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Kumar, Anita, Antara Banerjee, Dipty Singh, Gargi Thakur, Nandini Kasarpalkar, Shubhangi Gavali, Sushama Gadkar et al. "Estradiol: A Steroid with Multiple Facets". Hormone and Metabolic Research 50, n.º 05 (22 de marzo de 2018): 359–74. http://dx.doi.org/10.1055/s-0044-100920.
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AbstractSeventy-five glorious years have passed since estradiol was discovered by Edward Doisy. From discovery in the ovaries to delineation of diverse physiological effects, research on estrogens has covered a lot of ground. Estrogen receptors that mediate estrogenic effects, have been detected not only in reproductive organs, but also in other body organs. Estrogen receptors function either as conventional transcription factors or as rapid signal transducers. These different modes of action are opted by estrogens to elicit an array of reproductive and non-reproductive functions. It is well established that estrogens promote cell proliferation in various tissues and hence are also linked to carcinogenesis. Anti-estrogens are being used as adjunct therapies for cancers since several years. On the other hand, estrogen-based strategies are used to alleviate adverse effects of menopause. Apart from estrogens synthesized in various organs, exposure to environmental estrogens can also impact physiology. Thus, too much or too less of estrogens can tip the balance and lead to unfavorable consequences. Multiple estrogen receptors with their tissue- or cell type-specific expression eliciting dose-dependent effects make it perplexing to ‘unify’ estrogenic actions in diverse tissues/organs. This warrants more research on estrogen-mediated effects and their regulation in somatic and reproductive tissues. This review presents physiological and pathological aspects of estrogens thus highlighting the good, bad, and ugly facets of estrogens.
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Elger, W., A. Barth, A. Hedden, G. Reddersen, P. Ritter, B. Schneider, J. Züchner et al. "Estrogen sulfamates: a new approach to oral estrogen therapy". Reproduction, Fertility and Development 13, n.º 4 (2001): 297. http://dx.doi.org/10.1071/rd01029.
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Sulfamate substitution (-O-SO 2-NH 2) at carbon atom 3 of the steroid skeleton leads to orally active prodrugs of estrogens with much higher systemic, but lower hepatic, estrogenic activity than their parent steroids. This dissociation is achieved by first passage through the liver in erythrocytes, followed by systemic hydrolysis which releases the ‘parent’ estrogen. In the rat, orally administered tritiated estradiol sulfamate, unlike estradiol, appears in the circulation at high concentrations. At C max , approximately one third of the administered dose forms a depot in the circulation (98% in erythrocytes, 2% in plasma). Significant estradiol, estrone and estrone sulfate concentrations were recorded in plasma during depletion of the red blood cell pool. Estradiol sulfamate (J995) has no estrogen receptor affinity per se or estrogenic activity in vitro ( i.e. without hydrolysis). Its oral uterotropic activity in rats is approximately 100 times greater than that of estradiol, however, its hepatotropic activity is only marginally elevated. These functions include bile secretion, the secretion of angiotensinogen, lipoproteins (total and high-density lipoprotein cholesterol) and insulin-like growth factor I (IGF-I). Orally administred estradiol sulfamate led to systemic estrogenic effects without significant hepatic responses, whereas estradiol and other ‘conventional’ estrogens exerted parallel systemic and hepatic estrogenic effects. Sulfamate technology represents an approach to the use of natural estrogens for fertility control and hormone replacement therapy in both genders. In this context, reduced effects on hemostatic factors, angiotensinogen, bile and IGF-I secretion seem the most important aspects. In addition, blood concentrations of estrogens are less variable than with conventional estrogens.
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O’Leary, Emily, Connor Davis, Molly Mancheski, Peng Ma y Thomas Wiese. "PMON14 Estrogen Activity of Supplements Targeted for Post-Menopausal Women". Journal of the Endocrine Society 6, Supplement_1 (1 de noviembre de 2022): A440—A441. http://dx.doi.org/10.1210/jendso/bvac150.916.
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Abstract A wide variety of dietary supplements are available for the treatment of post-menopausal symptoms in women. Many women choose these supplements to avoid the potential unwanted side effects and long-term complications associated with traditional hormone therapy. In this study, we evaluated the in vitro estrogen activity of extracts from eleven supplements targeted for post-menopausal women to test the hypothesis that some of these supplements will induce estrogen activity in human breast cancer cell bioassays. Ethanol extracts (1 g: 1 mL) were prepared from the supplements: Amberen, Nature's Bounty Black Cohosh, Nature's Bounty St. John's Wort, Swanson Chasteberry Fruit, Nature's Way Red Clover, Promensil Real Health, Estroven, Relizen, Remifemin, and Equelle. Black cohosh, St. John's Wort, Chasteberry fruit, and red clover are standalone products that are not sold under a brand name. Promensil, Estroven, and Equelle contain isoflavones that have been reported to be estrogenic. Estroven and Remifemin contain black cohosh. Relizen contains a purified Swedish flower pollen extract and Amberen contains succinates, amino acids, minerals, and vitamin E. The estrogen activity of each extract was measured using both the T47D-kb-Luc estrogen responsive reporter gene and MCF-7 E3 proliferation estrogen bio-assays. The extracts from Nature's Way Red Clover, Promensil Real Health, and Equelle induced full estrogen agonist efficacy in the MCF-7 proliferation assay and more than full efficacy in the T47D-kb-Luc assay compared to estradiol. The agonist activity of these extracts in both bio-assays was inhibited by fulvestrant. Extracts from Nature's Bounty Black Cohosh, Nature's Bounty St. John's Wort, Swanson Chasteberry Fruit and Relizen induced less than full agonist estrogen activity only in the MCF-7 proliferation assay that was not, or not completely inhibited by fulvestrant. Thus, some supplements in this study likely target the estrogen receptor as agonists while others may be only weak estrogens that may also activate other proliferative pathways. While estrogen therapy is known to provide relief of some post-menopausal symptoms, estrogen use is associated with increased breast cancer risk. Consumers may benefit from information about the estrogen activity of supplements targeted for post-menopausal women. The results of this study may allow women to make more informed decisions about the use of these supplements. This study may be a prototype for evaluating the estrogen activity of dietary supplements for the purpose of informing consumers. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
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Matsui, S., H. Takigami, T. Matsuda, N. Taniguchi, J. Adachi, H. Kawami y Y. Shimizu. "Estrogen and estrogen mimics contamination in water and the role of sewage treatment". Water Science and Technology 42, n.º 12 (1 de diciembre de 2000): 173–79. http://dx.doi.org/10.2166/wst.2000.0265.
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The yeast estrogen screen was applied to sewage treatment process waters to identify the presence of estrogenic activity and to investigate the fate and behavior of estrogenic substances through treatment. Hydrophobic fractions in the water phase were extracted and concentrated using C18 cartridges for the effective extraction of 17β-estradiol (E2) and other estrogen mimics. Clear dose-dependent elevation in the synthesis of β-galactosidase in the yeast screen was observed with all the samples tested, demonstrating that these samples were estrogenic. However, estrogenic activity tended to reduce during the treatment, especiallyiin the biological process. Quantification results of the yeast estrogen screen in terms of E2 equivalent were compared with actual E2 concentrations measured by an ELISA. E2 occupied 34% of the whole estrogenicity in the raw sewage, while almost 100% in the final effluent. The analyses of the sewage treatment process waters revealed that human estrogens are major causative substances in terms of estrogenic activity in sewage and its treated effluent. Although findings of possible correlation of environmental estrogens with the real impact on human health and the ecosystem are still the focus of scientific debate and investigation, proper management should be established in the sewage treatment process which receives various environmental contaminants.
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Liang, Rubing, Jing Zhou y Jianhua Liu. "Construction of a Bacterial Assay for Estrogen Detection Based on an Estrogen-Sensitive Intein". Applied and Environmental Microbiology 77, n.º 7 (11 de febrero de 2011): 2488–95. http://dx.doi.org/10.1128/aem.02336-10.
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ABSTRACTEscherichia colistrain DIER was constructed for estrogen detection by inserting an estrogen-sensitive intein (VMAERintein) into the specific site of the constitutively expressed chromosomallacZgene. This VMAERintein was generated by replacing the endonuclease region of theSaccharomyces cerevisiaeVMA intein with the estrogen binding region of the human estrogen receptor α (hERα). When there were estrogens or analogs, the splicing of the VMAERintein was induced to produce the mature LacZ protein, which was detected through a β-galactosidase colorimetric assay. Eight typical chemicals (17-β-estradiol, bisphenol A, chrysene, 6-OH-chrysene, benz[a]anthracene, pyrene, progesterone, and testosterone) were detected using this DIER strain, and the whole detection procedure was accomplished in 2 h. Their 50% effective concentrations (EC50), relative estrogenic activities, and estradiol equivalency factors were calculated and were quite consistent with those detected with the yeast estrogen screening (YES) system. Furthermore, the estrogenic activities of the synthetic musk samples extracted from the wastewater and waste sludge of a sewage treatment plant of Shanghai (China) were detected, and their results were comparable to those obtained from the YES system and gas chromatography-mass spectrometry (GC-MS). In conclusion, the DIER bioassay could fill a niche for the efficient, rapid, high-throughput screening of estrogenic compounds and has potential for the remote, near-real-time monitoring of environmental estrogens.
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O’Donnell, Liza, Kirsten M. Robertson, Margaret E. Jones y Evan R. Simpson. "Estrogen and Spermatogenesis*". Endocrine Reviews 22, n.º 3 (1 de junio de 2001): 289–318. http://dx.doi.org/10.1210/edrv.22.3.0431.
