Phytoestrogens: Potential Endocrine Disruptors in Males
Identifieur interne : 001707 ( Istex/Corpus ); précédent : 001706; suivant : 001708Phytoestrogens: Potential Endocrine Disruptors in Males
Auteurs : Risto Santti ; Sari M Kel ; Leena Strauss ; Johanna Korkman ; Marja-Lsa KostianSource :
- Toxicology and Industrial Health [ 0748-2337 ] ; 1998-01.
Abstract
Exposure to diethylstilbestrol (DES) induces persistent structural and functional alterations in the developing reproductive tract of males. It is possible that xenoestrogens other than DES alter sexual differentiation in males and account for the increasing incidence of developmental disorders of the reproductive tract in men and wild animals. Phytoestrogens (coumestans, isoflavonoids, flavonoids, and lignans) present in numerous edible plants are quantitatively the most important environmental estrogens when their hormonal potency is assessed in vitro. They exert their estrogenic activity by interacting with estrogen receptors (ERs) in vitro. They may also act as antiestrogens by competing for the binding sites of estrogen receptors or the active site of the estrogen biosynthesizing and metabolizing enzymes, such as aromatase and estrogen-specific 17β-hydroxysteroid oxidoreductase (type 1). In theory, phytoestrogens and structurally related compounds could harm the reproductive health of males also by acting as antiestrogens. There are very little data on effects of phytoestrogens in males. Estrogenic effects in wildlife have been described but the evidence for the role of phytoestrogens is indirect and seen under conditions of excessive exposure. In doses comparable to the daily intake from soy- based feed, isoflavonoids such as genistein were estrogen agonists in the prostate of adult laboratory rodents. When given neonatally, no persistent effects were observed. In contrast, the central nervous system (CNS)-gonadal axis and the male sexual behavior of the rat appear to be sensitive to phytoestrogens during development. The changes were similar but not identical to those seen after neonatal treatment with DES, but higher doses of phytoestrogens were needed.There are no data on effects of phytoestrogens given as pure compounds to humans, and all evidence currently available is indirect and based on experiments with phytoestrogen- rich diets. The hormonal effects have so far been marginal. It is known that the intake of phytoestrogens is higher in countries where the incidence rates of clinical conditions linked to estrogen exposure, such as hypospadia or testicular and prostatic cancers, are low. This makes it unlikely that phytoestrogens, or structurally related compounds in amounts present in Asian diets, would have DES-like actions. This does not exclude possibilities that they influence concentrations of endogenous sex hormones and interact with the ER, and that through these mechanisms they alter male sex differentiation, and consequently increase the risks of male genital tract tumors or developmental disorders, particularly in doses exceeding the daily intake of phytoestrogens in Asian diets.
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DOI: 10.1177/074823379801400114
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Research Laboratory Turku, Finland</mods:affiliation></affiliation></author><author wicri:is="90%"><name sortKey="Korkman, Johanna" sort="Korkman, Johanna" uniqKey="Korkman J" first="Johanna" last="Korkman">Johanna Korkman</name><affiliation><mods:affiliation>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</mods:affiliation></affiliation></author><author wicri:is="90%"><name sortKey="Kostian, Marja Lsa" sort="Kostian, Marja Lsa" uniqKey="Kostian M" first="Marja-Lsa" last="Kostian">Marja-Lsa Kostian</name><affiliation><mods:affiliation>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:59A7ECC10D6F3EC62D28B8108E557384595A5749</idno><date when="1998" year="1998">1998</date><idno type="doi">10.1177/074823379801400114</idno><idno 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Finland</mods:affiliation></affiliation></author><author wicri:is="90%"><name sortKey="Strauss, Leena" sort="Strauss, Leena" uniqKey="Strauss L" first="Leena" last="Strauss">Leena Strauss</name><affiliation><mods:affiliation>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</mods:affiliation></affiliation></author><author wicri:is="90%"><name sortKey="Korkman, Johanna" sort="Korkman, Johanna" uniqKey="Korkman J" first="Johanna" last="Korkman">Johanna Korkman</name><affiliation><mods:affiliation>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</mods:affiliation></affiliation></author><author wicri:is="90%"><name sortKey="Kostian, Marja Lsa" sort="Kostian, Marja Lsa" uniqKey="Kostian M" first="Marja-Lsa" last="Kostian">Marja-Lsa Kostian</name><affiliation><mods:affiliation>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Toxicology and Industrial Health</title><idno type="ISSN">0748-2337</idno><idno type="eISSN">1477-0393</idno><imprint><publisher>Sage Publications</publisher><pubPlace>Sage CA: Thousand Oaks, CA</pubPlace><date type="published" when="1998-01">1998-01</date><biblScope unit="volume">14</biblScope><biblScope unit="issue">1-2</biblScope><biblScope unit="page" from="223">223</biblScope><biblScope unit="page" to="237">237</biblScope></imprint><idno type="ISSN">0748-2337</idno></series><idno type="istex">59A7ECC10D6F3EC62D28B8108E557384595A5749</idno><idno type="DOI">10.1177/074823379801400114</idno><idno type="ArticleID">10.1177_074823379801400114</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0748-2337</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Exposure to diethylstilbestrol (DES) induces persistent structural and functional alterations in the developing reproductive tract of males. It is possible that xenoestrogens other than DES alter sexual differentiation in males and account for the increasing incidence of developmental disorders of the reproductive tract in men and wild animals. Phytoestrogens (coumestans, isoflavonoids, flavonoids, and lignans) present in numerous edible plants are quantitatively the most important environmental estrogens when their hormonal potency is assessed in vitro. They exert their estrogenic activity by interacting with estrogen receptors (ERs) in vitro. They may also act as antiestrogens by competing for the binding sites of estrogen receptors or the active site of the estrogen biosynthesizing and metabolizing enzymes, such as aromatase and estrogen-specific 17β-hydroxysteroid oxidoreductase (type 1). In theory, phytoestrogens and structurally related compounds could harm the reproductive health of males also by acting as antiestrogens. There are very little data on effects of phytoestrogens in males. Estrogenic effects in wildlife have been described but the evidence for the role of phytoestrogens is indirect and seen under conditions of excessive exposure. In doses comparable to the daily intake from soy- based feed, isoflavonoids such as genistein were estrogen agonists in the prostate of adult laboratory rodents. When given neonatally, no persistent effects were observed. In contrast, the central nervous system (CNS)-gonadal axis and the male sexual behavior of the rat appear to be sensitive to phytoestrogens during development. The changes were similar but not identical to those seen after neonatal treatment with DES, but higher doses of phytoestrogens were needed.There are no data on effects of phytoestrogens given as pure compounds to humans, and all evidence currently available is indirect and based on experiments with phytoestrogen- rich diets. The hormonal effects have so far been marginal. It is known that the intake of phytoestrogens is higher in countries where the incidence rates of clinical conditions linked to estrogen exposure, such as hypospadia or testicular and prostatic cancers, are low. This makes it unlikely that phytoestrogens, or structurally related compounds in amounts present in Asian diets, would have DES-like actions. This does not exclude possibilities that they influence concentrations of endogenous sex hormones and interact with the ER, and that through these mechanisms they alter male sex differentiation, and consequently increase the risks of male genital tract tumors or developmental disorders, particularly in doses exceeding the daily intake of phytoestrogens in Asian diets.