{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T17:13:24Z","timestamp":1793121204859,"version":"4.5.0"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The objective of this systematic review was to evaluate the association between a soy-based infant diet and the onset of puberty. We included studies in which children were fed a soy-based diet, and we compared them with those who were not. The primary outcomes were the onset of puberty in girls (thelarche, pubarche, and menarche age), boys (pubarche, voice change, testicular and penis enlargement age), and both (risk of delayed and precocious puberty [PP]). Search strategies were performed in PubMed, Embase, LILACS, and CENTRAL databases. Two reviewers selected eligible studies, assessed the risk of bias, and extracted data from the included studies. The odds ratio (OR) and mean difference (MD) were calculated with a 95% confidence interval (CI) as a measure of the association between soy consumption and outcomes. We used a random-effects model to pool results across studies and the Grading of Recommendations Assessment, Development, and Evaluation to evaluate the certainty of evidence. We included eight studies in which 598 children consumed a soy-based diet but 2957 did not. The primary outcomes that could be plotted in the meta-analysis were the risk of PP and age at menarche. There was no statistical difference between groups for PP (OR: 0.51, 95% CI: 0.09 to 2.94, 3 studies, 206 participants, low certainty of evidence). No between-group difference was observed in menarche age (MD 0.14 years, 95% CI -0.16 to 0.45, 3 studies, 605 children, low certainty of evidence). One study presented this outcome in terms of median and interquartile range, and although the onset of menarche was marginally increased in girls who received a soy-based diet, the reported age was within the normal age range for menarche. We did not find any association between a soy-based infant diet and the onset of puberty in boys or girls.<\/jats:p>\n<jats:p><jats:bold>Trial Registration<\/jats:bold>: PROSPERO registration: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?ID=CRD42018088902\" xlink:type=\"simple\">CRD42018088902<\/jats:ext-link>.<\/jats:p>","DOI":"10.1371\/journal.pone.0251241","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T17:46:04Z","timestamp":1621359964000},"page":"e0251241","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Association between a soy-based infant diet and the onset of puberty: A systematic review and meta-analysis"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0978-8282","authenticated-orcid":true,"given":"Fl\u00e1via Ramos Kazan","family":"Oliveira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Flora Silva e","family":"Gustavo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renan Braga","family":"Gon\u00e7alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda","family":"Bolfi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana L\u00facia","family":"Mendes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9316-4167","authenticated-orcid":true,"given":"Vania dos Santos","family":"Nunes-Nogueira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,5,18]]},"reference":[{"key":"pone.0251241.ref001","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/1475-2891-13-54","article-title":"Is soy intake related to age at onset of menarche? A cross-sectional study among adolescents with a wide range of soy food consumption","volume":"13","author":"G Segovia-Siapco","year":"2014","journal-title":"Nutrition journal"},{"issue":"3","key":"pone.0251241.ref002","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1002\/ptr.5966","article-title":"Comprehensive evaluation of the role of soy and isoflavone supplementation in humans and animals over the past two decades","volume":"32","author":"Y Xiao","year":"2018","journal-title":"Phytother Res"},{"issue":"7","key":"pone.0251241.ref003","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1093\/nutrit\/nux016","article-title":"Health impact of childhood and adolescent soy consumption","volume":"75","author":"M Messina","year":"2017","journal-title":"Nutrition reviews"},{"issue":"10","key":"pone.0251241.ref004","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.1210\/endo.139.10.6216","article-title":"Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta","volume":"139","author":"GG Kuiper","year":"1998","journal-title":"Endocrinology"},{"issue":"13","key":"pone.0251241.ref005","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1055\/s-0028-1088304","article-title":"Selective estrogen receptor modulators and phytoestrogens","volume":"74","author":"T Oseni","year":"2008","journal-title":"Planta medica"},{"issue":"5","key":"pone.0251241.ref006","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1081\/CNV-120023773","article-title":"Soy isoflavones and cancer prevention","volume":"21","author":"FH Sarkar","year":"2003","journal-title":"Cancer Invest"},{"issue":"9","key":"pone.0251241.ref007","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1080\/09513590802596461","article-title":"Isoflavones are safe compounds for therapeutical applications\u2014evaluation of in vitro data","volume":"25","author":"E Reiter","year":"2009","journal-title":"Gynecological endocrinology: the official journal of the International Society of Gynecological Endocrinology"},{"issue":"4","key":"pone.0251241.ref008","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1210\/er.2009-0002","article-title":"Endocrine-disrupting chemicals: an Endocrine Society scientific statement","volume":"30","author":"E Diamanti-Kandarakis","year":"2009","journal-title":"Endocr