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Abstract Although it has been known for many years that estrogen administration has deleterious effects on male fertility, data from transgenic mice deficient in estrogen receptors or aromatase point to an essential physiological role for estrogen in male fertility. This review summarizes the current knowledge on the localization of estrogen receptors and aromatase in the testis in an effort to understand the likely sites of estrogen action. The review also discusses the many studies that have used models employing the administration of estrogenic substances to show that male fertility is responsive to estrogen, thus providing a mechanism by which inappropriate exposure to estrogenic substances may cause adverse effects on spermatogenesis and male fertility. The reproductive phenotypes of mice deficient in estrogen receptors α and/or β and aromatase are also compared to evaluate the physiological role of estrogen in male fertility. The review focuses on the effects of estrogen administration or deprivation, primarily in rodents, on the hypothalamo-pituitary-testis axis, testicular function (including Leydig cell, Sertoli cell, and germ cell development and function), and in the development and function of the efferent ductules and epididymis. The requirement for estrogen in normal male sexual behavior is also reviewed, along with the somewhat limited data on the fertility of men who lack either the capacity to produce or respond to estrogen. This review highlights the ability of exogenous estrogen exposure to perturb spermatogenesis and male fertility, as well as the emerging physiological role of estrogens in male fertility, suggesting that, in this local context, estrogenic substances should also be considered “male hormones.”
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Chmielewska, Małgorzata, Izabela Skibińska y Małgorzata Kotwicka. "Mitochondria: Target organelles for estrogen action". Postępy Higieny i Medycyny Doświadczalnej 71, n.º 1 (8 de junio de 2017): 0. http://dx.doi.org/10.5604/01.3001.0010.3828.
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Estrogens belong to a group of sex hormones, which have been shown to act in multidirectional way. Estrogenic effects are mediated by two types of intracellular receptors: estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2). There are two basic mechanisms of estrogen action: 1) classical-genomic, in which the ligand-receptor complex acts as a transcriptional factor and 2) a nongenomic one, which is still not fully understood, but has been seen to lead to distinct biological effects, depending on tissue and ligand type. It is postulated that nongenomic effects may be associated with membrane signaling and the presence of classical nuclear receptors within the cell membrane. Estrogens act in a multidirectional way also within cell organelles. It is assumed that there is a mechanism which manages the migration of ESR into the mitochondrial membrane, wherein the exogenous estrogen affect the morphology of mitochondria. Estrogen, through its receptor, can directly modulate mitochondrial gene expression. Moreover, by regulating the level of reactive oxygen species, estrogens affect the biology of mitochondria. The considerations presented in this paper indicate the pleiotropic effects of estrogens, which represent a multidirectional pathway of signal transduction.
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Lee, Richard R. y Karen P. Phillips. "Role of Estrogen Receptors in Male Reproductive Physiology". Revue interdisciplinaire des sciences de la santé - Interdisciplinary Journal of Health Sciences 3, n.º 1 (10 de marzo de 2016): 40–45. http://dx.doi.org/10.18192/riss-ijhs.v3i1.1452.
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Canonical estrogen receptors (ER α/β) have a genomic mechanism of action, functioning as nuclear transcription factors for estrogen-dependent genes. Estrogen receptors are well established within the male reproductive tract with estrogen playing an essential role for male fertility. The recent characterization of novel G-protein coupled estrogen receptor GPR30 (alternatively known as GPER1), depending on non-genomic intracellular signaling pathways to transduce estrogenic signals, requires a re-examination of the roles of estrogen receptors in male reproduction. Further, the affinity of environmental estrogens (xenoestrogens) for estrogen receptor subtypes may provide additional understanding of the reproductive effects of these chemicals on male fertility. Here we review the structure and functions of each estrogen receptor within the context of male reproduction, with special consideration of the reproductive implications of xenoestrogen exposure.
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Hashimoto, T., K. Takahashi y T. Murakami. "Characteristics of estrogen decomposition by ozonation". Water Science and Technology 54, n.º 10 (1 de noviembre de 2006): 87–93. http://dx.doi.org/10.2166/wst.2006.806.
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Since the natural estrogens 17 β-estradiol (E2) and estron (E1), and the synthetic estrogen 17 α-ethynyl estradiol (EE2) have strong endocrine disrupting effects and the tendency to persist in effluent from wastewater treatment plants, effective measures are needed to remove them from wastewater. In this research, to gain an understanding of the characteristics of estrogen decomposition by ozonation, experiments were conducted using effluent from an actual wastewater treatment plant. In this experiment, estrogen was added to effluent at a concentration of 200 ng/l and 20 ng/l before the ozonation experiments. The results showed 90% or more of estrogen concentration and estrogenic activity of E2, E1 and EE2 to be removed at an ozone dose of 1 mg/l. At an ozone dose of 3 mg/l, the estrogen concentration and estrogenic activity of E2, E1 and EE2 in the treated water fell below the detection limit. The removal rate was not influenced by the kind of estrogen. No generation of byproducts with estrogenic activity was observed. The authors conclude that estrogen in secondary treated wastewater can be almost entirely removed at the practical ozone dose rate applied for the purpose of disinfection, which is up to about 5 mg/l.
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Chang, Minsun, Kuan-wei Peng, Irida Kastrati, Cassia R. Overk, Zhi-Hui Qin, Ping Yao, Judy L. Bolton y Gregory R. J. Thatcher. "Activation of Estrogen Receptor-Mediated Gene Transcription by the Equine Estrogen Metabolite, 4-Methoxyequilenin, in Human Breast Cancer Cells". Endocrinology 148, n.º 10 (1 de octubre de 2007): 4793–802. http://dx.doi.org/10.1210/en.2006-1568.
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4-Methoxyequilenin (4-MeOEN) is an O-methylated metabolite in equine estrogen metabolism. O-methylation of catechol estrogens is considered as a protective mechanism; however, comparison of the properties of 4-MeOEN with estradiol (E2) in human breast cancer cells showed that 4-MeOEN is a proliferative, estrogenic agent that may contribute to carcinogenesis. 4-MeOEN results from O-methylation of 4-hydroxyequilenin, a major catechol metabolite of the equine estrogens present in hormone replacement therapeutics, which causes DNA damage via quinone formation, raising the possibility of synergistic hormonal and chemical carcinogenesis. 4-MeOEN induced cell proliferation with nanomolar potency and induced estrogen response element (ERE)-mediated gene transcription of an ERE-luciferase reporter and the endogenous estrogen-responsive genes pS2 and TGF-α. These estrogenic actions were blocked by the antiestrogen ICI 182,780. In the standard radioligand estrogen receptor (ER) binding assay, 4-MeOEN showed very weak binding. To test for alternate ligand-ER-independent mechanisms, the possibility of aryl hydrocarbon receptor (AhR) binding and ER-AhR cross talk was examined using a xenobiotic response element-luciferase reporter and using AhR small interfering RNA silencing in the ERE-luciferase reporter assay. The results negated the possibility of AhR-mediated estrogenic activity. Comparison of gene transcription time course, ER degradation, and rapid activation of MAPK/ERK in MCF-7 cells demonstrated that the actions of 4-MeOEN mirrored those of E2 with potency for classical and nonclassical estrogenic pathways bracketing that of E2. Methylation of 4-OHEN may not represent a detoxification pathway because 4-MeOEN is a full, potent estrogen agonist.
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Arterburn, Jeffrey B. y Eric R. Prossnitz. "G Protein–Coupled Estrogen Receptor GPER: Molecular Pharmacology and Therapeutic Applications". Annual Review of Pharmacology and Toxicology 63, n.º 1 (20 de enero de 2023): 295–320. http://dx.doi.org/10.1146/annurev-pharmtox-031122-121944.
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The actions of estrogens and related estrogenic molecules are complex and multifaceted in both sexes. A wide array of natural, synthetic, and therapeutic molecules target pathways that produce and respond to estrogens. Multiple receptors promulgate these responses, including the classical estrogen receptors of the nuclear hormone receptor family (estrogen receptors α and β), which function largely as ligand-activated transcription factors, and the 7-transmembrane G protein–coupled estrogen receptor, GPER, which activates a diverse array of signaling pathways. The pharmacology and functional roles of GPER in physiology and disease reveal important roles in responses to both natural and synthetic estrogenic compounds in numerous physiological systems. These functions have implications in the treatment of myriad disease states, including cancer, cardiovascular diseases, and metabolic disorders. This review focuses on the complex pharmacology of GPER and summarizes major physiological functions of GPER and the therapeutic implications and ongoing applications of GPER-targeted compounds.
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Ansell, P. J., C. Espinosa-Nicholas, E. M. Curran, B. M. Judy, B. J. Philips, M. Hannink y D. B. Lubahn. "In Vitro and in Vivo Regulation of Antioxidant Response Element-Dependent Gene Expression by Estrogens". Endocrinology 145, n.º 1 (1 de enero de 2004): 311–17. http://dx.doi.org/10.1210/en.2003-0817.
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Abstract Understanding estrogen’s regulation of phase II detoxification enzymes is important in explaining how estrogen exposure increases the risk of developing certain cancers. Phase II enzymes such as glutathione-S-transferases (GST) and quinone reductase protect against developing chemically induced cancers by metabolizing reactive oxygen species. Phase II enzyme expression is regulated by a cis-acting DNA sequence, the antioxidant response element (ARE). It has previously been reported that several antiestrogens, but not 17β-estradiol, could regulate ARE-mediated gene transcription. Our goal was to determine whether additional estrogenic compounds could regulate ARE-mediated gene expression both in vitro and in vivo. We discovered that physiological concentrations (10 nm) of 17β-estradiol repressed GST Ya ARE-dependent gene expression in vitro. Treatment with other endogenous and anti-, xeno-, and phytoestrogens showed that estrogen receptor/ARE signaling is ligand, receptor subtype, and cell type specific. Additionally, GST and quinone reductase activities were significantly lowered in a dose-dependent manner after 17β-estradiol exposure in the uteri of mice. In conclusion, we have shown that 17β-estradiol, and other estrogens, down-regulate phase II enzyme activities. We propose estrogen-mediated repression of phase II enzyme activities may increase cellular oxidative DNA damage that ultimately can result in the formation of cancer in some estrogen-responsive tissues.
