds using in vitro reporter gene assays.

    PubMed

    Legler, Juliette; Dennekamp, Martine; Vethaak, A Dick; Brouwer, Abraham; Koeman, Jan H; van der Burg, Bart; Murk, Albertinka J

    2002-07-01

    Sediments may be the ultimate sink for persistent (xeno-)estrogenic compounds released into the aquatic environment. Sediment-associated estrogenic potency was measured with an estrogen receptor-mediated luciferase reporter gene (ER-CALUX) assay and compared with a recombinant yeast screen. The ER-CALUX assay was more sensitive to 17beta-estradiol (E2) than the recombinant yeast screen, with an EC50 of 6 pM E2 compared to 100 pM in the yeast screen. Yeast cells were unable to distinguish the anti-estrogens ICI 182,780 and (4-hydroxy)tamoxifen, which were agonistic in the yeast. Acetone-soluble fractions of hexane/acetone extracts of sediments showed higher estrogenic potency than hexane-soluble extracts in the ER-CALUX assay. Sediments obtained from industrialized areas such as the Port of Rotterdam showed the highest estrogenic potency of the 12 marine sediments tested (up to 40 pmol estradiol equivalents per gram sediment). The estrogenic activity of individual chemicals that can be found in sediments including: alkylphenol ethoxylates and carboxylates; phthalates; and pesticides, was tested. Increasing sidechain length of various nonylphenol ethoxylates resulted in decreased estrogenic activity. Of the phthalates tested, butylbenzylphthalate was the most estrogenic, though with a potency approximately 100,000 times less than E2. The organochlorine herbicides atrazine and simazine failed to induce reporter gene activity. As metabolic activation may be required to induce estrogenic activity, a metabolic transformation step was added to the ER-CALUX assay using incubation of compounds with liver microsomes obtained from PCB-treated rats. Results indicate that metabolites of E2, NP and bisphenol A were less active than the parent compounds, while metabolites of methoxychlor were more estrogenic following microsomal incubations. PMID:12109482

  20. Effects of Estrogen on Platelet Reactivity After Transient Forebrain Ischemia in Rats

    PubMed Central

    Littleton-Kearney, Marguerite T.; Gaines, Jessica M.; Callahan, Kevin P.; Murphy, Stephanie J.; Hurn, Patricia D.

    2009-01-01

    Estrogen’s prothrombotic effects are of increasing concern, particularly in stroke risk and recovery. Using an ischemic rodent model, the authors sought to determine (a) if estrogen replacement increases post-ischemic platelet reactivity, (b) if changes in estrogen status alter intraplatelet endothelial nitric oxide synthase (eNOS) synthesis, and (c) if estrogen-mediated effects on platelets alter cerebral blood flow during reperfusion. Intact (I), ovariectomized (OVX), and OVX + 17β-estradiol (E50) rats were subjected to 30 min of forebrain ischemia and 60 min of reperfusion. Using the platelet activation marker P-selectin, postischemic platelet reactivity was quantified by flow cytometry. In a separate cohort (I, OVX, E50), the authors quantified platelet eNOS by Western blot. Another cohort (OVX, E50) was subjected to ischemia/reperfusion, and cerebral blood flow was determined using the iodoantipyrine technique. Collagen-stimulated platelet P-selectin expression was increased in the OVX rats at 60 min of reperfusion, and this effect was reversed by estrogen treatment. No differences in platelet eNOS expression were detected among groups. Cerebral blood flow at 60 min reperfusion was comparable between the OVX and the E50 rats. The authors conclude that during reperfusion, estrogen deficiency increases postischemic platelet sensitivity to stimuli in estrogen-deficient rats. Estrogen treatment mitigates effects of estrogen loss on platelets, but this early effect is apparently not caused by intraplatelet eNOS depression. Neither estrogen deficiency nor estrogen treatment changes early postischemic regional brain blood flow. In this rodent global cerebral ischemic model, physiologic doses of estrogen are not deleterious to platelet reactivity and may initially reduce postischemic platelet reactivity. PMID:16267375

  1. The effects of soil and Trifolium repens (white clover) on the fate of estrogen.

    PubMed

    Sakurai, Shinji; Fujikawa, Yoko; Kakumoto, Masumi; Sugahara, Masataka; Hamasaki, Tatsuhide; Umeda, Mikio; Fukui, Masami

    2009-03-01

    In this study, we investigated the behavior of estrogens in the rhizosphere of white clover (Trifolium repens, clover hereafter) with two different pot tests, using soil and agar as growth media. In a pot test using agar spiked with estrogen, the estrogen concentration in the agar with clover decreased to non-detectable levels within one month, while in the agar without clover, 60% of initially added estrogen remained after one month. The half-lives of estrone (E1) and 17beta -estradiol (E2) in the agar with clover were 2.4-3.8 and 13.2 d, respectively. The dissipation of E1 followed first-order rate law, while that of E2 fitted a zero-order reaction, indicating that they had different mechanisms of dissipation from agar. In the soil pot test, the behavior of E1 and E2 was not influenced by clover. An initial rapid decrease in the amount of estrogen extracted by methanol/acetic acid was followed by persistence for 1-3 months, regardless of presence of clover. Moreover, in three weeks E1 and E2 were only partly degraded by microbes extracted from the soil used in the pot test. In this study, abiotic degradation of estrogens and sorption of estrogen to soil, rather than the effects of soil microbes and clover, contributed to the initial rapid dissipation of estrogens in the soil. However, the results of the agar pot test suggested that vegetation such as clover may significantly contribute to removal of estrogens when estrogens in aqueous phase are discharged with surface runoff and preferential flow after heavy rain in agricultural fields, or when present in soils with low estrogen sorptivity. PMID:19280482

  2. Estimating estrogen release and load from humans and livestock in shanghai, china.

    PubMed

    Liu, Xiaowei; Shi, Jianghong; Zhang, Hui; Zhan, Xinmin; Shen, Genxiang; Hu, Shuangqing

    2014-03-01

    The estrogens estrone (E1), 17β-estradiol (E2), and 17α-ethynylestradiol (EE2) cause potent endocrine disruptive effects on aquatic wildlife. Currently, four sources of released estrogens exist in Shanghai: treated effluent from municipal wastewater treatment plants (WTPs); wastewater discharge from livestock farms; untreated or simply digested sewage from rural households; and runoff from farmland with livestock manure (LM) applied and irrigated with livestock wastewater (LW). A modified estimation method for estrogen release, in consideration of the difference in estrogen excretion rates between Caucasian and Oriental people and estrogen reduction in livestock wastes, was presented in the study. Based on the estimation method, we estimated the amount of estrogen release from humans and livestock and analyzed the spatially explicit distribution of estrogen loads. By comparing the four estrogen sources, the amount of estrogens released to water environments from livestock (56.8 g d), in terms of E2 equivalents (EEQ), was nearly twofold higher than the EEQ from humans (35.2 g d), which accounted for 61.0% of the total EEQ in Shanghai. Regarding the livestock EEQ, land-applied and irrigated EEQ via surface runoff to water environments (0.11 g d) was obviously low compared with the EEQ of LW directly released into adjacent waterways (56.7 g d). Therefore, the LW was the major contributor to estrogenic risk to the water environment in Shanghai. The spatial distribution of estrogen loads indicated that the highest EEQ loads were in the southern region of Pudong New Area and the eastern and central regions of Fengxian District. PMID:25602658

  3. Factors Affecting Distribution of Estrogenicity in the Influents, Effluents, and Biosolids of Canadian Wastewater Treatment Plants.

