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      Effects of isoflavones on breast tissue and the thyroid hormone system in humans: a comprehensive safety evaluation

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          Abstract

          Isoflavones are secondary plant constituents of certain foods and feeds such as soy, linseeds, and red clover. Furthermore, isoflavone-containing preparations are marketed as food supplements and so-called dietary food for special medical purposes to alleviate health complaints of peri- and postmenopausal women. Based on the bioactivity of isoflavones, especially their hormonal properties, there is an ongoing discussion regarding their potential adverse effects on human health. This review evaluates and summarises the evidence from interventional and observational studies addressing potential unintended effects of isoflavones on the female breast in healthy women as well as in breast cancer patients and on the thyroid hormone system. In addition, evidence from animal and in vitro studies considered relevant in this context was taken into account along with their strengths and limitations. Key factors influencing the biological effects of isoflavones, e.g., bioavailability, plasma and tissue concentrations, metabolism, temporality (pre- vs. postmenopausal women), and duration of isoflavone exposure, were also addressed. Final conclusions on the safety of isoflavones are guided by the aim of precautionary consumer protection.

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          The online version of this article (10.1007/s00204-018-2279-8) contains supplementary material, which is available to authorized users.

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          Most cited references257

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          Thyroid hormone regulation of metabolism.

          Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.
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            Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta.

            The rat estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study we investigated the messenger RNA expression of both ER subtypes in rat tissues by RT-PCR and compared the ligand binding specificity of the ER subtypes. Saturation ligand binding analysis of in vitro synthesized human ER alpha and rat ER beta protein revealed a single binding component for 16 alpha-iodo-17 beta-estradiol with high affinity [dissociation constant (Kd) = 0.1 nM for ER alpha protein and 0.4 nM for ER beta protein]. Most estrogenic substances or estrogenic antagonists compete with 16 alpha-[125I]iodo-17 beta-estradiol for binding to both ER subtypes in a very similar preference and degree; that is, diethylstilbestrol > hexestrol > dienestrol > 4-OH-tamoxifen > 17 beta-estradiol > coumestrol, ICI-164384 > estrone, 17 alpha-estradiol > nafoxidine, moxestrol > clomifene > estriol, 4-OH-estradiol > tamoxifen, 2-OH-estradiol, 5-androstene-3 beta, 17 beta-diol, genistein for the ER alpha protein and dienestrol > 4-OH-tamoxifen > diethylstilbestrol > hexestrol > coumestrol, ICI-164384 > 17 beta-estradiol > estrone, genistein > estriol > nafoxidine, 5-androstene-3 beta, 17 beta-diol > 17 alpha-estradiol, clomifene, 2-OH-estradiol > 4-OH-estradiol, tamoxifen, moxestrol for the ER beta protein. The rat tissue distribution and/or the relative level of ER alpha and ER beta expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ER alpha and prostate, ovary, lung, bladder, brain, uterus, and testis for ER beta. The described differences between the ER subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues.
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              Breast cancer and hormone-replacement therapy in the Million Women Study.

              Current use of hormone-replacement therapy (HRT) increases the incidence of breast cancer. The Million Women Study was set up to investigate the effects of specific types of HRT on incident and fatal breast cancer. 1084110 UK women aged 50-64 years were recruited into the Million Women Study between 1996 and 2001, provided information about their use of HRT and other personal details, and were followed up for cancer incidence and death. Half the women had used HRT; 9364 incident invasive breast cancers and 637 breast cancer deaths were registered after an average of 2.6 and 4.1 years of follow-up, respectively. Current users of HRT at recruitment were more likely than never users to develop breast cancer (adjusted relative risk 1.66 [95% CI 1.58-1.75], p<0.0001) and die from it (1.22 [1.00-1.48], p=0.05). Past users of HRT were, however, not at an increased risk of incident or fatal disease (1.01 [0.94-1.09] and 1.05 [0.82-1.34], respectively). Incidence was significantly increased for current users of preparations containing oestrogen only (1.30 [1.21-1.40], p<0.0001), oestrogen-progestagen (2.00 [1.88-2.12], p<0.0001), and tibolone (1.45 [1.25-1.68], p<0.0001), but the magnitude of the associated risk was substantially greater for oestrogen-progestagen than for other types of HRT (p<0.0001). Results varied little between specific oestrogens and progestagens or their doses; or between continuous and sequential regimens. The relative risks were significantly increased separately for oral, transdermal, and implanted oestrogen-only formulations (1.32 [1.21-1.45]; 1.24 [1.11-1.39]; and 1.65 [1.26-2.16], respectively; all p<0.0001). In current users of each type of HRT the risk of breast cancer increased with increasing total duration of use. 10 years' use of HRT is estimated to result in five (95% CI 3-7) additional breast cancers per 1000 users of oestrogen-only preparations and 19 (15-23) additional cancers per 1000 users of oestrogen-progestagen combinations. Use of HRT by women aged 50-64 years in the UK over the past decade has resulted in an estimated 20000 extra breast cancers, 15000 associated with oestrogen-progestagen; the extra deaths cannot yet be reliably estimated. Current use of HRT is associated with an increased risk of incident and fatal breast cancer; the effect is substantially greater for oestrogen-progestagen combinations than for other types of HRT.
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                Author and article information