</div></front></TEI><istex><corpusName>sage</corpusName><author><json:item><name>Risto Santti</name><affiliations><json:string>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</json:string></affiliations></json:item><json:item><name>Sari Mäkelä</name><affiliations><json:string>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</json:string></affiliations></json:item><json:item><name>Leena Strauss</name><affiliations><json:string>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</json:string></affiliations></json:item><json:item><name>Johanna Korkman</name><affiliations><json:string>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</json:string></affiliations></json:item><json:item><name>Marja-Lsa Kostian</name><affiliations><json:string>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>3. Key words: diethylstilbestrol</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>flavonoids</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>17β-hydroxysteroid oxidoreductase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>male</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>prostate.</value></json:item></subject><articleId><json:string>10.1177_074823379801400114</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Exposure to diethylstilbestrol (DES) induces persistent structural and functional alterations in the developing reproductive tract of males. It is possible that xenoestrogens other than DES alter sexual differentiation in males and account for the increasing incidence of developmental disorders of the reproductive tract in men and wild animals. Phytoestrogens (coumestans, isoflavonoids, flavonoids, and lignans) present in numerous edible plants are quantitatively the most important environmental estrogens when their hormonal potency is assessed in vitro. They exert their estrogenic activity by interacting with estrogen receptors (ERs) in vitro. They may also act as antiestrogens by competing for the binding sites of estrogen receptors or the active site of the estrogen biosynthesizing and metabolizing enzymes, such as aromatase and estrogen-specific 17β-hydroxysteroid oxidoreductase (type 1). In theory, phytoestrogens and structurally related compounds could harm the reproductive health of males also by acting as antiestrogens. There are very little data on effects of phytoestrogens in males. Estrogenic effects in wildlife have been described but the evidence for the role of phytoestrogens is indirect and seen under conditions of excessive exposure. In doses comparable to the daily intake from soy- based feed, isoflavonoids such as genistein were estrogen agonists in the prostate of adult laboratory rodents. When given neonatally, no persistent effects were observed. In contrast, the central nervous system (CNS)-gonadal axis and the male sexual behavior of the rat appear to be sensitive to phytoestrogens during development. The changes were similar but not identical to those seen after neonatal treatment with DES, but higher doses of phytoestrogens were needed.There are no data on effects of phytoestrogens given as pure compounds to humans, and all evidence currently available is indirect and based on experiments with phytoestrogen- rich diets. The hormonal effects have so far been marginal. It is known that the intake of phytoestrogens is higher in countries where the incidence rates of clinical conditions linked to estrogen exposure, such as hypospadia or testicular and prostatic cancers, are low. This makes it unlikely that phytoestrogens, or structurally related compounds in amounts present in Asian diets, would have DES-like actions. This does not exclude possibilities that they influence concentrations of endogenous sex hormones and interact with the ER, and that through these mechanisms they alter male sex differentiation, and consequently increase the risks of male genital tract tumors or developmental disorders, particularly in doses exceeding the daily intake of phytoestrogens in Asian diets.</abstract><qualityIndicators><score>8.5</score><pdfVersion>1.4</pdfVersion><pdfPageSize>474 x 719 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>2751</abstractCharCount><pdfWordCount>5567</pdfWordCount><pdfCharCount>37788</pdfCharCount><pdfPageCount>15</pdfPageCount><abstractWordCount>397</abstractWordCount></qualityIndicators><title>Phytoestrogens: Potential Endocrine Disruptors in 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from="223">223</biblScope><biblScope unit="page" to="237">237</biblScope></imprint></monogr><idno type="istex">59A7ECC10D6F3EC62D28B8108E557384595A5749</idno><idno type="DOI">10.1177/074823379801400114</idno><idno type="ArticleID">10.1177_074823379801400114</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1998</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Exposure to diethylstilbestrol (DES) induces persistent structural and functional alterations in the developing reproductive tract of males. It is possible that xenoestrogens other than DES alter sexual differentiation in males and account for the increasing incidence of developmental disorders of the reproductive tract in men and wild animals. Phytoestrogens (coumestans, isoflavonoids, flavonoids, and lignans) present in numerous edible plants are quantitatively the most important environmental estrogens when their hormonal potency is assessed in vitro. They exert their estrogenic activity by interacting with estrogen receptors (ERs) in vitro. They may also act as antiestrogens by competing for the binding sites of estrogen receptors or the active site of the estrogen biosynthesizing and metabolizing enzymes, such as aromatase and estrogen-specific 17β-hydroxysteroid oxidoreductase (type 1). In theory, phytoestrogens and structurally related compounds could harm the reproductive health of males also by acting as antiestrogens. There are very little data on effects of phytoestrogens in males. Estrogenic effects in wildlife have been described but the evidence for the role of phytoestrogens is indirect and seen under conditions of excessive exposure. In doses comparable to the daily intake from soy- based feed, isoflavonoids such as genistein were estrogen agonists in the prostate of adult laboratory rodents. When given neonatally, no persistent effects were observed. In contrast, the central nervous system (CNS)-gonadal axis