Science.gov

Sample records for early exogenous estrogen

  1. Immunosuppression Following Exposure to Exogenous Estrogens

    DTIC Science & Technology

    1983-08-01

    and laboratory animals aad has been associated with endo- metrial cancer, breast cancer, and vaginal adenocarcinoma (McLachlan, 1980). In mice, DES ... DES ), a nonsteroidal synthet- ic estrogen with potent estrogenic activity was examined. This compound has been employed as a therapeutic agent in...humans as well as a growth promotant in livestock (McMartin, 1978). There is mounting evidence, however, that DES is potentially carcinogenic in humans

  2. 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 ...

  3. Exogenous estrogen as mediator of racial differences in bioactive insulin-like growth factor-I levels among postmenopausal women.

    PubMed

    Jung, Su Yon; Vitolins, Mara Z; Paskett, Electra D; Chang, Shine

    2015-04-01

    The role of exogenous estrogen use in racial differences in insulin-like growth factor-I (IGF-I) levels which affect cancer risk is unclear. We investigated whether the relationship between race and circulating bioactive IGF-I proteins was mediated by exogenous estrogen and the extent to which exogenous estrogen influenced the race-IGF-I relationship in postmenopausal women. This cross-sectional study included 636 white and 133 African American postmenopausal women enrolled in an ancillary study of the Women's Health Initiative Observational Study. To assess exogenous estrogen use (nonusers [n = 262] vs users [n = 507]) as a mediator of the race-IGF-I relationship, we used the Baron-Kenny method and an estimation of the proportional change in the odd ratios for IGF-I levels on race plus a bootstrapping test for the significance of the mediation effect. Compared with white women, African American women were more likely to have high IGF-I levels and less likely to use exogenous estrogen. After accounting for race, estrogen nonusers had higher IGF-I levels than estrogen users did. Among oral contraceptive ever users, exogenous estrogen had a strong mediation effect (67%; p = .018) in the race-IGF-I relationship. In the women with a history of hypertension, exogenous estrogen explained racial differences in IGF-I levels to a modest degree (23%; p = .029). Exogenous estrogen use has a potentially important role in disparities in IGF-I bioactivity between postmenopausal African American and white women. A history of oral contraceptive use and hypertension may be part of the interconnected hormonal pathways related to racial differences in IGF-I levels. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Exogenous Estrogen as Mediator of Racial Differences in Bioactive Insulin-Like Growth Factor-I Levels Among Postmenopausal Women

    PubMed Central

    Vitolins, Mara Z.; Paskett, Electra D.; Chang, Shine

    2015-01-01

    Background. The role of exogenous estrogen use in racial differences in insulin-like growth factor-I (IGF-I) levels which affect cancer risk is unclear. We investigated whether the relationship between race and circulating bioactive IGF-I proteins was mediated by exogenous estrogen and the extent to which exogenous estrogen influenced the race–IGF-I relationship in postmenopausal women. Methods. This cross-sectional study included 636 white and 133 African American postmenopausal women enrolled in an ancillary study of the Women’s Health Initiative Observational Study. To assess exogenous estrogen use (nonusers [n = 262] vs users [n = 507]) as a mediator of the race–IGF-I relationship, we used the Baron–Kenny method and an estimation of the proportional change in the odd ratios for IGF-I levels on race plus a bootstrapping test for the significance of the mediation effect. Results. Compared with white women, African American women were more likely to have high IGF-I levels and less likely to use exogenous estrogen. After accounting for race, estrogen nonusers had higher IGF-I levels than estrogen users did. Among oral contraceptive ever users, exogenous estrogen had a strong mediation effect (67%; p = .018) in the race–IGF-I relationship. In the women with a history of hypertension, exogenous estrogen explained racial differences in IGF-I levels to a modest degree (23%; p = .029). Conclusions. Exogenous estrogen use has a potentially important role in disparities in IGF-I bioactivity between postmenopausal African American and white women. A history of oral contraceptive use and hypertension may be part of the interconnected hormonal pathways related to racial differences in IGF-I levels. PMID:25238773

  5. Reproductive factors, exogenous estrogen use and risk of Parkinson’s disease

    PubMed Central

    Simon, Kelly Claire; Chen, Honglei; Gao, Xiang; Schwarzschild, Michael A.; Ascherio, Alberto

    2009-01-01

    To determine if reproductive factors or exogenous estrogen are associated with risk of Parkinson’s disease (PD), we conducted a prospective study with 22 years of follow-up among post-menopausal participants in the Nurses’ Health Study. Relative risks (RRs) and 95% confidence intervals (CIs) of PD were estimated from a Cox proportional hazards model adjusting for potential confounders. Risk of PD was not significantly associated with any of the reproductive factors measured or exogenous estrogen use. Use of post-menopausal hormones, however, may modify the associations of smoking and caffeine intake with PD risk. The inverse relation between smoking and PD risk was attenuated among ever users of post-menopausal hormones (p for interaction = 0.05). Similar results were obtained for caffeine (p for interaction = 0.09). In exploratory analyses, women using progestin-only hormones were found to have an increased PD risk, but this result was based on a very small number of cases (n=4). In this large longitudinal study, we found no evidence of a beneficial effect of exogenous or endogenous estrogens on risk of PD. The use of post-menopausal hormone use may interact with other risk factors, but findings are preliminary and need confirmation in other populations. PMID:19424986

  6. Reproductive failure of the red shiner (Cyprinella lutrensis) after exposure to an exogenous estrogen

    USGS Publications Warehouse

    McGree, M.M.; Winkelman, D.L.; Vieira, N.K.M.; Vajda, A.M.

    2010-01-01

    Endocrine disrupting chemicals (EDCs) have been detected in surface waters worldwide and can lead to developmental and reproductive disruption in exposed fishes. In the US Great Plains, EDCs are impacting streams and rivers and may be causing adverse reproductive effects. To examine how estrogenic EDCs might affect reproductive success of plains fishes, we experimentally exposed male red shiners (Cyprinella lutrensis) to exogenous 17b-estradiol. We characterized the effects of estradiol on male gonadal histology and secondary sexual characteristics, determined whether exposure reduced reproductive success, and examined the effects of depuration. Adults were exposed to a mean concentration of 70 ng L-1 estradiol, a solvent control, or a water control for at least 83 days. Male exposure to estradiol resulted in elevated plasma vitellogenin concentrations, changes in spermatogenesis, reduced mating coloration and tubercles, altered mating behaviors, and reduced reproductive success with no viable progeny produced. Reproductive endpoints improved upon depuration (28 days). Exposure to estradiol had significant adverse effects on red shiners, indicating that wild populations may face developmental and reproductive difficulties if they are chronically exposed to estradiol.

  7. Feeding a higher plane of nutrition and providing exogenous estrogen increases mammary gland development in Holstein heifer calves.

    PubMed

    Geiger, A J; Parsons, C L M; Akers, R M

    2016-09-01

    Feeding heifers a higher plane of nutrition postweaning but before puberty can negatively affect mammary gland development and future milk yield. However, enhanced nutrition preweaning may promote development and future production. Our objectives were to determine the effects of enhanced feeding preweaning and exogenous estrogen immediately postweaning on mammary gland development and the composition of the mammary parenchyma (PAR) and mammary fat pad (MFP). Thirty-six Holstein heifer calves (<1 wk old) were reared on 1 of 2 dietary treatments for 8 wk: (1) a restricted milk replacer fed at 0.45 kg/d (R; 20% crude protein, 20% fat), or (2) an enhanced milk replacer fed at 1.13 kg/d (EH; 28% crude protein, 25% fat). Upon weaning, calves from each diet (n=6) were given either a placebo or estrogen implant for 2 wk, creating 4 treatments: R, R + estrogen (R-E2), EH, and EH + estrogen (EH-E2). Calves were housed individually with ad libitum access to water. Starter feeding began at wk 5 and was balanced between treatments. Udders were evaluated by palpation and physical measurements weekly. Subsets of calves were killed at weaning (n=6 per diet) and at the conclusion of the trial (n=6 per treatment). Udders were removed, dissected, and weighed. At wk 8, EH calves had longer front and rear teats. Providing estrogen to EH calves increased the length of rear teats during wk 9 and 10. Enhanced-fed calves had 5.2-fold more trimmed mammary gland mass than R calves. Providing estrogen to EH calves further increased mammary gland weight. Masses of PAR and MFP were markedly greater for EH calves than for R calves (e.g., 7.3-fold greater PAR tissue). Estrogen increased the mass of both PAR and MFP in EH calves. Feeding a higher plane of nutrition increased total protein, DNA, and fat in the MFP and total protein and DNA in the PAR. Dual-energy x-ray absorptiometry estimates of mammary fat mass were highly correlated with biochemical analyses of fat content. From histological

  8. Endogenous and Exogenous Estrogen, Cognitive Function and Dementia in Postmenopausal Women: Evidence from Epidemiologic Studies and Clinical Trials

    PubMed Central

    Laughlin, Gail A.

    2009-01-01

    There are more than 200 published scientific papers showing that estrogen has favorable effects on brain tissue and physiology in cell culture and animal models including nonhuman primates. The biological plausibility for a neuroprotective estrogen effect is overwhelming. However, most studies of endogenous estrogen and cognitive decline or dementia fail to show protection, and some suggest harm. Failure to find any consistent association might reflect the limitations of a single time of estrogen assay or poor assay sensitivity. More than half of the observational studies of hormone therapy suggest benefit. Nearly all long term clinical trials fail to show benefit and the longer trials tend to show harm. Failure to adequately adjust for self-selection of healthier and wealthier women and publication bias could account for some, or all, of the protective effect attributed to estrogen in observational studies. Overall, the evidence does not convincingly support the prescription of early or late postmenopausal estrogen therapy to preserve cognitive function or prevent dementia. PMID:19401958

  9. Exogenous estrogen protects mice from the consequences of obesity and alcohol.

    PubMed

    Holcomb, Valerie B; Hong, Jina; Núñez, Nomelí P

    2012-06-01

    Breast cancer is the second leading cause of cancer death among American women. Risk factors for breast cancer include obesity, alcohol consumption, and estrogen therapy. In the present studies, we determine the simultaneous effects of these three risk factors on wingless int (Wnt)-1 mammary tumor growth. Ovariectomized female mice were fed diets to induce different body weights (calorie restricted, low fat, high fat), provided water or 20% alcohol, implanted with placebo or estrogen pellets and injected with Wnt-1 mouse mammary cancer cells. Our results show that obesity promoted the growth of Wnt-1 tumors and induced fatty liver. Tumors tended to be larger in alcohol-consuming mice and alcohol exacerbated fatty liver in obese mice. Estrogen treatment promoted weight loss in obese mice, which was associated with the suppression of tumor growth and fatty liver. In summary, we show that estrogen protects against obesity, which is associated with the inhibition of fatty liver and tumor growth.

  10. Growth, intake, and health of Holstein heifer calves fed an enhanced preweaning diet with or without postweaning exogenous estrogen.

    PubMed

    Geiger, A J; Parsons, C L M; James, R E; Akers, R M

    2016-05-01

    Research has shown that changes in nutrition both before and after weaning can affect mammary development. Additionally, estrogen is known to be a potent mammogenic stimulant. Our objectives were to determine effects of altered preweaning feeding and exogenous estradiol postweaning on growth, intake, and health. Thirty-six Holstein heifer calves were reared on (1) a restricted milk replacer (MR) diet fed at 0.44kg powder dry matter (DM)/day [R; 20.9% crude protein (CP), 19.8% fat, DM basis], or (2) an enhanced MR fed at 1.08kg powder DM/d (EH; 28.9% CP, 26.2% fat, DM basis). The MR feeding was reduced 50% during wk 8 to prepare for weaning. Starter was offered after wk 4 but balanced between treatments. Body weight and frame were measured weekly with intakes and health monitored daily. At weaning, a subset of calves were slaughtered (n=6/diet). Enhanced-fed calves had greater carcass, thymus, liver, spleen, and mammary gland (parenchyma and mammary fat pad) weights. The EH calves also had greater average daily gain (ADG) starting during wk 1 (0.36 vs. -0.06kg/d) and lasting through wk 7 (1.00 vs. 0.41kg/d). Remaining calves received estrogen implants or placebo and were slaughtered at the end of wk 10, creating 4 treatments: (1) R, (2) R + estrogen (R-E2), (3) EH, and (4) EH + estrogen (EH-E2). Postweaning ADG was similar between R, EH, and EH-E2 calves, but greater in R-E2 calves than E calves. The EH-E2 calves had the heaviest mammary glands, and R-E2 calves had heavier mammary glands than R calves. The EH calves consumed more MR DM, CP, and fat preweaning. The R-fed calves consumed more starter DM preweaning. Fecal score was greater for EH calves (1.74 vs. 1.50) preweaning, but days medicated did not differ. Fecal scores were lower for R-E2 calves postweaning. Improved preweaning feeding of calves increased body weights and frame measures. Differences in body weights remained postweaning. Enhanced-fed calves showed greater ADG during the preweaning period but

  11. Environmental estrogens alter early development in Xenopus laevis.

    PubMed

    Bevan, Cassandra L; Porter, Donna M; Prasad, Anita; Howard, Marthe J; Henderson, Leslie P

    2003-04-01

    A growing number of environmental toxicants found in pesticides, herbicides, and industrial solvents are believed to have deleterious effects on development by disrupting hormone-sensitive processes. We exposed Xenopus laevis embryos at early gastrula to the commonly encountered environmental estrogens nonylphenol, octylphenol, and methoxychlor, the antiandrogen, p,p-DDE, or the synthetic androgen, 17 alpha-methyltestosterone at concentrations ranging from 10 nM to 10 microM and examined them at tailbud stages (approximately 48 hr of treatment). Exposure to the three environmental estrogens, as well as to the natural estrogen 17 beta-estradiol, increased mortality, induced morphologic deformations, increased apoptosis, and altered the deposition and differentiation of neural crest-derived melanocytes in tailbud stage embryos. Although neural crest-derived melanocytes were markedly altered in embryos treated with estrogenic toxicants, expression of the early neural crest maker Xslug, a factor that regulates both the induction and subsequent migration of neural crest cells, was not affected, suggesting that the disruption induced by these compounds with respect to melanocyte development may occur at later stages of their differentiation. Co-incubation of embryos with the pure antiestrogen ICI 182,780 blocked the ability of nonylphenol to induce abnormalities in body shape and in melanocyte differentiation but did not block the effects of methoxychlor. Our data indicate not only that acute exposure to these environmental estrogens induces deleterious effects on early vertebrate development but also that different environmental estrogens may alter the fate of a specific cell type via different mechanisms. Finally, our data suggest that the differentiation of neural crest-derived melanocytes may be particularly sensitive to the disruptive actions of these ubiquitous chemical contaminants.

  12. Estrogenicity of parabens revisited: impact of parabens on early pregnancy and an uterotrophic assay in mice.

    PubMed

    Shaw, Jordan; deCatanzaro, Denys

    2009-07-01

    Parabens, a class of preservatives routinely added to cosmetics, pharmaceuticals, and foods, have estrogenic properties. Given that intrauterine implantation of fertilized ova in inseminated females can be disrupted by minute levels of exogenous estrogens, we assessed the impact of parabens upon early gestation. In Experiment 1, butylparaben was administered subcutaneously in several doses ranging from 0.05 to 35 mg/animal/day to inseminated CF-1 mice on days 1-4 of pregnancy. Butylparaben exposure did not affect litter size, the number of pups born, postnatal day 3 litter weights, or the number of pups surviving to postnatal day 5. In contrast, administration of 500 ng/animal/day 17beta-estradiol terminated all pregnancies. In Experiment 2, propylparaben was subcutaneously administered to inseminated CF-1 mice on gestational days 1-4. Dams were sacrificed on gestation day 6 and the number of implantation sites was counted. Propylparaben had no impact on the number of implantation sites observed. Since Experiments 1 and 2 did not yield the anticipated results, an uterotrophic assay was conducted in Experiment 3 to re-evaluate the in vivo estrogenicity of parabens. Ovariectomized CF-1 and CD-1 mice were administered butylparaben in doses ranging from 0.735 to 35 mg per animal for three consecutive days. Mice were sacrificed on the fourth day, and uterine mass was recorded. There was no effect of butylparaben on uterine wet or dry mass at any dose in either strain. In contrast, administration of 17beta-estradiol consistently increased uterine mass in both strains. These data indicate that the estrogen-sensitive period of implantation is not vulnerable to paraben exposure, and that the in vivo estrogenicity of parabens may not be as potent as previously reported.

  13. Estrogen

    MedlinePlus

    ... life', the end of monthly menstrual periods). Some brands of estrogen are also used to treat vaginal ... prevent osteoporosis should consider a different treatment. Some brands of estrogen are also to relieve symptoms of ...

  14. Bioavailable Insulin-Like Growth Factor-I Inversely Related to Weight Gain in Postmenopausal Women regardless of Exogenous Estrogen

    PubMed Central

    Jung, Su Yon; Hursting, Stephen D.; Guindani, Michele; Vitolins, Mara Z.; Paskett, Electra; Chang, Shine

    2014-01-01

    Background Weight gain, insulin-like growth factor-I (IGF-I) levels, and excess exogenous steroid hormone use are putative cancer risk factors, yet their interconnected pathways have not been fully characterized. This cross-sectional study investigated the relationship between plasma IGF-I levels and weight gain according to body mass index (BMI), leptin levels, and exogenous estrogen use among postmenopausal women. Methods This study included 794 postmenopausal women who enrolled in an ancillary study of the Women's Health Initiative Observational Study between February 1995 and July 1998. The relationship between IGF-I levels and weight gain was analyzed using ordinal logistic regression. We used the molar ratio of IGF-I to IGF binding protein-3 (IGF-I/IGFBP-3) or circulating IGF-I levels adjusting for IGFBP-3 as a proxy of bioavailable IGF-I. The plasma concentrations were expressed as quartiles. Results Among the obese group, women in the third quartile (Q3) of IGF-I and highest quartile of IGF-I/IGFBP-3 were less likely to gain weight (>3% from baseline) than were women in the first quartiles (Q1). Among the normal weight group, women in Q2 and Q3 of IGF-I/IGFBP-3 were 70% less likely than those in Q1 to gain weight. Among current estrogen users, Q3 of IGF-I/IGFBP-3 had 0.5 times the odds of gaining weight than Q1. Conclusions Bioavailable IGF-I levels were inversely related to weight gain overall. Impact Although weight gain was not consistent with increases in IGF-I levels among postmenopausal women in this report, avoidance of weight gain as a strategy to reduce cancer risk may be recommend. PMID:24363252

  15. Do factors related to endogenous and exogenous estrogens modify the relationship between obesity and risk of colorectal adenomas in women?

    PubMed

    Wolf, Lesley A; Terry, Paul D; Potter, John D; Bostick, Roberd M

    2007-04-01

    Obesity has consistently been associated with increased colorectal cancer risk in men, but not in women. In the absence of postmenopausal hormone use (PMH), adipose-derived estrogen is the primary determinant of circulating estrogen levels in postmenopausal women, perhaps ameliorating the mitogenic effects of obesity in this group. Using data from a case-control study in the United States, we examined associations among obesity, potential modifying effects of factors related to endogenous and exogenous estrogen levels, and risk of colorectal adenoma. Cases (n = 219) were women of ages 30 to 74 years with colonoscopy proven, incident, sporadic, pathology-confirmed, adenomatous polyps of the colon and rectum. Two control groups were recruited: colonoscopy-confirmed polyp-free women (n = 438) and age- and zip code frequency-matched women randomly selected from the community (n = 247). Multivariate odds ratios and 95% confidence intervals (95% CI) for obese [body mass index (BMI) >or=30.0; compared with nonobese, BMI <25.0] premenopausal women were 2.09 (95% CI, 0.81-5.41) versus colonoscopy controls, and 5.18 (95% CI, 1.40-19.32) versus population controls. For PMH users, the corresponding odds ratios were 0.29 (95% CI, 0.12-0.70) versus colonoscopy controls and 0.64 (95% CI, 0.23-1.83) versus population controls. There was no significant association of BMI with adenoma risk for PMH nonusers. Findings for waist-to-hip ratio were similar to those for BMI. These data support the hypothesis that risk for colorectal adenoma may be increased with obesity among premenopausal women but decreased among postmenopausal women, especially if they also take PMH.

  16. A summary of the influence of exogenous estrogen administration across the lifespan on the GH/IGF-1 axis and implications for bone health.

    PubMed

    Southmayd, Emily A; De Souza, Mary Jane

    2017-02-01

    Bone growth, development, and remodeling are modulated by numerous circulating hormones. Throughout the lifespan, the extent to which each of the hormones impacts bone differs. Understanding the independent and combined impact of these hormones on controlling bone remodeling allows for the development of more informed decision making regarding pharmacology, specifically the use of hormonal medication, at all ages. Endocrine control of bone health in women is largely dictated by the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis and the hypothalamic-pituitary-ovarian (HPO) axis. Growth hormone, secreted from the pituitary gland, stimulates cells in almost every tissue to secrete IGF-1, although the majority of circulating IGF-1 is produced hepatically. Indeed, systemic IGF-1 concentrations have been found to be correlated with bone mineral density (BMD) in both pre- and post-menopausal women and is often used as a marker of bone formation. Sex steroids produced by the ovaries, namely estradiol, mediate bone resorption through binding to estrogen receptors on osteoclasts and osteoblasts. Specifically, by increasing osteoclast apoptosis and decreasing osteoblast apoptosis, adequate estrogen levels prevent excessive bone resorption, which helps to explain the rapid decline in bone mass that occurs with the menopausal decrease in estrogen production. Though there are documented correlations between endogenous estrogen concentrations and GH/IGF-1 dynamics, this relationship changes across the lifespan as sex-steroid dynamics fluctuate and, possibly, as tissue responsiveness to GH stimulation decreases. Aside from the known role of endogenous sex steroids on bone health, the impact of exogenous estrogen administration is of interest, as exogenous formulations further modulate GH and IGF-1 production. However, the effect and extent of GH and IGF-1 modulation seems to be largely dependent on age at administration and route of administration. Specifically

  17. Defective bone formation and anabolic response to exogenous estrogen in mice with targeted disruption of endothelial nitric oxide synthase.

    PubMed

    Armour, K E; Armour, K J; Gallagher, M E; Gödecke, A; Helfrich, M H; Reid, D M; Ralston, S H

    2001-02-01

    Nitric oxide (NO) is a pleiotropic signaling molecule that is produced by bone cells constitutively and in response to diverse stimuli such as proinflammatory cytokines, mechanical strain, and sex hormones. Endothelial nitric oxide synthase (eNOS) is the predominant NOS isoform expressed in bone, but its physiological role in regulating bone metabolism remains unclear. Here we studied various aspects of bone metabolism in female mice with targeted disruption of the eNOS gene. Mice with eNOS deficiency (eNOS KO) had reduced bone mineral density, and cortical thinning when compared with WT controls and histomorphometric analysis of bone revealed profound abnormalities of bone formation, with reduced osteoblast numbers, surfaces and mineral apposition rate. Studies in vitro showed that osteoblasts derived from eNOS KO mice had reduced rates of growth when compared with WT and were less well differentiated as reflected by lower levels of alkaline phosphatase activity. Mice with eNOS deficiency lost bone normally following ovariectomy but exhibited a significantly blunted anabolic response to high dose exogenous estrogen. We conclude that the eNOS pathway plays an essential role in regulating bone mass and bone turnover by modulating osteoblast function.

  18. The human estrogen receptor can regulate exogenous but not endogenous vitellogenin gene promoters in a Xenopus cell line

    SciTech Connect

    Seiler-Tuyns, A.; Merillat, A.M.; Haefliger, D.N.

    Transfection of a human estrogen receptor cDNA expression vector (HEO) into cultured Xenopus kidney cells confers estrogen responsiveness to the recipient cells as demonstrated by the hormone dependent expression of co-transfected Xenopus vitellogenin-CAT chimeric genes. The estrogen stimulation of these vit-CAT genes is dependent upon the presence of the vitellogenin estrogen responsive element (ERE) in their 5{prime} flanking region. Thus, functional human estrogen receptor (hER) can be synthesized in heterologous lower vertebrate cells and can act as a trans-acting regulatory factor that is necessary, together with estradiol, for the induction of the vit-CAT constructs in these cells. In addition, vitellogeninmore » minigenes co-transfected with the HEO expression vector also respond to hormonal stimulation. Their induction is not higher than that of the vit-CAT chimeric genes. It suggests that in the Xenopus kidney cell line B 3.2, the structural parts of the vitellogenin minigenes do not play a role in the induction process. Furthermore, no stabilizing effect of estrogen on vitellogenin mRNA is observed in these cells.« less

  19. Decreased serum estrogen improves fat graft retention by enhancing early macrophage infiltration and inducing adipocyte hypertrophy.

    PubMed

    Mok, Hsiaopei; Feng, Jingwei; Hu, Wansheng; Wang, Jing; Cai, Junrong; Lu, Feng

    2018-06-18

    Fat grafting is a commonly used procedure; however, the mechanisms that regulate graft outcomes are not clear. Estrogen has been associated with vascularization, inflammation and fat metabolism, yet its role in fat grafting is unclear. Mice were implanted with 17β-estradiol pellets (high estrogen, HE), underwent ovariectomy (low estrogen level, OVX) or sham surgery (normal estrogen level, CON). 45 days later, inguinal fat of mice was autografted subcutaneously. At 1, 2, 4, and 12 weeks post-transplantation, grafts were dissected, weighed, and assessed for histology, angiogenesis and inflammation level. Serum estrogen level correlated to estrogen manipulation. 12 weeks after autografting, the retention rate was significantly higher in the OVX (79% ± 30%) than in the HE (16% ± 8%) and CON (35% ± 13%) groups. OVX-grafts had the least necrosis and most hypertrophic fat. OVX recruited the most pro-inflammatory macrophages and demonstrated a faster dead tissue removal process, however a higher fibrogenic tendency was found in this group. HE grafts had the most Sca1+ local stem cells and CD31  +  capillary content; however, with a low level of acute inflammation and insufficient adipokine PPAR-γ expression, their retention rate was impaired. Elevated serum estrogen increased stem cell density and early vascularization; however, by inhibiting the early inflammation, it resulted in delayed necrotic tissue removal and finally led to impaired adipose restoration. A low estrogen level induced favorable inflammation status and adipocyte hypertrophy to improve fat graft retention, but a continuing decreased estrogen level led to fat graft fibrosis. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Estrogens in Male Physiology.

    PubMed

    Cooke, Paul S; Nanjappa, Manjunatha K; Ko, CheMyong; Prins, Gail S; Hess, Rex A

    2017-07-01

    Estrogens have historically been associated with female reproduction, but work over the last two decades established that estrogens and their main nuclear receptors (ESR1 and ESR2) and G protein-coupled estrogen receptor (GPER) also regulate male reproductive and nonreproductive organs. 17β-Estradiol (E2) is measureable in blood of men and males of other species, but in rete testis fluids, E2 reaches concentrations normally found only in females and in some species nanomolar concentrations of estrone sulfate are found in semen. Aromatase, which converts androgens to estrogens, is expressed in Leydig cells, seminiferous epithelium, and other male organs. Early studies showed E2 binding in numerous male tissues, and ESR1 and ESR2 each show unique distributions and actions in males. Exogenous estrogen treatment produced male reproductive pathologies in laboratory animals and men, especially during development, and studies with transgenic mice with compromised estrogen signaling demonstrated an E2 role in normal male physiology. Efferent ductules and epididymal functions are dependent on estrogen signaling through ESR1, whose loss impaired ion transport and water reabsorption, resulting in abnormal sperm. Loss of ESR1 or aromatase also produces effects on nonreproductive targets such as brain, adipose, skeletal muscle, bone, cardiovascular, and immune tissues. Expression of GPER is extensive in male tracts, suggesting a possible role for E2 signaling through this receptor in male reproduction. Recent evidence also indicates that membrane ESR1 has critical roles in male reproduction. Thus estrogens are important physiological regulators in males, and future studies may reveal additional roles for estrogen signaling in various target tissues. Copyright © 2017 the American Physiological Society.

  1. Ritonavir binds to and downregulates estrogen receptors: molecular mechanism of promoting early atherosclerosis.

    PubMed

    Xiang, Jin; Wang, Ying; Su, Ke; Liu, Min; Hu, Peng-Chao; Ma, Tian; Li, Jia-Xi; Wei, Lei; Zheng, Zhongliang; Yang, Fang

    2014-10-01

    Estrogenic actions are closely related to cardiovascular disease. Ritonavir (RTV), a human immunodeficiency virus (HIV) protease inhibitor, induces atherosclerosis in an estrogen-related manner. However, how RTV induce pathological phenotypes through estrogen pathway remains unclear. In this study, we found that RTV increases thickness of coronary artery walls of Sprague Dawley rats and plasma free fatty acids (FFA) levels. In addition, RTV could induce foam cell formation, downregulate both estrogen receptor α (ERα) and ERβ expression, upregulate G protein-coupled estrogen receptor (GPER) expression, and all of them could be partially blocked by 17β-estradiol (E2), suggesting RTV acts as an antagonist for E2. Computational modeling shows a similar interaction with ERα between RTV and 2-aryl indoles, which are highly subtype-selective ligands for ERα. We also found that RTV directly bound to ERα and selectively inhibited the nuclear localization of ERα, and residue Leu536 in the hydrophobic core of ligand binding domain (LBD) was essential for the interaction with RTV. In addition, RTV did not change the secondary structure of ERα-LBD like E2, which explained how ERα lost the capacity of nuclear translocation under the treatment of RTV. All of the evidences suggest that ritonavir acts as an antagonist for 17β-estradiol in regulating α subtype estrogen receptor function and early events of atherosclerosis. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Early-life estrogen exposure and uterine pathogenesis: ?A model for gene-environment interactions

    EPA Science Inventory

    Aberrant cellular differentiation early in life can contribute to increased cancer risk later in life. In a classic model of this effect, female mice exposed on postnatal day (PND) 1-5 to the synthetic estrogen diethylstilbestrol (DES) have a high incidence of uterine carcinoma. ...

  3. Ritonavir binds to and downregulates estrogen receptors: Molecular mechanism of promoting early atherosclerosis

    SciTech Connect

    Xiang, Jin; Wang, Ying; Su, Ke

    Estrogenic actions are closely related to cardiovascular disease. Ritonavir (RTV), a human immunodeficiency virus (HIV) protease inhibitor, induces atherosclerosis in an estrogen-related manner. However, how RTV induce pathological phenotypes through estrogen pathway remains unclear. In this study, we found that RTV increases thickness of coronary artery walls of Sprague Dawley rats and plasma free fatty acids (FFA) levels. In addition, RTV could induce foam cell formation, downregulate both estrogen receptor α (ERα) and ERβ expression, upregulate G protein-coupled estrogen receptor (GPER) expression, and all of them could be partially blocked by 17β-estradiol (E2), suggesting RTV acts as an antagonist formore » E2. Computational modeling shows a similar interaction with ERα between RTV and 2-aryl indoles, which are highly subtype-selective ligands for ERα. We also found that RTV directly bound to ERα and selectively inhibited the nuclear localization of ERα, and residue Leu536 in the hydrophobic core of ligand binding domain (LBD) was essential for the interaction with RTV. In addition, RTV did not change the secondary structure of ERα-LBD like E2, which explained how ERα lost the capacity of nuclear translocation under the treatment of RTV. All of the evidences suggest that ritonavir acts as an antagonist for 17β-estradiol in regulating α subtype estrogen receptor function and early events of atherosclerosis. - Graphical abstract: RTV directly binds to ERα and Leu536 in the hydrophobic core of ligand binding domain is essential for the interaction. - Highlights: • RTV increases the thickness of rat coronary artery wall and foam cell formation. • RTV downregulates the expression of ERα and ERβ. • RTV inhibits ERα promoter activity. • RTV directly binds to ERα and the key amino acid is Leu536. • RTV inhibits the nuclear translocation of ERα and GPER.« less

  4. Exogenous determinants of early-life conditions, and mortality later in life.

    PubMed

    van den Berg, Gerard J; Doblhammer, Gabriele; Christensen, Kaare

    2009-05-01

    We analyze causal effects of conditions early in life on the individual mortality rate later in life. Conditions early in life are captured by transitory features of the macro-environment around birth, notably the state of the business cycle around birth, but also food price deviations, weather indicators, and demographic indicators. We argue that these features can only affect high-age mortality by way of the individual early-life conditions. Moreover, they are exogenous from the individual point of view, which is a methodological advantage compared to the use of unique characteristics of the newborn individual or his or her family or household as early-life indicators. We collected national annual time-series data on the above-mentioned indicators, and we combine these to the individual data records from the Danish Twin Registry covering births in 1873-1906. The empirical analyses (mostly based on the estimation of duration models) indicate a significant negative causal effect of economic conditions early in life on individual mortality rates at higher ages. If the national economic performance in the year of birth exceeds its trend value (i.e., if the business cycle is favorable) then the mortality rate later in life is lower. The implied effect on the median lifetime of those who survive until age 35 is about 10 months. A systematic empirical exploration of all macro-indicators reveals that economic conditions in the first years after birth also affect mortality rates later in life.

  5. Activation of Protease Activated Receptor 2 by Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine

    SciTech Connect

    Wang Junru; Boerma, Marjan; Kulkarni, Ashwini

    2010-07-15

    Purpose: Protease-activated receptor-2 (PAR{sub 2}) is highly expressed throughout the gut and regulates the inflammatory, mitogenic, fibroproliferative, and nociceptive responses to injury. PAR{sub 2} is strikingly upregulated and exhibits increased activation in response to intestinal irradiation. We examined the mechanistic significance of radiation enteropathy development by assessing the effect of exogenous PAR{sub 2} activation. Methods and Materials: Rat small bowel was exposed to localized single-dose radiation (16.5 Gy). The PAR{sub 2} agonist (2-furoyl-LIGRLO-NH{sub 2}) or vehicle was injected intraperitoneally daily for 3 days before irradiation (before), for 7 days after irradiation (after), or both 3 days before and 7 daysmore » after irradiation (before-after). Early and delayed radiation enteropathy was assessed at 2 and 26 weeks after irradiation using quantitative histologic examination, morphometry, and immunohistochemical analysis. Results: The PAR{sub 2} agonist did not elicit changes in the unirradiated (shielded) intestine. In contrast, in the irradiated intestine procured 2 weeks after irradiation, administration of the PAR{sub 2} agonist was associated with more severe mucosal injury and increased intestinal wall thickness in all three treatment groups (p <.05) compared with the vehicle-treated controls. The PAR{sub 2} agonist also exacerbated the radiation injury score, serosal thickening, and mucosal inflammation (p <.05) in the before and before-after groups. The short-term exogenous activation of PAR{sub 2} did not affect radiation-induced intestinal injury at 26 weeks. Conclusion: The results of the present study support a role for PAR{sub 2} activation in the pathogenesis of early radiation-induced intestinal injury. Pharmacologic PAR{sub 2} antagonists might have the potential to reduce the intestinal side effects of radiotherapy and/or as countermeasures in radiologic accidents or terrorism scenarios.« less

  6. Long-term effects of early life exposure to environmental estrogens on ovarian function: Role of epigenetics

    PubMed Central

    Cruz, Gonzalo; Foster, Warren; Paredes, Alfonso; Yi, Kun Don; Uzumcu, Mehmet

    2014-01-01

    Estrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is thought that developmental exposure to environmental estrogens can disrupt neural and reproductive tract development potentially resulting in long-term alterations in neurobehavior and reproductive function. Many chemicals have been shown to have estrogenic activity whereas others affect estrogen production and turnover resulting in disruption of estrogen signaling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on estrogen sensitive target tissues. Hence, alternative mechanisms are thought to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including estrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying disruption of ovarian follicular development. In addition, we discuss how exposure to environmental estrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. PMID:25040227

  7. Estrogen and Cytochrome P450 1B1 Contribute to Both Early- and Late-Stage Head and Neck Carcinogenesis

    PubMed Central

    Shatalova, Ekaterina G.; Klein-Szanto, Andres J.P.; Devarajan, Karthik; Cukierman, Edna; Clapper, Margie L.

    2010-01-01

    Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common type of cancer in the U.S. The goal of this study was to evaluate the contribution of estrogens to the development of HNSCCs. Various cell lines derived from early- and late-stage head and neck lesions were used to: characterize the expression of estrogen synthesis and metabolism genes, including cytochrome P450 (CYP)1B1, examine the effect of estrogen on gene expression and evaluate the role of CYP1B1 and/or estrogen in cell motility, proliferation and apoptosis. Estrogen metabolism genes (CYP1B1, CYP1A1, catechol-o-methyltransferase, UDP-glucuronosyltransferase 1A1, and glutathione-S-transferase P1) and estrogen receptor (ER)β were expressed in cell lines derived from both premalignant (MSK-Leuk1) and malignant (HNSCC) lesions. Exposure to estrogen induced CYP1B1 2.3 to 3.6 fold relative to vehicle-treated controls (P=0.0004) in MSK-Leuk1 cells but not in HNSCC cells. CYP1B1 knockdown by shRNA reduced the migration and proliferation of MSK-Leuk1 cells by 57% and 45%, respectively. Exposure of MSK-Leuk1 cells to estrogen inhibited apoptosis by 26%, while supplementation with the antiestrogen fulvestrant restored estrogen-dependent apoptosis. Representation of the estrogen pathway in human head and neck tissues from 128 patients was examined using tissue microarrays. The majority of the samples exhibited immunohistochemical staining for ERβ (91.9%), CYP1B1 (99.4%) and 17β-estradiol (88.4%). CYP1B1 and ERβ were elevated in HNSCCs relative to normal epithelium (P=0.024 and 0.008, respectively). These data provide novel insight into the mechanisms underlying head and neck carcinogenesis and facilitate the identification new targets for chemopreventive intervention. PMID:21205741

  8. Estrogens and development

    SciTech Connect

    McLachlan, J.A.; Newbold, R.R.

    1987-11-01

    The normal development of the genital organs of mammals, including humans, is under hormonal control. A role for the female sex hormone estrogen in this process is still unclear. However, exposure of experimental animals or humans to the potent exogenous estrogen, diethylstilbestrol (DES), results in persistent differentiation effects. Since many chemicals in the environment are weakly estrogenic, the possibility of hormonally altered differentiation must be considered.

  9. Response of adult mouse uterus to early disruption of estrogen receptor-alpha signaling is influenced by Krüppel-like factor 9

    USDA-ARS?s Scientific Manuscript database

    Inappropriate early exposure of the hormone-responsive uterus to estrogenic compounds is associated with increased risk for adult reproductive diseases including endometrial cancers. While the dysregulation of estrogen receptor-alpha (ESR1) signaling is a well-acknowledged early event in tumor initi...

  10. Exposure to Zearalenone During Early Pregnancy Causes Estrogenic Multitoxic Effects in Mice.

    PubMed

    Kunishige, Kohji; Kawate, Noritoshi; Inaba, Toshio; Tamada, Hiromichi

    2017-03-01

    Although zearalenone (ZEN; Sigma Chemicals, St Louis, Missouri) is a well-known mycotoxin with estrogenic activity, the toxic effects of ZEN during pregnancy are unknown. This study compared the effects of daily subcutaneous injections of ZEN (2, 4, or 8 mg/kg) with those of 17β-estradiol (E2; [Sigma Chemicals] 0.8, 1.6, or 3.2 μg/kg) in mice. Injections were administered on gestational days (GDs) 1 to 5, the period including implantation which is sensitive to hormonal balance. The effects of ZEN or E2 were evaluated by comparing the number of live fetuses, their weight, and absorbed conceptuses on GD 18, with those in vehicle-treated controls. In addition, implantation, embryos in the oviducts and those in uteri without implantation sites were investigated on GD 5. In mice treated with the highest dose of ZEN or E2, decidual responses and plasma progesterone concentrations were measured on GDs 5 and 6, respectively, and delayed implantation was investigated on GDs 9 and 14. The results showed that treatment with ZEN, in a manner similar to that seen for E2, led to obstruction of essential processes for establishing and maintaining pregnancy, such as embryo migration from oviducts to uteri, the decidual response, and activation of luteal function. Zearalenone also induced delayed implantation and loss of conceptuses and at low doses caused a retarded growth of the fetuses after normal implantation. It was therefore concluded that ZEN causes multiple estrogenic toxic actions when administered during early pregnancy in mice.

  11. Thin metal organic frameworks coatings by cathodic electrodeposition for solid-phase microextraction and analysis of trace exogenous estrogens in milk.

    PubMed

    Lan, Hangzhen; Pan, Daodong; Sun, Yangying; Guo, Yuxing; Wu, Zhen

    2016-09-21

    Cathodic electrodeposition (CED) has received great attention in metal-organic frameworks (MOFs) synthesis due to its distinguished properties including simplicity, controllability, mild synthesis conditions, and product continuously. Here, we report the fabrication of thin (Et3NH)2Zn3(BDC)4 (E-MOF-5) film coated solid phase microextraction (SPME) fiber by a one-step in situ cathodic electrodeposition strategy. Several etched stainless steel fibers were placed in parallel in order to achieve simultaneously electrochemical polymerization. The influence of different polymerization parameters Et3NHCl concentration and polymerization time were evaluated. The proposed method requires only 20 min for the preparation of E-MOF-5 coating. The optimum coating showed excellent thermal stability and mechanical durability with a long lifetime of more than 120 repetitions SPME operations, and also exhibited higher extraction selectivity and capacity to four estrogens than commonly-used commercial PDMS coating. The limits of detection for the estrogens were 0.17-0.56 ng mL(-1). Fiber-to-fiber reproducibility (n = 8) was in the respective ranges of 3.5%-6.1% relative standard deviation (RSD) for four estrogens for triplicate measurements at 200 ng mL(-1). Finally, the (E-MOF-5) coated fiber was evaluated for ethinylestradiol (EE2), bisphenol A (BPA), diethylstilbestrol (DES), and hexestrol (HEX) extraction in the spiked milk samples. The extraction performance of this new coating was satisfied enough for repeatable use without obvious decline. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Exogenous γ-aminobutyric Acid (GABA) Application Improved Early Growth, Net Photosynthesis, and Associated Physio-Biochemical Events in Maize.

    PubMed

    Li, Wu; Liu, Jianhua; Ashraf, Umair; Li, Gaoke; Li, Yuliang; Lu, Wenjia; Gao, Lei; Han, Fuguang; Hu, Jianguang

    2016-01-01

    γ-aminobutyric acid (GABA) is an endogenous signaling molecule and involved in growth regulations and plant development, however, a little information is available on the consequences of exogenous GABA application on growth, development, and associated physio-biochemical processes in maize. The present study examined the GABA-induced regulations in early growth, net photosynthetic rate, gas exchange, osmoregulation, and enzymatic activities in three maize cultivars, i.e., Yuecainuo 6, Zhengtian 68, and Yuecainuo 2. Two levels of GABA, i.e., 0 mg L(-1) and 50 mg L(-1), in solution form, with total application volume of 100 ml per pot containing 15 maize seedlings were exogenously applied. Results revealed that exogenous GABA application improved seedling growth in terms of seedling length and biomass accumulation in all maize cultivars at both 3 and 7 days after treatment (DAT). It also promoted net photosynthesis and variably affected gas exchange attributes, i.e., stomatal conductance (Gs), intercellular CO2 concentration (Ci), and transpiration rate (Tr), as well as leaves SPAD value. Furthermore, lipid peroxidation [in terms of malondialdehyde (MDA)] under GABA treated maize seedlings were also remained variable; however, osmolyte accumulation (protein and proline) and activities of anti-oxidants enzymes, i.e., super-oxide dismutase and peroxidase were also affected differently at both 3 and 7 DAT in all maize cultivars. Furthermore, enzymes involved in nitrogen metabolism, e.g., nitrate reductase and glutamine synthetase were improved. These results suggest the involvement of GABA in various physio-metablical mechanisms which might lead to improvement in morphological growth of maize. In future, research is still needed at molecular and genetic levels to unravel the involvement of GABA-mediated regulations in growth and its associated physio-biochemical mechanisms.

  13. Effect of exogenous transforming growth factor β1 (TGF-β1) on early bovine embryo development.

    PubMed

    Barrera, Antonio D; García, Elina V; Miceli, Dora C

    2018-06-08

    SummaryDuring preimplantation development, embryos are exposed and have the capacity to respond to different growth factors present in the maternal environment. Among these factors, transforming growth factor β1 (TGF-β1) is a well known modulator of embryonic growth and development. However, its action during the first stages of development, when the embryo transits through the oviduct, has not been yet elucidated. The objective of the present study was to examine the effect of early exposure to exogenous TGF-β1 on embryo development and expression of pluripotency (OCT4, NANOG) and DNA methylation (DNMT1, DNMT3A, DNMT3B) genes in bovine embryos produced in vitro. First, gene expression analysis of TGF-β receptors confirmed a stage-specific expression pattern, showing greater mRNA abundance of TGFBR1 and TGFBR2 from the 2- to the 8-cell stage, before embryonic genome activation. Second, embryo culture for the first 48 h in serum-free CR1aa medium supplemented with 50 or 100 ng/ml recombinant TGF-β1 did not affect the cleavage and blastocyst rate (days 7 and 8). However, RT-qPCR analysis showed a significant increase in the relative abundance of NANOG and DNMT3A in the 8-cell stage embryos and expanded blastocysts (day 8) derived from TGF-β1 treated embryos. These results suggest an early action of exogenous TGF-β1 on the bovine embryo, highlighting the importance to provide a more comprehensive understanding of the role of TGF-β signalling during early embryogenesis.

  14. Early Estrogen Action: Stimulation of the Metabolism of High Molecular Weight and Ribosomal RNAs

    PubMed Central

    Luck, Dennis N.; Hamilton, Terrell H.

    1972-01-01

    Samples of RNA, isolated from uteri of ovariectomized adult rats treated with estrogen, have been analyzed on sucrose gradients. Treatment with estrogen either for 20 min or 2 hr increased the specific activity of all classes of uterine RNA, but produced no significant alteration in the distribution of radioactivity in the gradients, when animals received [3H]uridine intraperitoneally 15 min before they were killed. After labeling periods of 30 min, 1 hr, or 2 hr, however, the RNAs isolated from animals treated with estrogen had a smaller percentage of rapidly sedimenting (faster than 28S) species of RNA than did RNA from animals not treated with the hormone. The decreased percentage of high molecular weight RNA correlated with increases in both the specific activity of 28S and 18S RNA and the concentration of RNA in the whole organ. The labeled RNA of high molecular weight was also demonstrated, by the use of actinomycin D in vivo, to have a more rapid turnover rate in the estrogen-stimulated uterus. Our results indicate that estrogen increases not only the rate of synthesis of ribosomal RNA in the uterus of the ovariectomized adult rat, but also the rate or efficiency of processing of precursor RNA species of high molecular weight. PMID:4500546

  15. Exogenous testosterone affects early threat processing in socially anxious and healthy women.

    PubMed

    van Peer, Jacobien M; Enter, Dorien; van Steenbergen, Henk; Spinhoven, Philip; Roelofs, Karin

    2017-10-01

    Testosterone plays an important role in social threat processing. Recent evidence suggests that testosterone administration has socially anxiolytic effects, but it remains unknown whether this involves early vigilance or later, more sustained, processing-stages. We investigated the acute effects of testosterone administration on social threat processing in 19 female patients with Social Anxiety Disorder (SAD) and 19 healthy controls. Event-related potentials (ERPs) were recorded during an emotional Stroop task with subliminally presented faces. Testosterone induced qualitative changes in early ERPs (<200ms after stimulus onset) in both groups. An initial testosterone-induced spatial shift reflected a change in the basic processing (N170/VPP) of neutral faces, which was followed by a shift for angry faces suggesting a decrease in early threat bias. These findings suggest that testosterone specifically affects early automatic social information processing. The decreased attentional bias for angry faces explains how testosterone can decrease threat avoidance, which is particularly relevant for SAD. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. [Local injection of exogenous nerve growth factor improves early bone maturation of implants].

    PubMed

    Yao, Yang; Du, Yu; Gu, Xia; Guang, Meng-Kai; Huang, Bo; Gong, Ping

    2018-04-01

    To investigate the effects of nerve growth factor (NGF) in the osteogenic action of implants and the maturation and reconstruction changes in bone tissues in the early stage of osseointegration. The mouse implant model was established by placing titanium in the femoral head of the mouse and locally injecting NGF in the implant zone. On 1, 2 and 4 weeks after operation, stain samples were collected from animals using hematoxylin-eosin (HE) staining and Masson staining. The effect of NGF on the bone maturation was compared at different time points of early stage osseointegration. The results of HE and Masson staining indicated that the local injection of external NGF can up-regulate bone mass, amount of bone trabecula, and bone maturity in the mouse model. The mature bone rate in treatment group of 1 week and 4 weeks after operation were significantly higher than those in the control group (P<0.05). NGF can shorten the period of bone maturation.

  17. 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

  18. [Effects of exogenous high mobility group protein box 1 on angiogenesis in ischemic zone of early scald wounds of rats].

    PubMed

    Dai, L; Guo, X; Huang, H J; Liao, X M; Luo, X Q; Li, D; Zhou, H; Gao, X C; Tan, M Y

    2018-04-20

    Objective: To observe effects of exogenous high mobility group protein box 1 (HMGB1) on angiogenesis in ischemic zone of early scald wounds of rats. Methods: Thirty-six Sprague-Dawley rats were divided into HMGB1 group and simple scald (SS) group according to the random number table, with 18 rats in each group. Comb-like copper mould was placed on the back of rats for 20 s after being immersed in 100 ℃ hot water for 3 to 5 min to make three ischemic zones of wound. Immediately after scald, rats in HMGB1 group were subcutaneously injected with 0.4 μg HMGB1 and 0.1 mL phosphate buffer solution (PBS), and rats in SS group were subcutaneously injected with 0.1 mL PBS from boarders of ischemic zone of scald wound. At post scald hour (PSH) 24, 48, and 72, 6 rats in each group were collected. Protein expressions of vascular endothelial growth factor (VEGF) in ischemic zone of wound at PSH 24, 48, and 72 and protein expressions of CD31 in ischemic zone of wound at PSH 48 and 72 were detected by immunohistochemistry. The number of microvessel in CD31 immunohistochemical sections of ischemic zone of wound at PSH 48 and 72 was calculated after observing by the microscope. The mRNA expressions of VEGF and CD31 in ischemic zone of wound were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction at PSH 24, 48, and 72. Data were processed with analysis of variance of factorial design, t test, and Bonferroni correction. Results: (1) At PSH 24, 48, and 72, protein expressions of VEGF in ischemic zone of wound of rats in HMGB1 group were significantly higher than those of rats in SS group ( t =7.496, 4.437, 5.402, P <0.05 or P <0.01). At PSH 48 and 72, protein expressions of CD31 in ischemic zone of wound of rats in HMGB1 group were 0.038 8±0.007 9 and 0.057 7±0.001 2 respectively, significantly higher than 0.013 4±0.004 9 and 0.030 3±0.004 0 of rats in SS group ( t =10.257, 15.055, P <0.01). (2) At PSH 48 and 72, the number of

  19. Estrogen treatment up-regulates female genes but does not suppress all early testicular markers during rainbow trout male-to-female gonadal transdifferentiation.

    PubMed

    Vizziano-Cantonnet, Denise; Baron, Daniel; Mahè, Sophie; Cauty, Chantal; Fostier, Alexis; Guiguen, Yann

    2008-11-01

    In non-mammalian vertebrates, estrogens are key players in ovarian differentiation, but the mechanisms by which they act remain poorly understood. The present study on rainbow trout was designed to investigate whether estrogens trigger the female pathway by activating a group of early female genes (i.e. cyp19a1, foxl2a, foxl2b, fst, bmp4, and fshb) and by repressing early testicular markers (i.e. dmrt1, nr0b1, sox9a1 and sox9a2). Feminization was induced in genetically all-male populations using 17alpha-ethynylestradiol (EE2, 20 mg/kg of food during 2 months). The expression profiles of 100 candidate genes were obtained by real-time RT-PCR and 45 expression profiles displayed a significant differential expression between control populations (males and females) and EE2-treated populations. These expression profiles were grouped in five temporally correlated expression clusters. The estrogen treatment induced most of the early ovarian differentiation genes (foxl2a, foxl2b, fst, bmp4, and fshb) and in particular foxl2a, which was strongly and quickly up-regulated. Simultaneously, Leydig cell genes, involved in androgen synthesis, as well as some Sertoli cell markers (amh, sox9a2) were strongly repressed. However, in contrast to our initial hypothesis, some genes considered as essential for mammalian and fish testis differentiation were not suppressed during the early process of estrogen-induced feminization (dmrt1, nr0b1, sox9a1 and pax2a) and some were even strongly up-regulated (nr0b1, sox9a1and pax2a). In conclusion, estrogens trigger male-to-female transdifferentiation by up-regulating most ovarian specific genes and this up-regulation appears to be crucial for an effective feminization, but estrogens do not concomitantly down-regulate all the testicular differentiation markers.

  20. Severe malformations of eelpout (Zoarces viviparus) fry are induced by maternal estrogenic exposure during early embryogenesis.

    PubMed

    Morthorst, Jane E; Korsgaard, Bodil; Bjerregaard, Poul

    2016-02-01

    Pregnant eelpout were exposed via the water to known endocrine disrupting compounds (EDCs) to clarify if EDCs could be causing the increased eelpout fry malformation frequencies observed in coastal areas receiving high anthropogenic input. The presence of a teratogenic window for estrogen-induced malformations was also investigated by starting the exposure at different times during eelpout pregnancy. Both 17α-ethinylestradiol (EE2) (17.8 ng/L) and pyrene (0.5 μg/L) significantly increased fry malformation frequency whereas 4-t-octylphenol (4-t-OP) up to 14.3 μg/L did not. Vitellogenin was significantly induced by EE2 (5.7 and 17.8 ng/L) but not by 4-t-OP and pyrene. A critical period for estrogen-induced fry malformations was identified and closed between 14 and 22 days post fertilization (dpf). Exposure to 17β-estradiol (E2) between 0 and 14 dpf caused severe malformations and severity increased the closer exposure start was to fertilization, whereas malformations were absent by exposure starting later than 14 dpf. Data on ovarian fluid volume and larval length supported the suggested teratogenic window. Larval mortality also increased when exposure started right after fertilization. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Estrogen Effects on Wound Healing

    PubMed Central

    Horng, Huann-Cheng; Chang, Wen-Hsun; Yeh, Chang-Ching; Huang, Ben-Shian; Chang, Chia-Pei; Chen, Yi-Jen; Tsui, Kuan-Hao

    2017-01-01

    Wound healing is a physiological process, involving three successive and overlapping phases—hemostasis/inflammation, proliferation, and remodeling—to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing. PMID:29099810

  2. G protein-coupled estrogen receptor 1 (GPER, GPR 30) in normal human endometrium and early pregnancy decidua.

    PubMed

    Kolkova, Z; Noskova, V; Ehinger, A; Hansson, S; Casslén, B

    2010-10-01

    The recently identified trans-membrane G protein-coupled estrogen receptor 1 (GPER, GPR30) has been implicated in rapid non-genomic effects of estrogens. This focuses on expression and localization of GPER mRNA and protein in normal cyclic endometrium and early pregnancy decidua. Real-time PCR, western blotting, in situ hybridization and immuno-histochemistry were used. Endometrial expression of GPER mRNA was lower in the secretory phase than in the proliferative phase, and even lower in the decidua. The expression pattern was similar to that of ERα mRNA, but different from that of ERβ mRNA. Western blot detected GPER protein as a 54 kDa band in all endometrial and decidual samples. In contrast to the mRNA, GPER protein did not show cyclic variations. Apparently, a lower amount of mRNA is sufficient to maintain protein levels in the secretory phase. GPER mRNA was predominantly localized in the epithelium of mid- and late-proliferative phase endometrium, whereas expression in early proliferative and secretory glands could not be distinguished from the diffuse stromal signal, which was present throughout the cycle. Immuno-staining for GPER was stronger in glandular and luminal epithelium than in the stroma throughout the cycle. The cyclic variations of GPER mRNA obviously relate to strong epithelial expression in the proliferative phase, and the expression pattern suggests regulation by ovarian steroids. GPER protein is present in endometrial tissue throughout the cycle, and the epithelial localization suggests potential functions during sperm migration at mid-cycle, as well as decidualization and blastocyst implantation in the mid-secretory phase.

  3. Exogenous Ochronosis

    PubMed Central

    Bhattar, Prachi A; Zawar, Vijay P; Godse, Kiran V; Patil, Sharmila P; Nadkarni, Nitin J; Gautam, Manjyot M

    2015-01-01

    Exogenous ochronosis (EO) is a cutaneous disorder characterized by blue-black pigmentation resulting as a complication of long-term application of skin-lightening creams containing hydroquinone but may also occur due to topical contact with phenol or resorcinol in dark-skinned individuals. It can also occur following the use of systemic antimalarials such as quinine. EO is clinically and histologically similar to its endogenous counterpart viz., alkaptonuria, which, however, exhibits systemic effects and is an inherited disorder. Dermoscopy and in vivo skin reflectance confocal microscopy are noninvasive in vivo diagnostic tools. It is very difficult to treat EO, a cosmetically disfiguring and troubling disorder with disappointing treatment options. PMID:26677264

  4. A Suppressive Antagonism Evidences Progesterone and Estrogen Receptor Pathway Interaction with Concomitant Regulation of Hand2, Bmp2 and ERK during Early Decidualization

    PubMed Central

    Mestre-Citrinovitz, Ana C.; Kleff, Veronika; Vallejo, Griselda

    2015-01-01

    Progesterone receptor and estrogen receptor participate in growth and differentiation of the different rat decidual regions. Steroid hormone receptor antagonists were used to study steroid regulation of decidualization. Here we describe a suppressive interaction between progesterone receptor (onapristone) and estrogen receptor (ICI182780) antagonists and their relation to a rescue phenomenon with concomitant regulation of Hand2, Bmp2 and p-ERK1/2 during the early decidualization steps. Phenotypes of decidua development produced by antagonist treatments were characterized by morphology, proliferation, differentiation, angiogenesis and expression of signaling molecules. We found that suppression of progesterone receptor activity by onapristone treatment resulted in resorption of the implantation sites with concomitant decrease in progesterone and estrogen receptors, PCNA, KI67 antigen, DESMIN, CCND3, CX43, Prl8a2, and signaling players such as transcription factor Hand2, Bmp2 mRNAs and p-ERK1/2. Moreover, FGF-2 and Vegfa increased as a consequence of onapristone treatment. Implantation sites from antagonist of estrogen receptor treated rats developed all decidual regions, but showed an anomalous blood vessel formation at the mesometrial part of the decidua. The deleterious effect of onapristone was partially counteracted by the impairment of estrogen receptor activity with rescue of expression levels of hormone steroid receptors, proliferation and differentiation markers, and the induction of a probably compensatory increase in signaling molecules Hand2, Bmp2 and ERK1/2 activation compared to oil treated controls. This novel drug interaction during decidualization could be applied to pathological endometrial cell proliferation processes to improve therapies using steroid hormone receptor targets. PMID:25897495

  5. Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it?

    PubMed Central

    Koebele, Stephanie V.; Bimonte-Nelson, Heather A.

    2015-01-01

    Estrogens impact the organization and activation of the mammalian brain in both sexes, with sex-specific critical windows. Throughout the female lifespan estrogens activate brain substrates previously organized by estrogens, and estrogens can induce non-transient brain and behavior changes into adulthood. Therefore, from early life through the transition to reproductive senescence and beyond, estrogens are potent modulators of the brain and behavior. Organizational, reorganizational, and activational hormone events likely impact the trajectory of brain profiles during aging. A “brain profile,” or quantitative brain measurement for research purposes, is typically a snapshot in time, but in life a brain profile is anything but static – it is in flux, variable, and dynamic. Akin to this, the only thing continuous and consistent about hormone exposures across a female's lifespan is that they are noncontinuous and inconsistent, building and rebuilding on past exposures to create a present brain and behavioral landscape. Thus, hormone variation is especially rich in females, and is likely the destiny for maximal responsiveness in the female brain. The magnitude and direction of estrogenic effects on the brain and its functions depend on a myriad of factors; a “Goldilocks” phenomenon exists for estrogens, whereby if the timing, dose, and regimen for an individual are just right, markedly efficacious effects present. Data indicate that exogenously-administered estrogens can bestow beneficial cognitive effects in some circumstances, especially when initiated in a window of opportunity such as the menopause transition. Could it be that the age-related reduction in efficacy of estrogens reflects the closure of a late-in-life critical window occurring around the menopause transition? Information from classic and contemporary works studying organizational/activational estrogen actions, in combination with acknowledging the tendency for maximal responsiveness to

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

    PubMed Central

    Murakami, Gen

    2016-01-01

    to exogenous estrogen treatment, and thereby results in different effects on maternal behavior. PMID:27007402

  7. Effect of exogenous progesterone administration on luteal sensitivity to PGF during the early development of the corpus luteum in mares and cows.