    PubMed

    Shieh, Ben H H; Louie, Alvin; Law, Francis C P

    2016-05-01

    Canadian wastewater treatment plants (WWTPs) release significant amounts of estrogenic chemicals to nearby surface waters. Environmental estrogens have been implicated as the causative agents of many developmental and reproductive problems in animals, including fish. The goals of this study were to assess the estrogenic activity in the influents, effluents, and biosolids of thirteen Canadian WWTPs using the yeast estrogen screen (YES) bioassay and to investigate whether factors, such as wastewater treatment method, sample storage, extraction efficiency, population, and summer/winter temperature had any effects on the distribution of estrogenicity in the WWTPs. Results of the study showed that estrogenicity from the influent to the effluent decreased in seven WWTPs, increased in two WWTPs, and did not change in four WWTPs during the winter. Estrogenic concentrations generally decreased in the order of biosolids > influents > effluents and ranged from 1.57 to 24.6, 1.25E-02 to 3.84E-01, and 9.46E-03 to 3.90E-01 ng estradiol equivalents/g or ml, respectively. The estrogenicity in the final effluents, but not those in the influents and biosolids, was significantly higher in the summer than the winter. Among the WWTP treatment methods, advanced, biological nutrient removal appeared to be the most effective method to remove estrogenic chemicals from wastewaters in Canada. Our studies help to identify factors or mechanisms that affect the distribution of estrogenicity in WWTPs, providing a better understanding on the discharges of estrogenic chemicals from WWTPs. PMID:26433808

  4. Effects of Estrogens on Adipokines and Glucose Homeostasis in Female Aromatase Knockout Mice

    PubMed Central

    Van Sinderen, Michelle L.; Steinberg, Gregory R.; Jørgensen, Sebastian B.; Honeyman, Jane; Chow, Jenny D.; Herridge, Kerrie A.; Winship, Amy L.; Dimitriadis, Evdokia; Jones, Margaret E. E.; Simpson, Evan R.; Boon, Wah Chin

    2015-01-01

    The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO) mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2) treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental) adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule) in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα) and interleukin 6 (IL6). Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile. PMID:26317527

  5. Expression and function of a novel variant of estrogen receptor-α36 in murine airways.

    PubMed

    Jia, Shuping; Zhang, Xintian; He, David Z Z; Segal, Manav; Berro, Abdo; Gerson, Trevor; Wang, Zhaoyi; Casale, Thomas B

    2011-11-01

    Evidence suggests that estrogen signaling is involved in sex differences in the prevalence rates and control of asthma, but the expression patterns of estrogen receptor variants and estrogen function in the lung are not well established. We investigated the expression of major estrogen receptor variants occurring naturally and after the development of allergen-induced airway hyperreactivity in a murine model of allergic asthma, along with the role of estrogen signaling in small-airway ciliary motion and smooth muscle contraction. Female BALB/c mice were sensitized with ovalbumin, and estrogen receptor expression patterns were examined by immunofluorescence and Western blot analysis. Time-lapse video and photodiode-based displacement measurement systems were used to assess the effects of estrogen signaling on airway ciliary beat frequency and smooth muscle contraction. We found that a novel variant of estrogen receptor (ER)-α, ER-α36, is expressed in airway epithelial and smooth muscle cells. ER-α36 was predominately localized on the plasma membranes of airway cells. After sensitization to allergen, the expression levels of ER-α36 increased significantly (P < 0.01), whereas the expression of ER-β and ER-α66 did not significantly change. Estrogen treatment in vitro resulted in a rapid increase in airway cilia motion in a dose-dependent fashion, but did not exert any effect on airway smooth muscle contraction. We speculate that the up-regulation of estrogen receptor expression associated with allergen-induced airway hyperresponsiveness may constitute a protective mechanism to facilitate the clearance of mucus. The identification and localization of specific estrogen receptor subtypes in the lung could lead to newer therapeutic avenues aimed at addressing sex differences of asthma susceptibility. PMID:21642591

  6. Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays.

    PubMed Central

    Shelby, M D; Newbold, R R; Tully, D B; Chae, K; Davis, V L

    1996-01-01

    Because of rampant concern that estrogenic chemicals in the environment may be adversely affecting the health of humans and wildlife, reliable methods for detecting and characterizing estrogenic chemicals are needed. It is important that general agreement be reached on which tests to use and that these tests then be applied to the testing of both man-made and naturally occurring chemicals. As a step toward developing a comprehensive approach to screening chemicals for estrogenic activity, three assays for detecting estrogenicity were conducted on 10 chemicals with known or suspected estrogenic activity. The assays were 1) competitive binding with the mouse uterine estrogen receptor, 2) transcriptional activation in HeLa cells transfected with plasmids containing an estrogen receptor and a response element, and 3) the uterotropic assay in mice. The chemicals studied were 17 beta-estradiol, diethylstilbestrol, tamoxifen, 4-hydroxytamoxifen, methoxychlor, the methoxychlor metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), endosulfan, nonylphenol, o,p'-DDT, and kepone. These studies were conducted to assess the utility of this three-assay combination in the routine screening of chemicals, or combinations of chemicals, for estrogenic activity. Results were consistent among the three assays with respect to what is known about the estrogenic activities of the chemicals tested and their requirements for metabolic activation. By providing information on three levels of hormonal activity (receptor binding, transcriptional activation, and an in vivo effect in an estrogen-responsive tissue), an informative profile of estrogenic activity is obtained with a reasonable investment of resources. Images p1296-a Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. PMID:9118870

  7. STANDARDIZATION AND VALIDATION OF PROPOSED PROTOCOLS FOR IN VITRO SCREENING ASSAYS AND QSAR FOR ESTROGEN RECEPTOR AND ANDROGEN RECEPTOR

    EPA Science Inventory

    Screening EDCs for androgenic and antiandrogenic activities was recommended by the EDSTAC Committee in it Final Report. This research will develop in vitro approaches to assess estrogen receptor binding, develop cell lines that stably express estrogen receptor for screening EDC...

  8. Chronic estrogen deficiency in mice alters FoxO1 signaling in a mixed fiber skeletal muscle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Menopause, characterized by reduced estrogen levels, is associated with increased adiposity and metabolic pathology. Molecular mechanisms underlying this association between low estrogen status and metabolic disease are not fully elucidated. Dysregulated skeletal muscle fatty acid oxidation (FAO) pr...

  9. Missing links in our understanding of estrogenic compounds; chemical quantitation vs. biological assessment – where do we go from here?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The literature has become replete with reports quantifying estrogenic chemicals in the environment ranging from natural hormones to plasticizers. Laboratories have developed in vitro assays to assess estrogenic activity of both environmental samples and pure chemicals. Information pertaining to th...

