{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:01:37Z","timestamp":1791925297317,"version":"4.3.4"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by reproductive and metabolic disturbances, which causes a chronic lack of ovulation that leads to increased incidence of atypical endometrial hyperplasia and carcinogenesis. Increasing evidence indicates that metabolic changes may play a crucial role in PCOS pathogenesis; however, the metabolic profile of fluid in PCOS-related endometrium has not yet been characterized. In this study, we successfully constructed three cases of endometrial organoids derived from clinically healthy endometrium. We established a high-androgen model by adding different ratios of estradiol and testosterone to simulate PCOS-like characteristics. Through scanning electron microscopy and immunofluorescence detection, we found that extra androgen treatment-induced cellular damage led to cellular fragments and apoptosis. The intra-organoid fluid (IOF) and extra-organoid fluid (EOF) of the organoids were separated and analyzed by high-throughput quantitative metabolomics. The results showed that amino acid metabolism, specifically glutamine metabolic changes, was the major metabolic pathway altered in the EOF; meanwhile, changes in fatty acids were the main metabolites in the IOF among the groups. Specifically, the\n                    <jats:italic>in vitro<\/jats:italic>\n                    model confirmed that glutamine enhances endometrial stromal cell decidualization with altered mitochondrial function during the implantation process, which may provide the basis for metabolic marker screening and for identifying potential metabolic targets for intervention in female infertility related to PCOS.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1751258","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T05:41:12Z","timestamp":1774417272000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Metabolic profiling of a polycystic ovary syndrome-like organoid model reveals the critical role of glutamine in local endometrial dysregulation related to implantation failure"],"prefix":"10.3389","volume":"14","author":[{"given":"Haoxuan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University","place":["Guangzhou, Guangdong, China"]},{"name":"Fisheries College, Hunan Agricultural University","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhuan","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongqi","family":"Luo","sequence":"additional","affiliation":[{"name":"Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Azziz","sequence":"additional","affiliation":[{"name":"Department of Health Policy, Management, and Behavior, School of Public Health, University at Albany, SUNY","place":["Rensselaer, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chichiu","family":"Wang","sequence":"additional","affiliation":[{"name":"Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong","place":["Hong KongSAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenming","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomiao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1093\/molehr\/gay024","article-title":"Expression of adhesion and extracellular matrix genes in human blastocysts upon attachment in a 2D co-culture system","volume":"24","author":"Aberkane","year":"2018","journal-title":"Mol. Hum. Reprod."},{"key":"B2","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1530\/JOE-19-0530","article-title":"Androgen signaling pathways driving reproductive and metabolic phenotypes in a PCOS mouse model","volume":"245","author":"Aflatounian","year":"2020","journal-title":"J. Endocrinol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1038\/s41556-019-0360-z","article-title":"Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening","volume":"21","author":"Boretto","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1175384","DOI":"10.3389\/fimmu.2023.1175384","article-title":"Shared diagnostic genes and potential mechanism between PCOS and recurrent implantation failure revealed by integrated transcriptomic analysis and machine learning","volume":"14","author":"Chen","year":"2023","journal-title":"Front. Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/nrendo.2018.24","article-title":"Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment","volume":"14","author":"Escobar-Morreale","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"23132","DOI":"10.1073\/pnas.1915389116","article-title":"'Self-renewing endometrial epithelial organoids of the human uterus","volume":"116","author":"Fitzgerald","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B7","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/j.immuni.2018.03.030","article-title":"Trained memory of human uterine NK cells enhances their function in subsequent pregnancies","volume":"48","author":"Gamliel","year":"2018","journal-title":"Immunity"},{"key":"B8","doi-asserted-by":"publisher","first-page":"441","DOI":"10.2147\/JIR.S260770","article-title":"'Peripheral blood inflammatory-immune cells as a predictor of infertility in women with polycystic ovary syndrome","volume":"13","author":"He","year":"2020","journal-title":"J. Inflamm. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/s41574-024-01057-w","article-title":"Polycystic ovary syndrome as a metabolic disease","volume":"21","author":"Helvaci","year":"2025","journal-title":"Nat. Rev. Endocrinol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1093\/biolre\/ioab101","article-title":"Multi-omics reveals a relationship between endometrial amino acid metabolism and autophagy in women with recurrent miscarriage","volume":"105","author":"Hong","year":"2021","journal-title":"Biol. Reproduction"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1210\/clinem\/dgaa951","article-title":"TLR4-Associated IRF-7 and NFkappaB Signaling Act as a molecular link between androgen and metformin activities and cytokine synthesis in the PCOS endometrium","volume":"106","author":"Hu","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.3389\/fimmu.2020.01023","article-title":"Role of regulatory T cells in regulating fetal-maternal immune tolerance in healthy pregnancies and reproductive diseases","volume":"11","author":"Huang","year":"2020","journal-title":"Front. Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1210\/jc.2014-2401","article-title":"'Reduced Tregs in peripheral blood of PCOS patients - a consequence of aberrant Il2 signaling","volume":"100","author":"Krishna","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3284","DOI":"10.1016\/j.cell.2024.05.010","article-title":"Capturing totipotency in human cells through spliceosomal repression","volume":"187","author":"Li","year":"2024","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e2400524","DOI":"10.1002\/adhm.202400524","article-title":"'Self-Assembled peptide hydrogels loaded with umbilical cord-derived mesenchymal stem cells repairing injured endometrium and restoring fertility","volume":"13","author":"Lv","year":"2024","journal-title":"Adv. Healthc. Mater"},{"key":"B16","doi-asserted-by":"publisher","first-page":"865748","DOI":"10.3389\/fendo.2022.865748","article-title":"Arachidonic acid in follicular fluid of PCOS induces oxidative stress in a human ovarian Granulosa tumor cell line (KGN) and upregulates GDF15 expression as a response","volume":"13","author":"Ma","year":"2022","journal-title":"Front. Endocrinol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e171806","DOI":"10.1172\/jci.insight.171806","article-title":"Antigen-specific decidual CD8+ T cells include distinct effector memory and tissue-resident memory cells","volume":"8","author":"Mahajan","year":"2023","journal-title":"JCI Insight"},{"key":"B18","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1093\/humupd\/dmu006","article-title":"'Ion channels in the endometrium: regulation of endometrial receptivity and embryo implantation","volume":"20","author":"Ruan","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"B19","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.mcna.2022.10.004","article-title":"Polycystic ovarian syndrome","volume":"107","author":"Shrivastava","year":"2023","journal-title":"Med. Clin. North Am."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e2026804118","DOI":"10.1073\/pnas.2026804118","article-title":"Capture and metabolomic analysis of the human endometrial epithelial organoid secretome","volume":"118","author":"Simintiras","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B21","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.fertnstert.2018.05.004","article-title":"Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome","volume":"110","author":"Teede","year":"2018","journal-title":"Fertil. Steril."},{"key":"B22","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1038\/ncb3516","article-title":"'Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium","volume":"19","author":"Turco","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1210\/clinem\/dgz100","article-title":"Scaffold-Free endometrial organoids respond to excess androgens associated with polycystic ovarian syndrome","volume":"105","author":"Wiwatpanit","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B24","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s13048-020-00650-7","article-title":"The effect of glutamine on Dehydroepiandrosterone-induced polycystic ovary syndrome rats","volume":"13","author":"Wu","year":"2020","journal-title":"J. Ovarian Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"5709","DOI":"10.1021\/acs.analchem.0c04686","article-title":"A metabolite array technology for precision medicine","volume":"93","author":"Xie","year":"2021","journal-title":"Anal. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e13819","DOI":"10.1111\/cpr.13819","article-title":"Ciliary IFT-B transportation plays an important role in human endometrial receptivity establishment and is disrupted in recurrent implantation failure patients","volume":"58","author":"Yang","year":"2025","journal-title":"Cell Prolif."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1751258\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T05:41:15Z","timestamp":1774417275000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1751258\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":26,"alternative-id":["10.3389\/fcell.2026.1751258"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1751258","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]},"article-number":"1751258"}}