    PubMed

    Garcia-Muñoz, A; Valldecabres-Torres, X; Newcombe, J R; Cuervo-Arango, J; Garcia-Rosello, E

    2017-12-01

    The objective of this study was to determine the effect of exogenous progesterone administration at ovulation and during the early development of the CL, on its future sensitivity to a single administration of PGF2a in mares and cows. Horse Retrospective reproductive data from an equine clinic in the UK during three breeding seasons were used. Mares were divided into: control group, cycles with single ovulations; double ovulation group cycles with asynchronous double ovulations; and PRID group: cycles with single ovulations and treatment with intravaginal progesterone device (CIDR) immediately after the ovulation. All mares were treated with d-cloprostenol (PGF) at either: (i) 88 hr; (ii) 96 hr; (iii) 104 hr; or (iv) 112 hr after the last ovulation. Cattle A total of nine non-lactating Holstein cows were used. All cows were administered PGF14 d apart and allocated to one of two groups control group GnRH was administered 56 hr after the second PGF administration. CIDR group CIDR was inserted at the same time of GnRH administration. All cows were administered PGF at 120 hr post-ovulation. The complete luteolysis rate of mares with double ovulation (66.7%) and those treated with exogenous progesterone (68.4%) was significantly higher than the rate of mares with single ovulation (35.6%) at 104 hr. In the cow, however, the treatment with CIDR did not increase the luteolytic response in cows treated at 120 hr post-ovulation. In conclusion, the degree of complete luteolysis can be influenced by increasing the concentration of progesterone during the early luteal development in mares. © 2017 Blackwell Verlag GmbH.

  8. Estrogenic Mechanisms and Cardiac Responses Following Early Life Exposure to Bisphenol A (BPA) and Its Metabolite 4-Methyl-2,4-bis( p-hydroxyphenyl)pent-1-ene (MBP) in Zebrafish.

    PubMed

    Moreman, John; Takesono, Aya; Trznadel, Maciej; Winter, Matthew J; Perry, Alexis; Wood, Mark E; Rogers, Nicola J; Kudoh, Tetsuhiro; Tyler, Charles R

    2018-06-05

    Environmental exposure to Bisphenol A (BPA) has been associated with a range of adverse health effects, including on the cardiovascular system in humans. Lack of agreement on its mechanism(s) of action likely stem from comparisons between in vivo and in vitro test systems and potential multiple effects pathways. In rodents, in vivo, metabolic activation of BPA produces 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), which is reported to be up to 1000 times more potent as an estrogen than BPA. We investigated the estrogenic effects and estrogen receptor signaling pathway(s) of BPA and MBP following early life exposure using a transgenic, estrogen responsive (ERE-TG) zebrafish and a targeted morpholino approach to knockdown the three fish estrogen receptor (ER) subtypes. The functional consequences of BPA exposure on the cardiovascular system of zebrafish larvae were also examined. The heart atrioventricular valves and the bulbus arteriosus were primary target tissues for both BPA and MBP in the ERE-TG zebrafish, and MBP was approximately 1000-fold more potent than BPA as an estrogen in these tissues. Estrogen receptor knockdown with morpholinos indicated that the estrogenic responses in the heart for both BPA and MBP were mediated via an estrogen receptor 1 (esr1) dependent pathway. At the highest BPA concentration tested (2500 μg/L), alterations in the atrial:ventricular beat ratio indicated a functional impact on the heart of 5 days post fertilization (dpf) larvae, and there was also a significantly reduced heart rate in these larvae at 14 dpf. Our findings indicate that some of the reported adverse effects on heart function associated with BPA exposure (in mammals) may act through an estrogenic mechanism, but that fish are unlikely to be susceptible to adverse effects on heart development for environmentally relevant exposures.

  9. INTRODUCTION OF THE VITELLOGENIN GENE IN EARLY LIFE STAGE FATHEAD MINNOWS AS AN EFFECTIVE EXPOSURE INDICATOR FOR ESTROGENIC COMPOUNDS

    EPA Science Inventory

    Vitellogenin (Vg) gene expression in adult male fathead minnows (FHM) has previously been used successfully to detect exposures to estrogenic compounds in aquatic systems; however, sample volume(s)required for >24h exposure durations and the logistics of sampling pose some limita...

  10. Estrogen Injection

    MedlinePlus

    ... used to treat hot flushes (hot flashes; sudden strong feelings of heat and sweating) and/or vaginal ... the symptoms of certain types of prostate (a male reproductive organ) cancer. The conjugated estrogens form of ...

  11. Characterization of Atrazine-Induced Gonadal Malformations in African Clawed Frogs (Xenopus laevis) and Comparisons with Effects of an Androgen Antagonist (Cyproterone Acetate) and Exogenous Estrogen (17β-Estradiol): Support for the Demasculinization/Feminization Hypothesis

    PubMed Central

    Hayes, Tyrone B.; Stuart, A. Ali; Mendoza, Magdalena; Collins, Atif; Noriega, Nigel; Vonk, Aaron; Johnston, Gwynne; Liu, Roger; Kpodzo, Dzifa

    2006-01-01

    Atrazine is a potent endocrine disruptor that both chemically castrates and feminizes male amphibians. It depletes androgens in adult frogs and reduces androgen-dependent growth of the larynx in developing male larvae. It also disrupts normal gonadal development and feminizes the gonads of developing males. Gonadal malformations induced by atrazine include hermaphrodites and males with multiple testes [single sex polygonadism (SSP)], and effects occur at concentrations as low as 0.1 ppb (μg/L). Here, we describe the frequencies at which these malformations occur and compare them with morphologies induced by the estrogen, 17β-estradiol (E2), and the antiandrogen cyproterone acetate, as a first step in testing the hypothesis that the effects of atrazine are a combination of demasculinization and feminization. The various forms of hermaphroditism did not occur in controls. Nonpigmented ovaries, which occurred at relatively high frequencies in atrazine-treated larvae, were found in four individuals out of more than 400 controls examined (1%). Further, we show that several types of gonadal malformations (SSP and three forms of hermaphroditism) are produced by E2 exposure during gonadal differentiation, whereas a final morphology (nonpigmented ovaries) appears to be the result of chemical castration (disruption of androgen synthesis and/or activity) by atrazine. These experimental findings suggest that atrazine-induced gonadal malformations result from the depletion of androgens and production of estrogens, perhaps subsequent to the induction of aromatase by atrazine, a mechanism established in fish, amphibians, reptiles, and mammals (rodents and humans). PMID:16818259

  12. Downregulation of GLUT4 contributes to effective intervention of estrogen receptor-negative/HER2-overexpressing early stage breast disease progression by lapatinib

    PubMed Central

    Acharya, Sunil; Xu, Jia; Wang, Xiao; Jain, Shalini; Wang, Hai; Zhang, Qingling; Chang, Chia-Chi; Bower, Joseph; Arun, Banu; Seewaldt, Victoria; Yu, Dihua

    2016-01-01

    Tamoxifen and aromatase inhibitors (AIs) have shown efficacy in prevention of estrogen receptor-positive (ER+) breast cancer; however, there exists no proven prevention strategy for estrogen receptor-negative (ER-) breast cancer. Up to 40% of ER- breast cancers have human epidermal growth factor receptor 2 overexpression (HER2+), suggesting HER2 signaling might be a good target for chemoprevention for certain ER- breast cancers. Here, we tested the feasibility of the HER2-targeting agent lapatinib in prevention and/or early intervention of an ER-/HER2+ early-stage breast disease model. We found that lapatinib treatment forestalled the progression of atypical ductal hyperplasia (ADH)-like acini to ductal carcinoma in situ (DCIS)-like acini in ER-/HER2+ human mammary epithelial cells (HMECs) in 3D culture. Mechanistically, we found that inhibition of HER2/Akt signaling by lapatinib led to downregulation of GLUT4 and a reduced glucose uptake in HER2-overexpressing cells, resulting in decreased proliferation and increased apoptosis of these cells in 3D culture. Additionally, our data suggest that HER2-driven glycolytic metabolic dysregulation in ER-/HER2+ HMECs might promote early-stage breast disease progression, which can be reversed by lapatinib treatment. Furthermore, low-dose lapatinib treatment, starting at the early stages of mammary grand transformation in the MMTV-neu* mouse model, significantly delayed mammary tumor initiation and progression, extended tumor-free survival, which corresponded to effective inhibition of HER2/Akt signaling and downregulation of GLUT4 in vivo. Taken together, our results indicate that lapatinib, through its inhibition of key signaling pathways and tumor-promoting metabolic events, is a promising agent for the prevention/early intervention of ER-/HER2+ breast cancer progression. PMID:27293993

  13. Metabolic responses to exogenous ghrelin in obesity and early after Roux-en-Y gastric bypass in humans.

    PubMed

    Tamboli, Robyn A; Antoun, Joseph; Sidani, Reem M; Clements, Austin; Harmata, Emily E; Marks-Shulman, Pam; Gaylinn, Bruce D; Williams, Brandon; Clements, Ronald H; Albaugh, Vance L; Abumrad, Naji N

    2017-09-01

    Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB). We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg -1  min -1 ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp. Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion. These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB. © 2017 John Wiley & Sons Ltd.

  14. Distribution of aromatase and sex steroid receptors in the baculum during the rat life cycle: effects of estrogen during the early development of the baculum.

    PubMed

    Yonezawa, Tomohiro; Higashi, Mayuko; Yoshioka, Kazuki; Mutoh, Ken-ichiro

    2011-07-01

    The baculum, also called os penis, plays an important role during copulation. However, the hormonal regulation of its development remains to be elucidated. To determine the direct involvement of sex steroids in the development of the baculum of rats, the distributions of androgen receptors (ARs), aromatase, and estrogen receptor alpha (ESR1) were observed immunohistochemically. On Postnatal Day 1, the rudiment of the baculum expressed ARs, aromatase, and ESR1. In the proximal segment of the baculum of neonatal rats, ARs were expressed in the parosteal layer but not in the periosteum or osteoblasts. Aromatase was expressed from the parosteal layer to the endosteum, particularly in the inner osteogenic layer. ESR1 was also abundantly expressed in almost all cells from the parosteal layer to the endosteum. ARs, aromatase, and ESR1 were all abundantly expressed during the neonatal period in the hyaline cartilage of the proximal segment and in fibrocartilage of the distal segment of the baculum. Expression in all the tissues was attenuated in an age-dependent manner and became quite weak at puberty. To determine the effect of estrogen on the growth of the baculum, the aromatase inhibitor 1,4,6-androstatrien-3,17-dione (ATD) was subcutaneously injected daily into pregnant rats from Days 19 to 23 of gestation and into pups on postnatal Days 1, 3, 5, 7, and 9. On Day 10, the length of the baculum in the ATD-treated rats was significantly shorter than that in the controls, although the body weight did not change. These findings suggest that not only androgen but also locally aromatized estrogen is involved in the early growth and development of the baculum.

  15. Impact of smoking on estrogenic efficacy.

    PubMed

    Ruan, X; Mueck, A O

    2015-02-01

    Depending on the type, duration and intensity of cigarette smoking, the efficacy of endogenous and exogenous estrogen can be reduced or completely cancelled. Not only does smoking diminish the beneficial effects of estrogen on hot flushes and urogenital symptoms and its positive effects on lipid metabolism, but smoking also can reduce estrogen's ability to prevent osteoporosis and perhaps also cardiovascular diseases. This is mainly caused by dose-dependent elevated hepatic clearance, partially in conjunction with lower estrogen levels, and has been demonstrated so far only with oral estrogen applications. Compensation for the failure of therapeutic action should not be made by increasing the dose in smokers since this might result in the production of potentially mutagenic estrogen metabolites associated with a higher risk of breast cancer. Since the favorable effects of estrogens seem to be not lost in smokers when estrogens are applied transdermally, this route should be preferred in smokers. The most important conclusion from the data presented is that the effects of smoking are very complex and dependent on a multiplicity of factors, so that different types of clinically relevant negative effects must be expected. Women who continue to smoke despite all warnings should be informed that smoking, in addition to all its other negative effects, can also jeopardize the success of hormone replacement therapy.

  16. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study.

    PubMed

    Santoro, Nanette; Allshouse, Amanda; Neal-Perry, Genevieve; Pal, Lubna; Lobo, Rogerio A; Naftolin, Frederick; Black, Dennis M; Brinton, Eliot A; Budoff, Matthew J; Cedars, Marcelle I; Dowling, N Maritza; Dunn, Mary; Gleason, Carey E; Hodis, Howard N; Isaac, Barbara; Magnani, Maureen; Manson, JoAnn E; Miller, Virginia M; Taylor, Hugh S; Wharton, Whitney; Wolff, Erin; Zepeda, Viola; Harman, S Mitchell

    2017-03-01

    The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n = 230) or transdermal estradiol (t-E2) 50 μg (n = 225; both with micronized progesterone 200 mg for 12 d each mo), or placebos (PBOs; n = 275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P < 0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P = 0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P = 0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower

  17. Longitudinal Changes in Menopausal Symptoms Comparing Women Randomized to Low-Dose Oral Conjugated Estrogens or Transdermal Estradiol Plus Micronized Progesterone Versus Placebo: the Kronos Early Estrogen Prevention Study (KEEPS)

    PubMed Central

    Santoro, Nanette; Allshouse, Amanda; Neal-Perry, Genevieve; Pal, Lubna; Lobo, Rogerio A.; Naftolin, Frederick; Black, Dennis M.; Brinton, Eliot A.; Budoff, Matthew J.; Cedars, Marcelle I.; Dowling, N. Maritza; Dunn, Mary; Gleason, Carey E.; Hodis, Howard N.; Isaac, Barbara; Magnani, Maureen; Manson, JoAnn E.; Miller, Virginia M.; Taylor, Hugh S.; Wharton, Whitney; Wolff, Erin; Zepeda, Viola; Harman, S. Mitchell

    2016-01-01

    Objective To compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early menopausal women over four years. Methods 727 women, aged 42–58, within three years of their final menstrual period were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n=230) or transdermal estradiol (t-E2) 50mcg (n=225; both with micronized progesterone 200mg for 12 days each month), or placebos (PBO; n=275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36 and 48 months post-randomization. Differences in proportions of women with symptoms at baseline and at each followup timepoint were compared by treatment arm using exact chi-square tests in an intent-to-treat (ITT) analysis. Differences in treatment effect by race/ethnicity and body mass index (BMI) were tested using generalized linear mixed effects modeling. Results Moderate-to-severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2 and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2 and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared to PBO (P<0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months post randomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms vs PBO, with o-CEE more effective than PBO at 36 and 48 months (p=0.002mad 0.05) and t-E2 more effective than PBO at 48 months (p=0.004). Neither hormone treatment significantly affected irritability compared to PBO. Symptom relief for active treatment vs PBO was not significantly modified by BMI or race/ethnicity. Conclusions Recently-menopausal women had similar and substantial reductions in hot flashes and night sweats with lower than conventional doses of oral or transdermal estrogen. These reductions were

  18. The G protein-coupled estrogen receptor (GPER/GPR30) may serve as a prognostic marker in early-stage cervical cancer.

    PubMed

    Friese, Klaus; Kost, Bernd; Vattai, Aurelia; Marmé, Frederik; Kuhn, Christina; Mahner, Sven; Dannecker, Christian; Jeschke, Udo; Heublein, Sabine

    2018-01-01

    were detected. Finally, immunopositivity of GPER cyt was predictive for favourable overall as well as recurrence-free survival in cervical cancer of early stage (FIGO I). This retrospective study reports GPER cyt to be associated with improved overall and recurrence-free survival in early-stage cervical cancer. Further investigations are needed thus to determine whether this observation may be of clinical impact. Interestingly, Raloxifene-a GPER-activating selective estrogen receptor modulator-has recently been demonstrated to be preventive for cervical cancer relapse in mice. Whether this effect is only reliant on raloxifene blocking ERα or may also be related to activation of GPER remains to be determined.

  19. Early postnatal virus inoculation into the scala media achieved extensive expression of exogenous green fluorescent protein in the inner ear and preserved auditory brainstem response thresholds.

    PubMed

    Wang, Yunfeng; Sun, Yu; Chang, Qing; Ahmad, Shoeb; Zhou, Binfei; Kim, Yeunjung; Li, Huawei; Lin, Xi

    2013-01-01

    Gene transfer into the inner ear is a promising approach for treating sensorineural hearing loss. The special electrochemical environment of the scala media raises a formidable challenge for effective gene delivery at the same time as keeping normal cochlear function intact. The present study aimed to define a suitable strategy for preserving hearing after viral inoculation directly into the scala media performed at various postnatal developmental stages. We assessed transgene expression of green fluorescent protein (GFP) mediated by various types of adeno-associated virus (AAV) and lentivirus (LV) in the mouse cochlea. Auditory brainstem responses were measured 30 days after inoculation to assess effects on hearing. Patterns of GFP expression confirmed extensive exogenous gene expression in various types of cells lining the endolymphatic space. The use of different viral vectors and promoters resulted in specific cellular GFP expression patterns. AAV2/1 with cytomegalovirus promoter apparently gave the best results for GFP expression in the supporting cells. Histological examination showed normal cochlear morphology and no hair cell loss after either AAV or LV injections. We found that hearing thresholds were not significantly changed when the injections were performed in mice younger than postnatal day 5, regardless of the type of virus tested. Viral inoculation and expression in the inner ear for the restoration of hearing must not damage cochlear function. Using normal hearing mice as a model, we have achieved this necessary step, which is required for the treatment of many types of congenital deafness that require early intervention. Copyright © 2013 John Wiley & Sons, Ltd.

  20. Human chorionic gonadotrophin in early gestation induces growth of estrogenic ovarian follicles and improves primiparous sow fertility during summer.

    PubMed

    Seyfang, Jemma; Langendijk, P; Chen, T Y; Bouwman, E; Kirkwood, R N

    2016-09-01

    Reduced summer farrowing rates may be due to inadequate corpora luteal (CL) support. Porcine CL become dependent on LH from 12 d of pregnancy and the embryonic estrogen signal for maternal recognition of pregnancy (MRP) is initiated at about 11-12 d after insemination. We hypothesised that injection of the LH analogue human chorionic gonadotropin (hCG) would induce growth of estrogenic follicles and, by mimicking the signal for MRP and stimulating progesterone secretion, increase primiparous sow fertility. In Experiment 1, during a 28 d lactation 53 mixed parity sows were full-fed either throughout lactation (n=16) or until 18 d and then feed restricted during the last 10 d of lactation (n=36). At 12 d after mating restrict-fed sows were injected with 1000IU hCG (n=17) or were not injected (n=19); the full-fed sows acted as non-treated positive controls. Transrectal ovarian ultrasound exams were performed on days 12, 16, 20, 24, and 28; blood samples were obtained on days 12, 14, and 15 for estradiol and progesterone assay. For Experiment 2, during the summer months primiparous sows received 1000IU hCG 12 d after mating (n=28) or were non-injected controls (n=27). Pregnancy status was determined at 28 d and sows allowed to go to term to determine farrowing rates and litter sizes. In Experiment 1, injection of hCG increased (P<0.001) follicle diameter and serum concentrations of estradiol (P<0.01) and progesterone (P<0.05). There were no effects of lactation feeding level on wean-estrus interval, farrowing rate or subsequent litter size. In Experiment 2, hCG injection was associated with a higher pregnancy rate (P<0.05) and farrowing rate (P<0.08). There was no effect on litter size. These data confirm that hCG stimulates growth of estrogenic follicles and CL function, and improves primiparous sow fertility during the summer months. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Sustained attention is favored by progesterone during early luteal phase and visuo-spatial memory by estrogens during ovulatory phase in young women.

    PubMed

    Solís-Ortiz, S; Corsi-Cabrera, M

    2008-08-01

    Studies examining the influence of the menstrual cycle on cognitive function have been highly contradictory. The maintenance of attention is key to successful information processing, however how it co-vary with other cognitive functions and mood in function of phases of the menstrual cycle is not well know. Therefore, neuropsychological performance of nine healthy women with regular menstrual cycles was assessed during ovulation (OVU), early luteal (EL), late luteal (LL) and menstrual (MEN) phases. Neuropsychological test scores of sustained attention, executive functions, manual coordination, visuo-spatial memory, verbal fluency, spatial ability, anxiety and depression were obtained and submitted to a principal components analysis (PCA). Five eigenvectors that accounted the 68.31% of the total variance were identified. Performance of the sustained attention was grouped in an independent eigenvector (component 1), and the scores on verbal fluency and visuo-spatial memory were grouped together in an eigenvector (component 5), which explained 17.69% and 12.03% of the total variance, respectively. The component 1 (p<0.034) and the component 5 (p<0.003) showed significant variations during the menstrual cycle. Sustained attention showed an increase in the EL phase, when the progesterone is high. Visuo-spatial memory was increased, while that verbal fluency was decreased during the OVU phase, when the estrogens levels are high. These results indicate that sustained attention is favored by early luteal phase progesterone and do not covaried with any other neuropsychological variables studied. The influence of the estrogens on visuo-spatial memory was corroborated, and covaried inversely with verbal fluency.

  2. Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung.

    PubMed

    Seyedmousavi, Seyedmojtaba; Davis, Michael J; Sugui, Janyce A; Pinkhasov, Tzvia; Moyer, Shannon; Salazar, Andres M; Chang, Yun C; Kwon-Chung, Kyung J

    2018-03-27

    Invasive aspergillosis (IA) remains the primary cause of morbidity and mortality in chronic granulomatous disease (CGD) patients, often due to infection by Aspergillus species refractory to antifungals. This motivates the search for alternative treatments, including immunotherapy. We investigated the effect of exogenous type I interferon (IFN) activation on the outcome of IA caused by three Aspergillus species, A. fumigatus , A. nidulans , and A. tanneri , in CGD mice. The animals were treated with poly(I):poly(C) carboxymethyl cellulose poly-l-lysine (PICLC), a mimetic of double-stranded RNA, 24 h preinfection and postinfection. The survival rates and lung fungal burdens were markedly improved by PICLC immunotherapy in animals infected with any one of the three Aspergillus species. While protection from IA was remarkable, PICLC induction of type I IFN in the lungs surged 24 h posttreatment and returned to baseline levels by 48 h, suggesting that PICLC altered early events in protection against IA. Immunophenotyping of recruited leukocytes and histopathological examination of tissue sections showed that PICLC induced similar cellular infiltrates as those in untreated-infected mice, in both cases dominated by monocytic cells and neutrophils. However, the PICLC immunotherapy resulted in a marked earlier recruitment of the leukocytes. Unlike with conidia, infection with A. nidulans germlings reduced the protective effect of PICLC immunotherapy. Additionally, antibody depletion of neutrophils totally reversed the protection, suggesting that neutrophils are crucial for PICLC-mediated protection. Together, these data show that prophylactic PICLC immunotherapy prerecruits these cells, enabling them to attack the conidia and thus resulting in a profound protection from IA. IMPORTANCE Patients with chronic granulomatous disease (CGD) are highly susceptible to invasive aspergillosis (IA). While Aspergillus fumigatus is the most-studied Aspergillus species, CGD patients

  3. Developmental estrogen exposures and disruptions to maternal behavior and brain: Effects of ethinyl estradiol, a common positive control.

    PubMed

    Catanese, Mary C; Vandenberg, Laura N

    2017-11-07

    Due of its structural similarity to the endogenous estrogen 17β-estradiol (E2), the synthetic estrogen 17α-ethinyl estradiol (EE2) is widely used to study the effects of estrogenic substances on sensitive organs at multiple stages of development. Here, we investigated the effects of EE2 on maternal behavior and the maternal brain in females exposed during gestation and the perinatal period. We assessed several components of maternal behavior including nesting behavior and pup retrieval; characterized the expression of estrogen receptor (ER)α in the medial preoptic area (MPOA), a brain region critical for the display of maternal behavior; and measured expression of tyrosine hydroxylase, a marker for dopaminergic cells, in the ventral tegmental area (VTA), a brain region important in maternal motivation. We found that developmental exposure to EE2 induces subtle effects on several aspects of maternal behavior including time building the nest and time spent engaged in self-care. Developmental exposure to EE2 also altered ERα expression in the central MPOA during both early and late lactation and led to significantly reduced tyrosine hydroxylase immunoreactivity in the VTA. Our results demonstrate both dose- and postpartum stage-related effects of developmental exposure to EE2 on behavior and brain that manifest later in adulthood, during the maternal period. These findings provide further evidence for effects of exposure to exogenous estrogenic compounds during the critical periods of fetal and perinatal development. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Exogenous and endogenous hormones and breast cancer

    PubMed Central

    ChenMD, Wendy Y.

    2008-01-01

    Exposure to higher levels of both exogenous and endogenous hormone is associated with breast cancer risk. Because of the association between breast cancer and HRT, only the minimal duration of HRT use is recommended for symptom control, and it is not recommended for chronic disease management. Current research issues include the role of progestins, other types of HRT, duration of unopposed estrogen use, and characteristics of cancers that develop on HRT. Circulating sex steroid levels are associated with breast cancer risk, but multiple issues need to be addressed before they are used routinely in clinical practice. Current research issues include measurement of levels for routine clinical practice, integration with standard breast cancer risk models and genetic polymorphism data, and applicability to estrogen-receptor-negative cancers. PMID:18971119

  5. Estrogen receptor 1 and 2 mRNA expression and protein localization in the porcine endometrium during the estrous cycle and early pregnancy

    USDA-ARS?s Scientific Manuscript database

    Between d 10 and 12 of gestation, the pig embryo undergoes elongation and produces estrogen, which serves as the key molecule for maternal recognition of pregnancy. Around d 15 of gestation, the embryo begins its superficial implantation with the endometrium and a second spike in estrogen occurs fro...

  6. Activation of G-protein coupled estrogen receptor 1 improves early-onset cognitive impairment via PI3K/Akt pathway in rats with traumatic brain injury.

    PubMed

    Wang, Ze-Fen; Pan, Zhi-Yong; Xu, Cheng-Shi; Li, Zhi-Qiang

    2017-01-22

    Previous studies experimentally reveal that G-protein coupled estrogen receptor 1(GPER) has neuroprotection against ischemic injury. However, its effect on traumatic brain injury (TBI) is less well-established. Cognitive impairment following human TBI is a common clinical observation, and TBI is considered as a risk factor for Alzheimer's disease (AD). This study aimed to observe the possible protective effect of GPER on early-onset cognitive impairment after a single TBI and investigate the cellular mechanism underlying its actions. We found that selective GPER agonist G-1 significantly reduced hippocampal CA1 neuronal loss and improved cognitive impairment in TBI rats. Although previous studies have shown that AD-like tau pathology occurs many years after both repetitive and single TBI, accumulation of hyperphosphorylated tau was not observed within days (detected at 24 h and 7d) after TBI. Furthermore, tau phosphorylation was not altered by G-1 treatment. It was found that G-1 administration caused an increase in p-Akt level. However, the neuroprotective effects of G-1 on spatial cognition and neuronal death were attenuated by PI3K/Akt inhibitor LY294002. These findings indicate that GPER agonist G-1 had protection on cognitive function via activation of PI3K/Akt signaling. Early-onset cognitive impairment following a single TBI was closely associated with acute hippocampal neuronal loss rather than tau pathology. This study suggests that early activation of GPER might be a promising therapeutic strategy for improvement of TBI-induced cognitive outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Self-Reported Menopausal Symptoms, Coronary Artery Calcification and Carotid Intima-Media Thickness in Recently Menopausal Women Screened for the Kronos Early Estrogen Prevention Study (KEEPS)

    PubMed Central

    Wolff, Erin Foran; He, Yunxiao; Black, Dennis M.; Brinton, Eliot A.; Budoff, Mathew J.; Cedars, Marcelle I.; Hodis, Howard N.; Lobo, Rogerio A.; Manson, JoAnn E.; Merriam, George R.; Miller, Virginia M.; Naftolin, Fredrick; Pal, Lubna; Santoro, Nanette; Zhang, Heping; Harman, S. Mitchell; Taylor, Hugh S.

    2012-01-01

    Objective To determine whether self-reported menopausal symptoms are associated with measures of subclinical atherosclerosis. Setting Multi-center, randomized controlled trial. Patients Recently menopausal women (n=868) screened for the Kronos Early Estrogen Prevention Study (KEEPS). Design Cross sectional analysis. Interventions None Main Outcome Measures Baseline menopausal symptoms (hot flashes, dyspareunia, vaginal dryness, night sweats, palpitations, mood swings, depression, insomnia, irritability), serum estradiol (E2) levels and measures of atherosclerosis were assessed. Atherosclerosis was quantified using Coronary Artery Calcium (CAC) Agatston scores (n=771) and Carotid Intima-Media Thickness (CIMT). Logistic regression model of menopausal symptoms and E2 was used to predict CAC. Linear regression model of menopausal symptoms and E2 was used to predict CIMT. Correlation between length of time in menopause with menopausal symptoms, estradiol (E2), CAC, and CIMT were assessed. Results In early menopausal women screened for KEEPS, neither E2 nor climacteric symptoms predicted the extent of subclinical atherosclerosis. Palpitations (p=0.09) and depression (p=0.07) approached significance as predictors of CAC. Other symptoms of insomnia, irritability, dyspareunia, hot flashes, mood swings, night sweats, and vaginal dryness were not associated with CAC. Women with significantly elevated CAC scores were excluded from further participation in KEEPS; in women meeting inclusion criteria, neither baseline menopausal symptoms nor E2 predicted CIMT. Years since menopause onset correlated with CIMT, dyspareunia, vaginal dryness and E2. Conclusions Self-reported symptoms in recently menopausal women are not strong predictors of subclinical atherosclerosis. Continued follow-up of this population will be performed to determine if baseline or persistent symptoms in the early menopause are associated with progression of cardiovascular disease. PMID:23312232

  8. Cost-effectiveness assessment of lumpectomy cavity boost in elderly women with early stage estrogen receptor positive breast cancer receiving adjuvant radiotherapy.

    PubMed

    Lester-Coll, Nataniel H; Rutter, Charles E; Evans, Suzanne B

    2016-04-01

    Breast radiotherapy (RT) for elderly women with estrogen receptor positive early stage breast cancer (ER+ESBC) improves local recurrence (LR) rates without benefitting overall survival. Breast boost is a common practice, although the absolute benefit decreases with age. Consequently, an analysis of its cost-effectiveness in the elderly ESBC populations is warranted. A Markov model was used to compare cost-effectiveness of RT with or without a boost in elderly ER+ESBC patients. The ten-year probability of LR with boost was derived from the CALGB 9343 trial and adjusted by the hazard ratio for LR from boost radiotherapy trial data, yielding the LR rate without boost. Remaining parameters were estimated using published data. Boost RT was associated with an increase in mean cost ($7139 vs $6193) and effectiveness (5.66 vs 5.64 quality adjusted life years; QALYs) relative to no boost. The incremental cost-effectiveness ratio (ICER) for boost was $55,903 per QALY. On one-way sensitivity analysis, boost remained cost-effective if the hazard ratio of LR with boost was <0.67. Boost RT for ER+ESBC patients was cost-effective over a wide range of assumptions and inputs over commonly accepted willingness-to pay-thresholds, but particularly in women at higher risk for LR. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Estrogen action and prostate cancer

    PubMed Central

    Nelles, Jason L; Hu, Wen-Yang; Prins, Gail S

    2011-01-01

    Early work on the hormonal basis of prostate cancer focused on the role of androgens, but more recently estrogens have been implicated as potential agents in the development and progression of prostate cancer. In this article, we review the epidemiological, laboratory and clinical evidence that estrogen may play a causative role in human prostate cancer, as well as rodent and grafted in vivo models. We then review recent literature highlighting potential mechanisms by which estrogen may contribute to prostate cancer, including estrogenic imprinting and epigenetic modifications, direct genotoxicity, hyperprolactinemia, inflammation and immunologic changes, and receptor-mediated actions. We discuss the work performed so far separating the actions of the different known estrogen receptors (ERs), ERα and ERβ, as well as G-protein-coupled receptor 30 and their specific roles in prostate disease. Finally, we predict that future work in this field will involve more investigations into epigenetic changes, experiments using new models of hormonal dysregulation in developing human prostate tissue, and continued delineation of the roles of the different ER subtypes, as well as their downstream signaling pathways that may serve as therapeutic targets. PMID:21765856

  10. Effects of the soya isoflavone genistein in early life stages of the Senegalese sole, Solea senegalensis: Thyroid, estrogenic and metabolic biomarkers.

    PubMed

    Sarasquete, Carmen; Úbeda-Manzanaro, Maria; Ortiz-Delgado, Juan Bosco

    2017-09-01

    This study examines the effects induced by environmentally relevant concentrations of the isoflavone genistein (3mg/L and 10mg/L) during early life stages of the Senegalese sole. Throughout the hypothalamus-pituitary-thyroid (HPT) axis, several neurohormonal regulatory thyroid signalling patterns (thyroglobulin/Tg, thyroid peroxidase/TPO, transthyretin/TTR, thyroid receptors/TRβ, and iodothrynonine deiodinases, Dio2 and Dio3) were analysed. Furthermore, the expression patterns of estrogen receptor ERβ and haemoprotein Cyp1a were also evaluated. In the control larvae, progressive increases of constitutive hormonal signalling pathways have been evidenced from the pre-metamorphosis phase onwards, reaching the highest expression basal levels at the metamorphosis (Tg, TPO, Dio2) and/or during post-metamorphosis (TTR, TRβ, ERβ). When the early larvae were exposed to both genistein concentrations (3mg/L and 10mg/L), a statistically significant down-regulation of TPO, TTR and Tg mRNA levels was clearly detected at the metamorphic stages. In addition, the Dio2 and Dio3 transcript expression levels were also down and up-regulated when exposed to both genistein concentrations. In the larvae exposed to genistein, no statistically significant responses were recorded for the TRβ expression patterns. Nevertheless, the ERβ and Cyp1a transcript levels were up-regulated at the middle metamorphic stage (S2, at 16 dph) in the larvae exposed to high genistein concentrations and, only the ERβ was down-regulated (S1, at 12dph) at the lower doses. Finally, all these pointed out imbalances were only temporarily disrupted by exposure to genistein, since most of the modulated transcriptional signals (i.e. up or down-regulation) were quickly restored to the baseline levels. Additionally, the control and genistein-exposed Senegalese sole specimens showed characteristic ontogenetic patterns and completely suitable for an optimal development, metamorphosis, and growth. Copyright © 2017

  11. Estrogens and aging skin.

    PubMed

    Thornton, M Julie

    2013-04-01

    Estrogen deficiency following menopause results in atrophic skin changes and acceleration of skin aging. Estrogens significantly modulate skin physiology, targeting keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, and improve angiogenesis, wound healing and immune responses. Estrogen insufficiency decreases defense against oxidative stress; skin becomes thinner with less collagen, decreased elasticity, increased wrinkling, increased dryness and reduced vascularity. Its protective function becomes compromised and aging is associated with impaired wound healing, hair loss, pigmentary changes and skin cancer.   Skin aging can be significantly delayed by the administration of estrogen. This paper reviews estrogen effects on human skin and the mechanisms by which estrogens can alleviate the changes due to aging. The relevance of estrogen replacement, selective estrogen receptor modulators (SERMs) and phytoestrogens as therapies for diminishing skin aging is highlighted. Understanding estrogen signaling in skin will provide a basis for interventions in aging pathologies.

  12. 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...

  13. Estrogen promotes cutaneous wound healing via estrogen receptor β independent of its antiinflammatory activities

    PubMed Central

    Campbell, Laura; Emmerson, Elaine; Davies, Faith; Gilliver, Stephen C.; Krust, Andre; Chambon, Pierre; Ashcroft, Gillian S.

    2010-01-01

    Post-menopausal women have an increased risk of developing a number of degenerative pathological conditions, linked by the common theme of excessive inflammation. Systemic estrogen replacement (in the form of hormone replacement therapy) is able to accelerate healing of acute cutaneous wounds in elderly females, linked to its potent antiinflammatory activity. However, in contrast to many other age-associated pathologies, the detailed mechanisms through which estrogen modulates skin repair, particularly the cell type–specific role of the two estrogen receptors, ERα and ERβ, has yet to be determined. Here, we use pharmacological activation and genetic deletion to investigate the role of both ERα and ERβ in cutaneous tissue repair. Unexpectedly, we report that exogenous estrogen replacement to ovariectomised mice in the absence of ERβ actually delayed wound healing. Moreover, healing in epidermal-specific ERβ null mice (K14-cre/ERβL2/L2) largely resembled that in global ERβ null mice. Thus, the beneficial effects of estrogen on skin wound healing are mediated by epidermal ERβ, in marked contrast to most other tissues in the body where ERα is predominant. Surprisingly, agonists to both ERα and ERβ are potently antiinflammatory during skin repair, indicating clear uncoupling of inflammation and overall efficiency of repair. Thus, estrogen-mediated antiinflammatory activity is not the principal factor in accelerated wound healing. PMID:20733032

  14. 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)

  15. Racial Disparities in Recurrence Among Patients with Early Stage Endometrial Cancer: Is Recurrence Increased in Black Patients on Estrogen Replacement Therapy?: A Gynecologic Oncology Group Study

    PubMed Central

    Maxwell, G. Larry; Tian, Chunqiao; Risinger, John I; Hamilton, Chad A.; Barakat, Richard R.

    2008-01-01

    Objective Population-based studies suggest that Black women with localized endometrial cancer have shorter survival compared to White patients because of inequalities in treatment. The purpose of this investigation was to determine if there is a racial disparity in outcome between Black and White patients with early stage endometrial cancer treated similarly in a clinical trial setting. Methods A retrospective review of 110 Black and 1049 White patients with stage I and II endometrial cancer was performed using data from a randomized, placebo controlled trial performed by the Gynecologic Oncology Group (GOG) that evaluated postoperative estrogen replacement therapy (ERT) and the risk of cancer recurrence. Demographic, pathologic, treatment and outcome related data were collected and analyzed using regression and survival analysis. Results Estimates of recurrence-free survival (RFS) suggested that Black patients may be more likely to have disease recurrence, particularly those on ERT. Within a median follow-up of three years, 5 of 56 Black endometrial cancer patients in the ERT group were identified with recurrent disease compared to only 8 of 521 White patients. Adjusted for age, BMI and tumor grade, the relative risk of recurrence among Blacks in the ERT group was 11.2 (95% CI: 2.86-43.59, p=0.0005). Conclusions Our findings suggest that RFS may be shorter among Black women with stage I endometrial cancer, even in a clinical trials setting in which patients receive similar treatment and followup. This increased risk of recurrence appears to be most evident in Black women with endometrial cancer who maintain ERT following primary treatment. PMID:18698590

  16. Exogenous hormonal regulation in breast cancer cells by phytoestrogens and endocrine disruptors.

    PubMed

    Albini, A; Rosano, C; Angelini, G; Amaro, A; Esposito, A I; Maramotti, S; Noonan, D M; Pfeffer, U

    2014-01-01

    Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERβ and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor modulators (SERMs).

  17. Exogenous Hormonal Regulation in Breast Cancer Cells by Phytoestrogens and Endocrine Disruptors

    PubMed Central

    Albini, A.; Rosano, C.; Angelini, G.; Amaro, A.; Esposito, A.I.; Maramotti, S.; Noonan, D.M.; Pfeffer, U.

    2014-01-01

    Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERβ and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor modulators (SERMs). PMID:24304271

  18. GPER Mediates Non-Genomic Effects of Estrogen.

    PubMed

    Pupo, Marco; Maggiolini, Marcello; Musti, Anna Maria

    2016-01-01

    Estrogens are important modulators of a broad spectrum of physiological functions in humans. However, despite their beneficial actions, a number of lines of evidence correlate the sustained exposure to exogenous estrogen with increased risk of the onset of various cancers. Mainly these steroid hormones induce their effects by binding and activating estrogen receptors (ERα and ERβ). These receptors belong to the family of ligand-regulated transcription factors, and upon activation they regulate the expression of different target genes by binding directly to specific DNA sequences. On the other hand, in recent years it has become clear that the G protein-coupled estrogen receptor 30 (GPR30/GPER) is able to mediate non-genomic action of estrogens in different cell contexts. In particular, GPER has been shown to specifically bind estrogens, and in turn to functionally cross-react with diverse cell signaling systems such as the epidermal growth factor receptor (EGFR) pathway, the Notch signaling pathway and the mitogen-activated protein kinases (MAPK) pathway. In this chapter we will present some of the different experimental techniques currently used to demonstrate the functional role of GPER in mediating non-genomic actions of estrogens, such as the dual luciferase assay, assessment of the involvement of GPER in the stimulation of cell migration in breast cancer cell lines and in cancer-associated fibroblasts, and chromatin immunoprecipitation assay. Overall, the experimental procedures described herein represent key instruments for assessing the biological role of GPER in mediating non-genomic signals of estrogen.

  19. Expression of the IGF and the aromatase/estrogen receptor systems in human adrenal tissues from early infancy to late puberty: implications for the development of adrenarche.

    PubMed

    Belgorosky, Alicia; Baquedano, María Sonia; Guercio, Gabriela; Rivarola, Marco A

    2009-03-01

    Adrenarche is a process of postnatal sexual maturation occurring in higher primates, in which there is an increase in the secretion of adrenal androgens. It is the consequence of a process of postnatal organogenesis characterized by the development of a new zone in the adrenal cortex, the zona reticularis (ZR). The mechanism of this phenomenon remains poorly understood, suggesting that it might be a multifactorial event. A relationship between circulating IGF-I, insulin sensitivity, and adrenal androgens has been postulated. Boys and girls have different patterns of changes in insulin sensitivity at puberty, perhaps secondary to differences in the estrogen milieu. Estrogen effects may also play a role in premature adrenarche. Peripheral or local IGF-1 actions could regulate adrenal progenitor cell proliferation and migration. Since adrenal progenitor cells as well as IGF-I and the IGF-R1 are located in the outer zone of the adrenal cortex during childhood and adolescence, this peripheral cell layer, below the capsule, may contain undifferentiated progenitor cells. Therefore, the IGF-R1 signaling pathway might positively modulate the proliferation and migration of adrenal progenitor cell to stimulate the development of adrenal zones, including ZR. However, no evidence of a direct action of IGF-I on ZR was found. In addition, a role for estrogens in the ontogenesis of ZR is suggested by the presence of aromatase (CYP19) in the subcapsular zona glomerulosa and in the adrenal medulla. Estrogens produced locally could act on ZR by interacting with estrogen receptor beta (ERbeta), but not alpha, and membrane estrogen receptor GPR-30. An estradiol-induced increase in DHEA/cortisol ratio was indeed seen in cultures of adrenocortical cells from post-adrenarche adrenals. In summary, several lines of evidence point to the action of multiple factors, such as local adrenal maturational changes and peripheral metabolic signals, on postnatal human adrenal gland ZR formation.

  20. 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

  1. 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

  2. The role of estrogen in cutaneous ageing and repair.

    PubMed

    Wilkinson, Holly N; Hardman, Matthew J

    2017-09-01

    Combined advances in modern medical practice and increased human longevity are driving an ever-expanding elderly population. Females are particularly at risk of age-associated pathology, spending more of their lives in a post-menopausal state. Menopause, denoted by a rapid decline in serum sex steroid levels, accelerates biological ageing across the body's tissues. Post-menopause physiological changes are particularly noticeable in the skin, which loses structural architecture and becomes prone to damage. The sex steroid most widely discussed as an intrinsic contributor to skin ageing and pathological healing is 17β-estradiol (or estrogen), although many others are involved. Estrogen deficiency is detrimental to many wound-healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment widely reverses these effects. Over recent decades, many of the molecular and cellular correlates to estrogen's beneficial effect on normal skin homeostasis and wound healing have been reported. However, disparities still exist, particularly in the context of mechanistic studies investigating estrogen receptor signalling and its potential cellular effects. New molecular techniques, coupled with increased understanding of estrogen in skin biology, will provide further opportunities to develop estrogen receptor-targeted therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Effects of transdermal estrogen replacement therapy on cardiovascular risk factors.

    PubMed

    Menon, Dileep V; Vongpatanasin, Wanpen

    2006-01-01

    key enzymes involved in plaque disruption, while transdermal estrogen does not have these adverse effects.Whether the advantages of transdermal estrogen with regards to these risk factors will translate into improved clinical outcomes remains to be determined. Two ongoing clinical trials, KEEPS (Kronos Early Estrogen Prevention Study) and ELITE (Early versus Late Intervention Trial with Estradiol) are likely to provide invaluable information regarding the role of oral versus transdermal estrogen in younger postmenopausal women.

  4. Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens.

    PubMed Central

    Newbold, R

    1995-01-01

    Concerns have been raised regarding the role of environmental and dietary estrogens as possible contributors to an increased incidence of various abnormalities in estrogen-target tissues of both sexes. These abnormalities include breast cancer, endometriosis, fibroids, and uterine adenocarcinoma in females, as well as alterations in sex differentiation, decreased sperm concentrations, benign prostatic hyperplasia, prostatic cancer, testicular cancer, and reproductive problems in males. Whether these concerns are valid remains to be determined; however, studies with the potent synthetic estrogen diethylstilbestrol (DES) suggest that exogenous estrogen exposure during critical stages of development can result in permanent cellular and molecular alterations in the exposed organism. These alterations manifest themselves in the female and male as structural, functional, or long-term pathological changes including neoplasia. Although DES has potent estrogenic activity, it may be used as a model compound to study the effects of weaker environmental estrogens, many of which may fit into the category of endocrine disruptors. PMID:8593881

  5. Estrogen receptor agonists/antagonists in breast cancer therapy: A critical review.

    PubMed

    Jameera Begam, A; Jubie, S; Nanjan, M J

    2017-04-01

    Estrogens display intriguing tissue selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer. There are also strong evidences to show that both endogenous and exogenous estrogens are involved in the pathogenesis of breast cancer. Tamoxifen has been the only drug of choice for more than 30years to treat patients with estrogen related (ER) positive breast tumors. There is a need therefore, for identifying newer, potential and novel candidates for breast cancer. Keeping this in view, the present review focuses on selective estrogen receptor modulators and estrogen antagonists such as sulfatase and aromatase inhibitors involved in breast cancer therapy. A succinct and critical overview of the structure of estrogen receptors, their signaling and involvement in breast carcinogenesis are herein described. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. 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

  7. Circulating microparticles and endogenous estrogen in newly menopausal women

    PubMed Central

    Jayachandran, M.; Litwiller, R. D.; Owen, W. G.; Miller, V. M.

    2011-01-01

    Background Estrogen modulates antithrombotic characteristics of the vascular endothelium and the interaction of blood elements with the vascular surface. A marker of these modulatory activities is formation of cell-specific microparticles. This study examined the relationship between blood-borne microparticles and endogenous estrogen at menopause. Methods Platelet activation and plasma microparticles were characterized from women being screened (n = 146) for the Kronos Early Estrogen Prevention Study. Women were grouped according to serum estrogen (< 20 pg/ml; low estrogen, n = 21 or > 40 pg/ml; high estrogen, n = 11). Results Age, body mass index, blood pressure and blood chemistries were the same in both groups. No woman was hypertensive, diabetic or a current smoker. Platelet counts, basal and activated expression of P-selectin on platelet membranes were the same, but activated expression of glycoprotein IIb/IIIa was greater in the high-estrogen group. Numbers of endothelium-, platelet-, monocyte- and granulocyte-derived microparticles were greater in the low-estrogen group. Of the total numbers of microparticles, those positive for phosphatidylserine and tissue factor were also greater in the low-estrogen group. Conclusion These results suggest that, with declines in endogenous estrogen at menopause, numbers of procoagulant microparticles increase and thus may provide a means to explore mechanisms for cardiovascular risk development in newly menopausal women. PMID:19051075

  8. Estrogenic effects of nonylphenol and octylphenol isomers in vitro by recombinant yeast assay (RYA) and in vivo with early life stages of zebrafish.

    PubMed

    Puy-Azurmendi, E; Olivares, A; Vallejo, A; Ortiz-Zarragoitia, M; Piña, B; Zuloaga, O; Cajaraville, M P

    2014-01-01

    Commercial OP and NP are complex isomer mixtures that can be individually present in the environment, showing different estrogenic potencies. The aims of this study were to establish the estrogenic potency of some AP isomers in comparison to the commercial NP (cNP) mixture in vitro and to investigate in vivo their possible effects during the embryo and larval development of zebrafish. An in vitro estrogen receptor-based recombinant yeast assay was used to test the estrogenicity of specific AP isomers (22-OP, 33-OP, 22-NP, 33-NP and 363-NP) and cNP. The EC₅₀ was in the range of 0.6-7.7 mg/L. Both OP isomers and 363-NP exhibited higher estrogenic activity than cNP. For in vivo experiments, one-day postfertilisation (dpf) embryos were exposed to cNP (50, 250 and 500 μg/L), 363-NP and 33-OP (50 μg/L), 17β-estradiol (100 ng/L) and DMSO (0.01% v/v) for 4weeks. After exposure fish were maintained for 2 weeks in clean water in order to evaluate a possible recovery. Fish of groups exposed to cNP and 363-NP were the last to hatch. Histological alterations were not observed after 7, 28 or 42 dpf. Exposure to 33-OP increased transcriptional levels of erα, vtg and cyp19a1b genes. However, transcriptional response in E2 exposure was observed at later stages and with higher fold induction levels. Exposure to cNP decreased levels of erα whereas increased levels of rxrγ and cyp19a1b. Exposure to 363-NP did not cause changes in transcriptional levels of studied genes. The differences in response of the OP isomer compared to the NP isomer in zebrafish could be related to the rapid decay in concentration of the latter. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Lifetime exposure to estrogens and Parkinson's disease in California teachers.

    PubMed

    Gatto, N M; Deapen, D; Stoyanoff, S; Pinder, R; Narayan, S; Bordelon, Y; Ritz, B

    2014-11-01

    Parkinson's disease (PD) is consistently observed to occur less frequently in women than men, prompting investigation into whether estrogen protects against neurodegeneration of dopaminergic neurons. We used baseline data in the California Teachers Study, a prospective cohort of women, to investigate whether reproductive factors indicating higher long-term estrogen levels are associated with PD using a nested case-control approach. We identified 228 PD cases and 3349 unaffected controls frequency matched by age and race. Women who reported using combined estrogen/progesterone therapy or progesterone only formulations had a 57% increase in PD risk (OR = 1.57, 95% CI = 1.06, 2.34) compared to never having used HT. Compared to women with menopause at 50-52 years, menopause at younger (<35-46 years: OR = 0.59, 95% CI = 0.37, 0.94) and older ages (≥53 years: OR = 0.54, 95% CI = 0.36, 0.83) had lower PD risk. A derived composite estrogen summary score for women's exposure to both endogenous and exogenous estrogens throughout life indicated that women with presumed higher cumulative lifetime levels of estrogen (a score of 3-5) had a significantly reduced PD risk [(OR = 0.57, 95% CI = 0.35, 0.91) relative to those with lower lifetime estrogen exposure or a composite estrogen summary score of 0-1]. These results provide some support for the hypothesis that lifelong high estrogen is protective in PD, suggesting that the level and persistence of exposure over the long term may be important in PD risk reduction. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: preventive and therapeutic implications

    PubMed Central

    Suba, Zsuzsanna

    2014-01-01

    Epidemiologic studies strongly support that triple-negative breast cancers (TNBCs) may be distinct entities as compared with estrogen receptor (ER)+ tumors, suggesting that the etiologic factors, clinical characteristics, and therapeutic possibilities may vary by molecular subtypes. Many investigations propose that reproductive factors and exogenous hormone use differently or even quite inversely affect the risk of TNBCs and ER+ cancers. Controversies concerning the exact role of even the same risk factor in TNBC development justify that the biological mechanisms behind the initiation of both TNBCs and non-TNBCs are completely obscure. To arrive at a comprehensive understanding of the etiology of different breast cancer subtypes, we should also reconsider our traditional concepts and beliefs regarding cancer risk factors. Malignancies are multicausal, but the disturbance of proper estrogen signaling seems to be a crucial risk factor for the development of mammary cancers. The grade of defect in metabolic and hormonal equilibrium is directly associated with TNBC risk for women during their whole life. Inverse impact of menopausal status or parity on the development of ER+ and ER− breast cancers may not be possible; these controversial results derive from the misinterpretation of percentage-based statistical evaluations. Exogenous or parity-associated excessive estrogen supply is suppressive against breast cancer, though the lower the ER expression of tumors, the weaker the anticancer capacity. In women, the most important preventive strategy against breast cancers – included TNBCs – is the strict control and maintenance of hormonal equilibrium from early adolescence through the whole lifetime, particularly during the periods of great hormonal changes. PMID:24482576

  11. Early intervention with an estrogen receptor β-selective phytoestrogenic formulation prolongs survival, improves spatial recognition memory, and slows progression of amyloid pathology in a female mouse model of Alzheimer's disease.

    PubMed

    Zhao, Liqin; Mao, Zisu; Chen, Shuhua; Schneider, Lon S; Brinton, Roberta D

    2013-01-01

    Our recent developments have yielded a novel phytoestrogenic formulation, referred to as the phyto-β-SERM formulation, which exhibits an 83-fold binding selectivity for the estrogen receptor subtype β (ERβ) over ERα. Earlier studies indicate that the phyto-β-SERM formulation is neuroprotective and promotes estrogenic mechanisms in the brain while devoid of feminizing activity in the periphery. Further investigation in a mouse model of human menopause indicates that chronic exposure to the phyto-β-SERM formulation at a clinically relevant dosage prevents/alleviates menopause-related climacteric symptoms. This study assessed the efficacy, in an early intervention paradigm, of the phyto-β-SERM formulation in the regulation of early stages of physical and neurological changes associated with Alzheimer's disease (AD) in a female triple transgenic mouse model of AD. Results demonstrated that, when initiated prior to the appearance of AD pathology, a 9-month dietary supplementation with the phyto-β-SERM formulation promoted physical health, prolonged survival, improved spatial recognition memory, and attenuated amyloid-β deposition and plaque formation in the brains of treated AD mice. In comparison, dietary supplementation of a commercial soy extract preparation showed no effect on cognitive measures, although it appeared to have a positive impact on amyloid pathology. In overall agreement with the behavioral and histological outcomes, results from a gene expression profiling analysis offered insights on the underlying molecular mechanisms associated with the two dietary treatments. In particular, the data suggests that there may be a crosstalk between ERβ and glycogen synthase kinase 3 signaling pathways that could play a role in conferring ERβ-mediated neuroprotection against AD. Taken together, these results support the therapeutic potential of the phyto-β-SERM formulation for prevention and/or early intervention of AD, and warrants further investigations

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

    PubMed

    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.

  13. 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).

  14. Adjuvant chemotherapy decisions in clinical practice for early-stage node-negative, estrogen receptor-positive, HER2-negative breast cancer: challenges and considerations.

    PubMed

    Nagaraj, Gayathri; Ma, Cynthia X

    2013-03-01

    Decisions regarding adjuvant chemotherapy for patients with estrogen receptor (ER)-positive, HER2-negative, lymph node-negative breast cancer have traditionally relied on clinical and pathologic parameters. However, the molecular heterogeneity and the complex tumor genome demand more sophisticated approaches to the problem. Several multigene-based assays have been developed to better prognosticate the risk of recurrence and death and predict benefit of therapy in this patient population. Oncologists are often faced with the challenge of incorporating these various complex genome-based biomarkers along with the traditional biomarkers in clinical decision-making. The NCCN Clinical Practice Guidelines in Oncology for Breast Cancer are helpful in providing a general recommendation. However, uncertainty remains in the absence of definitive data for various clinical scenarios. This case report describes a postmenopausal woman with stage I breast cancer that is low-grade and ER-rich, and has an intermediate Oncotype DX recurrence score of 28.

  15. Androgens and estrogens in benign prostatic hyperplasia: past, present and future

    PubMed Central

    Nicholson, Tristan M.; Ricke, William A.

    2011-01-01

    Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology. While the precise molecular etiology remains unclear, sex steroids have been implicated in the development and maintenance of BPH. Sufficient data exists linking androgens and androgen receptor pathways to BPH and use of androgen reducing compounds, such as 5α-reductase inhibitors which block the conversion of testosterone into dihydrotestosterone, are a component of the standard of care for men with LUTS attributed to an enlarged prostate. However, BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors other than androgens are involved. Testosterone, the primary circulating androgen in men, can also be metabolized via CYP19/aromatase into the potent estrogen, estradiol-17β. The prostate is an estrogen target tissue and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation signifying potential roles in BPH. Recent research has demonstrated that estrogen receptor signaling pathways may be important in the development and maintenance of BPH and LUTS; however, new models are needed to genetically dissect estrogen regulated molecular mechanisms involved in BPH. More work is needed to identify estrogens and associated signaling pathways in BPH in order to target BPH with dietary and therapeutic SERMs. PMID:21620560

  16. 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. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. 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

  18. 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%.

  19. Effects of hormones on skin wrinkles and rigidity vary by race/ethnicity: four-year follow-up from the ancillary skin study of the Kronos Early Estrogen Prevention Study.

    PubMed

    Owen, Carter M; Pal, Lubna; Mumford, Sunni L; Freeman, Ruth; Isaac, Barbara; McDonald, Linda; Santoro, Nanette; Taylor, Hugh S; Wolff, Erin F

    2016-10-01

    To measure skin wrinkles and rigidity in menopausal women of varying race/ethnicity with or without hormone therapy (HT) for up to four years. Randomized, double-blind, placebo-controlled trial. Academic medical centers. Women (42-58 years of age) within 36 months of last menstrual period and enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Treatment with 0.45 mg oral conjugated equine estrogens (CEE), transdermal E 2 (50 μg/d) with micronized P (200 mg daily), or placebo for 4 years. Skin wrinkles were assessed at 11 locations on the face and neck, and skin rigidity was assessed at the forehead and cheek at baseline and yearly for 4 years. Neither total wrinkle score nor total rigidity score was significantly different at baseline or over the 4-year follow-up among patients randomized to CEE, E 2 , or placebo. Skin wrinkle and rigidity scores were primarily affected by race/ethnicity, with scores being significantly different between races for almost all of the wrinkle parameters and for all of the rigidity measures. There was no association between race and response to HT for total wrinkle or rigidity scores. Black women had the lowest wrinkle scores compared with white women across all 4 years. In general, skin rigidity decreased in all groups over time, but black women had significantly reduced total facial rigidity compared with white women after 4 years. Race is the strongest predictor of the advancement of skin aging in the 4 years following menopause. HT does not appear to affect skin wrinkles or rigidity at most facial locations. NCT00154180. Published by Elsevier Inc.

  20. Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS).

    PubMed

    Cintron, Dahima; Lahr, Brian D; Bailey, Kent R; Santoro, Nanette; Lloyd, Robin; Manson, JoAnn E; Neal-Perry, Genevieve; Pal, Lubna; Taylor, Hugh S; Wharton, Whitney; Naftolin, Fredrick; Harman, S Mitchell; Miller, Virginia M

    2018-02-01

    This study determined whether two different formulations of hormone therapy (HT): oral conjugated equine estrogens (o-CEE; 0.45 mg/d, n = 209), transdermal 17β-estradiol (t-E2; 50 μg/d, n = 201) plus cyclic progesterone (Prometrium, 200 mg) or placebo (PBO, n = 243) affected sleep domains in participants of the Kronos Early Estrogen Prevention Study. Participants completed the Pittsburgh Sleep Quality Index at baseline and during the intervention at 6, 18, 36, and 48 months. Global sleep quality and individual sleep domain scores were compared between treatments using analysis of covariance, and correlated with vasomotor symptom (VMS) scores using Spearman correlation coefficients. Global Pittsburgh Sleep Quality Index scores (mean 6.3; 24% with score >8) were similar across groups at baseline and were reduced (improved sleep quality) by both HT (average change -1.27 [o-CEE] and -1.32 [t-E2]) when compared with PBO (-0.60; P = 0.001 [o-CEE vs PBO] and P = 0.002 [t-E2 vs PBO]). Domain scores for sleep satisfaction and latency improved with both HT. The domain score for sleep disturbances improved more with t-E2 than o-CEE or PBO. Global sleep scores significantly correlated with VMS severity (rs = 0.170, P < 0.001 for hot flashes; rs = 0.177, P < 0.001 for night sweats). Change in scores for all domains except sleep latency and sleep efficiency correlated with change in severity of VMS. Poor sleep quality is common in recently menopausal women. Sleep quality improved with both HT formulations. The relationship of VMS with domains of sleep suggests that assessing severity of symptoms and domains of sleep may help direct therapy to improve sleep for postmenopausal women.

  1. Nitric oxide is cytoprotective to breast cancer spheroids vulnerable to estrogen-induced apoptosis

    PubMed Central

    Shafran, Yana; Zurgil, Naomi; Ravid-Hermesh, Orit; Sobolev, Maria; Afrimzon, Elena; Hakuk, Yaron; Shainberg, Asher; Deutsch, Mordechai

    2017-01-01

    Estrogen-induced apoptosis has become a successful treatment for postmenopausal metastatic, estrogen receptor-positive breast cancer. Nitric oxide involvement in the response to this endocrine treatment and its influence upon estrogen receptor-positive breast cancer progression is still unclear. Nitric oxide impact on the MCF7 breast cancer line, before and after estrogen-induced apoptosis, was investigated in 3D culture systems using unique live-cell imaging methodologies. Spheroids were established from MCF7 cells vulnerable to estrogen-induced apoptosis, before and after exposure to estrogen. Spheroids derived from estrogen-treated cells exhibited extensive apoptosis levels with downregulation of estrogen receptor expression, low proliferation rate and reduced metabolic activity, unlike spheroids derived from non-treated cells. In addition to basic phenotypic differences, these two cell cluster types are diverse in their reactions to exogenous nitric oxide. A dual effect of nitric oxide was observed in the breast cancer phenotype sensitive to estrogen-induced apoptosis. Nitric oxide, at the nanomolar level, induced cell proliferation, high metabolic activity, downregulation of estrogen receptor and enhanced collective invasion, contributing to a more aggressive phenotype. Following hormone supplementation, breast cancer 3D clusters were rescued from estrogen-induced apoptosis by these low nitric oxide-donor concentrations, since nitric oxide attenuates cell death levels, upregulates survivin expression and increases metabolic activity. Higher nitric oxide concentrations (100nM) inhibited cell growth, metabolism and promoted apoptosis. These results suggest that nitric oxide, in nanomolar concentrations, may inhibit estrogen-induced apoptosis, playing a major role in hormonal therapy. Inhibiting nitric oxide activity may benefit breast cancer patients and ultimately reduce tumor recurrence. PMID:29312577

  2. 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...

