{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:46:54Z","timestamp":1787021214579,"version":"build-2736575974"},"reference-count":32,"publisher":"The Endocrine Society","issue":"8","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HD097087"],"award-info":[{"award-number":["R01HD097087"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["1ZIAES070065"],"award-info":[{"award-number":["1ZIAES070065"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD097087"],"award-info":[{"award-number":["R01HD097087"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>At birth, all female mice, including those that either lack estrogen receptor \u03b1 (ER\u03b1-knockout) or that express mutated forms of ER\u03b1 (AF2ERKI), have a hypoplastic uterus. However, uterine growth and development that normally accompany pubertal maturation does not occur in ER\u03b1-knockout or AF2ERKI mice, indicating ER\u03b1-mediated estrogen (E2) signaling is essential for this process. Mice that lack Cyp19 (aromatase knockout, ArKO mice), an enzyme critical for E2 synthesis, are unable to make E2 and lack pubertal uterine development. A single injection of E2 into ovariectomized adult (10 weeks old) females normally results in uterine epithelial cell proliferation; however, we observe that although ER\u03b1 is present in the ArKO uterine cells, no proliferative response is seen. We assessed the impact of exposing ArKO mice to E2 during pubertal and postpubertal windows and observed that E2-exposed ArKO mice acquired growth responsiveness. Analysis of differential gene expression between unexposed ArKO samples and samples from animals exhibiting the ability to mount an E2-induced uterine growth response (wild-type [WT] or E2-exposed ArKO) revealed activation of enhancer of zeste homolog 2 (EZH2) and heart- and neural crest derivatives-expressed protein 2 (HAND2) signaling and inhibition of GLI Family Zinc Finger 1 (GLI1) responses. EZH2 and HAND2 are known to inhibit uterine growth, and GLI1 is involved in Indian hedgehog signaling, which is a positive mediator of uterine response. Finally, we show that exposure of ArKO females to dietary phytoestrogens results in their acquisition of uterine growth competence. Altogether, our findings suggest that pubertal levels of endogenous and exogenous estrogens impact biological function of uterine cells later in life via ER\u03b1-dependent mechanisms.<\/jats:p>","DOI":"10.1210\/endocr\/bqaa081","type":"journal-article","created":{"date-parts":[[2020,7,5]],"date-time":"2020-07-05T01:04:09Z","timestamp":1593911049000},"source":"Crossref","is-referenced-by-count":10,"title":["Peri- and Postpubertal Estrogen Exposures of Female Mice Optimize Uterine Responses Later in Life"],"prefix":"10.1210","volume":"161","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7713-0805","authenticated-orcid":false,"given":"Sylvia C","family":"Hewitt","sequence":"first","affiliation":[{"name":"Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, NIH, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marleny","family":"Carmona","sequence":"additional","affiliation":[{"name":"Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, NIH, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K Grace","family":"Foley","sequence":"additional","affiliation":[{"name":"Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, NIH, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren J","family":"Donoghue","sequence":"additional","affiliation":[{"name":"Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, NIH, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney L","family":"Lierz","sequence":"additional","affiliation":[{"name":"Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, NIH, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5196-8471","authenticated-orcid":false,"given":"Wipawee","family":"Winuthayanon","sequence":"additional","affiliation":[{"name":"Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, NIH, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7765-418X","authenticated-orcid":false,"given":"Kenneth S","family":"Korach","sequence":"additional","affiliation":[{"name":"Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, NIH, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2020,7,5]]},"reference":[{"issue":"2","key":"2021121822254826700_CIT0001","doi-asserted-by":"crossref","first-page":"R55","DOI":"10.1530\/JME-15-0254","article-title":"What\u2019s new in estrogen receptor action in the female reproductive tract","volume":"56","author":"Hewitt","year":"2016","journal-title":"J Mol Endocrinol."},{"issue":"5","key":"2021121822254826700_CIT0002","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1210\/er.2018-00087","article-title":"Estrogen receptors: new directions in the new millennium","volume":"39","author":"Hewitt","year":"2018","journal-title":"Endocr Rev."