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Lucà, Rossella, Giorgia di Blasio, Daniela Gallo, Valentina Monteleone, Isabella Manni, Laura Fici, Marianna Buttarelli et al. "Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4". Cancers 11, n.º 9 (12 de septiembre de 2019): 1349. http://dx.doi.org/10.3390/cancers11091349.
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Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impact of estrogens on both MDM4 activities. In Mdm4 transgenic mouse, Mdm4 accelerates the formation of fibrosarcoma and increases tumor sensitivity to cisplatin as well, thus confirming in vivo Mdm4 dual mode of action. Noteworthy, Mdm4 enhances chemo- and radio-sensitivity in male but not in female animals, whereas its tumor-promoting activity is not affected by mouse gender. Combination therapy of transgenic females with cisplatin and fulvestrant, a selective estrogen receptor degrader, was able to recover tumor cisplatin-sensitivity, demonstrating the relevance of estrogens in the observed sexual dimorphism. Molecularly, estrogen receptor-α alters intracellular localization of MDM4 by increasing its nuclear fraction correlated to decreased cell death, in a p53-independent manner. Importantly, MDM4 nuclear localization and intra-tumor estrogen availability correlate with decreased platinum-sensitivity and apoptosis and predicts poor disease-free survival in high-grade serous ovarian carcinoma. These data demonstrate estrogen ability to modulate chemo-sensitivity of MDM4-expressing tumors and to impinge on intracellular trafficking. They support potential usefulness of combination therapy involving anti-estrogenic drugs.
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Gea, Marta, Chao Zhang, Roberta Tota, Gianfranco Gilardi, Giovanna Di Nardo y Tiziana Schilirò. "Assessment of Five Pesticides as Endocrine-Disrupting Chemicals: Effects on Estrogen Receptors and Aromatase". International Journal of Environmental Research and Public Health 19, n.º 4 (10 de febrero de 2022): 1959. http://dx.doi.org/10.3390/ijerph19041959.
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Pesticides are widely applied all over the world, and pesticide exposure can induce different biological effects posing a possible threat to human health. Due to their effects on the endocrine system, some pesticides are classified as endocrine disruptors. The aim of the study is to assess the interference of five pesticides on estrogen biosynthesis and estrogen signaling. Three neonicotinoid insecticides (Acetamiprid, Clothianidin, and Thiamethoxam), a carbamate insecticide (Methiocarb) and a herbicide (Oxadiazon) were tested. The effect of pesticides on estrogen biosynthesis was studied through an ELISA assay using a recombinant form of human aromatase, the enzyme that catalyzes the transformation of androgens to estrogens. Moreover, the effect of pesticides on estrogen signaling was assessed using a gene reporter assay on MELN cells, which measures estrogen receptor-mediated estrogenic activity. The results of the ELISA assay showed that the pesticides did not alter aromatase activity (no interference with estrogen biosynthesis), while the results of the gene reporter assay showed that only Methiocarb was able to alter estrogen signaling at high doses. The estrogenic activity of Methiocarb, expressed as 17β-estradiol equivalency factor (EEF), was equal to 8.0 × 10−8. In conclusion, this study suggested that Methiocarb should be considered a potential endocrine disruptor.
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Liu, Yan Qun y Xiong Bing Lu. "Establishing a Assay for Detection of Nonylphenol Estrogenic Effects". Applied Mechanics and Materials 71-78 (julio de 2011): 3003–6. http://dx.doi.org/10.4028/www.scientific.net/amm.71-78.3003.
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Environmental estrogen could mimic natural estrogens thereby disrupting the endocrine systems of human and animals. The actions of such endocrine disruptors have been studied mainly on reproduction and development. To explore the estrogenic effects of NP by reporter genebased assays we developed. pERE-GFP plamid was generated by inserting estrogen response element fragment into pGADD153-GFP. the recombinant was confirmed by restriction enzyme map and transfected into SPC-A1 cells to ensure the expression of green fluorescent protein．The assay we established in usful, NP could induce the estrogenic activities at any of the tested concentrations.
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Schenck, Kathleen, Laura Rosenblum, Thomas E. Wiese, Larry Wymer, Nicholas Dugan, Daniel Williams, Heath Mash, Betty Merriman y Thomas Speth. "Removal of estrogens and estrogenicity through drinking water treatment". Journal of Water and Health 10, n.º 1 (16 de octubre de 2011): 43–55. http://dx.doi.org/10.2166/wh.2011.135.
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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%.
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Wojnarowski, Konrad, Paulina Cholewińska, Dušan Palić, Małgorzata Bednarska, Magdalena Jarosz y Iga Wiśniewska. "Estrogen Receptors Mediated Negative Effects of Estrogens and Xenoestrogens in Teleost Fishes—Review". International Journal of Molecular Sciences 23, n.º 5 (26 de febrero de 2022): 2605. http://dx.doi.org/10.3390/ijms23052605.
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Estrogen receptors (ERs) play a key role in many biochemical and physiological processes, that are involved in maintaining organism homeostasis. At the most basic level, they can be divided into nuclear estrogen receptors and membrane estrogen receptors that imply their effect in two ways: slower genomic, and faster non-genomic. In these ways, estrogens and xenoestrogens can negatively affect animal health and welfare. Most of the available literature focuses on human and mammalian physiology, and clearly, we can observe a need for further research focusing on complex mutual interactions between different estrogens and xenoestrogens in aquatic animals, primarily fishes. Understanding the mechanisms of action of estrogenic compounds on the ERs in fishes and their negative consequences, may improve efforts in environmental protection of these animals and their environment and benefit society in return. In this review, we have summarized the ER-mediated effects of xenoestrogens and estrogens on teleost fishes metabolism, their carcinogenic potential, immune, circulatory, and reproductive systems.
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Rodrigo, Manoj C., Douglas S. Martin y Kathleen M. Eyster. "Estrogen decreases biglycan mRNA expression in resistance blood vessels". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 285, n.º 4 (octubre de 2003): R754—R761. http://dx.doi.org/10.1152/ajpregu.00540.2002.
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This study was designed to identify new gene targets of estrogen in the mesenteric arteries and to determine whether the soy phytoestrogens could mimic estrogen effects. Ovariectomized rats were treated with estradiol, genistein, or daidzein for 4 days. The mesenteric arteries were harvested, total RNA was extracted, mRNA was reverse transcribed in the presence of [33P]dCTP, and the labeled probes were hybridized with DNA microarrays. Analysis of the microarray data identified biglycan as a target of estrogenic regulation. Semiquantitative RT-PCR was used to confirm and quantitate the decrease in biglycan gene expression in response to estrogen (-37%), genistein (-15%), and daidzein (-10%). Treatment with the pure estrogen receptor antagonist ICI-182,780 reversed the inhibition of biglycan gene expression. The decrease in biglycan gene expression in response to estrogens was paralleled with a decrease in biglycan protein expression. Biglycan protein was localized to the media of the mesenteric arteries by immunohistochemistry. Collectively, these data suggest that biglycan is a vascular protein regulated at the genomic level by estrogens.
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Mérot, Yohann, François Ferrière, Edith Debroas, Gilles Flouriot, Dominique Duval y Christian Saligaut. "Estrogen receptor alpha mediates neuronal differentiation and neuroprotection in PC12 cells: critical role of the A/B domain of the receptor". Journal of Molecular Endocrinology 35, n.º 2 (octubre de 2005): 257–67. http://dx.doi.org/10.1677/jme.1.01826.
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Numerous studies, both in vivo and in vitro, have reported neuronal differentiating and neuroprotective actions of estrogens. Most of these estrogenic effects are mediated through specific receptors termed estrogen receptors. The aim of this study was to assess the importance of the N-terminal A/B domain of the estrogen receptor-alpha (ERα) in its neuronal aspects. Consequently, estrogen effects on (i) the transcriptional activity of target genes, (ii) neuronal differentiation and (iii) neuroprotection in PC12 cells transfected with either a full length form of ERα or an A/B domain truncated form (ERαCF), have been studied. We demonstrate that the maximal estrogen-induced transcriptional activity of reporter genes requires a full length ERα, especially when cells are differentiated. Precisely, the transcriptional activity of ERα in differentiated cells relies, predominantly, on the activation function AF-1, located in the A/B domain. Furthermore, in PC12 cells stably expressing ERα, 17β-estradiol markedly enhances the neurite outgrowth triggered by treatment with nerve growth factor and protects cells from oxidative shocks induced by depletion of glutathione. These estrogenic effects are not observed in non-transfected cells and in cells transfected with the truncated ER, devoid of the A/B domain. Altogether, these results underline the importance of the A/B domain of ERα in both the differentiating and the neuroprotective effects of estrogens.
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Jordan, V. Craig. "The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer". Endocrine-Related Cancer 22, n.º 1 (22 de octubre de 2014): R1—R31. http://dx.doi.org/10.1530/erc-14-0448.
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The successful use of high-dose synthetic estrogens to treat postmenopausal metastatic breast cancer is the first effective ‘chemical therapy’ proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) in postmenopausal hysterectomized women, which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen-induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long-term estrogen deprivation. However, estrogen-independent growth occurs through trial and error. At the cellular level, estrogen-induced apoptosis is dependent upon the presence of the estrogen receptor (ER), which can be blocked by nonsteroidal or steroidal antiestrogens. The shape of an estrogenic ligand programs the conformation of the ER complex, which, in turn, can modulate estrogen-induced apoptosis: class I planar estrogens (e.g., estradiol) trigger apoptosis after 24 h, whereas class II angular estrogens (e.g., bisphenol triphenylethylene) delay the process until after 72 h. This contrasts with paclitaxel, which causes G2 blockade with immediate apoptosis. The process is complete within 24 h. Estrogen-induced apoptosis is modulated by glucocorticoids and cSrc inhibitors, but the target mechanism for estrogen action is genomic and not through a nongenomic pathway. The process is stepwise through the creation of endoplasmic reticulum stress and inflammatory responses, which then initiate an unfolded protein response. This, in turn, initiates apoptosis through the intrinsic pathway (mitochondrial) with the subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a 5-year gap is necessary after menopause to permit the selection of estrogen-deprived breast cancer cell populations to cause them to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around menopause encourages growth of ER-positive tumor cells, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen-induced apoptosis can be orchestrated in the laboratory in estrogen-deprived breast cancers now supports the clinical findings regarding the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long-term antihormonal adjuvant therapy, and the results of treatment with ERT and ERT plus progestin in the Women's Health Initiative for women over the age of 60. Principles have emerged for understanding and applying physiological estrogen therapy appropriately by targeting the correct patient populations.