  10. The selective estrogen enzyme modulators in breast cancer: a review.

    PubMed

    Pasqualini, Jorge R

    2004-06-01

    It is well established that increased exposure to estradiol (E(2)) is an important risk factor for the genesis and evolution of breast tumors, most of which (approximately 95-97%) in their early stage are estrogen-sensitive. However, two thirds of breast cancers occur during the postmenopausal period when the ovaries have ceased to be functional. Despite the low levels of circulating estrogens, the tissular concentrations of these hormones are significantly higher than those found in the plasma or in the area of the breast considered as normal tissue, suggesting a specific tumoral biosynthesis and accumulation of these hormones. Several factors could be implicated in this process, including higher uptake of steroids from plasma and local formation of the potent E(2) by the breast cancer tissue itself. This information extends the concept of 'intracrinology' where a hormone can have its biological response in the same organ where it is produced. There is substantial information that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of E(2) from circulating precursors. Two principal pathways are implicated in the last steps of E(2) formation in breast cancer tissues: the 'aromatase pathway' which transforms androgens into estrogens, and the 'sulfatase pathway' which converts estrone sulfate (E(1)S) into E(1) by the estrone-sulfatase. The final step of steroidogenesis is the conversion of the weak E(1) to the potent biologically active E(2) by the action of a reductive 17beta-hydroxysteroid dehydrogenase type 1 activity (17beta-HSD-1). Quantitative evaluation indicates that in human breast tumor E(1)S 'via sulfatase' is a much more likely precursor for E(2) than is androgens 'via aromatase'. Human breast cancer tissue contains all the enzymes (estrone sulfatase, 17beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of E(2) biosynthesis. This tissue also contains sulfotransferase for the formation of the

  11. Estrogen Receptor Beta in the Brain: From Form to Function

    PubMed Central

    Weiser, Michael J.; Foradori, Chad D.; Handa, Robert J.

    2008-01-01

    Estrogens have numerous effects on the brain, both in adulthood and during development. These actions of estrogen are mediated by two distinct estrogen receptor (ER) systems, ER alpha (ERα) and ER beta (ERβ). In brain, ERα plays a critical role in regulating reproductive neuroendocrine function and behavior, however, a definitive role for ERβ in any neurobiological function has been slow in forthcoming. Clues to the function of ERβ in the central nervous system can be gleaned from the neuroanatomical distribution of ERβ and the phenotypes of neurons that express ERβ. ERβ immunoreactivity has been found in populations of GnRH, CRH, vasopressin, oxytocin and prolactin containing neurons in the hypothalamus. Utilizing subtype-selective estrogen receptor agonists can help determine the roles for ERβ in non-reproductive behaviors in rat models. ERβ selective agonists exert potent anxiolytic activity when animals were tested in a number of behavioral paradigms. Consistent with this, ERβ selective agonists also inhibited the ACTH and corticosterone response to stress. In contrast, ERα selective agonists were found to be anxiogenic and correspondingly increased the hormonal stress response. Taken together, our studies implicate ERβ as an important modulator of some non-reproductive neurobiological systems. The molecular and neuroanatomical targets of estrogen that are mediated by ERβ remain to be determined. A number of splice variants of ERβ mRNA have been reported in brain tissue. Imaging of eGFP labeled chimeric receptor proteins transfected into cell lines show that ERβ splice variation can alter trafficking patterns and function. The originally described ERβ (herein termed ER-β1) is characterized by possessing a high affinity for estradiol. Similar to ERα, it is localized in the nucleus and is trafficked to nuclear sites termed “hyperspeckles” following ligand binding. In contrast, ER-β2 contains an 18 amino acid insert within the ligand

  12. Molecular Characterization and Sex-Specific Tissue Expression of Estrogen Receptor Alpha (esr1), Estrogen Receptor Beta-a (esr2a) and Ovarian Aromatase (cyp19a1a) in Yellow Perch (Perca flavescens)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Yellow perch (Perca flavescens) exhibit an estrogen-stimulated sexual size dimorphism (SSD) wherein females grow faster and larger than males. To aid in the examination of this phenomenon, the cDNA sequences encoding estrogen receptor-alpha (esr1), estrogen receptor-beta-a (esr2a) and ovarian aroma...

  13. Universal assay of vitellogenin as a biomarker for environmental estrogens.

    PubMed Central

    Heppell, S A; Denslow, N D; Folmar, L C; Sullivan, C V

    1995-01-01

    Vitellogenin (VTG), the serum phospholipoglycoprotein precursor to egg yolk, is potentially an ideal biomarker for environmental estrogens. This study was undertaken to develop antibodies against conserved regions on the VTG molecule that could form the basis for establishing bioassays to detect estrogen exposure in any oviparous vertebrate. We developed monoclonal antibodies (mAbs) generated against purified rainbow trout (Oncorhynchus mykiss) VTG and selected for the property of specifically recognizing VTG purified from two phylogenetically distant vertebrates, trout and striped bass (Morone saxatilis). Results of enzyme-linked immunosorbent assay and Western blotting indicated that these mAbs specifically recognize purified VTG and VTG or other estrogen-inducible proteins in plasma or serum from representative species of four vertebrate classes (fish, amphibians, reptiles, and birds). All of the mAbs generated were IgM class. A polyclonal antiserum was raised against a synthetic consensus peptide representing the conserved N-terminal amino acid sequence of VTG. The results of Western blotting indicate that this antiserum specifically recognizes VTG in plasma or serum from teleost fish of diverse families. It was used to detect VTG in Western blots of serum from brown bullhead (Ameiurus nebulosus) with cancer (hepatocellular and cholangio-carcinoma) collected from a contaminated industrial site outside of their normal vitellogenic season. Our results indicate that it is feasible to generate antibodies capable of recognizing VTG without regard to species and that development of a universal VTG assay is an achievable goal. Images Figure 4. Figure 5. Figure 6. Figure 7. PMID:8593883

  14. Comparative endpoint sensitivity of in vitro estrogen agonist assays.

    PubMed

    Dreier, David A; Connors, Kristin A; Brooks, Bryan W

    2015-07-01

    Environmental and human health implications of endocrine disrupting chemicals (EDCs), particularly xenoestrogens, have received extensive study. In vitro assays are increasingly employed as diagnostic tools to comparatively evaluate chemicals, whole effluent toxicity and surface water quality, and to identify causative EDCs during toxicity identification evaluations. Recently, the U.S. Environmental Protection Agency (USEPA) initiated ToxCast under the Tox21 program to generate novel bioactivity data through high throughput screening. This information is useful for prioritizing chemicals requiring additional hazard information, including endocrine active chemicals. Though multiple in vitro and in vivo techniques have been developed to assess estrogen agonist activity, the relative endpoint sensitivity of these approaches and agreement of their conclusions remain unclear during environmental diagnostic applications. Probabilistic hazard assessment (PHA) approaches, including chemical toxicity distributions (CTD), are useful for understanding the relative sensitivity of endpoints associated with in vitro and in vivo toxicity assays by predicting the likelihood of chemicals eliciting undesirable outcomes at or above environmentally relevant concentrations. In the present study, PHAs were employed to examine the comparative endpoint sensitivity of 16 in vitro assays for estrogen agonist activity using a diverse group of compounds from the USEPA ToxCast dataset. Reporter gene assays were generally observed to possess greater endpoint sensitivity than other assay types, and the Tox21 ERa LUC BG1 Agonist assay was identified as the most sensitive in vitro endpoint for detecting an estrogenic response. When the sensitivity of this most sensitive ToxCast in vitro endpoint was compared to the human MCF-7 cell proliferation assay, a common in vitro model for biomedical and environmental monitoring applications, the ERa LUC BG1 assay was several orders of magnitude less

  15. Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis.

