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1
Wang, Po-Hsiang, Yi-Lung Chen, Sean Ting-Shyang Wei, et al. "Retroconversion of estrogens into androgens by bacteria via a cobalamin-mediated methylation." Proceedings of the National Academy of Sciences 117, no. 3 (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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Lee, Heehyoung, and Wenlong Bai. "Regulation of Estrogen Receptor Nuclear Export by Ligand-Induced and p38-Mediated Receptor Phosphorylation." Molecular and Cellular Biology 22, no. 16 (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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Kumar, Anita, Antara Banerjee, Dipty Singh, et al. "Estradiol: A Steroid with Multiple Facets." Hormone and Metabolic Research 50, no. 05 (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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Nwankudu, O. N. "Endocrine, Reproductive, Neurophysiologic and Extraneous Activities of Estrogen in Vertebrates." Nigerian Veterinary Journal 41, no. 2 (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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Birzniece, Vita, and Ken K. Y. Ho. "MECHANISMS IN ENDOCRINOLOGY: Paracrine and endocrine control of the growth hormone axis by estrogen." European Journal of Endocrinology 184, no. 6 (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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Henriksson, Peter, and Reinhard Stege. "Cost Comparison of Parenteral Estrogen and Conventional Hormonal Treatment in Patients With Prostatic Cancer." International Journal of Technology Assessment in Health Care 7, no. 2 (1991): 220–26. http://dx.doi.org/10.1017/s0266462300005110.
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AbstractThe present study compares the cost of antitumor therapy and adverse cardiovascular effects during the first year of treatment with oral estrogens, nonoral estrogens, or surgical castration in patients with prostatic cancer. We found a much higher cost for patients treated with orchidectomy and oral estrogens than for patients treated with nonoral estrogens. Twenty-five percent of the patients treated with oral estrogen suffered cardiovascular complications, compared to none of the patients treated by orchidectomy or nonoral estrogens. The initial cost of orchidectomy as compared to nonoral estrogen treatment was shown not to be balanced within the expected survival time of patients with advanced prostatic cancer. Furthermore, surgical castration causes psychological trauma to the patient. We recommend parenteral estrogen therapy as a low-cost therapeutic regimen in patients with prostatic cancer.
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Imai, Yuuki, Shino Kondoh, Alexander Kouzmenko та Shigeaki Kato. "Minireview: Osteoprotective Action of Estrogens Is Mediated by Osteoclastic Estrogen Receptor-α". Molecular Endocrinology 24, № 5 (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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Kassi, E., and 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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Lizcano, Fernando, and Guillermo Guzmán. "Estrogen Deficiency and the Origin of Obesity during Menopause." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/757461.
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Sex hormones strongly influence body fat distribution and adipocyte differentiation. Estrogens and testosterone differentially affect adipocyte physiology, but the importance of estrogens in the development of metabolic diseases during menopause is disputed. Estrogens and estrogen receptors regulate various aspects of glucose and lipid metabolism. Disturbances of this metabolic signal lead to the development of metabolic syndrome and a higher cardiovascular risk in women. The absence of estrogens is a clue factor in the onset of cardiovascular disease during the menopausal period, which is characterized by lipid profile variations and predominant abdominal fat accumulation. However, influence of the absence of these hormones and its relationship to higher obesity in women during menopause are not clear. This systematic review discusses of the role of estrogens and estrogen receptors in adipocyte differentiation, and its control by the central nervous systemn and the possible role of estrogen-like compounds and endocrine disruptors chemicals are discussed. Finally, the interaction between the decrease in estrogen secretion and the prevalence of obesity in menopausal women is examined. We will consider if the absence of estrogens have a significant effect of obesity in menopausal women.
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Liu, Jia Wei, Elisabeth Jeannin, and Didier Picard. "The Anti-Estrogen Hydroxytamoxifen Is a Potent Antagonist in a Novel Yeast System." Biological Chemistry 380, no. 11 (1999): 1341–45. http://dx.doi.org/10.1515/bc.1999.172.
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AbstractThe budding yeastSaccharomyces cerevisiaehas been used extensively as a biological ‘test tube’ to study the regulation of the human estrogen receptor (ER) α. However, anti-estrogens, which are of great importance as therapeutic agents and research tools, fail to antagonize the activation by estrogen in yeast. Here, we have surveyed the antagonistic potential of five different anti-estrogens of diverse chemical nature. While they all act as agonists for wild-type ERα we have established a novel yeast assay system for anti-estrogens, in which at least the commonly used anti-estrogen hydroxytamoxifen is a potent antagonist.
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Tian, Kejian, Fanxing Meng, Qi Meng, et al. "The Analysis of Estrogen-Degrading and Functional Metabolism Genes in Rhodococcus equi DSSKP-R-001." International Journal of Genomics 2020 (August 26, 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.
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Di Croce, Luciano, Guillermo P. Vicent, Adali Pecci, Giovannella Bruscalupi, Anna Trentalance, and Miguel Beato. "The Promoter of the Rat 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Gene Contains a Tissue-Specific Estrogen-Responsive Region." Molecular Endocrinology 13, no. 8 (1999): 1225–36. http://dx.doi.org/10.1210/mend.13.8.0333.
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Abstract The isoprenoid metabolic pathway is mainly regulated at the level of conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to mevalonate, catalyzed by HMG CoA reductase. As estrogens are known to influence cholesterol metabolism, we have explored the potential regulation of the HMG CoA reductase gene promoter by estrogens. The promoter contains an estrogen-responsive element-like sequence at position −93 (termed Red-ERE), which differs from the ERE consensus by one mismatch in each half of the palindrome. A Red-ERE oligonucleotide specifically bound estrogen receptor in vitro and conferred receptor-dependent estrogen responsiveness to a heterologous promoter in all cell lines tested. However, expression of a reporter driven by the rat HMG CoA reductase promoter was induced by estrogen treatment after transient transfection into the breast cancer cell line MCF-7 cells but not in hepatic cell lines expressing estrogen receptor. Estrogen induction in MCF-7 cells was dependent on the Red-ERE and was strongly inhibited by the antiestrogen ICI 164,384. A functional cAMP-responsive element is located immediately upstream of the Red-ERE, but cAMP and estrogens inhibit each other in terms of transactivation of the promoter. Similarly, induction by estrogens was inhibited by micromolar concentrations of cholesterol, likely acting via changes in occupancy of the sterol-responsive element located 70 bp upstream of the Red-ERE. Thus, within its natural context, Red-ERE is able to mediate hormonal regulation of the HMG CoA reductase gene in tissues that respond to estrogens with enhanced cell proliferation, while it is not operative in liver cells. We postulate that this tissue-specific regulation of HMG CoA reductase by estrogens could partially explain the protective effect of estrogens against heart disease.
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Chmielewska, Małgorzata, Izabela Skibińska, and Małgorzata Kotwicka. "Mitochondria: Target organelles for estrogen action." Postępy Higieny i Medycyny Doświadczalnej 71, no. 1 (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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Watanabe, H., A. Suzuki, M. Kobayashi, DB Lubahn, H. Handa, and T. Iguchi. "Similarities and differences in uterine gene expression patterns caused by treatment with physiological and non-physiological estrogens." Journal of Molecular Endocrinology 31, no. 3 (2003): 487–97. http://dx.doi.org/10.1677/jme.0.0310487.