  3. Prospective Clinical Utility Study of the Use of the 21-Gene Assay in Adjuvant Clinical Decision Making in Women With Estrogen Receptor-Positive Early Invasive Breast Cancer: Results From the SWITCH Study

    PubMed Central

    Pivot, Xavier B.; Jacot, William; Naman, Hervé L.; Spaeth, Dominique; Misset, Jean-Louis; Largillier, Rémy; Sautiere, Jean-Loup; de Roquancourt, Anne; Pomel, Christophe; Rouanet, Philippe; Rouzier, Roman; Penault-Llorca, Frederique M.

    2015-01-01

    Background. The 21-gene Oncotype DX Recurrence Score assay is a validated assay to help decide the appropriate treatment for estrogen receptor-positive (ER+), early-stage breast cancer (EBC) in the adjuvant setting. The choice of adjuvant treatments might vary considerably in different countries according to various treatment guidelines. This prospective multicenter study is the first to assess the impact of the Oncotype DX assay in the French clinical setting. Methods. A total of 100 patients with ER+, human epidermal growth factor receptor 2-negative EBC, and node-negative (pN0) disease or micrometastases in up to 3 lymph nodes (pN1mi) were enrolled. Treatment recommendations, physicians’ confidence before and after knowing the Recurrence Score value, and physicians’ perception of the assay were recorded. Results. Of the 100 patients, 95 were evaluable (83 pN0, 12 pN1mi). Treatment recommendations changed in 37% of patients, predominantly from chemoendocrine to endocrine treatment alone. The proportion of patients recommended chemotherapy decreased from 52% pretest to 25% post-test. Of patients originally recommended chemotherapy, 61% were recommended endocrine treatment alone after receiving the Recurrence Score result. For both pN0 and pN1mi patients, post-test recommendations appeared to follow the Recurrence Score result for low and high values. Physicians’ confidence improved significantly. Conclusion. These are the first prospective data on the impact of the Oncotype DX assay on adjuvant treatment decisions in France. Using the assay was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use. These data are consistent with those presented from European and non-European studies. Implications for Practice: This study shows that in estrogen receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer (either node-negative or with micrometastases in up to 3 lymph nodes

  4. Clinical Overestimation of HER2 Positivity in Early Estrogen and Progesterone Receptor–Positive Breast Cancer and the Value of Molecular Subtyping Using BluePrint

    PubMed Central

    Langenhoven, Lizanne; Grant, Kathleen A.; van der Merwe, Lize; Kotze, Maritha J.

    2017-01-01

    Purpose Human epidermal growth factor receptor 2 (HER2) positivity is an important prognostic and predictive indicator in breast cancer. HER2 status is determined by immunohistochemistry and fluorescent in situ hybridization (FISH), which are potentially inaccurate techniques as a result of several technical factors, polysomy of chromosome 17, and amplification or overexpression of CEP17 (centromeric probe for chromosome 17) and/or HER2. In South Africa, HER2-positive tumors are excluded from a MammaPrint (MP; Agendia BV, Amsterdam, Netherlands) pretest algorithm. Clinical HER2 status has been reported to correlate poorly with molecular subtype. The aim of this study was to investigate the correlation of clinical HER2 status with BluePrint (BP) molecular subtyping. Methods Clinico-pathologic and genomic information was extracted from a prospectively collected central MP database containing records of 256 estrogen receptor–positive and/or progesterone receptor–positive tumors. Twenty-one tumors considered HER2 positive on immunohistochemistry or FISH were identified for this study. Results The median age of patients was 56 years (range, 34 to 77 years), with a median tumor size of 16 mm (3 to 27 mm). Four (19%) tumors were confirmed HER2-enriched subtype, six (29%) were luminal A, and 11 (52%) were luminal B. The positive predictive values of HER2/CEP17 ratio ≥ 2 and HER2 copy number ≥ 6 were only 29% and 40%, respectively. The differences in means for HER2/CEP17 ratio were significant between BP HER2-enriched versus luminal (P = .0249; 95% CI, 0.12 to 1.21) and MP high-risk versus low-risk tumors (P = .0002; 95% CI, 0.40 to 1.06). Conclusion Of the 21 tumors considered clinically HER2 positive, only four were HER2-enriched subtype with BP, indicating an overestimation of HER2 positivity. FISH testing has a poor positive predictive value. PMID:28831439

  5. Clinical Overestimation of HER2 Positivity in Early Estrogen and Progesterone Receptor-Positive Breast Cancer and the Value of Molecular Subtyping Using BluePrint.

    PubMed

    Myburgh, Ettienne J; Langenhoven, Lizanne; Grant, Kathleen A; van der Merwe, Lize; Kotze, Maritha J

    2017-08-01

    Human epidermal growth factor receptor 2 (HER2) positivity is an important prognostic and predictive indicator in breast cancer. HER2 status is determined by immunohistochemistry and fluorescent in situ hybridization (FISH), which are potentially inaccurate techniques as a result of several technical factors, polysomy of chromosome 17, and amplification or overexpression of CEP17 (centromeric probe for chromosome 17) and/or HER2. In South Africa, HER2-positive tumors are excluded from a MammaPrint (MP; Agendia BV, Amsterdam, Netherlands) pretest algorithm. Clinical HER2 status has been reported to correlate poorly with molecular subtype. The aim of this study was to investigate the correlation of clinical HER2 status with BluePrint (BP) molecular subtyping. Clinico-pathologic and genomic information was extracted from a prospectively collected central MP database containing records of 256 estrogen receptor-positive and/or progesterone receptor-positive tumors. Twenty-one tumors considered HER2 positive on immunohistochemistry or FISH were identified for this study. The median age of patients was 56 years (range, 34 to 77 years), with a median tumor size of 16 mm (3 to 27 mm). Four (19%) tumors were confirmed HER2-enriched subtype, six (29%) were luminal A, and 11 (52%) were luminal B. The positive predictive values of HER2/CEP17 ratio ≥ 2 and HER2 copy number ≥ 6 were only 29% and 40%, respectively. The differences in means for HER2/CEP17 ratio were significant between BP HER2-enriched versus luminal ( P = .0249; 95% CI, 0.12 to 1.21) and MP high-risk versus low-risk tumors ( P = .0002; 95% CI, 0.40 to 1.06). Of the 21 tumors considered clinically HER2 positive, only four were HER2-enriched subtype with BP, indicating an overestimation of HER2 positivity. FISH testing has a poor positive predictive value.

  6. Estrogen in cardiovascular disease during systemic lupus erythematosus.

    PubMed

    Gilbert, Emily L; Ryan, Michael J

    2014-12-01

    Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension. PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against cardiovascular risk factors in

  7. Estrogen in Cardiovascular Disease during Systemic Lupus Erythematosus

    PubMed Central

    Gilbert, Emily L.; Ryan, Michael J.

    2015-01-01

    Purpose Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension. Methods PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. Findings The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against

  8. Characterization and Consequences of Estrogen Receptor Exon Five Deletion.

    DTIC Science & Technology

    1998-08-01

    and ending with ovulation), and the luteal or secretory phase (beginning with ovulation and ending with the onset of menses) (7). Early in the...7), the primary site of both progesterone and estrogen biosynthesis during the luteal phase 3 (estrogen production remains elevated through most of...the luteal phase, 250ug/day, and progesterone production peaks in the mid- luteal phase, 10-40mg/day) (7). If implantation does not occur gonadotropin

  9. Exogenous carbonaceous matter in ancient martian sediments

    NASA Astrophysics Data System (ADS)

    Mojzsis, S. J.; Abramov, O.; Kereszturi, A.

    2015-12-01

    We re-evaluate the early evolution of an organic-matter rich (~10 wt. %) interplanetary dust particle flux to early Mars. Our work builds upon physical models that rely on plausible sources of exogenous debris and their dynamical rates of decay, the martian cratering record, and preservation of Noachian-Hesperian sedimentary units that have the potential to host organics. Post primary-accretionary scenarios that would have delivered abundant exogenous carbon to Mars can be imagined in two ways: a simple exponential decay with an approximately 100 Myr half-life, or as a "Sawtooth" timeline characterized by both faster-than-exponential decay from primary accretion and reduced total delivered mass. Indications are that a late bombardment spike was superposed on an otherwise broadly monotonic decline from primary accretion, of which two types are explored: a classical "Late Heavy Bombardment" (LHB) peak of impactors centered at ca. 3950 Ma and lasting 100 Myr, and a protracted bombardment typified by a sudden increase in impactor flux at ca. 4240-4100 Ma with a correspondingly longer decay time (400 Myr). Numerical models for each of the four bombardment scenarios explored in this work shows that exogenous organic matter could be a significant component of Noachian (ca. 4200-3700 Ma) and pre-Noachian (4500-4200 Ma) sediments. The discovery of organic-matter in martian sediments will be obfuscated by material of extra-areological origin. We predict that an earmark for the origin of this carbon would be correlated siderophile element abundances (e.g. Ni, Cr, and the platinoids). A time-dependent compositional relationship of C:HSEs would allow us to derive a chemochronology for pre-Hesperian (pre-3700 Ma) sedimentary units.

  10. Estrogens, Neuroinflammation, and Neurodegeneration

    PubMed Central

    Villa, Alessandro; Vegeto, Elisabetta; Poletti, Angelo

    2016-01-01

    Inflammatory activation of microglia is a hallmark of several disorders of the central nervous system. In addition to protecting the brain against inflammatory insults, microglia are neuroprotective and play a significant role in maintaining neuronal connectivity, but the prolongation of an inflammatory status may limit the beneficial functions of these immune cells. The finding that estrogen receptors are present in monocyte-derived cells and that estrogens prevent and control the inflammatory response raise the question of the role that this sex steroid plays in the manifestation and progression of pathologies that have a clear sex difference in prevalence, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The present review aims to provide a critical review of the current literature on the actions of estrogen in microglia and on the involvement of estrogen receptors in the manifestation of selected neurological disorders. This current understanding highlights a research area that should be expanded to identify appropriate replacement therapies to slow the progression of such diseases. PMID:27196727

  11. Endogenous versus exogenous shocks in systems with memory

    NASA Astrophysics Data System (ADS)

    Sornette, D.; Helmstetter, A.

    2003-02-01

    Systems with long-range persistence and memory are shown to exhibit different precursory as well as recovery patterns in response to shocks of exogenous versus endogenous origins. By endogenous, we envision either fluctuations resulting from an underlying chaotic dynamics or from a stochastic forcing origin which may be external or be an effective coarse-grained description of the microscopic fluctuations. In this scenario, endogenous shocks result from a kind of constructive interference of accumulated fluctuations whose impacts survive longer than the large shocks themselves. As a consequence, the recovery after an endogenous shock is in general slower at early times and can be at long times either slower or faster than after an exogenous perturbation. This offers the tantalizing possibility of distinguishing between an endogenous versus exogenous cause of a given shock, even when there is no “smoking gun”. This could help in investigating the exogenous versus self-organized origins in problems such as the causes of major biological extinctions, of change of weather regimes and of the climate, in tracing the source of social upheaval and wars, and so on. Sornette et al., Volatility fingerprints of large stocks: endogenous versus exogenous, cond-mat/0204626 has already shown how this concept can be applied concretely to differentiate the effects on financial markets of the 11 September 2001 attack or of the coup against Gorbachev on 19 August 1991 (exogenous) from financial crashes such as October 1987 (endogenous).

  12. Estrogen Metabolites Are Not Associated With Colorectal Cancer Risk In Postmenopausal Women

    PubMed Central

    Falk, Roni T.; Dallal, Cher M.; Lacey, James V.; Bauer, Douglas C.; Buist, Diana SM; Cauley, Jane A.; Hue, Trisha F.; LaCroix, Andrea; Tice, Jeffrey A.; Pfeiffer, Ruth M.; Xu, Xia; Veenstra, Timothy D.; Brinton, Louise A.

    2015-01-01

    Background A potential protective role for estrogen in colon carcinogenesis has been suggested based on exogenous hormone use, but it is unclear from previous studies whether endogenous estrogens are related to colorectal cancer (CRC) risk. These few prior studies focused on parent estrogens; none evaluated effects of estrogen metabolism in postmenopausal women. Methods We followed 15,595 women (ages 55–80) enrolled in B~FIT (Breast and Bone Follow-up to the Fracture Intervention Trial (FIT)) who donated blood between 1992 and 1993 for cancer through December 2004. A panel of 15 estrogen metabolites (EM), including estradiol and estrone, were measured in serum from 187 CRC cases and a subcohort of 501 women not using exogenous hormones at blood draw. We examined EM individually, grouped by pathway (hydroxylation at the C-2, C-4, or C-16 position), and by ratios of the groupings using Cox proportional hazards regression models. Results No significant associations were seen for estrone (HRQ4 v Q1=1.15, 95% CI=0.69–1.93, ptrend=0.54), estradiol (HRQ4 v Q1= 0.98, 95% CI=0.58–1.64, ptrend>0.99) or total EM (the sum of all EM; HRQ4 v Q1=1.35. 95% CI=0.81–2.24, ptrend=0.33). Most metabolites in the 2-, 4- or 16-pathway were unrelated to risk, although a borderline trend in risk was associated with high levels of 17-epiestriol. Conclusion Circulating estrogens and their metabolites were generally unrelated to CRC risk in postmenopausal women. Impact Additional studies are needed to understand how exogenous estrogen may prevent CRC PMID:26104910

  13. The genetics of response to estrogen treatment

    PubMed Central

    Langdahl, Bente L

    2009-01-01

    It has been demonstrated that the response to estrogen treatment in postmenopausal women shows considerable variability. It has been speculated that this at least partly could be determined by heritable factors. The most obvious genes to investigate in this context are the estrogen receptor genes. It has been demonstrated that women with short alleles of the TA-repeat polymorphism in the estrogen receptor α gene respond to hormone treatment with greater increases in bone mass at the lumbar spine. Also the two polymorphisms in the first intron of the same gene have been found to be associated with the response to estrogen. Several studies have found that women carrying the Pand the X-alleles respond to hormone therapy with greater increases in bone mass and sustain fewer fractures. Polymorphisms in the collagen type Iα1 have been found to influence BMD. Conflicting results have been obtained with respect to the influence of these genetic variants on postmenopausal bone loss and response to hormone treatment. Furthermore, two polymorphisms in the promoter of the transforming growth factor β gene and one polymorphism in the first exon of the osteoprotegerin gene have been demonstrated to interact with the response to hormone treatment in early postmenopausal women. The above mentioned results are obtained from relatively small studies and needs confirmation before the information can be used in the clinic. PMID:22461097

  14. Reprint of: From the 90׳s to now: A brief historical perspective on more than two decades of estrogen neuroprotection.

    PubMed

    Engler-Chiurazzi, E B; Singh, M; Simpkins, J W

    2016-08-15

    Historical perspective abstract:From the 90׳s to now: a historical perspective on more than two decades of estrogen neuroprotection: In the early 90׳s, estrogens were known to exert organizational and activational effects on reproductive tissues and sexual behavior. As well, the role of sex and gonadal hormones in altering the risk for developing Alzheimer׳s Disease (AD) was only beginning to be elucidated. Preliminary investigations suggested that estrogen-containing therapies typically given for the management of disruptive menopausal symptoms could reduce AD risk, attenuate disease-associated cognitive deficits, and modulate brain substrates known to be dysregulated by the condition, such as the cholingeric system. The findings from our seminal paper demonstrating cognitive benefits and cholinergic impacts with exogenous estrogen treatment in a rodent model of surgical hormone depletion provided initial support for use of estrogen-containing therapies as a treatment for age-related brain disorders. We then went on to demonstrate neuroprotective actions of estrogen in several other in vivo and in vitro models of neurological challenge, including stroke and AD. Further, our findings of the chemical structure requirements for estrogen׳s neuroprotective effects identified a novel approach for optimizing future estrogen-containing hormone therapy options. These early efforts laid the groundwork for later, large-scale clinical investigations into the potential of estrogen-based menopausal hormone therapies for the prevention of a variety of age-related disorders. Although findings of these studies were equivocal, the neuroprotective actions of estrogen, and specifically 17β-estradiol, identified by early investigations, remain well-documented. Future development of interventions that optimize cognitive aging are crucial and, with proper understanding of the factors that influence the realization of beneficial impacts, estrogen-containing treatments may still be

  15. Exogenous Attention Enables Perceptual Learning

    PubMed Central

    Szpiro, Sarit F. A.; Carrasco, Marisa

    2015-01-01

    Practice can improve visual perception, and these improvements are considered to be a form of brain plasticity. Training-induced learning is time-consuming and requires hundreds of trials across multiple days. The process of learning acquisition is understudied. Can learning acquisition be potentiated by manipulating visual attentional cues? We developed a protocol in which we used task-irrelevant cues for between-groups manipulation of attention during training. We found that training with exogenous attention can enable the acquisition of learning. Remarkably, this learning was maintained even when observers were subsequently tested under neutral conditions, which indicates that a change in perception was involved. Our study is the first to isolate the effects of exogenous attention and to demonstrate its efficacy to enable learning. We propose that exogenous attention boosts perceptual learning by enhancing stimulus encoding. PMID:26502745

  16. Exogenous Attention Enables Perceptual Learning.

    PubMed

    Szpiro, Sarit F A; Carrasco, Marisa

    2015-12-01

    Practice can improve visual perception, and these improvements are considered to be a form of brain plasticity. Training-induced learning is time-consuming and requires hundreds of trials across multiple days. The process of learning acquisition is understudied. Can learning acquisition be potentiated by manipulating visual attentional cues? We developed a protocol in which we used task-irrelevant cues for between-groups manipulation of attention during training. We found that training with exogenous attention can enable the acquisition of learning. Remarkably, this learning was maintained even when observers were subsequently tested under neutral conditions, which indicates that a change in perception was involved. Our study is the first to isolate the effects of exogenous attention and to demonstrate its efficacy to enable learning. We propose that exogenous attention boosts perceptual learning by enhancing stimulus encoding. © The Author(s) 2015.

  17. 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

  18. Differences in expression of the cancer stem cell marker aldehyde dehydrogenase 1 among estrogen receptor-positive/human epidermal growth factor receptor type 2-negative breast cancer cases with early, late, and no recurrence.

    PubMed

    Miyoshi, Yuichiro; Shien, Tadahiko; Ogiya, Akiko; Ishida, Naoko; Yamazaki, Kieko; Horii, Rie; Horimoto, Yoshiya; Masuda, Norikazu; Yasojima, Hiroyuki; Inao, Touko; Osako, Tomofumi; Takahashi, Masato; Tomioka, Nobumoto; Endo, Yumi; Hosoda, Mitsuchika; Doihara, Hiroyoshi; Miyoshi, Shinichiro; Yamashita, Hiroko

    2016-07-02

    The significance of the expression of aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, for predicting the recurrence of estrogen receptor (ER)-positive/human epidermal growth factor receptor type 2 (HER2)-negative breast cancer is still poorly understood. The value of ALDH1 in predicting the time of recurrence remains unknown. In total, 184 patients with early distant recurrence, 134 patients with late distant recurrence, and 321 control patients without recurrence for more than 10 years after starting initial treatment for ER-positive/HER2-negative breast cancer, registered in 9 institutions, were analyzed. We assessed relationships between ALDH1 and other clinicopathological features, and ALDH1 expression was compared among the three groups. The relationship between ALDH1 expression and overall survival after recurrence was also evaluated in each group. The rates of ALDH1 expression positivity (more than 1 %) in the early, late, and no recurrence groups were 18.4 %, 13.4 %, and 8.4 %, respectively. ALDH1 expression correlated significantly with lymph node metastases (p = 0.048) and the Ki-67 labeling index (p < 0.001) in the early recurrence group. Multivariate analysis revealed ALDH1 expression to be significantly higher in the early recurrence group than in the no recurrence group (adjusted OR 2.140, 95 % CI 1.144-4.003, p = 0.016). Moreover, there was a significant difference in ALDH1 expression between the early and no recurrence groups receiving adjuvant endocrine therapy and chemotherapy (adjusted OR 4.625, 95 % CI 1.881-12.474, p < 0.001). However, there was no difference in ALDH1 expression between the late and no recurrence groups in univariate analysis (OR 1.507, 95 % CI 0.738-2.998, p = 0.253). In multivariate analysis, ALDH1 was not a factor independently predicting overall survival after the detection of recurrence (adjusted OR 1.451, 95 % CI 0.985-2.085, p = 0.059). Among patients with ER-positive/HER2

  19. Endogenous estrogens and breast cancer risk: the case for prospective cohort studies.

    PubMed Central

    Toniolo, P G

    1997-01-01

    It is generally agreed that estrogens, and possibly androgens, are important in the etiology of breast cancer, but no consensus exists as to the precise estrogenic or androgenic environment that characterizes risk, or the exogenous factors that influence the hormonal milieu. Nearly all the epidemiological studies conducted in the 1970s and 1980s were hospital-based case-control studies in which specimen sampling was performed well after the clinical appearance of the disease. Early prospective cohort studies also had limitations in their small sample sizes or short follow-up periods. However, more recent case-control studies nested within large cohorts, such as the New York University Women's Health Study and the Ormoni e Dieta nell'Eziologia dei Tumori study in Italy, are generating new data indicating that increased levels of estrone, estradiol and bioavailable estradiol, as well as their androgenic precursors, may be associated with a 4- to 6-fold increase in the risk of postmenopausal breast cancer. Further new evidence, which complements and expands the observations from the latter studies, shows that women with the thickest bone density, which may be a surrogate for cumulated exposure to hormones, experience severalfold increased risk of subsequent breast cancer as compared to women with thin bones. These data suggests that endogenous sex hormones are a key factor in the etiology of postmenopausal breast cancer. New prospective cohort studies should be conducted to examine the role of endogenous sex hormones in blood and urine samples obtained early in the natural history of breast cancer jointly with an assessment of bone density and of other important risk factors, such as mammographic density, physical activity, body weight, and markers of individual susceptibility, which may confer increased risk through an effect on the metabolism of endogenous hormones or through specific metabolic responses to Western lifestyle and diet. PMID:9168000

  20. Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS)

    PubMed Central

    Cintron, Dahima; Lahr, Brian D.; Bailey, Kent R.; Santoro, Nanette; Lloyd, Robin; Manson, JoAnn E.; Neal-Perry, Genevieve; Pal, Lubna; Taylor, Hugh S.; Wharton, Whitney; Naftolin, Fredrick; Harman, S. Mitchell; Miller, Virginia M.

    2018-01-01

    Abstract Objective: This study determined whether two different formulations of hormone therapy (HT): oral conjugated equine estrogens (o-CEE; 0.45 mg/d, n = 209), transdermal 17β-estradiol (t-E2; 50 μg/d, n = 201) plus cyclic progesterone (Prometrium, 200 mg) or placebo (PBO, n = 243) affected sleep domains in participants of the Kronos Early Estrogen Prevention Study. Methods: Participants completed the Pittsburgh Sleep Quality Index at baseline and during the intervention at 6, 18, 36, and 48 months. Global sleep quality and individual sleep domain scores were compared between treatments using analysis of covariance, and correlated with vasomotor symptom (VMS) scores using Spearman correlation coefficients. Results: Global Pittsburgh Sleep Quality Index scores (mean 6.3; 24% with score >8) were similar across groups at baseline and were reduced (improved sleep quality) by both HT (average change −1.27 [o-CEE] and −1.32 [t-E2]) when compared with PBO (−0.60; P = 0.001 [o-CEE vs PBO] and P = 0.002 [t-E2 vs PBO]). Domain scores for sleep satisfaction and latency improved with both HT. The domain score for sleep disturbances improved more with t-E2 than o-CEE or PBO. Global sleep scores significantly correlated with VMS severity (rs = 0.170, P < 0.001 for hot flashes; rs = 0.177, P < 0.001 for night sweats). Change in scores for all domains except sleep latency and sleep efficiency correlated with change in severity of VMS. Conclusions: Poor sleep quality is common in recently menopausal women. Sleep quality improved with both HT formulations. The relationship of VMS with domains of sleep suggests that assessing severity of symptoms and domains of sleep may help direct therapy to improve sleep for postmenopausal women. PMID:28832429

  1. Epidemiology of estrogen and dementia in women with Down syndrome.

    PubMed

    Schupf, Nicole; Lee, Joseph H; Pang, Deborah; Zigman, Warren B; Tycko, Benjamin; Krinsky-McHale, Sharon; Silverman, Wayne

    2018-01-01

    Several lines of investigation have shown a protective role for estrogen in Alzheimer's disease through a number of biological actions. This review examines studies of the role of estrogen-related factors in age at onset and risk for Alzheimer's disease in women with Down syndrome, a population at high risk for early onset of dementia. The studies are consistent in showing that early age at menopause and that low levels of endogenous bioavailable estradiol in postmenopausal women with Down syndrome are associated with earlier age at onset and overall risk for dementia. Polymorphisms in genes associated with estrogen receptor activity and in genes for estrogen biosynthesis affecting endogenous estrogen are related to age at onset and cumulative incidence of dementia, and may serve as biomarkers of risk. To date, no clinical trials of estrogen or hormone replacement therapy (ERT/HRT) have been published for women with Down syndrome. While findings from clinical trials of ERT or HRT for dementia have generally been negative among women in the neurotypical population, the short interval between menopause and onset of cognitive decline, together with a more positive balance between potential benefits and risks, suggests an opportunity to evaluate the efficacy of ERT/HRT for delaying or preventing dementia in this high risk population, although questions concerning the optimal formulation and timing of the hormone therapy are not yet resolved. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. From the 90's to now: A brief historical perspective on more than two decades of estrogen neuroprotection.

    PubMed

    Engler-Chiurazzi, E B; Singh, M; Simpkins, J W

    2016-02-15

    Historical perspective abstract:From the 90's to now: a historical perspective on more than two decades of estrogen neuroprotection: In the early 90's, estrogens were known to exert organizational and activational effects on reproductive tissues and sexual behavior. As well, the role of sex and gonadal hormones in altering the risk for developing Alzheimer's Disease (AD) was only beginning to be elucidated. Preliminary investigations suggested that estrogen-containing therapies typically given for the management of disruptive menopausal symptoms could reduce AD risk, attenuate disease-associated cognitive deficits, and modulate brain substrates known to be dysregulated by the condition, such as the cholingeric system. The findings from our seminal paper demonstrating cognitive benefits and cholinergic impacts with exogenous estrogen treatment in a rodent model of surgical hormone depletion provided initial support for use of estrogen-containing therapies as a treatment for age-related brain disorders. We then went on to demonstrate neuroprotective actions of estrogen in several other in vivo and in vitro models of neurological challenge, including stroke and AD. Further, our findings of the chemical structure requirements for estrogen's neuroprotective effects identified a novel approach for optimizing future estrogen-containing hormone therapy options. These early efforts laid the groundwork for later, large-scale clinical investigations into the potential of estrogen-based menopausal hormone therapies for the prevention of a variety of age-related disorders. Although findings of these studies were equivocal, the neuroprotective actions of estrogen, and specifically 17β-estradiol, identified by early investigations, remain well-documented. Future development of interventions that optimize cognitive aging are crucial and, with proper understanding of the factors that influence the realization of beneficial impacts, estrogen-containing treatments may still be among

  3. Recurrence of Cervical Cancer in Mice after Selective Estrogen Receptor Modulator Therapy

    PubMed Central

    Spurgeon, Megan E.; Chung, Sang-Hyuk; Lambert, Paul F.

    2015-01-01

    Estrogen and its nuclear receptor, estrogen receptor α, are necessary cofactors in the initiation and multistage progression of carcinogenesis in the K14E6/E7 transgenic mouse model of human papillomavirus–associated cervical cancer. Recently, our laboratory reported that raloxifene, a selective estrogen receptor modulator, promoted regression of high-grade dysplasia and cancer that arose in the cervix of K14E6/E7 transgenic mice treated long-term with estrogen. Herein, we evaluated the recurrence of cervical cancer after raloxifene therapy in our preclinical model of human papillomavirus–associated cervical carcinogenesis. We observed recurrence of cervical cancer in mice re-exposed to estrogen after raloxifene treatment, despite evidence suggesting the antagonistic effects of raloxifene persisted in the reproductive tract after treatment had ceased. We also observed recurrence of neoplastic disease in mice that were not retreated with exogenous estrogen, although the severity of disease was less. Recurrent neoplastic disease and cancers retained functional estrogen receptor α and responded to retreatment with raloxifene. Moreover, continuous treatment of mice with raloxifene prevented the emergence of recurrent disease seen in mice in which raloxifene was discontinued. These data suggest that cervical cancer cells are not completely eradicated by raloxifene and rapidly expand if raloxifene treatment is ceased. These findings indicate that a prolonged treatment period with raloxifene might be required to prevent recurrence of neoplastic disease and lower reproductive tract cancers. PMID:24418098

  4. 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

  5. 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)

  6. Estrogen and the female heart.

    PubMed

    Knowlton, A A; Korzick, D H

    2014-05-25

    Estrogen has a plethora of effects in the cardiovascular system. Studies of estrogen and the heart span human clinical trials and basic cell and molecular investigations. Greater understanding of cell and molecular responses to estrogens can provide further insights into the findings of clinical studies. Differences in expression and cellular/intracellular distribution of the two main receptors, estrogen receptor (ER) α and β, are thought to account for the specificity and differences in responses to estrogen. Much remains to be learned in this area, but cellular distribution within the cardiovascular system is becoming clearer. Identification of GPER as a third ER has introduced further complexity to the system. 17β-estradiol (E2), the most potent human estrogen, clearly has protective properties activating a signaling cascade leading to cellular protection and also influencing expression of the protective heat shock proteins (HSP). E2 protects the heart from ischemic injury in basic studies, but the picture is more involved in the whole organism and clinical studies. Here the complexity of E2's widespread effects comes into play and makes interpretation of findings more challenging. Estrogen loss occurs primarily with aging, but few studies have used aged models despite clear evidence of differences between the response to estrogen deficiency in adult and aged animals. Thus more work is needed focusing on the effects of aging vs. estrogen loss on the cardiovascular system. Published by Elsevier Ireland Ltd.

  7. [Farmer's lung--a form of exogenous allergic alveolitis].

    PubMed

    Sambale, M; Liebetrau, G

    1990-11-15

    Exogenic allergic alveolitides are caused by organic dusts which contain bacteria, moulds or vegetable and animal antigens. The farmer's lung as a form of the exogenic allergic alveolitis is a rare disease. The uncharacteristic symptomatology in the initial phase and in particular the retarded beginning of the symptom after several hours handicap the timely recognition in an early phase of the disease so that curative therapeutic measures are rarely possible. The cases of the disease are found only at the chronic stage, at the stage of the pulmonary fibrosis. Then the prognosis is unfavourable. In the Central Clinic for Heart and Lung Diseases Bad Berka 1,110 patients with alveolitides and lung fibroses were diagnosed in the period from 1975 to 1988. 306 of them could be clarified as exogenic allergic alveolitis, 61 of them (19.8%) were farmer's lungs.

  8. Exogenous proteases for meat tenderization.

    PubMed

    Bekhit, Alaa A; Hopkins, David L; Geesink, Geert; Bekhit, Adnan A; Franks, Philip

    2014-01-01

    The use of exogenous proteases to improve meat tenderness has attracted much interest recently, with a view to consistent production of tender meat and added value to lower grade meat cuts. This review discusses the sources, characteristics, and use of exogenous proteases in meat tenderization to highlight the specificity of the proteases toward meat proteins and their impact on meat quality. Plant enzymes (such as papain, bromelain, and ficin) have been extensively investigated as meat tenderizers. New plant proteases (actinidin and zingibain) and microbial enzyme preparations have been of recent interest due to controlled meat tenderization and other advantages. Successful use of these enzymes in fresh meat requires their enzymatic kinetics and characteristics to be determined, together with an understanding of the impact of the surrounding environmental conditions of the meat (pH, temperature) on enzyme function. This enables the optimal conditions for tenderizing fresh meat to be established, and the elimination or reduction of any negative impacts on other quality attributes.

  9. Exogenic and endogenic Europa minerals

    NASA Astrophysics Data System (ADS)

    Maynard-Casely, H. E.; Brand, H. E. A.; Wilson, S. A.

    2016-12-01

    The Galileo Near Infrared Mapping Spectrometer (NIMS) identified a significant `non-ice' component upon the surface of Jupiter's moon Europa. Current explanations invoke both endogenic and exogenic origins for this material. It has long been suggested that magnesium and sodium sulfate minerals could have leached from the rock below a putative ocean (endogenic) 1 and that sulfuric acid hydrate minerals could have been radiologically produced from ionised sulfur originally from Io's volcanoes (exogenic) 2. However, a more recent theory proposes that the `non-ice' component could be radiation damaged NaCl leached from Europa's speculative ocean 3. What if the minerals are actually from combination of both endogenic and exogenic sources? To investigate this possibility we have focused on discovering new minerals that might form in the combination of the latter two cases, that is a mixture of leached sulfates hydrates with radiologically produced sulfuric acid. To this end we have explored a number of solutions in the MgSO4-H2SO4-H2O and Na2SO4-H2SO4-H2O systems, between 80 and 280 K with synchrotron x-ray powder diffraction. We report a number of new materials formed in this these ternary systems. This suggests that it should be considered that the `non-ice' component of the Europa's surface could be a material derived from endogenic and exogenic components. 1 Kargel, J. S. Brine volcanism and the interior structures of asteroids and icy satellites. Icarus 94, 368-390 (1991). 2 Carlson, R. W., Anderson, M. S., Mehlman, R. & Johnson, R. E. Distribution of hydrate on Europa: Further evidence for sulfuric acid hydrate. Icarus 177, 461-471, doi:10.1016/j.icarus.2005.03.026 (2005). 3 Hand, K. P. & Carlson, R. W. Europa's surface color suggests an ocean rich with sodium chloride. Geophysical Research Letters, 2015GL063559, doi:10.1002/2015gl063559 (2015).

  10. The effect of grape seed extract on estrogen levels of postmenopausal women: a pilot study.

    PubMed

    Wahner-Roedler, Dietlind L; Bauer, Brent A; Loehrer, Laura L; Cha, Stephen S; Hoskin, Tanya L; Olson, Janet E

    2014-06-01

    The role of estrogens in breast cancer (BC) development is widely accepted, leading to the development of selective estrogen receptor modulators and aromatase inhibitors for BC treatment and prevention. However, because of potential adverse effects, healthy women with high risk of BC are hesitant to take them. Preliminary evidence from animal studies shows that grapes may have an aromatase-inhibiting effect, decreasing estrogen synthesis and increasing androgen precursors. We conducted a randomized, double-blind, dose-finding early-phase trial on the effect of grape seed extract (GSE) on estrogen levels. Postmenopausal women who met study inclusion criteria (N = 46) were randomly assigned to daily GSE at a dose of 200, 400, 600, or 800 mg for 12 weeks. Primary outcome was change in plasma levels of estrogen conjugates from baseline to 12 weeks posttreatment. Thirty-nine participants (84.8%) completed the study. GSE in the 4 daily doses did not significantly decrease estrogen or increase androgen precursors.

  11. Prospective study of the impact of the Prosigna assay on adjuvant clinical decision-making in unselected patients with estrogen receptor positive, human epidermal growth factor receptor negative, node negative early-stage breast cancer.

    PubMed

    Martín, Miguel; González-Rivera, Milagros; Morales, Serafín; de la Haba-Rodriguez, Juan; González-Cortijo, Lucía; Manso, Luis; Albanell, Joan; González-Martín, Antonio; González, Sónia; Arcusa, Angels; de la Cruz-Merino, Luis; Rojo, Federico; Vidal, María; Galván, Patricia; Aguirre, Elena; Morales, Cristina; Ferree, Sean; Pompilio, Kristen; Casas, Maribel; Caballero, Rosalía; Goicoechea, Uxue; Carrasco, Eva; Michalopoulos, Steven; Hornberger, John; Prat, Aleix

    2015-06-01

    Improved understanding of risk of recurrence (ROR) is needed to reduce cases of recurrence and more effectively treat breast cancer patients. The purpose of this study was to examine how a gene-expression profile (GEP), identified by Prosigna, influences physician adjuvant treatment selection for early breast cancer (EBC) and the effects of this influence on optimizing adjuvant treatment recommendations in clinical practice. A prospective, observational, multicenter study was carried out in 15 hospitals across Spain. Participating medical oncologists completed pre-assessment, post-assessment, and follow-up questionnaires recording their treatment recommendations and confidence in these recommendations, before and after knowing the patient's ROR. Patients completed questionnaires on decision-making, anxiety, and health status. Between June 2013 and January 2014, 217 patients enrolled and a final 200 were included in the study. Patients were postmenopausal, estrogen receptor positive, human epidermal growth hormone factor negative, and node negative with either stage 1 or stage 2 tumors. After receiving the GEP results, treatment recommendations were changed for 40 patients (20%). The confidence of medical oncologists in their treatment recommendations increased in 41.6% and decreased in 6.5% of total cases. Patients reported lower anxiety after physicians made treatment recommendations based on the GEP results (p < 0.05). Though this study does not include evaluation of the impact of GEP on long-term outcomes, it was found that GEP results influenced the treatment decisions of medical oncologists and their confidence in adjuvant therapy selection. Patients' anxiety about the selected adjuvant therapy decreased with use of the GEP.

  12. Prospective Clinical Utility Study of the Use of the 21-Gene Assay in Adjuvant Clinical Decision Making in Women With Estrogen Receptor-Positive Early Invasive Breast Cancer: Results From the SWITCH Study.

    PubMed

    Gligorov, Joseph; Pivot, Xavier B; Jacot, William; Naman, Hervé L; Spaeth, Dominique; Misset, Jean-Louis; Largillier, Rémy; Sautiere, Jean-Loup; de Roquancourt, Anne; Pomel, Christophe; Rouanet, Philippe; Rouzier, Roman; Penault-Llorca, Frederique M

    2015-08-01

    The 21-gene Oncotype DX Recurrence Score assay is a validated assay to help decide the appropriate treatment for estrogen receptor-positive (ER+), early-stage breast cancer (EBC) in the adjuvant setting. The choice of adjuvant treatments might vary considerably in different countries according to various treatment guidelines. This prospective multicenter study is the first to assess the impact of the Oncotype DX assay in the French clinical setting. A total of 100 patients with ER+, human epidermal growth factor receptor 2-negative EBC, and node-negative (pN0) disease or micrometastases in up to 3 lymph nodes (pN1mi) were enrolled. Treatment recommendations, physicians' confidence before and after knowing the Recurrence Score value, and physicians' perception of the assay were recorded. Of the 100 patients, 95 were evaluable (83 pN0, 12 pN1mi). Treatment recommendations changed in 37% of patients, predominantly from chemoendocrine to endocrine treatment alone. The proportion of patients recommended chemotherapy decreased from 52% pretest to 25% post-test. Of patients originally recommended chemotherapy, 61% were recommended endocrine treatment alone after receiving the Recurrence Score result. For both pN0 and pN1mi patients, post-test recommendations appeared to follow the Recurrence Score result for low and high values. Physicians' confidence improved significantly. These are the first prospective data on the impact of the Oncotype DX assay on adjuvant treatment decisions in France. Using the assay was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use. These data are consistent with those presented from European and non-European studies. ©AlphaMed Press.

  13. Estrogen modulates sexually dimorphic contextual fear extinction in rats through estrogen receptor beta.

    PubMed

    Chang, Yao-Ju; Yang, Chih-Hao; Liang, Ying-Ching; Yeh, Che-Ming; Huang, Chiung-Chun; Hsu, Kuei-Sen

    2009-11-01

    Females and males are different in brain and behavior. These sex differences occur early during development due to a combination of genetic and hormonal factors and continue throughout the lifespan. Previous studies revealed that male rats exhibited significantly higher levels of contextual fear memory than female rats. However, it remains unknown whether a sex difference exists in the contextual fear extinction. To address this issue, male, normally cycling female, and ovariectomized (OVX) female Sprague-Dawley rats were subjected to contextual fear conditioning and extinction trials. Here we report that although male rats exhibited higher levels of freezing than cycling female rats after contextual fear conditioning, female rats subjected to conditioning in the proestrus and estrus stage exhibited an enhancement of fear extinction than male rats. An estrogen receptor (ER) beta agonist diarylpropionitrile but not an ERalpha agonist propyl-pyrazole-triol administration also enhanced extinction of contextual fear in OVX female rats, suggesting that estrogen-mediated facilitation of extinction involves the activation of ERbeta. Intrahippocampal injection of estradiol or diarylpropionitrile before extinction training in OVX female rats remarkably reduced the levels of freezing response during extinction trials. In addition, the locomotion or anxiety state of female rats does not vary across the ovarian cycle. These results reveal a crucial role for estrogen in mediating sexually dimorphic contextual fear extinction, and that estrogen-mediated enhancement of fear extinction involves the activation of ERbeta.

  14. Estrogen supports urothelial defense mechanisms.

    PubMed

    Lüthje, Petra; Brauner, Hanna; Ramos, Nubia L; Ovregaard, Amanda; Gläser, Regine; Hirschberg, Angelica Lindén; Aspenström, Pontus; Brauner, Annelie

    2013-06-19

    Epidemiological data imply a role of estrogen in the pathogenesis of urinary tract infections (UTIs), although the underlying mechanisms are not well understood. However, it is thought that estrogen supplementation after menopause decreases the risk of recurrent infections. We sought to investigate the influence of estrogen on host-pathogen interactions and the consequences for UTI pathogenesis. We analyzed urothelial cells from menstruating and postmenopausal women before and after a 2-week period of estrogen supplementation, and also studied the influence of estradiol during Escherichia coli UTI in a mouse infection model. Important findings were confirmed in two human urothelial cell lines. We identified two epithelial defense mechanisms modulated by estrogen. Estrogen induced the expression of antimicrobial peptides, thereby enhancing the antimicrobial capacity of the urothelium and restricting bacterial multiplication. In addition, estrogen promoted the expression and redistribution of cell-cell contact-associated proteins, thereby strengthening the epithelial integrity and preventing excessive loss of superficial cells during infection. These two effects together may prevent bacteria from reaching deeper layers of the urinary tract epithelium and developing reservoirs that can serve as a source for recurrent infections. Thus, this study presents some underlying mechanisms for the beneficial effect of estradiol after menopause and supports the application of estrogen in postmenopausal women suffering from recurrent UTI.

  15. Transgenic zebrafish reveal tissue-specific differences in estrogen signaling in response to environmental water samples

    USGS Publications Warehouse

    Gorelick, Daniel A.; Iwanowicz, Luke R.; Hung, Alice L.; Blazer, Vicki; Halpern, Marnie E.

    2014-01-01

    Background: Environmental endocrine disruptors (EED) are exogenous chemicals that mimic endogenous hormones, such as estrogens. Previous studies using a zebrafish transgenic reporter demonstrated that the EEDs bisphenol A and genistein preferentially activate estrogen receptors (ER) in the larval heart compared to the liver. However, it was not known whether the transgenic zebrafish reporter was sensitive enough to detect estrogens from environmental samples, whether environmental estrogens would exhibit similar tissue-specific effects as BPA and genistein or why some compounds preferentially target receptors in the heart. Methods: We tested surface water samples using a transgenic zebrafish reporter with tandem estrogen response elements driving green fluorescent protein expression (5xERE:GFP). Reporter activation was colocalized with tissue-specific expression of estrogen receptor genes by RNA in situ hybridization. Results: Selective patterns of ER activation were observed in transgenic fish exposed to river water samples from the Mid-Atlantic United States, with several samples preferentially activating receptors in embryonic and larval heart valves. We discovered that tissue-specificity in ER activation is due to differences in the expression of estrogen receptor subtypes. ERα is expressed in developing heart valves but not in the liver, whereas ERβ2 has the opposite profile. Accordingly, subtype-specific ER agonists activate the reporter in either the heart valves or the liver. Conclusion: The use of 5xERE:GFP transgenic zebrafish has revealed an unexpected tissue-specific difference in the response to environmentally relevant estrogenic compounds. Exposure to estrogenic EEDs in utero is associated with adverse health effects, with the potentially unanticipated consequence of targeting developing heart valves.

  16. The anticancer estrogen receptor antagonist tamoxifen impairs consolidation of inhibitory avoidance memory through estrogen receptor alpha.

    PubMed

    Lichtenfels, Martina; Dornelles, Arethuza da Silva; Petry, Fernanda Dos Santos; Blank, Martina; de Farias, Caroline Brunetto; Roesler, Rafael; Schwartsmann, Gilberto

    2017-11-01

    Over two-thirds of women with breast cancer have positive tumors for hormone receptors, and these patients undergo treatment with endocrine therapy, tamoxifen being the most widely used agent. Despite being very effective in breast cancer treatment, tamoxifen is associated with side effects that include cognitive impairments. However, the specific aspects and mechanisms underlying these impairments remain to be characterized. Here, we have investigated the effects of tamoxifen and interaction with estrogen receptors on formation of memory for inhibitory avoidance conditioning in female rats. In the first experiment, Wistar female rats received a single oral dose of tamoxifen (1, 3, or 10 mg/kg) or saline by gavage immediately after training and were tested for memory consolidation 24 h after training. In the second experiment, rats received a single dose of 1 mg/kg tamoxifen or saline by gavage 3 h after training and were tested 24 h after training for memory consolidation. In the third experiment, rats received a subcutaneous injection with estrogen receptor α agonist or estrogen receptor beta agonist 30 min before the training. After training, rats received a single oral dose of tamoxifen 1 mg/kg or saline and were tested 24 h after training. In the fourth experiment, rats were trained and tested 24 h later. Immediately after test, rats received a single dose of tamoxifen (1 mg/kg) or saline by gavage and were given four additional daily test trials followed by a re-instatement. Tamoxifen at 1 mg/kg impaired memory consolidation when given immediately after training and the estrogen receptor alpha agonist improved the tamoxifen-related memory impairment. Moreover, tamoxifen impairs memory consolidation of the test. These findings indicate that estrogen receptors regulate the early phase of memory consolidation and the effects of tamoxifen on memory consolidation.

  17. Modulation of pain by estrogens.

    PubMed

    Craft, Rebecca M

    2007-11-01

    It has become increasingly apparent that women suffer a disproportionate amount of pain during their lifetime compared to men. Over the past 15 years, a growing number of studies have suggested a variety of causes for this sex difference, from cellular to psychosocial levels of analysis. From a biological perspective, sexual differentiation of pain appears to occur similarly to sexual differentiation of other phenomena: it results in large part from organizational and activational effects of gonadal steroid hormones. The focus of this review is the activational effects of a single group of ovarian hormones, the estrogens, on pain in humans and animals. The effects of estrogens (estradiol being the most commonly examined) on experimentally induced acute pain vs. clinical pain are summarized. For clinical pain, the review is limited to a few syndromes for which there is considerable evidence for estrogenic involvement: migraine, temporomandibular disorder (TMD) and arthritis. Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain. Forging a more complete understanding of the myriad ways that estrogens can ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men.

  18. [THE ROLE OF ESTROGENS IN THE CARCINOGENESIS OF LUNG CANCER].

    PubMed

    Uchikova, E; Uchikov, A; Dimitrakova, E; Uchikov, P

    2016-01-01

    Morbidity and mortality from lung cancer has dramatically increased in women as compared to men over the past few years. Historically, smoking has been considered the major risk factor for lung cancer regardless of gender. Several recent lines of evidence implicate gender differences in the observed differences in prevalence and histologic type which cannot be explained based on the carcinogenic action of nicotine. Several recent studies underscore the importance of reproductive and hormonal factors in the carcinogenesis of lung cancer Lung cancer morbidity and mortality in Bulgaria was 16.2/100000 women and 14.6/ 100000 women, resp. Lung cancer morbidity in Europe was 39/100000 women. Lung cancer is extremely sensitive to estrogens. The latter act directly or as effect modifiers for the relationship between smoking and lung cancer. Further research examining the relationship between serum estrogen levels and the estrogen receptor expression in normal and tumor lung tissue samples can help elucidate the importance of reproductive and hormonal (exogenous and endogenous) factors in the carcinogenesis of lung cancer.

  19. Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors

    PubMed Central

    2013-01-01

    Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators. PMID:24010861

  20. Matching cue size and task properties in exogenous attention.

    PubMed

    Burnett, Katherine E; d'Avossa, Giovanni; Sapir, Ayelet

    2013-01-01

    Exogenous attention is an involuntary, reflexive orienting response that results in enhanced processing at the attended location. The standard view is that this enhancement generalizes across visual properties of a stimulus. We test whether the size of an exogenous cue sets the attentional field and whether this leads to different effects on stimuli with different visual properties. In a dual task with a random-dot kinematogram (RDK) in each quadrant of the screen, participants discriminated the direction of moving dots in one RDK and localized one red dot. Precues were uninformative and consisted of either a large or a small luminance-change frame. The motion discrimination task showed attentional effects following both large and small exogenous cues. The red dot probe localization task showed attentional effects following a small cue, but not a large cue. Two additional experiments showed that the different effects on localization were not due to reduced spatial uncertainty or suppression of RDK dots in the surround. These results indicate that the effects of exogenous attention depend on the size of the cue and the properties of the task, suggesting the involvement of receptive fields with different sizes in different tasks. These attentional effects are likely to be driven by bottom-up mechanisms in early visual areas.

  1. Estrogen plus Progestin and Risk of Benign Proliferative Breast Disease

    PubMed Central

    Rohan, Thomas E; Negassa, Abdissa; Chlebowski, Rowan T; Lasser, Norman L.; McTiernan, Anne; Schenken, Robert S.; Ginsberg, Mindy; Wassertheil-Smoller, Sylvia; Page, David L.

    2008-01-01

    Women with benign proliferative breast disease are at increased risk of subsequent breast cancer. Estrogens and progesterone exert proliferative effects on mammary epithelium and combined hormone replacement therapy has been associated with increased breast cancer risk. We tested the effect of conjugated equine estrogen plus progestin on risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial. In the WHI trial of estrogen plus progestin, 16608 postmenopausal women were randomly assigned either to 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate or to placebo. Baseline and annual breast exams and mammograms were required. The trial was terminated early (average follow-up, 5.5 years). We identified women who had had a biopsy for benign breast disease and subjected histologic sections from the biopsies to standardized review. Overall, 178 incident cases of benign proliferative breast disease were ascertained in the estrogen plus progestin group and 99 in the placebo group. Use of estrogen plus progestin was associated with a 74% increase in risk of benign proliferative breast disease (hazard ratio 1.74, 95% CI 1.35-2.25). For benign proliferative breast disease without atypia the hazard ratio was 2.00 (95% CI 1.50-2.66), while for atypical hyperplasia it was 0.76 (95% CI 0.38-1.52). Risk varied little by levels of baseline characteristics. The results of this study suggest that use of estrogen plus progestin may increase the risk of benign proliferative breast disease. PMID:18725513

  2. Modulation of steroidogenesis and estrogen signalling in the estuarine killifish (Fundulus heteroclitus) exposed to ethinylestradiol.

    PubMed

    Hogan, Natacha S; Currie, Suzanne; LeBlanc, Sacha; Hewitt, L Mark; MacLatchy, Deborah L

    2010-06-10

    Previous studies have shown that mummichog (Fundulus heteroclitus; a lunar, asynchronous-spawning killifish of the western Atlantic) exposed to 17alpha-ethynylestradiol (EE2) exhibit decreased plasma reproductive steroid levels, decreased gonadal steroid production, increased plasma vitellogenin, decreased fecundity and impaired fertilization. The objective of this study was to determine the potential mechanisms by which EE2 depresses gonadal steroidogenesis and influences estrogen signalling in the mummichog. Adult recrudesced fish were exposed to the potent synthetic estrogen, ethinylestradiol (EE2; 0-270ng/L) for 14 days. Following exposure, gonadal tissue was removed and incubated for 24h with stimulators of steroidogenesis, including forskolin; 25-OH cholesterol; or pregnenolone. Testosterone production was decreased in basal, forskolin-stimulated and pregnenolone-stimulated EE2-exposed males, indicating effects on the steroidogenic pathway both at and downstream of cholesterol mobilization to P450 side-chain cleavage (P450scc) and/or P450scc conversion of cholesterol to pregnenolone. Hepatic transcript levels of estrogen receptor alpha (ERalpha) and vitellogenin were increased in EE2-treated males compared to control recrudescing males and females confirming an estrogenic response. Hepatic heat shock protein 90 (Hsp90), a chaperoning molecule involved in estrogen signalling, was not affected by EE2 exposure at either the transcript or protein level. However, higher levels of Hsp90 observed in the membrane fractions of female fish raise interesting questions regarding the influence of gender on Hsp90's role in estrogen signalling. These results demonstrate that EE2 can alter steroid production at specific sites within the steroidogenic pathway and can stimulate hepatic estrogen signalling, providing important information regarding the molecular mechanisms underlying the endocrine response of the mummichog to exogenous estrogen.

  3. G protein-coupled estrogen receptor regulates embryonic heart rate in zebrafish

    PubMed Central

    Romano, Shannon N.; Edwards, Hailey E.; Ryan, Kevin J.

    2017-01-01

    Estrogens act by binding to estrogen receptors alpha and beta (ERα, ERβ), ligand-dependent transcription factors that play crucial roles in sex differentiation, tumor growth and cardiovascular physiology. Estrogens also activate the G protein-coupled estrogen receptor (GPER), however the function of GPER in vivo is less well understood. Here we find that GPER is required for normal heart rate in zebrafish embryos. Acute exposure to estrogens increased heart rate in wildtype and in ERα and ERβ mutant embryos but not in GPER mutants. GPER mutant embryos exhibited reduced basal heart rate, while heart rate was normal in ERα and ERβ mutants. We detected gper transcript in discrete regions of the brain and pituitary but not in the heart, suggesting that GPER acts centrally to regulate heart rate. In the pituitary, we observed gper expression in cells that regulate levels of thyroid hormone triiodothyronine (T3), a hormone known to increase heart rate. Compared to wild type, GPER mutants had reduced levels of T3 and estrogens, suggesting pituitary abnormalities. Exposure to exogenous T3, but not estradiol, rescued the reduced heart rate phenotype in gper mutant embryos, demonstrating that T3 acts downstream of GPER to regulate heart rate. Using genetic and mass spectrometry approaches, we find that GPER regulates maternal estrogen levels, which are required for normal embryonic heart rate. Our results demonstrate that estradiol plays a previously unappreciated role in the acute modulation of heart rate during zebrafish embryonic development and suggest that GPER regulates embryonic heart rate by altering maternal estrogen levels and embryonic T3 levels. PMID:29065151

  4. Transgenic Zebrafish Reveal Tissue-Specific Differences in Estrogen Signaling in Response to Environmental Water Samples

    PubMed Central

    Iwanowicz, Luke R.; Hung, Alice L.; Blazer, Vicki S.; Halpern, Marnie E.

    2014-01-01

    Background: Environmental endocrine disruptors (EEDs) are exogenous chemicals that mimic endogenous hormones such as estrogens. Previous studies using a zebrafish transgenic reporter demonstrated that the EEDs bisphenol A and genistein preferentially activate estrogen receptors (ERs) in the larval heart compared with the liver. However, it was not known whether the transgenic zebrafish reporter was sensitive enough to detect estrogens from environmental samples, whether environmental estrogens would exhibit tissue-specific effects similar to those of BPA and genistein, or why some compounds preferentially target receptors in the heart. Methods: We tested surface water samples using a transgenic zebrafish reporter with tandem estrogen response elements driving green fluorescent protein expression (5xERE:GFP). Reporter activation was colocalized with tissue-specific expression of ER genes by RNA in situ hybridization. Results: We observed selective patterns of ER activation in transgenic fish exposed to river water samples from the Mid-Atlantic United States, with several samples preferentially activating receptors in embryonic and larval heart valves. We discovered that tissue specificity in ER activation was due to differences in the expression of ER subtypes. ERα was expressed in developing heart valves but not in the liver, whereas ERβ2 had the opposite profile. Accordingly, subtype-specific ER agonists activated the reporter in either the heart valves or the liver. Conclusion: The use of 5xERE:GFP transgenic zebrafish revealed an unexpected tissue-specific difference in the response to environmentally relevant estrogenic compounds. Exposure to estrogenic EEDs in utero was associated with adverse health effects, with the potentially unanticipated consequence of targeting developing heart valves. Citation: Gorelick DA, Iwanowicz LR, Hung AL, Blazer VS, Halpern ME. 2014. Transgenic zebrafish reveal tissue-specific differences in estrogen signaling in response to

  5. Cancer genes induced by malathion and parathion in the presence of estrogen in breast cells.

    PubMed

    Calaf, G M; Roy, D

    2008-02-01

    The identification of genes involved in the process of neoplastic transformation is essential for analyzing the progression of breast cancer when induced by endogenous and exogenous agents, among which are the estrogens and the organophosphorous pesticides, respectively. It is important to consider the impact of such substances when they are present in combination. In vitro experimental models are needed in order to understand breast carcinogenesis. The aim of this work was to examine the effect of 17beta estradiol (estrogen) combined with either malathion or parathion on the transformation of human breast epithelial cells in vitro. Results showed that estrogen combined with either malathion or parathion altered cell proliferation and induced cell transformation as well as exhibited significant invasive capabilities as compared to the control MCF-10F cell line. Several genes were up-regulated by the effect of all of the treatments, such as the cyclins, cyclin D1 and cyclin-dependent kinase 4, IGFBP3 and IGFBP5, and keratin 18. The c-Ha-ras oncogene was up-regulated by the effect of malathion alone and with the combination of estrogen and either malathion or parathion. The DVL1 gene was up-regulated only with malathion alone and the combination of parathion with estrogen. Expression of the HSP 27, MCM2 and TP53 inducible protein 3 genes was up-regulated with malathion alone and with the combination of estrogen and either malathion or parathion while TP53 (Li-Fraumeni syndrome) was up-regulated by estrogen alone and malathion alone. Thus, we suggest that pesticides and estrogens affect human breast cells inducing molecular changes indicative of transformation.

  6. G protein-coupled estrogen receptor regulates embryonic heart rate in zebrafish.

    PubMed

    Romano, Shannon N; Edwards, Hailey E; Souder, Jaclyn Paige; Ryan, Kevin J; Cui, Xiangqin; Gorelick, Daniel A

    2017-10-01

    Estrogens act by binding to estrogen receptors alpha and beta (ERα, ERβ), ligand-dependent transcription factors that play crucial roles in sex differentiation, tumor growth and cardiovascular physiology. Estrogens also activate the G protein-coupled estrogen receptor (GPER), however the function of GPER in vivo is less well understood. Here we find that GPER is required for normal heart rate in zebrafish embryos. Acute exposure to estrogens increased heart rate in wildtype and in ERα and ERβ mutant embryos but not in GPER mutants. GPER mutant embryos exhibited reduced basal heart rate, while heart rate was normal in ERα and ERβ mutants. We detected gper transcript in discrete regions of the brain and pituitary but not in the heart, suggesting that GPER acts centrally to regulate heart rate. In the pituitary, we observed gper expression in cells that regulate levels of thyroid hormone triiodothyronine (T3), a hormone known to increase heart rate. Compared to wild type, GPER mutants had reduced levels of T3 and estrogens, suggesting pituitary abnormalities. Exposure to exogenous T3, but not estradiol, rescued the reduced heart rate phenotype in gper mutant embryos, demonstrating that T3 acts downstream of GPER to regulate heart rate. Using genetic and mass spectrometry approaches, we find that GPER regulates maternal estrogen levels, which are required for normal embryonic heart rate. Our results demonstrate that estradiol plays a previously unappreciated role in the acute modulation of heart rate during zebrafish embryonic development and suggest that GPER regulates embryonic heart rate by altering maternal estrogen levels and embryonic T3 levels.

  7. 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

  8. Neural correlates of endogenous attention, exogenous attention and inhibition of return in touch.

    PubMed

    Jones, Alexander; Forster, Bettina

    2014-07-01

    Selective attention helps process the myriad of information constantly touching our body. Both endogenous and exogenous mechanisms are relied upon to effectively process this information; however, it is unclear how they relate in the sense of touch. In three tasks we contrasted endogenous and exogenous event-related potential (ERP) and behavioural effects. Unilateral tactile cues were followed by a tactile target at the same or opposite hand. Clear behavioural effects showed facilitation of expected targets both when the cue predicted targets at the same (endogenous predictive task) and opposite hand (endogenous counter-predictive task), and these effects also correlated with ERP effects of endogenous attention. In an exogenous task, where the cue was non-informative, inhibition of return (IOR) was observed. The electrophysiological results demonstrated early effects of exogenous attention followed by later endogenous attention modulations. These effects were independent in both the endogenous predictive and exogenous tasks. However, voluntarily directing attention away from a cued body part influenced the early exogenous marker (N80). This suggests that the two mechanisms are interdependent, at least when the task requires more demanding shifts of attention. The early marker of exogenous tactile attention, the N80, was not directly related to IOR, which may suggest that exogenous attention and IOR are not necessarily two sides of the same coin. This study adds valuable new insight into how we process and select information presented to our body, showing both independent and interdependent effects of endogenous and exogenous attention in touch. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  9. Interaction between parathyroid hormone and endogenous estrogen in normal women.

