{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:28:46Z","timestamp":1792801726752,"version":"4.5.0"},"reference-count":80,"publisher":"The Endocrine Society","issue":"4","license":[{"start":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T00:00:00Z","timestamp":1609372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100006310","name":"Swedish Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006310","id-type":"DOI","asserted-by":"publisher"}]},{"name":"LUA\/ALF","award":["10380"],"award-info":[{"award-number":["10380"]}]},{"name":"LUA\/ALF","award":["ALFGBG-147791"],"award-info":[{"award-number":["ALFGBG-147791"]}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Guangzhou Medical University High-level University Construction Talents Fund","id":[{"id":"https:\/\/ror.org\/00zat6v61","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100014437","name":"Wenner-Gren Foundations","doi-asserted-by":"publisher","award":["019A1515110265"],"award-info":[{"award-number":["019A1515110265"]}],"id":[{"id":"10.13039\/100014437","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014437","name":"Wenner-Gren Foundations","doi-asserted-by":"publisher","award":["B185006010046"],"award-info":[{"award-number":["B185006010046"]}],"id":[{"id":"10.13039\/100014437","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014437","name":"Wenner-Gren Foundations","doi-asserted-by":"publisher","award":["HJSV2014047"],"award-info":[{"award-number":["HJSV2014047"]}],"id":[{"id":"10.13039\/100014437","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81774136"],"award-info":[{"award-number":["81774136"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81572555"],"award-info":[{"award-number":["81572555"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Royal Society Dorothy Hodgkin Research Fellowship and Lister Institute Research Prize","id":[{"id":"https:\/\/ror.org\/03356n642","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Low-grade chronic inflammation is commonly seen in polycystic ovary syndrome (PCOS) patients with elevated levels of inflammatory cytokines in the endometrium.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This work aimed to increase the limited understanding of the mechanisms underlying cytokine synthesis and increased endometrial inflammation in PCOS patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Endometrial biopsy samples were collected from non-PCOS (n\u2005=\u200517) and PCOS (n\u2005=\u200522) patients either during the proliferative phase of the menstrual cycle or with hyperplasia. Endometrial explants were prepared from PCOS patients and underwent pharmacological manipulation in vitro. The expression and localization of toll-like receptor 2 (TLR2)\/4, key elements of innate immune signal transduction and nuclear factor \u03baB (NF\u03baB) signaling pathways, and multiple cytokines were comprehensively evaluated by Western blotting, immunohistochemistry, and immunofluorescence in endometrial tissues.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We demonstrated the distribution of protein expression and localization associated with the significantly increased androgen receptor, TLR2, and TLR4-mediated activation of interferon regulatory factor-7 (IRF-7) and NF\u03baB signaling, cytokine production, and endometrial inflammation in PCOS patients compared to non-PCOS patients with and without endometrial hyperplasia. In vitro experiments showed that 5-dihydrotestosterone (DHT) enhanced androgen receptor, TLR4, IRF-7, and p-NF\u03baB p65 protein expression along with increased interferon \u03b1 (IFN\u03b1) and IFN\u0263 abundance. The effects of DHT on IRF-7, p-NF\u03baB p65, and IFN abundance were abolished by flutamide, an antiandrogen. Although 17\u03b2-estradiol (E2) decreased p-IRF-7 expression with little effect on TLR-mediated IRF7 and NF\u03baB signaling or on cytokine protein levels, exposure to metformin alone or in combination with E2 suppressed interleukin-1 receptor\u2013associated kinase 4 (IRAK4), p-IRF-7, IRF-7, I\u03baB kinase \u03b1 (IKK\u03b1), p-NF\u03baB p65, IFN\u0263, and tumor necrosis factor \u03b1 protein expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Cytokine