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Administration of physiological and non-physiological estrogens during pregnancy or after birth is known to have adverse effects on the development of the reproductive tract and other organs. Although it is believed that both estrogens have similar effects on gene expression, this view has not been tested systematically. To compare the effects of physiological (estradiol; E2) and non-physiological (diethylstilbestrol; DES) estrogens, we used DNA microarray analysis to examine the uterine gene expression patterns induced by the two estrogens. Although E2 and DES induced many genes to respond in the same way, different groups of genes showed varying levels of maximal activities to each estrogen, resulting in different dose-response patterns. Thus, each estrogen has a distinct effect on uterine gene expression. The genes were classified into clusters according to their dose-responses to the two estrogens. Of the eight clusters, only two correlated well with the uterotropic effect of different doses of E2. One of these clusters contained genes that were upregulated by E2, which included genes encoding several stress proteins and transcription factors. The other cluster contained genes that were downregulated by E2, including genes related to metabolism, transcription and detoxification processes. The expression of these genes in estrogen receptor-deficient mice was not affected by E2 treatment, indicating that these genes are affected by the E2-bound estrogen receptor. Thus, of the many genes that are affected by estrogen, it was suggested that only a small number are directly involved in the uterotropic effects of estrogen treatment.
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Britt, KL, and JK Findlay. "Estrogen actions in the ovary revisited." Journal of Endocrinology 175, no. 2 (2002): 269–76. http://dx.doi.org/10.1677/joe.0.1750269.
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Estrogens are synonymous with fertility and infertility in mammals. Our knowledge of the biological actions of estrogens, however, is incomplete. Three recent developments have thrown new light on the actions of estrogens in mammalian reproduction that will lead to a greater understanding of their functions. They are (a) the identification of a second estrogen receptor, called ERbeta, (b) the identification of ligand-specific ER coactivators and (c) mouse models with targeted disruption of the genes encoding both ER and the aromatase enzyme. These models provide for the first time animals which are either unable to respond to endogenous or exogenous estrogens (ER 'knockouts'), or can respond to exogenous estrogen but do not make endogenous estrogen (aromatase 'knockout' or ArKO). Furthermore, the ArKO mouse has provided a model to study the effects on the ovary of exogenous estrogens of plant and synthetic origin that are of clinical relevance. The data show that estrogens are essential for fertility but not for survival after birth or for the formation of the reproductive tract. This commentary focuses on the roles of estrogen in folliculogenesis and in the maintenance of the ovarian somatic cell phenotype in the mouse. We also hypothesize that the ERalpha and ERbeta may subserve the proliferative and differentiative actions of estrogen, respectively, within a follicle. In summary, estrogen is obligatory for normal folliculogenesis beyond the antral stage and for the maintenance of the female phenotype of the somatic cells within the ovaries. This clearly demonstrates a major role for sex steroids in somatic cell differentiation in the gonads of eutherian mammals and challenges the central paradigm that the ovary is the default gonad, arising due to the absence of testicular defining signals. Evidence is also provided for the plasticity of the adult female gonad. Understanding the mechanisms of estrogen actions will provide an insight into the regulation of reproductive disorders afflicting women today, notably ovarian dysfunction and the menopause.
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Borisova, Juliya A., G. B. Smirnova, I. Zh Shubina, Z. S. Shprakh, and E. M. Treshchalina. "Phyto-anti-estrogens are potential selective modifiers of biological reactions in breast cancer." Russian Journal of Oncology 21, no. 4 (2016): 212–19. http://dx.doi.org/10.18821/1028-9984-201621-4-212-219.
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The review analyzes up-to-date information about specific characteristics of anti-estrogen therapeutic agents with different mechanisms of action with regard to present knowledge of endocrine therapy for estrogen-positive breast cancer (ER+ BC). The paper presents some agents for anti-estrogen therapy of breast cancer - aromatase inhibitors and selective modifiers of biological reactions (SMBR) and their mechanisms of anti-proliferative action. The authors describe significant therapeutic and side effects as well as different options for anti-estrogen combinations. Special emphasis is made on national herbal estrogens/anti-estrogens that have no toxicity associated with the well-known SMBRs. The review presents the structure and characteristics of a perspective phyto-anti-estrogen sekoizolaricirezinol (SEKO), which demonstrated significant anti-proliferative activity with no pro-estrogen action in the in vivo models of ER+ BC.
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Vásárhelyi, Barna, Katalin Mészáros, Gellért Karvaly, and Attila Patócs. "Fókuszban a szöveti biomarkerek. Az ösztrogének mint a szövetspecifikus immunválasz és autoimmunitás modulálásának kulcsszereplői." Orvosi Hetilap 156, no. 51 (2015): 2070–76. http://dx.doi.org/10.1556/650.2015.30317.
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Estrogens modulate the immune response as well as the risk and progression of autoimmune disorders. Their effects are mediated by nuclear receptors (i.e. estrogen receptor alpha and beta), membrane receptors, and are influenced by their interactions with other hormones. Locally produced hormones and cytokines are the main factors in maintaining tissue homeostasis. The response of immune cells to estrogens is related to their developmental stage. The diverse effects of estrogens on various autoimmune disorders are the result of the versatility of their pathomechanism. In general, progression of B-cell mediated disorders is aggravated by estrogens. Their effects on T-cell mediated disorders, on the other hand, are driven by Th1 or Th2 dominance. As estrogens promote the escalation of the Th2 immune response, Th2-dominant disorders are aggravated, while Th1-dominant disorders are ameliorated upon high estrogen levels. Inflammation on its own also modulates the impact of estrogens. Inflammatory cytokines alter the expression of the alpha and beta estrogen receptors as well as the activity of estrogen metabolizing enzymes. Monitoring the local, tissue-wide interaction between hormones and immune cells would provide a better tool for identification and characterization of molecules involved in this system. To date, routinely used laboratory methods have a limited role in monitoring the local effects of estrogens. In this current paper the authors summarize the role of estrogens in immune system and overview those novel methods which are useful in the investigation of local endocrine milieu. Orv. Hetil., 2015, 156(51), 2070–2076.
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Nilsson, Stefan, Sari Mäkelä, Eckardt Treuter, et al. "Mechanisms of Estrogen Action." Physiological Reviews 81, no. 4 (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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Lazari, Maria Fatima Magalhães, Thais Fabiana Gameiro Lucas, Fabiana Yasuhara, et al. "Estrogen receptors and function in the male reproductive system." Arquivos Brasileiros de Endocrinologia & Metabologia 53, no. 8 (2009): 923–33. http://dx.doi.org/10.1590/s0004-27302009000800005.
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A substantial advance in our understanding on the estrogen signaling occurred in the last decade. Estrogens interact with two receptors, ESR1 and ESR2, also known as ERα and ERβ, respectively. ESR1 and ESR2 belong to the nuclear receptor family of transcription factors. In addition to the well established transcriptional effects, estrogens can mediate rapid signaling, triggered within seconds or minutes. These rapid effects can be mediated by ESRs or the G protein-coupled estrogen receptor GPER, also known as GPR30. The effects of estrogen on cell proliferation, differentiation and apoptosis are often mediated by growth factors. The understanding of the cross-talk between androgen, estrogen and growth factors signaling pathways is therefore essential to understand the physiopathological mechanisms of estrogen action. In this review we focused on recent discoveries about the nature of the estrogen receptors, and on the signaling and function of estrogen in the male reproductive system.