Rev"},{"issue":"3","key":"pone.0251241.ref009","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.yfrne.2008.02.002","article-title":"Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems","volume":"29","author":"AC Gore","year":"2008","journal-title":"Frontiers in neuroendocrinology"},{"issue":"3","key":"pone.0251241.ref010","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/S0031-9384(01)00579-0","article-title":"Effects of neonatal polychlorinated biphenyl exposure on female sexual behavior","volume":"74","author":"YW Chung","year":"2001","journal-title":"Physiology & behavior"},{"issue":"4","key":"pone.0251241.ref011","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.yhbeh.2003.12.006","article-title":"A soy supplement and tamoxifen inhibit sexual behavior in female rats","volume":"45","author":"HB Patisaul","year":"2004","journal-title":"Hormones and behavior"},{"issue":"2","key":"pone.0251241.ref012","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1074\/jbc.M209483200","article-title":"Peroxisome proliferator-activated receptor gamma (PPARgamma) as a molecular target for the soy phytoestrogen genistein","volume":"278","author":"ZC Dang","year":"2003","journal-title":"J Biol Chem"},{"issue":"12","key":"pone.0251241.ref013","doi-asserted-by":"crossref","first-page":"5740","DOI":"10.1210\/en.2006-0365","article-title":"Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner","volume":"147","author":"M Penza","year":"2006","journal-title":"Endocrinology"},{"key":"pone.0251241.ref014","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.reprotox.2013.12.003","article-title":"Postweaning dietary genistein exposure advances puberty without significantly affecting early pregnancy in C57BL\/6J female mice","volume":"44","author":"R Li","year":"2014","journal-title":"Reproductive toxicology (Elmsford, NY)"},{"issue":"3","key":"pone.0251241.ref015","doi-asserted-by":"crossref","first-page":"556","DOI":"10.3945\/ajcn.2010.29394","article-title":"Relation of isoflavones and fiber intake in childhood to the timing of puberty","volume":"92","author":"G Cheng","year":"2010","journal-title":"The American journal of clinical nutrition"},{"issue":"6","key":"pone.0251241.ref016","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1007\/s00394-017-1504-1","article-title":"Soy isoflavone consumption and age at pubarche in adolescent males","volume":"57","author":"G Segovia-Siapco","year":"2018","journal-title":"European journal of nutrition"},{"issue":"7","key":"pone.0251241.ref017","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1001\/jama.286.7.807","article-title":"Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood","volume":"286","author":"BL Strom","year":"2001","journal-title":"Jama"},{"key":"pone.0251241.ref018","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1146\/annurev.nutr.24.101603.064950","article-title":"Isoflavones in soy infant formula: a review of evidence for endocrine and other activity in infants","volume":"24","author":"A Chen","year":"2004","journal-title":"Annu Rev Nutr"},{"issue":"4","key":"pone.0251241.ref019","doi-asserted-by":"crossref","first-page":"W65","DOI":"10.7326\/0003-4819-151-4-200908180-00136","article-title":"The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration","volume":"151","author":"A Liberati","year":"2009","journal-title":"Ann Intern Med"},{"issue":"1","key":"pone.0251241.ref020","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan-a web and mobile app for systematic reviews","volume":"5","author":"M Ouzzani","year":"2016","journal-title":"Syst Rev"},{"key":"pone.0251241.ref021","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1471-2288-8-22","article-title":"Recommendations by Cochrane Review Groups for assessment of the risk of bias in studies","volume":"8","author":"A Lundh","year":"2008","journal-title":"BMC Med Res Methodol"},{"key":"pone.0251241.ref022","unstructured":"The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [Internet]. 2000."},{"issue":"8","key":"pone.0251241.ref023","doi-asserted-by":"crossref","first-page":"e010983","DOI":"10.1136\/bmjopen-2015-010983","article-title":"Impact of including or excluding both-armed zero-event studies on using standard meta-analysis methods for rare event outcome: a simulation study","volume":"6","author":"J Cheng","year":"2016","journal-title":"BMJ Open"},{"key":"pone.0251241.ref024","doi-asserted-by":"crossref","DOI":"10.1002\/9781119536604","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions","author":"JPTT, J. Higgins","year":"2019","edition":"2"},{"issue":"4","key":"pone.0251241.ref025","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.jclinepi.2010.04.026","article-title":"GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.","volume":"64","author":"G Guyatt","year":"2011","journal-title":"J Clin Epidemiol"},{"issue":"7650","key":"pone.0251241.ref026","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: an emerging consensus on rating quality of evidence and strength of recommendations","volume":"336","author":"GH Guyatt","year":"2008","journal-title":"BMJ (Clinical research ed)"},{"issue":"12","key":"pone.0251241.ref027","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/j.jclinepi.2011.06.004","article-title":"GRADE guidelines: 9. Rating up the quality of evidence","volume":"64","author":"GH Guyatt","year":"2011","journal-title":"J Clin Epidemiol"},{"issue":"5","key":"pone.0251241.ref028","doi-asserted-by":"crossref","first-page":"871","DOI":"10.3945\/jn.114.206201","article-title":"Compared with feeding infants breast milk or cow-milk formula, soy formula feeding does not affect subsequent reproductive organ size at 5 