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Le, Hoa H. y Scott M. Belcher. "Rapid Signaling Actions of Environmental Estrogens in Developing Granule Cell Neurons Are Mediated by Estrogen Receptor β". Endocrinology 151, n.º 12 (6 de octubre de 2010): 5689–99. http://dx.doi.org/10.1210/en.2010-0710.
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Estrogenic endocrine disrupting chemicals (EDCs) constitute a diverse group of man-made chemicals and natural compounds derived from plants and microbial metabolism. Estrogen-like actions are mediated via the nuclear hormone receptor activity of estrogen receptor (ER)α and ERβ and rapid regulation of intracellular signaling cascades. Previous study defined cerebellar granule cell neurons as estrogen responsive and that granule cell precursor viability was developmentally sensitive to estrogens. In this study experiments using Western blot analysis and pharmacological approaches have characterized the receptor and signaling modes of action of selective and nonselective estrogen ligands in developing cerebellar granule cells. Estrogen treatments were found to briefly increase ERK1/2-phosphorylation and then cause prolonged depression of ERK1/2 activity. The sensitivity of granule cell precursors to estrogen-induced cell death was found to require the integrated activation of membrane and intracellular ER signaling pathways. The sensitivity of granule cells to selective and nonselective ER agonists and a variety of estrogenic and nonestrogenic EDCs was also examined. The ERβ selective agonist DPN, but not the ERα selective agonist 4,4′,4′-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol or other ERα-specific ligands, stimulated cell death. Only EDCs with selective or nonselective ERβ activities like daidzein, equol, diethylstilbestrol, and bisphenol A were observed to induce E2-like neurotoxicity supporting the conclusion that estrogen sensitivity in granule cells is mediated via ERβ. The presented results also demonstrate the utility of estrogen sensitive developing granule cells as an in vitro assay for elucidating rapid estrogen-signaling mechanisms and to detect EDCs that act at ERβ to rapidly regulate intracellular signaling.
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Delarue, F., S. Daunes, R. Elhage, A. Garcia, F. Bayard y J. C. Faye. "Estrogens modulate bovine vascular endothelial cell permeability and HSP 25 expression concomitantly". American Journal of Physiology-Heart and Circulatory Physiology 275, n.º 3 (1 de septiembre de 1998): H1011—H1015. http://dx.doi.org/10.1152/ajpheart.1998.275.3.h1011.
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The atheroprotective properties of estrogens are supported by clinical data from postmenopausal women who use estrogen replacement therapy. However, the mechanisms mediating activity remain unknown, and it has been suggested that estrogens may help to modulate endothelial permeability to atherogenic lipoproteins. In these studies we used bovine vascular endothelial cells as an in vitro model to show that estrogens were able to regulate low-density lipoprotein transport and permeability of the endothelial monolayer. Macromolecular transport was observed to be a second-order polynomial function of estrogen concentration. Moreover, this regulation was correlated with expression of heat shock protein (HSP) 25, which is known to influence fluid phase pinocytosis and cytoskeleton remodeling, thus suggesting a role for HSP 25 in the estrogenic control of transcellular permeability of the endothelium monolayer.
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Lee, Heehyoung y Wenlong Bai. "Regulation of Estrogen Receptor Nuclear Export by Ligand-Induced and p38-Mediated Receptor Phosphorylation". Molecular and Cellular Biology 22, n.º 16 (15 de agosto de 2002): 5835–45. http://dx.doi.org/10.1128/mcb.22.16.5835-5845.2002.
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ABSTRACT Estrogen receptors are phosphoproteins which can be activated by ligands, kinase activators, or phosphatase inhibitors. Our previous study showed that p38 mitogen-activated protein kinase was involved in estrogen receptor activation by estrogens and MEKK1. Here, we report estrogen receptor-dependent p38 activation by estrogens in endometrial adenocarcinoma cells and in vitro and in vivo phosphorylation of the estrogen receptor α mediated through p38. The phosphorylation site was identified as threonine-311 (Thr311), located in helix 1 of the hormone-binding domain. The mutation of threonine-311 to alanine did not affect estrogen binding of the receptor but compromised its interaction with coactivators. Suppression of p38 activity or mutation of the site inhibited the estrogen-induced receptor nuclear localization as well as its transcriptional activation by estrogens and MEKK1. The inhibition of the p38 signal pathway by a specific chemical inhibitor blocked the biological activities of estrogens in regulating endogenous gene expression as well as endometrial cancer cell growth. Our studies demonstrate the role of estrogen receptor phosphorylation induced by the natural ligand in estrogen receptor's cellular distribution and its significant contribution to the growth-stimulating activity of estrogens in endometrial cancer cells.
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Harrington, William R., Sung Hoon Kim, Cory C. Funk, Zeynep Madak-Erdogan, Rachel Schiff, John A. Katzenellenbogen y Benita S. Katzenellenbogen. "Estrogen Dendrimer Conjugates that Preferentially Activate Extranuclear, Nongenomic Versus Genomic Pathways of Estrogen Action". Molecular Endocrinology 20, n.º 3 (1 de marzo de 2006): 491–502. http://dx.doi.org/10.1210/me.2005-0186.
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Abstract Estrogenic hormones are classically thought to exert their effects by binding to nuclear estrogen receptors and altering target gene transcription, but estrogens can also have nongenomic effects through rapid activation of membrane-initiated kinase cascades. The development of ligands that selectively activate only the nongenomic pathways would provide useful tools to investigate the significance of these pathways. We have prepared large, abiotic, nondegradable poly(amido)amine dendrimer macromolecules that are conjugated to multiple estrogen molecules through chemically robust linkages. Because of their charge and size, these estrogen-dendrimer conjugates (EDCs) remain outside the nucleus. They stimulate ERK, Shc, and Src phosphorylation in MCF-7 breast cancer cells at low concentrations, yet they are very ineffective in stimulating transcription of endogenous estrogen target genes, being approximately 10,000-fold less potent than estradiol in genomic actions. In contrast to estradiol, EDC was not effective in stimulating breast cancer cell proliferation. Because these EDC ligands activate nongenomic activity at concentrations at which they do not alter the transcription of estrogen target genes, they should be useful in studying extranuclear initiated pathways of estrogen action in a variety of target cells.
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K., Singh Ashok. "Fate of Conjugated and Free Estrogens in Swine Manure Collected from areas Housing Piglets, Pregnant Sows and Finisher Pigs". Journal of Agricultural Studies 4, n.º 2 (11 de abril de 2016): 85. http://dx.doi.org/10.5296/jas.v4i2.9298.
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Occurrence and fate of estrogens and their metabolites were studied in pig manure collected during winter and summer seasons from sites housing piglets (Nursery (Nur)-manure), pregnant and nursing sows (PS manure) and finisher pigs (FPig manure). The liquid and solid fractions of manure were analyzed for (1) total solids (TS), volatile solids (VS) and total organic carbon (TOC), (2) E coli and M fujisawaense enumeration, (3) total and individual estrogens and (4) estrogenic activity. This study showed that VS and OC values, E coli and M fujisawaense enumerations, estrogen concentrations and estrogenic activity exhibited the following pattern: Nur-manure << FPig-manure < PS-manure. The values for summer and winter Nur-manure did not differ significantly, while the values in summer PS-manure or FPig manure samples were significantly higher than values in corresponding winter samples. Although, estrogens distributed between liquid and solid fractions of manure, concentrations of free, but not conjugated, estrogens depended on manures’ TOC values: an increase in TOC associated with an increase in free estrogen concentrations in liquid manure. However, an increase in TOC decreased the bacterial population in manure liquid by increasing their translocation from liquid into the in solids and ensuing bacterial stabilization. This may increase estrogens’ deconjugation and/or degradation. Estrone (E1) sulfate (sE1), free E1 (fE1), E1 glucuronide (gE1) and E1 metabolites were major steroids present in Nur- and PS-manure, while fE2 and gE2 were predominant estrogens in FPig-manure. In total, the winter estrogen load in liquid was 5.1 mg/L and the load in solid was 4.93 mg/kg. Assuming that 2.3 x 108 kg of manure is produced in the USA per day, approximate hormone load will be 2.3 tons/day. However, manure contains microorganisms that hydrolyze estrogens, thus actual hormone load will be considerably lower.
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Nwankudu, O. N. "Endocrine, Reproductive, Neurophysiologic and Extraneous Activities of Estrogen in Vertebrates". Nigerian Veterinary Journal 41, n.º 2 (16 de abril de 2021): 85–107. http://dx.doi.org/10.4314/nvj.v41i2.2.