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Molina, Luis, Felipe A. Bustamante, Kanti D. Bhoola, Carlos D. Figueroa, and Pamela Ehrenfeld. "Possible role of phytoestrogens in breast cancer via GPER-1/GPR30 signaling." Clinical Science 132, no. 24 (2018): 2583–98. http://dx.doi.org/10.1042/cs20180885.
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Estrogens generated within endocrine organs and the reproductive system act as ligands for at least three types of estrogen receptors. Estrogen receptors α (ERα) and β (ERβ) belong to the so-called classical family of estrogen receptors, whereas the G protein-coupled receptor GPR30, also known as GPER-1, has been described as a novel estrogen receptor sited in the cell membrane of target cells. Furthermore, these receptors are under stimulation of a family of exogenous estrogens, known as phytoestrogens, which are a diverse group of non-steroidal plant compounds derived from plant food consumed by humans and animals. Because phytoestrogens are omnipresent in our daily diet, they are becoming increasingly important in both human health and disease. Recent evidence indicates that in addition to classical estrogen receptors, phytoestrogens also activate GPER-1 a relevant observation since GPER-1 is involved in several physiopathological disorders and especially in estrogen-dependent diseases such as breast cancer. The first estrogen receptors discovered were the classical ERα and ERβ, but from an evolutionary point of view G protein-coupled receptors trace their origins in history to over a billion years ago suggesting that estrogen receptors like GPER-1 may have been the targets of choice for ancient phytoestrogens and/or estrogens. This review provides a comprehensive and systematic literature search on phytoestrogens and its relationship with classical estrogen receptors and GPER-1 including its role in breast cancer, an issue still under discussion.
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Kitajima, Yuriko, and Yusuke Ono. "Estrogens maintain skeletal muscle and satellite cell functions." Journal of Endocrinology 229, no. 3 (2016): 267–75. http://dx.doi.org/10.1530/joe-15-0476.
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Estrogens have crucial roles in an extensive range of physiological functions regulating cellular proliferation and differentiation, development, homeostasis, and metabolism. Therefore, prolonged estrogen insufficiency influences various types of tissues expressing estrogen receptors (ERs). Although ERs are expressed in skeletal muscle and its stem cells, called satellite cells, how prolonged estrogen insufficiency affects their function remains unclear. In this study, we investigated the effect of estrogen reduction on muscle in young ovariectomized (OVX) female mice. We found that reduced estrogens resulted in muscle atrophy in a time-dependent manner. Muscle force generation was reduced in OVX mice. Interestingly, prolonged estrogen insufficiency shifted fiber types toward faster myosin heavy chain isoforms. The number of satellite cells per isolated myofiber was unchanged, while satellite cell expansion, differentiation, and self-renewal were all markedly impaired in OVX mice. Indeed, muscle regeneration was significantly compromised in OVX mice. Taken together, our results demonstrate that estrogens are essential for comprehensively maintaining muscle function with its insufficiency affecting muscle strength and regeneration in young female mice.
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Lasiuk, G. C., and K. M. Hegadoren. "The Effects of Estradiol on Central Serotonergic Systems and Its Relationship to Mood in Women." Biological Research For Nursing 9, no. 2 (2007): 147–60. http://dx.doi.org/10.1177/1099800407305600.
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Lifetime prevalence rates of depression are higher in women than men. Because this gender disparity appears after the onset of puberty and declines after menopause, gonadal hormones may play a role in women's increased vulnerability to dysphoric states. Estrogens have powerful effects beyond their role in reproduction. Fluctuations in estrogen occur naturally throughout the reproductive years and can be associated with disruptions in mood. Treatment for depression with exogenous estrogen has produced equivocal results. To shed light on the complex interactions among estrogens, serotonin, and mood, we briefly examine (a) central serotonin systems and their relationship to mood and mood disorders, (b) nonreproductive effects of estrogens on those systems, (c) potential points of intersection between serotonin systems and estrogens, and (d) research into the use of exogenous estrogen in depression in women. In conclusion, we reiterate the call for carefully controlled research into the etiology and treatment of depression in women.
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Blakemore, Jennifer, and Fredrick Naftolin. "Aromatase: Contributions to Physiology and Disease in Women and Men." Physiology 31, no. 4 (2016): 258–69. http://dx.doi.org/10.1152/physiol.00054.2015.
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Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products.
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Gorodeski, George I. "Estrogen increases the permeability of the cultured human cervical epithelium by modulating cell deformability." American Journal of Physiology-Cell Physiology 275, no. 3 (1998): C888—C899. http://dx.doi.org/10.1152/ajpcell.1998.275.3.c888.
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Estrogens increase secretion of cervical mucus in females. The objective of this research was to study the mechanisms of estrogen action. The experimental models were human CaSki (endocervical) and hECE (ectocervical) epithelial cells cultured on filters. Incubation in steroid-free medium increased transepithelial electrical resistance ( RTE) and decreased epithelial permeability to the cell-impermeant acid pyranine. Estrogen treatment reversed the effects, indicating estrogen decreases epithelial paracellular resistance. The estrogen effect was time and dose related (EC50∼1 nM) and specific (estradiol = diethylstilbestrol > estrone, estriol; no effect by progesterone, testosterone, or cortisol) and was blocked by progesterone, tamoxifen, and ICI-182780 (an estrogen receptor antagonist). Estrogen treatment did not modulate dilution potential or changes in RTEin response to diC8 or to low extracellular Ca2+(modulators of tight junctional resistance). In contrast, estrogen augmented decreases in RTEin response to hydrostatic and hypertonic gradients [modulators of resistance of lateral intercellular space ( RLIS)], suggesting estrogen decreases RLIS. Estrogen decreased cervical cell size, shortened response time relative to changes in cell size after hypertonic challenge, and augmented the decrease in cell size in response to hypertonic and hydrostatic gradients. Lowering luminal NaCl had no significant effect on RTE, and the Cl−channel blocker diphenylamine-2-carboxylate attenuated the hypertonicity-induced decrease in cell size to the same degree in control and estrogen-treated cells, suggesting estrogen effects on permeability and cell size are not mediated by modulating Na+or Cl−transport. In contrast, estrogen increased cellular G-actin levels, suggesting estrogens shift actin steady-state toward G-actin and the cervical cell cytoskeleton toward a more flexible structure. We suggest that the mechanism by which estrogens decrease RLISand increase permeability is by fragmenting the cytoskeleton and facilitating deformability and decreases in cervical cell size.
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Santen, Richard J., Risa Kagan, Corrado J. Altomare, Barry Komm, Sebastian Mirkin, and Hugh S. Taylor. "Current and Evolving Approaches to Individualizing Estrogen Receptor-Based Therapy for Menopausal Women." Journal of Clinical Endocrinology & Metabolism 99, no. 3 (2014): 733–47. http://dx.doi.org/10.1210/jc.2013-3680.