and the male sexual behavior of the rat appear to be sensitive to phytoestrogens during development. The changes were similar but not identical to those seen after neonatal treatment with DES, but higher doses of phytoestrogens were needed.There are no data on effects of phytoestrogens given as pure compounds to humans, and all evidence currently available is indirect and based on experiments with phytoestrogen- rich diets. The hormonal effects have so far been marginal. It is known that the intake of phytoestrogens is higher in countries where the incidence rates of clinical conditions linked to estrogen exposure, such as hypospadia or testicular and prostatic cancers, are low. This makes it unlikely that phytoestrogens, or structurally related compounds in amounts present in Asian diets, would have DES-like actions. This does not exclude possibilities that they influence concentrations of endogenous sex hormones and interact with the ER, and that through these mechanisms they alter male sex differentiation, and consequently increase the risks of male genital tract tumors or developmental disorders, particularly in doses exceeding the daily intake of phytoestrogens in Asian diets.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>3. Key words: diethylstilbestrol</term></item><item><term>flavonoids</term></item><item><term>17β-hydroxysteroid oxidoreductase</term></item><item><term>male</term></item><item><term>prostate.</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1998-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/59A7ECC10D6F3EC62D28B8108E557384595A5749/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus sage not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article" dtd-version="2.3" xml:lang="EN"><front><journal-meta><journal-id journal-id-type="hwp">sptih</journal-id><journal-id journal-id-type="publisher-id">TIH</journal-id><journal-title>Toxicology and Industrial Health</journal-title><issn pub-type="ppub">0748-2337</issn><publisher><publisher-name>Sage Publications</publisher-name><publisher-loc>Sage CA: Thousand Oaks, CA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1177/074823379801400114</article-id><article-id pub-id-type="publisher-id">10.1177_074823379801400114</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Phytoestrogens: Potential Endocrine Disruptors in Males</article-title></title-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Santti</surname><given-names>Risto</given-names></name><aff>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</aff></contrib></contrib-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Mäkelä</surname><given-names>Sari</given-names></name><aff>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</aff></contrib></contrib-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Strauss</surname><given-names>Leena</given-names></name><aff>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</aff></contrib></contrib-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Korkman</surname><given-names>Johanna</given-names></name><aff>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</aff></contrib></contrib-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Kostian</surname><given-names>Marja-Lsa</given-names></name><aff>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</aff></contrib></contrib-group><pub-date pub-type="ppub"><month>01</month><year>1998</year></pub-date><volume>14</volume><issue>1-2</issue><fpage>223</fpage><lpage>237</lpage><abstract><p><italic>Exposure to diethylstilbestrol (DES) induces persistent structural and functional alterations in the developing reproductive tract of males. It is possible that xenoestrogens other than DES alter sexual differentiation in males and account for the increasing incidence of developmental disorders of the reproductive tract in men and wild animals. Phytoestrogens (coumestans, isoflavonoids, flavonoids, and lignans) present in numerous edible plants are quantitatively the most important environmental estrogens when their hormonal potency is assessed in vitro. They exert their estrogenic activity by interacting with estrogen receptors (ERs) in vitro. They may also act as antiestrogens by competing for the binding sites of estrogen receptors or the active site of the estrogen biosynthesizing and metabolizing enzymes, such as aromatase and estrogen-specific 17β-hydroxysteroid oxidoreductase (type 1). In theory, phytoestrogens and structurally related compounds could harm the reproductive health of males also by acting as antiestrogens.</italic></p><p><italic>There are very little data on effects of phytoestrogens in males. Estrogenic effects in wildlife have been described but the evidence for the role of phytoestrogens is indirect and seen under conditions of excessive exposure. In doses comparable to the daily intake from soy- based feed, isoflavonoids such as genistein were estrogen agonists in the prostate of adult laboratory rodents. When given neonatally, no persistent effects were observed. In contrast, the central nervous system (CNS)-gonadal axis and the male sexual behavior of the rat appear to be sensitive to phytoestrogens during development. The changes were similar but not identical to those seen after neonatal treatment with DES, but higher doses of phytoestrogens were needed.There are no data on effects of phytoestrogens given as pure compounds to humans, and all evidence currently available is indirect and based on experiments with phytoestrogen- rich diets. The hormonal effects have so far been marginal. It is known that the intake of phytoestrogens is higher in countries where the incidence rates of clinical conditions linked to estrogen exposure, such as hypospadia or testicular and prostatic cancers, are low. This makes it unlikely that phytoestrogens, or structurally related compounds in amounts present in Asian diets, would have DES-like actions. This does not exclude possibilities that they influence concentrations of endogenous sex hormones and interact with the ER, and that through these mechanisms they alter male sex differentiation, and consequently increase the risks of male genital tract tumors or developmental disorders, particularly in doses exceeding the daily intake of phytoestrogens in Asian diets.</italic></p></abstract><kwd-group><kwd>3. Key words: diethylstilbestrol</kwd><kwd>flavonoids</kwd><kwd>17β-hydroxysteroid oxidoreductase</kwd><kwd>male</kwd><kwd>prostate.