    PubMed

    MacKenzie-Graham, Allan J; Rinek, Gilda A; Avedisian, Andrea; Morales, Laurie B; Umeda, Elizabeth; Boulat, Benoit; Jacobs, Russell E; Toga, Arthur W; Voskuhl, Rhonda R

    2012-07-01

    Gray matter atrophy is an important correlate to clinical disability in multiple sclerosis (MS), and many treatment trials include atrophy as an outcome measure. Atrophy has been shown to occur in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The clinical severity of EAE is reduced in estrogen-reated mice, but it remains unknown whether estrogen treatment can reduce gray matter atrophy in EAE. In this study, mice with EAE were treated with either estrogen receptor (ER)-α ligand or ER-β ligand, and diffusion tensor images (DTI) were collected and neuropathology was performed. DTI showed atrophy in the cerebellar gray matter of vehicle-treated EAE mice compared with healthy controls but not in ER-α or ER-β ligand-treated EAE mice. Neuropathology demonstrated that Purkinje cell numbers were decreased in vehicle-treated EAE mice, whereas neither ER ligand-treated EAE groups showed a decrease. This is the first report of a neuroprotective therapy in EAE that unambiguously prevents gray matter atrophy while sparing a major neuronal cell type. Fractional anisotropy (FA) in the cerebellar white matter was decreased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Inflammatory cell infiltration was increased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Myelin staining was decreased in vehicle-treated EAE mice and was spared in both ER ligand-treated groups. This is consistent with decreased FA as a potential biomarker for inflammation rather than myelination or axonal damage in the cerebellum in EAE. PMID:22411609

  16. Decreased Estrogen May Contribute to Osteopenia in Unloaded Bones

    NASA Technical Reports Server (NTRS)

    Tou, Janet; Arnaud, Sara; Grindeland, Richard; Wade, Charles

    2004-01-01

    Progressive loss of weight-bearing bone in astronauts is one of the most serious impediments to long-duration spaceflight. Estrogen deficiency in women is an established factor in bone loss. Reduced sex hormone levels have been reported in male astronauts, but no data is available regarding spaceflight effects on female sex hormones. The objective of our study was to determine the role of estrogen in disuse osteopenia. The NASA developed hindlimb suspension (HLS) model was used to simulate the unloading disuse of weight-bearing bones experienced in space. Female Sprague-Dawley rats (age 77d; n = 20/group) were HLS or kept ambulatory (AMB) for 38 d and endocrine and bone indices determined. HLS of rats resulted in lower (p less than 0.01) bone mass (9%0), bone mineral content (BMC 13%) and mechanical strength (28%) compared to AMB animals. Plasma estradiol (E2) was lower (p = 0.03) in HLS (10.1 +/- 1.4 pg/ml) compared to AMB rats (16.7 +/- 2.6 pg/ml). E2 was positively correlated to BMC r(sup 2) = 0.67 and mechanical strength r(sup 2) = 0.61. These results suggest that reduced E2 plays a role in disuse osteopenia induced by HLS. Plasma or pituitary lutenizing hormone (LH) and follicle stimulating hormone (FSH) levels were not different in HLS versus AMB rats. However, pituitary LH was correlated to E2 (r(sup 2) = 0.57), suggesting changes in E2 were exerted at the level of the hypothalamus-pituitary axis. Understanding the role of estrogen in disuse osteopenia is necessary to the development of efficacious therapies for female astronauts, bed rest patients and the increasing number of individuals in our sedentary population suffering bone loss.

  17. Rapid screening of environmental chemicals for estrogen receptor binding capacity.

    PubMed Central

    Bolger, R; Wiese, T E; Ervin, K; Nestich, S; Checovich, W

    1998-01-01

    Over the last few years, an increased awareness of endocrine disrupting chemicals (EDCs) and their potential to affect wildlife and humans has produced a demand for practical screening methods to identify endocrine activity in a wide range of environmental and industrial chemicals. While it is clear that in vivo methods will be required to identify adverse effects produced by these chemicals, in vitro assays can define particular mechanisms of action and have the potential to be employed as rapid and low-cost screens for use in large scale EDC screening programs. Traditional estrogen receptor (ER) binding assays are useful for characterizing a chemical's potential to be an estrogen-acting EDC, but they involve displacement of a radioactive ligand from crude receptor preparations at low temperatures. The usefulness of these assays for realistically determining the ER binding interactions of weakly estrogenic environmental and industrial compounds that have low aqueous solubility is unclear. In this report, we present a novel fluorescence polarization (FP) method that measures the capacity of a competitor chemical to displace a high affinity fluorescent ligand from purified, recombinant human ER-[alpha] at room temperature. The ER-[alpha] binding interactions generated for 15 natural and synthetic compounds were found to be similar to those determined with traditional receptor binding assays. We also discuss the potential to employ this FP technology to binding studies involving ER-ss and other receptors. Thus, the assay introduced in this study is a nonradioactive receptor binding method that shows promise as a high throughput screening method for large-scale testing of environmental and industrial chemicals for ER binding interactions. Images Figure 2 Figure 3 Figure 4 PMID:9721254

  18. Early estrogen exposure induces abnormal development of Fundulus heteroclitus.

    PubMed

    Urushitani, Hiroshi; Shimizu, Akio; Katsu, Yoshinao; Iguchi, Taisen

    2002-12-01

    Many chemicals released into the environment exhibit estrogenic activity, having the potential to disrupt development and the functioning of the endocrine system. In order to establish a model system to study the effects of such environmental chemicals on aquatic animals, we examined the effects of a natural estrogen, 17 beta-estradiol (E(2)), on early development of Fundulus heteroclitus. Embryos of F. heteroclitus were reared in seawater containing 10(-10), 10(-8), and 10(-6) M E(2) throughout the experiment. Hatching and survival rates decreased in a dose-dependent manner, and fry treated with 10(-6) M E(2) and 10(-8) M E(2) were dead by two weeks and 12 weeks after hatching, respectively. More than 85% of fry treated with 10(-8) M E(2) showed malformations: i.e., eye extrusion, crooked vertebral column, faded lateral-stripe pattern eight weeks after hatching. Body weight and head and body lengths were significantly reduced in E(2)-treated fry when compared to controls. Ossification was not completed in vertebrae, cranial bones, and other bones in fry treated with 10(-8) M E(2) even 12 weeks after hatching. Sex ratio of control fry was 57% male and 43% female, whereas fry treated with 10(-8) M E(2) were 100% female eight weeks after hatching. The present results demonstrate that exogenous estrogen induced death of embryos and fry, malformations, sex reversal, and incomplete ossification of vertebrae and cranial bones, which would result in shorter body and head lengths and in malformed vertebrae leading to a hunchback condition. PMID:12410597

  19. Identification and Biological Evaluation of Coactivator Binding Inhibitors for the Estrogen Receptor

    ERIC Educational Resources Information Center

    Gunther, Jillian Rebecca

    2009-01-01

    The physiologic effects of estrogen action through the estrogen receptor (ER) are widespread, as this hormone exerts actions in both reproductive (e.g., uterus) and non-reproductive (e.g., bone, brain) tissues in both men and women. As such, the regulation of the activity of this ligand-activated transcription factor is highly relevant to the…

  20. Canonical Pathways and Networks Regulated by Estrogen in the Bovine Mammary Glands

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many attempts have been made to identify estrogen-responsive genes using high-throughput approaches such as microarray, SAGE, and in silico prediction. However, few studies have systematically analyzed regulatory networks and pathways affected by estrogen. In this report, we analyzed the transcript...