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Estrogens are reproductive hormones synthesized in the gonads of both male and female vertebrates. This review is geared towards uncovering some endocrine, reproductive, neurophysiologic and extraneous activities of estrogen in vertebrates. The three most common naturally occurring estrogens are: Estrone (E1), estradiol (E2), and estriol (E3). In primates, estradiol is the most potent and predominant estrogen during reproductive years. Estrogens are synthesized primarily in the female ovaries and in small quantities in the male testes and the adrenal glands, brain, and fat of both sexes. Estrogens are steroid hormones. The adipose tissues are considered to be the major source of circulating estrogen after the gonads in both men and women. In essence, the presence of aromatase expression in a local tissue confirms extra-gonadal estrogen synthesis. In reproduction, estrogen promote secondary sexual characteristics in females and regulates maturation of sperm (spermiogenesis) in males. Neurophysiologically, estrogen promote glutamate activity in the central nervous system, facilitates dopaminergic neurotransmission but blocks gammaaminobutyric acid. Extraneously, estrogen decrease serum cholesterol and osteoporosis especially in menopausal females. However, acute estrogen droppostpartum leads to depressed mood experienced by most post parturient females. In this review, it is observed that, while serum estrogen decreases with age in females, in male it increases with age due to the extraneous synthesis of estrogen especially in the adipose tissue.
Keywords: Estrogen, Female, Aromatase, Male, adipose tissue
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Wang, Po-Hsiang, Yi-Lung Chen, Sean Ting-Shyang Wei, Kan Wu, Tzong-Huei Lee, Tien-Yu Wu y Yin-Ru Chiang. "Retroconversion of estrogens into androgens by bacteria via a cobalamin-mediated methylation". Proceedings of the National Academy of Sciences 117, n.º 3 (17 de diciembre de 2019): 1395–403. http://dx.doi.org/10.1073/pnas.1914380117.
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Steroid estrogens modulate physiology and development of vertebrates. Conversion of C19 androgens into C18 estrogens is thought to be an irreversible reaction. Here, we report a denitrifying Denitratisoma sp. strain DHT3 capable of catabolizing estrogens or androgens anaerobically. Strain DHT3 genome contains a polycistronic gene cluster, emtABCD, differentially transcribed under estrogen-fed conditions and predicted to encode a cobalamin-dependent methyltransferase system conserved among estrogen-utilizing anaerobes; an emtA-disrupted DHT3 derivative could catabolize androgens but not estrogens. These data, along with the observed androgen production in estrogen-fed strain DHT3 cultures, suggested the occurrence of a cobalamin-dependent estrogen methylation to form androgens. Consistently, the estrogen conversion into androgens in strain DHT3 cell extracts requires methylcobalamin and is inhibited by propyl iodide, a specific inhibitor of cobalamin-dependent enzymes. The identification of the cobalamin-dependent estrogen methylation thus represents an unprecedented metabolic link between cobalamin and steroid metabolism and suggests that retroconversion of estrogens into androgens occurs in the biosphere.
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Melissa, Poh Su Wei, Yong Voon Chen Phelim, Visweswaran Navaratnam y Chia Yoke Yin. "DNA Microarray Analysis of Estrogen Responsive Genes in Ishikawa Cells by Glabridin". Biochemistry Insights 10 (1 de enero de 2017): 117862641772167. http://dx.doi.org/10.1177/1178626417721676.
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Based on a previous study, glabridin displayed a dose-dependent increase in estrogenic activity and cell proliferative activity in Ishikawa cells. However, when treated in combination with 17β-E2, synergistic estrogenic effect was observed but without the same synergistic increase in cell proliferative effect. This study aimed to identify the estrogen and nonestrogen-regulated activities induced by glabridin and in combination with 17β-E2 in comparison with 17β-E2. The results showed that 10 µM glabridin and the combination treatment of 100 nM glabridin with 1 nM 17β-E2 regulated both the genomic and nongenomic estrogen pathways to possibly provide benefits of estrogens in cardiovascular, circulatory, and vasculature systems. Meanwhile, the combination of 100 nM glabridin with 1 nM 17β-E2 seems to be more suitable to be used as an estrogen replacement. Finally, the results of this study have added on to the present knowledge of glabridin’s function as a phytoestrogen and suggested new ideas for the usage of glabridin.
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Tynan, Sharon, Emmanuel Pacia, Donna Haynes-Johnson, Danielle Lawrence, Michael R. D’Andrea, Jian-Zhong Guo, Scott Lundeen y George Allan. "The Putative Tumor Suppressor Deleted in Malignant Brain Tumors 1 Is an Estrogen-Regulated Gene in Rodent and Primate Endometrial Epithelium". Endocrinology 146, n.º 3 (1 de marzo de 2005): 1066–73. http://dx.doi.org/10.1210/en.2004-1304.
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Deleted in malignant brain tumors 1 (DMBT1) is a candidate suppressor of malignancies of the brain, lung, gut, and breast. We have been studying gene expression in the uterus in the presence of estrogens and their antagonists. Here, we show that DMBT1 RNA levels are robustly increased by estrogen treatment in the uteri of ovariectomized monkeys and rats. In monkeys, the progestin antagonist mifepristone inhibits estrogen-dependent uterine proliferation. As determined by a microarray experiment and quantitative analysis of RNA levels, mifepristone inhibited estrogenic induction of DMBT1. DMBT1 was not expressed in intact monkeys that were treated with a gonadotropin agonist to suppress steroidogenesis. An in vitro transfection study with human DMBT1 promoter constructs showed that an Alu site approximately 3000 nucleotides upstream of the gene mediates estrogenic regulation. Surprisingly, the estrogen antagonists tamoxifen, raloxifene, and ICI 182,780 also induced gene expression via this Alu site. Rodents represent a more convenient model system for studying uterine biology than monkeys. In rats, uterine DMBT1 RNA levels were dramatically up-regulated by estrogen. Consistent with the transfection study, tamoxifen and raloxifene increased DMBT1 RNA levels in vivo, but ICI 182,780 inhibited an estrogen-induced increase. Immunohistochemical studies showed that DMBT1 is specifically induced in glandular and luminal epithelia of the rat endometrium. Our experiments establish that DMBT1 is an estrogen-responsive gene with a possible role in endometrial proliferation or differentiation, and they have implications for the putative tumor suppressive and mucosal protective functions of DMBT1 in the uterus.
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Maharjan, Chandra K., Jiao Mo, Lei Wang, Myung-Chul Kim, Sameul Wang, Nicholas Borcherding, Praveen Vikas y Weizhou Zhang. "Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer". Cancers 14, n.º 1 (31 de diciembre de 2021): 206. http://dx.doi.org/10.3390/cancers14010206.
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The oncogenic role of estrogen receptor (ER) signaling in breast cancer has long been established. Interaction of estrogen with estrogen receptor (ER) in the nucleus activates genomic pathways of estrogen signaling. In contrast, estrogen interaction with the cell membrane-bound G-protein-coupled estrogen receptor (GPER) activates the rapid receptor-mediated signaling transduction cascades. Aberrant estrogen signaling enhances mammary epithelial cell proliferation, survival, and angiogenesis, hence is an important step towards breast cancer initiation and progression. Meanwhile, a growing number of studies also provide evidence for estrogen’s pro- or anti-inflammatory roles. As other articles in this issue cover classic ER and GPER signaling mediated by estrogen, this review will discuss the crucial mechanisms by which estrogen signaling influences chronic inflammation and how that is involved in breast cancer. Xenoestrogens acquired from plant diet or exposure to industrial products constantly interact with and alter innate estrogen signaling at various levels. As such, they can modulate chronic inflammation and breast cancer development. Natural xenoestrogens generally have anti-inflammatory properties, which is consistent with their chemoprotective role in breast cancer. In contrast, synthetic xenoestrogens are proinflammatory and carcinogenic compounds that can increase the risk of breast cancer. This article also highlights important xenoestrogens with a particular focus on their role in inflammation and breast cancer. Improved understanding of the complex relationship between estrogens, inflammation, and breast cancer will guide clinical research on agents that could advance breast cancer prevention and therapy.
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Eskin, Bernard A., David L. Snyder, Jay Roberts y Vincent J. Aloyo. "Cardiac Norepinephrine Release: Modulation by Ovariectomy and Estrogen". Experimental Biology and Medicine 228, n.º 2 (febrero de 2003): 194–99. http://dx.doi.org/10.1177/153537020322800210.
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Previously, we have demonstrated that in contrast to male rats, female rats do not show an age-related reduction of depolarization-elicited norepinephrine (NE) release from cardiac synaptosomes (resealed nerve terminals). These results suggest that sex hormones such as estrogen may modulate NE release from cardiac synaptosomes prepared from female rats. The present study was designed to test the hypotheses that long-term estrogen depletion, resulting from ovariectomy, and estrogen replacement alters depolarization-elicited NE release from cardiac synaptosomes. Female F344 rats were divided into two groups, one of which underwent bilateral ovariectomy, whereas the other underwent a sham operation. Three ovariectomized subgroups received daily injections of conjugated equine estrogens, Δ8,9-dehydroestrone or 17α-dihydroequilenin. Another ovariectomized control subgroup and the sham-operated animals received daily injections of vehicle. After 90 or 270 days of treatment, the animals were sacrificed. Cardiac synaptosomes were prepared from each heart, incubated with [3H]-NE, and used to evaluate NE release capacity by exposure to 50 mM K+. The effectiveness of the ovariectomy and the estrogenic actions of the test compounds was confirmed by evaluating vaginal smears, determining uterine weights, and measuring serum luteinizing hormone (LH) concentrations. Ovariectomy (after both 90 and 270 days) significantly increased depolarization-induced NE release compared with sham-operated rats. Treatment with all three estrogenic preparations reduced NE release in ovariectomized rats to values similar to those observed in sham-operated animals. Interestingly, NE release rates from rats treated with conjugated estrogens for 270 but not 90 days were significantly below that observed in age-matched sham animals. These results demonstrate that estrogen modulates depolarization-elicited NE release from cardiac nerve terminals. Such modulation may represent a protective action by estrogen at the cardiac synapse.
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Coss, Christopher C., Amanda Jones, Deanna N. Parke, Ramesh Narayanan, Christina M. Barrett, Jeffrey D. Kearbey, Karen A. Veverka et al. "Preclinical Characterization of a Novel Diphenyl Benzamide Selective ERα Agonist for Hormone Therapy in Prostate Cancer". Endocrinology 153, n.º 3 (1 de marzo de 2012): 1070–81. http://dx.doi.org/10.1210/en.2011-1608.