                Contributors
                +49-721-6625-500 , sabine.kulling@mri.bund.de
                Journal
                Arch Toxicol
                Arch. Toxicol
                Archives of Toxicology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-5761
                1432-0738
                21 August 2018
                21 August 2018
                2018
                : 92
                : 9
                : 2703-2748
                Affiliations
                [1 ]ISNI 0000 0001 0126 6191, GRID grid.412970.9, Institute for Food Toxicology, Senate Commission on Food Safety, , University of Veterinary Medicine Hannover, ; Hannover, Germany
                [2 ]ISNI 0000 0004 0390 0098, GRID grid.418213.d, Department of Experimental Diabetology, , German Institute of Human Nutrition (DIfE), ; Nuthetal, Germany
                [3 ]Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Haid-und-Neu-Str. 9, 76131 Karlsruhe, Germany
                [4 ]Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, CVK, Berlin, Germany
                [5 ]ISNI 0000 0001 0126 6191, GRID grid.412970.9, Department of Biometry, Epidemiology and Information Processing, , University of Veterinary Medicine Hannover, ; Hannover, Germany
                [6 ]ISNI 0000 0001 2244 5164, GRID grid.27593.3a, Department of Molecular and Cellular Sports Medicine, Institute of Cardiovascular Research and Sports Medicine, , German Sport University Cologne, ; Cologne, Germany
                [7 ]Chemisches und Veterinäruntersuchungsamt Karlsruhe, Karlsruhe, Germany
                [8 ]ISNI 0000 0001 2155 0333, GRID grid.7645.0, Division of Food Chemistry and Toxicology, Molecular Nutrition, Department of Chemistry, , Technische Universität Kaiserslautern, ; Kaiserslautern, Germany
                [9 ]ISNI 0000 0001 2111 7257, GRID grid.4488.0, Department of Biology, Molecular Cell Physiology and Endocrinology, , Technische Universität Dresden, ; Dresden, Germany
                [10 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Department of Nutrition and Food Sciences, Nutritional Epidemiology, , Rheinische Friedrich-Wilhelms University Bonn, ; Bonn, Germany
                [11 ]ISNI 0000 0001 2286 1424, GRID grid.10420.37, Department of Food Chemistry and Toxicology, Faculty of Chemistry, , University of Vienna, ; Vienna, Austria
                [12 ]ISNI 0000 0001 1958 8658, GRID grid.8379.5, Department of Toxicology, , University of Würzburg, ; Würzburg, Germany
                [13 ]ISNI 0000 0004 0390 0098, GRID grid.418213.d, Department of Molecular Toxicology, , German Institute of Human Nutrition (DIfE), ; Nuthetal, Germany
                [14 ]ISNI 0000 0001 1958 8658, GRID grid.8379.5, Department of Food Chemistry, Institute for Pharmacy and Food Chemistry, , University of Würzburg, ; Würzburg, Germany
                [15 ]ISNI 0000 0001 0126 6191, GRID grid.412970.9, Institute for Food Toxicology, , University of Veterinary Medicine Hannover, ; Hannover, Germany
                [16 ]Present Address: Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Haid-und-Neu-Str. 9, 76131 Karlsruhe, Germany
                Article
                2279
                10.1007/s00204-018-2279-8
                6132702
                30132047
                c351ab57-a7d2-47e7-a413-2c81a1a2d11e
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 5 May 2018
                : 31 July 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Categories
                Review Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                Toxicology
                isoflavones,human intervention studies,observational studies,breast tissue,thyroid hormone system,safety evaluation

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