  1. Determination of steroidal estrogens in flushed dairy manure wastewater by gas chromatography-mass spectrometry.

    PubMed

    Hanselman, Travis A; Graetz, Donald A; Wilkie, Ann C; Szabo, Nancy J; Diaz, Carolyn S

    2006-01-01

    There is a critical need to accurately measure the concentrations of natural steroidal estrogens in flushed dairy manure wastewater (FDMW) to assess any potential risk of waterway contamination resulting from land application. Estrogens are a concern because low concentrations (10-100 ng L-1) in water can adversely affect aquatic vertebrate species such as fish, turtles, and frogs by disrupting the normal function of their endocrine systems. The objective of this study was to develop a sample preparation method that permits the quantification of four natural steroidal estrogens (17alpha-estradiol, 17beta-estradiol, estrone, and estriol) in FDMW by gas chromatography-mass spectrometry (GC-MS). Solid-phase extraction with graphitized carbon black was used for the bulk extraction of estrogens from FDMW and additional sample purification was accomplished with C-18. The sample preparation method allowed estrogens to be detected accurately by GC-MS in FDMW. Spiked recovery experiments indicated that the method is satisfactory for measuring the estrogens of interest in FDMW with average recovery of >90%. As expected in FDMW, characterization of the estrogen profile revealed a large abundance of 17alpha-estradiol relative to 17beta-estradiol and estrone. Estriol was not detected in FDMW. The methodology developed in this research helps provide an analytical foundation for the quantification of steroidal estrogens in FDMW by GC-MS. PMID:16585610

  2. Association between estrogen levels and temporomandibular disorders: a systematic literature review

    PubMed Central

    Berger, Marcin; Szalewski, Leszek; Bakalczuk, Magdalena; Bakalczuk, Szymon; Szkutnik, Jacek

    2015-01-01

    Introduction To evaluate whether the hypothesis that estrogen levels are associated with temporomandibular disorders (TMD) in humans can be confirmed or contradicted by available literature. Material and methods A systematic review based on the content of PubMed, Scopus, and Cochrane Library databases was performed. Studies were identified using a combination of key words ‘temporomandibular disorder’ and ‘estrogen’. Nine studies were included into our review. Results The relationship between estrogen levels and TMD was found in seven out of nine reviewed papers. Results from two papers suggest that a high estrogen level is associated with an increased prevalence of TMD. Five additional papers found a relationship between a low estrogen level and an increase in TMD pain. In considering the value of evidence and inconsistencies of results in the reviewed publications, we state that there is weak evidence to support the hypothesis that estrogen levels are associated with TMD. Conclusions Results of reviewed studies were divergent and sometimes contradictory. One possible explanation is that estrogen influences TMD pain processing differently than temporomandibular joints (TMJ) structures, as shown in many animal studies. Estrogen may influence TMD pain processing differently than TMJ structures. We suggest consideration of the dual action of estrogen when planning future studies on its association with TMD. PMID:26848299

  3. The role of estrogens in seizures and epilepsy: the bad guys or the good guys?

    PubMed

    Velísková, J

    2006-01-01

    Estrogens influence neuronal activity and are important for normal brain functions. Effects of estrogens on seizures are contradictory. It is commonly accepted that estrogens may increase neuronal excitability and thus mediate proconvulsant effects. However, clinical and animal data show that estrogen may also have no effect or anticonvulsant effects. The action of estrogens on seizures depends on various factors, such as treatment duration and latency prior to the seizure testing, estrogen dose, hormonal status (naïve vs gonadectomized animals), estrogenic substance, the region/neurotransmitter system involved, the seizure type/model used, and sex. Besides the effects on seizure susceptibility, estrogens may also play an important role in seizure-induced damage. Pretreatment with beta-estradiol in ovariectomized female rats has neuroprotective effects on status epilepticus-induced hippocampal damage and prevents the loss of inhibition in the dentate gyrus during the early post-status epilepticus period determined by the in vitro paired pulse paradigm. Several signaling pathways may be involved in the neuroprotective effects of beta-estradiol on status epilepticus-induced hippocampal damage but at least one of these pathways involves interactions with neuropeptide Y. PMID:16310960

  4. Phytoestrogens and Mycoestrogens Induce Signature Structure Dynamics Changes on Estrogen Receptor α.

    PubMed

    Chen, Xueyan; Uzuner, Ugur; Li, Man; Shi, Weibing; Yuan, Joshua S; Dai, Susie Y

    2016-01-01

    Endocrine disrupters include a broad spectrum of chemicals such as industrial chemicals, natural estrogens and androgens, synthetic estrogens and androgens. Phytoestrogens are widely present in diet and food supplements; mycoestrogens are frequently found in grains. As human beings and animals are commonly exposed to phytoestrogens and mycoestrogens in diet and environment, it is important to understand the potential beneficial or hazardous effects of estrogenic compounds. Many bioassays have been established to study the binding of estrogenic compounds with estrogen receptor (ER) and provided rich data in the literature. However, limited assays can offer structure information with regard to the ligand/ER complex. Our current study surveys the global structure dynamics changes for ERα ligand binding domain (LBD) when phytoestrogens and mycoestrogens bind. The assay is based on the structure dynamics information probed by hydrogen deuterium exchange mass spectrometry and offers a unique viewpoint to elucidate the mechanism how phytoestrogens and mycoestrogens interact with estrogen receptor. The cluster analysis based on the hydrogen deuterium exchange (HDX) assay data reveals a unique pattern when phytoestrogens and mycoestrogens bind with ERα LBD compared to that of estradiol and synthetic estrogen modulators. Our study highlights that structure dynamics could play an important role in the structure function relationship when endocrine disrupters interact with estrogen receptors. PMID:27589781

  5. Estrogenic Environmental Chemicals and Drugs: Mechanisms for Effects on the Developing Male Urogenital System

    PubMed Central

    Taylor, Julia A.; Richter, Catherine A.; Ruhlen, Rachel L.; vom Saal, Frederick S.