    PubMed

    Buchanan, J R; Santen, R J; Cavaliere, A; Cauffman, S W; Greer, R B; Demers, L M

    1986-06-01

    It has been hypothesized that estrogens conserve bone substance by blocking the resorbing effect of parathyroid hormone (PTH). We evaluated this hypothesis by examining the relation of circulating PTH to endogenous estrogen fluctuation during four quarters of a single menstrual cycle in 20 normal women. The hypothesis predicts that PTH should vary directly with estrogen, since PTH should increase following estrogen elevation to satisfy physiologic demands for calcium. Contrary to the predicted direct variation, PTH remained constant throughout the menstrual cycle despite sharply fluctuating estrogen levels. Furthermore, PTH was negatively associated with estrone during the early follicular (r = -.65, P less than 0.005) and late follicular (r = -.84, P less than 0.0001) phases. We attempted to determine whether this unexpected relationship between estrone and PTH signified a direct physiologic link, by excluding factors which could have spuriously engendered the inverse correlation. Stepwise multiple regression and partial correlation showed that estrone contributed significantly to circulating PTH independent of the effects of dietary calcium, 25-hydroxyvitamin D, serum calcium, 1,25-dihydroxyvitamin D, phosphate, estradiol, progesterone, and body weight. Therefore, it is possible that the inverse correlation between estrone and PTH signified a direct physiologic link, as an artifactual cause for the relationship could not be identified. These data imply that estrone interacts with PTH, but not by blocking PTH-mediated bone resorption. We conclude that estrone is associated with reduced circulating PTH through an as yet undetermined mechanism.

  10. Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model

    PubMed Central

    Brake, Tiffany; Lambert, Paul F.

    2005-01-01

    Cervical cancer is a leading cause of death by cancer among women worldwide. High-risk human papillomaviruses (HPVs) are the major etiological agents for cervical cancer, but other factors likely contribute to cervical cancer, because these cancers commonly arise decades after initial exposure to HPV. Estrogen is thought to be one such cofactor; however, its temporal requirements in human cervical cancer are not known. Here we evaluate the temporal requirements of estrogen in cervical carcinogenesis in a mouse model for HPV-associated cervical cancer. Tumors arising in HPV16 transgenic mice treated with estrogen for 9 months were greatly increased in their size compared with tumors developing after 6 months of estrogen treatment. HPV16 transgenic mice treated 6 months with estrogen followed by 3 months without exogenous estrogen had significantly fewer tumors and the tumors were smaller and less aggressive than those arising in mice treated the full 9 months. Importantly, cervical cancers that arose in the mice treated the first 6 of 9 months with estrogen must have regressed, based upon the reduced incidence of cancers in these mice compared with those treated for 6 months with estrogen, then immediately analyzed. We conclude that estrogen plays a critical role not only in the genesis of cervical cancer but also in its persistence and continued development in this mouse model. These findings raise the clinically relevant possibility that, if human cervical cancer has a similar dependence on estrogen for continued tumor growth, then antiestrogen therapy may be effective in the treatment of cervical cancer. PMID:15699322

  11. Steroid Signaling and Temperature-Dependent Sex Determination – Reviewing the Evidence for Early Action of Estrogen during Ovarian Determination in the Red-Eared Slider Turtle (Trachemys scripta elegans)

    PubMed Central

    Ramsey, Mary; Crews, David

    2009-01-01

    The developmental processes underlying gonadal differentiation are conserved across vertebrates, but the triggers initiating these trajectories are extremely variable. The red-eared slider turtle (Trachemys scripta elegans) exhibits temperature-dependent sex determination (TSD), a system where incubation temperature during a temperature-sensitive period of development determines offspring sex. However, gonadal sex is sensitive to both temperature and hormones during this period – particularly estrogen. We present a model for temperature-based differences in aromatase expression as a critical step in ovarian determination. Localized estrogen production facilitates ovarian development while inhibiting male-specific gene expression. At male-producing temperatures aromatase is not upregulated, thereby allowing testis development. PMID:18992835

  12. Exogenous fatty acid metabolism in bacteria.

    PubMed

    Yao, Jiangwei; Rock, Charles O

    2017-10-01

    Bacterial type II fatty acid synthesis (FASII) is a target for novel antibiotic development. All bacteria encode for mechanisms to incorporate exogenous fatty acids, and some bacteria can use exogenous fatty acids to bypass FASII inhibition. Bacteria encode three different mechanisms for activating exogenous fatty acids for incorporation into phospholipid synthesis. Exogenous fatty acids are converted into acyl-CoA in Gammaproteobacteria such as E. coli. Acyl-CoA molecules constitute a separate pool from endogenously synthesized acyl-ACP. Acyl-CoA can be used for phospholipid synthesis or broken down by β-oxidation, but cannot be used for lipopolysaccharide synthesis. Exogenous fatty acids are converted into acyl-ACP in some Gram-negative bacteria. The resulting acyl-ACP undergoes the same fates as endogenously synthesized acyl-ACP. Exogenous fatty acids are converted into acyl-phosphates in Gram-positive bacteria, and can be used for phospholipid synthesis or become acyl-ACP. Only the order Lactobacillales can use exogenous fatty acids to bypass FASII inhibition. FASII shuts down completely in presence of exogenous fatty acids in Lactobacillales, allowing Lactobacillales to synthesize phospholipids entirely from exogenous fatty acids. Inhibition of FASII cannot be bypassed in other bacteria because FASII is only partially down-regulated in presence of exogenous fatty acid or FASII is required to synthesize essential metabolites such as β-hydroxyacyl-ACP. Certain selective pressures such as FASII inhibition or growth in biofilms can select for naturally occurring one step mutations that attenuate endogenous fatty acid synthesis. Although attempts have been made to estimate the natural prevalence of these mutants, culture-independent metagenomic methods would provide a better estimate. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  13. Vaginal estrogen: a dual-edged sword in postoperative healing of the vaginal wall.

    PubMed

    Ripperda, Christopher M; Maldonado, Pedro Antonio; Acevedo, Jesus F; Keller, Patrick W; Akgul, Yucel; Shelton, John M; Word, Ruth Ann

    2017-07-01

    Reconstructive surgery for pelvic organ prolapse is plagued with high failure rates possibly due to impaired healing or regeneration of the vaginal wall. Here, we tested the hypothesis that postoperative administration of local estrogen, direct injection of mesenchymal stem cells (MSCs), or both lead to improved wound healing of the injured vagina in a menopausal rat model. Ovariectomized rats underwent surgical injury to the posterior vaginal wall and were randomized to treatment with placebo (n = 41), estrogen cream (n = 47), direct injection of MSCs (n = 39), or both (n = 43). MSCs did not survive after injection and had no appreciable effects on healing of the vaginal wall. Acute postoperative administration of vaginal estrogen altered the response of the vaginal wall to injury with decreased stiffness, decreased collagen content, and decreased expression of transcripts for matrix components in the stromal compartment. Conversely, vaginal estrogen resulted in marked proliferation of the epithelial layer and increased expression of genes related to epithelial barrier function and protease inhibition. Transcripts for genes involved in chronic inflammation and adaptive immunity were also down-regulated in the estrogenized epithelium. Collectively, these data indicate that, in contrast to the reported positive effects of preoperative estrogen on the uninjured vagina, acute administration of postoperative vaginal estrogen has adverse effects on the early phase of healing of the stromal layer. In contrast, postoperative estrogen plays a positive role in healing of the vaginal epithelium after injury.

  14. Vaginal estrogen: a dual-edged sword in postoperative healing of the vaginal wall

    PubMed Central

    Ripperda, Christopher M.; Maldonado, Pedro Antonio; Acevedo, Jesus F.; Keller, Patrick W.; Akgul, Yucel; Shelton, John M.; Word, Ruth Ann

    2017-01-01

    Abstract Objective: Reconstructive surgery for pelvic organ prolapse is plagued with high failure rates possibly due to impaired healing or regeneration of the vaginal wall. Here, we tested the hypothesis that postoperative administration of local estrogen, direct injection of mesenchymal stem cells (MSCs), or both lead to improved wound healing of the injured vagina in a menopausal rat model. Methods: Ovariectomized rats underwent surgical injury to the posterior vaginal wall and were randomized to treatment with placebo (n = 41), estrogen cream (n = 47), direct injection of MSCs (n = 39), or both (n = 43). Results: MSCs did not survive after injection and had no appreciable effects on healing of the vaginal wall. Acute postoperative administration of vaginal estrogen altered the response of the vaginal wall to injury with decreased stiffness, decreased collagen content, and decreased expression of transcripts for matrix components in the stromal compartment. Conversely, vaginal estrogen resulted in marked proliferation of the epithelial layer and increased expression of genes related to epithelial barrier function and protease inhibition. Transcripts for genes involved in chronic inflammation and adaptive immunity were also down-regulated in the estrogenized epithelium. Conclusions: Collectively, these data indicate that, in contrast to the reported positive effects of preoperative estrogen on the uninjured vagina, acute administration of postoperative vaginal estrogen has adverse effects on the early phase of healing of the stromal layer. In contrast, postoperative estrogen plays a positive role in healing of the vaginal epithelium after injury. PMID:28169915

  15. Exogenous attention facilitates location transfer of perceptual learning.

    PubMed

    Donovan, Ian; Szpiro, Sarit; Carrasco, Marisa

    2015-01-01

    Perceptual skills can be improved through practice on a perceptual task, even in adulthood. Visual perceptual learning is known to be mostly specific to the trained retinal location, which is considered as evidence of neural plasticity in retinotopic early visual cortex. Recent findings demonstrate that transfer of learning to untrained locations can occur under some specific training procedures. Here, we evaluated whether exogenous attention facilitates transfer of perceptual learning to untrained locations, both adjacent to the trained locations (Experiment 1) and distant from them (Experiment 2). The results reveal that attention facilitates transfer of perceptual learning to untrained locations in both experiments, and that this transfer occurs both within and across visual hemifields. These findings show that training with exogenous attention is a powerful regime that is able to overcome the major limitation of location specificity.

  16. Exogenous attention facilitates location transfer of perceptual learning

    PubMed Central

    Donovan, Ian; Szpiro, Sarit; Carrasco, Marisa

    2015-01-01

    Perceptual skills can be improved through practice on a perceptual task, even in adulthood. Visual perceptual learning is known to be mostly specific to the trained retinal location, which is considered as evidence of neural plasticity in retinotopic early visual cortex. Recent findings demonstrate that transfer of learning to untrained locations can occur under some specific training procedures. Here, we evaluated whether exogenous attention facilitates transfer of perceptual learning to untrained locations, both adjacent to the trained locations (Experiment 1) and distant from them (Experiment 2). The results reveal that attention facilitates transfer of perceptual learning to untrained locations in both experiments, and that this transfer occurs both within and across visual hemifields. These findings show that training with exogenous attention is a powerful regime that is able to overcome the major limitation of location specificity. PMID:26426818

  17. 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

  18. Estrogen administered after cardiac arrest and cardiopulmonary resuscitation ameliorates acute kidney injury in a sex- and age-specific manner.

    PubMed

    Ikeda, Mizuko; Swide, Thomas; Vayl, Alexandra; Lahm, Tim; Anderson, Sharon; Hutchens, Michael P

    2015-09-18

    There is a sex difference in the risk of ischemic acute kidney injury (AKI), and estrogen mediates the protective effect of female sex. We previously demonstrated that preprocedural chronic restoration of physiologic estrogen to ovariectomized female mice ameliorated AKI after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). In the present study, we hypothesized that male mice and aged female mice would benefit from estrogen administration after CA/CPR. We tested the effect of estrogen in a clinically relevant manner by administrating it after CA/CPR. CA/CPR was performed in young (10-15 weeks), middle-aged (43-48 weeks), and aged (78-87 weeks) C57BL/6 male and female mice. Mice received intravenous 17β-estradiol or vehicle 15 min after resuscitation. Serum chemistries and unbiased stereological assessment of renal injury were completed 24 h after CA. Regional renal cortical blood flow was measured by a laser Doppler, and renal levels of estrogen receptor alpha (ERα) and G protein-coupled estrogen receptor (GPER) were evaluated with immunoblotting. Post-arrest estrogen administration reduced injury in young males without significant changes in renal blood flow (percentage reduction compared with vehicle: serum urea nitrogen, 30 %; serum creatinine (sCr), 41 %; volume of necrotic tubules (VNT), 31 %; P < 0.05). In contrast, estrogen did not affect any outcomes in young females. In aged mice, estrogen significantly reduced sCr (80 %) and VNT (73 %) in males and VNT (51 %) in females. Serum estrogen levels in aged female mice after CA/CPR were the same as levels in male mice. With age, renal ERα was upregulated in females. Estrogen administration after resuscitation from CA ameliorates renal injury in young males and aged mice in both sexes. Because injury was small, young females were not affected. The protective effect of exogenous estrogen may be detectable with loss of endogenous estrogen in aged females and could be mediated by differences in renal

  19. Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.

    PubMed

    Mukhopadhyay, Keya De; Liu, Zhao; Bandyopadhyay, Abhik; Kirma, Nameer B; Tekmal, Rajeshwar R; Wang, Shui; Sun, Lu-Zhe

    2015-01-01

    In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα) positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.

  20. A crucial role for thiol antioxidants in estrogen-deficiency bone loss

    PubMed Central

    Lean, Jenny M.; Davies, Julie T.; Fuller, Karen; Jagger, Christopher J.; Kirstein, Barrie; Partington, Geoffrey A.; Urry, Zoë L.; Chambers, Timothy J.

    2003-01-01

    The mechanisms through which estrogen prevents bone loss are uncertain. Elsewhere, estrogen exerts beneficial actions by suppression of reactive oxygen species (ROS). ROS stimulate osteoclasts, the cells that resorb bone. Thus, estrogen might prevent bone loss by enhancing oxidant defenses in bone. We found that glutathione and thioredoxin, the major thiol antioxidants, and glutathione and thioredoxin reductases, the enzymes responsible for maintaining them in a reduced state, fell substantially in rodent bone marrow after ovariectomy and were rapidly normalized by exogenous 17-β estradiol. Moreover, administration of N-acetyl cysteine (NAC) or ascorbate, antioxidants that increase tissue glutathione levels, abolished ovariectomy-induced bone loss, while L-buthionine-(S,R)-sulphoximine (BSO), a specific inhibitor of glutathione synthesis, caused substantial bone loss. The 17-β estradiol increased glutathione and glutathione and thioredoxin reductases in osteoclast-like cells in vitro. Furthermore, in vitro NAC prevented osteoclast formation and NF-κB activation. BSO and hydrogen peroxide did the opposite. Expression of TNF-α, a target for NF-κB and a cytokine strongly implicated in estrogen-deficiency bone loss, was suppressed in osteoclasts by 17-β estradiol and NAC. These observations strongly suggest that estrogen deficiency causes bone loss by lowering thiol antioxidants in osteoclasts. This directly sensitizes osteoclasts to osteoclastogenic signals and entrains ROS-enhanced expression of cytokines that promote osteoclastic bone resorption. PMID:12975476

  1. Emotional and cognitive functional imaging of estrogen and progesterone effects in the female human brain: a systematic review.

    PubMed

    Toffoletto, Simone; Lanzenberger, Rupert; Gingnell, Malin; Sundström-Poromaa, Inger; Comasco, Erika

    2014-12-01

    Ovarian hormones are pivotal for the physiological maintenance of the brain function as well as its response to environmental stimuli. There is mounting evidence attesting the relevance of endogenous ovarian hormones as well as exogenous estradiol and progesterone for emotional and cognitive processing. The present review systematically summarized current knowledge on sex steroid hormonal modulation of neural substrates of emotion and cognition revealed by functional magnetic resonance imaging (fMRI). Twenty-four studies of healthy naturally cycling and combined oral contraceptives (COC) user women, or women undergoing experimental manipulations, during their reproductive age, were included. Furthermore, six studies of premenstrual dysphoric disorder (PMDD), a hormonally based mood disorder, and three of gender dysphoria (GD), which provides an intriguing opportunity to examine the effect of high-dose cross-sex hormone therapy (CSHT) on brain functioning, were included. Globally, low (early follicular and the entire follicular phase for estrogen and progesterone, respectively) and high (COC, CSHT, late follicular and luteal phase for estrogen; COC, mid- and late-luteal phase for progesterone) hormonal milieu diversely affected the response of several brain regions including the amygdala, anterior cingulate cortex, and inferior frontal gyrus, but their functional recruitment across groups and domains was scattered. The constellation of findings provides initial evidence of the influence of sex steroid hormones on cortical and subcortical regions implicated in emotional and cognitive processing. Further well-powered and multimodal neuroimaging studies will be needed to identify the neural mechanism of functional brain alterations induced by sex steroid hormones. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Estrogen and Progestin (Hormone Replacement Therapy)

    MedlinePlus

    ... progestin are two female sex hormones. Hormone replacement therapy works by replacing estrogen hormone that is no ... Progestin is added to estrogen in hormone replacement therapy to reduce the risk of uterine cancer in ...

  3. 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...

  4. Exogenous spatial attention decreases audiovisual integration.

    PubMed

    Van der Stoep, N; Van der Stigchel, S; Nijboer, T C W

    2015-02-01

    Multisensory integration (MSI) and spatial attention are both mechanisms through which the processing of sensory information can be facilitated. Studies on the interaction between spatial attention and MSI have mainly focused on the interaction between endogenous spatial attention and MSI. Most of these studies have shown that endogenously attending a multisensory target enhances MSI. It is currently unclear, however, whether and how exogenous spatial attention and MSI interact. In the current study, we investigated the interaction between these two important bottom-up processes in two experiments. In Experiment 1 the target location was task-relevant, and in Experiment 2 the target location was task-irrelevant. Valid or invalid exogenous auditory cues were presented before the onset of unimodal auditory, unimodal visual, and audiovisual targets. We observed reliable cueing effects and multisensory response enhancement in both experiments. To examine whether audiovisual integration was influenced by exogenous spatial attention, the amount of race model violation was compared between exogenously attended and unattended targets. In both Experiment 1 and Experiment 2, a decrease in MSI was observed when audiovisual targets were exogenously attended, compared to when they were not. The interaction between exogenous attention and MSI was less pronounced in Experiment 2. Therefore, our results indicate that exogenous attention diminishes MSI when spatial orienting is relevant. The results are discussed in terms of models of multisensory integration and attention.

  5. Transgenic zebrafish reveal tissue-specific differences in estrogen signaling in response to environmental water samples.

    PubMed

    Gorelick, Daniel A; Iwanowicz, Luke R; Hung, Alice L; Blazer, Vicki S; Halpern, Marnie E

    2014-04-01

    Environmental endocrine disruptors (EEDs) are exogenous chemicals that mimic endogenous hormones such as estrogens. Previous studies using a zebrafish transgenic reporter demonstrated that the EEDs bisphenol A and genistein preferentially activate estrogen receptors (ERs) in the larval heart compared with the liver. However, it was not known whether the transgenic zebrafish reporter was sensitive enough to detect estrogens from environmental samples, whether environmental estrogens would exhibit tissue-specific effects similar to those of BPA and genistein, or why some compounds preferentially target receptors in the heart. We tested surface water samples using a transgenic zebrafish reporter with tandem estrogen response elements driving green fluorescent protein expression (5xERE:GFP). Reporter activation was colocalized with tissue-specific expression of ER genes by RNA in situ hybridization. We observed selective patterns of ER activation in transgenic fish exposed to river water samples from the Mid-Atlantic United States, with several samples preferentially activating receptors in embryonic and larval heart valves. We discovered that tissue specificity in ER activation was due to differences in the expression of ER subtypes. ERα was expressed in developing heart valves but not in the liver, whereas ERβ2 had the opposite profile. Accordingly, subtype-specific ER agonists activated the reporter in either the heart valves or the liver. The use of 5xERE:GFP transgenic zebrafish revealed an unexpected tissue-specific difference in the response to environmentally relevant estrogenic compounds. Exposure to estrogenic EEDs in utero was associated with adverse health effects, with the potentially unanticipated consequence of targeting developing heart valves.

  6. International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

    PubMed Central

    2015-01-01

    Estrogens are critical mediators of multiple and diverse physiologic effects throughout the body in both sexes, including the reproductive, cardiovascular, endocrine, nervous, and immune systems. As such, alterations in estrogen function play important roles in many diseases and pathophysiological conditions (including cancer), exemplified by the lower prevalence of many diseases in premenopausal women. Estrogens mediate their effects through multiple cellular receptors, including the nuclear receptor family (ERα and ERβ) and the G protein–coupled receptor (GPCR) family (GPR30/G protein–coupled estrogen receptor [GPER]). Although both receptor families can initiate rapid cell signaling and transcriptional regulation, the nuclear receptors are traditionally associated with regulating gene expression, whereas GPCRs are recognized as mediating rapid cellular signaling. Estrogen-activated pathways are not only the target of multiple therapeutic agents (e.g., tamoxifen, fulvestrant, raloxifene, and aromatase inhibitors) but are also affected by a plethora of phyto- and xeno-estrogens (e.g., genistein, coumestrol, bisphenol A, dichlorodiphenyltrichloroethane). Because of the existence of multiple estrogen receptors with overlapping ligand specificities, expression patterns, and signaling pathways, the roles of the individual receptors with respect to the diverse array of endogenous and exogenous ligands have been challenging to ascertain. The identification of GPER-selective ligands however has led to a much greater understanding of the roles of this receptor in normal physiology and disease as well as its interactions with the classic estrogen receptors ERα and ERβ and their signaling pathways. In this review, we describe the history and characterization of GPER over the past 15 years focusing on the pharmacology of steroidal and nonsteroidal compounds that have been employed to unravel the biology of this most recently recognized estrogen receptor. PMID

  7. International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators.

    PubMed

    Prossnitz, Eric R; Arterburn, Jeffrey B

    2015-07-01

    Estrogens are critical mediators of multiple and diverse physiologic effects throughout the body in both sexes, including the reproductive, cardiovascular, endocrine, nervous, and immune systems. As such, alterations in estrogen function play important roles in many diseases and pathophysiological conditions (including cancer), exemplified by the lower prevalence of many diseases in premenopausal women. Estrogens mediate their effects through multiple cellular receptors, including the nuclear receptor family (ERα and ERβ) and the G protein-coupled receptor (GPCR) family (GPR30/G protein-coupled estrogen receptor [GPER]). Although both receptor families can initiate rapid cell signaling and transcriptional regulation, the nuclear receptors are traditionally associated with regulating gene expression, whereas GPCRs are recognized as mediating rapid cellular signaling. Estrogen-activated pathways are not only the target of multiple therapeutic agents (e.g., tamoxifen, fulvestrant, raloxifene, and aromatase inhibitors) but are also affected by a plethora of phyto- and xeno-estrogens (e.g., genistein, coumestrol, bisphenol A, dichlorodiphenyltrichloroethane). Because of the existence of multiple estrogen receptors with overlapping ligand specificities, expression patterns, and signaling pathways, the roles of the individual receptors with respect to the diverse array of endogenous and exogenous ligands have been challenging to ascertain. The identification of GPER-selective ligands however has led to a much greater understanding of the roles of this receptor in normal physiology and disease as well as its interactions with the classic estrogen receptors ERα and ERβ and their signaling pathways. In this review, we describe the history and characterization of GPER over the past 15 years focusing on the pharmacology of steroidal and nonsteroidal compounds that have been employed to unravel the biology of this most recently recognized estrogen receptor. Copyright

  8. Aerobic Exercise, Estrogens, and Breast Cancer Risk

    DTIC Science & Technology

    2011-11-01

    on endogenous sex hormone levels, menstrual cycle characteristics, and estrogen metabolism in sedentary, eumenorrheic, healthy premenopausal women...changes in menstrual cycle length, and 4) limited changes in estrogen metabolism. The resulting increases in urinary 2-hydroxyestrone levels and 2...effects of a 16-week, aerobic exercise intervention on endogenous sex hormone levels, menstrual cycle characteristics, and estrogen metabolism of young

  9. Role of exogenous estrogen in initiation of estrus and induction of an LH surge

    USDA-ARS?s Scientific Manuscript database

    Among cattle the LH surge that causes ovulation occurs shortly after the onset of a spontaneous estrus. In addition an injection of 100 'g of GnRH can induce an LH surge capable of inducing ovulation. We hypothesized that different preovulatory estradiol profiles would result in different ovulator...

  10. Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol-A) exposure

    PubMed Central

    Jorgensen, Elisa M.; Alderman, Myles H.; Taylor, Hugh S.

    2016-01-01

    Bisphenol-A (BPA) is an environmentally ubiquitous estrogen-like endocrine-disrupting compound. Exposure to BPA in utero has been linked to female reproductive disorders, including endometrial hyperplasia and breast cancer. Estrogens are an etiological factor in many of these conditions. We sought to determine whether in utero exposure to BPA altered the global CpG methylation pattern of the uterine genome, subsequent gene expression, and estrogen response. Pregnant mice were exposed to an environmentally relevant dose of BPA or DMSO control. Uterine DNA and RNA were examined by using methylated DNA immunoprecipitation methylation microarray, expression microarray, and quantitative PCR. In utero BPA exposure altered the global CpG methylation profile of the uterine genome and subsequent gene expression. The effect on gene expression was not apparent until sexual maturation, which suggested that estrogen response was the primary alteration. Indeed, prenatal BPA exposure preferentially altered adult estrogen-responsive gene expression. Changes in estrogen response were accompanied by altered methylation that preferentially affected estrogen receptor-α (ERα)–binding genes. The majority of genes that demonstrated both altered expression and ERα binding had decreased methylation. BPA selectively altered the normal developmental programming of estrogen-responsive genes via modification of the genes that bind ERα. Gene–environment interactions driven by early life xenoestrogen exposure likely contributes to increased risk of estrogen-related disease in adults.—Jorgensen, E. M., Alderman, M. H., III, Taylor, H. S. Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol-A) exposure. PMID:27312807

  11. Pharmacology of conjugated equine estrogens: efficacy, safety and mechanism of action.

    PubMed

    Bhavnani, Bhagu R; Stanczyk, Frank Z

    2014-07-01

    Oral conjugated equine estrogens (CEE) are the most used estrogen formulation for postmenopausal hormone therapy either alone or in combination with a progestin. CEE is most commonly used for the management of early menopausal symptoms such as hot flashes, vaginitis, insomnia, and mood disturbances. Additionally, if used at the start of the menopausal phase (age 50-59 years), CEE prevents osteoporosis and may in some women reduce the risk of cardiovascular disease (CVD) and Alzheimer's disease (AD). There appears to be a common mechanism through which estrogens can protect against CVD and AD. CEE is a natural formulation of an extract prepared from pregnant mares' urine. The product monogram lists the presence of only 10 estrogens consisting of the classical estrogens, estrone and 17β-estradiol, and a group of unique ring B unsaturated estrogens such as equilin and equilenin. The ring B unsaturated estrogens are formed by an alternate steroidogenic pathway in which cholesterol is not an obligatory intermediate. Both the route of administration and structure of these estrogens play a role in the overall pharmacology of CEE. In contrast to 17β-estradiol, ring B unsaturated estrogens express their biological effects mainly mediated by the estrogen receptor β and not the estrogen receptor α. All estrogen components of CEE are antioxidants, and some ring B unsaturated estrogens have several fold greater antioxidant activity than estrone and 17β-estradiol. The cardioprotective and neuroprotective effects of CEE appear to be, to some extent, due to its ability to prevent the formation of oxidized LDL and HDL, and by inhibiting or modulating some of the key proteases involved in programmed cell death (apoptosis) induced by the excess neurotransmitter glutamate and other neurotoxins. Selective combinations of ring B unsaturated estrogens have the potential of being developed as novel therapeutic agents for the prevention of cardiovascular disease and Alzheimer

  12. Atypical hyperplasia, proliferative fibrocystic change, and exogenous hormone use.

    PubMed

    Zera, R T; Danielson, D; Van Camp, J M; Schmidt-Steinbrunn, B; Hong, J; McCoy, M; Anderson, W R; Linzie, B M; Rodriguez, J L

    2001-10-01

    The association between breast cancer development and exogenous hormone use (EHU) is suggested by indirect clinical evidence. We undertook this study to better define the relationship that EHU has with proliferative fibrocystic change (PFC) and atypical hyperplasia (AH). Women diagnosed with AH without associated carcinoma from January 1990 to December 1999 were compared with control subjects who underwent breast biopsy procedures during the same interval and who were diagnosed with either a proliferative fibrocystic change (PFC) or a nonproliferative fibrocystic change (NPFC). EHU was defined as the use of estrogen or progesterone taken together or separately within 3 months of biopsy. EHU was significantly higher in patients with AH compared with women with NPFC (P =.01). This observation was also significant if all proliferative change (both AH and PFC) was compared with NPFC (P =.03); it was not significant when PFC alone was compared with NPFC. No significant difference in EHU was demonstrated between women with AH and those with PFC. There is strong association between AH and EHU. These results support the theory that a continuum exists between hyperplasia and carcinoma and that EHU may influence the transition from one to the other in an undefined subset of women. We encourage our patients with AH to discontinue EHU.

  13. CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells

    SciTech Connect

    Lau, Wen Min; Doucet, Michele; Huang, David

    2013-07-26

    Highlights: •The effects of elevated CITED2 on ER function in breast cancer cells are examined. •CITED2 enhances cell growth in the absence of estrogen and presence of tamoxifen. •CITED2 functions as a transcriptional co-activator of ER in breast cancer cells. -- Abstract: Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) is a member of the CITED family of non-DNA binding transcriptional co-activators of the p300/CBP-mediated transcription complex. Previously, we identified CITED2 as being overexpressed in human breast tumors relative to normal mammary epithelium. Upon further investigation within the estrogen receptor (ER)-positive subset of these breast tumor samples, we found thatmore » CITED2 mRNA expression was elevated in those associated with poor survival. In light of this observation, we investigated the effect of elevated CITED2 levels on ER function. While ectopic overexpression of CITED2 in three ER-positive breast cancer cell lines (MCF-7, T47D, and CAMA-1) did not alter cell proliferation in complete media, growth was markedly enhanced in the absence of exogenous estrogen. Correspondingly, cells overexpressing CITED2 demonstrated reduced sensitivity to the growth inhibitory effects of the selective estrogen receptor modulator, 4-hydroxytamoxifen. Subsequent studies revealed that basal ER transcriptional activity was elevated in CITED2-overexpressing cells and was further increased upon the addition of estrogen. Similarly, basal and estrogen-induced expression of the ER-regulated genes trefoil factor 1 (TFF1) and progesterone receptor (PGR) was higher in cells overexpressing CITED2. Concordant with this observation, ChIP analysis revealed higher basal levels of CITED2 localized to the TFF-1 and PGR promoters in cells with ectopic overexpression of CITED2, and these levels were elevated further in response to estrogen stimulation. Taken together, these data indicate that CITED2 functions as a

  14. Visible propagation from invisible exogenous cueing.

    PubMed

    Lin, Zhicheng; Murray, Scott O

    2013-09-20

    Perception and performance is affected not just by what we see but also by what we do not see-inputs that escape our awareness. While conscious processing and unconscious processing have been assumed to be separate and independent, here we report the propagation of unconscious exogenous cueing as determined by conscious motion perception. In a paradigm combining masked exogenous cueing and apparent motion, we show that, when an onset cue was rendered invisible, the unconscious exogenous cueing effect traveled, manifesting at uncued locations (4° apart) in accordance with conscious perception of visual motion; the effect diminished when the cue-to-target distance was 8° apart. In contrast, conscious exogenous cueing manifested in both distances. Further evidence reveals that the unconscious and conscious nonretinotopic effects could not be explained by an attentional gradient, nor by bottom-up, energy-based motion mechanisms, but rather they were subserved by top-down, tracking-based motion mechanisms. We thus term these effects mobile cueing. Taken together, unconscious mobile cueing effects (a) demonstrate a previously unknown degree of flexibility of unconscious exogenous attention; (b) embody a simultaneous dissociation and association of attention and consciousness, in which exogenous attention can occur without cue awareness ("dissociation"), yet at the same time its effect is contingent on conscious motion tracking ("association"); and (c) underscore the interaction of conscious and unconscious processing, providing evidence for an unconscious effect that is not automatic but controlled.

  15. Human papillomavirus oncogenes reprogram the cervical cancer microenvironment independently of and synergistically with estrogen

    PubMed Central

    Spurgeon, Megan E.; den Boon, Johan A.; Horswill, Mark; Barthakur, Sonalee; Forouzan, Omid; Rader, Janet S.; Beebe, David J.; Roopra, Avtar; Ahlquist, Paul; Lambert, Paul F.

    2017-01-01

    High-risk human papillomaviruses (HPVs) infect epithelial cells and are causally associated with cervical cancer, but HPV infection is not sufficient for carcinogenesis. Previously, we reported that estrogen signaling in the stromal tumor microenvironment is associated with cervical cancer maintenance and progression. We have now determined how HPV oncogenes and estrogen treatment affect genome-wide host gene expression in laser-captured regions of the cervical epithelium and stroma of untreated or estrogen-treated nontransgenic and HPV-transgenic mice. HPV oncogene expression in the cervical epithelium elicited significant gene-expression changes in the proximal stromal compartment, and estrogen treatment uniquely affected gene expression in the cervical microenvironment of HPV-transgenic mice compared with nontransgenic mice. Several potential estrogen-induced paracrine-acting factors were identified in the expression profile of the cervical tumor microenvironment. The microenvironment of estrogen-treated HPV-transgenic mice was significantly enriched for chemokine/cytokine activity and inflammatory and immune functions associated with carcinogenesis. This inflammatory signature included several proangiogenic CXCR2 receptor ligands. A subset of the same CXCR2 ligands was likewise increased in cocultures of early-passage cells from human cervical samples, with levels highest in cocultures of cervical fibroblasts and cancer-derived epithelial cells. Our studies demonstrate that high-risk HPV oncogenes profoundly reprogram the tumor microenvironment independently of and synergistically with estrogen. These observations illuminate important means by which HPVs can cause cancer through alterations in the tumor microenvironment. PMID:29073104

  16. Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration.

    PubMed

    Somerville, B W

    1975-03-01

    The minimum exposure to estrogen required to cause estrogen-withdrawal migraine has been studied by giving long-acting estradiol valerate to four women and short-acting estradiol benzoate to two women. It was found that several days of exposure to high estrogen levels were needed to cause migraine on estrogen withdrawal. Oral administration of estrogen supplements in the form of estradiol valerate or as conjugated equine estrogens during the premenstrual phase in four women did not significantly affect plasma levels of estradiol, nor was it effective in preventing menstrual migraine.

  17. Targeted Radiotherapy of Estrogen Receptor Positive Tumors

    SciTech Connect

    Raghavan Rajagopalan

    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 formore » 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.« less

  18. Phosphoinositide 3-Kinase p110δ Mediates Estrogen- and FSH-Stimulated Ovarian Follicle Growth

    PubMed Central

    Li, Qian; He, Hui; Zhang, Yin-Li; Li, Xiao-Meng; Guo, Xuejiang; Huo, Ran; Bi, Ye; Li, Jing

    2013-01-01

    In the mammalian ovary, primordial follicles are generated early in life and remain dormant for prolonged periods. Their growth resumes via primordial follicle activation, and they continue to grow until the preovulatory stage under the regulation of hormones and growth factors, such as estrogen, FSH, and IGF-1. Both FSH and IGF-1 activate the phosphatidylinositol-3 kinase (PI3K)/Akt (acute transforming retrovirus thymoma protein kinase) signaling pathway in granulosa cells (GCs), yet it remains inconclusive whether the PI3K pathway is crucial for follicle growth. In this study, we investigated the p110δ isoform (encoded by the Pik3cd gene) of PI3K catalytic subunit expression in the mouse ovary and its function in fertility. Pik3cd-null females were subfertile, exhibited fewer growing follicles and more atretic antral follicles in the ovary, and responded poorly to exogenous gonadotropins compared with controls. Ovary transplantation showed that Pik3cd-null ovaries responded poorly to FSH stimulation in vitro; this confirmed that the follicle growth defect was intrinsically ovarian. In addition, estradiol (E2)-stimulated follicle growth and GC proliferation in preantral follicles was impaired in Pik3cd-null ovaries. FSH and E2 substantially activated the PI3K/Akt pathway in GCs of control mice but not in those of Pik3cd-null mice. However, primordial follicle activation and oocyte meiotic maturation were not affected by Pik3cd knockout. Taken together, our findings indicate that the p110δ isoform of the PI3K catalytic subunit is a key component of the PI3K pathway for both FSH and E2-stimulated follicle growth in ovarian GCs; however, it is not required for primordial follicle activation and oocyte development. PMID:23820902

  19. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    PubMed Central

    May, Felicity EB

    2014-01-01

    The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

  20. Investigation of Metabolism of Exogenous Glucose at the Early Stage and Onset of Diabetes Mellitus in Otsuka Long-Evans Tokushima Fatty Rats Using [1, 2, 3-13C]Glucose Breath Tests

    PubMed Central

    Kijima, Sho; Tanaka, Hideki

    2016-01-01

    This study aimed to evaluate changes in glucose metabolism at the early stage and onset of diabetes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Specifically, after the oral administration of [1, 2, 3-13C]glucose, the levels of exhaled 13CO2, which most likely originated from pyruvate decarboxylation and tricarboxylic acid, were measured. Eight OLETF rats and eight control rats (Long-Evans Tokushima Otsuka [LETO]) were administered 13C-glucose. Three types of 13C-glucose breath tests were performed thrice in each period at 2-week intervals. [3-13C]glucose results in a 13C isotope at position 1 in the pyruvate molecule, which provides 13CO2. The 13C at carbons 1 and 2 of glucose is converted to 13C at carbons 2 and 1 of acetate, respectively, which produce 13CO2. Based on metabolic differences of the labeled sites, glucose metabolism was evaluated using the results of three breath tests. The increase in 13CO2 excretion in OLETF rats was delayed in all three breath tests compared to that in control rats, suggesting that OLETF rats had a lower glucose metabolism than control rats. In addition, overall glucose metabolism increased with age in both groups. The utilization of [2-13C]glucose was suppressed in OLETF rats at 6–12 weeks of age, but they showed higher [3-13C]glucose oxidation than control rats at 22–25 weeks of age. In the [1-13C]glucose breath test, no significant differences in the area under the curve until 180 minutes (AUC180) were observed between OLETF and LETO rats of any age. Glucose metabolism kinetics were different between the age groups and two groups of rats; however, these differences were not significant based on the overall AUC180 of [1-13C]glucose. We conclude that breath 13CO2 excretion is reduced in OLETF rats at the primary stage of prediabetes, indicating differences in glucose oxidation kinetics between OLETF and LETO rats. PMID:27483133

  1. Investigation of Metabolism of Exogenous Glucose at the Early Stage and Onset of Diabetes Mellitus in Otsuka Long-Evans Tokushima Fatty Rats Using [1, 2, 3-13C]Glucose Breath Tests.

    PubMed

    Kawagoe, Naoyuki; Kano, Osamu; Kijima, Sho; Tanaka, Hideki; Takayanagi, Masaaki; Urita, Yoshihisa

    2016-01-01

    This study aimed to evaluate changes in glucose metabolism at the early stage and onset of diabetes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Specifically, after the oral administration of [1, 2, 3-13C]glucose, the levels of exhaled 13CO2, which most likely originated from pyruvate decarboxylation and tricarboxylic acid, were measured. Eight OLETF rats and eight control rats (Long-Evans Tokushima Otsuka [LETO]) were administered 13C-glucose. Three types of 13C-glucose breath tests were performed thrice in each period at 2-week intervals. [3-13C]glucose results in a 13C isotope at position 1 in the pyruvate molecule, which provides 13CO2. The 13C at carbons 1 and 2 of glucose is converted to 13C at carbons 2 and 1 of acetate, respectively, which produce 13CO2. Based on metabolic differences of the labeled sites, glucose metabolism was evaluated using the results of three breath tests. The increase in 13CO2 excretion in OLETF rats was delayed in all three breath tests compared to that in control rats, suggesting that OLETF rats had a lower glucose metabolism than control rats. In addition, overall glucose metabolism increased with age in both groups. The utilization of [2-13C]glucose was suppressed in OLETF rats at 6-12 weeks of age, but they showed higher [3-13C]glucose oxidation than control rats at 22-25 weeks of age. In the [1-13C]glucose breath test, no significant differences in the area under the curve until 180 minutes (AUC180) were observed between OLETF and LETO rats of any age. Glucose metabolism kinetics were different between the age groups and two groups of rats; however, these differences were not significant based on the overall AUC180 of [1-13C]glucose. We conclude that breath 13CO2 excretion is reduced in OLETF rats at the primary stage of prediabetes, indicating differences in glucose oxidation kinetics between OLETF and LETO rats.

  2. Endogenous versus Exogenous Origins of Crises

    NASA Astrophysics Data System (ADS)

    Sornette, Didier

    Are large biological extinctions such as the Cretaceous/Tertiary KT boundary due to a meteorite, extreme volcanic activity or self-organized critical extinction cascades? Are commercial successes due to a progressive reputation cascade or the result of a well orchestrated advertisement? Determining the chain of causality for Xevents in complex systems requires disentangling interwoven exogenous and endogenous contributions with either no clear signature or too many signatures. Here, I review several efforts carried out with collaborators which suggest a general strategy for understanding the organizations of several complex systems under the dual effect of endogenous and exogenous fluctuations. The studied examples are: internet download shocks, book sale shocks, social shocks, financial volatility shocks, and financial crashes. Simple models are offered to quantitatively relate the endogenous organization to the exogenous response of the system. Suggestions for applications of these ideas to many other systems are offered.

  3. GPER - novel membrane estrogen receptor

    PubMed Central

    Zimmerman, Margaret A.; Budish, Rebecca A.; Kashyap, Shreya; Lindsey, Sarah H.

    2016-01-01

    The recent discovery of the G protein-coupled estrogen receptor (GPER) presents new challenges and opportunities for understanding the physiology, pathophysiology, and pharmacology of many diseases. This review will focus on the expression and function of GPER in hypertension, kidney disease, atherosclerosis, vascular remodeling, heart failure, reproduction, metabolic disorders, cancer, environmental health, and menopause. Furthermore, this review will highlight the potential of GPER as a therapeutic target. PMID:27154744

  4. Factors Modulating Estrogen Receptor Activity

    DTIC Science & Technology

    1997-07-01

    public release; distribution unlimited The views, opinions and/or findings contained in this report are those of the author( s ) and should not be...TITLE AND SUBTITLE Activity Factors Modulating Estrogen Receptor 6. AUTHOR( S ) Michael J. Garabedian, Ph.D. 7. PERFORMING ORGANIZATION NAME( S ) AND...ADDRESS(ES) New York University Medical Center New York, New York 10016 9. SPONSORING/MONITORING AGENCY NAME( S ) AND ADDRESS(ES) Commander U.S

  5. Analysis of exogenous components of mortality risks.

    PubMed

    Blinkin, V L

    1998-04-01

    A new technique for deriving exogenous components of mortality risks from national vital statistics has been developed. Each observed death rate Dij (where i corresponds to calendar time (year or interval of years) and j denotes the number of corresponding age group) was represented as Dij = Aj + BiCj, and unknown quantities Aj, Bi, and Cj were estimated by a special procedure using the least-squares principle. The coefficients of variation do not exceed 10%. It is shown that the term Aj can be interpreted as the endogenous and the second term BiCj as the exogenous components of the death rate. The aggregate of endogenous components Aj can be described by a regression function, corresponding to the Gompertz-Makeham law, A(tau) = gamma + beta x e alpha tau, where gamma, beta, and alpha are constants, tau is age, A(tau) [symbol: see text] tau = tau j identical to A(tau j) identical to Aj and tau j is the value of age tau in jth age group. The coefficients of variation for such a representation does not exceed 4%. An analysis of exogenous risk levels in the Moscow and Russian populations during 1980-1995 shows that since 1992 all components of exogenous risk in the Moscow population had been increasing up to 1994. The greatest contribution to the total level of exogenous risk was lethal diseases, and their death rate was 387 deaths per 100,000 persons in 1994, i.e., 61.9% of all deaths. The dynamics of exogenous mortality risk change during 1990-1994 in the Moscow population and in the Russian population without Moscow had been identical: the risk had been increasing and its value in the Russian population had been higher than that in the Moscow population.

  6. Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner

    PubMed Central

    Gertz, Jason; Reddy, Timothy E.; Varley, Katherine E.; Garabedian, Michael J.; Myers, Richard M.

    2012-01-01

    Endogenous estrogens that are synthesized in the body impact gene regulation by activating estrogen receptors in diverse cell types. Exogenous compounds that have estrogenic properties can also be found circulating in the blood in both children and adults. The genome-wide impact of these environmental estrogens on gene regulation is unclear. To obtain an integrated view of gene regulation in response to environmental and endogenous estrogens on a genome-wide scale, we performed ChIP-seq to identify estrogen receptor 1 (ESR1; previously estrogen receptor α) binding sites, and RNA-seq in endometrial cancer cells exposed to bisphenol A (BPA; found in plastics), genistein (GEN; found in soybean), or 17β-estradiol (E2; an endogenous estrogen). GEN and BPA treatment induces thousands of ESR1 binding sites and >50 gene expression changes, representing a subset of E2-induced gene regulation changes. Genes affected by E2 were highly enriched for ribosome-associated proteins; however, GEN and BPA failed to regulate most ribosome-associated proteins and instead enriched for transporters of carboxylic acids. Treatment-dependent changes in gene expression were associated with treatment-dependent ESR1 binding sites, with the exception that many genes up-regulated by E2 harbored a BPA-induced ESR1 binding site but failed to show any expression change after BPA treatment. GEN and BPA exhibited a similar relationship to E2 in the breast cancer line T-47D, where cell type specificity played a much larger role than treatment specificity. Overall, both environmental estrogens clearly regulate gene expression through ESR1 on a genome-wide scale, although with lower potency resulting in less ESR1 binding sites and less gene expression changes compared to the endogenous estrogen, E2. PMID:23019147

  7. Developmental Exposure to Estrogen Alters Differentiation and Epigenetic Programming in a Human Fetal Prostate Xenograft Model

    PubMed Central

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

    2015-01-01

    Prostate cancer is the most frequent non-cutaneous malignancy in men. There is strong evidence in rodents that neonatal estrogen exposure plays a role in the development of this disease. However, there is little information regarding the effects of estrogen in human fetal prostate tissue. This study explored early life estrogen exposure, with and without a secondary estrogen and testosterone treatment in a human fetal prostate xenograft model. Histopathological lesions, proliferation, and serum hormone levels were evaluated at 7, 30, 90, and 200-day time-points after xenografting. The expression of 40 key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors and tumor suppressors was evaluated using a custom PCR array. Epigenome-wide analysis of DNA methylation was performed on whole tissue, and laser capture-microdissection (LCM) isolated epithelial and stromal compartments of 200-day prostate xenografts. Combined initial plus secondary estrogenic exposures had the most severe tissue changes as revealed by the presence of hyperplastic glands at day 200. Gene expression changes corresponded with the cellular events in the KEGG prostate cancer pathway, indicating that initial plus secondary exposure to estrogen altered the PI3K-Akt signaling pathway, ultimately resulting in apoptosis inhibition and an increase in cell cycle progression. DNA methylation revealed that differentially methylated CpG sites significantly predominate in the stromal compartment as a result of estrogen-treatment, thereby providing new targets for future investigation. By using human fetal prostate tissue and eliminating the need for species extrapolation, this study provides novel insights into the gene expression and epigenetic effects related to prostate carcinogenesis following early life estrogen exposure. PMID:25799167

  8. 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...

  9. Estrogenic activity, estrogens, and calcium in runoff post-layer litter application from rainfall simulated events

    USDA-ARS?s Scientific Manuscript database

    Estrogens in runoff from fields fertilized with animal wastes have been implicated as endocrine disruptors of fish in recipient surface waters. The goal of this study was to measure estrogenic activity in runoff post-application of animal waste with the greatest potential for estrogenic activity - ...

  10. 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

  11. Environmental estrogenic effects of alkylphenol ethoxylates.

    PubMed

    Nimrod, A C; Benson, W H

    1996-05-01

    Alkylphenol ethoxylates (APEs) and related compounds recently have been reported to be estrogenic because it has been demonstrated in laboratory studies that they mimic the effects of estradiol both in vitro and in vivo. Chemicals referred to as "environmental estrogens" are suspected of causing health effects in both humans and wildlife through disruption of the endocrine system. In this review, the occurrence, environmental fate, and biological effects of APEs are presented. To provide understanding of the potential for endocrine disruption due to environmental estrogens, the physiology of estrogens in mammals and fish is also reviewed. The estrogenic potency of other environmental estrogens is compared to the potency of APE degradation products. The reproductive effects of estrogenic compounds are considered when evaluating the potential health effects of APEs. Given the reported environmental concentrations and bioconcentration factors of APE products, the potential for these compounds to produce estrogenic effects in the environment appears low. Although questions concerning the physiological effects of APEs and other environmental estrogens remain unanswered, there are indications that research is in progress that will lead to better understanding of the risks to humans and wildlife.

  12. Effects of Estrogen and Estrus Cycle on Pharmacokinetics, Absorption and Disposition of Genistein in Female Sprague-Dawley Rats

    PubMed Central

    Kulkarni, Kaustubh H.; Yang, Zhen; Tao, Niu; Hu, Ming

    2014-01-01

    Genistein is an active soy isoflavone with anticancer activities but it is unknown why it has a higher oral bioavailability in female than in male rats. Our study determined the effects of estrus cycle on genistein’s oral bioavailability. Female rats with various levels of estrogen were orally administered with genistein or used in a four-site rat intestinal perfusion experiment. Rats in “proestrus” group (with elevated estrogen) had significantly reduced (57% decrease, p<0.05) oral bioavailability of total genistein (aglycone+conjugates) than those in “metoestrus” group (with basal level of estrogen). Female ovariectomized rats, due to lack of estrogen, showed oral bioavailability of total genistein similar to the “metoestrus” group but higher (155% increase, p<0.05) than the “proestrus” group. Based on intestinal perfusion studies, the increased bioavailability was partially attributed to the higher (>100% increase, p<0.05) hepatic disposition via glucuronidation and possibly more efficient enterohepatic recycling of genistein in the “metoestrus” group. Furthermore, chronic exogenous supplementation of estradiol in ovariectomized rats significantly reduced (77%, p<0.05) the oral bioavailability of total genistein, mostly via increased sulfation (>10 folds) in liver, to a level comparable to those in the “proestrus” group. In conclusion, the oral bioavailability of total genistein was inversely proportional to elevated estrogen levels in female rats, which is partially mediated through the regulation of hepatic enzymes responsible disposition of genistein. PMID:22757747

  13. Estrogenic Exposure Alters the Spermatogonial Stem Cells in the Developing Testis, Permanently Reducing Crossover Levels in the Adult

    PubMed Central

    Vrooman, Lisa A.; Oatley, Jon M.; Griswold, Jodi E.; Hassold, Terry J.; Hunt, Patricia A.

    2015-01-01

    Bisphenol A (BPA) and other endocrine disrupting chemicals have been reported to induce negative effects on a wide range of physiological processes, including reproduction. In the female, BPA exposure increases meiotic errors, resulting in the production of chromosomally abnormal eggs. Although numerous studies have reported that estrogenic exposures negatively impact spermatogenesis, a direct link between exposures and meiotic errors in males has not been evaluated. To test the effect of estrogenic chemicals on meiotic chromosome dynamics, we exposed male mice to either BPA or to the strong synthetic estrogen, ethinyl estradiol during neonatal development when the first cells initiate meiosis. Although chromosome pairing and synapsis were unperturbed, exposed outbred CD-1 and inbred C3H/HeJ males had significantly reduced levels of crossovers, or meiotic recombination (as defined by the number of MLH1 foci in pachytene cells) by comparison with placebo. Unexpectedly, the effect was not limited to cells exposed at the time of meiotic entry but was evident in all subsequent waves of meiosis. To determine if the meiotic effects induced by estrogen result from changes to the soma or germline of the testis, we transplanted spermatogonial stem cells from exposed males into the testes of unexposed males. Reduced recombination was evident in meiocytes derived from colonies of transplanted cells. Taken together, our results suggest that brief exogenous estrogenic exposure causes subtle changes to the stem cell pool that result in permanent alterations in spermatogenesis (i.e., reduced recombination in descendent meiocytes) in the adult male. PMID:25615633

  14. Impact of Estrogens and Estrogen Receptor Alpha (ESR1) in Brain Lipid Metabolism.

    PubMed

    Morselli, Eugenia; de Souza Santos, Roberta; Gao, Su; Ávalos, Yenniffer; Criollo, Alfredo; Palmer, Biff F; Clegg, Deborah J

    2018-03-06

    Estrogens and their receptors play key roles in regulating body weight, energy expenditure, and metabolic homeostasis. It is known that lack of estrogens promotes increased food intake and induces the expansion of adipose tissues, for which much is known. An area of estrogenic research that has received less attention is the role of estrogens and their receptors in influencing intermediary lipid metabolism in organs such as the brain. In this review, we highlight the actions of estrogens and their receptors in regulating their impact on modulating fatty acid content, utilization, and oxidation through their direct impact on intracellular signaling cascades within the central nervous system.

  15. Hepatic gene expression patterns following trauma-hemorrhage: effect of posttreatment with estrogen.

    PubMed

    Yu, Huang-Ping; Pang, See-Tong; Chaudry, Irshad H

    2013-01-01

    The aim of this study was to examine the role of estrogen on hepatic gene expression profiles at an early time point following trauma-hemorrhage in rats. Groups of injured and sham controls receiving estrogen or vehicle were killed 2 h after injury and resuscitation, and liver tissue was harvested. Complementary RNA was synthesized from each RNA sample and hybridized to microarrays. A large number of genes were differentially expressed at the 2-h time point in injured animals with or without estrogen treatment. The upregulation or downregulation of a cohort of 14 of these genes was validated by reverse transcription-polymerase chain reaction. This large-scale microarray analysis shows that at the 2-h time point, there is marked alteration in hepatic gene expression following trauma-hemorrhage. However, estrogen treatment attenuated these changes in injured animals. Pathway analysis demonstrated predominant changes in the expression of genes involved in metabolism, immunity, and apoptosis. Upregulation of low-density lipoprotein receptor, protein phosphatase 1, regulatory subunit 3C, ring-finger protein 11, pyroglutamyl-peptidase I, bactericidal/permeability-increasing protein, integrin, αD, BCL2-like 11, leukemia inhibitory factor receptor, ATPase, Cu transporting, α polypeptide, and Mk1 protein was found in estrogen-treated trauma-hemorrhaged animals. Thus, estrogen produces hepatoprotection following trauma-hemorrhage likely via antiapoptosis and improving/restoring metabolism and immunity pathways.

  16. Estrogen, aging and the cardiovascular system

    PubMed Central

    Stice, James P.; Lee, Jennifer S.; Pechenino, Angela S.; Knowlton, Anne A.

    2014-01-01

    Estrogen is a powerful hormone with pleiotropic effects. Estrogens have potent antioxidant effects and are able to reduce inflammation, induce vasorelaxation and alter gene expression in both the vasculature and the heart. Estrogen treatment of cultured cardiac myocytes and endothelial cells rapidly activates NFκB, induces heat-shock protein (HSP)-72, a potent intracellular protective protein, and protects cells from simulated ischemia. In in vivo models, estrogens protect against ischemia and trauma/hemorrhage. Estrogens may decrease the expression of soluble epoxide hydrolase, which has deleterious effects on the cardiovascular system through metabolism of epoxyeicosatrienoic acids. Natural (endogenous) estrogens in premenopausal women appear to protect against cardiovascular disease and yet controlled clinical trials have not indicated a benefit from estrogen replacement postmenopause. Much remains to be understood in regards to the many properties of this powerful hormone and how changes in this hormone interact with aging-associated changes. The unexpected negative results of trials of estrogen replacement postmenopause probably arise from our lack of understanding of the many effects of this hormone. PMID:19371207

  17. Quantum chemical studies of estrogenic compounds

    USDA-ARS?s Scientific Manuscript database

    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 ...

  18. EADB: An Estrogenic Activity Database for Assessing ...

    EPA Pesticide Factsheets

    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 endocrine disruptors are estrogenic and affect the normal estrogen signaling pathways. However, ERs can also serve as therapeutic targets for various medical conditions, such as menopausal symptoms, osteoporosis, and ER-positive breast cancer. Because of the decades-long interest in the safety and therapeutic utility of estrogenic chemicals, a large number of chemicals have been assayed for estrogenic activity, but these data exist in various sources and different formats that restrict the ability of regulatory and industry scientists to utilize them fully for assessing risk-benefit. To address this issue, we have developed an Estrogenic Activity Database (EADB; http://www.fda.gov/ScienceResearch/ BioinformaticsTools/EstrogenicActivityDatabaseEADB/default. htm) and made it freely available to the public. EADB contains 18,114 estrogenic activity data points collected for 8212 chemicals tested in 1284 binding, reporter gene, cell proliferation, and in vivo assays in 11 different species. The chemicals cover a broad chemical structure space and the data span a wide range of activities. A set of tools allow users to access EADB and evaluate potential endocrine activity of

  19. Disruption of 3D MCF-12A Breast Cell Cultures by Estrogens – An In Vitro Model for ER-Mediated Changes Indicative of Hormonal Carcinogenesis

    PubMed Central

    Marchese, Stephanie; Silva, Elisabete

    2012-01-01

    Introduction Estrogens regulate the proliferation of normal and neoplastic breast epithelium. Although the intracellular mechanisms of estrogens in the breast are largely understood, little is known about how they induce changes in the structure of the mammary epithelium, which are characteristic of breast cancer. In vitro three dimensional (3D) cultures of immortalised breast epithelial cells recapitulate features of the breast epithelium in vivo, including formation of growth arrested acini with hollow lumen and basement membrane. This model can also reproduce features of malignant transformation and breast cancer, such as increased cellular proliferation and filling of the lumen. However, a system where a connection between estrogen receptor (ER) activation and disruption of acini formation can be studied to elucidate the role of estrogens is still missing. Methods/Principal Findings We describe an in vitro 3D model for breast glandular structure development, using breast epithelial MCF-12A cells cultured in a reconstituted basement membrane matrix. These cells are estrogen receptor (ER)α, ERβ and G-protein coupled estrogen receptor 1 (GPER) competent, allowing the investigation of the effects of estrogens on mammary gland formation and disruption. Under normal conditions, MCF-12A cells formed organised acini, with deposition of basement membrane and hollow lumen. However, treatment with 17β-estradiol, and the exogenous estrogens bisphenol A and propylparaben resulted in deformed acini and filling of the acinar lumen. When these chemicals were combined with ER and GPER inhibitors (ICI 182,780 and G-15, respectively), the deformed acini recovered normal features, such as a spheroid shape, proliferative arrest and luminal clearing, suggesting a role for the ER and GPER in the estrogenic disruption of acinar formation. Conclusion This new model offers the opportunity to better understand the role of the ER and GPER in the morphogenesis of breast glandular

  20. Exogenous sample contamination. Sources and interference.

    PubMed

    Cornes, Michael P

    2016-12-01

    Clinical laboratory medicine is involved in the vast majority of patient care pathways. It has been estimated that pathology results inform 60-70% of critical patient care decisions. The primary goal of the laboratory is to produce precise and accurate results which reflect the true situation in vivo. It is not surprising that interference occurs in laboratory analysis given the complexity of some of the assays used to perform them. Interference is defined as "the effect of a substance upon any step in the determination of the concentration or catalytic activity of the metabolite". Exogenous interferences are defined as those that derive from outside of the body and are therefore not normally found in a specimen and can cause either a positive or negative bias in analytical results. Interferences in analysis can come from various sources and can be classified as endogenous or exogenous. Exogenous substances could be introduced at any point in the sample journey. The laboratory must take responsibility for the quality of results produced. It has a responsibility to have processes in place to identify and minimise the occurrence and effect contamination and interference. To do this well the laboratory needs to work with clinicians and manufacturers. Failure to identify an erroneous result could have an impact on patient care, patient safety and also on hospital budgets. However it is not always easy to recognise interferences. This review summarises the types and sources of exogenous interference and some steps to minimise the impact they have. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

  1. 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

  2. Endoxifen, 4-Hydroxytamoxifen and an Estrogenic Derivative Modulate Estrogen Receptor Complex Mediated Apoptosis in Breast Cancer.

    PubMed

    Maximov, Philipp Y; Abderrahman, Balkees; Fanning, Sean W; Sengupta, Surojeet; Fan, Ping; Curpan, Ramona F; Quintana Rincon, Daniela Maria; Greenland, Jeffery A; Rajan, Shyamala S; Greene, Geoffrey L; Jordan, V Craig

    2018-05-08

    Estrogen therapy was used to treat advanced breast cancer in postmenopausal women for decades until the introduction of tamoxifen. Resistance to long-term estrogen deprivation (LTED) with tamoxifen and aromatase inhibitors used as a treatment for breast cancer inevitably occurs, but unexpectedly low dose estrogen can cause regression of breast cancer and increase disease free survival in some patients. This therapeutic effect is attributed to estrogen-induced apoptosis in LTED breast cancer. Here we describe modulation of the estrogen receptor liganded with antiestrogens (endoxifen, 4-hydroxytamoxifen) and an estrogenic triphenylethylene (TPE) EthoxyTPE (EtOXTPE) on estrogen-induced apoptosis in LTED breast cancer cells. Our results show that the angular TPE estrogen (EtOXTPE) is able to induce the ER-mediated apoptosis only at a later time compared to planar estradiol in these cells. Using RT-PCR, ChIP, Western blotting, molecular modelling and X-ray crystallography techniques we report novel conformations of the ER complex with an angular estrogen EtOXTPE and endoxifen. We propose that alteration of the conformation of the ER complexes, with changes in coactivator binding, governs estrogen-induced apoptosis through the PERK sensor system to trigger an Unfolded Protein Response (UPR). The American Society for Pharmacology and Experimental Therapeutics.