},{"issue":"12","key":"2021121822254826700_CIT0003","doi-asserted-by":"crossref","first-page":"6535","DOI":"10.1073\/pnas.94.12.6535","article-title":"Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium","volume":"94","author":"Cooke","year":"1997","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"6","key":"2021121822254826700_CIT0004","doi-asserted-by":"crossref","first-page":"3287","DOI":"10.1073\/pnas.96.6.3287","article-title":"Insulin-like growth factor 1 is required for G2 progression in the estradiol-induced mitotic cycle","volume":"96","author":"Adesanya","year":"1999","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"10","key":"2021121822254826700_CIT0005","doi-asserted-by":"crossref","first-page":"8531","DOI":"10.1074\/jbc.M109592200","article-title":"Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1\/estrogen receptor cross-talk","volume":"277","author":"Klotz","year":"2002","journal-title":"J Biol Chem."},{"issue":"12","key":"2021121822254826700_CIT0006","doi-asserted-by":"crossref","first-page":"4660","DOI":"10.1096\/fj.10-163428","article-title":"Biological and biochemical consequences of global deletion of exon 3 from the ER alpha gene","volume":"24","author":"Hewitt","year":"2010","journal-title":"FASEB J."},{"issue":"48","key":"2021121822254826700_CIT0007","doi-asserted-by":"crossref","first-page":"18350","DOI":"10.1073\/pnas.0608861103","article-title":"Role of estrogen receptor beta in uterine stroma and epithelium: insights from estrogen receptor beta-\/- mice","volume":"103","author":"Wada-Hiraike","year":"2006","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"36","key":"2021121822254826700_CIT0008","doi-asserted-by":"crossref","first-page":"14986","DOI":"10.1073\/pnas.1109180108","article-title":"Estrogen receptor \u03b1 AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators","volume":"108","author":"Arao","year":"2011","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"51","key":"2021121822254826700_CIT0009","doi-asserted-by":"crossref","first-page":"21140","DOI":"10.1073\/pnas.1216189110","article-title":"Transactivating function (AF) 2-mediated AF-1 activity of estrogen receptor \u03b1 is crucial to maintain male reproductive tract function","volume":"109","author":"Arao","year":"2012","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"12","key":"2021121822254826700_CIT0010","doi-asserted-by":"crossref","first-page":"6965","DOI":"10.1073\/pnas.95.12.6965","article-title":"Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene","volume":"95","author":"Fisher","year":"1998","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"7","key":"2021121822254826700_CIT0011","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1210\/endo.141.7.7578","article-title":"An age-related ovarian phenotype in mice with targeted disruption of the Cyp 19 (aromatase) gene","volume":"141","author":"Britt","year":"2000","journal-title":"Endocrinology."},{"issue":"8","key":"2021121822254826700_CIT0012","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1210\/en.2017-00349","article-title":"Role of ER\u03b1 in mediating female uterine transcriptional responses to IGF1","volume":"158","author":"Hewitt","year":"2017","journal-title":"Endocrinology."},{"key":"2021121822254826700_CIT0013"},{"key":"2021121822254826700_CIT0014"},{"key":"2021121822254826700_CIT0015","author":"Hewitt"},{"issue":"6","key":"2021121822254826700_CIT0016","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1016\/j.ajpath.2019.02.016","article-title":"Enhancer of Zeste 2 polycomb repressive complex 2 subunit is required for uterine epithelial integrity","volume":"189","author":"Fang","year":"2019","journal-title":"Am J Pathol."},{"issue":"6019","key":"2021121822254826700_CIT0017","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1126\/science.1197454","article-title":"The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2","volume":"331","author":"Li","year":"2011","journal-title":"Science."},{"issue":"2","key":"2021121822254826700_CIT0018","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1093\/biolre\/ioz097","article-title":"The histone methyltransferase EZH2 is required for normal uterine development and function in mice\u2020","volume":"101","author":"Nanjappa","year":"2019","journal-title":"Biol Reprod."},{"issue":"2","key":"2021121822254826700_CIT0019","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1152\/physiolgenomics.00098.2019","article-title":"Mice lacking uterine enhancer of zeste homolog 2 have transcriptomic changes associated with uterine epithelial proliferation","volume":"52","author":"Mesa","year":"2020","journal-title":"Physiol Genomics."