    2011-01-01

    Development and differentiation of the prostate from the fetal urogenital sinus (UGS) is dependent on androgen action via androgen receptors (AR) in the UGS mesenchyme. Estrogens are not required for prostate differentiation but do act to modulate androgen action. In mice exposure to exogenous estrogen during development results in permanent effects on adult prostate size and function, which is mediated through mesenchymal estrogen receptor (ER) alpha. For many years estrogens were thought to inhibit prostate growth because estrogenic drugs studied were administered at very high concentrations that interfered with normal prostate development. There is now extensive evidence that exposure to estrogen at very low concentrations during the early stages of prostate differentiation can stimulate fetal/neonatal prostate growth and lead to prostate disease in adulthood. Bisphenol A (BPA) is an environmental endocrine disrupting chemical that binds to both ER receptor subtypes as well as to AR. Interest in BPA has increased because of its prevalence in the environment and its detection in over 90% of people in the USA. In tissue culture of fetal mouse UGS mesenchymal cells, BPA and estradiol stimulated changes in the expression of several genes. We discuss here the potential involvement of estrogen in regulating signaling pathways affecting cellular functions relevant to steroid hormone signaling and metabolism and to inter- and intra-cellular communications that promote cell growth. The findings presented here provide additional evidence that BPA and the estrogenic drug ethinylestradiol disrupt prostate development in male mice at administered doses relevant to human exposures. PMID:21827855

  6. Integration of Nuclear- and Extranuclear-Initiated Estrogen Receptor Signaling in Breast Cancer Cells

    ERIC Educational Resources Information Center

    Madak Erdogan, Zeynep

    2009-01-01

    Estrogenic hormones exert their effects through binding to Estrogen Receptors (ERs), which work in concert with coregulators and extranuclear signaling pathways to control gene expression in normal as well as cancerous states, including breast tumors. In this thesis, we have used multiple genome-wide analysis tools to elucidate various ways that…

  7. EVALUATION OF ESTROGENIC ACTIVITY FROM A MUNICIPAL WASTEWATER TREATMENT PLANT WITH PREDOMINANTLY DOMESTIC INPUT

    EPA Science Inventory

    The purpose of this study was to survey estrogenic releases from two primarily domestic wastewater treatment plants over three seasons (1996-1999). Mature male channel catfish were maintained at two sites within each WWTP and a reference site for 21 days. Estrogenic activity of e...

  8. 21 CFR 201.301 - Notice to manufacturers, packers, and distributors of estrogenic hormone preparations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... of estrogenic hormone preparations. 201.301 Section 201.301 Food and Drugs FOOD AND DRUG... estrogenic hormone preparations. Some drug preparations fabricated wholly or in part from estradiol and... activity have been marketed. The international unit of the estrus-producing hormone was established by...

  9. 21 CFR 201.301 - Notice to manufacturers, packers, and distributors of estrogenic hormone preparations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... of estrogenic hormone preparations. 201.301 Section 201.301 Food and Drugs FOOD AND DRUG... estrogenic hormone preparations. Some drug preparations fabricated wholly or in part from estradiol and... activity have been marketed. The international unit of the estrus-producing hormone was established by...

  10. 21 CFR 201.301 - Notice to manufacturers, packers, and distributors of estrogenic hormone preparations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... of estrogenic hormone preparations. 201.301 Section 201.301 Food and Drugs FOOD AND DRUG... estrogenic hormone preparations. Some drug preparations fabricated wholly or in part from estradiol and... activity have been marketed. The international unit of the estrus-producing hormone was established by...

  11. Comprehensive assessment of hormones, phytoestrogens, and estrogenic activity in an anaerobic swine waste lagoon

    USGS Publications Warehouse

    Yost, Erin E.; Meyer, Michael T.; Dietze, Julie E.; Meissner, Benjamin M.; Williams, Mike; Worley-Davis, Lynn; Lee, Boknam; Kullman, Seth W.

    2013-01-01

    In this study, the distribution of steroid hormones, phytoestrogens, and estrogenic activity was thoroughly characterized within the anaerobic waste lagoon of a typical commercial swine sow operation. Three independent rounds of sampling were conducted in June 2009, April 2010, and February 2011. Thirty-seven analytes in lagoon slurry and sludge were assessed using LC/MS-MS, and yeast estrogen screen was used to determine estrogenic activity. Of the hormone analytes, steroidal estrogens were more abundant than androgens or progesterone, with estrone being the predominant estrogen species. Conjugated hormones were detected only at low levels. The isoflavone metabolite equol was by far the predominant phytoestrogen species, with daidzein, genistein, formononetin, and coumestrol present at lower levels. Phytoestrogens were often more abundant than steroidal estrogens, but contributed minimally towards total estrogenic activity. Analytes were significantly elevated in the solid phases of the lagoon; although low observed log KOC values suggest enhanced solubility in the aqueous phase, perhaps due to dissolved or colloidal organic carbon. The association with the solid phase, as well as recalcitrance of analytes to anaerobic degradation, results in a markedly elevated load of analytes and estrogenic activity within lagoon sludge. Overall, findings emphasize the importance of adsorption and transformation processes in governing the fate of these compounds in lagoon waste, which is ultimately used for broadcast application as a fertilizer.

  12. 21 CFR 201.301 - Notice to manufacturers, packers, and distributors of estrogenic hormone preparations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... of estrogenic hormone preparations. 201.301 Section 201.301 Food and Drugs FOOD AND DRUG... estrogenic hormone preparations. Some drug preparations fabricated wholly or in part from estradiol and... activity have been marketed. The international unit of the estrus-producing hormone was established by...

  13. 21 CFR 201.301 - Notice to manufacturers, packers, and distributors of estrogenic hormone preparations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... of estrogenic hormone preparations. 201.301 Section 201.301 Food and Drugs FOOD AND DRUG... estrogenic hormone preparations. Some drug preparations fabricated wholly or in part from estradiol and... activity have been marketed. The international unit of the estrus-producing hormone was established by...

  14. Estrogen receptor mutations in breast cancer--new focus on an old target.

    PubMed

    Segal, Corrinne V; Dowsett, Mitch

    2014-04-01

    Recent studies have provided strong evidence for the emergence of substantial numbers of constitutively active ESR1 mutations in estrogen receptor-positive metastatic breast cancer that are undetected in primary disease. Some of these mutants remain partially sensitive to current anti-estrogen therapies but effective therapeutics targeted at them may require new approaches. PMID:24583794

  15. Estrogen and phenol red free medium for osteoblast culture: study of the mineralization ability.

    PubMed

    de Faria, A N; Zancanela, D C; Ramos, A P; Torqueti, M R; Ciancaglini, P

    2016-08-01

    To design an estrogen and phenol red free medium for cell culture and check its effectiveness and safety on osteoblast growth it is necessary to maintain the estrogen receptors free for tests. For this purpose, we tested some modifications of the traditional culture media: estrogen depleted fetal bovine serum; estrogen charcoal stripped fetal bovine serum and phenol red free α-MEM. The aim of this work is to examine the effects of its depletion in the proliferation, differentiation, and toxicity of mesenchymal stromal cells differentiated into osteoblasts to obtain an effective interference free culture medium for in vitro studies, focused on non-previously studied estrogen receptors. We performed viability tests using the following techniques: MTT, alkaline phosphatase specific activity, formation of mineralized matrix by Alizarin technique and analysis of SEM/EDX of mineralized nodules. The results showed that the culture media with estrogen free α-MEM + phenol red free α-MEM did not impact viability, alkaline phosphatase activity and mineralization of the osteoblasts culture compared to control. In addition, its nodules possess Ca/P ratio similar to hydroxyapatite nodules on the 14th and 21st day. In conclusion, the modified culture medium with phenol red free α-MEM with estrogen depleted fetal bovine serum can be safely used in experiments where the estrogen receptors need to be free. PMID:25634598

  16. EFFECTS OF EXPOSURE TO ENVIRONMENTAL ESTROGENS ON REPRODUCTIVE PARAMETERS IN A MARINE FISH, TAUTOGOLABRUS ADSPERSUS

    EPA Science Inventory

    Estradiol (E2), ethynylestradiol (EE2) and estrone (E4) are steroidal estrogens that are released into the aquatic environment in sewage treatment effluent. To determine whether these estrogens could impact reproductive parameters in a model fish species, actively spawning male ...