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Context: Adding progestogens to estrogens changes the risk profile of hormonal therapy for menopausal women, and recent data support the need for progestogen-free options. Several current and evolving approaches to managing estrogen deficiency allow for progestogen omission. We review the mechanisms of estrogen activity and provide an overview of emerging and available estrogen receptor (ER)–based therapies. Evidence Acquisition: PubMed was searched for relevant English-language articles using keywords pertaining to estrogen deficiency, menopause, hormone therapy, and estrogen-only therapy. Pivotal or recent randomized controlled trials, large observational studies, comprehensive meta-analyses, and established therapeutic guidelines were compiled. Evidence Synthesis: Advances in our understanding of ER pharmacology have led to therapies designed to optimize ER activity, including selective ER modulators (SERMs) and tissue-selective estrogen complexes (TSECs). Each estrogen, SERM, and TSEC exhibits a unique profile of tissue-specific activity, spanning the spectrum from ER agonism to antagonism. Systemic estrogens unopposed by progestogens effectively manage menopausal symptoms in hysterectomized postmenopausal women but require progestogen use in postmenopausal women with a uterus. SERMs are effective for managing certain aspects of estrogen deficiency in postmenopausal women, but data suggest that pairing a SERM with estrogens to form a TSEC provides a more optimal therapeutic profile for women with a uterus. Conclusions: Treating signs and symptoms of estrogen deficiency requires an individualized approach based on a woman's goals and the purported risks of different therapies. New and emerging agents have demonstrated efficacy in postmenopausal women with a uterus, while allowing these women to avoid progestogens and their possible adverse effects.
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Kaludjerovic, Jovana, and Wendy E. Ward. "The Interplay between Estrogen and Fetal Adrenal Cortex." Journal of Nutrition and Metabolism 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/837901.
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Estrogen is a steroid hormone that regulates embryogenesis, cell proliferation and differentiation, organogenesis, the timing of parturition, and fetal imprinting by carrying chemical messages from glands to cells within tissues or organs in the body. During development, placenta is the primary source of estrogen production but estrogen can only be produced if the fetus or the mother supplies dehydroepiandrosterone (DHEA), the estrogen prohormone. Studies show that the fetal zone of the fetal adrenal cortex supplies 60% of DHEA for placental estrogen production, and that placental estrogen in turn modulates the morphological and functional development of the fetal adrenal cortex. As such, in developed countries where humans are exposed daily to environmental estrogens, there is concern that the development of fetal adrenal cortex, and in turn, placental estrogen production may be disrupted. This paper discusses fetal adrenal gland development, how endogenous estrogen regulates the structure and function of the fetal adrenal cortex, and highlights the potential role that early life exposure to environmental estrogens may have on the development and endocrinology of the fetal adrenal cortex.
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De Giorgi, Vincenzo, Alessia Gori, Marta Grazzini, et al. "Estrogens, estrogen receptors and melanoma." Expert Review of Anticancer Therapy 11, no. 5 (2011): 739–47. http://dx.doi.org/10.1586/era.11.42.
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Jeremic, Katarina, Spasoje Petkovic, Gordana Lazovic, Mirka Ilic, Miroslava Gojnic, and Jelena Stojnic. "Effects of hormone replacement therapy on serum lipids and other risk factors of coronary diseases." Jugoslovenska medicinska biohemija 24, no. 1 (2005): 41–44. http://dx.doi.org/10.2298/jmh0501041j.
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Our aim was to compare the effects of transdermal versus oral estrogens on mean arterial pressure, serum lipid concentrations, estradiol and body weight. The investigation includes ten postmenopausal women receiving transdermal estrogen plus cyclic oral progesterone for 6 months. Responses were compared with those of 23 women receiving oral conjugated estrogens plus cyclic progesterone also for 6 months. We concluded that both oral and transdermal estrogen significantly (p<0.05) decreased mean arterial pressure, total and low-density lipoprotein cholesterol level to a similar extent. But only oral estrogen increased HDL cholesterol and triglycerides with statistical significans (p<0.05). Transdermal estrogen group exhibited no significant changes (p>0.05) in values of HDL cholesterol and triglycerides before and after the treatment. The serum estradiol level increased significantly (p<0.05) in oral estrogen group but in lesser extent in transdermal estrogen group (p<0.002). Studies in future should include multiple risk factors to allow better assessment of their impact on coronary artery health.
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POTIER, MYLENE, SHARON J. ELLIOT, IVAN TACK, et al. "Expression and Regulation of Estrogen Receptors in Mesangial Cells: Influence on Matrix Metalloproteinase-9." Journal of the American Society of Nephrology 12, no. 2 (2001): 241–51. http://dx.doi.org/10.1681/asn.v122241.
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Abstract. Diabetic glomerulosclerosis is characterized by the accumulation of extracellular matrix (ECM) in the mesangium. Estrogens seem to retard whereas estrogen deficiency seems to accelerate progressive glomerulosclerosis. Thus, mesangial cells (MC) may be a target for estrogens. Estrogen action is mediated via estrogen receptor (ER) subtypes ERα and ERβ. Both ER subtypes were expressed in human and mouse MC. Using an estrogen-responsive reporter construct in transfection assays, it also was demonstrated that the nuclear ER were transcriptionally active. In the presence of 17β-estradiol (E2; 10-10to 10-8M), there was a progressive increase in the mRNA levels of both ERα (approximately 1.8-fold and approximately 2.7-fold after 24 and 72 h, respectively) and ERβ (approximately 1.3-fold and approximately 2.2-fold after 24 and 72 h, respectively). ERα protein levels increased approximately 2.5-fold after 24 h (10-10M, E2) and up to approximately 5.4-fold after 72 h (10-9M, E2). ERβ protein levels increased approximately 2.1-fold in the presence of E2(10-9M) after 24 h. Thus, estrogens positively regulate the expression of the ER subtypes, thereby maintaining or increasing MC responsiveness to estrogens. Because diabetic glomerulosclerosis may be due partly to a decrease in ECM degradation, the effects of estrogens on matrix metalloproteinases (MMP) were studied. It was found that E2(10-10to 10-8M) increased both MMP-9 mRNA and MMP-9 activity in MC. This may be an important mechanism by which estrogens influence ECM turnover and protect against progression of diabetic glomerulosclerosis.
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Pentikäinen, Virve, Krista Erkkilä, Laura Suomalainen, Martti Parvinen, and Leo Dunkel. "Estradiol Acts as a Germ Cell Survival Factor in the Human Testis in Vitro*." Journal of Clinical Endocrinology & Metabolism 85, no. 5 (2000): 2057–67. http://dx.doi.org/10.1210/jcem.85.5.6600.
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Abstract The necessity of estrogens for male fertility was recently discovered in studies on both estrogen receptor α knockout and aromatase (cyp 19 gene) knockout mice. However, direct testicular effects of estrogens in male reproduction have remained unclear. Here we studied the protein expression of ERα and the recently described estrogen receptor β in the human seminiferous epithelium and evaluated the role of 17β-estradiol, the main physiological estrogen, in male germ cell survival. Interestingly, both estrogen receptors α and β were found in early meiotic spermatocytes and elongating spermatids of the human testis. Furthermore, low concentrations of 17β-estradiol (10−9 and 10−10 mol/L) effectively inhibited male germ cell apoptosis, which was induced in vitro by incubating segments of human seminiferous tubules without survival factors (i.e. serum and hormones). Dihydrotestosterone, which, in addition to estradiol, is an end metabolite of testosterone, was also capable of inhibiting testicular apoptosis, but at a far higher concentration (10−7 mol/L) than estradiol. Thus, estradiol appears to be a potent germ cell survival factor in the human testis. The novel findings of the present study together with the previously reported indirect effects of estrogens on male germ cells indicate the importance of estrogens for the normal function of the testis.