  3. Dissolved organic matter and estrogen interactions regulate estrogen removal in the aqueous environment: A review.

    PubMed

    Ma, Li; Yates, Scott R

    2018-06-03

    This review summarizes the characterization and quantification of interactions between dissolved organic matter (DOM) and estrogens as well as the effects of DOM on aquatic estrogen removal. DOM interacts with estrogens via binding or sorption mechanisms like π-π interaction and hydrogen bonding. The binding affinity is evaluated in terms of organic-carbon-normalized sorption coefficient (Log K OC ) which varies with types and composition of DOM. DOM has been suggested to be a more efficient sorbent compared with other matrices, such as suspended particulate matter, sediment and soil; likely associated with its large surface area and concentrated carbon content. As a photosensitizer, DOM enhanced estrogen photodegradation when the concentration of DOM was below a threshold value, and when above, the acceleration effect was not observed. DOM played a dual role in affecting biodegradation of estrogens depending on the recalcitrance of the DOM and the nutrition status of the degraders. DOM also acted as an electron shuttle (redox mediator) mediating the degradation of estrogens. DOM hindered enzyme-catalyzed removal of estrogens while enhanced their transformation during the simultaneous photo-enzymatic process. Membrane rejection of estrogens was pronounced for hydrophobic DOM with high aromaticity and phenolic moiety content. Elimination of estrogens via photolysis, biodegradation, enzymolysis and membrane rejection in the presence of DOM is initiated by sorption, accentuating the role of DOM as a mediator in regulating aquatic estrogen removal. Published by Elsevier B.V.

  4. Nicotine and estrogen synergistically exacerbate cerebral ischemic injury.

    PubMed

    Raval, A P; Hirsch, N; Dave, K R; Yavagal, D R; Bramlett, H; Saul, I

    2011-05-05

    The greater incidence of myocardial infarction, cardiac arrest, and ischemic stroke among women who smoke and use oral contraception (OC) compared to women who do not smoke and who do or do not use OC may be due in part to how nicotine influences endocrine function in women. For example, we recently demonstrated that chronic exposure to nicotine, the addictive agent in tobacco smoke responsible for the elevated risk of cardiac arrest, abolishes the endogenous or exogenous 17β-estradiol-conferred protection of the hippocampus against global cerebral ischemia (a potential outcome of cardiac arrest) in naive or ovariectomized female rats. In the current study we examined the hypotheses that (1) a synergistic deleterious effect of nicotine plus oral contraceptives exacerbates post-ischemic hippocampal damage in female rats, and (2) nicotine directly inhibits estrogen-mediated intracellular signaling in the hippocampus. To test first hypothesis and to simulate smoking behavior-induced nicotine levels in the human body, we implanted osmotic pumps containing nicotine in the female rats for 16 days. Furthermore, we mimicked the use of oral contraceptives in females by administering oral contraceptives orally to the rat. Rats exposed to either nicotine alone or in combination with oral contraceptives were subjected to an episode of cerebral ischemia and the resultant brain damage was quantified. These results showed for the first time that nicotine with oral contraceptives did indeed exacerbate post-ischemic CA1 damage as compared to nicotine alone in naive female rats. In ex vivo hippocampal slice cultures, we found that nicotine alone or with 17β-estradiol directly hinders estrogen receptors-mediated phosphorylation of cyclic-AMP element binding protein, a process required for neuronal survival and also exacerbates ischemic damage. Thus, nicotine can affect the outcome of cerebral ischemia by influencing brain endocrine function directly rather than through indirect

  5. Exogenous attention to fear: Differential behavioral and neural responses to snakes and spiders.

    PubMed

    Soares, Sandra C; Kessel, Dominique; Hernández-Lorca, María; García-Rubio, María J; Rodrigues, Paulo; Gomes, Nuno; Carretié, Luis

    2017-05-01

    Research has consistently shown that threat stimuli automatically attract attention in order to activate the defensive response systems. Recent findings have provided evidence that snakes tuned the visual system of evolving primates for their astute detection, particularly under challenging perceptual conditions. The goal of the present study was to measure behavioral and electrophysiological indices of exogenous attention to snakes, compared with spiders - matched for rated fear levels but for which sources of natural selection are less well grounded, and to innocuous animals (birds), which were presented as distracters, while participants were engaged in a letter discrimination task. Duration of stimuli, consisting in a letter string and a concurrent distracter, was either presented for 180 or 360ms to explore if the stimulus duration was a modulating effect of snakes in capturing attention. Results showed a specific early (P1) exogenous attention-related brain potential with maximal amplitude to snakes in both durations, which was followed by an enhanced late attention-related potential (LPP) showing enhanced amplitudes to spiders, particularly under the longer exposure durations. These results suggest that exogenous attention to different classes of threat stimuli follows a gradual process, with the most evolutionary-driven stimulus, i.e., snakes, being more efficient at attracting early exogenous attention, thus more dependent on bottom-up processes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Estrogen Receptors Alpha and Beta in Bone

    PubMed Central

    Khalid, Aysha B.; Krum, Susan A.

    2016-01-01

    Estrogens are important for bone metabolism via a variety of mechanisms in osteoblasts, osteocytes, osteoclasts, immune cells and other cells to maintain bone mineral density. Estrogens bind to estrogen receptor alpha (ERα) and ERβ, and the roles of each of these receptors are beginning to be elucidated through whole body and tissue-specific knockouts of the receptors. In vitro and in vivo experiments have shown that ERα and ERβ antagonize each other in bone and in other tissues. This review will highlight the role of these receptors in bone, with particular emphasis on their antagonism. PMID:27072516

  7. Steinach and Young, Discoverers of the Effects of Estrogen on Male Sexual Behavior and the "Male Brain".

    PubMed

    Södersten, Per

    2015-01-01

    In the 1930s, Eugen Steinach's group found that estradiol induces lordosis in castrated rats and reduces the threshold dose of testosterone that is necessary for the induction of ejaculation, and that estradiol-treated intact rats display lordosis as well as mounting and ejaculation. The bisexual, estrogen-sensitive male had been demonstrated. Another major, albeit contrasting, discovery was made in the 1950s, when William Young's group reported that male guinea pigs and prenatally testosterone-treated female guinea pigs are relatively insensitive to estrogen when tested for lordosis as adults. Reduced estrogen sensitivity was part of the new concept of organization of the neural tissues mediating the sexual behavior of females into tissues similar to those of males. The importance of neural organization by early androgen stimulation was realized immediately and led to the discovery of a variety of sex differences in the brains of adult animals. By contrast, the importance of the metabolism of testosterone into estrogen in the male was recognized only after a delay. While the finding that males are sensitive to estrogen was based on Bernhard Zondek's discovery in 1934 that testosterone is metabolized into estrogen in males, the finding that males are insensitive to estrogen was based on the hypothesis that testosterone-male sexual behavior is the typical relationship in the male. It is suggested that this difference in theoretical framework explains the discrepancies in some of the reported results.

  8. Female Mice Avoid Male Odor from the Same Strain via the Vomeronasal System in an Estrogen-Dependent Manner.

    PubMed

    Yano, Saori; Sakamoto, Kentaro Q; Habara, Yoshiaki

    2015-11-01

    Inbreeding avoidance is essential to providing offspring with genetic diversity. Females' mate choice is more crucial than males' for successful reproduction because of the high cost of producing gametes and limited chances to mate. However, the mechanism of female inbreeding avoidance is still unclear. To elucidate the mechanism underlying inbreeding avoidance by females, we conducted Y-maze behavioral assays using BALB/c and C57BL/6 female mice. In both strains, the avoidance of male urine from the same strain was lower in the low estrogen phase than in the high estrogen phase. The estrous cycle-dependent avoidance was completely prevented by vomeronasal organ (VNO) removal. To assess the regulation of the vomeronasal system by estrogen, the neural excitability was evaluated by immunohistochemistry of the immediate early gene products. Although estrogen did not affect neural excitability in the VNO, estrogen enhanced the neural excitability of the mitral cell layer in the AOB induced by urine from the cognate males. These results suggest that female mice avoid odor from genetically similar males in an estrogen-dependent manner via the vomeronasal system and the excitability of the mitral cells in the AOB is presumed to be regulated by estrogen. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Effects of estrogen and gender on cataractogenesis induced by high-LET radiation

    SciTech Connect

    Henderson, M.A.; Rusek, A.; Valluri, S.

    2010-02-01

    Planning for long-duration manned lunar and interplanetary missions requires an understanding of radiation-induced cataractogenesis. Previously, it was demonstrated that low-linear energy transfer (LET) irradiation with 10 Gy of {sup 60}Co {gamma} rays resulted in an increased incidence of cataracts in male rats compared to female rats. This gender difference was not due to differences in estrogen, since male rats treated with the major secreted estrogen 17-{beta}-estradiol (E2) showed an identical increase compared to untreated males. We now compare the incidence and rate of progression of cataracts induced by high-LET radiation in male and female Sprague-Dawley rats. Rats received a singlemore » dose of 1 Gy of 600 MeV {sup 56}Fe ions. Lens opacification was measured at 2-4 week intervals with a slit lamp. The incidence and rate of progression of radiation-induced cataracts was significantly increased in the animals in which estrogen was available from endogenous or exogenous sources. Male rats with E2 capsules implanted had significantly higher rates of progression compared to male rats with empty capsules implanted (P = 0.025) but not compared to the intact female rats. These results contrast with data obtained after low-LET irradiation and suggest the possibility that the different types of damage caused by high- and low-LET radiation may be influenced differentially by steroid sex hormones.« less

  10. Transient reversal of olfactory preference following castration in male rats: Implication for estrogen receptor involvement.

    PubMed

    Xiao, Kai; Chiba, Atsuhiko; Sakuma, Yasuo; Kondo, Yasuhiko

    2015-12-01

    We examined the effects of the sex steroid milieu on sexual odor preference of sexually-experienced male rats using an alternate choice paradigm after endocrine manipulations. Gonadally intact (GI) males showed a male typical preference, i.e. spent longer time sniffing estrous females than males or ovariectomized females. At 1-2 weeks after orchidectomy (ORx), the males exhibited a transient preference for sexually vigorous males, a female typical preference pattern, followed by a total loss of preference after 4 weeks. Subcutaneous implantation of a Silastic capsule containing formestane (4-OHA), an aromatase inhibitor, had no effect on the preference of gonadally intact rats, but successfully prevented the emergence of the female typical preference after ORx. Capsules containing testosterone (T), dihydrotestosterone (DHT), or estradiol benzoate (EB), but not those with cholesterol (CH), restored masculine typical preference in ORx males at 2 weeks after the placement. The feminine preference for males was observed at 2-3 weeks after removal of T or EB capsules, but not by the removal of DHT and CH capsules. The results suggest that either exogenous androgen or estrogen maintains the masculine typical odor preference. Estrogen itself or produced through aromatization of circulating T, induces a transient feminine typical preference at a certain decreased titer during its disappearance from the circulation. Estrogen at different titers might determine appearance of masculine or feminine typical olfactory preference in adult ORx rats. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Changes in plasma volume during bed rest - Effects of menstrual cycle and estrogen administration

    NASA Technical Reports Server (NTRS)

    Fortney, S. M.; Beckett, W. S.; Carpenter, A. J.; Davis, J.; Drew, H.

    1988-01-01

    The effect of increased blood estrogen concentration, caused either during normal menstrual cycles or by exogenous administration of premarin, on the bed-rest (BR) induced decrease in plasma volume (PV) was investigated. In women who underwent duplicate 11-day BR without estrogen supplementation, the PV was found to decrease significantly, during the first 5 days of BR, to a lower level at which it remained for the rest of the BR period. In women who began BR in the periovulatory stage of the menstrual cycle, the loss of PV was delayed, while women who began BR during other stages of the cycle exhibited the usual trend of the PV decrease during the BR. In women who underwent a single 12-day BR period while taking premarin (1.25 mg/day), PV was found to decrease during the first 4-5 days of BR, but then returned toward the pre-BR level during the remainder of the BR, indicating that estrogens have a role in stabilizing body fluid volume.

  12. Estrogenic Activity of Hyperforin in MCF-7 Human Breast Cancer Cells Transfected with Estrogen Receptor.

    PubMed

    Kwon, Joseph; Oh, Kyung Seo; Cho, Se-Young; Bang, Mi Ae; Kim, Hwan Seon; Vaidya, Bipin; Kim, Duwoon

    2016-11-01

    Hyperforin, a major active compound of St. John's wort extract, affects estrogenic activity. In this study, the compound evoked estrogen response element-dependent luciferase activity and cell proliferation in MCF-7 cells. Hyperforin-induced cell proliferation was significantly inhibited by the estrogen receptor antagonist ICI 182,780. These results suggested that hyperforin had estrogenic and cell proliferation activities, which were stimulated via the estrogen receptor. Compared to 17 β -estradiol, hyperforin showed significantly lower estrogenic activity and cell proliferation. The mechanism underlying the estrogenic activity of hyperforin was unknown, therefore, in this study, for the first time, the expression and post-translational modification of proteins were determined and compared among control, 17 β -estradiol-treated, and hyperforin-treated cells using proteomic techniques. A total of 453 proteins were identified, of which 282 proteins were significantly modulated in hyperforin-treated cells compared to 17 β -estradiol-treated cells. Ingenuity pathway analysis also demonstrated that hyperforin treatment induced less cell proliferation than 17 β -estradiol by downregulating estrogen receptor 1. Protein network analysis showed that cell proliferation was regulated mainly by cyclin D1 and extracellular signal-regulated kinases. In conclusion, although, hyperforin exhibited lower estrogenic activity than 17 β -estradiol, the compound induced lower levels of cancer cell proliferation in vitro . Georg Thieme Verlag KG Stuttgart · New York.

  13. Effects of environmental estrogenic chemicals on AP1 mediated transcription with estrogen receptors alpha and beta.

    PubMed

    Fujimoto, Nariaki; Honda, Hiroaki; Kitamura, Shigeyuki

    2004-01-01

    There has been much discussion concerning endocrine disrupting chemicals suspected of exerting adverse effects in both wildlife and humans. Since the majority of these compounds are estrogenic, a large number of in vitro tests for estrogenic characteristics have been developed for screening purpose. One reliable and widely used method is the reporter gene assay employing estrogen receptors (ERs) and a reporter gene with a cis-acting estrogen responsive element (ERE). Other elements such as AP1 also mediate estrogenic signals and the manner of response could be quite different from that of ERE. Since this has yet to be explored, the ER mediated AP1 activity in response to a series of environmental estrogens was investigated in comparison with ERE findings. All the compounds exhibited estrogenic properties with ERE-luc and their AP1 responses were quite similar. These was one exception, however, p,p'-DDT (1,1,1,-trichloro-2,2-bis(p-chlorophenyl)ethane) did not exert any AP1-luc activity, while it appeared to be estrogenic at 10(-7) to 10(-5)M with the ERE action. None of the compounds demonstrated ER beta:AP1 activity. These data suggest that significant differences can occur in responses through the two estrogen pathways depending on environmental chemicals.

  14. 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 ...

  15. A pilot retrospective study of the relationship between estrogen use and pancreatitis/pancreatic function in women with chronic abdominal pain.

    PubMed

    Lieb, John G; Toskes, Phillip P

    2013-05-10

    Estrogens are thought to cause pancreatitis by raising triglyceride levels but whether there are other effects on the pancreas is debatable. To better elucidate the relationship between estrogens and pancreatitis and pancreatic function in a pilot study. Our retrospectively collected database of 224 patients who had undergone secretin stimulation testing was queried for females with available medication histories, who were then divided into two groups: those taking estrogens (E) and those not on estrogens (N). Mann Whitney U and Fisher's exact tests were used. Seventy of the patients in the database were females with available medication histories. Thirty-five (50.0%) were taking estrogens. Twenty-nine (82.9%) of the E patients experienced any type of pancreatitis (i.e., acute pancreatitis, acute relapsing pancreatitis, chronic pancreatitis) while only 19 (54.3%) of the N patients did (P=0.019). During secretin stimulation testing, the peak bicarbonate levels for E and N patients were 80±18 and 90±23 mEq/L, respectively (P=0.058). When patients with any type of pancreatitis were excluded, E patients still displayed decreased peak bicarbonate levels in response to secretin (90±18 vs. 104±19 mEq/L; P=0.021). Weight, age, triglyceride levels, frequency of patients with cholecystectomy and biliary stones did not significantly differ between the two groups (E and N respectively). These pilot data suggest exogenous estrogens may be related to the development of acute pancreatitis and acute relapsing pancreatitis, and probably to a lesser degree chronic pancreatitis, perhaps through a triglyceride independent mechanism. During secretin stimulation testing, peak bicarbonate production may be diminished in women on estrogens (even in those who have never had pancreatitis). Further study is necessary to better define the relationship between estrogen use, pancreatitis, and pancreatic function.

  16. Cross-sex testosterone therapy in ovariectomized mice: addition of low-dose estrogen preserves bone architecture.

    PubMed

    Goetz, Laura G; Mamillapalli, Ramanaiah; Devlin, Maureen J; Robbins, Amy E; Majidi-Zolbin, Masoumeh; Taylor, Hugh S

    2017-11-01

    Cross-sex hormone therapy (XHT) is widely used by transgender people to alter secondary sex characteristics to match their desired gender presentation. Here, we investigate the long-term effects of XHT on bone health using a murine model. Female mice underwent ovariectomy at either 6 or 10 wk and began weekly testosterone or vehicle injections. Dual-energy X-ray absorptiometry (DXA) was performed (20 wk) to measure bone mineral density (BMD), and microcomputed tomography was performed to compare femoral cortical and trabecular bone architecture. The 6-wk testosterone group had comparable BMD with controls by DXA but reduced bone volume fraction, trabecular number, and cortical area fraction and increased trabecular separation by microcomputed tomography. Ten-week ovariectomy/XHT maintained microarchitecture, suggesting that estrogen is critical for bone acquisition during adolescence and that late, but not early, estrogen loss can be sufficiently replaced by testosterone alone. Given these findings, we then compared effects of testosterone with effects of weekly estrogen or combined testosterone/low-dose estrogen treatment after a 6-wk ovariectomy. Estrogen treatment increased spine BMD and microarchitecture, including bone volume fraction, trabecular number, trabecular thickness, and connectivity density, and decreased trabecular separation. Combined testosterone-estrogen therapy caused similar increases in femur and spine BMD and improved architecture (increased bone volume fraction, trabecular number, trabecular thickness, and connectivity density) to estrogen therapy and were superior compared with mice treated with testosterone only. These results demonstrate estradiol is critical for bone acquisition and suggest a new cross-sex hormone therapy adding estrogens to testosterone treatments with potential future clinical implications for treating transgender youth or men with estrogen deficiency. Copyright © 2017 the American Physiological Society.

  17. Estrogens and progression of diabetic kidney damage.

    PubMed

    Doublier, Sophie; Lupia, Enrico; Catanuto, Paola; Elliot, Sharon J

    2011-01-01

    It is generally accepted that estrogens affect and modulate the development and progression of chronic kidney diseases (CKD) not related to diabetes. Clinical studies have indeed demonstrated that the severity and rate of progression of renal damage tends to be greater among men, compared with women. Experimental studies also support the notion that female sex is protective and male sex permissive, for the development of CKD in non-diabetics, through the opposing actions of estrogens and testosterone. However, when we consider diabetes-induced kidney damage, in the setting of either type 1 or type 2 diabetes, the contribution of gender to the progression of renal disease is somewhat uncertain. Previous studies on the effects of estrogens in the pathogenesis of progressive kidney damage have primarily focused on mesangial cells. More recently, data on the effects of estrogens on podocytes, the cell type whose role may include initiation of progressive diabetic renal disease, became available. The aim of this review will be to summarize the main clinical and experimental data on the effects of estrogens on the progression of diabetes-induced kidney injury. In particular, we will highlight the possible biological effects of estrogens on podocytes, especially considering those critical for the pathogenesis of diabetic kidney damage.

  18. Effect of halogenated substituents on the metabolism and estrogenic effects of the equine estrogen, equilenin.

    PubMed

    Liu, Xuemei; Zhang, Fagen; Liu, Hong; Burdette, Joanna E; Li, Yan; Overk, Cassia R; Pisha, Emily; Yao, Jiaqin; van Breemen, Richard B; Swanson, Steven M; Bolton, Judy L

    2003-06-01

    Estrogen replacement therapy has been correlated with an increased risk for developing breast and endometrial cancers. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols, which are further oxidized to electrophilic/redox active o-quinones that have the potential to both initiate and promote the carcinogenic process. Previously, we showed that the equine estrogens, equilin and equilenin, which are major components of the estrogen replacement formulation Premarin (Wyeth-Ayerst), are primarily metabolized to the catechol, 4-hydroxyequilenin. This catechol was found to autoxidize to an o-quinone causing oxidation and alkylation of DNA in vitro and in vivo. To block catechol formation from equilenin, 4-halogenated equilenin derivatives were synthesized. These derivatives were tested for their ability to bind to the estrogen receptor, induce estrogen sensitive genes, and their potential to form catechol metabolites. We found that the 4-fluoro derivatives were more estrogenic than the 4-chloro and 4-bromo derivatives as demonstrated by a higher binding affinity for estrogen receptors alpha and beta, an enhanced induction of alkaline phosphatase activity in Ishikawa cells, pS2 expression in S30 cells, and PR expression in Ishikawa cells. Incubation of these compounds with tyrosinase in the presence of GSH showed that the halogenated equilenin compounds formed less catechol GSH conjugates than the parent compounds, equilenin and 17beta-hydroxyequilenin. In addition, these halogenated compounds showed less cytotoxicity in the presence of tyrosinase than the parent compounds in S30 cells. Also, as stated above, the 4-fluoro derivatives showed similar estrogenic effects as compared with parent compounds; however, they were less toxic in S30 cells as compared to equilenin and 17beta-equilenin. Because 17beta-hydroxy-4-halogenated equilenin derivatives showed higher estrogenic effects than the halogenated

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

    PubMed Central

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

    1997-01-01

    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

  20. The Molecular, Cellular and Clinical Consequences of Targeting the Estrogen Receptor Following Estrogen Deprivation Therapy

    PubMed Central

    Fan, Ping; Maximov, Philipp Y.; Curpan, Ramona F.; Abderrahman, Balkees; Jordan, V. Craig

    2015-01-01

    During the past twenty years our understanding of the control of breast tumor development, growth and survival has changed dramatically. The once long forgotten application of high dose synthetic estrogen therapy as the first chemical therapy to treat any cancer has been resurrected, refined and reinvented as the new biology of estrogen-induced apoptosis. High dose estrogen therapy was cast aside once tamoxifen, from its origins as a failed “morning after pill”, was reinvented as the first targeted therapy to treat any cancer. The current understanding of the mechanism of estrogen-induced apoptosis is described as a consequence of acquired resistance to long term antihormone therapy in estrogen receptor (ER) positive breast cancer. The ER signal transduction pathway remains a target for therapy in breast cancer despite “antiestrogen” resistance, but becomes a regulator of resistance. Multiple mechanisms of resistance come into play: Selective ER Modulator (SERM) stimulated growth, growth factor/ER crosstalk, estrogen-induced apoptosis and mutations of ER. But it is with the science of estrogen-induced apoptosis that the next innovation in women’s health will be developed. Recent evidence suggests that the glucocorticoid properties of medroxyprogesterone acetate blunt estrogen-induced apoptosis in estrogen deprived breast cancer cell populations. As a result breast cancer develops during long-term Hormone Replacement Therapy (HRT). A new synthetic progestin with estrogen-like properties, such as the 19 nortestosterone derivatives used in oral contraceptives, will continue to protect the uterus from unopposed estrogen stimulation but at the same time, reinforce apoptosis in vulnerable populations of nascent breast cancer cells. PMID:26052034

  1. Denitrifying SUP05 Require Exogenous Nitrogen

    NASA Astrophysics Data System (ADS)

    Shah, V.; Chang, B. X.; Morris, R. M.

    2016-02-01

    Members of the SUP05 clade of gamma-proteobacteria are among the most abundant chemoautotrophs in the ocean. Environmental sequencing studies suggest that they have critical roles in mediating carbon fixation, denitrification, and sulfur oxidation in oxygen minimum zones (OMZs). They have evaded cultivation and little is known about the specific growth requirements or substrate ranges that determine their abundance, distribution and impact on marine biogeochemical cycles. We evaluated the genetic potential of an isolate from the SUP05 clade "Ca. Thioglobus autotrophica strain EF1" to fix carbon, reduce nitrogen and oxidize sulfur under anaerobic growth conditions. Growth experiments support genomic predictions, indicating that strain EF1 is a facultatively anaerobic sulfur-oxidizing chemolithoautotroph that reduces nitrate to nitrite and nitric oxide to nitrous oxide. These experiments also revealed that strain EF1 is limited for growth by ammonium, which indicates that it requires an exogenous source of nitrogen for biosynthesis. Evidence that SUP05 cells produce nitrite and nitrous oxide and require exogenous nitrogen suggests that they have important roles in nitrogen cycling and that their growth is ultimately limited by the degradation of sinking organic matter.

  2. Atrial fibrillation associated with exogenous subclinical hyperthyroidism.

    PubMed

    Patanè, Salvatore; Marte, Filippo

    2010-11-19

    Subclinical hyperthyroidism is an increasingly recognized entity that is defined as a normal serum free thyroxine and free triiodothyronine levels with a thyroid-stimulating hormone level suppressed below the normal range and usually undetectable. It has been reported that subclinical hyperthyroidism is not associated with coronary heart disease or mortality from cardiovascular causes but it is sufficient to induce arrhythmias including atrial fibrillation and atrial flutter. It has also been reported that increased factor X activity in patients with subclinical hyperthyroidism represents a potential hypercoagulable state. Moreover acute myocardial infarction has been reported during L-thyroxine substitution therapy. Far more common and relatively less studied is exogenous subclinical hyperthyroidism caused by L-thyroxine administration to thyroidectomized or hypothyroid patients or patients with simple or nodular goiter. We present a case of atrial fibrillation associated with exogenous subclinical hyperthyroidism, in a 72-year-old Italian woman. Also this case focuses attention on the importance of a correct evaluation of subclinical hyperthyroidism. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

  3. Modeling an exogenic origin for the equatorial ridge on Iapetus

    NASA Astrophysics Data System (ADS)

    Stickle, Angela M.; Roberts, James H.

    2018-06-01

    Iapetus has a ridge along the equator that extends continuously for more than 110° in longitude. Parts of the ridge rise as much as 20 km above the surrounding terrains. Most models for the formation of this enigmatic ridge are endogenic, generally requiring the formation of a fast-spinning Iapetus with an oblate shape due to the rotation speed. Many of these require specific scenarios and have constraining parameters in order to generate a ridge comparable to what is seen today. An exogenic formation mechanism has also been proposed, that the ridge represents the remains of an early ring system around Iapetus that collapsed onto the surface. Thus far, none of the models have conclusively identified the origin of the ridge. In this study, an exogenic origin for the ridge is assumed, which is derived from a collapsing disk of debris around Iapetus, without invoking any specific model for the generation of the debris disk. Here, we evaluate whether it is possible to generate a ridge of the size and shape as observed by simulating the impact of the collapsing debris using the CTH hydrocode. Pi-scaling calculations suggest that extremely oblique impact angles (1°-10°) are needed to add to ridge topography. These extreme impact angles severely reduce the cratering efficiency compared to a vertical impact, adding material rather than eroding it during crater formation. Furthermore, material is likely to be excavated at low angles, enhancing downrange accumulation. Multiple impacts from debris pieces will heighten this effect. Because infalling debris is predicted to impact at extremely low angles, both of these effects might have contributed to ridge formation on Iapetus. The extreme grazing angles of the impacts modeled here decouple much of the projectile energy from the target, and impact heating of the surface is not significant. These models suggest that a collapsing disk of debris should have been able to build topography to create a ridge around Iapetus.

  4. Estrogen levels modify scopolamine-induced amnesia in gonadally intact rats.

    PubMed

    de Macêdo Medeiros, André; Izídio, Geison Souza; Sousa, Diego Silveira; Macedo, Priscila Tavares; Silva, Anatildes Feitosa; Shiramizu, Victor Kenji Medeiros; Cabral, Alicia; Ribeiro, Alessandra Mussi; Silva, Regina Helena

    2014-08-04

    Previous studies suggested that estrogen plays a role in cognitive function by modulating the cholinergic transmission. However, most of the studies dealing with this subject have been conducted using ovariectomized rats. In the present study we evaluated the effects of physiological and supra-physiological variation of estrogen levels on scopolamine-induced amnesia in gonadally intact female rats. We used the plus-maze discriminative avoidance task (PMDAT) in order to evaluate anxiety levels and motor activity concomitantly to the memory performance. In experiment 1, female Wistar rats in each estrous cycle phase received scopolamine (1 mg/kg) or saline i.p. 20 min before the training session in the PMDAT. In experiment 2, rats in diestrus received estradiol valerate (1 mg/kg) or sesame oil i.m., and scopolamine (1 mg/kg) or saline i.p., 45 min and 20 min before the training, respectively. In experiment 3, rats in diestrus received scopolamine (1 mg/kg) or saline i.p. 20 min before the training, and estradiol valerate (1 mg/kg) or sesame oil i.m. immediately after the training session. In all experiments, a test session was performed 24 h later. The main results showed that: (1) scopolamine impaired retrieval and induced anxiolytic and hyperlocomotor effects in all experiments; (2) this cholinergic antagonist impaired acquisition only in animals in diestrus; (3) acute administration of estradiol valerate prevented the learning impairment induced by scopolamine and (4) interfered with memory consolidation process. The results suggest that endogenous variations in estrogen levels across the estrous cycle modulate some aspects of memory mediated by the cholinergic system. Indeed, specifically in diestrus, a stage with low estrogen levels, the impairment produced by scopolamine on the acquisition was counteracted by exogenous administration of the hormone, whereas the posttraining treatment potentiated the negative effects of scopolamine during the consolidation phase

  5. Estrogen enhances mismatch repair by induction of MLH1 expression via estrogen receptor-β

    PubMed Central

    Lu, Jun-Yu; Jin, Peng; Gao, Wei; Wang, De-Zhi; Sheng, Jian-Qiu

    2017-01-01

    Epidemiological data demonstrated that hormone replace treatment has protective effect against colorectal cancer (CRC). Our previous studies showed that this effect may be associated with DNA mismatch repair. This study aims to investigate the mechanism of estrogen induction of MLH1, and whether colorectal tumor proliferation can be inhibited through induction of MLH1 by estrogen signal pathway. Human CRC cell lines were used to examine the regulation of MLH1 expression by over-expression and depletion of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), under the treatment with 17β-estradiol or β-Estradiol 6-(O-carboxy-methyl)oxime:BSA, followed by a real-time Q-PCR and Western blotting analysis. Luciferase reporter and chromatin immunoprecipitation assays were used to identify the estrogen response elements in the proximal promoter of MLH1 gene. Then, the influence of estrogen-induced MLH1 on CRC tumor growth were determined in vitro and in vivo. We found that mismatch repair ability and microsatellite stability of cells were enhanced by estrogen via induction of MLH1 expression, which was mediated by ERβ, through a transcriptional activation process. Furthermore, we identified that ERβ exerted an inhibitory effect on CRC tumor proliferation in vitro and in vivo, combined with 5-FU, through up-regulation of MLH1 expression. Finally, we concluded that estrogen enhances mismatch repair ability and tumor inhibition effect in vitro and in vivo, via induction of MLH1 expression mediated by ERβ. PMID:28404976

  6. Estrogen enhances mismatch repair by induction of MLH1 expression via estrogen receptor-β.

    PubMed

    Lu, Jun-Yu; Jin, Peng; Gao, Wei; Wang, De-Zhi; Sheng, Jian-Qiu

    2017-06-13

    Epidemiological data demonstrated that hormone replace treatment has protective effect against colorectal cancer (CRC). Our previous studies showed that this effect may be associated with DNA mismatch repair. This study aims to investigate the mechanism of estrogen induction of MLH1, and whether colorectal tumor proliferation can be inhibited through induction of MLH1 by estrogen signal pathway. Human CRC cell lines were used to examine the regulation of MLH1 expression by over-expression and depletion of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), under the treatment with 17β-estradiol or β-Estradiol 6-(O-carboxy-methyl)oxime:BSA, followed by a real-time Q-PCR and Western blotting analysis. Luciferase reporter and chromatin immunoprecipitation assays were used to identify the estrogen response elements in the proximal promoter of MLH1 gene. Then, the influence of estrogen-induced MLH1 on CRC tumor growth were determined in vitro and in vivo. We found that mismatch repair ability and microsatellite stability of cells were enhanced by estrogen via induction of MLH1 expression, which was mediated by ERβ, through a transcriptional activation process. Furthermore, we identified that ERβ exerted an inhibitory effect on CRC tumor proliferation in vitro and in vivo, combined with 5-FU, through up-regulation of MLH1 expression. Finally, we concluded that estrogen enhances mismatch repair ability and tumor inhibition effect in vitro and in vivo, via induction of MLH1 expression mediated by ERβ.

  7. 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. ...

  8. 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

  9. Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study.

    PubMed

    Flores, Roberto; Shi, Jianxin; Fuhrman, Barbara; Xu, Xia; Veenstra, Timothy D; Gail, Mitchell H; Gajer, Pawel; Ravel, Jacques; Goedert, James J

    2012-12-21

    High systemic estrogen levels contribute to breast cancer risk for postmenopausal women, whereas low levels contribute to osteoporosis risk. Except for obesity, determinants of non-ovarian systemic estrogen levels are undefined. We sought to identify members and functions of the intestinal microbial community associated with estrogen levels via enterohepatic recirculation. Fifty-one epidemiologists at the National Institutes of Health, including 25 men, 7 postmenopausal women, and 19 premenopausal women, provided urine and aliquots of feces, using methods proven to yield accurate and reproducible results. Estradiol, estrone, 13 estrogen metabolites (EM), and their sum (total estrogens) were quantified in urine and feces by liquid chromatography/tandem mass spectrometry. In feces, β-glucuronidase and β-glucosidase activities were determined by realtime kinetics, and microbiome diversity and taxonomy were estimated by pyrosequencing 16S rRNA amplicons. Pearson correlations were computed for each loge estrogen level, loge enzymatic activity level, and microbiome alpha diversity estimate. For the 55 taxa with mean relative abundance of at least 0.1%, ordinal levels were created [zero, low (below median of detected sequences), high] and compared to loge estrogens, β-glucuronidase and β-glucosidase enzymatic activity levels by linear regression. Significance was based on two-sided tests with α=0.05. In men and postmenopausal women, levels of total urinary estrogens (as well as most individual EM) were very strongly and directly associated with all measures of fecal microbiome richness and alpha diversity (R≥0.50, P≤0.003). These non-ovarian systemic estrogens also were strongly and significantly associated with fecal Clostridia taxa, including non-Clostridiales and three genera in the Ruminococcaceae family (R=0.57-0.70, P=0.03-0.002). Estrone, but not other EM, in urine correlated significantly with functional activity of fecal β-glucuronidase (R=0.36, P=0

  10. Estrogen Degraders and Estrogen Degradation Pathway Identified in an Activated Sludge.

    PubMed

    Chen, Yi-Lung; Fu, Han-Yi; Lee, Tzong-Huei; Shih, Chao-Jen; Huang, Lina; Wang, Yu-Sheng; Ismail, Wael; Chiang, Yin-Ru

    2018-05-15

    The environmental release and fate of estrogens are becoming an increasing public concern. Bacterial degradation has been considered the main process for eliminating estrogens from wastewater treatment plants. Various bacterial isolates are reportedly capable of aerobic estrogen degradation, and several estrogen degradation pathways have been proposed in proteobacteria and actinobacteria. However, the ecophysiological relevance of estrogen-degrading bacteria in the environment is unclear. In this study, we investigated the estrogen degradation pathway and corresponding degraders in activated sludge collected from the Dihua Sewage Treatment Plant, Taipei, Taiwan. Cultivation-dependent and cultivation-independent methods were used to assess estrogen biodegradation in the collected activated sludge. Estrogen metabolite profile analysis revealed the production of pyridinestrone acid and two A/B-ring cleavage products in activated sludge incubated with estrone (1 mM), which are characteristic of the 4,5- seco pathway. PCR-based functional assays detected sequences closely related to alphaproteobacterial oecC , a key gene of the 4,5- seco pathway. Metagenomic analysis suggested that Novosphingobium spp. are major estrogen degraders in estrone-amended activated sludge. Novosphingobium sp. strain SLCC, an estrone-degrading alphaproteobacterium, was isolated from the examined activated sludge. The general physiology and metabolism of this strain were characterized. Pyridinestrone acid and the A/B-ring cleavage products were detected in estrone-grown strain SLCC cultures. The production of pyridinestrone acid was also observed during the aerobic incubation of strain SLCC with 3.7 nM (1 μg/liter) estrone. This concentration is close to that detected in many natural and engineered aquatic ecosystems. The presented data suggest the ecophysiological relevance of Novosphingobium spp. in activated sludge. IMPORTANCE Estrogens, which persistently contaminate surface water

  11. Estrogen Receptor β Activation Rapidly Modulates Male Sexual Motivation through the Transactivation of Metabotropic Glutamate Receptor 1a

    PubMed Central

    Seredynski, Aurore L.; Balthazart, Jacques; Ball, Gregory F.

    2015-01-01

    In addition to the transcriptional activity of their liganded nuclear receptors, estrogens, such as estradiol (E2), modulate cell functions, and consequently physiology and behavior, within minutes through membrane-initiated events. The membrane-associated receptors (mERs) underlying the acute effects of estrogens on behavior have mostly been documented in females where active estrogens are thought to be of ovarian origin. We determined here, by acute intracerebroventricular injections of specific agonists and antagonists, the type(s) of mERs that modulate rapid effects of brain-derived estrogens on sexual motivation in male Japanese quail. Brain aromatase blockade acutely inhibited sexual motivation. Diarylpropionitrile (DPN), an estrogen receptor β (ERβ)-specific agonist, and to a lesser extent 17α-estradiol, possibly acting through ER-X, prevented this effect. In contrast, drugs targeting ERα (PPT and MPP), GPR30 (G1 and G15), and the Gq-mER (STX) did not affect sexual motivation. The mGluR1a antagonist LY367385 significantly inhibited sexual motivation but mGluR2/3 and mGluR5 antagonists were ineffective. LY367385 also blocked the behavioral restoration induced by E2 or DPN, providing functional evidence that ERβ interacts with metabotropic glutamate receptor 1a (mGluR1a) signaling to acutely regulate male sexual motivation. Together these results show that ERβ plays a key role in sexual behavior regulation and the recently uncovered cooperation between mERs and mGluRs is functional in males where it mediates the acute effects of estrogens produced centrally in response to social stimuli. The presence of an ER–mGluR interaction in birds suggests that this mechanism emerged relatively early in vertebrate history and is well conserved. SIGNIFICANCE STATEMENT The membrane-associated receptors underlying the acute effects of estrogens on behavior have mostly been documented in females, where active estrogens are thought to be of ovarian origin. Using acute

  12. Estrogen Receptor β Activation Rapidly Modulates Male Sexual Motivation through the Transactivation of Metabotropic Glutamate Receptor 1a.

    PubMed

    Seredynski, Aurore L; Balthazart, Jacques; Ball, Gregory F; Cornil, Charlotte A

    2015-09-23

    In addition to the transcriptional activity of their liganded nuclear receptors, estrogens, such as estradiol (E2), modulate cell functions, and consequently physiology and behavior, within minutes through membrane-initiated events. The membrane-associated receptors (mERs) underlying the acute effects of estrogens on behavior have mostly been documented in females where active estrogens are thought to be of ovarian origin. We determined here, by acute intracerebroventricular injections of specific agonists and antagonists, the type(s) of mERs that modulate rapid effects of brain-derived estrogens on sexual motivation in male Japanese quail. Brain aromatase blockade acutely inhibited sexual motivation. Diarylpropionitrile (DPN), an estrogen receptor β (ERβ)-specific agonist, and to a lesser extent 17α-estradiol, possibly acting through ER-X, prevented this effect. In contrast, drugs targeting ERα (PPT and MPP), GPR30 (G1 and G15), and the Gq-mER (STX) did not affect sexual motivation. The mGluR1a antagonist LY367385 significantly inhibited sexual motivation but mGluR2/3 and mGluR5 antagonists were ineffective. LY367385 also blocked the behavioral restoration induced by E2 or DPN, providing functional evidence that ERβ interacts with metabotropic glutamate receptor 1a (mGluR1a) signaling to acutely regulate male sexual motivation. Together these results show that ERβ plays a key role in sexual behavior regulation and the recently uncovered cooperation between mERs and mGluRs is functional in males where it mediates the acute effects of estrogens produced centrally in response to social stimuli. The presence of an ER-mGluR interaction in birds suggests that this mechanism emerged relatively early in vertebrate history and is well conserved. Significance statement: The membrane-associated receptors underlying the acute effects of estrogens on behavior have mostly been documented in females, where active estrogens are thought to be of ovarian origin. Using acute

  13. The Estrogen Receptors: An Overview from Different Perspectives.

    PubMed

    Eyster, Kathleen M

    2016-01-01

    The estrogen receptors, ERα, ERβ, and GPER, mediate the effects of estrogenic compounds on their target tissues. Estrogen receptors are located in the tissues of the female reproductive tract and breast as one would expect, but also in tissues as diverse as bone, brain, liver, colon, skin, and salivary gland. The purpose of this discussion of the estrogen receptors is to provide a brief overview of the estrogen receptors and estrogen action from perspectives such as the historical, physiological, pharmacological, pathological, structural, and ligand perspectives.

  14. EXOGENOUS CYTOCHROME C RESTORES MYOCARDIAL CYTOCHROME OXIDASE ACTIVITY INTO THE LATE PHASE OF SEPSIS

    PubMed Central

    Piel, David A.; Deutschman, Clifford S.; Levy, Richard J.

    2009-01-01

    Mitochondrial dysfunction is thought to play a role in the pathogenesis of a variety of disease states, including sepsis. An acquired defect in oxidative phosphorylation potentially causes sepsis-induced organ dysfunction. Cytochrome oxidase (CcOX), the terminal oxidase of the respiratory chain, is competitively inhibited early in sepsis and progresses, becoming noncompetitive during the late phase. We have previously demonstrated that exogenous cytochrome c can overcome myocardial CcOX competitive inhibition and improve cardiac function during murine sepsis at the 24-h point. Here, we evaluate the effect of exogenous cytochrome c on CcOX activity and survival in mice at the later time points. Exogenous cytochrome c (800 μg) or saline was intravenously injected 24 h after cecal ligation and puncture (CLP) or sham operation. Steady-state mitochondrial cytochrome c levels and heme c content increased significantly 48 h post-CLP and remained elevated at 72 h in cytochrome c-injected mice compared with saline injection. Cecal ligation and puncture inhibited CcOX at 48 h in saline-injected mice. However, cytochrome c injection abrogated this inhibition and restored CcOX kinetic activity to sham values at 48 h. Survival after CLP to 96 h after cytochrome c injection approached 50% compared with only 15% after saline injection. Thus, a single injection of exogenous cytochrome c 24 h post-CLP repletes mitochondrial substrate levels for up to 72 h, restores myocardial COX activity, and significantly improves survival. PMID:18414235

  15. Effect of vaginal estrogen on pessary use

    PubMed Central

    Dessie, Sybil G.; Armstrong, Katherine; Modest, Anna M.; Hacker, Michele R.

    2016-01-01

    Introduction and hypothesis Many providers recommend concurrent estrogen therapy with pessary use to limit complications; however, limited data exist to support this practice. We hypothesized that vaginal estrogen supplementation decreases incidence of pessary-related complications and discontinuation. Methods We performed a retrospective cohort study of women who underwent a pessary fitting from 1 January 2007 through 1 September 2013 at one institution; participants were identified by billing code and were eligible if they were post-menopausal and had at least 3 months of pessary use and 6 months of follow-up. All tests were two sided, and P values < 0.05 were considered statistically significant. Results Data from 199 women were included; 134 used vaginal estrogen and 65 did not. Women who used vaginal estrogen had a longer median follow-up time (29.5 months) compared with women who did not (15.4 months) and were more likely to have at least one pessary check (98.5 % vs 86.2 %, P < 0.001). Those in the estrogen group were less likely to discontinue using their pessary (30.6 % vs 58.5 %, P < 0.001) and less likely to develop increased vaginal discharge than women who did not [hazard ratio (HR) 0.31, 95 % confidence interval (CI) 0.17–0.58]. Vaginal estrogen was not protective against erosions (HR 0.93, 95 % CI 0.54–1.6) or vaginal bleeding (HR 0.78, 95 % CI 0.36–1.7). Conclusions Women who used vaginal estrogen exhibited a higher incidence of continued pessary use and lower incidence of increased vaginal discharge than women who did not. PMID:26992727

  16. Estrogen receptor-independent catechol estrogen binding activity: protein binding studies in wild-type, Estrogen receptor-alpha KO, and aromatase KO mice tissues.

    PubMed

    Philips, Brian J; Ansell, Pete J; Newton, Leslie G; Harada, Nobuhiro; Honda, Shin-Ichiro; Ganjam, Venkataseshu K; Rottinghaus, George E; Welshons, Wade V; Lubahn, Dennis B

    2004-06-01

    Primary evidence for novel estrogen signaling pathways is based upon well-documented estrogenic responses not inhibited by estrogen receptor antagonists. In addition to 17beta-E2, the catechol estrogen 4-hydroxyestradiol (4OHE2) has been shown to elicit biological responses independent of classical estrogen receptors in estrogen receptor-alpha knockout (ERalphaKO) mice. Consequently, our research was designed to biochemically characterize the protein(s) that could be mediating the biological effects of catechol estrogens using enzymatically synthesized, radiolabeled 4-hydroxyestrone (4OHE1) and 4OHE2. Scatchard analyses identified a single class of high-affinity (K(d) approximately 1.6 nM), saturable cytosolic binding sites in several ERalphaKO estrogen-responsive tissues. Specific catechol estrogen binding was competitively inhibited by unlabeled catechol estrogens, but not by 17beta-E2 or the estrogen receptor antagonist ICI 182,780. Tissue distribution studies indicated significant binding differences both within and among various tissues in wild-type, ERalphaKO, and aromatase knockout female mice. Ligand metabolism experiments revealed extensive metabolism of labeled catechol estrogen, suggesting that catechol estrogen metabolites were responsible for the specific binding. Collectively, our data provide compelling evidence for the interaction of catechol estrogen metabolites with a novel binding protein that exhibits high affinity, specificity, and selective tissue distribution. The extensive biochemical characterization of this binding protein indicates that this protein may be a receptor, and thus may mediate ERalpha/beta-independent effects of catechol estrogens and their metabolites.

  17. Effects of estrogen on cerebrovascular function: age-dependent shifts from beneficial to detrimental in small cerebral arteries of the rat

    PubMed Central

    Deer, Rachel R.

    2016-01-01

    In the present study, interactions of age and estrogen in the modulation of cerebrovascular function were examined in small arteries <150 μM. The hypothesis tested was that age enhances deleterious effects of exogenous estrogen by augmenting constrictor prostanoid (CP)-potentiated reactivity of the female (F) cerebrovasculature. F Sprague-Dawley rats approximating key stages of “hormonal aging” in humans were studied: perimenopausal (mature multi-gravid, MA, cyclic, 5–6 mo of age) and postmenopausal (reproductively senescent, RS, acyclic 10–12 mo of age). Rats underwent bilateral ovariectomy and were given estrogen replacement therapy (E) or placebo (O) for 14–21 days. Vasopressin reactivity (VP, 10−12–10−7 M) was measured in pressurized middle cerebral artery segments, alone or in the presence of COX-1- (SC560, 1 μM) or COX-2- (NS398, 10 μM) selective inhibitors. VP-stimulated release of prostacyclin (PGI2) and thromboxane (TXA2) were assessed by radioimmunoassay of 6-keto-PGF1α and TXB2 (stable metabolites). VP-induced vasoconstriction was attenuated in ovariectomized + estrogen-replaced, multigravid adult rats (5–6 mo; MAE) but potentiated in older ovariectomized + estrogen-replaced, reproductively senescent rats (12–14 mo; RSE). SC560 and NS398 reduced reactivity similarly in ovariectomized multigravid adult rats (5–6 mo; MAO) and ovariectomized reproductively senescent rat (12–14 mo; RSO). In MAE, reactivity to VP was reduced to a greater extent by SC560 than by NS398; however, in RSE, this effect was reversed. VP-stimulated PGI2 was increased by estrogen, yet reduced by age. VP-stimulated TXA2 was increased by estrogen and age in RSE but did not differ in MAO and RSO. Taken together, these data reveal that the vascular effects of estrogen are distinctly age-dependent in F rats. In younger MA, beneficial and protective effects of estrogen are evident (decreased vasoconstriction, increased dilator prostanoid function). Conversely, in

  18. Exogenously triggered response inhibition in developmental stuttering.

    PubMed

    Eggers, Kurt; De Nil, Luc F; Van den Bergh, Bea R H

    2018-06-01

    The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. Effect of Exogenous Penicillin on Penicillin Biosynthesis

    PubMed Central

    Gordee, Elizabeth Z.; Day, L. E.

    1972-01-01

    The addition of phenoxymethylpenicillin (10 mg/ml) at any time during the penicillin fermentation inhibited further accumulation of the antibiotic in broth but had no effect on growth. Benzylpenicillin, 6-aminopenicillanic acid (6-APA), and some semisynthetic penicillins also showed this effect, but penicillin N, penicilloic acid, cephalosporin C, and 7-aminocephalosporanic acid did not limit penicillin accretion. Incorporation of radioactive precursors (cysteine, valine, and sodium phenoxyacetate) into penicillin in the presence of inhibitory concentrations of the antibiotic indicated that penicillin synthesis continued despite the lack of accretion of the antibiotic in broth. The rates of penicillin synthesis in a 48-hr and a 136-hr culture were compared by short-term exposure to Na235SO4, and no significant difference in the biosynthetic rate was observed. Exogenous penicillin in the range of 1 to 15 mg/ml of culture broth had no effect on utilization of acetate or glucose by Penicillium chrysogenum. The antibiotic-synthesizing capacity of the organism was not irreversibly inhibited by exogenous penicillin. The degradation of penicillin during the fermentation was also studied. Penicillin V was stable in broth filtrate. Catabolic enzymes such as penicillinase and penicillin-acylase were not demonstrated in whole broth, nor was the accumulation of 6-APA, penicilloic acid, or other degradation products detected. An examination of the intracellular penicillin concentration and the amount of penicillin associated with the mycelium revealed that cells contained significantly more penicillin late in the fermentation than earlier in the cycle. This cell-associated antibiotic may be a regulatory factor in further penicillin synthesis. PMID:4208897

  20. Modeling the interaction of binary and ternary mixtures of estradiol with bisphenol A and bisphenol A F in an in vitro estrogen mediated transcriptional activation assay (T47D-KBluc)

    EPA Science Inventory

    Exposure to xenoestrogens occurs against a backdrop to physiological levels of endogenous estrogens. Endogenous estrogen levels vary from low levels in early childhood to high levels during pregnancy and in young women. For example, children have circulating E2concentrations rang...

  1. Is Estrogen a Therapeutic Target for Glaucoma?

    PubMed Central

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

    2016-01-01

    Objective To provide an overview of the association between estrogen and glaucoma. Methods A literature synthesis of articles published in peer review journals screened through May 05, 2015 using the PubMed database. Key words used were “estrogen and glaucoma,” “reproductive factors and glaucoma,” “estrogen, nitric oxide and eye.” Forty three journal articles were included. Results 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 (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 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 post-menopausal 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 endothelial nitric oxide synthase, a gene receptive to

  2. Estrogen and colorectal cancer incidence and mortality.

    PubMed

    Lavasani, Sayeh; Chlebowski, Rowan T; Prentice, Ross L; Kato, Ikuko; Wactawski-Wende, Jean; Johnson, Karen C; Young, Alicia; Rodabough, Rebecca; Hubbell, F Allan; Mahinbakht, Ali; Simon, Michael S

    2015-09-15

    The preponderance of observational studies describe an association between the use of estrogen alone and a lower incidence of colorectal cancer. In contrast, no difference in the incidence of colorectal cancer was seen in the Women's Health Initiative (WHI) randomized, placebo-controlled trial with estrogen alone after a mean intervention of 7.1 years and cumulative follow-up of 13.2 years. This study extends these findings by providing detailed analyses of the effects of estrogen alone on the histology, grade, and stage of colorectal cancer, relevant subgroups, and deaths from and after colorectal cancer. The WHI study was a randomized, double-blind, placebo-controlled trial involving 10,739 postmenopausal women with prior hysterectomy. Participants were assigned to conjugated equine estrogen at 0.625 mg/d (n = 5279) or a matching placebo (n = 5409). Rates of colorectal cancer diagnoses and deaths from and after colorectal cancer were assessed throughout the study. Colorectal cancer rates in the estrogen-alone and placebo groups were comparable: 0.14% and 0.12% per year, respectively (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.83-1.58; P = .43). Bowel screening examinations were comparable between the 2 groups throughout the study. The grade, stage, and location of colorectal cancer did not differ between the randomization groups. There were more colorectal cancer deaths in the estrogen-alone group (34 [0.05%] vs 24 [0.03%]; HR, 1.46, 95% CI, 0.86-2.46; P = .16), but the difference was not statistically significant. The colorectal cancer incidence was higher for participants with a history of colon polyp removal in the estrogen-alone group (0.23% vs 0.02%; HR, 13.47; nominal 95% CI, 1.76-103.0; P < .001). The use of estrogen alone in postmenopausal women with prior hysterectomy does not influence the incidence of colorectal cancer or deaths from or after colorectal cancer. A possibly higher risk of colorectal cancer in women with

  3. Personal care products that contain estrogens or xenoestrogens may increase breast cancer risk.

    PubMed

    Donovan, Maryann; Tiwary, Chandra M; Axelrod, Deborah; Sasco, Annie J; Jones, Lovell; Hajek, Richard; Sauber, Erin; Kuo, Jean; Davis, Devra L

    2007-01-01

    Established models of breast cancer risk, such as the Gail model, do not account for patterns of the disease in women under the age of 35, especially in African Americans. With the possible exceptions of ionizing radiation or inheriting a known genetic mutation, most of the known risk factors for breast cancer are related to cumulative lifetime exposure to estrogens. Increased risk of breast cancer has been associated with earlier onset of menses or later age at menopause, nulliparity or late first parity, use of hormonal contraceptives or hormone replacement therapy, shorter lactation history, exposure to light at night, obesity, and regular ingestion of alcohol, all of which increase circulating levels of unbound estradiol. Among African Americans at all ages, use of hormone-containing personal care products (PCPs) is more common than among whites, as is premature appearance of secondary sexual characteristics among infants and toddlers. We hypothesize that the use of estrogen and other hormone-containing PCPs in young African American women accounts, in part, for their increased risk of breast cancer prior to menopause, by subjecting breast buds to elevated estrogen exposure during critical windows of vulnerability in utero and in early life. These early life and continuing exposures to estrogenic and xenoestrogenic agents may also contribute to the increased lethality of breast cancer in young women in general and in African American women of all ages. Public disclosure by manufacturers of proprietary hormonally active ingredients is required for this research to move forward.

  4. Gender-specific effects of endogenous testosterone: female alpha-estrogen receptor-deficient C57Bl/6J mice develop glomerulosclerosis.

    PubMed

    Elliot, S J; Berho, M; Korach, K; Doublier, S; Lupia, E; Striker, G E; Karl, M

    2007-08-01

    Young female mice on a C57Bl/6J (B6) background are considered glomerulosclerosis (GS)-resistant but aging B6 mice develop mild GS. Estrogen deficiency accelerates while estrogen replacement retards GS in young sclerosis-prone oligosyndactyly mutant mice on an ROP background. To explore the effects of sex hormones on glomerular structure and function in the context of gender and genetic background, we studied mice in which the estrogen-receptor (ER) genes alpha- or -beta were deleted (alpha- or betaER knockout (KO)) and crossed into the B6 background. We also studied ovariectomized (Ovx) B6 mice given testosterone. Male and female betaERKO and male alphaERKO mice had no glomerular dysfunction at 9 months of age; however, alphaERKO female mice displayed albuminuria and GS. Ovx prevented glomerular dysfunction in alphaERKO female mice by eliminating endogenous testosterone production while exogenous testosterone induced GS in Ovx B6 mice. Androgen receptor (AR) expression and function was found in microdissected glomeruli and cultured mesangial cells. Testosterone compared to placebo increased both AR expression and TGF-beta1 mRNA levels in glomeruli isolated from female B6 mice. Estrogen deficiency had no deleterious effects on the glomeruli in B6 mice. Our study shows that genetic traits strongly influence the GS-promoting effects of estrogen deficiency while testosterone induces GS in a gender-specific manner.

  5. Aromatase and estrogen receptors in male reproduction.

    PubMed

    Carreau, Serge; Delalande, Christelle; Silandre, Dorothée; Bourguiba, Sonia; Lambard, Sophie

    2006-02-26

    Aromatase is a terminal enzyme which transforms irreversibly androgens into estrogens and it is present in the endoplasmic reticulum of numerous tissues. We have demonstrated that mature rat germ cells express a functional aromatase with a production of estrogens equivalent to that of Leydig cells. In humans in addition to Leydig cells, we have shown the presence of aromatase in ejaculated spermatozoa and in immature germ cells. In most tissues, high affinity estrogen receptors, ERalpha and/or ERbeta, mediate the role of estrogens. Indeed, in human spermatozoa, we have successfully amplified ERbeta mRNA but the protein was not detectable. Using ERalpha antibody we have detected two proteins in human immature germ cells: one at the expected size 66 kDa and another at 46 kDa likely corresponding to the ERalpha isoform lacking exon 1. In spermatozoa only the 46 kDa isoform was present, and we suggest that it may be located on the membrane. In addition, in men genetically deficient in aromatase, it is reported that alterations of spermatogenesis occur both in terms of the number and motility of spermatozoa. All together, these observations suggest that endogenous estrogens are important in male reproduction.

  6. Estrogen receptor ligands: a patent review update.

    PubMed

    Paterni, Ilaria; Bertini, Simone; Granchi, Carlotta; Macchia, Marco; Minutolo, Filippo

    2013-10-01

    The role of estrogens is mostly mediated by two nuclear receptors (ERα and ERβ) and a membrane-associated G-protein (GPR30 or GPER), and it is not limited to reproduction, but it extends to the skeletal, cardiovascular and central nervous systems. Various pathologies such as cancer, inflammatory, neurodegenerative and metabolic diseases are often associated with dysfunctions of the estrogenic system. Therapeutic interventions by agents that affect the estrogenic signaling pathway might be useful in the treatment of many dissimilar diseases. The massive chemodiversity of ER ligands, limited to patented small molecules, is herein reviewed. The reported compounds are classified on the basis of their chemical structures. Non-steroidal derivatives, which mostly consist of diphenolic compounds, are further segregated into chemical classes based on their central scaffold. Estrogens have been used for almost a century and their earlier applications have concerned interventions in the female reproductive functions, as well as the treatment of some estrogen-dependent cancers and osteoporosis. Since the discovery of ERβ in 1996, the patent literature has started to pay a progressively increasing attention to this newer receptor subtype, which holds promise as a target for new indications, most of which still need to be clinically validated.

  7. 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...

  8. 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...

  9. Fluorescent characteristics of estrogenic compounds in landfill leachate.

    PubMed

    Zhanga, Hua; Changb, Cheng-Hsuan; Lü, Fan; Su, Ay; Lee, Duu-Jong; He, Pin-Jing; Shao, Li-Ming

    2009-08-01

    Estrogens in landfill leachate could probably contaminate receiving water sources if not properly polished before discharge. This work measured, using an estrogen receptor-alpha competitor screening assay, the estrogenic potentials of leachate samples collected at a local sanitary landfill in Shanghai, China and their compounds fractionated by molecular weights. The chemical structures of the constituent compounds were characterized using fluorescence excitation and emission matrix (EEM). The organic matters of molecular weight <600 Da and of 3000-14,000 Da contributed most of the estrogenic potentials of the raw leachates. The former were considered as the typical endocrine disrupting compounds in dissolved state; while the latter the fulvic acids with high aromaticity that were readily adsorbed with estrogens (bound state). Statistical analysis on EEM peaks revealed that the chemical structures of noted estrogens in dissolved state and in bound state were not identical. Aerobic treatment effectively removed dissolved estrogens, but rarely removed those bound estrogens.

  10. Coexposure to phytoestrogens and bisphenol a mimics estrogenic effects in an additive manner.

    PubMed

    Katchy, Anne; Pinto, Caroline; Jonsson, Philip; Nguyen-Vu, Trang; Pandelova, Marchela; Riu, Anne; Schramm, Karl-Werner; Samarov, Daniel; Gustafsson, Jan-Åke; Bondesson, Maria; Williams, Cecilia

    2014-03-01

    Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogen-induced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER-mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer.

  11. Coexposure to Phytoestrogens and Bisphenol A Mimics Estrogenic Effects in an Additive Manner

    PubMed Central

    Katchy, Anne; Pinto, Caroline; Williams, Cecilia

    2014-01-01

    Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogen-induced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER–mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer. PMID:24284790

  12. The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine.

    PubMed

    van Vollenhoven, Ronald F; Houbiers, Jos G A; Buttgereit, Frank; In 't Hout, Joanna; Boers, Maarten; Leij, Susanne; Kvien, Tore K; Dijkmans, Ben A C; Szczepański, Leszek; Szombati, Istvan; Sierakowski, Stanislaw; Miltenburg, André M M

    2010-02-01

    Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity. A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28). Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial. The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

  13. Estrogen-associated severe hypertriglyceridemia with pancreatitis.

    PubMed

    Aljenedil, Sumayah; Hegele, Robert A; Genest, Jacques; Awan, Zuhier

    Estrogen, whether therapeutic or physiologic, can cause hypertriglyceridemia. Hypertriglyceridemia-induced pancreatitis is a rare complication. We report 2 women who developed estrogen-associated severe hypertriglyceridemia with pancreatitis. The first patient developed pancreatitis secondary to hypertriglyceridemia associated with in vitro fertilization cycles. Marked reduction in her triglyceride was achieved with dietary restrictions and fibrate. The second patient developed pancreatitis secondary to hypertriglyceridemia during her pregnancies. She was noncompliant with the treatment; therefore, her triglyceride remained high after delivery. In both patients, no hypertriglyceridemia-associated genes mutations were identified, although the second patient had strong polygenic susceptibility to hypertriglyceridemia. Estrogen-induced severe hypertriglyceridemia with pancreatitis can be a life-threatening condition. Screening in high-risk patients is crucial to prevent subsequent complications. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  14. Estrogenic and anti-estrogenic activity of 23 commercial textile dyes.