synthesis and increased endometrial inflammation in PCOS patients are coupled to androgen-induced TLR4\/IRF-7\/NF\u03baB signaling, which is inhibited by metformin treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgaa951","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T13:40:17Z","timestamp":1609422017000},"page":"e1022-e1040","source":"Crossref","is-referenced-by-count":82,"title":["TLR4-Associated IRF-7 and NF\u03baB Signaling Act as a Molecular Link Between Androgen and Metformin Activities and Cytokine Synthesis in the PCOS Endometrium"],"prefix":"10.1210","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7731-5874","authenticated-orcid":false,"given":"Min","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China"},{"name":"Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"name":"Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"name":"Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4931-4233","authenticated-orcid":false,"given":"Amanda Nancy","family":"Sferruzzi-Perri","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats","family":"Br\u00e4nnstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1339-9570","authenticated-orcid":false,"given":"Linus R","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6140-9182","authenticated-orcid":false,"given":"H\u00e5kan","family":"Billig","sequence":"additional","affiliation":[{"name":"Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2020,12,31]]},"reference":[{"key":"2021122205213257100_CIT0001","doi-asserted-by":"crossref","first-page":"16057","DOI":"10.1038\/nrdp.2016.57","article-title":"Polycystic ovary syndrome","volume":"2","author":"Azziz","year":"2016","journal-title":"Nat Rev Dis Primers."},{"issue":"1","key":"2021122205213257100_CIT0002","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/REP-19-0197","article-title":"Mechanisms of intergenerational transmission of polycystic ovary syndrome","volume":"159","author":"Dumesic","year":"2020","journal-title":"Reproduction."},{"issue":"3","key":"2021122205213257100_CIT0003","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s40291-020-00463-w","article-title":"Deciphering the DNA methylome of polycystic ovary syndrome","volume":"24","author":"Tan","year":"2020","journal-title":"Mol Diagn Ther."},{"issue":"1","key":"2021122205213257100_CIT0004","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.fertnstert.2016.05.003","article-title":"Criteria, prevalence, and phenotypes of polycystic ovary syndrome","volume":"106","author":"Lizneva","year":"2016","journal-title":"Fertil Steril."},{"issue":"5","key":"2021122205213257100_CIT0005","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1210\/er.2015-1104","article-title":"The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited","volume":"37","author":"Rosenfield","year":"2016","journal-title":"Endocr Rev."},{"issue":"5","key":"2021122205213257100_CIT0006","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.fertnstert.2018.08.021","article-title":"Beyond fertility: polycystic ovary syndrome and long-term health","volume":"110","author":"Cooney","year":"2018","journal-title":"Fertil Steril."},{"issue":"4","key":"2021122205213257100_CIT0007","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nrendo.2010.217","article-title":"Polycystic ovary syndrome: etiology, pathogenesis and diagnosis","volume":"7","author":"Goodarzi","year":"2011","journal-title":"Nat Rev Endocrinol."},{"issue":"3","key":"2021122205213257100_CIT0008","doi-asserted-by":"crossref","first-page":"173","DOI":"10.7150\/jca.8009","article-title":"Combination of Diane-35 and metformin to treat early endometrial carcinoma in PCOS women with insulin resistance","volume":"5","author":"Li","year":"2014","journal-title":"J Cancer."},{"issue":"2","key":"2021122205213257100_CIT0009","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.rbmo.2019.03.203","article-title":"A meta-analysis of pregnancy-related outcomes and complications in women with polycystic ovary syndrome undergoing IVF","volume":"39","author":"Sha","year":"2019","journal-title":"Reprod Biomed Online."