},{"issue":"25","key":"2021121822254826700_CIT0020","doi-asserted-by":"crossref","first-page":"9746","DOI":"10.1074\/jbc.RA119.008759","article-title":"A distal super enhancer mediates estrogen-dependent mouse uterine-specific gene transcription of Igf1 (insulin-like growth factor 1)","volume":"294","author":"Hewitt","year":"2019","journal-title":"J Biol Chem."},{"issue":"25","key":"2021121822254826700_CIT0021","doi-asserted-by":"crossref","first-page":"8387","DOI":"10.1074\/jbc.RA120.013666","article-title":"Estrogen receptor \u03b1 (ER\u03b1)-binding super-enhancers drive key mediators that control uterine estrogen responses in mice","volume":"295","author":"Hewitt","year":"2020","journal-title":"J Biol Chem"},{"issue":"4","key":"2021121822254826700_CIT0022","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1095\/biolreprod.109.080259","article-title":"Ablation of Indian hedgehog in the murine uterus results in decreased cell cycle progression, aberrant epidermal growth factor signaling, and increased estrogen signaling","volume":"82","author":"Franco","year":"2010","journal-title":"Biol Reprod."},{"issue":"9","key":"2021121822254826700_CIT0023","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1210\/me.2014-1074","article-title":"Minireview: steroid-regulated paracrine mechanisms controlling implantation","volume":"28","author":"Pawar","year":"2014","journal-title":"Mol Endocrinol."},{"issue":"2","key":"2021121822254826700_CIT0024","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.biocel.2012.10.012","article-title":"Uterine epithelial cells: serving two masters","volume":"45","author":"Kaneko","year":"2013","journal-title":"Int J Biochem Cell Biol."},{"issue":"4","key":"2021121822254826700_CIT0025","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/rmb2.12103","article-title":"Molecular mechanisms of embryonic implantation in mammals: lessons from the gene manipulation of mice","volume":"17","author":"Namiki","year":"2018","journal-title":"Reprod Med Biol."},{"issue":"15","key":"2021121822254826700_CIT0026","doi-asserted-by":"crossref","DOI":"10.3390\/ijms20153822","article-title":"Progesterone and estrogen signaling in the endometrium: what goes wrong in endometriosis?","volume":"20","author":"Marquardt","year":"2019","journal-title":"Int J Mol Sci."},{"issue":"4","key":"2021121822254826700_CIT0027","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1172\/JCI41210","article-title":"Uterine disorders and pregnancy complications: insights from mouse models","volume":"120","author":"Lim","year":"2010","journal-title":"J Clin Invest."},{"issue":"4","key":"2021121822254826700_CIT0028","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1053\/j.semdp.2010.09.002","article-title":"Endometrial hyperplasia","volume":"27","author":"Mills","year":"2010","journal-title":"Semin Diagn Pathol."},{"issue":"4","key":"2021121822254826700_CIT0029","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1210\/er.2018-00242","article-title":"Endometriosis","volume":"40","author":"Bulun","year":"2019","journal-title":"Endocr Rev."},{"issue":"23","key":"2021121822254826700_CIT0030","first-page":"7677","article-title":"Uterine adenocarcinoma in mice following developmental treatment with estrogens: a model for hormonal carcinogenesis","volume":"50","author":"Newbold","year":"1990","journal-title":"Cancer Res."},{"issue":"11","key":"2021121822254826700_CIT0031","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1289\/ehp.1104018","article-title":"Permanent oviduct posteriorization after neonatal exposure to the phytoestrogen genistein","volume":"119","author":"Jefferson","year":"2011","journal-title":"Environ Health Perspect."},{"issue":"3","key":"2021121822254826700_CIT0032","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1530\/REP-11-0369","article-title":"Reproductive consequences of developmental phytoestrogen exposure","volume":"143","author":"Jefferson","year":"2012","journal-title":"Reproduction."}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqaa081\/33464816\/bqaa081.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/161\/8\/bqaa081\/41815129\/endo_161_8_bqaa081.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/161\/8\/bqaa081\/41815129\/endo_161_8_bqaa081.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T17:26:18Z","timestamp":1639848378000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqaa081\/5867540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,5]]},"references-count":32,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,8,1]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqaa081","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,8]]},"published":{"date-parts":[[2020,7,5]]},"article-number":"bqaa081"}}