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Jalabert, Cecilia, Maria A. Shock, Chunqi Ma, and Kiran K. Soma. "LC-MS/MS for Ultra-Sensitive Quantification of Multiple Estrogens in the Blood and Brain." Journal of the Endocrine Society 5, Supplement_1 (2021): A542. http://dx.doi.org/10.1210/jendso/bvab048.1104.
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Abstract Estrogens are steroid hormones that affect many aspects of brain function, including cognition, social behavior, and neuroprotection. It is well-known that estrogens are synthesized in the ovaries. Estrogens are also synthesized in the brain, where aromatase is expressed in specific regions. Importantly, estrogens play crucial roles in the brain, even at extremely low levels. Current assays lack the necessary sensitivity and/or specificity to measure brain-synthesized estrogens. Furthermore, current methods focus on only 17β-estradiol and generally disregard other estrogens that are synthesized in the brain. Here, we developed a method to measure several estrogens simultaneously, with high sensitivity and specificity. To improve sensitivity, we derivatized estrogens with 1,2-dimethylimidazole-5-sulfonyl-chloride (DMIS). We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to examine a panel of eight estrogens: 17β-estradiol, 17α-estradiol, estrone, estriol, 2-hydroxyestradiol, 4-hydroxyestradiol, 2-methoxyestradiol, and 4-methoxyestradiol. After derivatization, we have improved sensitivity 20-fold, detecting as little as 0.01 pg per sample, demonstrating that our method is extremely sensitive. For each analyte, we have identified a distinct retention time as well as 2 scheduled multiple reaction monitoring (sMRM) transitions that were used as quality control criteria for clear identification. Therefore, we are able to distinguish each estrogen (even stereoisomers) by the chromatographic separation and the sMRM, demonstrating that our method is highly specific. This method has been applied to microdissected brain samples. Initially, we used a songbird model because songbirds have high levels of aromatase and 17β-estradiol in specific brain regions. We were able to simultaneously quantify multiple estrogens in small amounts of brain sample (1-2 mg). We examined seasonal changes of estrogens in the brain and blood. Future work will apply this method to mouse, rat, and human samples and expand the panel of estrogens examined. Our ultra-sensitive assay is essential for small animal models, where estrogen measurement is extremely challenging because of the limited amount of brain tissue. This novel technique will also have wide-ranging applications for basic research and clinical testing, including estrogen measurement in humans with low estrogen levels, such as men, pre-pubertal children, and post-menopausal women.
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Abe, Hideki, Kim L. Keen, and Ei Terasawa. "Rapid Action of Estrogens on Intracellular Calcium Oscillations in Primate Luteinizing Hormone-Releasing Hormone-1 Neurons." Endocrinology 149, no. 3 (2007): 1155–62. http://dx.doi.org/10.1210/en.2007-0942.
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Feedback controls of estrogen in LHRH-1 neurons play a pivotal role in reproductive function. However, the mechanism of estrogen action in LHRH-1 neurons is still unclear. In the present study, the effect of estrogens on intracellular calcium ([Ca2+]i) oscillations in primate LHRH-1 neurons was examined. Application of 17β-estradiol (E2, 1 nm) for 10 min increased the frequency of [Ca2+]i oscillations within a few minutes. E2 also increased the frequency of [Ca2+]i synchronization among LHRH-1 neurons. Similar E2 effects on the frequency of [Ca2+]i oscillations were observed under the presence of tetrodotoxin, indicating that estrogen appears to cause direct action on LHRH-1 neurons. Moreover, application of a nuclear membrane-impermeable estrogen dendrimer conjugate, not control dendrimer, resulted in a robust increase in the frequencies of [Ca2+]i oscillations and synchronizations, indicating that effects estrogens on [Ca2+]i oscillations and their synchronizations do not require their entry into the cell nucleus. Exposure of cells to E2 in the presence of the estrogen receptor antagonist ICI 182,780 did not change the E2-induced increase in the frequency of [Ca2+]i oscillations or the E2-induced increase in the synchronization frequency. Collectively, estrogens induce rapid, direct stimulatory actions through receptors located in the cell membrane/cytoplasm of primate LHRH-1 neurons, and this action of estrogens is mediated by an ICI 182,780-insensitive mechanism yet to be identified.
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Jiang, Xinguo, Brent A. Orr, David M. Kranz, and David J. Shapiro. "Estrogen Induction of the Granzyme B Inhibitor, Proteinase Inhibitor 9, Protects Cells against Apoptosis Mediated by Cytotoxic T Lymphocytes and Natural Killer Cells." Endocrinology 147, no. 3 (2006): 1419–26. http://dx.doi.org/10.1210/en.2005-0996.
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Exposure to estrogens is associated with an increased risk of developing breast, cervical, and liver cancer. Estrogens strongly induce the human granzyme B inhibitor, proteinase inhibitor 9 (PI-9). Because cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells use the granzyme pathway to induce apoptosis of target cells, we tested the ability of activated CTLs and the human NK cell line, YT cells, to lyse human liver cells. Estrogen induction of PI-9 protected the liver cells against CTL and NK cell-mediated, granzyme-dependent, apoptosis. Knockdown of PI-9 by RNA interference blocked the protective effect of estrogen. This work demonstrates that estrogens can act on target cells to control their destruction by immune system cells and shows that induction of PI-9 expression can inhibit both CTL and NK cell-mediated apoptosis. Estrogen induction of PI-9 may reduce the ability of cytolytic lymphocytes-mediated immune surveillance to destroy newly transformed cells, possibly providing a novel mechanism for an estrogen-mediated increase in tumor incidence.
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McEwen, Bruce S. "Invited Review: Estrogens effects on the brain: multiple sites and molecular mechanisms." Journal of Applied Physiology 91, no. 6 (2001): 2785–801. http://dx.doi.org/10.1152/jappl.2001.91.6.2785.
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Besides their well-established actions on reproductive functions, estrogens exert a variety of actions on many regions of the nervous system that influence higher cognitive function, pain mechanisms, fine motor skills, mood, and susceptibility to seizures; they also appear to have neuroprotective actions in relation to stroke damage and Alzheimer's disease. Estrogen actions are now recognized to occur via two different intracellular estrogen receptors, ER-α and ER-β, that reside in the cell nuclei of some nerve cells, as well as by some less well-characterized mechanisms. In the hippocampus, such nerve cells are sparse in number and yet appear to exert a powerful influence on synapse formation by neurons that do not have high levels of nuclear estrogen receptors. However, we also find nonnuclear estrogen receptors outside of the cell nuclei in dendrites, presynaptic terminals, and glial cells, where estrogen receptors may couple to second messenger systems to regulate a variety of cellular events and signal to the nuclear via transcriptional regulators such as CREB. Sex differences exist in many of the actions of estrogens in the brain, and the process of sexual differentiation appears to affect many brain regions outside of the traditional brain areas involved in reproductive functions. Finally, the aging brain is responsive to actions of estrogens, which have neuroprotective effects both in vivo and in vitro. However, in an animal model, the actions of estrogens on the hippocampus appear to be somewhat attenuated with age. In the future, estrogen actions over puberty and in pregnancy and lactation should be further explored and should be studied in both the hypothalamus and the extrahypothalamic regions.