},{"issue":"5","key":"2021122205213257100_CIT0010","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1093\/humupd\/dmv029","article-title":"Pregnancy complications in women with polycystic ovary syndrome","volume":"21","author":"Palomba","year":"2015","journal-title":"Hum Reprod Update."},{"issue":"12","key":"2021122205213257100_CIT0011","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1007\/s10552-010-9658-7","article-title":"Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case-control study","volume":"21","author":"Fearnley","year":"2010","journal-title":"Cancer Causes Control."},{"issue":"10023","key":"2021122205213257100_CIT0012","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/S0140-6736(15)00130-0","article-title":"Endometrial cancer","volume":"387","author":"Morice","year":"2016","journal-title":"Lancet."},{"issue":"15","key":"2021122205213257100_CIT0013","first-page":"2965","article-title":"Fertility-preserving treatment and pregnancy outcomes in the early stage of endometrial carcinoma","volume":"126","author":"Tong","year":"2013","journal-title":"Chin Med J (Engl)."},{"key":"2021122205213257100_CIT0014","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.bbacli.2014.07.001","article-title":"Promising clinical practices of metformin in women with PCOS and early-stage endometrial cancer","volume":"2","author":"Shao","year":"2014","journal-title":"BBA Clin."},{"key":"2021122205213257100_CIT0015","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jsbmb.2018.04.008","article-title":"Polycystic ovary syndrome (PCOS), an inflammatory, systemic, lifestyle endocrinopathy","volume":"182","author":"Patel","year":"2018","journal-title":"J Steroid Biochem Mol Biol."},{"issue":"7","key":"2021122205213257100_CIT0016","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1080\/09513590.2017.1418851","article-title":"The peripheral blood transcriptome identifies dysregulation of inflammatory response genes in polycystic ovary syndrome","volume":"34","author":"Su","year":"2018","journal-title":"Gynecol Endocrinol."},{"issue":"10","key":"2021122205213257100_CIT0017","doi-asserted-by":"crossref","first-page":"e0164021","DOI":"10.1371\/journal.pone.0164021","article-title":"High serum tumor necrosis factor-alpha levels in women with polycystic ovary syndrome: a meta-analysis","volume":"11","author":"Gao","year":"2016","journal-title":"PloS One."},{"issue":"11","key":"2021122205213257100_CIT0018","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1038\/ijo.2016.154","article-title":"Proinflammatory environment and role of TNF-\u03b1 in endometrial function of obese women having polycystic ovarian syndrome","volume":"40","author":"Or\u00f3stica","year":"2016","journal-title":"Int J Obes (Lond)."},{"issue":"1","key":"2021122205213257100_CIT0019","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1007\/s43032-019-00026-3","article-title":"Pro-inflammatory markers negatively regulate IRS1 in endometrial cells and endometrium from women with obesity and PCOS","volume":"27","author":"Or\u00f3stica","year":"2020","journal-title":"Reprod Sci."},{"key":"2021122205213257100_CIT0020","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.bpobgyn.2016.03.008","article-title":"Polycystic ovary syndrome: endometrial markers","volume":"37","author":"Piltonen","year":"2016","journal-title":"Best Pract Res Clin Obstet Gynaecol."},{"issue":"9","key":"2021122205213257100_CIT0021","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1210\/jc.2013-1923","article-title":"Mesenchymal stem\/progenitors and other endometrial cell types from women with polycystic ovary syndrome (PCOS) display inflammatory and oncogenic potential","volume":"98","author":"Piltonen","year":"2013","journal-title":"J Clin Endocrinol Metab."},{"issue":"8","key":"2021122205213257100_CIT0022","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1038\/nm732","article-title":"Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice","volume":"8","author":"Alexopoulou","year":"2002","journal-title":"Nat Med."},{"key":"2021122205213257100_CIT0023","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jri.2015.09.072","article-title":"Association of TLR2 S450S and ICAM1 K469E polymorphisms with polycystic ovary syndrome (PCOS) and obesity","volume":"113","author":"Ojeda-Ojeda","year":"2016","journal-title":"J Reprod Immunol."