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Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.
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Lundholm, Lovisa, Milica Putnik, Michio Otsuki, Sandra Andersson, Claes Ohlsson, Jan-Åke Gustafsson y Karin Dahlman-Wright. "Effects of estrogen on gene expression profiles in mouse hypothalamus and white adipose tissue: target genes include glutathione peroxidase 3 and cell death-inducing DNA fragmentation factor, α-subunit-like effector A". Journal of Endocrinology 196, n.º 3 (21 de diciembre de 2007): 547–57. http://dx.doi.org/10.1677/joe-07-0277.
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Obesity has become a major health problem in many parts of the world. Estrogens are known to reduce adipose tissue mass in both humans and animals but the molecular mechanisms are not well characterized. We used gene expression profiling to study long-term effects of estrogen on gene expression in mouse white adipose tissue and hypothalamus. Overall, the effects of estrogen on hypothalamic gene expression were much smaller than the corresponding effects on white adipose tissue gene expression. We characterize in detail estrogenic regulation of glutathione peroxidase 3 (GPX3). Our studies suggest that GPX3 is a direct estrogen receptor α target gene in white adipose tissue. Since obesity is correlated with oxidative stress, and GPX3 has been demonstrated to be lower in obesity and higher after weight loss, we hypothesize that GPX3 is one important mediator of effects of estrogen in relation to fat mass. Additional genes that were affected by estrogen in adipose tissue include cell death-inducing DNA fragmentation factor, α-subunit-like effector A (CIDEA), a gene shown to be related to body fat in mice. We conclude that estrogen has large effects on gene expression in white adipose tissue and hypothesize that GPX3 and CIDEA could be important mediators of the effects of estrogen on fat mass.
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Ngo, Lynda, Caroline Baer, Emily Ragland, Peng Ma, Changde Zhang y Thomas E. Wiese. "Bisacodyl in Stimulant Laxatives Can Induce Estrogen Agonist/Antagonist Activity in Breast Cancer Cells in Culture". Journal of the Endocrine Society 5, Supplement_1 (1 de mayo de 2021): A483. http://dx.doi.org/10.1210/jendso/bvab048.988.
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Abstract Exposure to xenobiotic estrogens has the potential to induce estrogen activity that may contribute to a range of undesired physiological effects including the stimulation of estrogen responsive tumors. We have previously determined that extracts of OTC medications containing the stimulant laxative bisacodyl induce estrogenic activity in tissue culture bioassays. In this study, we tested the hypothesis that bisacodyl is responsible for the estrogen activity of these extracts and then characterized these effects. Ethanol extracts and dilutions were prepared from OTC medications containing Bisacodyl (1 gm:1 ml). The estrogen agonist and antagonist activity of each extract, as well as bisacodyl and then metabolite DA-bisacodyl was determined using the T47dkbluc estrogen reporter gene and the MCF-7 E3 estrogen responsive proliferation assays. LC-MS analysis was used to determine bisacodyl and DA-bisacodyl concentration in extracts as well as to trace the metabolism of bisacodyl to DA-bisacodyl in the cell culture bioassays. Molecular modeling “docking” simulations of the interactions of bisacodyl and the metabolite DA-bisacodyl with the estrogen receptor (ER) ligand binding domain was performed using MOE from Chemical Computing Group. Bisacodyl and the metabolite DA-bisacodyl induced mixed agonist/antagonist activity in MCF-7 E3 estrogen responsive proliferation assay similar to 4OH-tamoxifen. At the same time, both compounds stimulated only minimal estrogen activity in the T47dkbluc estrogen reporter gene assay. LC-MS analysis determinations identified that almost all bisacodyl was converted to the dihydroxy metabolite DA-bisacodyl in cell culture bioassays. Molecular modeling “docking” simulations determined that while bisacodyl does not fit into the agonist (estradiol) or antagonist (4OH-tamoxifen) conformations of the estrogen receptor ligand binding site, the metabolite DA-bisacodyl may fit into the antagonist induced binding pocket of the ER in a reasonable way. This study characterizes the observed estrogen activity of extracts from OTC medications containing bisacodyl as resulting from the bisacodyl metabolite DA-bisacodyl interacting with the estrogen receptor. Thus, bisacodyl is an OTC medication active ingredient that has potential to induce side effects and or toxicity involving estrogen signalling. The capacity for medications containing bisacodyl or other estrogenic substances to induce estrogen activity in patients is unclear. At the same time, consumers and practitioners should be aware of the potential estrogen activity of bisacodyl containing products.
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Almeida, Maria, Michaël R. Laurent, Vanessa Dubois, Frank Claessens, Charles A. O'Brien, Roger Bouillon, Dirk Vanderschueren y Stavros C. Manolagas. "Estrogens and Androgens in Skeletal Physiology and Pathophysiology". Physiological Reviews 97, n.º 1 (enero de 2017): 135–87. http://dx.doi.org/10.1152/physrev.00033.2015.
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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.
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Di Lorenzo, D., G. Roggeri, C. Iacobello, S. Belloli, M. Gion, D. T. Za Va, S. Ghielmi y A. Albertini. "Evaluation of a Radioreceptor Assay to Assess Exogenous Estrogen Activity in Serum of Patients with Breast Cancer". International Journal of Biological Markers 6, n.º 3 (julio de 1991): 151–58. http://dx.doi.org/10.1177/172460089100600303.
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A radioreceptor assay (RRA) for the determination of total estrogen activity, was set up and used to assess the possible presence of exogenous molecules with estrogen activity in serum; a comparison was made with the specific radioimmunoassay (RIA) for the endogenous estrogen 17-B estradiol (17-B-E2). The assay was first performed on sera from healthy people taking estrogens in the form of oral contraceptives or lotions for local application whose total estrogenic activity in the blood was assumed to be abnormal. The assay was then performed on serum from 98 patients with early breast cancer and 20 patients with metastasis, not undergoing hormone therapy. A higher estrogen activity was found in 2.5% of sera compared to the activity found using the RIA method which is specific for endogenous estrogen 17-B-E2, the RRA/17-B-E2 ratio being higher than 3. Increased estrogen activity was found in 10% serum samples from digoxin treated cardiopathic patients, with an RRA/17-B-E2 ratio ranging from 4.4 to 20. The RRA assay could prove useful for showing up exogenous estrogen activity from various sources (drugs, food) in sera of people in whom estrogen stimulation could be potentially dangerous (i.e. in patients with hormone-sensitive tumors). This exogenous activity could support a certain degree of neoplastic stimulation and, therefore, unfavourably condition the patients’ therapeutic response.
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Yu, Mengjie, Qianqian Tang, Bingli Lei, Yingxin Yang y Lanbing Xu. "Bisphenol AF Promoted the Growth of Uterus and Activated Estrogen Signaling Related Targets in Various Tissues of Nude Mice with SK-BR-3 Xenograft Tumor". International Journal of Environmental Research and Public Health 19, n.º 23 (26 de noviembre de 2022): 15743. http://dx.doi.org/10.3390/ijerph192315743.
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Environmental estrogens can promote the growth, migration, and invasion of breast cancer. However, few studies evaluate adverse health impacts of environmental estrogens on other organs of breast cancer patients. Therefore, the present study investigated the effects of environmental estrogen bisphenol AF (BPAF) on the main organs of female Balb/cA nude mice with SK-BR-3 xenograft tumor by detecting the organ development and gene expression of targets associated with G protein-coupled estrogen receptor 1 (GPER1)-mediated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways in hypothalamus, ovary, uterus, liver, and kidney. The results showed that BPAF at 20 mg/kg bw/day markedly increased the uterine weight and the uterine coefficient of nude mice compared to SK-BR-3 bearing tumor control, indicating that BPAF promoted the growth of uterus due to its estrogenic activity. Additionally, BPAF significantly up-regulated the mRNA relative expression of most targets related to nuclear estrogen receptor alpha (ERα) and GPER1-mediated signaling pathways in the hypothalamus, followed by the ovary and uterus, and the least in the liver and kidney, indicating that BPAF activated different estrogen activity related targets in different tissues. In addition, BPAF markedly up-regulated the mRNA expression of GPER1 in all tested tissues, and the molecular docking showed that BPAF could dock into GPER1. Because gene change is an early event of toxicity response, these findings suggested that BPAF might aggravate the condition of breast cancer patients through exerting its estrogenic activity via the GPER1 pathway in various organs.
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Risbridger, Gail, David Handelsman y Russell Jones. "Foreword to 'Estrogens and Male Health'". Reproduction, Fertility and Development 13, n.º 4 (2001): I. http://dx.doi.org/10.1071/rdv13n4_fo.
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Sulfamate substitution (-O-SO 2-NH 2) at carbon atom 3 of the steroid skeleton leads to orally active prodrugs of estrogens with much higher systemic, but lower hepatic, estrogenic activity than their parent steroids. This dissociation is achieved by first passage through the liver in erythrocytes, followed by systemic hydrolysis which releases the ‘parent’ estrogen. In the rat, orally administered tritiated estradiol sulfamate, unlike estradiol, appears in the circulation at high concentrations. At C max , approximately one third of the administered dose forms a depot in the circulation (98% in erythrocytes, 2% in plasma). Significant estradiol, estrone and estrone sulfate concentrations were recorded in plasma during depletion of the red blood cell pool. Estradiol sulfamate (J995) has no estrogen receptor affinity per se or estrogenic activity in vitro ( i.e. without hydrolysis). Its oral uterotropic activity in rats is approximately 100 times greater than that of estradiol, however, its hepatotropic activity is only marginally elevated. These functions include bile secretion, the secretion of angiotensinogen, lipoproteins (total and high-density lipoprotein cholesterol) and insulin-like growth factor I (IGF-I). Orally administred estradiol sulfamate led to systemic estrogenic effects without significant hepatic responses, whereas estradiol and other ‘conventional’ estrogens exerted parallel systemic and hepatic estrogenic effects. Sulfamate technology represents an approach to the use of natural estrogens for fertility control and hormone replacement therapy in both genders. In this context, reduced effects on hemostatic factors, angiotensinogen, bile and IGF-I secretion seem the most important aspects. In addition, blood concentrations of estrogens are less variable than with conventional estrogens.