    PubMed

    Bazin, Ingrid; Ibn Hadj Hassine, Aziza; Haj Hamouda, Yosra; Mnif, Wissem; Bartegi, Ahgleb; Lopez-Ferber, Miguel; De Waard, Michel; Gonzalez, Catherine

    2012-11-01

    The presence of dyes in wastewater effluent of textile industry is well documented. In contrast, the endocrine disrupting effects of these dyes and wastewater effluent have been poorly investigated. Herein, we studied twenty-three commercial dyes, usually used in the textile industry, and extracts of blue jean textile wastewater samples were evaluated for their agonistic and antagonistic estrogen activity. Total estrogenic and anti-estrogenic activities were measured using the Yeast Estrogen Screen bioassay (YES) that evaluates estrogen receptor binding-dependent transcriptional and translational activities. The estrogenic potencies of the dyes and wastewater samples were evaluated by dose-response curves and compared to the dose-response curve of 17β-estradiol (E2), the reference compound. The dose-dependent anti-estrogenic activities of the dyes and wastewater samples were normalized to the known antagonistic effect of 4-hydroxytamoxifen (4-OHT) on the induction of the lac Z reporter gene by E2. About half azo textile dyes have anti-estrogenic activity with the most active being Blue HFRL. Most azo dyes however have no or weak estrogenic activity. E2/dye or E2/waste water ER competitive binding assays show activity of Blue HFRL, benzopurpurine 4B, Everzol Navy Blue FBN, direct red 89 BNL 200% and waste water samples indicating a mechanism of action common to E2. Our results indicate that several textile dyes are potential endocrine disrupting agents. The presence of some of these dyes in textile industry wastewater may thus impact the aquatic ecosystem. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Membrane estrogen receptors - is it an alternative way of estrogen action?

    PubMed

    Soltysik, K; Czekaj, P

    2013-04-01

    The functions of estrogens are relatively well known, however the molecular mechanism of their action is not clear. The classical pathway of estrogen action is dependent on ERα and ERβ which act as transcription factors. The effects of this pathway occur within hours or days. In addition, so-called, non-classical mechanism of steroid action dependent on membrane estrogen receptors (mER) was described. In this mechanism the effects of estrogen action are observed in a much shorter time. Here we review the structure and cellular localization of mER, molecular basis of non-classical mER action, physiological role of mER as well as implications of mER action for cancer biology. Finally, some concerns about the new estrogen receptor - GPER and candidates for estrogen receptors - ER-X and ERx, are briefly discussed. It seems that mER is a complex containing signal proteins (signalosome), as IGF receptor, EGF receptor, Ras protein, adaptor protein Shc, non-receptor kinase c-Src and PI-3K, what rationalizes production of second messengers. Some features of membrane receptors are almost identical if compared to nuclear receptors. Probably, membrane and nuclear estrogen receptors are not separate units, but rather the components of a complex mechanism in which they both cooperate with each other. We conclude that the image of the estrogen receptor as a simple transcription factor is a far-reaching simplification. A better understanding of the mechanisms of estrogen action will help us to design more effective drugs affecting signal pathways depending on both membrane and nuclear receptors.

  16. Estrogen signaling through the G protein-coupled estrogen receptor regulates granulocyte activation in fish.

    PubMed

    Cabas, Isabel; Rodenas, M Carmen; Abellán, Emilia; Meseguer, José; Mulero, Victoriano; García-Ayala, Alfonsa

    2013-11-01

    Neutrophils are major participants in innate host responses. It is well known that estrogens have an immune-modulatory role, and some evidence exists that neutrophil physiology can be altered by these molecules. Traditionally, estrogens act via classical nuclear estrogen receptors, but the identification of a G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor that binds estradiol and other estrogens, has opened up the possibility of exploring additional estrogen-mediated effects. However, information on the importance of GPER for immunity, especially, in neutrophils is scant. In this study, we report that gilthead seabream (Sparus aurata L.) acidophilic granulocytes, which are the functional equivalent of mammalian neutrophils, express GPER at both mRNA and protein levels. By using a GPER selective agonist, G1, it was found that GPER activation in vitro slightly reduced the respiratory burst of acidophilic granulocytes and drastically altered the expression profile of several genes encoding major pro- and anti-inflammatory mediators. In addition, GPER signaling in vivo modulated adaptive immunity. Finally, a cAMP analog mimicked the effects of G1 in the induction of the gene coding for PG-endoperoxide synthase 2 and in the induction of CREB phosphorylation, whereas pharmacological inhibition of protein kinase A superinduced PG-endoperoxide synthase 2. Taken together, our results demonstrate for the first time, to our knowledge, that estrogens are able to modulate vertebrate granulocyte functions through a GPER/cAMP/protein kinase A/CREB signaling pathway and could establish therapeutic targets for several immune disorders in which estrogens play a prominent role.

  17. The Endogenous-Exogenous Partition in Attribution Theory

    ERIC Educational Resources Information Center

    Kruglanski, Arie W.

    1975-01-01

    Within lay explanation of actions, several significant inferences are assumed to follow from the partition between endogenous and exogenous attributions. An endogenous action is judged to constitute an end in itself; an exogenous action is judged to serve as a means to some further end. (Editor/RK)

  18. Explaining Cigarette Smoking: An Endogenous-Exogenous Analysis.

    ERIC Educational Resources Information Center

    McKillip, Jack

    Kruglanski's endogenous-exogenous partition, when applied to reasons given by smokers for smoking cigarettes, distinguishes two types of actions: (1) endogenous reasons implying that the behavior of consuming the cigarette is the goal of the action and the actor is positive toward the behavior, and (2) exogenous reasons implying that the behavior…

  19. The selective estrogen enzyme modulators in breast cancer: a review.

    PubMed

    Pasqualini, Jorge R

    2004-06-07

    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

  20. Alleviation of ischaemia-reperfusion injury by endogenous estrogen involves maintaining Bcl-2 expression via the ERα signalling pathway.

    PubMed

    Zhang, Zeng-Li; Qin, Pei; Liu, Yuhong; Zhang, Li-Xia; Guo, Hang; Deng, You-Liang; Yizhao-Liu; Hou, Yu-Shu; Wang, Li-Yang; Miao, Yi; Ma, Yu-Long; Hou, Wu-Gang

    2017-04-15

    The neuroprotective effects of estrogen against cerebral ischaemia have been confirmed by multiple basic and clinical studies. However, most of these studies used exogenous estrogen administered via different injection methods, and the neuroprotective effects of endogenous estrogen produced by ovaries during different phases of estrous cycle and the underlying mechanisms involved have rarely been explored. In this study, we first identified the stage of estrous cycle via vaginal smears and then measured serum estradiol levels at each phase via radioimmunoassay. We found that the estradiol level was highest in the proestrous and lowest in the diestrous. However, ovariectomy or treatment with the aromatase inhibitor letrozole significantly decreased estradiol levels compared to that of rats in diestrous. Western blotting showed that ovariectomy or letrozole treatment significantly decreased ERα and Bcl-2 protein expression and dramatically increased Bax protein expression compared with the rats in diestrous or proestrous. Rats also underwent 2h of ischaemia via middle cerebral artery occlusion followed by a 24-h reperfusion. Ovariectomy or letrozole treatment significantly decreased the neurological scores and the number of intact neurons detected via Nissl staining and dramatically increased the infarct volume detected via TTC staining and the extent of apoptosis detected via TUNEL staining and Western blotting for cleaved-caspase 3 protein expression. These results demonstrate that endogenous estrogen alleviates ischaemia-reperfusion injury by maintaining Bcl-2 expression via ERα signalling pathway and highlight the neuroprotective effects of endogenous estrogen during different stages of the estrous cycle, providing preliminary information on the underlying mechanism of this process. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. 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 ...

  2. 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…

  3. 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…

  4. 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... patient package insert containing information concerning the drug's benefits and risks. An estrogen drug...

  5. Exogenous acetaldehyde as a tool for modulating wine color and astringency during fermentation.

    PubMed

    Sheridan, Marlena K; Elias, Ryan J

    2015-06-15

    Wine tannins undergo modifications during fermentation and storage that can decrease their perceived astringency and increase color stability. Acetaldehyde acts as a bridging compound to form modified tannins and polymeric pigments that are less likely to form tannin-protein complexes than unmodified tannins. Red wines are often treated with oxygen in order to yield acetaldehyde, however this approach can lead to unintended consequences due to the generation of reactive oxygen species. The present study employs exogenous acetaldehyde at relatively low and high treatment concentrations during fermentation to encourage tannin modification without promoting potentially deleterious oxidation reactions. The high acetaldehyde treatment significantly increased polymeric pigments in the wine without increasing concentrations of free and sulfite-bound acetaldehyde. Protein-tannin precipitation was also significantly decreased with the addition of exogenous acetaldehyde. These results indicate a possible treatment of wines early in their production to increase color stability and lower astringency of finished wines. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Short Term Exogenic Climate Change Forcing

    NASA Astrophysics Data System (ADS)

    Krahenbuhl, Daniel

    Several short term exogenic forcings affecting Earth's climate are but recently identified. Lunar nutation periodicity has implications for numerical meteorological prediction. Abrupt shifts in solar wind bulk velocity, particle density, and polarity exhibit correlation with terrestrial hemispheric vorticity changes, cyclonic strengthening and the intensification of baroclinic disturbances. Galactic Cosmic ray induced tropospheric ionization modifies cloud microphysics, and modulates the global electric circuit. This dissertation is constructed around three research questions: (1): What are the biweekly declination effects of lunar gravitation upon the troposphere? (2): How do United States severe weather reports correlate with heliospheric current sheet crossings? and (3): How does cloud cover spatially and temporally vary with galactic cosmic rays? Study 1 findings show spatial consistency concerning lunar declination extremes upon Rossby longwaves. Due to the influence of Rossby longwaves on synoptic scale circulation, our results could theoretically extend numerical meteorological forecasting. Study 2 results indicate a preference for violent tornadoes to occur prior to a HCS crossing. Violent tornadoes (EF3+) are 10% more probable to occur near, and 4% less probable immediately after a HCS crossing. The distribution of hail and damaging wind reports do not mirror this pattern. Polarity is critical for the effect. Study 3 results confirm anticorrelation between solar flux and low-level marine-layer cloud cover, but indicate substantial regional variability between cloud cover altitude and GCRs. Ultimately, this dissertation serves to extend short term meteorological forecasting, enhance climatological modeling and through analysis of severe violent weather and heliospheric events, protect property and save lives.

  7. Determination of the Role of Estrogen Receptors and Estrogen Regulated Genes in B Cell Autoreactivity

    DTIC Science & Technology

    2008-07-01

    signaling strength was a consequence of enhanced expression of CD22 , an inhibitory regulator of the BCR. We now know this conjecture is incorrect as...estrogen causes an upregulation of CD22 in ERα-/- and ERβ-/- mice (Fig 4a) but there is no associated estrogen-induced reduction of BCR signalling... CD22 expression (Fig 4b). We believe the discrepancy between the analysis of genetically manipulated mice given estradiol and wildtype mice given

  8. GPR30: A G protein-coupled receptor for estrogen.

    PubMed

    Prossnitz, Eric R; Arterburn, Jeffrey B; Sklar, Larry A

    2007-02-01

    Estrogen is a critical steroid in human physiology exerting its effect both at the transcriptional level as well as at the level of rapid intracellular signaling through second messengers. Many of estrogen's transcriptional effects have long been known to be mediated through classical nuclear steroid receptors but recent studies also demonstrate the existence of a 7-transmembrane G protein-coupled receptor, GPR30 that responds to estrogen with rapid cellular signaling. There is currently controversy over the ability of classical estrogen receptors to recapitulate GPR30-mediated signaling mechanisms and vice versa. This article will summarize recent literature and address the relationship between GPR30 and conventional estrogen receptor signaling.

  9. 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)

  10. Characterizing the Estrogenic Potential of 1060 Environmental ...

    EPA Pesticide Factsheets

    In order to detect environmental chemicals that pose a risk of endocrine disruption, high-throughput screening (HTS) tests capable of testing thousands of environmental chemicals are needed. Alteration of estrogen signaling has been implicated in a variety of adverse health effects including cancer promotion, reproductive deficits, and vascular effects. Here we investigate the estrogenic potential of 1060 chemicals of environmental relevance using a real-time measure of growth kinetics by electrode impedance in the estrogen-responsive human ductal carcinoma, T47D cell line. Cells were treated in concentration response and measurements of cellular impedance were recorded every hour for six days. Progestens, androgens, and mineralocortocoids (progesterone, dihydrotestosterone, aldosterone) invoked a biphasic impedance signature that contrasted with the anticipated exponential impedance observed in response to known estrogen receptor agonists (17β-estradiol, genestein, bisphenol-A, nonylphenol, 4-tert-octylphenol). Several compounds, including bisphenol-A, and genestein caused impedance comparable to that of 17β-estradiol, although at much higher concentrations. Additionally, trenbolone and cyproterone acetate invoked the characteristic biphasic signature observed with other endogenous steroid hormones. The continuous real-time nature of this assay allows for the rapid detection of differential growth characteristics not easily detected by traditional cell prol

  11. 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...

  12. 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

  13. 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...

  14. 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...

  15. CENTRAL SEROUS CHORIORETINOPATHY IN POSTMENOPAUSAL WOMEN RECEIVING EXOGENOUS TESTOSTERONE.

    PubMed

    Conway, Mandi D; Noble, Jason A; Peyman, Gholam A

    2017-01-01

    Central serous chorioretinopathy (CSR) is a serous detachment of the neurosensory retina commonly associated with male sex, Type-A personality and corticosteroid use. Exogenous administration of androgens and development of CSR in men has been reported. Only one case of CSR in a postmenopausal woman receiving exogenous androgen therapy has been reported. The authors describe three cases of chronic CSR in postmenopausal women receiving exogenous testosterone therapy. Diagnosis was based on characteristic clinical, fluorescein angiographic, and optical coherence tomography findings. The three women were being treated with exogenous testosterone and progesterone therapy for symptoms of menopause and libido loss. Average age at presentation was 54.7 years (53-56 years), average duration of exogenous androgen use was 61 months (36-87 months), with average 19.7-month follow-up. Resolution of symptoms seemed correlated with cessation of androgen use despite treatment with oscillatory photodynamic therapy and intravitreal pharmacotherapy with antivascular endothelial growth factor agents. Exogenous testosterone is increasingly prescribed for menopausal symptoms and libido loss. Treatment with oscillatory photodynamic therapy, supplemental bevacizumab intravitreal pharmacotherapy, and cessation of exogenous androgen therapy was successful in three cases of chronic, therapy-resistant CSR. Ophthalmologists should inquire about androgen usage in patients who present with CSR, especially in the setting of therapy resistance.

  16. Estrogen promotes megakaryocyte polyploidization via estrogen receptor beta-mediated transcription of GATA1.

    PubMed

    Du, C; Xu, Y; Yang, K; Chen, S; Wang, X; Wang, S; Wang, C; Shen, M; Chen, F; Chen, M; Zeng, D; Li, F; Wang, T; Wang, F; Zhao, J; Ai, G; Cheng, T; Su, Y; Wang, J

    2017-04-01

    Estrogen is reported to be involved in thrombopoiesis and the disruption of its signaling may cause myeloproliferative disease, yet the underlying mechanisms remain largely unknown. GATA-binding factor 1 (GATA1) is a key regulator of megakaryocyte (MK) differentiation and its deficiency will lead to megakaryoblastic leukemia. Here we show that estrogen can dose-dependently promote MK polyploidization and maturation via activation of estrogen receptor beta (ERβ), accompanied by a significant upregulation of GATA1. Chromatin immunoprecipitation and a dual luciferase assay demonstrate that ERβ can directly bind the promoter region of GATA1 and activate its transcription. Steroid receptor coactivator 3 (SRC3) is involved in ERβ-mediated GATA1 transcription. The deficiency of ERβ or SRC3, similar to the inhibition of GATA1, leads to the impediment of estrogen-induced MK polyploidization and platelet production. Further investigations reveal that signal transducer and activator of transcription 1 signaling pathway downstream of GATA1 has a crucial role in estrogen-induced MK polyploidization, and ERβ-mediated GATA1 upregulation subsequently enhances nuclear factor erythroid-derived 2 expression, thereby promoting proplatelet formation and platelet release. Our study provides a deep insight into the molecular mechanisms of estrogen signaling in regulating thrombopoiesis and the pathogenesis of ER deficiency-related leukemia.

  17. [Equine estrogens vs. esterified estrogens in the climacteric and menopause. The controversy arrives in Mexico].

    PubMed

    Velasco-Murillo, V

    2001-01-01

    It exists controversies about if the effects and benefits of the esterified estrogens could be similar to those informed for equines, because its chemical composition and bioavailability are different. Esterified estrogens has not delta 8,9 dehydroestrone, and its absorption and level of maximum plasmatic concentrations are reached very fast. In United States of America and another countries, esterified estrogens has been marketed and using for treatment of climacteric syndrome and prevention of postmenopausal osteoporosis, based on the pharmacopoiea of that country, but the Food and Drug administration (FDA) has not yet authorized up today, a generic version of conjugated estrogens. In Instituto Mexicano del Seguro Social (IMSS) and another institutions of health sector in Mexico, starting in year 2000, it has been used esterified estrogens for medical treatment of climacteric and menopausal conditions. For this reason, in this paper we revised the most recent information about pharmacology, chemical composition, clinical use and costs of the conjugated estrogens with the purpose to guide the decisions to purchase this kind of drugs in Mexican heath institutions.

  18. Seasonal variation of red clover (Trifolium pratense L., Fabaceae) isoflavones and estrogenic activity

    PubMed Central

    Booth, Nancy L.; Overk, Cassia R.; Yao, Ping; Totura, Steve; Deng, Yunfan; Hedayat, A. S.; Bolton, Judy L.; Pauli, Guido F.; Farnsworth, Norman R.

    2007-01-01

    Red clover (Trifolium pratense L., Fabaceae) dietary supplements are currently used to treat menopausal symptoms because of their high content of the mildly estrogenic isoflavones daidzein, genistein, formononetin and biochanin A. These compounds are estrogenic in vitro and in vivo, but little information exists on the best time to harvest red clover fields to maximize content of the isoflavones and thus make an optimal product. Samples of cultivated red clover aboveground parts and flower heads were collected in parallel over one growing season in northeastern Illinois. Generally, autohydrolytic extracts of aboveground parts contained more isoflavones and had more estrogenic activity in Ishikawa endometrial cells, compared with extracts of flower heads. Daidzein and genistein content peaked around June to July, while formononetin and biochanin A content peaked in early September. Flower head and total aboveground parts extracts exhibited differential estrogenic activity in an Ishikawa (endometrial) cell-based alkaline phosphatase (AP) induction assay, whereas nondifferential activity was observed for most extracts tested in an MCF-7 (breast) cell proliferation assay when tested at the same final concentrations. Ishikawa assay results could be mapped onto the extracts’ content of individual isoflavones, but MCF-7 results did not show such a pattern. These results suggest that significant metabolism of isoflavones may occur in MCF-7 cells, but not in Ishikawa cells, and therefore caution is advised in the choice of bioassay used for the biological standardization of botanical dietary supplements. PMID:16478248

  19. Does estrogen play a role in response to adjuvant bone-targeted therapies?

    PubMed Central

    Russell, Kent; Amir, Eitan; Paterson, Alexander; Josse, Robert; Addison, Christina; Kuchuk, Iryna; Clemons, Mark

    2013-01-01

    Bone remains the most common site of breast cancer recurrence. The results of population studies, pre-clinical research and clinical studies in patients with metastatic disease provided a rationale for testing bone-targeted agents in the adjuvant setting. Despite the initial optimism, results from eight prospectively designed, randomized control studies powered to assess the value of adjuvant bone-targeted therapy in early breast cancer are conflicting. Data have shown that, where benefit exists, it tends to be in women with a “low estrogen environment”, either through menopause or suppression of ovarian function. In this manuscript, we review clinical data supporting the hypothesis that estrogen levels may play a part in explaining the response of patients to bone-targeted agents in the adjuvant setting. The results presented to date suggest that there may be data supporting a unifying role for estrogen in adjuvant trials. However, in the absence of any prospective randomized trials in which estrogen data has been systematically collected we cannot specifically answer this question. We await the results of the Oxford overview analysis of individual patient data with interest. PMID:26909288

  20. Evidence of estrogen modulation on memory processes for emotional content in healthy young women.

    PubMed

    Pompili, Assunta; Arnone, Benedetto; D'Amico, Mario; Federico, Paolo; Gasbarri, Antonella

    2016-03-01

    It is well accepted that emotional content can affect memory, interacting with the encoding and consolidation processes. The aim of the present study was to verify the effects of estrogens in the interplay of cognition and emotion. Images from the International Affective Pictures System, based on valence (pleasant, unpleasant and neutral), maintaining arousal constant, were viewed passively by two groups of young women in different cycle phases: a periovulatory group (PO), characterized by high level of estrogens and low level of progesterone, and an early follicular group (EF), characterized by low levels of both estrogens and progesterone. The electrophysiological responses to images were measured, and P300 peak was considered. One week later, long-term memory was tested by means of free recall. Intra-group analysis displayed that PO woman had significantly better memory for positive images, while EF women showed significantly better memory for negative images. The comparison between groups revealed that women in the PO phase had better memory performance for positive pictures than women in the EF phase, while no significant differences were found for negative and neutral pictures. According to the free recall results, the subjects in the PO group showed greater P300 amplitude, and shorter latency, for pleasant images compared with women in the EF group. Our results showed that the physiological hormonal fluctuation of estrogens during the menstrual cycle can influence memory, at the time of encoding, during the processing of emotional information. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Evaluation of Follicular Synchronization Caused by Estrogen Administration and Its Reproductive Outcome

    PubMed Central

    Wu, Bi; Shi, Yan; Gong, Xia; Yu, Lin; Chen, Qiuju; Wang, Jian; Sun, Zhaogui

    2015-01-01

    To evaluate multiple follicular development synchronization after estrogen stimulation in prepubertal mice, follicular responsiveness to gonadotropin superovulation, the prospective reproductive potential and ovarian polycystic ovary syndrome (PCOS)-like symptoms at adulthood, prepubertal mice were intraperitoneally injected with estrogen to establish an animal model with solvent as control. When synchronized tertiary follicles in ovaries, in vitro oocyte maturation and fertilization rates, blastocyst formation rate, developmental potential into offspring by embryo transfer, adult fertility and PCOS-like symptoms, and involved molecular mechanisms were focused, it was found that estrogen stimulation (10μg/gBW) leads to follicular development synchronization at the early tertiary stage in prepubertal mice; reproduction from oocytes to offspring could be realized by means of the artificial reproductive technology though the model mice lost their natural fertility when they were reared to adulthood; and typical symptoms of PCOS, except changes in inflammatory pathways, were not remained up to adulthood. So in conclusion, estrogen can lead to synchronization in follicular development in prepubertal mice, but does not affect reproductive outcome of oocytes, and no typical symptoms of PCOS remained at adulthood despite changes related to inflammation. PMID:26010950

  2. [The biological and clinical relevance of estrogen metabolome].

    PubMed

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

    2017-06-01

    Considerable knowledge has been gathered on the physiological role of estrogens. However, fairly little information is available on the role of compounds produced in the breakdown process of estrone and estradiol wich may play a role in various diseases associated with estrogen impact. To date, approximately 15 extragonadal estrogen-related compounds have been identified. These metabolites may exert protective, or, instead, pro-inflammatory and/or pro-oncogenic activity in a tissue-specific manner. Systemic and local estrogen metabolite levels are not necesserily correlated, which may promote the diagnostic significance of the locally produced estrogen metabolites in the future. The aim of the present study is a bibliographic review of the extragonadal metabolome in peripheral tissues, and to highlight the role of the peripheral tissue homeostasis of estrogens as well as the non-hormonal biological activity and clinical significance of the estrogen metabolome. Orv Hetil. 2017; 158(24): 929-937.

  3. Vitellogenin detection in Caiman latirostris (Crocodylia: Alligatoridae): a tool to assess environmental estrogen exposure in wildlife.

    PubMed

    Rey, Florencia; Ramos, Jorge G; Stoker, Cora; Bussmann, Leonardo E; Luque, Enrique H; Muñoz-de-Toro, Mónica

    2006-03-01

    Environmental pollution with endocrine disrupting compounds (EDCs) has adverse effects on the ecosystem's health. Caiman latirostris are widely distributed in South American aquatic ecosystems. Caimans have physiological and ecological characteristics that make them particularly vulnerable to EDCs exposure and suitable candidate as a sentinel species. Vitellogenin (Vtg) is a yolk pre-cursor protein synthesized by the liver of non-mammalian vertebrates and induced in response to estrogen. Purified plasma Vtg from caimans injected with estradiol-17beta (E2) was used to generate a polyclonal anti-body. Anti-body specificity was assessed using Western blot. The antiserum was also effective in detecting turtle Vtg, exhibiting high cross-reactivity with Vtg from Phrynops hilarii and Trachemys scripta dorbigni. We developed a specific and highly sensitive ELISA for caiman Vtg. This method has a detection limit of 0.1 ng/ml of plasma. The ELISA did not detect Vtg in plasma of non-induced male caimans. Induction of Vtg in male caimans was evaluated in response to one or two (7 days apart) doses of E2. Due to its high sensitivity, ELISA allows to measure the small increases in plasma Vtg after exposure to exogenous estrogen. A priming effect was observed following the second E2 dose, with a tenfold increase in circulating Vtg. Hepatic synthesis was confirmed by immunohistochemistry. The results presented herein suggest that detection of plasma Vtg in male caimans might become a valuable tool in biomonitoring xenoestrogen exposure in a polluted environment.

  4. Protective effect of estrogen in endothelin-induced middle cerebral artery occlusion in female rats.

    PubMed

    Glendenning, Michele L; Lovekamp-Swan, Tara; Schreihofer, Derek A

    2008-11-14

    Estrogen is a powerful endogenous and exogenous neuroprotective agent in animal models of brain injury, including focal cerebral ischemia. Although this protection has been demonstrated in several different treatment and injury paradigms, it has not been demonstrated in focal cerebral ischemia induced by intraparenchymal endothelin-1 injection, a model with many advantages over other models of experimental focal ischemia. Reproductively mature female Sprague-Dawley rats were ovariectomized and divided into placebo and estradiol-treated groups. Two weeks later, halothane-anesthetized rats underwent middle cerebral artery (MCA) occlusion by interparenchymal stereotactic injection of the potent vasoconstrictor endothelin 1 (180pmoles/2microl) near the middle cerebral artery. Laser-Doppler flowmetry (LDF) revealed similar reductions in cerebral blood flow in both groups. Animals were behaviorally evaluated before, and 2 days after, stroke induction, and infarct size was evaluated. In agreement with other models, estrogen treatment significantly reduced infarct size evaluated by both TTC and Fluoro-Jade staining and behavioral deficits associated with stroke. Stroke size was significantly correlated with LDF in both groups, suggesting that cranial perfusion measures can enhance success in this model.

  5. Early onset of puberty and early ovarian failure in CYP7B1 knockout mice

    PubMed Central

    Omoto, Yoko; Lathe, Richard; Warner, Margaret; Gustafsson, Jan-Åke

    2005-01-01

    CYP7B1 is the enzyme responsible for hydroxylation and termination of the estrogenic actions of the androgen metabolite, 5α-androstane-3β, 17β-diol (3βAdiol). 3βAdiol is estrogenic in ERα or ERβ positive cells only if they do not express CYP7B1. In this study we show that female CYP7B1–/– mice experience early onset of growth of the uterus and mammary glands and commence estrus cycles 2 days earlier than their wild-type littermates. Adult mammary glands and uteri appear to be under continuous estrogenic stimulation. We conclude that, by cell-specific regulation of the estrogenicity of 3βAdiol, CYP7B1 performs two major tasks: (i) it allows 3βAdiol to have growth inhibitory effects through ERβ and (ii) it permits estradiol-specific activation of estrogen receptors by protection of certain cells from the estrogenic effects of 3βAdiol. When CYP7B1 is inactivated, 3βAdiol activates estrogen receptors indiscriminately, and the overall effect is prolonged and inappropriate exposure to estrogen. PMID:15710898

  6. Early onset of puberty and early ovarian failure in CYP7B1 knockout mice.

    PubMed

    Omoto, Yoko; Lathe, Richard; Warner, Margaret; Gustafsson, Jan-Ake

    2005-02-22

    CYP7B1 is the enzyme responsible for hydroxylation and termination of the estrogenic actions of the androgen metabolite, 5alpha-androstane-3beta, 17beta-diol (3betaAdiol). 3betaAdiol is estrogenic in ERalpha or ERbeta positive cells only if they do not express CYP7B1. In this study we show that female CYP7B1(-/-) mice experience early onset of growth of the uterus and mammary glands and commence estrus cycles 2 days earlier than their wild-type littermates. Adult mammary glands and uteri appear to be under continuous estrogenic stimulation. We conclude that, by cell-specific regulation of the estrogenicity of 3betaAdiol, CYP7B1 performs two major tasks: (i) it allows 3betaAdiol to have growth inhibitory effects through ERbeta and (ii) it permits estradiol-specific activation of estrogen receptors by protection of certain cells from the estrogenic effects of 3betaAdiol. When CYP7B1 is inactivated, 3betaAdiol activates estrogen receptors indiscriminately, and the overall effect is prolonged and inappropriate exposure to estrogen.

  7. Steinach and Young, Discoverers of the Effects of Estrogen on Male Sexual Behavior and the “Male Brain”1,2

    PubMed Central

    2015-01-01

    Abstract In the 1930s, Eugen Steinach’s group found that estradiol induces lordosis in castrated rats and reduces the threshold dose of testosterone that is necessary for the induction of ejaculation, and that estradiol-treated intact rats display lordosis as well as mounting and ejaculation. The bisexual, estrogen-sensitive male had been demonstrated. Another major, albeit contrasting, discovery was made in the 1950s, when William Young’s group reported that male guinea pigs and prenatally testosterone-treated female guinea pigs are relatively insensitive to estrogen when tested for lordosis as adults. Reduced estrogen sensitivity was part of the new concept of organization of the neural tissues mediating the sexual behavior of females into tissues similar to those of males. The importance of neural organization by early androgen stimulation was realized immediately and led to the discovery of a variety of sex differences in the brains of adult animals. By contrast, the importance of the metabolism of testosterone into estrogen in the male was recognized only after a delay. While the finding that males are sensitive to estrogen was based on Bernhard Zondek’s discovery in 1934 that testosterone is metabolized into estrogen in males, the finding that males are insensitive to estrogen was based on the hypothesis that testosterone–male sexual behavior is the typical relationship in the male. It is suggested that this difference in theoretical framework explains the discrepancies in some of the reported results. PMID:26601123

  8. Dietary estrogens--a probable cause of infertility and liver disease in captive cheetahs.

    PubMed

    Setchell, K D; Gosselin, S J; Welsh, M B; Johnston, J O; Balistreri, W F; Kramer, L W; Dresser, B L; Tarr, M J

    1987-08-01

    The cheetah in the wild is "racing towards extinction" mostly due to habitat destruction. Its survival will probably depend on accelerated captive breeding. At this time, however, reproductive failure and liver disease threaten the future of the captive cheetah population. Histopathological evaluation of more than 100 cheetah livers identified venocclusive disease as the main hepatic lesion responsible for liver disease in this species. Analysis of the commercial feline diet by high-performance liquid chromatography and gas-liquid chromatography-mass spectrometry revealed large amounts of two phytoestrogens identified as daidzein and genistein. These compounds were found to be derived from a soybean product that was a component of the cheetah diet, and their concentrations both ranged from 18 to 35 micrograms/g diet. The adult cheetah consequently consumes approximately 50 mg/day of these weak estrogens. When extracts of the diet were tested for estrogenicity using a bioassay, a dose-related increase in uterine weight was observed. In 4 cheetahs studied, withdrawal of this feline diet by substitution with a chicken diet resulted in an improvement in conventional liver function tests and a normalization in the appearance of hepatic mitochondria. We conclude that the relatively high concentrations of phytoestrogens from soybean protein present in the commercial diet fed to captive cheetahs in North American zoos may be one of the major factors in the decline of fertility and in the etiology of liver disease in this species. The survival of the captive cheetah population could depend upon a simple change of diet by excluding exogenous estrogen.

  9. ESTROGEN LEVELS DO NOT RISE WITH TESTOSTERONE TREATMENT FOR TRANSGENDER MEN.

    PubMed

    Chan, Kelly J; Jolly, Divya; Liang, Jennifer J; Weinand, Jamie D; Safer, Joshua D

    2018-04-01

    Existing transgender treatment guidelines suggest that for transmasculine treatment, there is a possible need for estrogen-lowering strategies adjunct to testosterone therapy. Further, guidelines advocate consideration of prophylactic female reproductive tissue surgeries for transgender men to avoid the possibility of estrogen-related health risks. Despite the paucity of objective data, some transgender men seek conversion inhibitors. We sought to determine estradiol levels in transgender men treated with testosterone therapy and the change in those levels with treatment, if any. Estradiol levels were extracted from the electronic medical records of 34 anonymized transgender men treated with testosterone therapy at the Endocrinology Clinic at Boston Medical Center. Data were sufficient to observe 6 years of follow-up. With increased testosterone levels in trans-gender men, a significant decrease in estradiol levels was noted. There was a significant negative correlation between testosterone levels and body mass index, which may serve to explain part of the mechanism for the fall in estradiol levels. Even though the fall in estradiol levels was significant statistically, the actual levels remained within the normal male range, even with 6 years of follow-up. These data suggest that when exogenous testosterone is used to achieve normal serum male testosterone levels for transgender men, it is converted to normal male levels of estradiol, with some decline in those estradiol levels that might be attributable to a fall in fat mass. There appears to be no role for aromatase conversion inhibitors or other estrogen-reducing strategies in trans-gender men. Abbreviation: BMI = body mass index.

  10. Testosterone and estrogen impact social evaluations and vicarious emotions: A double-blind placebo-controlled study.

    PubMed

    Olsson, Andreas; Kopsida, Eleni; Sorjonen, Kimmo; Savic, Ivanka

    2016-06-01

    The abilities to "read" other peoples' intentions and emotions, and to learn from their experiences, are critical to survival. Previous studies have highlighted the role of sex hormones, notably testosterone and estrogen, in these processes. Yet it is unclear how these hormones affect social cognition and emotion using acute hormonal administration. In the present double-blind placebo-controlled study, we administered an acute exogenous dose of testosterone or estrogen to healthy female and male volunteers, respectively, with the aim of investigating the effects of these steroids on social-cognitive and emotional processes. Following hormonal and placebo treatment, participants made (a) facial dominance judgments, (b) mental state inferences (Reading the Mind in the Eyes Test), and (c) learned aversive associations through watching others' emotional responses (observational fear learning [OFL]). Our results showed that testosterone administration to females enhanced ratings of facial dominance but diminished their accuracy in inferring mental states. In men, estrogen administration resulted in an increase in emotional (vicarious) reactivity when watching a distressed other during the OFL task. Taken together, these results suggest that sex hormones affect social-cognitive and emotional functions at several levels, linking our results to neuropsychiatric disorders in which these functions are impaired. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  11. The unliganded long isoform of estrogen receptor beta stimulates brain ryanodine receptor single channel activity alongside with cytosolic Ca2+

    PubMed Central

    Rybalchenko, Volodymyr; Grillo, Michael A.; Gastinger, Matthew J.; Rybalchenko, Nataliya; Payne, Andrew J.; Koulen, Peter

    2010-01-01

    Ca2+ release from intracellular stores mediated by endoplasmic reticulum membrane ryanodine receptors (RyR) plays a key role in activating and synchronizing downstream Ca2+-dependent mechanisms, in different cells varying from apoptosis to nuclear transcription and development of defensive responses. Recently discovered, atypical “non-genomic” effects mediated by estrogen receptors (ER) include rapid Ca2+ release upon estrogen exposure in conditions implicitly suggesting involvement of RyRs. In the present study, we report various levels of co-localization between RyR type 2 (RyR2) and ER type β (ERβ) in the neuronal cell line HT-22, indicating a possible functional interaction. Electrophysiological analyses revealed a significant increase in single channel ionic currents generated by mouse brain RyRs after application of the soluble monomer of the long form ERβ (ERβ1). The effect was due to a strong increase in open probability of RyR higher open channel sublevels at cytosolic [Ca2+] concentrations of 100 nM, suggesting a synergistic action of ERβ1 and Ca2+ in RyR activation, and a potential contribution to Ca2+-induced Ca2+ release rather than to basal intracellular Ca2+ concentration level at rest. This RyR/ERβ interaction has potential effects on cellular physiology, including roles of shorter ERβ isoforms and modulation of the RyR/ERβ complexes by exogenous estrogens. PMID:19899956

  12. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. [Alleviation of salt stress during maize seed germination by presoaking with exogenous sugar].

    PubMed

    Zhao, Ying; Yang, Ke-jun; Li, Zuo-tong; Zhao, Chang-jiang; Xu, Jing-yu; Hu, Xue- wei; Shi, Xin-xin; Ma, Li-feng

    2015-09-01

    The maize variety Kenyu 6 was used to study the effects of exogenous glucose (Glc) and sucrose (Suc) on salt tolerance of maize seeds at germination stage under 150 mmol · L(-1) NaCl treatment. Results showed that under salt stress condition, 0.5 mmol · L(-1) exogenous Glc and Suc presoaking could promote seed germination and early seedling growth. Compared with the salt treatment, Glc presoaking increased the shoot length, radicle length and corresponding dry mass up to 1.5, 1.3, 2.1 and 1.8 times, and those of the Suc presoaking treatment increased up to 1.7, 1.3. 2.7 and 1.9 times, respectively. Exogenous Glc and Suc presoaking resulted in decreased levels of thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H2O2) content of maize shoot under salt stress, which were lowered by 24.9% and 20.6% respectively. Exogenous Glc and Suc presoaking could increase the activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione peroxidase (GPX), glutathione reductase (GR) and induce glucose-6-phosphate dehydrogenase (G6PDH) activity of maize shoot under salt stress. Compared with the salt treatment. Glc presoaking increased the activity of SOD, APX, GPX, GR and G6PDH by 66.2%, 62.9%, 32.0%, 38.5% and 50.5%, and those of the Suc presoaking increased by 67.5%, 59.8%, 30.0%, 38.5% and 50.4%, respectively. Glc and Suc presoaking also significantly increased the contents of ascorbic acid (ASA) and glutathione (GSH), ASA/DHA and GSH/GSSG. The G6PDH activity was found closely related with the strong antioxidation capacity induced by exogenous sugars. In addition, Glc and Suc presoaking enhanced K+/Na+ in maize shoot by 1.3 and 1.4 times of water soaking salt treatment, respectively. These results indicated that exogenous Glc and Suc presoaking could improve antioxidation capacity of maize seeds and maintain the in vivo K+/Na+ ion balance to alleviate the inhibitory effect of salt stress on maize seed germination.

  14. Exogenic and endogenic albedo and color patterns on Europa

    NASA Technical Reports Server (NTRS)

    Mcewen, A. S.

    1986-01-01

    New global and high-resolution multispectral mosaics of Europa have been produced from the Voyager imaging data. Photometric normalizations are based on multiple-image techniques that explicitly account for intrinsic albedo variations through pixel-by-pixel solutions. The exogenic color and albedo pattern on Europa is described by a second-order function of the cosine of the angular distance from the apex of orbital motion. On the basis of this second-order function and of color trends that are different on the leading and trailing hemispheres, the exogenic pattern is interpreted as being due to equilibrium between two dominant processes: (1) impact gardening and (2) magnetospheric interactions, including sulfur-ion implantation and sputtering redistribution. Removal of the model exogenic pattern in the mosaics reveals the endogenic variations, consisting of only two major units: darker (redder) and bright materials. Therefore Europa's visual spectral reflectivity is simple, having one continuous exogenic pattern and two discrete endogenic units.

  15. Minnesota urban partnership agreement national evaluation : exogenous factors test plan.

    DOT National Transportation Integrated Search

    2009-11-17

    This report presents the exogenous factors test plan for the national evaluation of the Minnesota Urban Partnership Agreement (UPA) under the United States Department of Transportation (U.S. DOT) UPA Program. The Minnesota UPA projects focus on reduc...

  16. Isolating Exogenous and Endogenous Modes of Temporal Attention

    ERIC Educational Resources Information Center

    Lawrence, Michael A.; Klein, Raymond M.

    2013-01-01

    The differential allocation of information processing resources over time, here termed "temporal attention," may be achieved by relatively automatic "exogenous" or controlled "endogenous" mechanisms. Over 100 years of research has confounded these theoretically distinct dimensions of temporal attention. The current…

  17. Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice

    PubMed Central

    Tuscher, Jennifer J.; Szinte, Julia S.; Starrett, Joseph R.; Krentzel, Amanda A.; Fortress, Ashley M.; Remage-Healey, Luke; Frick, Karyn M.

    2016-01-01

    The potent estrogen 17β-Estradiol (E2) plays a critical role in mediating hippocampal function, yet the precise mechanisms through which E2 enhances hippocampal memory remain unclear. In young adult female rodents, the beneficial effects of E2 on memory are generally attributed to ovarian-synthesized E2. However, E2 is also synthesized in the adult brain in numerous species, where it regulates synaptic plasticity and is synthesized in response to experiences such as exposure to females or conspecific song. Although de novo E2 synthesis has been demonstrated in rodent hippocampal cultures, little is known about the functional role of local E2 synthesis in mediating hippocampal memory function. Therefore, the present study examined the role of hippocampal E2 synthesis in hippocampal memory consolidation. Using bilateral dorsal hippocampal infusions of the aromatase inhibitor letrozole, we first found that blockade of dorsal hippocampal E2 synthesis impaired hippocampal memory consolidation. We next found that elevated levels of E2 in dorsal hippocampus observed 30 min after object training were blocked by dorsal hippocampal infusion of letrozole, suggesting that behavioral experience increases acute and local E2 synthesis. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory consolidation, indicating that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory. Combined, these data are consistent with the hypothesis that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation in rodents. PMID:27178577

  18. Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors.

    PubMed

    Roger, P; Daures, J P; Maudelonde, T; Pignodel, C; Gleizes, M; Chapelle, J; Marty-Double, C; Baldet, P; Mares, P; Laffargue, F; Rochefort, H

    2000-05-01

    The role of estrogen as a promoter agent of sporadic breast cancer has been considered by assaying, in benign breast disease (BBD) and in situ carcinomas (CIS), 2 markers, the estrogen receptor alpha (ERalpha) and cathepsin D (cath-D) involved in estrogen action on mammary tissue. ERalpha and cath-D were assayed by quantitative immunohistochemistry using an image analyzer in 170 lesions of varying histological risk (94 BBD and 76 CIS), and in "normal" glands close to these lesions. The ERalpha level increased significantly in proliferative BBD with atypia (P < .001), in non-high-grade CIS (P < .001), and in adjacent "normal" glands. ERalpha level was decreased in high-grade ductal CIS (DCIS) and also in adjacent "normal" glands. Cath-D level increased in ductal proliferative BBD (P < or = .01) and in high-grade DCIS (P < or = .003), but not in the other lesions. After menopause, ERalpha level was increased (P = .012) but not cath-D level. According to Mac Neman test, the high-grade DCIS were predominantly ERalpha negative and cath-D positive (P = .0017), and the other CIS were predominantly ERalpha positive and cath-D negative (P = .0002). The 2 markers are overexpressed early in premalignant lesions, but independently. This dissociation suggests a branched model of mammary carcinogenesis involving 1 estrogen-independent pathway with high cath-D and low ERalpha levels (including high-grade DCIS) and 1 estrogen-dependent pathway, with high ERalpha level (including proliferative BBD with atypia and low-grade DCIS). We propose that ERalpha-negative breast cancers may develop directly from high-grade DCIS and that ERalpha assay in preinvasive lesions should be considered in prevention trials with antiestrogens.

  19. Insulin, estrogen, inflammatory markers, and risk of benign proliferative breast disease.

    PubMed

    Catsburg, Chelsea; Gunter, Marc J; Chen, Chu; Cote, Michele L; Kabat, Geoffrey C; Nassir, Rami; Tinker, Lesley; Wactawski-Wende, Jean; Page, David L; Rohan, Thomas E

    2014-06-15

    Women with benign proliferative breast disease (BPBD) are at increased risk for developing breast cancer. Evidence suggests that accumulation of adipose tissue can influence breast cancer development via hyperinsulinemia, increased estrogen, and/or inflammation. However, there are limited data investigating these pathways with respect to risk of BPBD. We evaluated serologic markers from these pathways in a case-control study of postmenopausal women nested within the Women's Health Initiative Clinical Trial. Cases were the 667 women who developed BPBD during follow-up, and they were matched to 1,321 controls. Levels of insulin, estradiol, C-reactive protein (CRP), and adiponectin were measured in fasting serum collected at baseline. Conditional logistic regression models were used to estimate ORs for the association of each factor with BPBD risk. Among nonusers of hormone therapy, fasting serum insulin was associated with a statistically significant increase in risk of BPBD (OR for highest vs. lowest quartile = 1.80; 95% confidence interval, CI, 1.16-2.79; Ptrend = 0.003) as were levels of estradiol (OR for highest vs. lowest tertile = 1.89; 95% CI, 1.26-2.83; Ptrend = 0.02) and CRP (OR for highest vs. lowest quartile = 2.46; 95% CI, 1.59-3.80; Ptrend < 0.001). Baseline adiponectin level was inversely associated with BPBD risk (OR for highest vs. lowest quartile = 0.47; 95% CI, 0.31-0.71; Ptrend < 0.001). These associations persisted after mutual adjustment, but were not observed among users of either estrogen alone or of estrogen plus progestin hormone therapy. Our results indicate that serum levels of estrogen, insulin, CRP, and adiponectin are independent risk factors for BPBD and suggest that the estrogen, insulin, and inflammation pathways are associated with the early stages of breast cancer development. ©2014 American Association for Cancer Research.

  20. S-ketamine influences strategic allocation of attention but not exogenous capture of attention.

    PubMed

    Fuchs, Isabella; Ansorge, Ulrich; Huber-Huber, Christoph; Höflich, Anna; Lanzenberger, Rupert

    2015-09-01

    We investigated whether s-ketamine differentially affects strategic allocation of attention. In Experiment 1, (1) a less visible cue was weakly masked by the onsets of competing placeholders or (2) a better visible cue was not masked because it was presented in isolation. Both types of cue appeared more often opposite of the target (75%) than at target position (25%). With this setup, we tested for strategic attention shifts to the opposite side of the cues and for exogenous attentional capture toward the cue's side in a short cue-target interval, as well as for (reverse) cueing effects in a long cue-target interval after s-ketamine and after placebo treatment in a double-blind within-participant design. We found reduced strategic attention shifts after cues presented without placeholders for the s-ketamine compared to the placebo treatment in the short interval, indicating an early effect on the strategic allocation of attention. No differences between the two treatments were found for exogenous attentional capture by less visible cues, suggesting that s-ketamine does not affect exogenous attentional capture in the presence of competing distractors. Experiment 2 confirmed that the competing onsets of the placeholders prevented the strategic cueing effect. Taken together, the results indicate that s-ketamine affects strategic attentional capture, but not exogenous attentional capture. The findings point to a more prominent role of s-ketamine during top-down controlled forms of attention that require suppression of automatic capture than during automatic capture itself. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Exogenous vs. endogenous attention: Shifting the balance of fronto-parietal activity.

    PubMed

    Meyer, Kristin N; Du, Feng; Parks, Emily; Hopfinger, Joseph B

    2018-03-01

    Despite behavioral and electrophysiological evidence for dissociations between endogenous (voluntary) and exogenous (reflexive) attention, fMRI results have yet to consistently and clearly differentiate neural activation patterns between these two types of attention. This study specifically aimed to determine whether activity in the dorsal fronto-parietal network differed between endogenous and exogenous conditions. Participants performed a visual discrimination task in endogenous and exogenous attention conditions while undergoing fMRI scanning. Analyses revealed robust and bilateral activation throughout the dorsal fronto-parietal network for each condition, in line with many previous results. In order to investigate possible differences in the balance of neural activity within this network with greater sensitivity, a priori regions of interest (ROIs) were selected for analysis, centered on the frontal eye fields (FEF) and intraparietal sulcus (IPS) regions identified in previous studies. The results revealed a significant interaction between region, condition, and hemisphere. Specifically, in the left hemisphere, frontal areas were more active than parietal areas, but only during endogenous attention. Activity in the right hemisphere, in contrast, remained relatively consistent for these regions across conditions. Analysis of this activity over time indicates that this left-hemispheric regional imbalance is present within the FEF early, at 3-6.5 s post-stimulus presentation, whereas a regional imbalance in the exogenous condition is not evident until 6.5-8 s post-stimulus presentation. Overall, our results provide new evidence that although the dorsal fronto-parietal network is indeed associated with both types of attentional orienting, regions of the network are differentially engaged over time and across hemispheres depending on the type of attention. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

    PubMed

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

    2015-12-29

    The role of estrogen signaling in regulating prostate tumorigenesis is relatively underexplored. Although, an increasing body of evidence has linked estrogen receptor beta (ERß) 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.

  3. Dissociable endogenous and exogenous attention in disorders of consciousness.

    PubMed

    Chennu, Srivas; Finoia, Paola; Kamau, Evelyn; Monti, Martin M; Allanson, Judith; Pickard, John D; Owen, Adrian M; Bekinschtein, Tristan A

    2013-01-01

    Recent research suggests that despite the seeming inability of patients in vegetative and minimally conscious states to generate consistent behaviour, some might possess covert awareness detectable with functional neuroimaging. These findings motivate further research into the cognitive mechanisms that might support the existence of consciousness in these states of profound neurological dysfunction. One of the key questions in this regard relates to the nature and capabilities of attention in patients, known to be related to but distinct from consciousness. Previous assays of the electroencephalographic P300 marker of attention have demonstrated its presence and potential clinical value. Here we analysed data from 21 patients and 8 healthy volunteers collected during an experimental task designed to engender exogenous or endogenous attention, indexed by the P3a and P3b components, respectively, in response to a pair of word stimuli presented amongst distractors. Remarkably, we found that the early, bottom-up P3a and the late, top-down P3b could in fact be dissociated in a patient who fitted the behavioural criteria for the vegetative state. In juxtaposition with healthy volunteers, the patient's responses suggested the presence of a relatively high level of attentional abilities despite the absence of any behavioural indications thereof. Furthermore, we found independent evidence of covert command following in the patient, as measured by functional neuroimaging during tennis imagery. Three other minimally conscious patients evidenced non-discriminatory bottom-up orienting, but no top-down engagement of selective attentional control. Our findings present a persuasive case for dissociable attentional processing in behaviourally unresponsive patients, adding to our understanding of the possible levels and applications of consequent conscious awareness.

  4. Quality control of estrogen receptor assays.

    PubMed

    Godolphin, W; Jacobson, B

    1980-01-01

    Four types of material have been used for the quality control of routine assays of estrogen receptors in human breast tumors. Pieces of hormone-dependent Nb rat mammary tumors gave a precision about 40%. Rat uteri and rat tumors pulverized at liquid nitrogen temperature and stored as powder yielded precision about 30%. Powdered and lyophilised human tumors appear the best with precision as good as 17%.

  5. The E-screen assay as a tool to identify estrogens: An update on estrogenic environmental pollutants

    SciTech Connect

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

    1995-10-01

    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 ofmore » 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 {open_quotes}new{close_quotes} 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 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. 57 refs., 3 figs., 9 tabs.« less

  6. The effects of exogenous hormones on rooting process and the activities of key enzymes of Malus hupehensis stem cuttings.

    PubMed

    Zhang, Wangxiang; Fan, Junjun; Tan, Qianqian; Zhao, Mingming; Zhou, Ting; Cao, Fuliang

    2017-01-01

    Malus hupehensis is an excellent Malus rootstock species, known for its strong adverse-resistance and apomixes. In the present study, stem cuttings of M. hupehensis were treated with three types of exogenous hormones, including indole acetic acid (IAA), naphthalene acetic acid (NAA), or green growth regulator (GGR). The effects and mechanisms of exogenous hormone treatment and antioxidant enzyme activity on adventitious root formation were investigated. The results showed that the apparent morphology of the adventitious root had four stages, including root pre-emergence stage (S0), early stage of root formation (S1), massive root formation stage (S2), and later stage of root formation (S3). The suitable concentrations of the three exogenous hormones, IAA, NAA and GGR, were 100 mg·L-1, 300 mg·L-1, and 300 mg·L-1, respectively. They shortened the rooting time by 25-47.4% and increased the rooting percentages of cuttings by 0.9-1.3 times, compared with that in the control. The dispersion in S0 stage was 3.6 times of that in the S1 stage after exogenous hormone application. The earlier the third critical point (P3) appeared, the shorter the rooting time and the greater the rooting percentage of the cuttings. During rhizogenesis, the activities of three antioxidant enzymes (POD, SOD, and PPO) showed an A-shaped trend. However, peak values of enzyme activity appeared at different points, which were 9 d before the P3, P3, and the fourth critical point (P4), respectively. Exogenous hormone treatment reduced the time to reach the peak value by 18 days, although the peak values of the enzymatic activities did not significantly changed. Our results suggested that exogenous hormone treatment mainly acted during the root pre-emergence stage, accelerated the synthesis of antioxidant enzymes, reduced the rooting time, and consequently promoted root formation. The three kinds of antioxidant enzymes acted on different stages of rooting.

  7. Characterizing the Growth Kinetics in Estrogen Responsive ...

    EPA Pesticide Factsheets

    There is a need to develop high-throughput screening (HTS) tests capable of testing thousands of environmental chemicals for endocrine disrupting potential. The estrogen signaling pathway is a known xenobiotic target that has been implicated in a variety of adverse health effects including reproductive deficits and cancer promotion. Using real-time measurements of growth kinetics by electrode impedance, the estrogen-responsive human ductal carcinoma cell line, T47D, was treated with 2000 chemicals of environmental relevance. Cells were treated in concentration response and measurements of cellular impedance were recorded every hour for six days. Exponential impedance, signifying increased proliferation, was observed by prototypical estrogen receptor agonists (17β-estradiol, genestein, bisphenol-A, nonylphenol, 4-tert-octylphenol). Several compounds, including bisphenol-A and genestein, induced cell proliferation at comparable levels to 17β-estradiol, although at much higher concentrations. Progestins, and mineralocortocoids (progesterone, dihydrotestosterone, aldosterone) invoked a biphasic impedance signature. In conclusion, the real-time nature of this assay allows for rapid detection of differential growth characteristics shows potential, in combination with other ToxCast HTS assays, to detect environmental chemicals with potential endocrine activity. [This abstract does not necessarily reflect Agency policy]. Several compounds, including bisphenol-A and

  8. CERAPP: Collaborative Estrogen Receptor Activity Prediction Project

    EPA Pesticide Factsheets

    Data from a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) demonstrating using predictive computational models on high-throughput screening data to screen thousands of chemicals against the estrogen receptor.This dataset is associated with the following publication:Mansouri , K., A. Abdelaziz, A. Rybacka, A. Roncaglioni, A. Tropsha, A. Varnek, A. Zakharov, A. Worth, A. Richard , C. Grulke , D. Trisciuzzi, D. Fourches, D. Horvath, E. Benfenati , E. Muratov, E.B. Wedebye, F. Grisoni, G.F. Mangiatordi, G.M. Incisivo, H. Hong, H.W. Ng, I.V. Tetko, I. Balabin, J. Kancherla , J. Shen, J. Burton, M. Nicklaus, M. Cassotti, N.G. Nikolov, O. Nicolotti, P.L. Andersson, Q. Zang, R. Politi, R.D. Beger , R. Todeschini, R. Huang, S. Farag, S.A. Rosenberg, S. Slavov, X. Hu, and R. Judson. (Environmental Health Perspectives) CERAPP: Collaborative Estrogen Receptor Activity Prediction Project. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, USA, 1-49, (2016).

  9. 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.

  10. Autoimmune estrogen dermatitis in an infertile female.

    PubMed

    Elcin, Gonca; Gülseren, Duygu; Bayraktar, Miyase; Gunalp, Serdar; Gurgan, Timur

    2017-06-01

    Autoimmune estrogen dermatitis is a cyclical cutaneous eruption that occurs premenstrually and goes to the rapid resolution within a few days of menstrual cycles. The disorder has variable clinical manifestations consisting of macules, papules, vesicles, urticarial lesions, bullae, eczematous plaques, and erythema multiforme-like lesions. Herein, we present a case of a 30-year-old woman with attacks of edema and erosions involving the oral and genital mucosal sites on every first day of her menstruation period. She had also multiple endocrinological problems such as hypotroidism and infertility. To determine the sex hormon sensitivity, intradermal skin tests were performed. Based on her personal history and skin test findings, a diagnosis of autoimmune estrogen dermatitis was made. After the oophorectomy, she was free from the skin and mucosal symptoms. We propose that it is important to suspect the diagnosis of autoimmune estrogen dermatitis in patients who present with recurrent cylic eruptions and it must be kept in mind that these patients might have a concomitant infertility.

  11. Mitochondria, Estrogen and Female Brain Aging

    PubMed Central

    Lejri, Imane; Grimm, Amandine; Eckert, Anne

    2018-01-01

    Mitochondria play an essential role in the generation of steroid hormones including the female sex hormones. These hormones are, in turn, able to modulate mitochondrial activities. Mitochondria possess crucial roles in cell maintenance, survival and well-being, because they are the main source of energy as well as of reactive oxygen species (ROS) within the cell. The impairment of these important organelles is one of the central features of aging. In women’s health, estrogen plays an important role during adulthood not only in the estrous cycle, but also in the brain via neuroprotective, neurotrophic and antioxidant modes of action. The hypestrogenic state in the peri- as well as in the prolonged postmenopause might increase the vulnerability of elderly women to brain degeneration and age-related pathologies. However, the underlying mechanisms that affect these processes are not well elucidated. Understanding the relationship between estrogen and mitochondria might therefore provide better insights into the female aging process. Thus, in this review, we first describe mitochondrial dysfunction in the aging brain. Second, we discuss the estrogen-dependent actions on the mitochondrial activity, including recent evidence of the estrogen—brain-derived neurotrophic factor and estrogen—sirtuin 3 (SIRT3) pathways, as well as their potential implications during female aging. PMID:29755342

  12. Environmental transport of endogenous dairy manure estrogens.

    PubMed

    Popova, Inna E; Morra, Matthew J

    2017-11-02

    Although estrogens originating from dairy manure applied to agricultural soils as a fertilizer can potentially contaminate surface water and groundwater, the variables that control transport are poorly understood. Our objective was to assess the potential for off-site movement of endogenous dairy cattle estrogens when manure is applied on fields at agronomically relevant fertilization rates. Estrone (E1), 17α-estradiol (α-E2), and 17β-estradiol (β-E2) were used in laboratory sorption, desorption, and transformation incubations with both manure and an agriculturally relevant soil. Sorption on manure containing 44% organic carbon exceeded sorption on soil containing 0.8% organic carbon by 20 to 150 times, following the pattern of β-E2 > α-E2 > E1. Approximately 20% of E1 and 17% of α-E2 were desorbed from manure, whereas only about 4% of β-E2 was desorbed. Thirty to seventy percent of α-E2 and β-E2 were converted to E1 in soil and manure, making it imperative that transformation reactions be considered when predicting transport and potential biological effects in the environment. Overall results indicate that high organic carbon concentrations and relatively low amounts of desorption inhibit the potential for off-site transport of endogenous dairy manure estrogens.