},{"issue":"5","key":"2021122205213257100_CIT0024","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1507\/endocrj.EJ19-0558","article-title":"Common cytokine polymorphisms and predisposition to polycystic ovary syndrome: a meta-analysis","volume":"67","author":"Zhang","year":"2020","journal-title":"Endocr J."},{"issue":"2","key":"2021122205213257100_CIT0025","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1093\/humrep\/dep421","article-title":"An additive interaction between the NF\u03baB and estrogen receptor signalling pathways in human endometrial epithelial cells","volume":"25","author":"King","year":"2010","journal-title":"Hum Reprod."},{"issue":"7","key":"2021122205213257100_CIT0026","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1080\/01443615.2017.1315563","article-title":"Nuclear factor-\u03baB expression in the endometrium of normal and overweight women with polycystic ovary syndrome","volume":"37","author":"Koc","year":"2017","journal-title":"J Obstet Gynaecol."},{"key":"2021122205213257100_CIT0027","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.ebiom.2017.03.023","article-title":"Metformin ameliorates uterine defects in a rat model of polycystic ovary syndrome","volume":"18","author":"Zhang","year":"2017","journal-title":"EBioMedicine."},{"key":"2021122205213257100_CIT0028","doi-asserted-by":"crossref","first-page":"116681","DOI":"10.1016\/j.lfs.2019.116681","article-title":"Perturbed ovarian and uterine glucocorticoid receptor signaling accompanies the balanced regulation of mitochondrial function and NF\u03baB-mediated inflammation under conditions of hyperandrogenism and insulin resistance","volume":"232","author":"Hu","year":"2019","journal-title":"Life Sci."},{"issue":"12","key":"2021122205213257100_CIT0029","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.7150\/ijbs.13109","article-title":"Regulation of androgen receptor expression alters AMPK phosphorylation in the endometrium: in vivo and in vitro studies in women with polycystic ovary syndrome","volume":"11","author":"Li","year":"2015","journal-title":"Int J Biol Sci."},{"issue":"9","key":"2021122205213257100_CIT0030","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1007\/s00109-019-01809-6","article-title":"Delayed endometrial decidualisation in polycystic ovary syndrome; the role of AR-MAGEA11","volume":"97","author":"Younas","year":"2019","journal-title":"J Mol Med (Berl)."},{"issue":"6","key":"2021122205213257100_CIT0031","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1210\/er.2014-1045","article-title":"Cyclic decidualization of the human endometrium in reproductive health and failure","volume":"35","author":"Gellersen","year":"2014","journal-title":"Endocr Rev."},{"key":"2021122205213257100_CIT0032","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jri.2016.07.002","article-title":"Innate immunity and the sensing of infection, damage and danger in the female genital tract","volume":"119","author":"Sheldon","year":"2017","journal-title":"J Reprod Immunol."},{"issue":"1","key":"2021122205213257100_CIT0033","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.mce.2010.08.006","article-title":"Inflammatory pathways in endometrial disorders","volume":"335","author":"Maybin","year":"2011","journal-title":"Mol Cell Endocrinol."},{"issue":"6","key":"2021122205213257100_CIT0034","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.cell.2020.02.041","article-title":"Toll-like receptors and the control of immunity","volume":"180","author":"Fitzgerald","year":"2020","journal-title":"Cell."},{"issue":"5","key":"2021122205213257100_CIT0035","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1093\/humrep\/deh775","article-title":"Characterization of Toll-like receptors in the female reproductive tract in humans","volume":"20","author":"Fazeli","year":"2005","journal-title":"Hum Reprod."},{"issue":"2","key":"2021122205213257100_CIT0036","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1093\/humrep\/del388","article-title":"Menstrual cycle-dependent changes of Toll-like receptors in endometrium","volume":"22","author":"Aflatoonian","year":"2007","journal-title":"Hum Reprod."