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Penot, Graziella, Christine Le Péron, Yohann Mérot, Eva Grimaud-Fanouillère, François Ferrière, Noureddine Boujrad, Olivier Kah et al. "The Human Estrogen Receptor-α Isoform hERα46 Antagonizes the Proliferative Influence of hERα66 in MCF7 Breast Cancer Cells". Endocrinology 146, n.º 12 (1 de diciembre de 2005): 5474–84. http://dx.doi.org/10.1210/en.2005-0866.
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The expression of two human estrogen receptor-α (hERα) isoforms has been characterized within estrogen receptor-α-positive breast cancer cell lines such as MCF7: the full-length hERα66 and the N terminally deleted hERα46, which is devoid of activation function (AF)-1. Although hERα66 is known to mediate the mitogenic effects that estrogens have on MCF7 cells, the exact function of hERα46 in these cells remains undefined. Here we show that, during MCF7 cell growth, hERα46 is mainly expressed in the nucleus at relatively low levels, whereas hERα66 accumulates in the nucleus. When cells reach confluence, the situation reverses, with hERα46 accumulating within the nucleus. Although hERα46 expression remains rather stable during an estrogen-induced cell cycle, its overexpression in proliferating MCF7 cells provokes a cell-cycle arrest in G0/G1 phases. To gain further details on the influence of hERα46 on cell growth, we used PC12 estrogen receptor-α-negative cell line, in which stable transfection of hERα66 but not hERα46 allows estrogens to behave as mitogens. We next demonstrate that, in MCF7 cells, overexpression of hERα46 inhibits the hERα66-mediated estrogenic induction of all AF-1-sensitive reporters: c-fos and cyclin D1 as well as estrogen-responsive element-driven reporters. Our data indicate that this inhibition occurs likely through functional competitions between both isoforms. In summary, hERα46 antagonizes the proliferative action of hERα66 in MCF7 cells in part by inhibiting hERα66 AF-1 activity.
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Fontaine, Coralie, Florent Morfoisse, Florence Tatin, Audrey Zamora, Rana Zahreddine, Daniel Henrion, Jean-François Arnal, Françoise Lenfant y Barbara Garmy-Susini. "The Impact of Estrogen Receptor in Arterial and Lymphatic Vascular Diseases". International Journal of Molecular Sciences 21, n.º 9 (4 de mayo de 2020): 3244. http://dx.doi.org/10.3390/ijms21093244.
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The lower incidence of cardiovascular diseases in pre-menopausal women compared to men is well-known documented. This protection has been largely attributed to the protective effect of estrogens, which exert many beneficial effects against arterial diseases, including vasodilatation, acceleration of healing in response to arterial injury, arterial collateral growth and atheroprotection. More recently, with the visualization of the lymphatic vessels, the impact of estrogens on lymphedema and lymphatic diseases started to be elucidated. These estrogenic effects are mediated not only by the classic nuclear/genomic actions via the specific estrogen receptor (ER) α and β, but also by rapid extra-nuclear membrane-initiated steroid signaling (MISS). The ERs are expressed by endothelial, lymphatic and smooth muscle cells in the different vessels. In this review, we will summarize the complex vascular effects of estrogens and selective estrogen receptor modulators (SERMs) that have been described using different transgenic mouse models with selective loss of ERα function and numerous animal models of vascular and lymphatic diseases.
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Lemmen, JG, RJ Arends, AL van Boxtel, PT van der Saag y B. van der Burg. "Tissue- and time-dependent estrogen receptor activation in estrogen reporter mice". Journal of Molecular Endocrinology 32, n.º 3 (1 de junio de 2004): 689–701. http://dx.doi.org/10.1677/jme.0.0320689.
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With the aim of developing an in vivo model that directly detects activation of estrogen receptors (ERs), transgenic mice carrying a luciferase reporter gene were generated. The luciferase reporter gene was under the control of three consensus estrogen-responsive elements (EREs) coupled to a minimal TATA-box, with or without flanking chick beta-globin insulators. By using this model in combination with the IVIS imaging system, in vivo ER activation was measured. Dose- and time-dependent luciferase activity was induced in various organs of adult transgenic male mice exposed to diethylstilbestrol (DES) (10-1000 micro g/kg) and 17beta-estradiol dipropionate (EP) (10-1000 micro g/kg), when luciferase activity was measured ex vivo. The highest (>10 000-fold) induction of luciferase was measured in bone and kidney 24 h after exposure to 1000 micro g/kg EP. Other highly responsive organs include liver, testis, pituitary, brain, prostate and colon, which show different activity profiles. This in vivo model for detecting estrogenic activity can be used to assess tissue-specific action of ER agonists and antagonists. These could include selective ER modulators and environmental estrogens. In combination with the IVIS imaging system, this in vivo model is a powerful tool for assessing the kinetics of gene activation by estrogenic compounds.
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Peretz, Jackye, Andrew Pekosz, Andrew P. Lane y Sabra L. Klein. "Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors". American Journal of Physiology-Lung Cellular and Molecular Physiology 310, n.º 5 (1 de marzo de 2016): L415—L425. http://dx.doi.org/10.1152/ajplung.00398.2015.
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Influenza causes an acute infection characterized by virus replication in respiratory epithelial cells. The severity of influenza and other respiratory diseases changes over the life course and during pregnancy in women, suggesting that sex steroid hormones, such as estrogens, may be involved. Using primary, differentiated human nasal epithelial cell (hNEC) cultures from adult male and female donors, we exposed cultures to the endogenous 17β-estradiol (E2) or select estrogen receptor modulators (SERMs) and then infected cultures with a seasonal influenza A virus (IAV) to determine whether estrogenic signaling could affect the outcome of IAV infection and whether these effects were sex dependent. Estradiol, raloxifene, and bisphenol A decreased IAV titers in hNECs from female, but not male, donors. The estrogenic decrease in viral titer was dependent on the genomic estrogen receptor-2 (ESR2) as neither genomic ESR1 nor nongenomic GPR30 was expressed in hNEC cultures and addition of the genomic ER antagonist ICI 182,780 reversed the antiviral effects of E2. Treatment of hNECs with E2 had no effect on interferon or chemokine secretion but significantly downregulated cell metabolic processes, including genes that encode for zinc finger proteins, many of which contain estrogen response elements in their promoters. These data provide novel insights into the cellular and molecular mechanisms of how natural and synthetic estrogens impact IAV infection in respiratory epithelial cells derived from humans.
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Imai, Yuuki, Shino Kondoh, Alexander Kouzmenko y Shigeaki Kato. "Minireview: Osteoprotective Action of Estrogens Is Mediated by Osteoclastic Estrogen Receptor-α". Molecular Endocrinology 24, n.º 5 (1 de mayo de 2010): 877–85. http://dx.doi.org/10.1210/me.2009-0238.
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Abstract The osteoprotective action of estrogen in women has drawn considerable attention because estrogen deficiency-induced osteoporosis became one of the most widely spread diseases in developed countries. In men, the significance of estrogen action for bone health maintenance is also apparent from the osteoporotic phenotype seen in male patients with genetically impaired estrogen signaling. Severe bone loss and high bone turnover, including typical osteofeatures seen in postmenopausal women, can also be recapitulated in rodents after ovariectomy. However, the expected osteoporotic phenotype is not observed in female mice deficient in estrogen receptor (ER)-α or -β or both, even though the degenerative defects are clearly seen in other estrogen target tissues together with up-regulated levels of circulating testosterone. It has also been reported that estrogens may attenuate bone remodeling by cell autonomous suppressive effects on osteoblastogenesis and osteoclastogenesis. Hence, the effects of estrogens in bone appear to be complex, and the molecular role of bone estrogen receptors in osteoprotective estrogen action remains unclear. Instead, it has been proposed that estrogens indirectly control bone remodeling. For example, the enhanced production of cytokines under estrogen deficiency induces bone resorption through stimulation of osteoclastogenesis. However, the osteoporotic phenotype without systemic defects has been recapitulated in female (but not in male) mice by osteoclast-specific ablation of the ERα, proving that bone cells represent direct targets for estrogen action. An aberrant accumulation of mature osteoclasts in these female mutants indicates that in females, the inhibitory action of estrogens on bone resorption is mediated by the osteoclastic ERα through the shortened lifespan of osteoclasts.
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Dama, Aida, Chiara Baggio, Carlotta Boscaro, Mattia Albiero y Andrea Cignarella. "Estrogen Receptor Functions and Pathways at the Vascular Immune Interface". International Journal of Molecular Sciences 22, n.º 8 (20 de abril de 2021): 4254. http://dx.doi.org/10.3390/ijms22084254.
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Estrogen receptor (ER) activity mediates multiple physiological processes in the cardiovascular system. ERα and ERβ are ligand-activated transcription factors of the nuclear hormone receptor superfamily, while the G protein-coupled estrogen receptor (GPER) mediates estrogenic signals by modulating non-nuclear second messengers, including activation of the MAP kinase signaling cascade. Membrane localizations of ERs are generally associated with rapid, non-genomic effects while nuclear localizations are associated with nuclear activities/transcriptional modulation of target genes. Gender dependence of endothelial biology, either through the action of sex hormones or sex chromosome-related factors, is becoming increasingly evident. Accordingly, cardiometabolic risk increases as women transition to menopause. Estrogen pathways control angiogenesis progression through complex mechanisms. The classic ERs have been acknowledged to function in mediating estrogen effects on glucose metabolism, but 17β-estradiol also rapidly promotes endothelial glycolysis by increasing glucose transporter 1 (GLUT1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) levels through GPER-dependent mechanisms. Estrogens alter monocyte and macrophage phenotype(s), and induce effects on other estrogen-responsive cell lineages (e.g., secretion of cytokines/chemokines/growth factors) that impact macrophage function. The pharmacological modulation of ERs for therapeutic purposes, however, is particularly challenging due to the lack of ER subtype selectivity of currently used agents. Identifying the determinants of biological responses to estrogenic agents at the vascular immune interface and developing targeted pharmacological interventions may result in novel improved therapeutic solutions.