  17. A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic.

    PubMed Central

    Jobling, S; Reynolds, T; White, R; Parker, M G; Sumpter, J P

    1995-01-01

    Sewage, a complex mixture of organic and inorganic chemicals, is considered to be a major source of environmental pollution. A random screen of 20 organic man-made chemicals present in liquid effluents revealed that half appeared able to interact with the estradiol receptor. This was demonstrated by their ability to inhibit binding of 17 beta-estradiol to the fish estrogen receptor. Further studies, using mammalian estrogen screens in vitro, revealed that the two phthalate esters butylbenzyl phthalate (BBP) and di-n-butylphthalate (DBP) and a food antioxidant, butylated hydroxyanisole (BHA) were estrogenic; however, they were all less estrogenic than the environmental estrogen octylphenol. Phthalate esters, used in the production of various plastics (including PVC), are among the most common industrial chemicals. Their ubiquity in the environment and tendency to bioconcentrate in animal fat are well known. Neither BBP nor DBP were able to act as antagonists, indicating that, in the presence of endogenous estrogens, their overall effect would be cumulative. Recently, it has been suggested that environmental estrogens may be etiological agents in several human diseases, including disorders of the male reproductive tract and breast and testicular cancers. The current finding that some phthalate compounds and some food additives are weakly estrogenic in vitro, needs to be supported by further studies on their effects in vivo before any conclusions can be made regarding their possible role in the development of these conditions. Images Figure 1. Figure 2. Figure 3. Figure 4. PMID:7556011

  18. Development of a Competitive Binding Assay System with Recombinant Estrogen Receptors from Multiple Species

    EPA Science Inventory

    ABSTRACT In the current study, we developed a new system using full-length recombinant baculovirus-expressed estrogen receptors which allows for direct comparison of binding across species. Estrogen receptors representing five vertebrate classes were compared: human (hERα), quai...

  19. YEAST ESTROGEN SCREEN FOR EXAMINING THE RELATIVE EXPOSURE OF CELLS TO NATURAL AND XENOESTROGENS

    EPA Science Inventory

    Xenoestrogens, such as o,p'-DDT and octyl phenol (OP) have been associated with reproductive abnormalities in various wildlife species. Xenoestrogens mimic the natural estrogen 17b-estradiol and compete for binding to the estrogen receptor. Even though the affinity of o,p'-DDTan...

  20. Hormone Binding to Recombinant Estrogen Receptors from Human, Alligator, Quail, Salamander, and Fathead Minnow

    EPA Science Inventory

    In this work, a 96-well plate estrogen receptor binding assay was developed to facilitate the direct comparison of chemical binding to full-length recombinant estrogen receptors across vertebrate classes. Receptors were generated in a baculovirus expression system. This approach ...

  1. E-Screen - potential tool for assessment of relative serum estrogenicity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The E-Screen bioassay, used to measure estrogenic activity of environmental water samples, feedstuffs, and pure chemicals, was evaluated for its usefulness in estrogenicity assessment of porcine, ovine, bovine, and piscine serum. High concentrations of swine, cattle, and fish serum were toxic to th...

  2. Ethanolic extract of dandelion (Taraxacum mongolicum) induces estrogenic activity in MCF-7 cells and immature rats.

    PubMed

    Oh, Seung Min; Kim, Ha Ryong; Park, Yong Joo; Lee, Yong Hwa; Chung, Kyu Hyuck

    2015-11-01

    Plants of the genus Taraxacum, commonly known as dandelions, are used to treat breast cancer in traditional folk medicine. However, their use has mainly been based on empirical findings without sufficient scientific evidence. Therefore, we hypothesized that dandelions would behave as a Selective estrogen receptor modulator (SERM) and be effective as hormone replacement therapy (HRT) in the postmenopausal women. In the present study, in vitro assay systems, including cell proliferation assay, reporter gene assay, and RT-PCR to evaluate the mRNA expression of estrogen-related genes (pS2 and progesterone receptor, PR), were performed in human breast cancer cells. Dandelion ethanol extract (DEE) significantly increased cell proliferation and estrogen response element (ERE)-driven luciferase activity. DEE significantly induced the expression of estrogen related genes such as pS2 and PR, which was inhibited by tamoxifen at 1 μmol·L(-1). These results indicated that DEE could induce estrogenic activities mediated by a classical estrogen receptor pathway. In addition, immature rat uterotrophic assay was carried out to identify estrogenic activity of DEE in vivo. The lowest concentration of DEE slightly increased the uterine wet weight, but there was no significant effect with the highest concentration of DEE. The results demonstrate the potential estrogenic activities of DEE, providing scientific evidence supporting their use in traditional medicine. PMID:26614455

  3. The role of membrane ERα signaling in bone and other major estrogen responsive tissues.

    PubMed

    Gustafsson, K L; Farman, H; Henning, P; Lionikaite, V; Movérare-Skrtic, S; Wu, J; Ryberg, H; Koskela, A; Gustafsson, J-Å; Tuukkanen, J; Levin, E R; Ohlsson, C; Lagerquist, M K

    2016-01-01

    Estrogen receptor α (ERα) signaling leads to cellular responses in several tissues and in addition to nuclear ERα-mediated effects, membrane ERα (mERα) signaling may be of importance. To elucidate the significance, in vivo, of mERα signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ERα to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mERα signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40-70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mERα (<35% reduction in estrogen response in NOER mice). In conclusion, mERα signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ERα actions may provide means to develop new selective estrogen receptor modulators with improved profiles. PMID:27388455

  4. Estrogenic activity – a frame of reference for some foods, agricultural wastewaters, and animal feedstuffs.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In the last decade, several in vitro estrogenic activity assays have been used to assess municipal and agricultural wastewaters and surface waters. Some work has been published to provide context by measuring activity from waters collected in pristine or “control” sites, but the relative estrogenic...

  5. Triclosan exposure modulates estrogen-dependent responses in the rat uterotrophic assay.

    EPA Science Inventory

    Our previous studies in the juvenile rat indicated that the biocide triclosan may alter steroid hormone levels. Here, we hypothesize that triclosan possesses estrogenic activity. In the first study, we evaluated the potential estrogenicity of triclosan using the immature rat uter...

  6. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Estrogens regulate body weight and reproduction primarily through actions on estrogen receptor-a(ERa). However, ERalpha-expressing cells mediating these effects are not identified. We demonstrate that brain-specific deletion of ERalapha in female mice causes abdominal obesity stemming from both hype...