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Kovács, Krisztián, Barna Vásárhelyi, Katalin Mészáros, Attila Patócs, and Gellért Karvaly. "Az ösztrogénmetabolom biológiai és klinikai jelentősége lokális folyamatokban." Orvosi Hetilap 158, no. 24 (2017): 929–37. http://dx.doi.org/10.1556/650.2017.30778.
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Abstract: Considerable knowledge has been gathered on the physiological role of estrogens. However, fairly little information is available on the role of compounds produced in the breakdown process of estrone and estradiol wich may play a role in various diseases associated with estrogen impact. To date, approximately 15 extragonadal estrogen-related compounds have been identified. These metabolites may exert protective, or, instead, pro-inflammatory and/or pro-oncogenic activity in a tissue-specific manner. Systemic and local estrogen metabolite levels are not necesserily correlated, which may promote the diagnostic significance of the locally produced estrogen metabolites in the future. The aim of the present study is a bibliographic review of the extragonadal metabolome in peripheral tissues, and to highlight the role of the peripheral tissue homeostasis of estrogens as well as the non-hormonal biological activity and clinical significance of the estrogen metabolome. Orv Hetil. 2017; 158(24): 929–937.
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Bilezikian, John P. "The role of estrogens in male skeletal development." Reproduction, Fertility and Development 13, no. 4 (2001): 253. http://dx.doi.org/10.1071/rd00120.
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The developing human skeleton is known to be influenced by the presence of sex steroids. In girls, estrogens have been considered to be the dominant hormone, whereas in boys, androgens have occupied a primary physiological role in terms of bone mass accrual. Although these views are still current, recent observations made of rare defects in estrogen receptor sensitivity or estrogen synthesis have called attention to the importance of estrogens in the developing male skeleton. In these human genetic models, the affected men have demonstrated continuous linear skeletal growth, open epiphyses, lack of pubertal growth spurt, and reduced bone mass. In the example of men with aromatase deficiency, lacking estrogens from birth, administration of estrogen led to impressive increases in bone density, maturation of the skeletal growth plates, and cessation of linear growth. Animal models mimicking these human syndromes by knockout technology, have tended to support these observations. The data argue for a primary role of estrogens in the developing male skeleton, while not diminishing the important role for androgens.
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Lucà, Rossella, Giorgia di Blasio, Daniela Gallo, et al. "Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4." Cancers 11, no. 9 (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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McHugh, Nansie A., Gary F. Merrill, and Saul R. Powell. "Estrogen diminishes postischemic hydroxyl radical production." American Journal of Physiology-Heart and Circulatory Physiology 274, no. 6 (1998): H1950—H1954. http://dx.doi.org/10.1152/ajpheart.1998.274.6.h1950.
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Reperfusion of blood flow to an ischemic myocardium is imperative to survival; ironically, it may also manifest several pathophysiological conditions. The most important of these are reperfusion arrhythmias and tissue injury and/or death. The mechanisms involved in reperfusion arrhythmias remain to be fully elucidated; however, increasing evidence indicates that reperfusion-induced arrhythmias are a free radical-mediated phenomenon. Acute administration of conjugated equine estrogen to dogs attenuates ischemia- and reperfusion-induced arrhythmias. The cardioprotective effect of estrogens in postmenopausal women is well documented, and recent studies suggest that estrogens possess strong antioxidant properties, with equine estrogens most potent. In this study we show that administration of conjugated equine estrogen to fully anesthetized dogs abolishes the burst of ⋅ OH radicals typically produced on reperfusion of the myocardium. This indicates that estrogen might attenuate reperfusion-induced ventricular arrhythmias by virtue of its antioxidant properties, suggesting a novel cardioprotective effect of the hormone.
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Gilligan, Lorna C., Habibur P. Rahman, Anne-Marie Hewitt, et al. "Estrogen Activation by Steroid Sulfatase Increases Colorectal Cancer Proliferation via GPER." Journal of Clinical Endocrinology & Metabolism 102, no. 12 (2017): 4435–47. http://dx.doi.org/10.1210/jc.2016-3716.
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Abstract Context Estrogens affect the incidence and progression of colorectal cancer (CRC), although the precise molecular mechanisms remain ill-defined. Objective The present study investigated prereceptor estrogen metabolism through steroid sulphatase (STS) and 17β-hydroxysteroid dehydrogenase activity and subsequent nongenomic estrogen signaling in human CRC tissue, in The Cancer Genome Atlas colon adenocarcinoma data set, and in in vitro and in vivo CRC models. We aimed to define and therapeutically target pathways through which estrogens alter CRC proliferation and progression. Design, Setting, Patients, and Interventions Human CRC samples with normal tissue-matched controls were collected from postmenopausal female and age-matched male patients. Estrogen metabolism enzymes and nongenomic downstream signaling pathways were determined. CRC cell lines were transfected with STS and cultured for in vitro and in vivo analysis. Estrogen metabolism was determined using an ultra-performance liquid chromatography–tandem mass spectrometry method. Primary Outcome Measure The proliferative effects of estrogen metabolism were evaluated using 5-bromo-2′-deoxyuridine assays and CRC mouse xenograft studies. Results Human CRC exhibits dysregulated estrogen metabolism, favoring estradiol synthesis. The activity of STS, the fundamental enzyme that activates conjugated estrogens, is significantly (P &lt; 0.001) elevated in human CRC compared with matched controls. STS overexpression accelerates CRC proliferation in in vitro and in vivo models, with STS inhibition an effective treatment. We defined a G-protein–coupled estrogen receptor (GPER) proproliferative pathway potentially through increased expression of connective tissue growth factor in CRC. Conclusion Human CRC favors estradiol synthesis to augment proliferation via GPER stimulation. Further research is required regarding whether estrogen replacement therapy should be used with caution in patients at high risk of developing CRC.
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Karachentsev, A. N., V. G. Kukes, A. S. Kisrieva, and E. A. Mazerkina. "Cardiotropic activity of estrogens during hormone replacement therapy in postmenopausal women." Problems of Endocrinology 46, no. 1 (2000): 16–20. http://dx.doi.org/10.14341/probl11830.
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Cardiotropic activity of estrogens after a single administration and during 12-week substitute hormone therapy was studied during echocardiography and Doppler echocardiography in estrogen deficient women with natural or surgical postmenopause with negative cardiovascular (vasomotor) symptoms with hyperkinetic central hemodynamics, high arterial pressure, and disordered diastolic function of the left ventricle. The results confirm the cardioprotective and positive hemodynamic activity of substitute estrogens. Estrogens improved the initially disturbed diastolic and systolic function of the left ventricle, moderately decreased heart rate and systolic and diastolic arterial pressure. Time course of cardioprotective and hemodynamic effects of substitute monoestrogen therapy and estrogen/gestagen hormone therapy was virtually the same.