</kwd></kwd-group><custom-meta-wrap><custom-meta xlink:type="simple"><meta-name>sagemeta-type</meta-name><meta-value>Journal Article</meta-value></custom-meta><custom-meta xlink:type="simple"><meta-name>search-text</meta-name><meta-value>223 Phytoestrogens: Potential Endocrine Disruptors in Males SAGE Publications, Inc.1998DOI: 10.1177/074823379801400114 Risto Santti University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland Sari Mäkelä University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland Leena Strauss University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland Johanna Korkman University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland Marja-Lsa Kostian University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland Exposure to diethylstilbestrol (DES) induces persistent structural and functional alterations in the developing reproductive tract of males. It is possible that xenoestrogens other than DES alter sexual differentiation in males and account for the increasing incidence of developmental disorders of the reproductive tract in men and wild animals. Phytoestrogens (coumestans, isoflavonoids, flavonoids, and lignans) present in numerous edible plants are quantitatively the most important environmental estrogens when their hormonal potency is assessed in vitro. They exert their estrogenic activity by interacting with estrogen receptors (ERs) in vitro. They may also act as antiestrogens by competing for the binding sites of estrogen receptors or the active site of the estrogen biosynthesizing and metabolizing enzymes, such as aromatase and estrogen-specific 17β-hydroxysteroid oxidoreductase (type 1). In theory, phytoestrogens and structurally related compounds could harm the reproductive health of males also by acting as antiestrogens. There are very little data on effects of phytoestrogens in males. Estrogenic effects in wildlife have been described but the evidence for the role of phytoestrogens is indirect and seen under conditions of excessive exposure. In doses comparable to the daily intake from soy- based feed, isoflavonoids such as genistein were estrogen agonists in the prostate of adult laboratory rodents. When given neonatally, no persistent effects were observed. In contrast, the central nervous system (CNS)-gonadal axis and the male sexual behavior of the rat appear to be sensitive to phytoestrogens during development. The changes were similar but not identical to those seen after neonatal treatment with DES, but higher doses of phytoestrogens were needed.There are no data on effects of phytoestrogens given as pure compounds to humans, and all evidence currently available is indirect and based on experiments with phytoestrogen- rich diets. The hormonal effects have so far been marginal. It is known that the intake of phytoestrogens is higher in countries where the incidence rates of clinical conditions linked to estrogen exposure, such as hypospadia or testicular and prostatic cancers, are low. This makes it unlikely that phytoestrogens, or structurally related compounds in amounts present in Asian diets, would have DES-like actions. This does not exclude possibilities that they influence concentrations of endogenous sex hormones and interact with the ER, and that through these mechanisms they alter male sex differentiation, and consequently increase the risks of male genital tract tumors or developmental disorders, particularly in doses exceeding the daily intake of phytoestrogens in Asian diets. 3. Key words: diethylstilbestrol flavonoids 17β-hydroxysteroid oxidoreductase male prostate. 1. Address all correspondence to: Risto Santti, M.D., Institute of Biomedicine, Kiinamyllynkatu 10, FIN-20520, Turku, Finland. Tel.: +358-21-333 7316. Fax: +358-2-333 7352. E-mail: Santti@utu.fi. 2. Abbreviations: bw, body weight; CNS, central nervous system; DES, diethylstilbestrol; ER, estrogen receptor; ERE, estrogen responsive element; FSH, follicle stimulating hormone; hER, human estrogen receptor; 17β-HSOR, 17β-hydroxysteroid oxidoreductase; LH, luteinizing hormone; MIS, Müllerian inhibiting substance; neoDES, neonatally estrogenized; pERE-TK-CAT, estrogen-responsive reporter plasmid; PIN, prostatic intraepithelial neoplasia; SHBG, sex hormone binding globulin. 246224 INTRODUCTION Exposure to exogenous estrogens induces structural and functional alterations in the developing reproductive tract of males. Many of these changes are permanent, and some appear later in life. Men exposed to diethylstilbestrol (DES) in utero provide information concerning the effects of a potent nonsteroidal estrogen in human organisms (Gill, 1988). The DES-induced lesions range from relatively minor structural alterations such as epididymal cysts to more marked changes such as testicular hypoplasia. It is probable that cryptorchidism, testicular cancer, low sperm counts, hypospadia, microphalluses, and enlarged prostatic utricles are also DES-induced lesions (Gill, 1988). It is possible that xenoestrogens other than DES alter sexual differentiation in males and account for the increasing incidence of developmental disorders of the reproductive tract in men and wild animals. Planet estrogens are quantitatively the most important environmental estrogens when their hormonal potency is assessed in vitro (Miksicek, 1995; Safe, 1995). However, most of the data on plant estrogens concern their proliferative effects on breast cancer cells in cultures or the compromised fertility of females due to excessive exposure to phytoestrogen-rich diets, but there are very little data on effects of plant estrogens in males. In theory, phytoestrogens and structurally related compounds could harm the reproductive health of males not only by acting as estrogens but also by acting as antiestrogens. Recent experiments with estrogen receptor knockout mice suggest that, in addition to androgens and Mfllerian inhibiting substance (MIS), estrogens may be essential for normal male sex differentiation (Lubahn et al., 1993). In the absence of functioning estrogen receptors (ER), testis weight and sperm count are low, and fertility is decreased. _~ ~ _ The increasing use of phytoestrogen-rich foods or food dietary supplements as chemopreventive agents against breast and prostate cancers has made it necessary and urgent to assess the risks of phytoestrogen exposure to male reproductive health (Sheehan, 1995). 1. The epidemiological and ecological findings on the males have recently been summarized in Miljöprojekt 290. Male Reproductive Health and Environmental Chemicals with Estrogenic Effects. Danish Environmental Protection Agency, Ministry of Environment and Energy, Denmark 1995. 247225 POSSIBLE MECHANISMS OF PHYTOESTROGEN ACTION Plant-derived, nonsteroidal estrogenic compounds are either produced by plants themselves (phytoestrogens) or by fungi that infect plants (mycoestrogens). Structurally, the phytoestrogens are divided into three main classes: isoflavonoids, coumestans, and lignans (Figure 1). Isoflavonoids, e.g. biochanin A, daidzein, formonetin, and genistein, and coumestans, e.g. coumestrol, are formed in numerous plants, especially in soy and other leguminous plants. The richest sources of plant lignans, e.g. matairesinol and secoisolariciresinol, are unrefined grain such as flaxseed. Trace amounts of the estrogenic mycotoxin zearalenone are also found in human diets. Structurally zearalenone is resorcylic acid lactone. Isoflavonoids and Coumestans Coumestans and isoflavonoids exert their effects in estrogen-responsive cells by interacting with nuclear estrogen receptors (Mayr et al., 1992; Mdkeld et al., 1994; Miksicek, 1995): (1) They have high binding affinities for ER (Martin et al., 1978), and they increase the proliferation rate of ER-positive human breast cancer cells. (2) Coumestrol and genistein transactivate the reporter construct containing an estrogen responsive element (ERE) in cells which are transiently cotransfected with an expression vector for the estrogen receptor and the reporter construct. This transactivation is blocked by ICI 164 384, an effective antiestrogen, and does not take place in ER-negative cells. (3) In MCF-7 breast cancer cells, coumestrol and genistein induce the expression of three estrogen-responsive genes, c-myc, pS2, and the