  7. Pathogenic infection confounds induction of the estrogenic biomarker vitellogenin in rainbow trout

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To examine the behavior of the estrogenic biomarker vitellogenin (VTG) under the combined impact of estrogens and pathogens, parasite-infected or noninfected rainbow trout were exposed to two doses of 17 beta-estradiol (E2). Infected and E2-exposed fish showed significantly lower hepatic VTG mRNA le...

  8. Removal of Estrogenic Compounds in Dairy Waste Lagoons by Ferrate (VI): Oxidation/Coagulation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ferrate(VI) was used to break down and/or remove steroidal estrogens (SE) from dairy waste lagoon effluent (DWLE). Dairy lagoon sites were sampled for estrogenic content (EC) and assayed using high performance liquid chromatography coupled to triple quadrupole mass spectrometry. Effects of varying...

  9. Estrogenic Plant Extracts Reverse Weight Gain and Fat Accumulation without Causing Mammary Gland or Uterine Proliferation

    PubMed Central

    Saunier, Elise F.; Vivar, Omar I.; Rubenstein, Andrea; Zhao, Xiaoyue; Olshansky, Moshe; Baggett, Scott; Staub, Richard E.; Tagliaferri, Mary; Cohen, Isaac; Speed, Terence P.; Baxter, John D.; Leitman, Dale C.

    2011-01-01

    Long-term estrogen deficiency increases the risk of obesity, diabetes and metabolic syndrome in postmenopausal women. Menopausal hormone therapy containing estrogens might prevent these conditions, but its prolonged use increases the risk of breast cancer, as wells as endometrial cancer if used without progestins. Animal studies indicate that beneficial effects of estrogens in adipose tissue and adverse effects on mammary gland and uterus are mediated by estrogen receptor alpha (ERα). One strategy to improve the safety of estrogens to prevent/treat obesity, diabetes and metabolic syndrome is to develop estrogens that act as agonists in adipose tissue, but not in mammary gland and uterus. We considered plant extracts, which have been the source of many pharmaceuticals, as a source of tissue selective estrogens. Extracts from two plants, Glycyrrhiza uralensis (RG) and Pueraria montana var. lobata (RP) bound to ERα, activated ERα responsive reporters, and reversed weight gain and fat accumulation comparable to estradiol in ovariectomized obese mice maintained on a high fat diet. Unlike estradiol, RG and RP did not induce proliferative effects on mammary gland and uterus. Gene expression profiling demonstrated that RG and RP induced estradiol-like regulation of genes in abdominal fat, but not in mammary gland and uterus. The compounds in extracts from RG and RP might constitute a new class of tissue selective estrogens to reverse weight gain, fat accumulation and metabolic syndrome in postmenopausal women. PMID:22163294

  10. Notch-1 activates estrogen receptor-α-dependent transcription via IKKα in breast cancer cells

    PubMed Central

    Hao, L; Rizzo, P; Osipo, C; Pannuti, A; Wyatt, D; Cheung, LW-K; Sonenshein, G; Osborne, BA; Miele, L

    2016-01-01

    Approximately 80% of breast cancers express the estrogen receptor-α (ERα) and are treated with anti-estrogens. Resistance to these agents is a major cause of mortality. We have shown that estrogen inhibits Notch, whereas anti-estrogens or estrogen withdrawal activate Notch signaling. Combined inhibition of Notch and estrogen signaling has synergistic effects in ERα-positive breast cancer models. However, the mechanisms whereby Notch-1 promotes the growth of ERα-positive breast cancer cells are unknown. Here, we demonstrate that Notch-1 increases the transcription of ERα-responsive genes in the presence or absence of estrogen via a novel chromatin crosstalk mechanism. Our data support a model in which Notch-1 can activate the transcription of ERα-target genes via IKKα-dependent cooperative chromatin recruitment of Notch–CSL–MAML1 transcriptional complexes (NTC) and ERα, which promotes the recruitment of p300. CSL binding elements frequently occur in close proximity to estrogen-responsive elements (EREs) in the human and mouse genomes. Our observations suggest that a hitherto unknown Notch-1/ERα chromatin crosstalk mediates Notch signaling effects in ERα-positive breast cancer cells and contributes to regulate the transcriptional functions of ERα itself. PMID:19838210

  11. Factor XII mutations, estrogen-dependent inherited angioedema, and related conditions.

    PubMed

    Binkley, Karen E

    2010-01-01

    The clinical, biochemical and genetic features of the conditions known as estrogen-dependent inherited angioedema, estrogen-associated angioedema, hereditary angioedema with normal C-1 inhibitor, type III angioedema, or factor XII angioedema are reviewed. Discussion emphasizes pathogenesis, diagnosis, and management. PMID:20667119

  12. Importance of Estrogenic Signaling and Its Mediated Receptors in Prostate Cancer.

    PubMed

    Lau, Kin-Mang; To, Ka-Fai

    2016-01-01

    Prostate cancer (PCa) treatment was first established by Huggins and Hodges in 1941, primarily described as androgen deprivation via interference of testicular androgen production. The disease remains incurable with relapse of hormone-refractory cancer after treatments. Epidemiological and clinical studies disclosed the importance of estrogens in PCa. Discovery of estrogen receptor ERβ prompted direct estrogenic actions, in conjunction with ERα, on PCa cells. Mechanistically, ERs upon ligand binding transactivate target genes at consensus genomic sites via interactions with various transcriptional co-regulators to mold estrogenic signaling. With animal models, Noble revealed estrogen dependencies of PCa, providing insight into potential uses of antiestrogens in the treatment. Subsequently, various clinical trials were conducted and molecular and functional consequences of antiestrogen treatment in PCa were delineated. Besides, estrogens can also trigger rapid non-genomic signaling responses initiated at the plasma membrane, at least partially via an orphan G-protein-coupled receptor GPR30. Activation of GPR30 significantly inhibited in vitro and in vivo PCa cell growth and the underlying mechanism was elucidated. Currently, molecular networks of estrogenic and antiestrogenic signaling via ERα, ERβ and GPR30 in PCa have not been fully deciphered. This crucial information could be beneficial to further developments of effective estrogen- and antiestrogen-based therapy for PCa patients. PMID:27589731

  13. Identification of estrogenic activity change in sewage, industrial and livestock effluents by gamma-irradiation

    NASA Astrophysics Data System (ADS)

    Ahn, Byeong-Yong; Kang, Sung-Wook; Yoo, Jisu; Kim, Woong-Ki; Bae, Paek-Hyun; Jung, Jinho

    2012-11-01

    In this study, reduction of estrogenic activity in three different types of effluents from sewage, industrial and livestock wastewater treatment plants by gamma-irradiation was investigated using the yeast two-hybrid assay. After gamma-ray treatment at a dose of 10 kGy, estrogenic activities of sewage, industrial and livestock effluents decreased from 4.4 to 3.0, 1.5 to 1.0 and 16 to 9.9 ng-EEQ L-1, respectively. The substantial reduction of estrogenic activity in livestock effluent was attributable to the degradation of 17β-estradiol (E2), estrone (E1) and 17α-ethynylestradiol (EE2). Although bisphenol A (BPA) was found at the highest concentration in all effluents, its contribution to the estrogenic activity was not significant due to its low relative estrogenic potency. Meanwhile, the calcul