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Cooke, Paul S., Manjunatha K. Nanjappa, CheMyong Ko, Gail S. Prins, and Rex A. Hess. "Estrogens in Male Physiology." Physiological Reviews 97, no. 3 (2017): 995–1043. http://dx.doi.org/10.1152/physrev.00018.2016.
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Estrogens have historically been associated with female reproduction, but work over the last two decades established that estrogens and their main nuclear receptors (ESR1 and ESR2) and G protein-coupled estrogen receptor (GPER) also regulate male reproductive and nonreproductive organs. 17β-Estradiol (E2) is measureable in blood of men and males of other species, but in rete testis fluids, E2 reaches concentrations normally found only in females and in some species nanomolar concentrations of estrone sulfate are found in semen. Aromatase, which converts androgens to estrogens, is expressed in Leydig cells, seminiferous epithelium, and other male organs. Early studies showed E2 binding in numerous male tissues, and ESR1 and ESR2 each show unique distributions and actions in males. Exogenous estrogen treatment produced male reproductive pathologies in laboratory animals and men, especially during development, and studies with transgenic mice with compromised estrogen signaling demonstrated an E2 role in normal male physiology. Efferent ductules and epididymal functions are dependent on estrogen signaling through ESR1, whose loss impaired ion transport and water reabsorption, resulting in abnormal sperm. Loss of ESR1 or aromatase also produces effects on nonreproductive targets such as brain, adipose, skeletal muscle, bone, cardiovascular, and immune tissues. Expression of GPER is extensive in male tracts, suggesting a possible role for E2 signaling through this receptor in male reproduction. Recent evidence also indicates that membrane ESR1 has critical roles in male reproduction. Thus estrogens are important physiological regulators in males, and future studies may reveal additional roles for estrogen signaling in various target tissues.
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Borrás, C., M. Ferrando, M. Inglés, et al. "Estrogen Replacement Therapy Induces Antioxidant and Longevity-Related Genes in Women after Medically Induced Menopause." Oxidative Medicine and Cellular Longevity 2021 (September 9, 2021): 1–9. http://dx.doi.org/10.1155/2021/8101615.
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Females live longer than males in many species, including humans, and estrogens are in part responsible for this protection against aging. We reported previously that estrogens can protect rats against oxidative stress, by inducing antioxidant and longevity-related genes. Thus, this study was aimed at confirming the ability of estrogens to upregulate antioxidant and longevity-related genes in humans. For this purpose, we selected 16 women of reproductive age (18-42 years old) undergoing a fertility treatment that includes a medically induced menopause, at the Valencian Infertility Institute. We took blood samples at each time point of the treatment (basal, induced menopause, estrogen, and estrogen plus progesterone replacement therapy). mRNA expression of antioxidant and longevity-related genes in peripheral blood mononuclear cells (PBMC) was determined by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Determination of reduced glutathione (GSH) in total blood was carried out using high-performance liquid chromatography (HPLC). As expected, we found that medically induced menopause significantly decreased sexual hormone (estrogens and progesterone) levels. It also lowered glutathione peroxidase (GPx), 16S rRNA, P21, and TERF2 mRNA expression and blood GSH levels. Estrogen replacement therapy significantly restored estrogen levels and induced mRNA expression of manganese superoxide dismutase (MnSOD), GPx, 16S rRNA, P53, P21, and TERF2 and restored blood GSH levels. Progesterone replacement therapy induced a significant increase in MnSOD, P53, sestrin 2 (SENS2), and TERF2 mRNA expression when compared to basal conditions. These findings provide evidence for estrogen beneficial effects in upregulating antioxidant and longevity-related genes in women.
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Secky, Lena, Martin Svoboda, Lukas Klameth, et al. "The Sulfatase Pathway for Estrogen Formation: Targets for the Treatment and Diagnosis of Hormone-Associated Tumors." Journal of Drug Delivery 2013 (February 13, 2013): 1–13. http://dx.doi.org/10.1155/2013/957605.
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The extragonadal synthesis of biological active steroid hormones from their inactive precursors in target tissues is named “intracrinology.” Of particular importance for the progression of estrogen-dependent cancers is the in situ formation of the biological most active estrogen, 17beta-estradiol (E2). In cancer cells, conversion of inactive steroid hormone precursors to E2 is accomplished from inactive, sulfated estrogens in the “sulfatase pathway” and from androgens in the “aromatase pathway.” Here, we provide an overview about expression and function of enzymes of the “sulfatase pathway,” particularly steroid sulfatase (STS) that activates estrogens and estrogen sulfotransferase (SULT1E1) that converts active estrone (E1) and other estrogens to their inactive sulfates. High expression of STS and low expression of SULT1E1 will increase levels of active estrogens in malignant tumor cells leading to the stimulation of cell proliferation and cancer progression. Therefore, blocking the “sulfatase pathway” by STS inhibitors may offer an attractive strategy to reduce levels of active estrogens. STS inhibitors either applied in combination with aromatase inhibitors or as novel, dual aromatase-steroid sulfatase inhibiting drugs are currently under investigation. Furthermore, STS inhibitors are also suitable as enzyme–based cancer imaging agents applied in the biomedical imaging technique positron emission tomography (PET) for cancer diagnosis.
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Nadal, Angel, Mario Díaz, and Miguel A. Valverde. "The Estrogen Trinity: Membrane, Cytosolic, and Nuclear Effects." Physiology 16, no. 6 (2001): 251–55. http://dx.doi.org/10.1152/physiologyonline.2001.16.6.251.
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Estrogens have a wide array of biological effects, targeting both genomic and nongenomic mechanisms. Classically, the estrogen receptors activating the transcription machinery in the nucleus were thought to be distinct from the extranuclear estrogen receptors. Recently, this conceptual wall has started to be dismantled as the result of the identification of novel routes of estrogen action.
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Chakhtoura, Marita, Uma Sriram, Michelle Heayn, et al. "Bisphenol A Does Not Mimic Estrogen in the Promotion of the In Vitro Response of Murine Dendritic Cells to Toll-Like Receptor Ligands." Mediators of Inflammation 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/2034348.
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Sex hormones affect immune responses and might promote autoimmunity. Endocrine disrupting chemicals such as bisphenol A (BPA) may mimic their immune effects. Conventional dendritic cells (cDCs) are pivotal initiators of immune responses upon activation by danger signals coming from pathogens or distressed tissues through triggering of the Toll-like receptors (TLRs). We generated in vitro murine cDCs in the absence of estrogens and measured the effects of exogenously added estrogen or BPA on their differentiation and activation by the TLR ligands LPS and CpG. Estrogen enhanced the differentiation of GM-CSF-dependent cDCs from bone marrow precursors in vitro, and the selective estrogen receptor modulators (SERMs) tamoxifen and fulvestrant blocked these effects. Moreover, estrogen augmented the upregulation of costimulatory molecules and proinflammatory cytokines (IL-12p70 and TNFα) upon stimulation by TLR9 ligand CpG, while the response to LPS was less estrogen-dependent. These effects are partially explained by an estrogen-dependent regulation of TLR9 expression. BPA did not promote cDC differentiation nor activation upon TLR stimulation. Our results suggest that estrogen promotes immune responses by increasing DC activation, with a preferential effect on TLR9 over TLR4 stimulation, and highlight the influence of estrogens in DC cultures, while BPA does not mimic estrogen in the DC functions that we tested.