years of age","volume":"145","author":"A Andres","year":"2015","journal-title":"J Nutr"},{"issue":"3","key":"pone.0251241.ref029","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1289\/ehp.10409","article-title":"Pilot studies of estrogen-related physical findings in infants","volume":"116","author":"JC Bernbaum","year":"2008","journal-title":"Environmental health perspectives"},{"issue":"5","key":"pone.0251241.ref030","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1590\/S0102-311X2007000500003","article-title":"Exposi\u00e7\u00e3o ambiental a interferentes end\u00f3crinos com atividade estrog\u00eanica e sua associa\u00e7\u00e3o com dist\u00farbios puberais em crian\u00e7as","volume":"23","author":"C Alves","year":"2007","journal-title":"Cadernos de saude publica"},{"issue":"3","key":"pone.0251241.ref031","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1590\/S0004-27302007000300021","article-title":"Ingest\u00e3o excessiva de fitoestr\u00f3genos e telarca precoce: relato de caso com poss\u00edvel correla\u00e7\u00e3o","volume":"51","author":"EM Fortes","year":"2007","journal-title":"Arq Bras Endocrinol Metabol"},{"issue":"1","key":"pone.0251241.ref032","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1207\/s15327914nc5201_3","article-title":"Urinary sex steroid excretion levels during a soy intervention among young girls: a pilot study","volume":"52","author":"G Maskarinec","year":"2005","journal-title":"Nutrition and cancer"},{"key":"pone.0251241.ref033","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.fct.2016.12.030","article-title":"Prepubertal subchronic exposure to soy milk and glyphosate leads to endocrine disruption","volume":"100","author":"J Nardi","year":"2017","journal-title":"Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association"},{"issue":"12","key":"pone.0251241.ref034","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1289\/ehp.1103579","article-title":"Early-life soy exposure and gender-role play behavior in children","volume":"119","author":"MA Adgent","year":"2011","journal-title":"Environmental health perspectives"},{"issue":"1","key":"pone.0251241.ref035","doi-asserted-by":"crossref","first-page":"4332","DOI":"10.1038\/s41598-017-04610-y","article-title":"Sex Hormones, Gonadotropins, and Sex Hormone-binding Globulin in Infants Fed Breast Milk, Cow Milk Formula, or Soy Formula","volume":"7","author":"X Fang","year":"2017","journal-title":"Scientific reports"},{"issue":"2","key":"pone.0251241.ref036","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s00394-018-1668-3","article-title":"Consumption of soy-based infant formula is not associated with early onset of puberty","volume":"58","author":"T Sinai","year":"2019","journal-title":"European journal of nutrition"},{"issue":"2","key":"pone.0251241.ref037","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1515\/JPEM.2004.17.2.191","article-title":"Soy protein formulas in children: no hormonal effects in long-term feeding. Journal of pediatric endocrinology & metabolism","volume":"17","author":"PG Giampietro","year":"2004","journal-title":"JPEM"},{"issue":"2","key":"pone.0251241.ref038","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1365-3016.2011.01244.x","article-title":"Early-life soy exposure and age at menarche","volume":"26","author":"MA Adgent","year":"2012","journal-title":"Paediatric and perinatal epidemiology"},{"issue":"9","key":"pone.0251241.ref039","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1111\/jpc.13934","article-title":"Soy protein supplement intake for 12 months has no effect on sexual maturation and may improve nutritional status in pre-pubertal children","volume":"54","author":"SM Duitama","year":"2018","journal-title":"J Paediatr Child Health"},{"issue":"12","key":"pone.0251241.ref040","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/j.jclinepi.2011.01.011","article-title":"GRADE guidelines: 5. Rating the quality of evidence\u2014publication bias","volume":"64","author":"GH Guyatt","year":"2011","journal-title":"J Clin Epidemiol"},{"issue":"6","key":"pone.0251241.ref041","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1111\/j.1365-2265.2011.04127.x","article-title":"High serum isoflavone concentrations are associated with the risk of precocious puberty in Korean girls","volume":"75","author":"J Kim","year":"2011","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"8","key":"pone.0251241.ref042","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1080\/10934529.2013.762734","article-title":"Association between precocious puberty and some endocrine disruptors in human plasma","volume":"48","author":"T Yum","year":"2013","journal-title":"J Environ Sci Health A Tox Hazard Subst Environ Eng"},{"key":"pone.0251241.ref043","volume-title":"Gordis Epidemiology","author":"MS David D Celentano","year":"2019"},{"key":"pone.0251241.ref044","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.jclinepi.2020.03.020","article-title":"Exclusion of studies with no events in both arms in meta-analysis impacted the conclusions","volume":"123","author":"C Xu","year":"2020","journal-title":"J Clin Epidemiol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0251241","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T17:46:39Z","timestamp":1621359999000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0251241"}},"subtitle":[],"editor":[{"given":"Ivan D.","family":"Florez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,5,18]]},"references-count":44,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5,18]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0251241","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,18]]}}}