},{"issue":"1","key":"2021122205213257100_CIT0037","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/j.1600-0897.2004.00189.x","article-title":"Expression of Toll-like receptors in human endometrial epithelial cells and cell lines","volume":"52","author":"Young","year":"2004","journal-title":"Am J Reprod Immunol."},{"issue":"1","key":"2021122205213257100_CIT0038","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jri.2007.03.014","article-title":"Toll-like receptors in female reproductive tract and their menstrual cycle dependent expression","volume":"77","author":"Aflatoonian","year":"2008","journal-title":"J Reprod Immunol."},{"issue":"4","key":"2021122205213257100_CIT0039","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1210\/en.2013-1822","article-title":"Epithelial and stromal cells of bovine endometrium have roles in innate immunity and initiate inflammatory responses to bacterial lipopeptides in vitro via Toll-like receptors TLR2, TLR1, and TLR6","volume":"155","author":"Turner","year":"2014","journal-title":"Endocrinology."},{"issue":"3","key":"2021122205213257100_CIT0040","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/j.fertnstert.2010.11.036","article-title":"Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis","volume":"95","author":"Escobar-Morreale","year":"2011","journal-title":"Fertil Steril."},{"issue":"6","key":"2021122205213257100_CIT0041","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","article-title":"Metformin: from mechanisms of action to therapies","volume":"20","author":"Foretz","year":"2014","journal-title":"Cell Metab."},{"key":"2021122205213257100_CIT0042","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.intimp.2016.10.002","article-title":"AMPK activation by metformin inhibits local innate immune responses in the isolated rat heart by suppression of TLR 4-related pathway","volume":"40","author":"Vaez","year":"2016","journal-title":"Int Immunopharmacol."},{"issue":"10","key":"2021122205213257100_CIT0043","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s00592-017-1027-5","article-title":"Metformin attenuates the TLR4 inflammatory pathway in skeletal muscle of diabetic rats","volume":"54","author":"Peixoto","year":"2017","journal-title":"Acta Diabetol."},{"issue":"1","key":"2021122205213257100_CIT0044","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1186\/s12974-016-0754-9","article-title":"Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation","volume":"13","author":"Pan","year":"2016","journal-title":"J Neuroinflammation."},{"issue":"1","key":"2021122205213257100_CIT0045","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1056\/NEJMct0707092","article-title":"Metformin for the treatment of the polycystic ovary syndrome","volume":"358","author":"Nestler","year":"2008","journal-title":"N Engl J Med."},{"issue":"1","key":"2021122205213257100_CIT0046","doi-asserted-by":"crossref","first-page":"7802","DOI":"10.1038\/s41598-020-64776-w","article-title":"Effects of lifestyle modification in polycystic ovary syndrome compared to metformin only or metformin addition: a systematic review and meta-analysis","volume":"10","author":"Kim","year":"2020","journal-title":"Sci Rep."},{"key":"2021122205213257100_CIT0047","doi-asserted-by":"crossref","first-page":"341","DOI":"10.3389\/fonc.2018.00341","article-title":"Metformin as a therapeutic target in endometrial cancers","volume":"8","author":"Lee","year":"2018","journal-title":"Front Oncol."},{"issue":"2 Pt 2","key":"2021122205213257100_CIT0048","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1097\/AOG.0b013e3181719b92","article-title":"Reverse of progestin-resistant atypical endometrial hyperplasia by metformin and oral contraceptives","volume":"112","author":"Shen","year":"2008","journal-title":"Obstet Gynecol."},{"issue":"2","key":"2021122205213257100_CIT0049","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1002\/jcp.29051","article-title":"Treatment with metformin and sorafenib alleviates endometrial hyperplasia in polycystic ovary syndrome by promoting apoptosis via synergically regulating autophagy","volume":"235","author":"Wang","year":"2020","journal-title":"J Cell Physiol."