  13. Estrogen Receptors and Chronic Venous Disease.

    PubMed

    Serra, R; Gallelli, L; Perri, P; De Francesco, E M; Rigiracciolo, D C; Mastroroberto, P; Maggiolini, M; de Franciscis, S

    2016-07-01

    Chronic venous disease (CVD) is a common and relevant problem affecting Western people. The role of estrogens and their receptors in the venous wall seems to support the major prevalence of CVD in women. The effects of the estrogens are mediated by three estrogen receptors (ERs): ERα, ERβ, and G protein-coupled ER (GPER). The expression of ERs in the vessel walls of varicose veins is evaluated. In this prospective study, patients of both sexes, with CVD and varicose veins undergoing open venous surgery procedures, were enrolled in order to obtain vein samples. To obtain control samples of healthy veins, patients of both sexes without CVD undergoing coronary artery bypass grafting with autologous saphenous vein were recruited (control group). Samples were processed in order to evaluate gene expression. Forty patients with CVD (10 men [25%], 30 women [75%], mean age 54.3 years [median 52 years, range 33-74 years]) were enrolled. Five patients without CVD (three men, two women [aged 61-73 years]) were enrolled as the control group. A significant increase of tissue expression of ERα, ERβ and GPER in patients with CVD was recorded (p < .01), which was also related to the severity of venous disease. ERs seem to play a role in CVD; in this study, the expression of ERs correlated with the severity of the disease, and their expression was correlated with the clinical stage. Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  14. 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

  15. Estrogen receptor status of breast cancer in Ontario

    PubMed Central

    McKeown-Eyssen, Gail E.; Rogers-Melamed, Iris; Clarke, E. Aileen

    1985-01-01

    Data from a number of studies of breast cancer have suggested that after the ages associated with the menopause the rates of estrogen-receptor-positive tumours increase with age, whereas the rates of estrogen-receptor-negative tumours do not. Previous investigators studied cases in specific treatment centres, so there was a possibility that the findings were influenced by differences in patterns of case referral by age. A review of all the cases of breast cancer diagnosed in Ontario women in 1981 and assayed for estrogen receptors, however, confirmed the earlier findings. The results showed that the incidence of estrogen-receptor-positive and estrogen-receptor-negative tumours increased at about the same rate before age 45, but thereafter an increase in incidence was seen only for estrogen-receptor-positive tumours. These differences in patterns of incidence suggest the possibility that the two types of tumour may have different etiologic factors. PMID:4063915

  16. Exogenous reinfection of tuberculosis in a low-burden area.

    PubMed

    Schiroli, Consuelo; Carugati, Manuela; Zanini, Fabio; Bandera, Alessandra; Di Nardo Stuppino, Silvia; Monge, Elisa; Morosi, Manuela; Gori, Andrea; Matteelli, Alberto; Codecasa, Luigi; Franzetti, Fabio

    2015-12-01

    Recurrence of tuberculosis (TB) can be the consequence of relapse or exogenous reinfection. The study aimed to assess the factors associated with exogenous TB reinfection. Prospective cohort study based on the TB database, maintained at the Division of Infectious Diseases, Luigi Sacco Hospital (Milan, Italy). Time period: 1995-2010. (1) ≥2 episodes of culture-confirmed TB; (2) cure of the first episode of TB; (3) availability of one Mycobacterium tuberculosis isolate for each episode. Genotyping of the M. tuberculosis strains to differentiate relapse and exogenous reinfection. Logistic regression analysis was used to assess the influence of risk factors on exogenous reinfections. Of the 4682 patients with TB, 83 were included. Of these, exogenous reinfection was diagnosed in 19 (23 %). It was independently associated with absence of multidrug resistance at the first episode [0, 10 (0.01-0.95), p = 0.045] and with prolonged interval between the first TB episode and its recurrence [7.38 (1.92-28.32) p = 0.004]. However, TB relapses occurred until 4 years after the first episode. The risk associated with being foreign born, extrapulmonary site of TB, and HIV infection was not statistically significant. In the relapse and re-infection cohort, one-third of the patients showed a worsened drug resistance profile during the recurrent TB episode. Exogenous TB reinfections have been documented in low endemic areas, such as Italy. A causal association with HIV infection could not be confirmed. Relapses and exogenous reinfections shared an augmented risk of multidrug resistance development, frequently requiring the use of second-line anti-TB regimens.

  17. 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

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

    SciTech Connect

    Shyu, Conrad; Cavileer, Timothy D.; Nagler, James J.

    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 isoformsmore » 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.« less

  19. A recombinant estrogen receptor fragment-based homogeneous fluorescent assay for rapid detection of estrogens.

    PubMed

    Wang, Dan; Xie, Jiangbi; Zhu, Xiaocui; Li, Jinqiu; Zhao, Dongqin; Zhao, Meiping

    2014-05-15

    In this work, we demonstrate a novel estrogenic receptor fragment-based homogeneous fluorescent assay which enables rapid and sensitive detection of 17β-estradiol (E2) and other highly potent estrogens. A modified human estrogenic receptor fragment (N-His × 6-hER270-595-C-Strep tag II) has been constructed that contains amino acids 270-595 of wild-type human estrogenic receptor α (hER270-595) and two specific tags (6 × His and Strep tag II) fused to the N and C terminus, respectively. The designed receptor protein fragment could be easily produced by prokaryotic expression with high yield and high purity. The obtained protein exhibits high binding affinity to E2 and the two tags greatly facilitate the application of the recombinant protein. Taking advantage of the unique spectroscopic properties of coumestrol (CS), a fluorescent phytoestrogen, a CS/hER270-595-based fluorescent assay has been developed which can sensitively respond to E2 within 1.0 min with a linear working range from 0.1 to 20 ng/mL and a limit of detection of 0.1 ng/mL. The assay was successfully applied for rapid detection of E2 in the culture medium of rat hippocampal neurons. The method also holds great potential for high-throughput monitoring the variation of estrogen levels in complex biological fluids, which is crucial for investigation of the molecular basis of various estrogen-involved processes. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Estrogen via estrogen receptor beta partially inhibits mandibular condylar cartilage growth.

    PubMed

    Chen, J; Kamiya, Y; Polur, I; Xu, M; Choi, T; Kalajzic, Z; Drissi, H; Wadhwa, S

    2014-11-01

    Temporomandibular joint (TMJ) diseases predominantly afflict women, suggesting a role for female hormones in the disease process. However, little is known about the role of estrogen receptor (ER) signaling in regulating mandibular condylar cartilage growth. Therefore, the goal of this study was to examine the effects of altered estrogen levels on the mandibular condylar cartilage in wild type (WT) and ER beta Knockout (KO) mice. 21-day-old female WT (n = 37) and ER beta KO mice (n = 36) were either sham operated or ovariectomized, and treated with either placebo or estradiol. The mandibular condylar cartilage was evaluated by histomorphometry, proliferation was analyzed by double ethynyl-2'-deoxyuridine/bromodeoxyuridine (EdU/BrdU) labeling, and assays on gene and protein expression of chondrocyte maturation markers were performed. In WT mice, ovariectomy caused a significant increase in mandibular condylar cartilage cell numbers, a significant increase in Sox9 expression and a significant increase in proliferation compared with sham operated WT mice. In contrast, ovariectomy did not cause any of these effects in the ER beta KO mice. Estrogen replacement treatment in ovariectomized WT mice caused a significant decrease in ER alpha expression and a significant increase in Sost expression compared with ovariectomized mice treated with placebo. Estrogen replacement treatment in ovariectomized ER beta KO mice caused a significant increase in Col2 expression, no change in ER alpha expression, and a significant increase in Sost expression. Estrogen via ER beta inhibits proliferation and ER alpha expression while estrogen independent of ER beta induces Col2 and Sost expression. Copyright © 2014 China University of Geosciences (Beijing) and Peking University. Published by Elsevier Ltd. All rights reserved.

  1. Estrogen mediates innate and adaptive immune alterations to influenza infection in pregnant mice.

    PubMed

    Pazos, Michael A; Kraus, Thomas A; Muñoz-Fontela, César; Moran, Thomas M

    2012-01-01

    Pregnancy is a leading risk factor for severe complications during an influenza virus infection. Women infected during their second and third trimesters are at increased risk for severe cardiopulmonary complications, premature delivery, and death. Here, we establish a murine model of aerosolized influenza infection during pregnancy. We find significantly altered innate antiviral responses in pregnant mice, including decreased levels of IFN-β, IL-1α, and IFN-γ at early time points of infection. We also find reduced cytotoxic T cell activity and delayed viral clearance. We further demonstrate that pregnancy levels of the estrogen 17-β-estradiol are able to induce key anti-inflammatory phenotypes in immune responses to the virus independently of other hormones or pregnancy-related stressors. We conclude that elevated estrogen levels result in an attenuated anti-viral immune response, and that pregnancy-associated morbidities occur in the context of this anti-inflammatory phenotype.

  2. Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism.

    PubMed

    Sartorius, C A; Hanna, C T; Gril, B; Cruz, H; Serkova, N J; Huber, K M; Kabos, P; Schedin, T B; Borges, V F; Steeg, P S; Cittelly, D M

    2016-06-02

    Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER-) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER-, progesterone receptor-negative (PR-) and normal HER2) tumors. Young age is an independent risk factor for the development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of magnetic resonance imaging-detectable lesions by 56% as compared with estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated epidermal growth factor receptor (EGFR) ligands Egf, Ereg and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to the upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P<0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40±0.02-fold, P<0.01 compared with vehicle control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. Short hairpin RNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These

  3. Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism

    PubMed Central

    Sartorius, Carol A.; Hanna, Colton T.; Gril, Brunilde; Cruz, Hazel; Serkova, Natalie J.; Huber, Kendra M.; Kabos, Peter; Schedin, Troy B.; Borges, Virginia F.; Steeg, Patricia S.; Cittelly, Diana M.

    2015-01-01

    Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER−) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER−, progesterone receptor-negative (PR−) and normal HER2) tumors. Young age is an independent risk factor for development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of MRI detectable lesions by 56% as compared to estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated EGFR ligands Egf, Ereg, and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P<0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40±0.02 fold, P<0.01 compared to vehicle-control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. ShRNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes, and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These studies provide a novel mechanism by which estrogens, acting through ER

  4. Estrogen receptor mRNA in mineralized tissues of rainbow trout: calcium mobilization by estrogen.

    PubMed

    Armour, K J; Lehane, D B; Pakdel, F; Valotaire, Y; Graham, R; Russell, R G; Henderson, I W

    1997-07-07

    RT-PCR was undertaken on total RNA extracts from bone and scales of the rainbow trout, Oncorhynchus mykiss. The rainbow trout estrogen receptor (ER)-specific primers used amplified a single product of expected size from each tissue which, using Southern blotting, strongly hybridized with a 32P-labelled rtER probe under stringent conditions. These data provide the first in vivo evidence of ER mRNA in bone and scale tissues of rainbow trout and suggest that the effects of estrogen observed in this study (increased bone mineral and decreased scale mineral contents, respectively) may be mediated directly through ER.

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

    SciTech Connect

    Pinto, Caroline; Grimaldi, Marina; Boulahtouf, Abdelhay

    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 tomore » 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

  6. Estrogens and Androgens in Skeletal Physiology and Pathophysiology

    PubMed Central

    Almeida, Maria; Laurent, Michaël R.; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A.; Bouillon, Roger; Vanderschueren, Dirk

    2016-01-01

    Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution. PMID:27807202

  7. 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.

  8. Cumulative estrogen exposure and prospective memory in older women.

    PubMed

    Hesson, Jacqueline

    2012-10-01

    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 influence estrogen levels across the life span, and performance on prospective and retrospective memory measures in a group of 50 postmenopausal women (mean age=69.3years) who, if they were current or former users of estrogen therapy, had started therapy within 5years of menopause. The ICEE was found to be a significant predictor of performance on the Prospective Memory task (F(1)=4.21, p=.046, η(p)(2)=.084). No significant relationship was noted between the ICEE and performance on measures of retrospective memory. The results suggest that the level of cumulative lifetime exposure to estrogen a woman has influences her prospective memory performance later in life and that the influence of reproductive and biological markers of endogenous estrogen exposure are relevant factors to consider when studying the effect of estrogen therapy on cognitive functioning in postmenopausal women. In addition, the finding that performance on a measure of prospective memory, but not performance on measures of retrospective memory, was associated with the ICEE adds further support to the theory that the frontal cortex may be especially sensitive to estrogen. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Estrogens and Androgens in Skeletal Physiology and Pathophysiology.

    PubMed

    Almeida, Maria; Laurent, Michaël R; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A; Bouillon, Roger; Vanderschueren, Dirk; Manolagas, Stavros C

    2017-01-01

    Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution. Copyright © 2017 the American Physiological Society.

  10. Melatonin affects the dynamic steady-state equilibrium of estrogen sulfates in human umbilical vein endothelial cells by regulating the balance between estrogen sulfatase and sulfotransferase.

    PubMed

    González, Alicia; Martínez-Campa, Carlos; Alonso-González, Carolina; Cos, Samuel

    2015-12-01

    Melatonin is known to reduce the growth of endocrine-responsive breast cancers by interacting with estrogen signaling pathways. Estrogens play an important role in breast cancer, but also in various types of tissues, including vascular tissue. Estrogen sulfatase (STS) converts inactive estrogen sulfates into active estrogens, whereas estrogen sulfotransferase (EST) sulfonates estrogens to estrogen sulfates. Therefore, STS and EST are considered to be involved in the regulation of local estrogen levels in hormone‑dependent tumors and in non-pathologic tissues, such as those of the vascular system. Estrogens have a major impact on the vasculature, influencing vascular function, the expression of adhesion proteins, angiogenesis and the inflammatory state. In this study, we investigated the status of STS and EST in human umbilical vein endothelial cells (HUVECs) and the modulatory effects of melatonin. Both STS and EST were highly expressed in the HUVECs. The enzymatic activity correlated with the expression levels in these cells. Our findings also demonstrated that melatonin, at physiological concentrations, modulated the synthesis and transformation of biologically active estrogens in HUVECs through the inhibition of STS activity and expression, and the stimulation of EST activity and expression. Since melatonin decreased the STS levels and increased the EST levels, it modified the dynamic steady‑state equilibrium of estrogen sulfates by increasing the inactive estrogen levels and decreasing the active estrogen levels. Therefore, melatonin may modulate the known different biological actions of estrogens in endothelial cells, as well as in estrogen-dependent tumors and non-pathologic tissues.

  11. Distinct effects of 4-nonylphenol and estrogen-17β on expression of estrogen receptor α gene in smolting sockeye salmon

    USGS Publications Warehouse

    Luo, Qiong; Ban, Massatoshi; Ando, Hironori; Kitahashi, Takashi; Bhandari, Ramji K.; McCormick, Stephen D.; Urano, Akihisa

    2005-01-01

    Xenoestrogens such as 4-nonylphenol (4-NP) have been shown to affect the parr–smolt transformation, but their mechanisms of action are not known. We therefore examined effects of 4-NP and estradiol-17β (E2) on expression of estrogen receptor (ER) α gene in the liver, gill, pituitary and brain of sockeye salmon to elucidate molecular mechanisms of 4-NP and E2 and developmental differences in response during smolting. Fish were treated twice within a week with 4-NP (15 and 150 mg/kg BW), E2 (2 mg/kg BW) or only vehicle at three stages of smolting, pre-smolting in March, early smolting in April and late smolting in May. The absolute amounts of ERα mRNA were determined by real-time PCR. The basal amounts of ERα mRNA peaked in April in the liver, gill and pituitary. In March, E2 extensively increased the amounts in the liver, while 4-NP had no effects at this stage. In contrast, 4-NP (but not E2) decreased liver ERα mRNA in April. 4-NP also decreased the amount of ERα mRNA in the gill in April. In the pituitary, 4-NP increased ERα mRNA in March but decreased it in May. There were no significant effects in the brain. Changes in basal ERα mRNA observed in this study indicate that estrogen responsiveness of tissues may change during salmon smolting. Furthermore, 4-NP and E2 have different effects on expression of ERα gene in the liver and gill during smolting, and the response is dependent on smolt stage.

  12. Exogenous (automatic) attention to emotional stimuli: a review.

    PubMed

    Carretié, Luis

    2014-12-01

    Current knowledge on the architecture of exogenous attention (also called automatic, bottom-up, or stimulus-driven attention, among other terms) has been mainly obtained from studies employing neutral, anodyne stimuli. Since, from an evolutionary perspective, exogenous attention can be understood as an adaptive tool for rapidly detecting salient events, reorienting processing resources to them, and enhancing processing mechanisms, emotional events (which are, by definition, salient for the individual) would seem crucial to a comprehensive understanding of this process. This review, focusing on the visual modality, describes 55 experiments in which both emotional and neutral irrelevant distractors are presented at the same time as ongoing task targets. Qualitative and, when possible, meta-analytic descriptions of results are provided. The most conspicuous result is that, as confirmed by behavioral and/or neural indices, emotional distractors capture exogenous attention to a significantly greater extent than do neutral distractors. The modulatory effects of the nature of distractors capturing attention, of the ongoing task characteristics, and of individual differences, previously proposed as mediating factors, are also described. Additionally, studies reviewed here provide temporal and spatial information-partially absent in traditional cognitive models-on the neural basis of preattention/evaluation, reorienting, and sensory amplification, the main subprocesses involved in exogenous attention. A model integrating these different levels of information is proposed. The present review, which reveals that there are several key issues for which experimental data are surprisingly scarce, confirms the relevance of including emotional distractors in studies on exogenous attention.

  13. Exogenous spatial attention influences figure-ground assignment.

    PubMed

    Vecera, Shaun P; Flevaris, Anastasia V; Filapek, Joseph C

    2004-01-01

    In a hierarchical stage account of vision, figure-ground assignment is thought to be completed before the operation of focal spatial attention. Results of previous studies have supported this account by showing that unpredictive, exogenous spatial precues do not influence figure-ground assignment, although voluntary attention can influence figure-ground assignment. However, in these studies, attention was not summoned directly to a region in a figure-ground display. In three experiments, we addressed the relationship between figure-ground assignment and visuospatial attention. In Experiment 1, we replicated the finding that exogenous precues do not influence figure-ground assignment when they direct attention outside of a figure-ground stimulus. In Experiment 2, we demonstrated that exogenous attention can influence figure-ground assignment if it is directed to one of the regions in a figure-ground stimulus. In Experiment 3, we demonstrated that exogenous attention can influence figure-ground assignment in displays that contain a Gestalt figure-ground cue; this result suggests that figure-ground processes are not entirely completed prior to the operation of focal spatial attention. Exogenous spatial attention acts as a cue for figure-ground assignment and can affect the outcome of figure-ground processes.

  14. Diagnostic utility of dermatoscopy in hydroquinone-induced exogenous ochronosis.

    PubMed

    Mishra, Sunil N; Dhurat, Rachita S; Deshpande, Deepal J; Nayak, Chitra S

    2013-04-01

      Hydroquinone is the preferred topical bleaching agent used in the treatment of melasma. The adverse effects of its chronic use are confetti-like depigmentation and exogenous ochronosis. Exogenous ochronosis manifests clinically with gray-brown or blue-black hyperpigmentation, as well as pinpoint hyperchromic caviar-like papules over the malar region. Dermatoscopic findings of ochronosis are unique and point towards a clue for its diagnosis.   Three cases of suspected hydroquinone-induced exogenous ochronosis while treating melasma were subjected to dermatoscopy and histopathology studies.   Dermatoscopy in the areas of caviar-like hyperpigmentation revealed accentuation of the normal pseudo-rete of the facial skin with amorphous densely-pigmented structures obliterating some follicular opening and multiple thin, short arciform structures. On histopathological examination, curved ochre-colored structures, 'banana-shaped' fibers, were seen in the dermis of all patients.   Exogenous ochronosis is difficult to treat. Dermatologists should be able to differentiate it from melasma and immediately discontinue hydroquinone. Exogenous ochronosis has characteristic features on dermatoscopy which may obviate the need for an invasive procedure of biopsy for its diagnosis. © 2012 The International Society of Dermatology.

  15. G protein-coupled estrogen receptor (GPER) deficiency induces cardiac remodeling through oxidative stress.

    PubMed

    Wang, Hao; Sun, Xuming; Lin, Marina S; Ferrario, Carlos M; Van Remmen, Holly; Groban, Leanne

    2018-04-25

    Oxidative stress has been implicated in the unfavorable changes in cardiac function and remodeling that occur after ovarian estrogen loss. Using ovariectomized rat models, we previously reported that the cardioprotective actions of estrogen are mediated by the G protein-coupled estrogen receptor (GPER). Here, in 9-month-old, female cardiomyocyte-specific GPER knockout (KO) mice vs sex- and age-matched wild-type (WT) mice, we found increased cardiac oxidative stress and oxidant damage, measured as a decreased ratio of reduced glutathione to oxidized glutathione, increased 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine (8-oxo-DG) staining, and increased expression of oxidative stress-related genes. GPER KO mice also displayed increased heart weight, cardiac collagen deposition, and Doppler-derived filling pressure, and decreased percent fractional shortening and early mitral annular velocity compared with WT controls. Treatment of GPER KO mice for 8 weeks with phosphonium [10-(4,5-dimethoxy-2-methyl 3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenyl-,mesylate (MitoQ), a mitochondria-targeted antioxidant, significantly attenuated these measures of cardiac dysfunction, and MitoQ decreased 8-oxo-DG intensity compared with treatment with an inactive comparator compound, (1-decyl)triphenylphosphonium bromide (P <0.05). A real-time polymerase chain reaction array analysis of 84 oxidative stress and antioxidant defense genes revealed that MitoQ attenuates the increase in NADPH oxidase 4 and prostaglandin-endoperoxide synthase 2 and the decrease in uncoupling protein 3 and glutathione S-transferase kappa 1 seen in GPER KO mice. Our findings suggest that the cardioprotective effects of GPER include an antioxidant role and that targeted strategies to limit oxidative stress after early noncancerous surgical extirpation of ovaries or menopause may help limit alterations in cardiac structure and function related to estrogen loss. Copyright © 2018 Elsevier Inc. All rights

  16. Origin of Volatiles in Earth: Indigenous Versus Exogenous Sources Based on Highly Siderophile, Volatile Siderophile, and Light Volatile Elements

    NASA Technical Reports Server (NTRS)

    Righter, K.; Danielson, L.; Pando, K. M.; Marin, N.; Nickodem, K.

    2015-01-01

    Origin of Earth's volatiles has traditionally been ascribed to late accretion of material after major differentiation events - chondrites, comets, ice or other exogenous sources. A competing theory is that the Earth accreted its volatiles as it was built, thus water and other building blocks were present early and during differentiation and core formation (indigenous). Here we discuss geochemical evidence from three groups of elements that suggests Earth's volatiles were acquired during accretion and did not require additional sources after differentiation.

  17. Estrogens and cognition: Friends or foes?: An evaluation of the opposing effects of estrogens on learning and memory.

    PubMed

    Korol, Donna L; Pisani, Samantha L

    2015-08-01

    This article is part of a Special Issue "Estradiol and cognition". 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 showing that 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Dynamics of tuberculosis transmission with exogenous reinfections and endogenous reactivation

    NASA Astrophysics Data System (ADS)

    Khajanchi, Subhas; Das, Dhiraj Kumar; Kar, Tapan Kumar

    2018-05-01

    We propose and analyze a mathematical model for tuberculosis (TB) transmission to study the role of exogenous reinfection and endogenous reactivation. The model exhibits two equilibria: a disease free and an endemic equilibria. We observe that the TB model exhibits transcritical bifurcation when basic reproduction number R0 = 1. Our results demonstrate that the disease transmission rate β and exogenous reinfection rate α plays an important role to change the qualitative dynamics of TB. The disease transmission rate β give rises to the possibility of backward bifurcation for R0 < 1, and hence the existence of multiple endemic equilibria one of which is stable and another one is unstable. Our analysis suggests that R0 < 1 may not be sufficient to completely eliminate the disease. We also investigate that our TB transmission model undergoes Hopf-bifurcation with respect to the contact rate β and the exogenous reinfection rate α. We conducted some numerical simulations to support our analytical findings.

  19. Influence of exogenous lead pollution on enzyme activities and organic matter degradation in the surface of river sediment.

    PubMed

    Huang, Danlian; Xu, Juanjuan; Zeng, Guangming; Lai, Cui; Yuan, Xingzhong; Luo, Xiangying; Wang, Cong; Xu, Piao; Huang, Chao

    2015-08-01

    As lead is one of the most hazardous heavy metals in river ecosystem, the influence of exogenous lead pollution on enzyme activities and organic matter degradation in the surface of river sediment with high moisture content were studied at laboratory scale. The dynamic changes of urease, catalase, protease activities, organic matter content, and exchangeable or ethylenediaminetetraacetic acid (EDTA)-extractable Pb concentration in sediment were monitored during different levels of exogenous lead infiltrating into sediment. At the early stage of incubation, the activities of catalase and protease were inhibited, whereas the urease activities were enhanced with different levels of exogenous lead. Organic matter content in polluted sediment with exogenous lead was lower than control and correlated with enzyme activities. In addition, the effects of lead on the three enzyme activities were strongly time-dependent and catalase activities showed lower significant difference (P < 0.05) than urease and protease. Correlations between catalase activities and EDTA-extractable Pb in the experiment were significantly negative. The present findings will improve the understandings about the ecotoxicological mechanisms in sediment.

  20. Emerging Estrogenic Pollutants in the Aquatic Environment and Breast Cancer

    PubMed Central

    Lecomte, Sylvain; Charlier, Thierry D.; Pakdel, Farzad

    2017-01-01

    The number and amount of man-made chemicals present in the aquatic environment has increased considerably over the past 50 years. Among these contaminants, endocrine-disrupting chemicals (EDCs) represent a significant proportion. This family of compounds interferes with normal hormonal processes through multiple molecular pathways. They represent a potential risk for human and wildlife as they are suspected to be involved in the development of diseases including, but not limited to, reprotoxicity, metabolic disorders, and cancers. More precisely, several studies have suggested that the increase of breast cancers in industrialized countries is linked to exposure to EDCs, particularly estrogen-like compounds. Estrogen receptors alpha (ERα) and beta (ERβ) are the two main transducers of estrogen action and therefore important targets for these estrogen-like endocrine disrupters. More than 70% of human breast cancers are ERα-positive and estrogen-dependent, and their development and growth are not only influenced by endogenous estrogens but also likely by environmental estrogen-like endocrine disrupters. It is, therefore, of major importance to characterize the potential estrogenic activity from contaminated surface water and identify the molecules responsible for the hormonal effects. This information will help us understand how environmental contaminants can potentially impact the development of breast cancer and allow us to fix a maximal limit to the concentration of estrogen-like compounds that should be found in the environment. The aim of this review is to provide an overview of emerging estrogen-like compounds in the environment, sum up studies demonstrating their direct or indirect interactions with ERs, and link their presence to the development of breast cancer. Finally, we emphasize the use of in vitro and in vivo methods based on the zebrafish model to identify and characterize environmental estrogens. PMID:28914763

  1. VEGF-A is increased in exogenous endophthalmitis.

    PubMed

    Seamone, Mark E; Lewis, Darrell R; Haidl, Ian D; Gupta, R Rishi; O' Brien, Daniel M; Dickinson, John; Samad, Arif; Marshall, Jean S; Cruess, Alan F

    2017-06-01

    Exogenous endophthalmitis is an ophthalmologic emergency defined by panocular inflammation. Vascular endothelial growth factor A (VEGF-A) contributes to inflammation by promoting chemotaxis of monocytes and granulocytes and by increasing vascular permeability. The purpose of this article is to determine if VEGF-A is elevated in the vitreous samples obtained from individuals with exogenous endophthalmitis. Vitreous samples from individuals with exogenous endophthalmitis (n = 18) were analyzed via Luminex assay and enzyme-linked immunosorbent assay for the cytokines VEGF-A, tumor necrosis factor (TNF), interleukin 6 (IL-6), IL-8 (chemokine [CXCL]-8), IL-1β, IL-10, IL-12p70, IL-33, interferon (IFN)-γ, IFN-α, IFN-β, chemokine ligand (CCL)-3, IL-2, IL-5, IL-15, CXCL-10, CCL-2, IL-1Ra, CCL-5, IL-17, and CCL-11. Vitreous samples obtained at the time of macular hole surgery served as controls (n = 8). Concentrations of VEGF-A were significantly elevated in vitreous samples from individuals with exogenous endophthalmitis compared with macular hole (p < 0.001). VEGF-A was significantly upregulated in individuals with exogenous endophthalmitis after cataract surgery (p = 0.001), vitrectomy (p = 0.024), and intravitreal injection (p = 0.012). VEGF-A concentrations were similar in both culture-positive and culture-negative populations (p > 0.05). In a linear regression model, levels of VEGF-A correlated significantly with the chemokine CXCL-8 (p = 0.028). We demonstrate that VEGF-A is potently upregulated in exogenous endophthalmitis. This observation provides a foundation for future studies of targeted VEGF-A blockade in the management of endophthalmitis. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  2. Sex Hormones and Cardiometabolic Health: Role of Estrogen and Estrogen Receptors.

    PubMed

    Clegg, Deborah; Hevener, Andrea L; Moreau, Kerrie L; Morselli, Eugenia; Criollo, Alfredo; Van Pelt, Rachael E; Vieira-Potter, Victoria J

    2017-05-01

    With increased life expectancy, women will spend over three decades of life postmenopause. The menopausal transition increases susceptibility to metabolic diseases such as obesity, diabetes, cardiovascular disease, and cancer. Thus, it is more important than ever to develop effective hormonal treatment strategies to protect aging women. Understanding the role of estrogens, and their biological actions mediated by estrogen receptors (ERs), in the regulation of cardiometabolic health is of paramount importance to discover novel targeted therapeutics. In this brief review, we provide a detailed overview of the literature, from basic science findings to human clinical trial evidence, supporting a protective role of estrogens and their receptors, specifically ERα, in maintenance of cardiometabolic health. In so doing, we provide a concise mechanistic discussion of some of the major tissue-specific roles of estrogens signaling through ERα. Taken together, evidence suggests that targeted, perhaps receptor-specific, hormonal therapies can and should be used to optimize the health of women as they transition through menopause, while reducing the undesired complications that have limited the efficacy and use of traditional hormone replacement interventions. Copyright © 2017 Endocrine Society.

  3. Neuropsychiatric findings in Cushing syndrome and exogenous glucocorticoid administration.

    PubMed

    Starkman, Monica N

    2013-09-01

    This article reviews the neuropsychiatric presentations elicited by spontaneous hypercortisolism and exogenous supraphysiologic glucocorticoids. Patients with Cushing disease and syndrome develop a depressive syndrome: irritable and depressed mood, decreased libido, disrupted sleep and cognitive decrements. Exogenous short-term glucocorticoid administration may elicit a hypomanic syndrome with mood, sleep and cognitive disruptions. Treatment options are discussed. Brain imaging and neuropsychological studies indicate elevated cortisol and other glucocorticoids are especially deleterious to hippocampus and frontal lobe. The research findings also shed light on neuropsychiatric abnormalities in conditions that have substantial subgroups exhibiting elevated and dysregulated cortisol: aging, major depressive disorder and Alzheimer's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Estrogen receptors and the metabolic network.

    PubMed

    Barros, Rodrigo P A; Gustafsson, Jan-Åke

    2011-09-07

    The metabolic syndrome has reached pandemic level worldwide, and evidence is that estradiol plays a key role in its development. The discovery of the second estrogen receptor, ERβ, in tissues previously not considered targets of estradiol was a breakthrough in endocrinology. In the present review, we discuss how the presence of ERβ and the previously described ERα in tissues involved in glucose and lipid homeostasis (brain, skeletal muscle, adipose tissue, pancreas, liver, and heart) may have important implications to risk factors associated with the metabolic syndrome. Imbalance of ERα/ERβ ratio in this "metabolic network" may lead to the metabolic syndrome. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Estrogen regulates spatially distinct cardiac mitochondrial subpopulations.

    PubMed

    Ribeiro Junior, Rogério Faustino; Rodrigues, Paula Lopes; Morra, Elis Aguiar; Ronconi, Karoline Sousa; Do Val Lima, Patrícia Ribeiro; Porto, Marcella Leite; Simões, Maylla Ronacher; Vassallo, Dalton Valentim; Figueiredo, Suely Gomes; Stefanon, Ivanita

    2017-07-01

    Increased susceptibility to permeability transition pore (mPTP) is a significant concern to decreased cardiac performance in postmenopausal females. The goal of this study was to assess the effects of estrogen deficiency on the two spatially distinct mitochondrial subpopulations from left ventricle: subsarcolemmal mitochondria (SSM) and intermyofibrillar mitochondria (IFM) based on: morphology, membrane potential, oxidative phosphorylation, mPTP and reactive oxygen species production. Female rats (8weeks old) that underwent bilateral ovariectomy were randomly assigned to receive daily treatment with placebo (OVX), estrogen replacement (OVX+E2) and Sham for 60days. The yield for IFM was found higher in the OVX group and lower in the SSM. SSM internal complexity and size were higher in the OVX group, although membrane potential was not different. The maximal rate of mitochondrial respiration, states 3 and 4, using glutamate+malate as substrate, were higher in IFM and SSM from the OVX group. The respiratory control ratio (RCR - state3/state 4), was not different in both SSM and IFM with glutamate+malate. The ADP:O ratio was found lower in IFM and SSM from OVX compared to Sham. When pyruvate was used, state 3 was found unchanged in both IFM and SSM, state 4 was greater in IFM from OVX rats compared to Sham and the ADP/O ratio was decreased. The RCR was unchanged in both subpopulations. The IFM from OVX rats presented a lower Ca 2+ retention capacity compared to Sham, however, the SSM remained unchanged. Hydrogen peroxide formation was found increased in the IFM from OVX animals with glutamate+malate and rotenone+succinate as substrates. The SSM showed increased ROS production only with rotenone+succinate. Western blot analyzes showed decreased levels of PGC-1α and NRF-1 in the OVX group. Estrogen replacement was able to restore most of the alterations induced by ovariectomy. In conclusion, our data shows that estrogen deficiency has distinct effects on the two

  6. Estrogen signaling is not required for prostatic bud patterning or for its disruption by 2,3,7,8-tetrachlorodibenzo-p-dioxin

    SciTech Connect

    Allgeier, Sarah Hicks; Vezina, Chad M.; Lin, T.-M.

    2009-08-15

    Estrogens play an important role in prostatic development, health, and disease. While estrogen signaling is essential for normal postnatal prostate development, little is known about its prenatal role in control animals. We tested the hypothesis that estrogen signaling is needed for normal male prostatic bud patterning. Budding patterns were examined by scanning electron microscopy of urogenital sinus epithelium from wild-type mice, mice lacking estrogen receptor (ER){alpha}, ER{beta}, or both, and wild-type mice exposed to the antiestrogen ICI 182,780. Budding phenotypes did not detectably differ among any of these groups, strongly suggesting that estrogen signaling is not needed to establish themore » prototypical prostatic budding pattern seen in control males. This finding contributes to our understanding of the effects of low-level estrogen exposure on early prostate development. In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can greatly alter the pattern in which prostatic buds form and reduce their number. For several reasons, including a prior observation that inhibitory effects of TCDD on prostatic budding in rats depend heavily on the sex of adjacent fetuses, we tested the hypothesis that estrogen signaling is needed for TCDD to disrupt prostatic budding. However, budding did not detectably differ among wild-type mice, or mice lacking ER{alpha}, ER{beta}, or both, that were exposed prenatally to TCDD (5 {mu}g/kg on embryonic day 13.5). Nor did ICI 182,780 detectably affect the response to TCDD. These results strongly suggest that estrogen signaling is not needed for TCDD to inhibit prostatic epithelial budding.« less

  7. 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

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

    PubMed

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

    2015-08-01

    Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. 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. Compared with women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16α-hydroxyestrone (28% difference; Ptrend = 0.01) and 16-epiestriol (13% difference; Ptrend = 0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (Ptrend = 0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, ≥4 cups/day vs. ≤6 cups/week; Ptrend = 0.001) and 2-hydroxyestrone (52% difference; Ptrend = 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; Ptrend = 0.01) and 17-epiestriol (48% difference; Ptrend = 0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; Ptrend = 0.01). Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism. ©2015 American Association for Cancer Research.

  9. Importance of extranuclear estrogen receptor-alpha and membrane G protein-coupled estrogen receptor in pancreatic islet survival.

    PubMed

    Liu, Suhuan; Le May, Cedric; Wong, Winifred P S; Ward, Robert D; Clegg, Deborah J; Marcelli, Marco; Korach, Kenneth S; Mauvais-Jarvis, Franck

    2009-10-01

    We showed that 17beta-estradiol (E(2)) favors pancreatic beta-cell survival via the estrogen receptor-alpha (ERalpha) in mice. E(2) activates nuclear estrogen receptors via an estrogen response element (ERE). E(2) also activates nongenomic signals via an extranuclear form of ERalpha and the G protein-coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival. We used mice and islets deficient in estrogen receptor-alpha (alphaERKO(-/-)), estrogen receptor-beta (betaERKO(-/-)), estrogen receptor-alpha and estrogen receptor-beta (alphabetaERKO(-/-)), and GPER (GPERKO(-/-)); a mouse lacking ERalpha binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes. We show that ERalpha protection of islet survival is ERE independent and that E(2) favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERbeta plays a minor cytoprotective role compared to ERalpha. Accordingly, betaERKO(-/-) mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERalpha and ERbeta in mice does not synergize to provoke islet apoptosis. In alphabetaERKO(-/-) mice and their islets, E(2) partially prevents apoptosis suggesting that an alternative pathway compensates for ERalpha/ERbeta deficiency. We find that E(2) protection of islet survival is reproduced by a membrane-impermeant E(2) formulation and a selective GPER agonist. Accordingly, GPERKO(-/-) mice are susceptible to streptozotocin-induced insulin deficiency. E(2) protects beta-cell survival through ERalpha and ERbeta via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in beta-cells and identifies GPER as a target to protect islet survival.

  10. Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival

    PubMed Central

    Liu, Suhuan; Le May, Cedric; Wong, Winifred P.S.; Ward, Robert D.; Clegg, Deborah J.; Marcelli, Marco; Korach, Kenneth S.; Mauvais-Jarvis, Franck

    2009-01-01

    OBJECTIVE We showed that 17β-estradiol (E2) favors pancreatic β-cell survival via the estrogen receptor-α (ERα) in mice. E2 activates nuclear estrogen receptors via an estrogen response element (ERE). E2 also activates nongenomic signals via an extranuclear form of ERα and the G protein–coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival. RESEARCH DESIGN AND METHODS We used mice and islets deficient in estrogen receptor-α (αERKO−/−), estrogen receptor-β (βERKO−/−), estrogen receptor-α and estrogen receptor-β (αβERKO−/−), and GPER (GPERKO−/−); a mouse lacking ERα binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes. RESULTS We show that ERα protection of islet survival is ERE independent and that E2 favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERβ plays a minor cytoprotective role compared to ERα. Accordingly, βERKO−/− mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERα and ERβ in mice does not synergize to provoke islet apoptosis. In αβERKO−/− mice and their islets, E2 partially prevents apoptosis suggesting that an alternative pathway compensates for ERα/ERβ deficiency. We find that E2 protection of islet survival is reproduced by a membrane-impermeant E2 formulation and a selective GPER agonist. Accordingly, GPERKO−/− mice are susceptible to streptozotocin-induced insulin deficiency. CONCLUSIONS E2 protects β-cell survival through ERα and ERβ via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in β-cells and identifies GPER as a target to protect islet survival. PMID:19587358

  11. 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.

  12. Nonylphenol and estrogenic activity in aquatic environmental samples

    SciTech Connect

    Tanghe, T.; Devriese, G.; Verstraete, W.

    1999-03-01

    The authors surveyed a series of surface waters and sewage treatment plants in Flanders (north of Belgium) for the presence of estrogenic activity and a xeno-estrogenic compound para-nonylphenol (NP), respectively. The surface waters of rural origin, used for drinking water production were free of significant levels of estrogenic activity and NP. Domestic sewage, after proper treatment, appeared to be no major source of this chemical. Yet, in some industrial effluents and surface waters of highly industrialized regions, NP and/or estrogenic activity was prominent, that is, <1 to 122 {micro}g NP/L and 11 to 42 {micro}g NP/L, respectively. This is becausemore » of the ongoing use of NP polyethoxylates in industry. The response of the recombinant yeast estrogen assay to the environmental samples tested was not consistent with the detected concentrations of NP. Standard addition of a natural estrogen, 17{beta}-estradiol, generated no or a reduced response compared to the standard curve concentration. Application of humic acids to standard series of NP and 17{beta}-estradiol resulted in a dose-dependent decrease of the estrogenic response. It appears that this bioassay is subject to considerable interferences due to the complexity of environmental samples. Parallel implementation of extensive chemical screening for xenobiotics and use of the bioassay are needed for adequate assessment of the potential estrogenic hazard to avoid false negative evaluations.« less

  13. Estrogen receptor α is required for oviductal transport of embryos

    PubMed Central

    Li, Shuai; O’Neill, Sofia R. S.; Zhang, Yong; Holtzman, Michael J.; Takemaru, Ken-Ichi; Korach, Kenneth S.; Winuthayanon, Wipawee

    2017-01-01

    Newly fertilized embryos spend the first few days within the oviduct and are transported to the uterus, where they implant onto the uterine wall. An implantation of the embryo before reaching the uterus could result in ectopic pregnancy and lead to maternal death. Estrogen is necessary for embryo transport in mammals; however, the mechanism involved in estrogen-mediated cellular function within the oviduct remains unclear. In this study, we show in mouse models that ciliary length and beat frequency of the oviductal epithelial cells are regulated through estrogen receptor α (ESR1) but not estrogen receptor β (ESR2). Gene profiling indicated that transcripts in the WNT/β-catenin (WNT/CTNNB1) signaling pathway were regulated by estrogen in mouse oviduct, and inhibition of this pathway in a whole oviduct culture system resulted in a decreased embryo transport distance. However, selective ablation of CTNNB1 from the oviductal ciliated cells did not affect embryo transport, possibly because of a compensatory mechanism via intact CTNNB1 in the adjacent secretory cells. In summary, we demonstrated that disruption of estrogen signaling in oviductal epithelial cells alters ciliary function and impairs embryo transport. Therefore, our findings may provide a better understanding of etiology of the ectopic pregnancy that is associated with alteration of estrogen signals.—Li, S., O’Neill, S. R. S., Zhang, Y., Holtzman, M. J., Takemaru, K.-I., Korach, K. S., Winuthayanon, W. Estrogen receptor α is required for oviductal transport of embryos. PMID:28082352

  14. 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)...

  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. Genetic variation in sensitivity to estrogens and breast cancer risk

    USDA-ARS?s Scientific Manuscript database

    Breast cancer risk is intertwined with exposure to estrogens. While more than 160 breast cancer risk loci have been identified in humans, genetic interactions with estrogen exposure remain to be established. Strains of rodents exhibit striking differences in their responses to endogenous ovarian est...

  17. Estrogen synthesis and signaling pathways during ageing: from periphery to brain

    PubMed Central

    Cui, Jie; Shen, Yong; Li, Rena

    2012-01-01

    Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non-reproductive tissue as liver, heart, muscle, bone and brain. The tissue-specific estrogen synthesis is consistent with a diversity of estrogen actions. Here, we will focus on tissue and cell-specific estrogen synthesis and estrogen receptor signaling. This review will include three parts: (I) tissue and cell-specific estrogen synthesis and metabolism, (II) tissue and cell-specific distribution of estrogen receptors and signaling and (III) tissue-specific estrogen function and related disorders, including cardiovascular diseases, osteoporosis, Alzheimer's disease and Parkinson disease. This comprehensive review provides new insights into estrogens by giving a better understanding of the tissue-specific estrogen effects and their roles in various diseases. PMID:23348042

  18. Estrogen, Angiogenesis, Immunity and Cell Metabolism: Solving the Puzzle.

    PubMed

    Trenti, Annalisa; Tedesco, Serena; Boscaro, Carlotta; Trevisi, Lucia; Bolego, Chiara; Cignarella, Andrea

    2018-03-15

    Estrogen plays an important role in the regulation of cardiovascular physiology and the immune system by inducing direct effects on multiple cell types including immune and vascular cells. Sex steroid hormones are implicated in cardiovascular protection, including endothelial healing in case of arterial injury and collateral vessel formation in ischemic tissue. Estrogen can exert potent modulation effects at all levels of the innate and adaptive immune systems. Their action is mediated by interaction with classical estrogen receptors (ERs), ERα and ERβ, as well as the more recently identified G-protein coupled receptor 30/G-protein estrogen receptor 1 (GPER1), via both genomic and non-genomic mechanisms. Emerging data from the literature suggest that estrogen deficiency in menopause is associated with an increased potential for an unresolved inflammatory status. In this review, we provide an overview through the puzzle pieces of how 17β-estradiol can influence the cardiovascular and immune systems.

  19. Estrogen replacement therapy, Alzheimer's disease, and mild cognitive impairment.

    PubMed

    Mulnard, Ruth A; Corrada, Marìa M; Kawas, Claudia H

    2004-09-01

    This article highlights the latest findings regarding estrogen replacement therapy in the treatment and prevention of Alzheimer's disease (AD) and mild cognitive impairment in women. Despite considerable evidence from observational studies, recent randomized clinical trials of conjugated equine estrogens, alone and in combination with progestin, have shown no benefit for either the treatment of established AD or for the short-term prevention of AD, mild cognitive impairment, or cognitive decline. Based on the evidence, there is no role at present for estrogen replacement therapy in the treatment or prevention of AD or cognitive decline, despite intriguing results from the laboratory and from observational studies. However, numerous questions remain about the biologic effects of estrogens on brain structure and function. Additional basic and clinical investigations are necessary to examine different forms and dosages of estrogens, other populations, and the relevance of timing and duration of exposure.

  20. Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients

    PubMed Central

    Hu, Xiaolei

    2018-01-01

    Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs). IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS). The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS. PMID:29233817

  1. Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients.

    PubMed

    Hu, Xiaolei; Chen, Fengling

    2018-01-01

    Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs). IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS). The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS. © 2018 The authors.

  2. Status of estrogen receptor 1 (ESR1) gene in mastopathy predicts subsequent development of breast cancer.

    PubMed

    Soysal, Savas D; Kilic, Incken B; Regenbrecht, Christian R A; Schneider, Sandra; Muenst, Simone; Kilic, Nerbil; Güth, Uwe; Dietel, Manfred; Terracciano, Luigi M; Kilic, Ergin

    2015-06-01

    Mastopathy is a common disease of the breast likely associated with elevated estrogen levels and a putative risk factor for breast cancer. The role of estrogen receptor alpha (ESR1) in mastopathy has not been investigated previously. Here, we investigated the prevalence of ESR1 gene amplification in mastopathy and its prediction for breast cancer. Paraffin-embedded tissues from 58 women with invasive breast cancer were analyzed. For all women, tissues with mastopathy taken at least 1.5 years before first diagnosis of breast cancer were available. Tissue from 46 women with mastopathy without a diagnosis of breast carcinoma in the observed time frame (12-18 years) was used as control. Fluorescence in situ hybridization analysis revealed that ESR1 was amplified in nine of 58 (15.5 %) breast cancers. All ESR1-amplified breast cancers were strongly positive for estrogen receptor with ER immunohistochemistry. Interestingly, in women with ESR1 amplification in breast cancer, the amplification was detectable in mastopathic tissues prior to the first diagnosis of breast cancer but was absent in tissues from women with mastopathy who did not develop breast cancer. Our study suggests that ESR1 gene amplification is an early event in breast pathology and might be a helpful predictive marker to identify patients at high risk of developing breast cancer.

  3. Window Of Opportunity: Estrogen As A Treatment For Ischemic Stroke✰

    PubMed Central

    Liu, Ran; Yang, Shao-Hua

    2013-01-01

    The neuroprotection research in the last 2 decades has witnessed a growing interest in the functions of estrogens as neuroprotectants against neurodegenerative diseases including stroke. The neuroprotective action of estrogens has been well demonstrated in both in vitro and in vivo models of ischemic stroke. However, the major conducted clinical trials so far have raised concern for the protective effect of estrogen replacement therapy in postmenopausal women. The discrepancy could be partly due to the mistranslation between the experimental stroke research and clinical trials. While predominant experimental studies tested the protective action of estrogens on ischemic stroke using acute treatment paradigm, the clinical trials have mainly focused on the effect of estrogen replacement therapy on the primary and secondary stroke prevention which has not been adequately addressed in the experimental stroke study. Although the major conducted clinical trials have indicated that estrogen replacement therapy has an adverse effect and raise concern for long term estrogen replacement therapy for stroke prevention, these are not appropriate for assessing the potential effects of acute estrogen treatment on stroke protection. The well established action of estrogen in the neurovascular unit and its potential interaction with recombinant tissue plasminogen activator (rtPA) makes it a candidate for the combined therapy with rtPA for the acute treatment of ischemic stroke. On the other hand, the “critical period” and newly emerged “biomarkers window” hypotheses have indicated that many clinical relevant factors have been underestimated in the experimental ischemic stroke research. The development and application of ischemic stroke models that replicate the clinical condition is essential for further evaluation of acute estrogen treatment on ischemic stroke which might provide critical information for future clinical trials. PMID:23340160

  4. The human oxytocin gene promoter is regulated by estrogens.

    PubMed

    Richard, S; Zingg, H H

    1990-04-15

    Gonadal steroids affect brain function primarily by altering the expression of specific genes, yet the specific mechanisms by which neuronal target genes undergo such regulation are unknown. Recent evidence suggests that the expression of the neuropeptide gene for oxytocin (OT) is modulated by estrogens. We therefore examined the possibility that this regulation occurred via a direct interaction of the estrogen-receptor complex with cis-acting elements flanking the OT gene. DNA-mediated gene transfer experiments were performed using Neuro-2a neuroblastoma cells and chimeric plasmids containing portions of the human OT gene 5'-glanking region linked to the chloramphenicol acetyltransferase gene. We identified a 19-base pair region located at -164 to -146 upstream of the transcription start site which is capable of conferring estrogen responsiveness to the homologous as well as to a heterologous promoter. The hormonal response is strictly dependent on the presence of intracellular estrogen receptors, since estrogen induced stimulation occurred only in Neuro-2a cells co-transfected with an expression vector for the human estrogen receptor. The identified region contains a novel imperfect palindrome (GGTGACCTTGACC) with sequence similarity to other estrogen response elements (EREs). To define cis-acting elements that function in synergism with the ERE, sequences 3' to the ERE were deleted, including the CCAAT box, two additional motifs corresponding to the right half of the ERE palindrome (TGACC), as well as a CTGCTAA heptamer similar to the "elegans box" found in Caenorhabditis elegans. Interestingly, optimal function of the identified ERE was fully independent of these elements and only required a short promoter region (-49 to +36). Our studies define a molecular mechanism by which estrogens can directly modulate OT gene expression. However, only a subset of OT neurons are capable of binding estrogens, therefore, direct action of estrogens on the OT gene may be

  5. Mechanism of estrogen activation of c-myc oncogene expression.

    PubMed

    Dubik, D; Shiu, R P

    1992-08-01

    The estrogen receptor complex is a known trans-acting factor that regulates transcription of specific genes through an interaction with a specific estrogen-responsive cis-acting element (ERE). In previous studies we have shown that in estrogen-responsive human breast cancer cells estrogen rapidly activates c-myc expression. This activated expression occurs through enhanced transcription and does not require the synthesis of new protein intermediates; therefore, an ERE is present in the human c-myc gene regulatory region. To localize the ERE, constructs containing varying lengths of the c-myc 5'-flanking region ranging from -2327 to +25 (relative to the P1 promoter) placed adjacent to the chloramphenicol acetyl transferase reporter gene (CAT) were prepared. They were used in transient transfection studies in MCF-7 and HeLa cells co-transfected with an estrogen receptor expression vector. These studies reveal that all constructs containing the P2 promoter region exhibited estrogen-regulated CAT expression and that a 116-bp region upstream and encompassing the P2 TATA box is necessary for this activity. Analysis of this 116-bp region failed to identify a cis-acting element with sequences resembling the consensus ERE; however, co-transfection studies with mutant estrogen receptor expression vectors showed that the DNA-binding domain of the receptor is essential for estrogen-regulated CAT gene expression. We have also observed that anti-estrogen receptor complexes can weakly trans-activate from this 116-bp region but fail to do so from the ERE-containing ApoVLDLII-CAT construct. To explain these results we propose a new mechanism of estrogen trans-activation in the c-myc gene promoter.

  6. Postmenopausal estrogen and progestin effects on the serum proteome

    PubMed Central

    2009-01-01

    Background Women's Health Initiative randomized trials of postmenopausal hormone therapy reported intervention effects on several clinical outcomes, with some important differences between estrogen alone and estrogen plus progestin. The biologic mechanisms underlying these effects, and these differences, have yet to be fully elucidated. Methods Baseline serum samples were compared with samples drawn 1 year later for 50 women assigned to active hormone therapy in both the estrogen-plus-progestin and estrogen-alone randomized trials, by applying an in-depth proteomic discovery platform to serum pools from 10 women per pool. Results In total, 378 proteins were quantified in two or more of the 10 pooled serum comparisons, by using strict identification criteria. Of these, 169 (44.7%) showed evidence (nominal P < 0.05) of change in concentration between baseline and 1 year for one or both of estrogen-plus-progestin and estrogen-alone groups. Quantitative changes were highly correlated between the two hormone-therapy preparations. A total of 98 proteins had false discovery rates < 0.05 for change with estrogen plus progestin, compared with 94 for estrogen alone. Of these, 84 had false discovery rates <0.05 for both preparations. The observed changes included multiple proteins relevant to coagulation, inflammation, immune response, metabolism, cell adhesion, growth factors, and osteogenesis. Evidence of differential changes also was noted between the hormone preparations, with the strongest evidence in growth factor and inflammation pathways. Conclusions Serum proteomic analyses yielded a large number of proteins similarly affected by estrogen plus progestin and by estrogen alone and identified some proteins and pathways that appear to be differentially affected between the two hormone preparations; this may explain their distinct clinical effects. PMID:20034393

  7. Do Endogenous and Exogenous Action Control Compete for Perception?

    ERIC Educational Resources Information Center

    Pfister, Roland; Heinemann, Alexander; Kiesel, Andrea; Thomaschke, Roland; Janczyk, Markus

    2012-01-01

    Human actions are guided either by endogenous action plans or by external stimuli in the environment. These two types of action control seem to be mediated by neurophysiologically and functionally distinct systems that interfere if an endogenously planned action suddenly has to be performed in response to an exogenous stimulus. In this case, the…

  8. Endogenous versus Exogenous Growth Factor Regulation of Articular Chondrocytes

    PubMed Central

    Shi, Shuiliang; Chan, Albert G.; Mercer, Scott; Eckert, George J.; Trippel, Stephen B.

    2014-01-01

    Anabolic growth factors that regulate the function of articular chondrocytes are candidates for articular cartilage repair. Such factors may be delivered by pharmacotherapy in the form of exogenous proteins, or by gene therapy as endogenous proteins. It is unknown whether delivery method influences growth factor effectiveness in regulating articular chondrocyte reparative functions. We treated adult bovine articular chondrocytes with exogenous recombinant insulin-like growth factor-I (IGF-I) and transforming growth factor-beta1 (TGF-β1), or with the genes encoding these growth factors for endogenous production. Treatment effects were measured as change in chondrocyte DNA content, glycosaminoglycan production, and aggrecan gene expression. We found that IGF-I stimulated chondrocyte biosynthesis similarly when delivered by either exogenous or endogenous means. In contrast, exogenous TGF-ß1 stimulated these reparative functions, while endogenous TGF-ß1 had little effect. Endogenous TGF-ß1 became more bioactive following activation of the transgene protein product. These data indicate that effective mechanisms of growth factor delivery for articular cartilage repair may differ for different growth factors. In the case of IGF-I, gene therapy or protein therapy appear to be viable options. In contrast, TGF-ß1 gene therapy may be constrained by a limited ability of chondrocytes to convert latent complexes to an active form. PMID:24105960

  9. Do endogenous and exogenous action control compete for perception?

    PubMed

    Pfister, Roland; Heinemann, Alexander; Kiesel, Andrea; Thomaschke, Roland; Janczyk, Markus

    2012-04-01

    Human actions are guided either by endogenous action plans or by external stimuli in the environment. These two types of action control seem to be mediated by neurophysiologically and functionally distinct systems that interfere if an endogenously planned action suddenly has to be performed in response to an exogenous stimulus. In this case, the endogenous representation has to be deactivated first to give way to the exogenous system. Here we show that interference of endogenous and exogenous action control is not limited to motor-related aspects but also affects the perception of action-related stimuli. Participants associated two actions with contingent sensory effects in learning blocks. In subsequent test blocks, preparing one of these actions specifically impaired responding to the associated effect in an exogenous speeded detection task, yielding a blindness-like effect for arbitrary, learned action effects. In accordance with the theory of event coding, this finding suggests that action planning influences perception even in the absence of any physical similarities between action and to-be-perceived stimuli.

  10. Exogenous ethylene inhibits sprout growth in onion bulbs.

    PubMed

    Bufler, Gebhard

    2009-01-01

    Exogenous ethylene has recently gained commercial interest as a sprouting inhibitor of onion bulbs. The role of ethylene in dormancy and sprouting of onions, however, is not known. A cultivar (Allium cepa 'Copra') with a true period of dormancy was used. Dormant and sprouting states of onion bulbs were treated with supposedly saturating doses of ethylene or with the ethylene-action inhibitor 1-methylcyclopropene (1-MCP). Initial sprouting was determined during storage at 18 degrees C by monitoring leaf blade elongation in a specific size class of leaf sheaths. Changes in ATP content and sucrose synthase activity in the sprout leaves, indicators of the sprouting state, were determined. CO(2) and ethylene production of onion bulbs during storage were recorded. Exogenous ethylene suppressed sprout growth of both dormant and already sprouting onion bulbs by inhibiting leaf blade elongation. In contrast to this growth-inhibiting effect, ethylene stimulated CO(2) production by the bulbs about 2-fold. The duration of dormancy was not significantly affected by exogenous ethylene. However, treatment of dormant bulbs with 1-MCP caused premature sprouting. Exogenous ethylene proved to be a powerful inhibitor of sprout growth in onion bulbs. The dormancy breaking effect of 1-MCP indicates a regulatory role of endogenous ethylene in onion bulb dormancy.

  11. Exogenous ethylene inhibits sprout growth in onion bulbs

    PubMed Central

    Bufler, Gebhard

    2009-01-01

    Background and Aims Exogenous ethylene has recently gained commercial interest as a sprouting inhibitor of onion bulbs. The role of ethylene in dormancy and sprouting of onions, however, is not known. Methods A cultivar (Allium cepa ‘Copra’) with a true period of dormancy was used. Dormant and sprouting states of onion bulbs were treated with supposedly saturating doses of ethylene or with the ethylene-action inhibitor 1-methylcyclopropene (1-MCP). Initial sprouting was determined during storage at 18 °C by monitoring leaf blade elongation in a specific size class of leaf sheaths. Changes in ATP content and sucrose synthase activity in the sprout leaves, indicators of the sprouting state, were determined. CO2 and ethylene production of onion bulbs during storage were recorded. Key results Exogenous ethylene suppressed sprout growth of both dormant and already sprouting onion bulbs by inhibiting leaf blade elongation. In contrast to this growth-inhibiting effect, ethylene stimulated CO2 production by the bulbs about 2-fold. The duration of dormancy was not significantly affected by exogenous ethylene. However, treatment of dormant bulbs with 1-MCP caused premature sprouting. Conclusions Exogenous ethylene proved to be a powerful inhibitor of sprout growth in onion bulbs. The dormancy breaking effect of 1-MCP indicates a regulatory role of endogenous ethylene in onion bulb dormancy. PMID:18940850

  12. Endogenous versus exogenous generic reference pricing for pharmaceuticals.

    PubMed

    Antoñanzas, F; Juárez-Castelló, C A; Rodríguez-Ibeas, R

    2017-12-01

    In this paper we carry out a vertical differentiation duopoly model applied to pharmaceutical markets to analyze how endogenous and exogenous generic reference pricing influence competition between generic and branded drugs producers. Unlike the literature, we characterize for the exogenous case the equilibrium prices for all feasible relevant reference prices. Competition is enhanced after the introduction of a reference pricing system. We also compare both reference pricing systems on welfare grounds, assuming two different objective functions for health authorities: (i) standard social welfare and (ii) gross consumer surplus net of total pharmaceutical expenditures. We show that regardless of the objective function, health authorities will never choose endogenous reference pricing. When health authorities are paternalistic, the exogenous reference price that maximizes standard social welfare is such that the price of the generic drug is the reference price while the price of the branded drug is higher than the reference price. When health authorities are not paternalistic, the optimal exogenous reference price is such that the price of the branded drug is the reference price while the price of the generic drug is lower than the reference price.

  13. Accounting for Exogenous Influences in Performance Evaluations of Teachers

    ERIC Educational Resources Information Center

    De Witte, Kristof; Rogge, Nicky

    2011-01-01

    Students' evaluations of teacher performance (SETs) are increasingly used by universities. However, SETs are controversial mainly due to two issues: (1) teachers value various aspects of excellent teaching differently, and (2) SETs should not be determined on exogenous influences. Therefore, this paper constructs SETs using a tailored version of…

  14. Interactions between the cytomegalovirus promoter and the estrogen response element: implications for design of estrogen-responsive reporter plasmids.

    PubMed

    Derecka, K; Wang, C K; Flint, A P F

    2006-07-01

    We aimed to produce an estrogen-responsive reporter plasmid that would permit monitoring of estrogen receptor function in the uterus in vivo. The plasmid pBL-tk-CAT(+)ERE was induced by estrogen in bovine endometrial stromal cells. When the CAT gene was replaced by the secreted alkaline phosphatase SeAP, the resulting construct pBL-tk-SeAP(+)ERE remained estrogen responsive. However when the tk promoter was replaced by the cytomegalovirus (cmv) promoter, the resulting plasmid (pBL-cmv-SeAP(+)ERE) was not estrogen responsive. Inhibition of ERE function was not due to an effect in trans or due to lack of estrogen receptor. It was not due to an interaction between the cmv promoter and the SeAP gene. cmv promoter function was dependent on NF-kappaB, and mutagenesis in the NF-kappaB sites reduced basal reporter expression without imparting responsiveness to estrogen. A mutation in the TATA box also failed to impart estrogen responsiveness. Modeling of DNA accessibility indicated the ERE was inserted at a site accessible to transcription factors. We conclude that the cmv promoter inhibits ERE function in cis when the two sequences are located in the same construct, and that this effect does not involve an interaction between cmv and reporter gene, NF-kappaB sites or the TATA box, or DNA inaccessibility.