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Nilsson, Stefan, Sari Mäkelä, Eckardt Treuter, Michel Tujague, Jane Thomsen, Göran Andersson, Eva Enmark, Katarina Pettersson, Margaret Warner y Jan-Åke Gustafsson. "Mechanisms of Estrogen Action". Physiological Reviews 81, n.º 4 (10 de enero de 2001): 1535–65. http://dx.doi.org/10.1152/physrev.2001.81.4.1535.
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Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ERα and ERβ. Transgenic mice in which each of the receptors or both the receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This decade also saw the description of a male patient who had no functional ERα and whose continued bone growth clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally, crystal structures of the estrogen receptors with agonists and antagonists have revealed much about how ligand binding influences receptor conformation and how this conformation influences interaction of the receptor with coactivators or corepressors and hence determines cellular response to ligands.
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Kassi, E. y P. Moutsatsou. "Estrogen Receptor Signaling and Its Relationship to Cytokines in Systemic Lupus Erythematosus". Journal of Biomedicine and Biotechnology 2010 (2010): 1–14. http://dx.doi.org/10.1155/2010/317452.
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Dysregulation of cytokines is among the main abnormalities in Systemic Lupus Erythematosus (SLE). However, although, estrogens, which are known to be involved in lupus disease, influence cytokine production, the underlying molecular mechanisms remain poorly defined. Recent evidence demonstrates the presence of estrogen receptor in various cell types of the immune system, while divergent effects of estrogens on the cytokine regulation are thought to be implicated. In this paper, we provide an overview of the current knowledge as to how estrogen-induced modulation of cytokine production in SLE is mediated by the estrogen receptor while simultaneously clarifying various aspects of estrogen receptor signaling in this disease. The estrogen receptor subtypes, their structure, and the mode of action of estrogens by gene activation and via extranuclear effects are briefly presented. Results regarding the possible correlation between estrogen receptor gene polymorphisms and quantitative changes in the receptor protein to SLE pathology and cytokine production are reviewed.
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Birzniece, Vita y Ken K. Y. Ho. "MECHANISMS IN ENDOCRINOLOGY: Paracrine and endocrine control of the growth hormone axis by estrogen". European Journal of Endocrinology 184, n.º 6 (1 de junio de 2021): R269—R278. http://dx.doi.org/10.1530/eje-21-0155.
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There is a strong biological link between the growth hormone (GH) and gonadal systems in growth, development and metabolism; however, regulatory interactions are poorly understood. Advances in estrogen biology and endocrine physiology have provided insights into mechanistic links between the two systems. Estrogens are synthesized from androgens by aromatase which is widely distributed in extragonadal tissues. Local generation of estrogens raise the possibility of paracrine control as an additional level to classical endocrine regulation of the GH system. To explore the mechanistic links, we review the pharmacology of estrogen, the effects of estrogen replacement, antagonism, and the impact of aromatase inhibition on the GH system as well as the metabolic sequelae. In men, estrogens derived from androgens drive the central secretion of GH, independent of the androgen receptor. In hypogonadal women, physiological replacement via a parenteral route evokes no effect while estrogen receptor antagonism and estrogen deprivation induce disparate effects, providing no consistent evidence that estrogens regulate the central secretion of GH via paracrine or endocrine mechanisms. However, delivery of estrogen by the oral route inhibits hepatic IGF-1 production, in turn increasing GH secretion via reduced feedback inhibition. This endocrine route-dependent effect of oral estrogen compounds on hepatic function induces detrimental metabolic effects on hypogonadal women. In conclusion, estrogens regulate the secretion and action of GH via complex paracrine and endocrine interactions and impart metabolic effects in a route- and gender-dependent manner. The metabolic sequelae of compounds mimicking, antagonizing, or depleting estrogens, should be considered in tailoring and optimizing their use.
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Bühler, Miriam, Jeanine Fahrländer, Alexander Sauter, Markus Becker, Elisa Wistorf, Matthias Steinfath y Ailine Stolz. "GPER1 links estrogens to centrosome amplification and chromosomal instability in human colon cells". Life Science Alliance 6, n.º 1 (16 de noviembre de 2022): e202201499. http://dx.doi.org/10.26508/lsa.202201499.
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The role of the alternate G protein–coupled estrogen receptor 1 (GPER1) in colorectal cancer (CRC) development and progression is unclear, not least because of conflicting clinical and experimental evidence for pro- and anti-tumorigenic activities. Here, we show that low concentrations of the estrogenic GPER1 ligands, 17β-estradiol, bisphenol A, and diethylstilbestrol cause the generation of lagging chromosomes in normal colon and CRC cell lines, which manifest in whole chromosomal instability and aneuploidy. Mechanistically, (xeno)estrogens triggered centrosome amplification by inducing centriole overduplication that leads to transient multipolar mitotic spindles, chromosome alignment defects, and mitotic laggards. Remarkably, we could demonstrate a significant role of estrogen-activated GPER1 in centrosome amplification and increased karyotype variability. Indeed, both gene-specific knockdown and inhibition of GPER1 effectively restored normal centrosome numbers and karyotype stability in cells exposed to 17β-estradiol, bisphenol A, or diethylstilbestrol. Thus, our results reveal a novel link between estrogen-activated GPER1 and the induction of key CRC-prone lesions, supporting a pivotal role of the alternate estrogen receptor in colon neoplastic transformation and tumor progression.
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Wunder, Juliane, Daniela Pemp, Alexander Cecil, Maryam Mahdiani, René Hauptstein, Katja Schmalbach, Leo N. Geppert et al. "Influence of breast cancer risk factors on proliferation and DNA damage in human breast glandular tissues: role of intracellular estrogen levels, oxidative stress and estrogen biotransformation". Archives of Toxicology 96, n.º 2 (18 de diciembre de 2021): 673–87. http://dx.doi.org/10.1007/s00204-021-03198-7.
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AbstractBreast cancer etiology is associated with both proliferation and DNA damage induced by estrogens. Breast cancer risk factors (BCRF) such as body mass index (BMI), smoking, and intake of estrogen-active drugs were recently shown to influence intratissue estrogen levels. Thus, the aim of the present study was to investigate the influence of BCRF on estrogen-induced proliferation and DNA damage in 41 well-characterized breast glandular tissues derived from women without breast cancer. Influence of intramammary estrogen levels and BCRF on estrogen receptor (ESR) activation, ESR-related proliferation (indicated by levels of marker transcripts), oxidative stress (indicated by levels of GCLC transcript and oxidative derivatives of cholesterol), and levels of transcripts encoding enzymes involved in estrogen biotransformation was identified by multiple linear regression models. Metabolic fluxes to adducts of estrogens with DNA (E-DNA) were assessed by a metabolic network model (MNM) which was validated by comparison of calculated fluxes with data on methoxylated and glucuronidated estrogens determined by GC– and UHPLC–MS/MS. Intratissue estrogen levels significantly influenced ESR activation and fluxes to E-DNA within the MNM. Likewise, all BCRF directly and/or indirectly influenced ESR activation, proliferation, and key flux constraints influencing E-DNA (i.e., levels of estrogens, CYP1B1, SULT1A1, SULT1A2, and GSTP1). However, no unambiguous total effect of BCRF on proliferation became apparent. Furthermore, BMI was the only BCRF to indeed influence fluxes to E-DNA (via congruent adverse influence on levels of estrogens, CYP1B1 and SULT1A2).
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Tian, Kejian, Fanxing Meng, Qi Meng, Yan Gao, Lili Zhang, Le Wang, Yuqing Wang, Xue Li y Hongliang Huo. "The Analysis of Estrogen-Degrading and Functional Metabolism Genes in Rhodococcus equi DSSKP-R-001". International Journal of Genomics 2020 (26 de agosto de 2020): 1–13. http://dx.doi.org/10.1155/2020/9369182.
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Estrogen contamination is recognized as one of the most serious environmental problems, causing widespread concern worldwide. Environmental estrogens are mainly derived from human and vertebrate excretion, drugs, and agricultural activities. The use of microorganisms is currently the most economical and effective method for biodegradation of environmental estrogens. Rhodococcus equi DSSKP-R-001 (R-001) has strong estrogen-degrading capabilities. Our study indicated that R-001 can use different types of estrogen as its sole carbon source for growth and metabolism, with final degradation rates above 90%. Transcriptome analysis showed that 720 (E1), 983 (E2), and 845 (EE2) genes were significantly upregulated in the estrogen-treated group compared with the control group, and 270 differentially expressed genes (DEGs) were upregulated across all treatment groups. These DEGs included ABC transporters; estrogen-degrading genes, including those that perform initial oxidation and dehydrogenation reactions and those that further degrade the resulting substrates into small molecules; and metabolism genes that complete the intracellular transformation and utilization of estrogen metabolites through biological processes such as amino acid metabolism, lipid metabolism, carbohydrate metabolism, and the tricarboxylic acid cycle. In summary, the biodegradation of estrogens is coordinated by a metabolic network of estrogen-degrading enzymes, transporters, metabolic enzymes, and other coenzymes. In this study, the metabolic mechanisms by which Rhodococcus equi R-001 degrades various estrogens were analyzed for the first time. A new pollutant metabolism system is outlined, providing a starting point for the construction of engineered estrogen-degrading bacteria.