progestin receptor.2 2 There is no evidence for the antiestrogenicity of coumestrol or genistein in the estradiol-stimulation of breast cancer cell (MCF-7 or T-47D cell) proliferation. They both had additive effects with 17p- estradiol at a concentration of 10 pM giving submaximal stimulation, and none of the phytoestrogens studied (at concentrations below 1 pM) reduced the estrogen-dependent proliferation of breast cancer cells, i.e. there were no antiestrogenic effects in the presence of 17~3-estradiol (Mdkeld et al., 1994). In addition to the interaction with ER, dietary estrogens may compete with endogenous estrogens for active sites of estrogen biosynthesizing and metabolizing enzymes and thus alter the concentration of biologically active endogenous estrogens at the target cell level. They have been shown to inhibit the estrogen-specific 170-hydroxysteroid oxidoreductase ( 17(3-HSOR) enzyme type 1 (E.C. 1.1.1.62) (Makela et al., 1995b). In cultured breast cancer cells (T-47D cells), this enzyme is a reductase converting the weak endogenous estrogen (estrone) to the hormonally more potent estrogen (17p-estradiol). This estrogen-specific enzyme is found in steroidogenic tissues, placentas, and ovaries. Besides steroidogenic tissues this enzyme has also been found in cells considered to be estrogen sensitive (Poutanen et al., 1995). The enzyme protein has been localized in human breast epithelium and endometrium as well as in the epithelium of human and mouse prostatic urethra and collecting ducts (Pylkkdnen et al., 1994). 2. Santti, R., Mäkelä, S., Strauss, L., Korkman, J., and Kostian, M-J. (1996). Unpublished data, University of Turku, Turku, Finland. 248226 FIGURE 1. Chemical structures of 17(3-estradiol and some phytoestrogens (genistein, coumestrol, enterolactone, and enterodiol) and an estrogenic mycotoxin (zearalenone). However, isoflavone structures are not capable of discriminating between the binding sites of the receptor and the active sites of type 1 enzyme (Table 1). This means that isoflavonoids may compensate the reduced 17~-estradiol concentrations. The inhibitory capacity of the isoflavonoids correlates with their estrogenicity in in vitro tests. 249227 TABLE 1. The Estrogenicity and the Relative 17p HSOR Type 1 Inhibition of 17fi-Estradiol and Some Phytoestrogens *HeLa cells transiently transfected with hER plus pERE-TK-CAT (Miksicek, 1995) **~H-estrone conversion to 3H-estradiol by purified enzyme Flavonoids Flavonoids (Figure 2) are considered to be nonestrogenic or weakly estrogenic, and, therefore, they are not usually considered to be phytoestrogens. However, some of them (apigenin, kaempferol, and naringenin) have hormonal potencies comparable to those of isoflavonoids in breast cancer cell cultures and act through estrogen-receptor mediated mechanisms (Miksicek, 1995), and can thus be regarded as phytoestrogens. Flavonoids are widely distributed in the plant kingdom. The major sources of flavonoids in human diets are vegetables, fruits, tea, and red wine. A variety of plant-derived compounds belonging to flavone, flavonol, or flavanone families inhibit type 1 enzyme at the concentration of 1.2 ~mol/L. The most active compounds (apigenin and kaempferol) significantly inhibit estrone reduction at a concentration of 0.12 ~mol/L. Comparisons of the chemical requirements of estrogenicity and the inhibitory capacity suggested some differences (Mdkeld et al., 1995a) (Table 2). For instance, methoxylation of ring B in position 4' increased the inhibitory capacity of 4',5,7-trihydroxyflavone with or without the hydroxyl group in position 3 (apigenin versus acacetin and kaempferol versus kaempferide) but decreased the estrogenicity (kaempferol versus kaempferide) (Miksicek, 1995). Moreover, 3'-hydroxylation decreased the inhibitory capacity and the estrogenicity of the flavone if the 4'-position was occupied by the hydroxyl or methoxy group (apigenin versus luteolin and kaempferol versus quercetin). Some flavones also inhibit the 17(3-oxidation of testosterone and estradiol to the less active steroids, androstenedione and estrone, by 17p-HSOR type 2. The structural demands and kinetic properties for the inhibition of type 1 and 2 enzymes are different (Mdkeld et al., 1995a). As evidence for that, the hydroxyl group in position 3 of flavones (flavonol structure) markedly increased the inhibitory activity on 17(3-estradiol oxidation by type 2 enzyme in PC-3 prostate cancer cells, while it reduced the inhibitory activity on estrone reduction by type 1 enzyme in T-47D breast cancer cells. Thus, changes in the number and location of hydroxy groups may discriminate between the inhibition of estrone reduction and estradiol oxidation. 250228 FIGURE 2. Chemical structures of some flavones, flavanones, and isoflavones: chrysin (5,7-dihydroxyflavone), apigenin (4',5,7-trihydroxyflavone), acacetin (5,7-dihydroxy-4'-methoxy flavone), naringenin (4',5,7- trihydroxyflavanone), luteolin (3',4',5,7-tetrahydroxyflavone), fisetin (3,3',4',7-tetrahydroxyflavone), galangin (3,5,7-trihydroxyflavone), kaempferol (3,4',5,7-tetrahydroxyflavone), kaempferide (3,5,7-trihydroxy-4'- methoxyflavone), and quercetin (3,3',4',5,7-pentahydroxy flavone). Flavonoids also inhibit placental aromatase (Kellis and Vickery, 1984; Ibrahim and Abul-Hajj, 1990). The structural demands for the inhibition of aromatase seem to differ from those of 170- HSOR type 1. Flavone, flavanone, chrysin, and quercetin all inhibit placental aromatase with relative ic 50 values of less than 10 pmovL but were incapable of inhibiting the purified type 1 enzyme (Mdkeld et al., 1995a). Markaverich and coworkers (1988) have reported that quercetin and luteolin (two flavonoids) inhibit 17(3-estradiol-induced proliferation of MCF-7 cells when added in micromolar concentrations. In addition, recent studies have shown that naringenin, an estrogenic flavonoid, has an antiestrogenic action in MCF-7 breast cancer cells (Ruh et al., 1995). Cotreatment of the cells with 17(3-estradiol and naringenin significantly decreased the E2-induced MCF-7 cell proliferation and pS2-luciferase activity in MCF-7 cells transiently transfected with the pS2-luciferase reporter plasmid. The mechanism of these antiestrogenic effects are not known. According to McDonnel and coworkers (McDonnel et al., 1995), steroid receptor ligands may induce different structural alterations with the receptor. Biological activities of ER antagonists are not merely a consequence of their ability to inhibit the binding of 17(3-estradiol to ER, but also their ability to alter ER structure in such a way as to make it incapable of activating transcription. 