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Whayne, Thomas F. "Hypertriglyceridemia: An Infrequent, Difficult-to-predict, Severe Metabolic and Vascular Problem Associated with Estrogen Administration." Current Vascular Pharmacology 18, no. 3 (2020): 254–61. http://dx.doi.org/10.2174/1570161117666190306102322.
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Supplementary estrogen plays important roles for female patients as convenient birth control, relief of postmenopausal symptoms, and in the management of other selected problems. However, as is the case for essentially all medications, there are side effects. Short of a major pulmonary embolus, the most severe side effect of estrogen would appear to be sporadic, rare, and severe hypertriglyceridemia associated with acute pancreatitis. The occurrence of this fortunately rare problem usually happens in the presence of some preexisting and usually mild increase in triglycerides (TG). A case of chronic and severe recurrent acute pancreatitis is described in the introduction and the management was complete estrogen avoidance. Started close to menopause and continued for a relatively short period, estrogens may have some cardiovascular (CV) benefit but the general recommendation is not to prescribe them for CV disease prevention. Estrogens may contribute to decreased diabetes mellitus (DM) risk and control. Administration of estrogens by the transdermal route may decrease some problems such as venous thromboembolism (VTE) and elevation of TG. Administration of estrogen in the right situation brings significant benefit to the female patient but skillful, careful, and knowledgeable use is essential.
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Todiodi, Mina. "The Effects of Exogenous Estrogens on Estrogen Receptors in Male Reproductive Organs." Revue interdisciplinaire des sciences de la santé - Interdisciplinary Journal of Health Sciences 1, no. 1 (2010): 66. http://dx.doi.org/10.18192/riss-ijhs.v1i1.1537.
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There is an essential physiological role for estrogen in male reproduction. Conversely, exposure to exogenous sources of estrogen has negative effects on reproductive physiology and fertility in men. Infertility, affecting nearly 15% of couples, is defined as the inability to conceive after one year of unprotected sexual intercourse. In at least 20% of cases, male reproductive pathology is the major cause for a couple’s infertility. Thus, it is essential to investigate potential causes of infertility in adult males. Evidence shows that exposure to certain endocrine disruptors is associated with reduced semen quality and impaired fertility in men. Bisphenol A and Diethylstilbestrol are endocrine disruptors that act as exogenous sources of estrogen and have been associated with male reproductive pathology. This review will examine the role of exogenous estrogens on changes in gene expression of estrogen receptors ERα, ERβ, and GPR30. Previous studies have had conflictive results, suggesting that the effects of exogenous estrogens on male reproduction are multi-faceted. Future studies should focus on determining whether exogenous estrogens have a stimulatory and/or inhibitory effect on gene expression and whether this relationship is dose-dependent or if it follows a more complex dosage pattern.
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Duong, C. N., J. H. Lee, B. J. Lim, and S. D. Kim. "Biodegradation of estrogen conjugates by bacteria isolated from river sediments." Water Science and Technology 64, no. 8 (2011): 1750–58. http://dx.doi.org/10.2166/wst.2011.739.
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The objective of this study was to investigate the ability of E. coli in river sediments to degrade estrogen conjugates. Biodegradation experiments on glucuronide estrogens (E1-GLU, E2-GLU and E3-GLU) using E. coli, non-E. coli bacteria as well as sediment crude extracts were carried out in batch mode. A pure identified E. coli strain (KCTC 2571) was used for comparison of enzyme activity. The results showed that the degradation rate of estrogen conjugates by KCTC 2571 and E. coli isolated from sediments followed a similar trend. Fecal bacteria showed a high ability to deconjugate glucuronided estrogens. Approximately 50% of glucuronide moieties were cleaved within 4 h of contact time in experiments using pure E. coli. The degradation rate was slower in experiments using crude extracts of sediments, and conjugated estrogens were not completely degraded even after 12 h of reaction. These results provide a clear understanding of the fate and behavior of estrogen by bacteria in the environment.
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Hedges, Valerie L., Gang Chen, Lei Yu, et al. "Local Estrogen Synthesis Regulates Parallel Fiber–Purkinje Cell Neurotransmission Within the Cerebellar Cortex." Endocrinology 159, no. 3 (2018): 1328–38. http://dx.doi.org/10.1210/en.2018-00039.
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Abstract Estrogens affect cerebellar activity and cerebellum-based behaviors. Within the adult rodent cerebellum, the best-characterized action of estradiol is to enhance glutamatergic signaling. However, the mechanisms by which estradiol promotes glutamatergic neurotransmission remain unknown. Within the mouse cerebellum, we found that estrogen receptor activation of metabotropic glutamate receptor type 1a strongly enhances neurotransmission at the parallel fiber–Purkinje cell synapse. The blockade of local estrogen synthesis within the cerebellum results in a diminution of glutamatergic neurotransmission. Correspondingly, decreased estrogen availability via gonadectomy or blockade of aromatase activity negatively affects locomotor performance. These data indicate that locally derived, and not just gonad-derived, estrogens affect cerebellar physiology and function. In addition, estrogens were found to facilitate parallel fiber–Purkinje cell synaptic transmission in both sexes. As such, the actions of estradiol to support cerebellar neurotransmission and cerebellum-based behaviors might be fundamental to understanding the normal processing of activity within the cerebellar cortex.
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Estrada-Arriaga, E. B., and P. Mijaylova. "Calculation methods to perform mass balance of endocrine disrupting compounds in a submerged membrane bioreactor: fate and distribution of estrogens during the biological treatment." Water Science and Technology 64, no. 11 (2011): 2158–68. http://dx.doi.org/10.2166/wst.2011.799.
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The purpose of this paper is to report the study of the fate and distribution of three endocrine disrupting compounds (estrogens); Estrone (E1), 17β-estradiol (E2), and 17α-ethinylestradiol (EE2) in a laboratory scale submerged membrane bioreactor (SMBR). For this matter, both aqueous and solids phases were analyzed for the presence of E1, E2 and EE2. The outcome of this study was that three SMBRs showed enhanced elimination of estrogens in different operational conditions; the estrogen removal was close to 100% in SMBR. Additionally, E1, E2 and EE2 were detected in SMBR sludge at concentrations of up to 41.2, 37.3 and 36.9 ng g−1 dry weight, respectively. The estrogen removal in the SMBRs was directly influenced by a combination of simultaneous biodegradation–adsorption processes, indicating that the main removal mechanism of the estrogens in the SMBRs is the biodegradation process. The E1, E2 and EE2 were biologically degraded in the SMBR (87–100%). The sorption of estrogens onto activated sludge was from 2%. Therefore, a high potential for estrogen removal by biodegradation in the SMBR was observed, allowing less estrogen concentration in the dissolved phase available for the adsorption of these compounds onto biological flocs. Two different methods were carried out for mass balance calculations of estrogens in SMBR. For the first method, the measured data was used in both liquid and solid phases, whereas for the second one, it was in aqueous phase and solid–water distribution coefficients (Kd) value of E1, E2 and EE2. The purpose of these methodologies is to make easier the identification of the main mechanisms involved in the removal of E1, E2 and EE2 in a SMBR. Both methods can be applied in order to determine the mechanism, fate and distribution of estrogens in a SMBR.