},{"issue":"1","key":"2021122205213257100_CIT0050","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1097\/01.AOG.0000269047.46078.28","article-title":"Endometrial expression of Cyr61: a marker of estrogenic activity in normal and abnormal endometrium","volume":"110","author":"MacLaughlan","year":"2007","journal-title":"Obstet Gynecol."},{"issue":"1","key":"2021122205213257100_CIT0051","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/humrep\/deh098","article-title":"Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)","volume":"19","author":"Rotterdam-ESHRE\/ASRM-Sponsored-PCOS-Consensus-Workshop-Group","year":"2004","journal-title":"Hum Reprod."},{"issue":"2","key":"2021122205213257100_CIT0052","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/S0002-9378(16)33500-1","article-title":"Dating the endometrial biopsy","volume":"122","author":"Noyes","year":"1975","journal-title":"Am J Obstet Gynecol."},{"key":"2021122205213257100_CIT0053","article-title":"Data from: TLR4\/IRF-7\/NF\u0138B signaling is a molecular link between androgen and metformin activities and cytokine synthesis in the PCOS endometrium","author":"Hu"},{"issue":"2","key":"2021122205213257100_CIT0054","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1095\/biolreprod.104.036954","article-title":"Androgens induce relaxation of contractile activity in pregnant human myometrium at term: a nongenomic action on L-type calcium channels","volume":"73","author":"Perusqu\u00eda","year":"2005","journal-title":"Biol Reprod."},{"issue":"5","key":"2021122205213257100_CIT0055","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1093\/molehr\/gaaa023","article-title":"Alterations of endometrial epithelial-mesenchymal transition and MAPK signalling components in women with PCOS are partially modulated by metformin in vitro","volume":"26","author":"Hu","year":"2020","journal-title":"Mol Hum Reprod."},{"issue":"10","key":"2021122205213257100_CIT0056","doi-asserted-by":"crossref","first-page":"E1269","DOI":"10.1152\/ajpendo.00673.2011","article-title":"Coordinate regulation of heterogeneous nuclear ribonucleoprotein dynamics by steroid hormones in the human fallopian tube and endometrium in vivo and in vitro","volume":"302","author":"Shao","year":"2012","journal-title":"Am J Physiol Endocrinol Metab."},{"key":"2021122205213257100_CIT0057","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.bbacli.2015.08.004","article-title":"Lack of cyclical fluctuations of endometrial GLUT4 expression in women with polycystic ovary syndrome: evidence for direct regulation of GLUT4 by steroid hormones","volume":"4","author":"Cui","year":"2015","journal-title":"BBA Clin."},{"issue":"3","key":"2021122205213257100_CIT0058","first-page":"574","article-title":"Reversing the reduced level of endometrial GLUT4 expression in polycystic ovary syndrome: a mechanistic study of metformin action","volume":"7","author":"Li","year":"2015","journal-title":"Am J Transl Res."},{"issue":"5","key":"2021122205213257100_CIT0059","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1210\/me.2005-0324","article-title":"The corepressors silencing mediator of retinoid and thyroid hormone receptor and nuclear receptor corepressor are involved in agonist- and antagonist-regulated transcription by androgen receptor","volume":"20","author":"Yoon","year":"2006","journal-title":"Mol Endocrinol."},{"issue":"2","key":"2021122205213257100_CIT0060","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1530\/JOE-18-0086","article-title":"Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats","volume":"237","author":"Hu","year":"2018","journal-title":"J Endocrinol."},{"key":"2021122205213257100_CIT0061","doi-asserted-by":"crossref","first-page":"30679","DOI":"10.1038\/srep30679","article-title":"Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci Rep."},{"key":"2021122205213257100_CIT0062","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1600-0897.2011.01034.x","article-title":"Innate immunity in the human endometrium and ovary","volume":"66","author":"Sheldon","year":"2011","journal-title":"Am J Reprod Immunol."},{"issue":"3","key":"2021122205213257100_CIT0063","doi-asserted-by":"crossref","first-page":"R75","DOI":"10.1530\/JOE-20-0106","article-title":"Androgens, oestrogens and endometrium: a fine balance between perfection and pathology","volume":"246","author":"Gibson","year":"2020","journal-title":"J Endocrinol."