  15. CERAPP: Collaborative Estrogen Receptor Activity Prediction ...

    EPA Pesticide Factsheets

    Humans potentially 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. Many of these chemicals never have been tested for their ability to interact with the estrogen receptor (ER). Risk assessors need tools to prioritize chemicals for assessment in costly in vivo tests, for instance, within the EPA Endocrine Disruptor Screening Program. Here, we describe a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) demonstrating the efficacy of using predictive computational models on high-throughput screening data to screen thousands of chemicals against the ER. CERAPP combined multiple models developed in collaboration among 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 1677 compounds provided by EPA, to build a total of 40 categorical and 8 continuous models for binding, agonist, and antagonist ER activity. All predictions were tested using an evaluation set of 7522 chemicals collected from the literature. To overcome the limitations of single models, a consensus was built weighting models using a scoring function (0 to 1) based on their accuracies. Individual model scores ranged from 0.69 to 0.85, showing

  16. Epigenetic regulation of estrogen-dependent memory

    PubMed Central

    Fortress, Ashley M.; Frick, Karyn M.

    2014-01-01

    Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E2) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E2, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E2 and other hormones employ epigenetic alterations to shape behavior. This review discusses the epigenetic alterations shown thus far to regulate hippocampal memory, briefly reviews the effects of E2 on hippocampal function, and describes in detail our work on epigenetic regulation of estrogenic memory enhancement. PMID:24878494

  17. Androgens and estrogens in skeletal sexual dimorphism

    PubMed Central

    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 refined 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 deficiency 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 field of sex steroid actions in male bone homeostasis. PMID:24385015

  18. Epigenetic regulation of estrogen-dependent memory.

    PubMed

    Fortress, Ashley M; Frick, Karyn M

    2014-10-01

    Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E2) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E2, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E2 and other hormones employ epigenetic alterations to shape behavior. This review discusses the epigenetic alterations shown thus far to regulate hippocampal memory, briefly reviews the effects of E2 on hippocampal function, and describes in detail our work on epigenetic regulation of estrogenic memory enhancement. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. The analgesic effects of exogenous melatonin in humans.

    PubMed

    Andersen, Lars Peter Holst

    2016-10-01

    The hormone, melatonin is produced with circadian rhythm by the pineal gland in humans. The melatonin rhythm provides an endogenous synchronizer, modulating e.g. blood pressure, body temperature, cortisol rhythm, sleep-awake-cycle, immune function and anti-oxidative defence. Interestingly, a number of experimental animal studies demonstrate significant dose-dependent anti-nociceptive effects of exogenous melatonin. Similarly, recent experimental- and clinical studies in humans indicate significant analgesic effects. In study I, we systematically reviewed all randomized studies investigating clinical effects of perioperative melatonin. Meta-analyses demonstrated significant analgesic and anxiolytic effects of melatonin in surgical patients, equating reductions of 20 mm and 19 mm, respectively on a VAS, compared with placebo. Profound heterogeneity between the included studies was, however, present. In study II, we aimed to investigate the analgesic, anti-hyperalgesic and anti-inflammatory effects of exogenous melatonin in a validated human inflammatory pain model, the human burn model. The study was performed as a randomized, double blind placebo-controlled crossover study. Primary outcomes were pain during the burn injury and areas of secondary hyperalgesia. No significant effects of exogenous melatonin were observed with respect to primary or secondary outcomes, compared to placebo. Study III and IV estimated the pharmacokinetic variables of exogenous melatonin. Oral melatonin demonstrated a t max value of 41 minutes. Bioavailability of oral melatonin was only 3%. Elimination t 1/2 were approximately 45 minutes following both oral and intravenous administration, respectively. High-dose intravenous melatonin was not associated with increased sedation, in terms of simple reaction times, compared to placebo. Similarly, no other adverse effects were reported. In Study V, we aimed to re-analyse data obtained from a randomized analgesic drug trial by a selection of

  20. Estrogen-mediated inactivation of FOXO3a by the G protein-coupled estrogen receptor GPER.

    PubMed

    Zekas, Erin; Prossnitz, Eric R

    2015-10-15

    Estrogen (17β-estradiol) promotes the survival and proliferation of breast cancer cells and its receptors represent important therapeutic targets. The cellular actions of estrogen are mediated by the nuclear estrogen receptors ERα and ERβ as well as the 7-transmembrane spanning G protein-coupled estrogen receptor (GPER). We previously reported that estrogen activates the phosphoinositide 3-kinase (PI3Kinase) pathway via GPER, resulting in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production within the nucleus of breast cancer cells; however, the mechanisms and consequences of this activity remained unclear. MCF7 breast cancer cells were transfected with GFP-fused Forkhead box O3 (FOXO3) as a reporter to assess localization in response to estrogen stimulation. Inhibitors of PI3Kinases and EGFR were employed to determine the mechanisms of estrogen-mediated FOXO3a inactivation. Receptor knockdown with siRNA and the selective GPER agonist G-1 elucidated the estrogen receptor(s) responsible for estrogen-mediated FOXO3a inactivation. The effects of selective estrogen receptor modulators and downregulators (SERMs and SERDs) on FOXO3a in MCF7 cells were also determined. Cell survival (inhibition of apoptosis) was assessed by caspase activation. In the estrogen-responsive breast cancer cell line MCF7, FOXO3a inactivation occurs on a rapid time scale as a result of GPER, but not ERα, stimulation by estrogen, established by the GPER-selective agonist G-1 and knockdown of GPER and ERα. GPER-mediated inactivation of FOXO3a is effected by the p110α catalytic subunit of PI3Kinase as a result of transactivation of the EGFR. The SERMs tamoxifen and raloxifene, as well as the SERD ICI182,780, were active in mediating FOXO3a inactivation in a GPER-dependent manner. Additionally, estrogen-and G-1-mediated stimulation of MCF7 cells results in a decrease in caspase activation under proapoptotic conditions. Our results suggest that non-genomic signaling by GPER contributes

  1. Comparison of metabolic ratios of urinary estrogens between benign and malignant thyroid tumors in postmenopausal women

    PubMed Central

    2013-01-01

    Background Estrogen metabolism may be associated with the pathophysiological development of papillary thyroid carcinoma (PTC). Methods To evaluate the differential estrogen metabolism between benign and malignant PTCs, estrogen profiling by gas chromatography–mass spectrometry was applied to urine samples from postmenopausal patients with 9 benign tumors and 18 malignant stage I and III/IV PTCs. Results The urinary concentration of 2-methoxyestradiol was significantly lower in the stage I malignant patients (3.5-fold; P < 0.025) than in the benign group. The metabolic ratios of 16α-OH-estrone/estrone and estriol/estradiol, which are responsible for 16α-hydroxylase activity, were increased more than 2.5-fold in the advanced-stage malignant PTC (P < 0.02 each). The more than 6.2-fold decrease in the urinary 2-/16α-hydroxylase ratio in stage III/IV malignant PTC was consistent with the ratio in postmenopausal patients with endocrine gland cancers. In addition, reductive 17β-hydroxysteroid dehydrogenase (17β-HSD; estradiol/estrone or estriol/16α-OH-estrone) was present at significantly higher levels in subjects with stage III/IV malignant PTCs than in benign subjects (>3.5-fold difference; P < 0.002). In particular, the estriol/16α-OH-estrone ratio differentiated between the benign and early-stage malignant patients (P < 0.01). Conclusions Increased 16α-hydroxylation and/or a decreased 2-/16α-ratio, as well increased reductive 17β-HSD, with regard to estrogen metabolism could provide potential biomarkers. The devised profiles could be useful for differentiating malignant thyroid carcinomas from benign adenomas in postmenopausal women. PMID:24156385

  2. The role of estrogens and estrogen receptor signaling pathways in cancer and infertility: the case of schistosomes.

    PubMed

    Botelho, Mónica C; Alves, Helena; Barros, Alberto; Rinaldi, Gabriel; Brindley, Paul J; Sousa, Mário

    2015-06-01

    Schistosoma haematobium, a parasitic flatworm that infects more than 100 million people, mostly in the developing world, is the causative agent of urogenital schistosomiasis, and is associated with a high incidence of squamous cell carcinoma (SCC) of the bladder. Schistosomiasis haematobia also appears to negatively influence fertility, and is particularly associated with female infertility. Given that estrogens and estrogen receptors are key players in human reproduction, we speculate that schistosome estrogen-like molecules may contribute to infertility through hormonal imbalances. Here, we review recent findings on the role of estrogens and estrogen receptors on both carcinogenesis and infertility associated with urogenital schistosomiasis and discuss the basic hormonal mechanisms that might be common in cancer and infertility. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Exogenous transforming growth factor-β1 enhances smooth muscle differentiation in embryonic mouse jejunal explants.

    PubMed

    Coletta, Riccardo; Roberts, Neil A; Randles, Michael J; Morabito, Antonino; Woolf, Adrian S

    2017-01-13

    An ex vivo experimental strategy that replicates in vivo intestinal development would in theory provide an accessible setting with which to study normal and dysmorphic gut biology. The current authors recently described a system in which mouse embryonic jejunal segments were explanted onto semipermeable platforms and fed with chemically defined serum-free media. Over 3 days in organ culture, explants formed villi and they began to undergo spontaneous peristalsis. As defined in the current study, the wall of the explanted gut failed to form a robust longitudinal smooth muscle (SM) layer as it would do in vivo over the same time period. Given the role of transforming growth factor β1 (TGFβ1) in SM differentiation in other organs, it was hypothesized that exogenous TGFβ1 would enhance SM differentiation in these explants. In vivo, TGFβ receptors I and II were both detected in embryonic longitudinal jejunal SM cells and, in organ culture, exogenous TGFβ1 induced robust differentiation of longitudinal SM. Microarray profiling showed that TGFβ1 increased SM specific transcripts in a dose dependent manner. TGFβ1 proteins were detected in amniotic fluid at a time when the intestine was physiologically herniated. By analogy with the requirement for exogenous TGFβ1 for SM differentiation in organ culture, the TGFβ1 protein that was demonstrated to be present in the amniotic fluid may enhance intestinal development when it is physiologically herniated in early gestation. Future studies of embryonic intestinal cultures should include TGFβ1 in the defined media to produce a more faithful model of in vivo muscle differentiation. Copyright © 2017 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons, Ltd. Copyright © 2017 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons, Ltd.

  4. Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer

    PubMed Central

    Casneuf, Tineke; Axel, Amy E; King, Peter; Alvarez, John D; Werbeck, Jillian L; Verhulst, Tinne; Verstraeten, Karin; Hall, Brett M; Sasser, A Kate

    2016-01-01

    Introduction Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-α (ERα)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis. Methods The role of the phosphorylated signal transducer and activator of transcription 3 pathway was investigated in ERα-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ERα-positive breast cancer cell lines alone or following treatment with 10 ng/mL recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody) and grown in three-dimensional tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ERα-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ERα-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo. Results In eight of nine ERα-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3. Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ERα-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (≥10 pg/mL). When human IL-6 was provided in vivo, MCF-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment. Subsequently, we prophylactically treated mice at MCF-7

  5. 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, and...

  6. Analytical techniques for steroid estrogens in water samples - A review.

    PubMed

    Fang, Ting Yien; Praveena, Sarva Mangala; deBurbure, Claire; Aris, Ahmad Zaharin; Ismail, Sharifah Norkhadijah Syed; Rasdi, Irniza

    2016-12-01

    In recent years, environmental concerns over ultra-trace levels of steroid estrogens concentrations in water samples have increased because of their adverse effects on human and animal life. Special attention to the analytical techniques used to quantify steroid estrogens in water samples is therefore increasingly important. The objective of this review was to present an overview of both instrumental and non-instrumental analytical techniques available for the determination of steroid estrogens in water samples, evidencing their respective potential advantages and limitations using the Need, Approach, Benefit, and Competition (NABC) approach. The analytical techniques highlighted in this review were instrumental and non-instrumental analytical techniques namely gas chromatography mass spectrometry (GC-MS), liquid chromatography mass spectrometry (LC-MS), enzyme-linked immuno sorbent assay (ELISA), radio immuno assay (RIA), yeast estrogen screen (YES) assay, and human breast cancer cell line proliferation (E-screen) assay. The complexity of water samples and their low estrogenic concentrations necessitates the use of highly sensitive instrumental analytical techniques (GC-MS and LC-MS) and non-instrumental analytical techniques (ELISA, RIA, YES assay and E-screen assay) to quantify steroid estrogens. Both instrumental and non-instrumental analytical techniques have their own advantages and limitations. However, the non-instrumental ELISA analytical techniques, thanks to its lower detection limit and simplicity, its rapidity and cost-effectiveness, currently appears to be the most reliable for determining steroid estrogens in water samples. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Proapoptotic protein Bim attenuates estrogen-enhanced survival in lymphangioleiomyomatosis

    PubMed Central

    Li, Chenggang; Li, Na; Liu, Xiaolei; Zhang, Erik Y.; Sun, Yang; Masuda, Kouhei; Li, Jing; Sun, Julia; Morrison, Tasha; Li, Xiangke; Chen, Yuanguang; Wang, Jiang; Karim, Nagla A.; Zhang, Yi; Blenis, John; Reginato, Mauricio J.; Henske, Elizabeth P.; Yu, Jane J.

    2016-01-01

    Lymphangioleiomyomatosis (LAM) is a progressive lung disease that primarily affects young women. Genetic evidence suggests that LAM cells bearing TSC2 mutations migrate to the lungs, proliferate, and cause cystic remodeling. The female predominance indicates that estrogen plays a critical role in LAM pathogenesis, and we have proposed that estrogen promotes LAM cell metastasis by inhibition of anoikis. We report here that estrogen increased LAM patient–derived cells’ resistance to anoikis in vitro, accompanied by decreased accumulation of the proapoptotic protein Bim, an activator of anoikis. The resistance to anoikis was reversed by the proteasome inhibitor, bortezomib. Treatment of LAM patient–derived cells with estrogen plus bortezomib promoted anoikis compared with estrogen alone. Depletion of Bim by siRNA in TSC2-deficient cells resulted in anoikis resistance. Treatment of mice with bortezomib reduced estrogen-promoted lung colonization of TSC2-deficient cells. Importantly, molecular depletion of Bim by siRNA in Tsc2-deficient cells increased lung colonization in a mouse model. Collectively, these data indicate that Bim plays a key role in estrogen-enhanced survival of LAM patient–derived cells under detached conditions that occur with dissemination. Thus, targeting Bim may be a plausible future treatment strategy in patients with LAM. PMID:27882343

  8. Estrogen biology: new insights into GPER function and clinical opportunities.

    PubMed

    Prossnitz, Eric R; Barton, Matthias

    2014-05-25

    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 the activity of clinically used 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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Synthetic estrogen derivatives demonstrate the functionality of intracellular GPR30.

    PubMed

    Revankar, Chetana M; Mitchell, Hugh D; Field, Angela S; Burai, Ritwik; Corona, Cesear; Ramesh, Chinnasamy; Sklar, Larry A; Arterburn, Jeffrey B; Prossnitz, Eric R

    2007-08-17

    Estrogen mediates its effects through multiple cellular receptors. In addition to the classical nuclear estrogen receptors (ERalpha and ERbeta), estrogen also signals through the seven-transmembrane G-protein-coupled receptor (GPCR) GPR30. Although estrogen is a cell-permeable ligand, it is often assumed that all GPCRs function solely as cell surface receptors. Our previous results showed that GPR30 appeared to be expressed predominantly in the endoplasmic reticulum. A critical question that arises is whether this localization represents the site of functional receptor. To address this question, we synthesized a collection of cell-permeable and cell-impermeable estrogen derivatives. We hypothesized that if functional GPR30 were expressed at the cell surface, both permeable and impermeable derivatives would show activity. However, if functional GPR30 were predominantly intracellular, like ERalpha, only the permeable ligands should show activity. Cell permeability was assessed using cells expressing ERalpha as a model intracellular estrogen-binding receptor. Our results reveal that despite exhibiting similar binding affinities for GPR30, only the cell-permeable ligands are capable of stimulating rapid calcium mobilization and phosphoinositide 3-kinase (PI3K) activation. We conclude that GPR30 expressed intracellularly is capable of initiating cellular signaling and that there is insufficient GPR30 expressed on the cell surface to initiate signaling in response to impermeable ligands in the cell lines examined. To our knowledge, this is the first definitive demonstration of a functional intracellular transmembrane estrogen receptor.

  10. Glyphosate induces human breast cancer cells growth via estrogen receptors.

    PubMed

    Thongprakaisang, Siriporn; Thiantanawat, Apinya; Rangkadilok, Nuchanart; Suriyo, Tawit; Satayavivad, Jutamaad

    2013-09-01

    Glyphosate is an active ingredient of the most widely used herbicide and it is believed to be less toxic than other pesticides. However, several recent studies showed its potential adverse health effects to humans as it may be an endocrine disruptor. This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10⁻¹² to 10⁻⁶M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Determination of estrogenic potential in waste water without sample extraction.

    PubMed

    Avberšek, Miha; Žegura, Bojana; Filipič, Metka; Uranjek-Ževart, Nataša; Heath, Ester

    2013-09-15

    This study describes the modification of the ER-Calux assay for testing water samples without sample extraction (NE-(ER-Calux) assay). The results are compared to those obtained with ER-Calux assay and a theoretical estrogenic potential obtained by GC-MSD. For spiked tap and waste water samples there was no statistical difference between estrogenic potentials obtained by the three methods. Application of NE-(ER-Calux) to "real" influent and effluents from municipal waste water treatment plants and receiving surface waters found that the NE-(ER-Calux) assay gave higher values compared to ER-Calux assay and GC-MSD. This is explained by the presence of water soluble endocrine agonists that are usually removed during extraction. Intraday dynamics of the estrogenic potential of a WWTP influent and effluent revealed an increase in the estrogenic potential of the influent from 12.9 ng(EEQ)/L in the morning to a peak value of 40.0 ng(EEQ)/L in the afternoon. The estrogenic potential of the effluent was estrogenic potential was 92-98%. Daytime estrogenic potential values varied significantly. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. 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

  13. Estrogenic effects of marijuana smoke condensate and cannabinoid compounds

    SciTech Connect

    Lee, Soo Yeun; Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746; Oh, Seung Min

    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 tomore » 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.« less

  14. 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

  15. Estrogen Inhibits Dlk1/FA1 Production: A Potential Mechanism for Estrogen Effects on Bone Turnover

    PubMed Central

    Abdallah, B. M.; Bay-Jensen, A.; Srinivasan, B.; Tabassi, N. C.; Garnero, P.; Delaissé, J.; Khosla, S.; Kassem, M.

    2011-01-01

    We have recently identified Dlk1/FA1 (Delta-like 1/FA1) as a novel regulator of bone mass that functions to mediate bone loss, under estrogen deficiency, in mice. In this report, we investigated the effects of estrogen (E)-deficiency and E replacement on serum (s) levels of Dlk1/FA1 (s-Dlk1FA1) and its correlation with bone turnover markers. s-Dlk1/FA1 and bone turnover markers (s-CTx and s-osteocalcin), were measured in two cohorts: a group of pre- and postmenopausal women (n=100) and a group of postmenopausal women, where half had received estrogen replacement therapy (ERT) (n=166). s-Dlk1/FA1, and s-CTX were elevated in postmenopausal E-deficient compared to premenopausal E-replete women (both; P<0.001). s-Dlk1/FA1 was correlated with s-CTX (r=0.30, P<0.01). ERT, in postmenopausal women, decreased s-Dlk1/FA1, as well as s-CTX and s-osteoclacin (all; P<0.0001). Changes in s-Dlk1 were significantly correlated with those observed in s-CTx (r=0.18, P<0.05) and s-osteocalcin (r=0.28, P<0.001). In conclusion, s-Dlk1/FA1 is influenced by E-deficiency and is correlated with bone turnover. Increased levels of s-Dlk1/FA1 in post-menopausal women may be a mechanism mediating the effects estrogen deficiency on bone turnover. PMID:21681814

  16. Determination of the Role of Estrogen Receptors and Estrogen Regulated Genes in B Cell Autoreactivity

    DTIC Science & Technology

    2011-07-01

    Betty Diamond – DOD FINAL REPORT 9 Figure 3: (A) expression of estrogen receptors ERalpha( Esr1 ) and ERbeta (Esr2) in splenic B cells and (B...Urinary 16 OH-Estradiol metabolite in BALB/c and C57BL6 mice. Esr1 0 0.05 0.1 0.15 0.2 Transit. Mature Transit. Mature Transit. Mature Transit. mature P E2

  17. Determination of the Role of Estrogen Receptors and Estrogen Regulated Genes in B cell Autoreactivity. Addendum

    DTIC Science & Technology

    2012-07-01

    Betty Diamond – DOD FINAL REPORT 9 Figure 3: (A) expression of estrogen receptors ERalpha( Esr1 ) and ERbeta (Esr2) in splenic B cells and (B)Urinary...16 OH-Estradiol metabolite in BALB/c and C57BL6 mice. Esr1 0 0.05 0.1 0.15 0.2 Transit. Mature Transit. Mature Transit. Mature Transit. mature P E2 P

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

    PubMed Central

    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

  19. Contraceptive, estrogenic and anti-estrogenic potentials of methanolic root extract of Carpolobia lutea in rodents.

    PubMed

    Ettebong, Ette Okon; Nwafor, Paul Alozie; Ekpo, Memfin; Ajibesin, Kola Kayode

    2011-10-01

    Several plants are used in herbal medicine for family planning. Carpolobia lutea is a medicinal plant in South Eastern Nigeria used for family planning. The study was designed to investigate the contraceptive, estrogenic and antiestrogenic potentials of the methanolic root extract of Carpolobia lutea in both rats and mice. The contraceptive effect of extract (7 - 21mg/kg) administered by intraperitoneal route for four days in divided doses was tested in mice and rats. Sexually-active males were introduced on day 5 at the ratio of 3F:1M and kept with these females till the end of the experiment. Investigations on the estrogenic and antiestrogenic property of the extract (7-21mg/kg) were done in immature rats that had undergone surgical removal of both ovaries. The effects of the extract (vaginal opening, vaginal cornification, uterine wet weight) were compared with 17-beta-estradiol (0.1µg/rat/day) as standard drug. Twenty-four hours later, the animals were sacrificed following the last dose and the weights of uterus, kidney, liver and small intestine were recorded. The extract prevented conception in both mice and rats for two gestational periods. Significant changes (p<0.05-0.001) were observed in the length and weight of pups relative to control. There were no abnormalities observed in the pups over thirty days. In ovariectomized immature young rats, the extract showed estrogenic effect (vaginal opening, vaginal cornification and increased uterine wet weight) in low doses while in high doses, it showed anti-estrogenic effect. These findings agree with the traditional use of Carpolobia lutea in the control of fertility. The contraceptive property of the extract may be associated with the direct effects of its chemical constituents.

  20. 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. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Involvement of estrogen receptor variant ER-alpha36, not GPR30, in nongenomic estrogen signaling.

    PubMed

    Kang, Lianguo; Zhang, Xintian; Xie, Yan; Tu, Yaping; Wang, Dong; Liu, Zhenming; Wang, Zhao-Yi

    2010-04-01

    Accumulating evidence suggested that an orphan G protein-coupled receptor (GPR)30, mediates nongenomic responses to estrogen. The present study was performed to investigate the molecular mechanisms underlying GPR30 function. We found that knockdown of GPR30 expression in breast cancer SK-BR-3 cells down-regulated the expression levels of estrogen receptor (ER)-alpha36, a variant of ER-alpha. Introduction of a GPR30 expression vector into GPR30 nonexpressing cells induced endogenous ER-alpha36 expression, and cotransfection assay demonstrated that GPR30 activated the promoter activity of ER-alpha36 via an activator protein 1 binding site. Both 17beta-estradiol (E2) and G1, a compound reported to be a selective GPR30 agonist, increased the phosphorylation levels of the MAPK/ERK1/2 in SK-BR-3 cells, which could be blocked by an anti-ER-alpha36-specific antibody against its ligand-binding domain. G1 induced activities mediated by ER-alpha36, such as transcription activation activity of a VP16-ER-alpha36 fusion protein and activation of the MAPK/ERK1/2 in ER-alpha36-expressing cells. ER-alpha36-expressing cells, but not the nonexpressing cells, displayed high-affinity, specific E2 and G1 binding, and E2- and G1-induced intracellular Ca(2+) mobilization only in ER-alpha36 expressing cells. Taken together, our results demonstrated that previously reported activities of GPR30 in response to estrogen were through its ability to induce ER-alpha36 expression. The selective G protein-coupled receptor (GPR)30 agonist G1 actually interacts with ER-alpha36. Thus, the ER-alpha variant ER-alpha36, not GPR30, is involved in nongenomic estrogen signaling.

  2. Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice.

    PubMed

    Tuscher, Jennifer J; Szinte, Julia S; Starrett, Joseph R; Krentzel, Amanda A; Fortress, Ashley M; Remage-Healey, Luke; Frick, Karyn M

    2016-07-01

    The potent estrogen 17β-Estradiol (E2) plays a critical role in mediating hippocampal function, yet the precise mechanisms through which E2 enhances hippocampal memory remain unclear. In young adult female rodents, the beneficial effects of E2 on memory are generally attributed to ovarian-synthesized E2. However, E2 is also synthesized in the adult brain in numerous species, where it regulates synaptic plasticity and is synthesized in response to experiences such as exposure to females or conspecific song. Although de novo E2 synthesis has been demonstrated in rodent hippocampal cultures, little is known about the functional role of local E2 synthesis in mediating hippocampal memory function. Therefore, the present study examined the role of hippocampal E2 synthesis in hippocampal memory consolidation. Using bilateral dorsal hippocampal infusions of the aromatase inhibitor letrozole, we first found that blockade of dorsal hippocampal E2 synthesis impaired hippocampal memory consolidation. We next found that elevated levels of E2 in the dorsal hippocampus observed 30min after object training were blocked by dorsal hippocampal infusion of letrozole, suggesting that behavioral experience increases acute and local E2 synthesis. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory consolidation, indicating that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory. Combined, these data are consistent with the hypothesis that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation in rodents. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Alternative Dosing of Exemestane Before Surgery in Treating Postmenopausal Patients With Stage 0-II Estrogen Positive Breast Cancer | Division of Cancer Prevention

    Cancer.gov

    This randomized phase IIb trial studies how well alternative dosing of exemestane before surgery works in treating in postmenopausal patients with stage 0-II estrogen positive breast cancer. Chemoprevention is the use of drugs to keep breast cancer from forming or coming back. The use of exemestane may treat early stage (stage 0-II) breast cancer. Comparing the exemestane

  4. Exogenous Molecular Probes for Targeted Imaging in Cancer: Focus on Multi-modal Imaging

    PubMed Central

    Joshi, Bishnu P.; Wang, Thomas D.

    2010-01-01

    Cancer is one of the major causes of mortality and morbidity in our healthcare system. Molecular imaging is an emerging methodology for the early detection of cancer, guidance of therapy, and monitoring of response. The development of new instruments and exogenous molecular probes that can be labeled for multi-modality imaging is critical to this process. Today, molecular imaging is at a crossroad, and new targeted imaging agents are expected to broadly expand our ability to detect and manage cancer. This integrated imaging strategy will permit clinicians to not only localize lesions within the body but also to manage their therapy by visualizing the expression and activity of specific molecules. This information is expected to have a major impact on drug development and understanding of basic cancer biology. At this time, a number of molecular probes have been developed by conjugating various labels to affinity ligands for targeting in different imaging modalities. This review will describe the current status of exogenous molecular probes for optical, scintigraphic, MRI and ultrasound imaging platforms. Furthermore, we will also shed light on how these techniques can be used synergistically in multi-modal platforms and how these techniques are being employed in current research. PMID:22180839

  5. The impact of acute psychosocial stress on magnetoencephalographic correlates of emotional attention and exogenous visual attention.

    PubMed

    Elling, Ludger; Schupp, Harald; Bayer, Janine; Bröckelmann, Ann-Kathrin; Steinberg, Christian; Dobel, Christian; Junghofer, Markus

    2012-01-01

    Stress-induced acute activation of the cerebral catecholaminergic systems has often been found in rodents. However, little is known regarding the consequences of this activation on higher cognitive functions in humans. Theoretical inferences would suggest increased distractibility in the sense of increased exogenous attention and emotional attention. The present study investigated the influence of acute stress responses on magnetoencephalographic (MEG) correlates of visual attention. Healthy male subjects were presented emotional and neutral pictures in three subsequent MEG recording sessions after being exposed to a TSST-like social stressor, intended to trigger a HPA-response. The subjects anticipation of another follow-up stressor was designed to sustain the short-lived central catecholaminergic stress reactions throughout the ongoing MEG recordings. The heart rate indicates a stable level of anticipatory stress during this time span, subsequent cortisol concentrations and self-report measures of stress were increased. With regard to the MEG correlates of attentional functions, we found that the N1m amplitude remained constantly elevated during stressor anticipation. The magnetic early posterior negativity (EPNm) was present but, surprisingly, was not at all modulated during stressor anticipation. This suggests that a general increase of the influence of exogenous attention but no specific effect regarding emotional attention in this time interval. Regarding the time course of the effects, an influence of the HPA on these MEG correlates of attention seems less likely. An influence of cerebral catecholaminergic systems is plausible, but not definite.

  6. Fructose and Sucrose Intake Increase Exogenous Carbohydrate Oxidation during Exercise

    PubMed Central

    Trommelen, Jorn; Fuchs, Cas J.; Beelen, Milou; Lenaerts, Kaatje; Jeukendrup, Asker E.; Cermak, Naomi M.; van Loon, Luc J. C.

    2017-01-01

    Peak exogenous carbohydrate oxidation rates typically reach ~1 g·min−1 during exercise when ample glucose or glucose polymers are ingested. Fructose co-ingestion has been shown to further increase exogenous carbohydrate oxidation rates. The purpose of this study was to assess the impact of fructose co-ingestion provided either as a monosaccharide or as part of the disaccharide sucrose on exogenous carbohydrate oxidation rates during prolonged exercise in trained cyclists. Ten trained male cyclists (VO2peak: 65 ± 2 mL·kg−1·min−1) cycled on four different occasions for 180 min at 50% Wmax during which they consumed a carbohydrate solution providing 1.8 g·min−1 of glucose (GLU), 1.2 g·min−1 glucose + 0.6 g·min−1 fructose (GLU + FRU), 0.6 g·min−1 glucose + 1.2 g·min−1 sucrose (GLU + SUC), or water (WAT). Peak exogenous carbohydrate oxidation rates did not differ between GLU + FRU and GLU + SUC (1.40 ± 0.06 vs. 1.29 ± 0.07 g·min−1, respectively, p = 0.999), but were 46% ± 8% higher when compared to GLU (0.96 ± 0.06 g·min−1: p < 0.05). In line, exogenous carbohydrate oxidation rates during the latter 120 min of exercise were 46% ± 8% higher in GLU + FRU or GLU + SUC compared with GLU (1.19 ± 0.12, 1.13 ± 0.21, and 0.82 ± 0.16 g·min−1, respectively, p < 0.05). We conclude that fructose co-ingestion (0.6 g·min−1) with glucose (1.2 g·min−1) provided either as a monosaccharide or as sucrose strongly increases exogenous carbohydrate oxidation rates during prolonged exercise in trained cyclists. PMID:28230742

  7. Environmental estrogen(s) induced swimming behavioural alterations in adult zebrafish (Danio rerio).

    PubMed

    Goundadkar, Basavaraj B; Katti, Pancharatna

    2017-09-01

    The present study is an attempt to investigate the effects of long-term (75days) exposure to environmental estrogens (EE) on the swimming behaviour of zebrafish (Danio rerio). Adult zebrafish were exposed semi-statically to media containing commonly detected estrogenic water contaminants (EE2, DES and BPA) at a concentration (5ng/L) much lower than environmentally recorded levels. Time spent in swimming, surface preference, patterns and path of swimming were recorded (6mins) for each fish using two video cameras on day 15, 30 60 and 75. Video clips were analysed using a software program. Results indicate that chronic exposure to EE leads to increased body weight and size of females, reduced (P<0.05) swimming time, delay in latency, increased (P<0.05) immobility, erratic movements and freezing episodes. We conclude that estrogenic contamination of natural aquatic systems induces alterations in locomotor behaviour and associated physiological disturbances in inhabitant fish fauna. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. 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

  9. 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.

  10. Participation of Water in the Binding of Estrogen Receptor with Estrogen Responsive Element in vitro.

    PubMed

    Zhu, Guo-Zhang; Tang, Guo-Qing; Ruan, Kang-Cheng; Gong, Yue-Ting; Zhang, Yong-Lian

    1998-01-01

    Many reports have showed that bound water was involved in the interaction between/among the macromolecules. However, it has not been reported whether bound water is also involved in the binding of trans-factors and cis-elements in the regulation of the eukaryotic gene trans-cription or not. Preliminary studies have been made on the effect of bound water on the binding of estrogen receptor with estrogen responsive element in vitro. In the gel retardation assay using the cytosol extract of rat uterus as the supplier of estrogen receptor and 32 bp oligonucleotide containing a concensus vitellogenin A(2) ERE as the probe, various cosolvents, such as glycerol, sucrose, N-dimethylformamide and dimethylsulfoxide, were added respectively to the reaction mixture in varying concentrations to regulate the osmotic pressure. The results indicated that the binding of ER-ERE was enhanced with the increase in the final concentration of these individual cosolvents. On the other hand, when the reaction was carried out under an increasing hydrostatic pressure, the ER-ERE binding was decreased sharply. After decompression the binding of ER-ERE was gradually restored to the normal level with the lapse of time. These results suggested that bound water was directly involved in the binding of ER-ERE and may play an important role in the regulation of the eukaryotic gene transcription.

  11. [The estrogenic effect of formononetin and its effect on the expression of rats' atrium estrogen receptors].

    PubMed

    Xing, Dian-Xia; Liu, Xian-Ling; Xue, Cun-Kuan; Huang, Qi; Liu, Zhi-Gao; Xiong, Liang

    2010-09-01

    To observe the estrogenic effect of formononetin and its effect on the expressions of atrial estrogen receptor subtypes alpha and beta (ERalpha and ERbeta). 50 femal rats were randomly divided into five groups: sham group, model group, nilestriol group, formononetin groups of low and high dose. Rats in sham group were cut a piece of fat before closing the abdomen, the others were ovariectomized. Vaginal exfoliated cell were observed from the fifth day to the tenth after operation to test if the model is successful. The sham and model group were given nomal saline in 10 mL/kg by gavage, the remaining three groups were given nilestriol 2.5 mg/(kg x w), low [20 mg/(kg x d) land high dose [100 mg/(kg x d)) of formononetin by gavage respectively. In the 8th week, vaginal exfoliated cell were observed, then decapitated the rats, removed the uterus, weighed and take wright staining microscopy. The relative expressions of ERalpha and ERbeta of right atrium were detected by RT-PCR. The vaginal cells exhibit a change of estrus after had been fed with high dose of formononetin after 8 weeks. Formononetin increase the uterus coefficient and the expression of atrial ERbeta (P < 0.01), but it dose not have any effect on the expression of ERalpha (P > 0.05). Formononetin have estrogenic effect in ovariectomized rats, and it can markedly upregulate the expression of rats' atrial ERbeta.

  12. An overview of estrogen-associated endocrine disruption in fishes: evidence of effects on reproductive and immune physiology

    USGS Publications Warehouse

    Iwanowicz, L.R.; Blazer, V.S.

    2011-01-01

    Simply and perhaps intuitively defined, endocrine disruption is the abnormal modulation of normal hormonal physiology by exogenous chemicals. In fish, endocrine disruption of the reproductive system has been observed worldwide in numerous species and is known to affect both males and females. Observations of biologically relevant endocrine disruption most commonly occurs near waste water treatment plant outfalls, pulp and paper mills, and areas of high organic loading sometimes associated with agricultural practices. Estrogenic endocrine disrupting chemicals (EEDCs) have received an overwhelmingly disproportionate amount of scientific attention compared to other EDCs in recent years. In male fishes, exposure to EEDCs can lead to the induction of testicular oocytes (intersex), measurable plasma vitellogenin protein, altered sex steroid profiles, abnormal spawning behavior, skewed population sex ratios, and lessened reproductive success. Interestingly, contemporary research purports that EDCs modulate aspects of non-reproductive physiology including immune function. Here we present an overview of endocrine disruption in fishes associated with estrogenic compounds, implications of this phenomenon, and examples of EDC related research findings by our group in the Potomac River Watershed, USA.

  13. IL-8 expression and its possible relationship with estrogen-receptor-negative status of breast cancer cells

    PubMed Central

    Freund, Ariane; Chauveau, Corine; Brouillet, Jean-Paul; Lucas, Annick; Lacroix, Matthieu; Licznar, Anne; Vignon, Françoise; Lazennec, Gwendal

    2003-01-01

    Estrogen receptor (ER) status is an important parameter in breast cancer management as ER-positive breast cancers have a better prognosis than ER-negative tumors. This difference comes essentially from the lower aggressiveness and invasiveness of ER-positive tumors. Here, we demonstrate, that IL-8 was clearly overexpressed in most ER-negative breast, ovary cell lines and breast tumor samples tested, whereas no significant IL-8 level could be detected in ER-positive breast or ovarian cell lines. We have also cloned human IL-8 from ER-negative MDA-MB-231 cells and we show that IL-8 produced by breast cancer cells is identical to monocyte-derived IL-8. Interestingly, the invasion potential of ER-negative breast cancer cells is associated at least in part with expression of interleukin-8 (IL-8), but not with IL-8 receptors levels. Moreover, IL-8 increases the invasiveness of ER-positive breast cancer cells by 2 fold, thus confirming the invasion-promoting role of IL-8. On the other hand, exogenous expression of estrogen receptors in ER-negative cells led to a decrease of IL-8 levels. In summary, our data show that IL-8 expression is negatively linked to ER-status of breast and ovarian cancer cells. We also support the idea that IL-8 expression is associated with a higher invasiveness potential of cancer cells in vitro, which suggests that IL-8 could be a novel marker of tumor aggressiveness. PMID:12527894

  14. Minireview: The Year in Review of Estrogen Regulation of Metabolism

    PubMed Central

    2012-01-01

    Gonadal steroids are critical regulators of physiology, yet we approach physiology and science with the simplest perspective/model, the male one. Female models of whole animal physiology are complex to study and, therefore, are often not used in research. Estrogens are one of the sex hormones that we know are important for both men and women. Estrogens regulate key features of metabolism such as food intake, body weight, glucose homeostasis/insulin sensitivity, body fat distribution, lipolysis/lipogenesis, inflammation, locomotor activity, energy expenditure, reproduction, and cognition. Furthermore, estrogens have multiple sites of action including some unexpected ones, which was demonstrated elegantly through a series of papers this year. PMID:23051593

  15. Hpm of Estrogen Model on the Dynamics of Breast Cancer

    NASA Astrophysics Data System (ADS)

    Govindarajan, A.; Balamuralitharan, S.; Sundaresan, T.

    2018-04-01

    We enhance a deterministic mathematical model involving universal dynamics on breast cancer with immune response. This is population model so includes Normal cells class, Tumor cells, Immune cells and Estrogen. The eects regarding Estrogen are below incorporated in the model. The effects show to that amount the arrival of greater Estrogen increases the danger over growing breast cancer. Furthermore, approximate solution regarding nonlinear differential equations is arrived by Homotopy Perturbation Method (HPM). Hes HPM is good and correct technique after solve nonlinear differential equation directly. Approximate solution learnt with the support of that method is suitable same as like the actual results in accordance with this models.

  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).

  17. Maternal Regulation of Estrogen Receptor α Methylation

    PubMed Central

    Champagne, Frances A.; Curley, James P.

    2008-01-01

    Summary Advances in molecular biology have provided tools for studying the epigenetic factors which modulate gene expression. DNA methylation is an epigenetic modification which can have sustained effects on transcription and is associated with long-term gene silencing. In this review, we focus on the regulation of estrogen receptor alpha (ERα) expression by hormonal and environmental cues, the consequences of these cues for female maternal and sexual behavior and recent studies which explore the role of DNA methylation in mediating these developmental effects, with particular focus on the mediating role of maternal care. The methylation status of ERα has implications for reproductive behavior, cancer susceptibility and recovery from ischemic injury suggesting an epigenetic basis for risk and resilience across the life span. PMID:18644464

  18. Neonatal uterine and vaginal cell proliferation and adenogenesis are independent of estrogen receptor 1 (ESR1) in the mouse.

    PubMed

    Nanjappa, Manjunatha K; Medrano, Theresa I; March, Amelia G; Cooke, Paul S

    2015-03-01

    Neonatal uterus and vagina express estrogen receptor 1 (ESR1) and respond mitogenically to exogenous estrogens. However, neonatal ovariectomy does not inhibit preweaning uterine cell proliferation, indicating that this process is estrogen independent. Extensive literature suggests that ESR1 can be activated by growth factors in a ligand-independent manner and drive uterine cell proliferation. Alternatively, neonatal uterine cell proliferation could be ESR1 independent despite its obligatory role in adult luminal epithelial proliferation. To determine ESR1's role in uterine and vaginal development, we analyzed cell proliferation, apoptosis, and uterine gland development (adenogenesis) in wild-type (WT) and Esr1 knockout (Esr1KO) mice from Postnatal Day 2 to Postnatal Day 60. Uterine and vaginal cell proliferation, apoptosis, and uterine adenogenesis were comparable in WT and Esr1KO mice before weaning. By Days 29-60, glands had regressed, and uterine cell proliferation was reduced in Esr1KO mice in contrast to continued adenogenesis and proliferation in WT. Apoptosis in Esr1KO uterine epithelium was not increased compared to WT at any age, indicating that differences in cell proliferation, rather than apoptosis, cause divergence of uterine size in these two groups at puberty. Similarly, vaginal epithelial proliferation was reduced, and the epithelium became atrophic in Esr1KO mice by 29 days of age and later in Esr1KO mice. These results indicate that preweaning uterine and vaginal development is ESR1 independent but becomes dependent on ESR1 by Day 29 on. It is not yet clear what mechanisms drive preweaning vaginal and uterine development, but ligand-independent activation of ESR1 is not involved. © 2015 by the Society for the Study of Reproduction, Inc.

  19. Estrogens Can Disrupt Amphibian Mating Behavior

    PubMed Central

    Hoffmann, Frauke; Kloas, Werner

    2012-01-01

    The main component of classical contraceptives, 17α-ethinylestradiol (EE2), has high estrogenic activity even at environmentally relevant concentrations. Although estrogenic endocrine disrupting compounds are assumed to contribute to the worldwide decline of amphibian populations by adverse effects on sexual differentiation, evidence for EE2 affecting amphibian mating behaviour is lacking. In this study, we demonstrate that EE2 exposure at five different concentrations (0.296 ng/L, 2.96 ng/L, 29.64 ng/L, 2.96 µg/L and 296.4 µg/L) can disrupt the mating behavior of adult male Xenopus laevis. EE2 exposure at all concentrations lowered male sexual arousal, indicated by decreased proportions of advertisement calls and increased proportions of the call type rasping, which characterizes a sexually unaroused state of a male. Additionally, EE2 at all tested concentrations affected temporal and spectral parameters of the advertisement calls, respectively. The classical and highly sensitive biomarker vitellogenin, on the other hand, was only induced at concentrations equal or higher than 2.96 µg/L. If kept under control conditions after a 96 h EE2 exposure (2.96 µg/L), alterations of male advertisement calls vanish gradually within 6 weeks and result in a lower sexual attractiveness of EE2 exposed males toward females as demonstrated by female choice experiments. These findings indicate that exposure to environmentally relevant EE2 concentrations can directly disrupt male mate calling behavior of X. laevis and can indirectly affect the mating behavior of females. The results suggest the possibility that EE2 exposure could reduce the reproductive success of EE2 exposed animals and these effects might contribute to the global problem of amphibian decline. PMID:22355410

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

    PubMed

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

    2014-09-01

    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. Published by Elsevier Ltd.

  1. 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.

  2. Genetically-induced Estrogen Receptor Alpha mRNA (Esr1) Overexpression Does Not Adversely Affect Fertility or Penile Development in Male Mice

    PubMed Central

    Heath, John; Abdelmageed, Yazeed; Braden, Tim D.; Williams, Carol S.; Williams, John W.; Paulose, Tessie; Hernandez-Ochoa, Isabel; Gupta, Rupesh; Flaws, Jodi A.; Goyal, Hari O.

    2011-01-01

    Previously, we reported that estrogen receptor alpha mRNA (Esr1) or protein (ESR1) overexpression resulting from neonatal exposure to estrogens in rats was associated with infertility and mal-developed penis characterized by reduced length and weight and abnormal accumulation of fat cells. The objective of this study was to determine if mutant male mice overexpressing Esr1 are naturally infertile or have reduced fertility and/or develop abnormal penis. The fertility parameters, including fertility and fecundity indices, numbers of days from the day of cohabitation to the day of delivery, and numbers of pups per female, were not altered from controls, as a result of Esr1 overexpression. Likewise, penile morphology, including the length, weight, and diameter and os penis development, was not altered from controls. Conversely, weights of the seminal vesicles and bulbospongiosus and levator ani (BS/LA) muscles were significantly (P < 0.05) lower as compared to controls; however, the weight of the testis, the morphology of the testis and epididymis, and the plasma and testicular testosterone concentration were not different from controls. Hence, the genetically-induced Esr1 overexpression alone, without an exogenous estrogen exposure during the neonatal period, is unable to adversely affect the development of the penis as well as other male reproductive organs, except limited, but significant, reductions in weights of the seminal vesicles and BS/LA muscles. PMID:20930192

  3. 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.

  4. Exogenous melatonin improves Malus resistance to Marssonina apple blotch.

    PubMed

    Yin, Lihua; Wang, Ping; Li, Mingjun; Ke, Xiwang; Li, Cuiying; Liang, Dong; Wu, Shan; Ma, Xinli; Li, Chao; Zou, Yangjun; Ma, Fengwang

    2013-05-01

    We examined whether exogenously applied melatonin could improve resistance to Marssonina apple blotch (Diplocarpon mali) by apple [Malus prunifolia (Willd.) Borkh. cv. Donghongguo]. This serious disease leads to premature defoliation in the main regions of apple production. When plants were pretreated with melatonin, resistance was increased in the leaves. We investigated the potential roles for melatonin in modulating levels of hydrogen peroxide (H2O2), as well the activities of antioxidant enzymes and pathogenesis-related proteins during these plant-pathogen interactions. Pretreatment enabled plants to maintain intracellular H2O2 concentrations at steady-state levels and enhance the activities of plant defence-related enzymes, possibly improving disease resistance. Because melatonin is safe and beneficial to animals and humans, exogenous pretreatment might represent a promising cultivation strategy to protect plants against this pathogen infection. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

  5. Exogenous Lipoid Pneumonia in Laryngectomy Patients: Radiological Findings.

    PubMed

    García Latorre, Raquel; Rodríguez Díaz, Ricardo; Barrios Barreto, Deisy; Ayala Carbonero, Ana; García Gómez-Muriel, María Isabel; Gorospe Sarasúa, Luis

    2015-07-01

    Exogenous lipoid pneumonia (ELP) is a rare (incidence 1.0%-2.5%), often under-diagnosed disease, caused by the aspiration and accumulation of exogenous lipids within the pulmonary alveoli. Various cases have been described due to inhalation of lubricants via the nasal passages and oropharynx, aspiration of mineral oils in laxatives in patients with eating disorders, application of lip gloss, occupational exposure to liquid paraffin or mineral oils ("fire-eaters", industrial use in washing of machinery, automobile workshops, plastic paints, etc.) and application of Vaseline during the insertion of nasogastric tubes and in the care of tracheotomy patients. ELP usually presents radiologically as areas of low-attenuation peribronchial consolidation and ground glass opacities, with a predominantly bibasal distribution. We present 5 cases of long-standing laryngectomy patients diagnosed with ELP who admitted using Vaseline in their tracheal stoma care. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.

  6. Exogenous factors in panic disorder: clinical and research implications.

    PubMed

    Roy-Byrne, P P; Uhde, T W

    1988-02-01

    Because panic disorder has an underlying biologic and probably genetic basis, the role of factors outside the organism in initiating and sustaining panic is often overlooked. The authors review certain exogenous factors that seem capable of triggering attacks and/or increasing their frequency and intensity: self-administered pharmacologic agents (caffeine, alcohol, nicotine, over-the-counter cold preparations, cannabis, cocaine); habits (sleep deprivation, diet, exercise, relaxation, hyperventilation); and aspects of the environment (fluorescent lighting, life stressors). There may be a specificity to the action of some of these factors, because certain factors previously thought to trigger panic attacks (e.g., pain, hypoglycemia) have been proved not to have this effect. Although the clinical significance of many of the exogenous factors discussed still awaits empirical confirmation, attention to such factors during the initial evaluation of a patient with panic disorder may be helpful in formulating a successful treatment plan.

  7. Catabolism of exogenous deoxyinosine in cultured epithelial amniotic cells.

    PubMed

    Carta, M C; Mattana, A; Camici, M; Allegrini, S; Tozzi, M G; Sgarrella, F

    2001-10-03

    Uptake and catabolism of purine nucleosides have been commonly considered as means to salvage the purine ring for nucleic acid synthesis, usually neglecting the destiny of the pentose moiety. With the aim to ascertain if deoxyribose derived from exogenous DNA can be utilised as a carbon and energy source, we studied the catabolism of exogenous deoxyinosine in a cell line derived from human amnion epithelium (WISH). Intact WISH cells catabolise deoxyinosine by conversion into hypoxanthine. The nucleoside enters the cell through a nitrobenzylthioinosine-insensitive equilibrative transport. Deoxyinosine undergoes a phosphorolytic cleavage inside the cell. The purine base diffuses back to the external medium, while the phosphorylated pentose moiety can be further catabolised to glycolysis and citric acid cycle intermediates. Our results indicate that the catabolism of the deoxynucleoside can be considered mainly as a means to meet the carbon and energy requirements of growing cells.

  8. Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer.

    PubMed

    Guttery, David S; Page, Karen; Hills, Allison; Woodley, Laura; Marchese, Stephanie D; Rghebi, Basma; Hastings, Robert K; Luo, Jinli; Pringle, J Howard; Stebbing, Justin; Coombes, R Charles; Ali, Simak; Shaw, Jacqueline A

    2015-07-01

    Activating mutations in the estrogen receptor 1 (ESR1) gene are acquired on treatment and can drive resistance to endocrine therapy. Because of the spatial and temporal limitations of needle core biopsies, our goal was to develop a highly sensitive, less invasive method of detecting activating ESR1 mutations via circulating cell-free DNA (cfDNA) and tumor cells as a "liquid biopsy." We developed a targeted 23-amplicon next-generation sequencing (NGS) panel for detection of hot-spot mutations in ESR1, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), tumor protein p53 (TP53), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 2 (FGFR2) in 48 patients with estrogen receptor-α-positive metastatic breast cancer who were receiving systemic therapy. Selected mutations were validated using droplet digital PCR (ddPCR). Nine baseline cfDNA samples had an ESR1 mutation. NGS detected 3 activating mutations in ESR1, and 3 hot-spot mutations in PIK3CA, and 3 in TP53 in baseline cfDNA, and the ESR1 p.D538G mutation in 1 matched circulating tumor cell sample. ddPCR analysis was more sensitive than NGS and identified 6 additional baseline cfDNA samples with the ESR1 p.D538G mutation at a frequency of <1%. In serial blood samples from 11 patients, 4 showed changes in cfDNA, 2 with emergence of a mutation in ESR1. We also detected a low frequency ESR1 mutation (1.3%) in cfDNA of 1 primary patient who was thought to have metastatic disease but was clear by scans. Early identification of ESR1 mutations by liquid biopsy might allow for cessation of ineffective endocrine therapies and switching to other treatments, without the need for tissue biopsy and before the emergence of metastatic disease. © 2015 American Association for Clinical Chemistry.

  9. Expression and analysis of exogenous proteins in epidermal cells.

    PubMed

    Dagnino, Lina; Ho, Ernest; Chang, Wing Y

    2010-01-01

    In this chapter we review protocols for transient transfection of primary keratinocytes. The ability to transfect primary epidermal cells regardless of their differentiation status allows the biochemical and molecular characterization of multiple proteins. We review methods to analyze exogenous protein abundance in transfected keratinocytes by immunoblot and immunoprecipitation. We also present protocols to determine the subcellular distribution of these proteins by indirect immunofluorescence microscopy approaches.

  10. Computational analysis for biodegradation of exogenously depolymerizable polymer

    NASA Astrophysics Data System (ADS)

    Watanabe, M.; Kawai, F.

    2018-03-01

    This study shows that microbial growth and decay in a biodegradation process of exogenously depolymerizable polymer are controlled by consumption of monomer units. Experimental outcomes for residual polymer were incorporated in inverse analysis for a degradation rate. The Gauss-Newton method was applied to an inverse problem for two parameter values associated with the microbial population. A biodegradation process of polyethylene glycol was analyzed numerically, and numerical outcomes were obtained.

  11. Control of exogenous factors affecting plasma homovanillic acid concentration.

    PubMed

    Davidson, M; Giordani, A B; Mohs, R C; Mykytyn, V V; Platt, S; Aryan, Z S; Davis, K L

    1987-04-01

    Measurements of plasma homovanillic acid (pHVA) concentrations appear to be a valid research strategy in psychiatric disorders in which a central dopamine (DA) abnormality has been implicated. This study provides guidance about the control of some of the exogenous factors affecting pHVA concentrations. Fasting for 14 hours eliminates the dietary effects on pHVA in healthy human subjects. Changing position, walking for 30 minutes, or smoking two cigarettes has no effect on pHVA concentrations.

  12. 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

  13. Exogenous Glutamine in Respiratory Diseases: Myth or Reality?

    PubMed Central

    Oliveira, Gisele P.; de Abreu, Marcelo Gama; Pelosi, Paolo; Rocco, Patricia R. M.

    2016-01-01

    Several respiratory diseases feature increased inflammatory response and catabolic activity, which are associated with glutamine depletion; thus, the benefits of exogenous glutamine administration have been evaluated in clinical trials and models of different respiratory diseases. Recent reviews and meta-analyses have focused on the effects and mechanisms of action of glutamine in a general population of critical care patients or in different models of injury. However, little information is available about the role of glutamine in respiratory diseases. The aim of the present review is to discuss the evidence of glutamine depletion in cystic fibrosis (CF), asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and lung cancer, as well as the results of exogenous glutamine administration in experimental and clinical studies. Exogenous glutamine administration might be beneficial in ARDS, asthma, and during lung cancer treatment, thus representing a potential therapeutic tool in these conditions. Further experimental and large randomized clinical trials focusing on the development and progression of respiratory diseases are necessary to elucidate the effects and possible therapeutic role of glutamine in this setting. PMID:26861387

  14. Dermoscopic and reflectance confocal microscopic features of exogenous ochronosis.

    PubMed

    Gil, Inmaculada; Segura, Sonia; Martínez-Escala, Estela; Lloreta, Josep; Puig, Susana; Vélez, Mariano; Pujol, Ramón M; Herrero-González, Josep E

    2010-09-01

    Exogenous ochronosis presents as an acquired asymptomatic hyperpigmentation on photoexposed areas, predominantly over bony prominences, and is caused by the topical application of several skin-lightening agents. We describe a 63-year-old Hispanic woman who developed exogenous ochronosis lesions on her face after using topical bleaching creams containing hydroquinone, 2% to 3%, and oxybenzone, 2%, for several years. Dermoscopy revealed irregular brown-gray globular, annular, and arciform structures that corresponded to focal deposition of ochronotic pigment on the dermis. These deposits correlated with multiple banana-shaped nonrefractile structures seen using reflectance confocal microscopy. Histopathologic sections revealed the deposition of a banana-shaped, yellow to brown material in the papillary and middle dermis. Ultrastructural examination revealed an amorphous electron-dense material mostly located in the core of elastic fibers and also in smaller amounts in the interstitium with prominent degenerative changes in the elastic fibers. A good correlation was observed between the results of both noninvasive techniques and the diagnostic histologic features of this condition. We characterized by means of dermoscopy, reflectance confocal microscopy, and electronic microscopy a case of exogenous ochronosis. To our knowledge, this is the first description of reflectance confocal microscopic findings in this condition. Dermoscopy and reflectance confocal microscopy are proved to be useful noninvasive techniques for the diagnosis of this pigmentary disorder.

  15. Exogenous antioxidants—Double-edged swords in cellular redox state

    PubMed Central

    Bohn, Torsten

    2010-01-01

    The balance between oxidation and antioxidation is believed to be critical in maintaining healthy biological systems. Under physiological conditions, the human antioxidative defense system including e.g., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) and others, allows the elimination of excess reactive oxygen species (ROS) including, among others superoxide anions (O2.-), hydroxyl radicals (OH.), alkoxyl radicals (RO.) and peroxyradicals (ROO.). However, our endogenous antioxidant defense systems are incomplete without exogenous originating reducing compounds such as vitamin C, vitamin E, carotenoids and polyphenols, playing an essential role in many antioxidant mechanisms in living organisms. Therefore, there is continuous demand for exogenous antioxidants in order to prevent oxidative stress, representing a disequilibrium redox state in favor of oxidation. However, high doses of isolated compounds may be toxic, owing to prooxidative effects at high concentrations or their potential to react with beneficial concentrations of ROS normally present at physiological conditions that are required for optimal cellular functioning. This review aims to examine the double-edged effects of dietary originating antioxidants with a focus on the most abundant compounds, especially polyphenols, vitamin C, vitamin E and carotenoids. Different approaches to enrich our body with exogenous antioxidants such as via synthetic antioxidants, diets rich in fruits and vegetables and taking supplements will be reviewed and experimental and epidemiological evidences discussed, highlighting that antioxidants at physiological doses are generally safe, exhibiting interesting health beneficial effects. PMID:20972369

  16. Animal cells dependent on exogenous phosphatidylcholine for membrane biogenesis.

    PubMed Central

    Esko, J D; Nishijima, M; Raetz, C R

    1982-01-01

    A Chinese hamster ovary cell (CHO) mutant (strain 58), defective in CDP-choline synthetase (cholinephosphate cytidylyltransferase; CTP:cholinephosphate cytidylyltransferase, EC 2.7.7.15), is temperature sensitive for growth and contains less than half of the normal amount of phosphatidylcholine under nonpermissive conditions [Esko, J. D. & Raetz, C. R. H. (1980) Proc. Natl. Acad. Sci. USA 77, 5192-5196]. We now report that the addition of 40 microM egg phosphatidylcholine or lysophosphatidylcholine to the medium suppresses the temperature sensitivity of mutant 58 and permits the growth of colonies at the restrictive temperature. Phospholipids with different polar headgroups, lipoprotein-bound phospholipids, sphingomyelin, and glycerophosphocholine do not support prolonged growth at 40 degrees C, whereas phosphatidylcholine analogs such as phosphatidyldimethylethanolamine, D-phosphatidylcholine, and beta-phosphatidylcholine are quite effective. A broad range of saturated phosphatidylcholines, especially those with fatty acids 12-18 carbons in length, suppresses the phenotype. Phospholipids containing ether-linked hydrocarbons are ineffective, whereas polyunsaturated phosphatidylcholines are toxic. Residual endogenous synthesis of phosphatidylcholine by the mutant is not stimulated under conditions of phenotypic bypass, but the uptake of exogenous lipid is enhanced considerably compared to the wild type. Our findings demonstrate that exogenous phospholipid can provide at least 50% of the phosphatidylcholine required for membrane biogenesis in animal cells and that uptake of exogenous phospholipids may be regulated. PMID:6281780

  17. 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. ...

  18. 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...

  19. Direct radioimmunoassay of urinary estrogen and pregnanediol glucuronides during the menstrual cycle

    SciTech Connect

    Stanczyk, F.Z.; Miyakawa, I.; Goebelsmann, U.

    Assays measuring immunoreactive estrone glucuronide (E/sub 1/G), estradiol-3-glucuronide (E/sub 2/-3G), estradiol-17..beta..-glucuronide (E/sub 2/-17G), estriol-3-glucuronide (E/sub 3/-3G), estriol-16..cap alpha..-glucuronide (E/sub 3/-16G), and pregnanediol-3..cap alpha..-glucuronide (Pd-3G) directly in diluted urine were developed and validated. These estrogen and pregnanediol glucuronide fractions were measured in aliquots of 24-hour and overnight samples of urine collected daily from seven women for one menstrual cycle. Urinary hormone excretion was correlated with daily serum estradiol (E/sub 2/), progesterone (P), and lutenizing hormonee (LH) levels. A sharp midcycle LH peak preceded by a preovulatory rise in serum E/sub 2/ and followed by luteal phase serum P levels were notedmore » in each of the seven apparently ovulatory cycles. Twenty-four-hour and overnight urinary excretion patterns of estrogen glucuronides were similar to those of serum E/sub 2/. Of the five estrogen glucuronide fractions tested, excretion of E/sub 2/-17G exhibited the earliest and steepest ascending slope of the preovulatory estrogen surge and correlated best with serum E/sub 2/ levels. Urinary excretion of E/sub 1/-G, E/sub 2/-3G, and E/sub 3/-16G also showed an early and steep preovulatory rise and preceded that of E/sub 3/-3G, whereas urinary excretion of E/sub 3/-3G exhibited the poorest correlation with serum E/sub 2/ concentrations. The urinary excretion of Pd-3G rose parallel to serum P levels and was markedly elevated 2 to 3 days after the midcycle LH peak in both 24-hour and overnight collections of urine. These results indicate that among the urinary estrogen conjugate fractions tested, E/sub 2/-17G is the one that most suitably predicts ovulation.« less

  20. 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...

  1. 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.

  2. 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

  3. 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...

  4. 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...

  5. 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. © Society for the Experimental Analysis of Behavior.

  6. Estrogenic</