1. ' 251229 TABLE 2. The Estrogenicity and the Relative 17~-HSOR Type 1 Inhibition ' Capacity of 17(3-estradiol and Flavonoids *HeLa cells transiently transfected with hER plus pERE-TK-CAT (Miksicek, 1995). "3 H-estrone conversion to 3H-estradiol by purified enzyme. The antiestrogenic activity of flavonoids combined with their potential capability to inhibit enzymes in estrogen biosynthesis and metabolism (for instance estrone reduction) may represent a mechanism which accounts for the chemoprevention of breast and prostate carcinogenesis by soy- or other plant-based diets (Adlercreutz et al., 1993b). Phytoestrogens may have effects which are not related to their capability to interact with ER or the active sites of the estrogen synthesizing and metabolizing enzymes (Adlercreutz, 1995). Isoflavonoids, particularly genistein, are potent inhibitors of the tyrosine protein kinase activity of several growth factor receptors and oncogenes. Genistein is also an inhibitor of angiogenesis and DNA topoisomerases associated with tumor growth. Isoflavonoids have been reported to inhibit 252230 the formation of 5a-dihydrotestosterone from testosterone by the 5a-reductase enzyme (Evans et al., 1995). These in vitro effects, which also take place in ER-negative cells, have been observed at concentrations considerably exceeding those found in male serum (Table 3), and, therefore, are of doubtful pathophysiological significance and are not dealt with further in this communication. TABLE 3. Plasma Concentrations of Exogenous and Endogenous Estrogens in Men *Adlercreutz et al., 1993b 'de Jong et al., 1991 1 Lignans Mammalian lignans (enterodiol and enterolactone) have shown a weak estrogenic potency in different in vitro tests (Adlercreutz, 1995). Micromolar concentrations of enterolactone, the most abundant mammalian lignan, were needed to stimulate prolactin synthesis by cultured rat pituitary cells in vitro (Jordan et al., 1985), the rate of MCF-7 cell proliferation (Mousavi and Adlercreutz, 1992), the synthesis of sex hormone binding globulin (SHBG) in cultured HepG2 liver cancer cells (Adlercreutz et al., 1992), and the expression of the pS2 gene (Sathyamoorthy et al., 1994). Enterolactone acted synergistically with 17(3-estradiol at physiological concentrations on SHBG synthesis (Adlercreutz et al., 1992). In contrast, enterolactone had an antiproliferative action in the presence of a slightly stimulatory or nonstimulatory concentration of 17i-estradiol in MCF-7 cell cultures (Mousavi and Adlercreutz, 1992). The mechanism of this antiestrogenic action is not yet clear. Enterolactone has been shown to inhibit human placental aromatase in the in vitro assay using androstenedione as a substrate (Adlercreutz et al., 1993a). However, the lowest concentration of enterolactone showing a significant inhibition was 16 pmol/L which is much higher than the concentrations found in human serum. They rarely exceed 1 pmovL even after consumption of a diet supplemented with flax (Morton et al., 1994). The effects of phytoestrogens and structurally related compounds in vivo cannot be predicted on the basis of the in vitro findings. For instance, the availability of the compounds to the target cell may be crucial for the hormonal action of environmental estrogens (Arnold et al., 1996). Further studies are needed to confirm the in vivo estrogenicity or antiestrogenicity, based either on the inhibition of estrogen biosynthesis and metabolism or on interaction with the receptor, and to characterize their other actions. Induction of Vitellogenin Gene by Phytoestrogens in Fish Liver ' . Vitellogenin, an oocyte protein of all oviparous vertebrates, does not usually occur in juveniles or males. However, the liver of juveniles or males can be induced by estrogen to synthesize and secrete large amounts of this protein. This induction in male liver parenchymal cells is useful for 253231 the detection of environmental estrogens. Various phytoestrogens (daidzein, biochanin A, genistein, equol, and coumestrol) occurring in soy have been found to possess estrogenic activity as assayed by their induction of hepatic vitellogenin synthesis when administered intraperitoneally to the Siberian sturgeon or added to hepatocyte cultures of the rainbow trout (Pelissero et al., 1991, 1993). Wood also contains phytoestrogens, i.e. compounds with estrogenic activity such as sitosterols, stilbenes, and resin acids (MacLatchy and Van der Kraak, 1995; Mellanen et al., 1996). An increased level of mRNAs was found in juvenile whitesucker (Coregonus lavaretus) caged in the vicinity of a pulp mill, suggesting the effluent was a source of estrogenic contaminants (Mellanen et al., 1997). In accordance with this, the mill was shown to discharge wood-derived estrogenic compounds such as sterols and resin acids in amounts considerably exceeding those from other mills. The biological significance of vitellogenin gene induction in juvenile and male fish is not known. PHYTOESTROGEN ACTIONS IN THE MALE REPRODUCTIVE TRACT OF THE MOUSE AND RAT Male genital abnormalities have been reported in a variety of animal species following prenatal or neonatal exposure to DES. These are qualitatively comparable to those reported in DES-exposed men. There is a close quantitative correlation when the toxicological results observed in laboratory animals are extrapolated to humans (Hogan et al., 1987). This allows for the prediction of harmful effects in humans on the basis of animal experiments. Prenatal exposure to DES ( 1-100 pg/kg of maternal body weight) was associated with long-term structural and functional alterations in males (McLachlan et al., 1975). The affected animals had epididymal cysts and gonadal changes which included cryptorchid testes or testicular lesions, or both. The fertility of the DES-exposed males was reduced. Several factors appeared to be related to this decreased fertility: (1) abnormal sperm morphology and motility, (2) lesions in the reproductive tract, (3) abnormal secretions, and (4) inflammation (Newbold and McLachlan, 1985). In addition, significant alterations were seen in the accessory sex glands. The seminal vesicles did not grow and differentiate after neonatal exposure to DES (McLachlan et al., 1975). The neonatal period, when the prostatic glands develop, become branched and canalized, and when the secretory epithelium of the glands cytodifferentiates, is critical for the development of prostatic lesions. At this developmental stage, neonatal estrogenization of the male mouse with DES (2 fug/pup daily on the first three days of postnatal life) results in time-of-exposure and dose-dependent inhibition of prostatic growth and function (Table 4). Besides permanent growth inhibition, DES promotes epithelial hyperplasia and dysplasia in the posterior periurethral region. In addition to the emergence of nuclear anaplasia, the architectural patterns of the glands are disturbed. Histologically, the dysplastic lesions closely resemble the PIN (prostatic intraepithelial neoplasia)- lesions in the human prostate. There is evidence to suggest that dysplasia is an important precursor lesion for some adenocarcinomas of human as well as rodent prostates (Pylkkanen et al., 1996). In addition, early exposure of the male mouse to exogenous estrogens causes urodynamic changes typical for men with benign prostatic hyperplasia (Lehtimdki et al., 1996). 254232 TABLE 4. Effects of Neonatal Estrogenization in Mouse Urethroprostatic Complex (Treatment with 2 pig of Diethylstilbestrol/pup/day s.c. During Days 1-3 After Birth) Pylkkdnen et al., 1991, 1993; Lehtimdki et al., 1996 In neonatally estrogenized (neoDES) mice, the histological response to 17(3-estradiol in terms of metaplastic transformation and 17p-estradiol-induced expression of c-fos proto-oncogene genes is greatly enhanced in the epithelium of collecting ducts adjacent to the ER-positive stroma (Table 4). The increased estrogen sensitivity makes the neoDES mouse model particularly suitable for testing the acute effects of phytoestrogen-rich diets or phytoestrogens in the male organism. Roasted soybean meal rich in isoflavonoids had no significant inhibitory effect on the growth of prostatic lobes when dams and offspring were kept on a diet containing soy (fertilization-2 months) (Mdkeld et al., 1995c). In contrast, the soy diet reduced the prostatic growth inhibition due to neonatal DES treatment, and delayed the development of dysplastic changes. Both the number of animals showing dysplasia and also the severity of the alterations in the dysplastic epithelium were lower in animals given soy, suggesting an antiestrogenic action for soy. These findings suggest that dietary soy may have chemopreventive properties in neoDES mice. This chemopreventive action may be due to the antiestrogenicity of soy-derived compounds such as isoflavonoids. The presence of estrogenic isoflavonoids in feed containing soybean was confirmed by measuring the excretion of seven different plant estrogens in the urine of adult male mice (Mdkeld 255233 et al., 1995c). However, no evidence for estrogenicity or antiestrogenicity (capability to antagonize the action of 17~3-estradiol) of soy was found in short-term tests using development of epithelial metaplasia and expression of c-fos proto-oncogene in the prostate as determinants of estrogen action in adult castrated animals (Mdkeld et al., 1995d). Genistein, like 17~3-estradiol, transiently increased the expression of c-fos proto-oncogene in the prostate of adult castrated mice.' Genistein was active in doses between 25 tig-5 mg/kg body weight (bw). These doses are comparable to the amounts found in soy-containing feeds. Based on earlier reports on the genistein content in soy products, 5 g of feed (the amount consumed by adult mice per day) with 7% soy meal would contain about 100 pg of genistein (2 mg/kg bw). Genistein also induced squamous epithelial metaplasia, a classical sign of estrogen action in the prostate, when given daily at 250 ~g/kg bw for ten days. However, genistein treatment given neonatally up to 100 pg/pup/day (50 mg/kg bw) in the first three days failed to induce permanently increased c-fos expression and prostate weight reduction seen after neonatal DES treatment. In contrast to these marginal or lack of effects of genistein in the prostate of newborns, the CNS-gonadal axis and male sexual behavior appear to be sensitive to genistein during the neonatal period. Neonatal exposure (on days 1-10 after birth) to genistein ( 100 ~g) has been reported to alter pituitary responsiveness and basal LH secretion in castrated postpubertal rats (Faber and Hughes, 1991; Register et al., 1995). The changes were similar, but not identical, to those seen after neonatal DES (0.1 1 pg) exposure, but higher doses of phytoestrogen were required. Coumestrol (200 ~g/animal s.c.) induced c-fos expression when given to castrated neoDES mice at the age of three months (Mdkeld et al., 1995d). However, coumestrol (given s.c. in a dose of 50 pg per day for seven days) had no effect on the development of epithelial metaplasia in adult males, nor was any evidence found for the estrogenicity of coumestrol when the inhibitory effect on the CNS-gonadal axis was used as a determinant of estrogen action in the male rat (Makela et al., 1990). In normal males, the administration of estrogen reduces the size of the sex accessory glands. The primary effect is the reduction in plasma testosterone concentration which is due to reduced LH concentrations. In contrast to our findings in adult animals, Whitten and coworkers (1995a and 1995b) reported that lactational exposure of rat pups to coumestrol on days 1-10 (10 mg/100 g of diet fed to dams) resulted in suppression of testicular, but not serum, testosterone concentration at day 10, and caused a number of variants in sexual behavior in adulthood. In conclusion, phytoestrogens such as genistein and coumestrol show estrogenic activity in accessory sex glands of adult males. Given neonatally genistein failed to induce any persistent changes in accessory sex glands but caused alterations in the developing CNS. It is obvious that further studies are needed to confirm these developmental effects of genistein and to understand the significance of phytoestrogens for the development of male reproductive tract disorders. 3. Santti, R., Mäkelä, S., Strauss, L., Korkman, J., and Kostian, M-J. (1996). Unpublished data, University of Turku, Turku, Finland. 256234 POSSIBLE ACTIONS OF PHYTOESTROGENS IN THE HUMAN ORGANISM There are no data on the effects of phytoestrogens or flavonoids given as pure compounds to humans, and almost all evidence currently available is indirect and based on experiments with phytoestrogen-rich diets given to women. In postmenopausal women, soy-based foods have been shown to promote vaginal cell maturation, which is a sensitive and specific indicator of estrogen exposure (Wilcox et al., 1990; Baird et al., 1995). The effects on vaginal cytology were weak, and no estrogenic effects were seen on the liver (serum SHBG level) or pituitary gland (serum FSH and LH levels). In premenopausal women, soy and flax diets slightly lengthened the follicular phase of the menstrual cycle and suppressed the midcycle gonadotrophin surge (Phipps et al., 1993; Cassidy et al., 1994). These latter effects may be due to the weak estrogenic effect of phytoestrogens in the CNS-gonadal axis. According to a recent conference report, dietary soy supplementation (60 g soy containing 45 mg isoflavones taken daily over 14 days) stimulates epithelial proliferation in the normal human breast (McMichael-Phillips et al., 1995). The rate of cell proliferation was measured in biopsies of normal breast labeled with 3H-thymidine to detect the number of cells in S-phase and immunocytochemically stained for the proliferation antigen, Ki67. In healthy young men, a short-term (6 weeks) flaxseed supplementation of the diet had no significant effects on plasma total testosterone, free testosterone, or sex hormone binding globulin concentrations (Shultz et al., 1991 ). In conclusion, phytoestrogen-rich diets have so far shown weak estrogenic effects in both the adult male and female organism. Nothing is known about the effects of individual phytoestrogens. There is no direct evidence indicating that phytoestrogen-rich diets or phytoestrogens would have an antiestrogenic capacity in the human organism. It is possible that phytoestrogens could interfere at multiple steps in the ER-signal transduction pathway, and it is the cumulative effects of these actions that account for their biological effects. As an example, inhibition of aromatase and 17?- hydroxysteroid oxidoreductase (type 1) by flavonoids would result in the lower plasma estrogen concentrations found in vegetarians who consume a low-fat, high-fiber diet (Adlercreutz et al., 1993a). In addition, some flavonoids could act as antiestrogens regulating ER functions. It is obvious that more information about the bioavailability and metabolism of phytoestrogens and related compounds is needed, as well as more sensitive markers of estrogenic and antiestrogenic effects (Baird et al., 1995). Japanese men were shown to have considerably higher levels of isoflavonoids (daidzein and genistein) and lower levels of endogenous estrogens in serum than Finnish men (Table 3; Adlercreutz et al., 1993b). The genistein concentration found in sera of Japanese men on traditional Japanese diets gives maximum activation of breast cancer cell proliferation in vitro, while concentrations found in sera of Finnish men are too low to significantly stimulate the rate of cell proliferation (Table 3). In spite of this difference in serum concentrations, Finnish men have a higher risk of hypospadia and testicular and prostatic cancers (and probably also that of benign prostatic hyperplasia). This makes it unlikely that phytoestrogens or structurally related compounds in amounts present in Asian diets would, as estrogens, cause the male genital tract disorders. According to a recent study, Japanese men have smaller prostate volumes even after adjusting for differences in height, weight, and age (Masumori et al., 1996) and lower prostatic 5a-reductase activity than U.S. whites (Ross et al., 1992). It is possible that the relatively smaller prostatic size and the lower 257235 5a-reductase activity are due to lower concentrations of androgens (Ross and Henderson, 1994) induced by developmental exposure to higher concentrations of estrogenic isoflavones. At present, this conclusion is highly speculative. Because phytoestrogens and related compounds have been shown to be biologically active in livestock, wild animals (Kaldas and Hughes, 1989), and laboratory animals, and because one cannot exclude the possibility of harmful effects also in the developing human organism, particularly in doses exceeding the daily intake of phytoestrogens in Asian diets, phytoestrogens have to be regarded as potential endocrine disruptors. REFERENCES ... Adlercreutz, H. (1995). "Phytoestrogens: Epidemiology and a possible role in cancer protection." Environ. Health Perspect. 103 (Suppl. 7):103-112. 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"<article-title>Oestrogenic effects of plant foods in postmenopausal women</article-title>." <source>Br. J. Med.</source><volume>301</volume>:<fpage>905</fpage>-<lpage>906</lpage>.</citation></ref></ref-list></back></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Phytoestrogens: Potential Endocrine Disruptors in Males</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Phytoestrogens: Potential Endocrine Disruptors in Males</title></titleInfo><name type="personal"><namePart type="given">Risto</namePart><namePart type="family">Santti</namePart><affiliation>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</affiliation></name><name type="personal"><namePart type="given">Sari</namePart><namePart type="family">Mäkelä</namePart><affiliation>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</affiliation></name><name type="personal"><namePart type="given">Leena</namePart><namePart type="family">Strauss</namePart><affiliation>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</affiliation></name><name type="personal"><namePart type="given">Johanna</namePart><namePart type="family">Korkman</namePart><affiliation>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</affiliation></name><name type="personal"><namePart type="given">Marja-Lsa</namePart><namePart type="family">Kostian</namePart><affiliation>University of Thrku Institute of Biomedicine and Medicity Research Laboratory Turku, Finland</affiliation></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Sage Publications</publisher><place><placeTerm type="text">Sage CA: Thousand Oaks, CA</placeTerm></place><dateIssued encoding="w3cdtf">1998-01</dateIssued><copyrightDate encoding="w3cdtf">1998</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Exposure to diethylstilbestrol (DES) induces persistent structural and functional alterations in the developing reproductive tract of males. It is possible that xenoestrogens other than DES alter sexual differentiation in males and account for the increasing incidence of developmental disorders of the reproductive tract in men and wild animals. Phytoestrogens (coumestans, isoflavonoids, flavonoids, and lignans) present in numerous edible plants are quantitatively the most important environmental estrogens when their hormonal potency is assessed in vitro. They exert their estrogenic activity by interacting with estrogen receptors (ERs) in vitro. They may also act as antiestrogens by competing for the binding sites of estrogen receptors or the active site of the estrogen biosynthesizing and metabolizing enzymes, such as aromatase and estrogen-specific 17β-hydroxysteroid oxidoreductase (type 1). In theory, phytoestrogens and structurally related compounds could harm the reproductive health of males also by acting as antiestrogens. There are very little data on effects of phytoestrogens in males. Estrogenic effects in wildlife have been described but the evidence for the role of phytoestrogens is indirect and seen under conditions of excessive exposure. In doses comparable to the daily intake from soy- based feed, isoflavonoids such as genistein were estrogen agonists in the prostate of adult laboratory rodents. When given neonatally, no persistent effects were observed. In contrast, the central nervous system (CNS)-gonadal axis and the male sexual behavior of the rat appear to be sensitive to phytoestrogens during development. The changes were similar but not identical to those seen after neonatal treatment with DES, but higher doses of phytoestrogens were needed.There are no data on effects of phytoestrogens given as pure compounds to humans, and all evidence currently available is indirect and based on experiments with phytoestrogen- rich diets. The hormonal effects have so far been marginal. It is known that the intake of phytoestrogens is higher in countries where the incidence rates of clinical conditions linked to estrogen exposure, such as hypospadia or testicular and prostatic cancers, are low. This makes it unlikely that phytoestrogens, or structurally related compounds in amounts present in Asian diets, would have DES-like actions. This does not exclude possibilities that they influence concentrations of endogenous sex hormones and interact with the ER, and that through these mechanisms they alter male sex differentiation, and consequently increase the risks of male genital tract tumors or developmental disorders, particularly in doses exceeding the daily intake of phytoestrogens in Asian diets.</abstract><subject><genre>keywords</genre><topic>3. Key words: diethylstilbestrol</topic><topic>flavonoids</topic><topic>17β-hydroxysteroid oxidoreductase</topic><topic>male</topic><topic>prostate.</topic></subject><relatedItem type="host"><titleInfo><title>Toxicology and Industrial Health</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0748-2337</identifier><identifier type="eISSN">1477-0393</identifier><identifier type="PublisherID">TIH</identifier><identifier type="PublisherID-hwp">sptih</identifier><part><date>1998</date><detail type="volume"><caption>vol.</caption><number>14</number></detail><detail type="issue"><caption>no.</caption><number>1-2</number></detail><extent unit="pages"><start>223</start><end>237</end></extent></part></relatedItem><identifier type="istex">59A7ECC10D6F3EC62D28B8108E557384595A5749</identifier><identifier type="DOI">10.1177/074823379801400114</identifier><identifier type="ArticleID">10.1177_074823379801400114</identifier><recordInfo><recordContentSource>SAGE</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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