},{"issue":"1","key":"2021122205213257100_CIT0064","doi-asserted-by":"crossref","first-page":"16","DOI":"10.4110\/in.2015.15.1.16","article-title":"Immune cells in the female reproductive tract","volume":"15","author":"Lee","year":"2015","journal-title":"Immune Netw."},{"key":"2021122205213257100_CIT0065","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.3389\/fimmu.2019.02387","article-title":"Uterine immunity and microbiota: a shifting paradigm","volume":"10","author":"Agostinis","year":"2019","journal-title":"Front Immunol."},{"issue":"6","key":"2021122205213257100_CIT0066","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nri3446","article-title":"The history of Toll-like receptors\u2014redefining innate immunity","volume":"13","author":"O\u2019Neill","year":"2013","journal-title":"Nat Rev Immunol."},{"key":"2021122205213257100_CIT0067","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1476-4598-12-86","article-title":"The complexity of NF-\u03baB signaling in inflammation and cancer","volume":"12","author":"Hoesel","year":"2013","journal-title":"Mol Cancer."},{"issue":"1-2","key":"2021122205213257100_CIT0068","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.bbapap.2005.08.017","article-title":"MAPK signalling pathways as molecular targets for anti-inflammatory therapy\u2014from molecular mechanisms to therapeutic benefits","volume":"1754","author":"Kaminska","year":"2005","journal-title":"Biochim Biophys Acta."},{"issue":"2","key":"2021122205213257100_CIT0069","first-page":"232","article-title":"New concepts for an old problem: the diagnosis of endometrial hyperplasia","volume":"23","author":"Sanderson","year":"2017","journal-title":"Hum Reprod Update."},{"issue":"12","key":"2021122205213257100_CIT0070","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nri2873","article-title":"Sterile inflammation: sensing and reacting to damage","volume":"10","author":"Chen","year":"2010","journal-title":"Nat Rev Immunol."},{"issue":"10","key":"2021122205213257100_CIT0071","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat Rev Immunol."},{"issue":"5","key":"2021122205213257100_CIT0072","doi-asserted-by":"crossref","first-page":"E848","DOI":"10.1210\/jc.2013-4109","article-title":"Hyperandrogenism induces a proinflammatory TNF\u03b1 response to glucose ingestion in a receptor-dependent fashion","volume":"99","author":"Gonz\u00e1lez","year":"2014","journal-title":"J Clin Endocrinol Metab."},{"issue":"1-2","key":"2021122205213257100_CIT0073","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.mce.2011.08.007","article-title":"Androgen receptor coregulators: recruitment via the coactivator binding groove","volume":"352","author":"van de Wijngaart","year":"2012","journal-title":"Mol Cell Endocrinol."},{"issue":"1","key":"2021122205213257100_CIT0074","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1210\/jc.2006-1151","article-title":"The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes","volume":"92","author":"Kusminski","year":"2007","journal-title":"J Clin Endocrinol Metab."},{"issue":"1","key":"2021122205213257100_CIT0075","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1756-9966-33-41","article-title":"Direct effects of metformin in the endometrium: a hypothetical mechanism for the treatment of women with PCOS and endometrial carcinoma","volume":"33","author":"Shao","year":"2014","journal-title":"J Exp Clin Cancer Res."},{"issue":"1","key":"2021122205213257100_CIT0076","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1423-0127-21-2","article-title":"Endometrial progesterone resistance and PCOS","volume":"21","author":"Li","year":"2014","journal-title":"J Biomed Sci."},{"issue":"1","key":"2021122205213257100_CIT0077","first-page":"73","article-title":"PCOS and obesity: insulin resistance might be a common etiology for the development of type I endometrial carcinoma","volume":"4","author":"Li","year":"2014","journal-title":"Am J Cancer Res."},{"issue":"4","key":"2021122205213257100_CIT0078","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.jhep.2018.11.034","article-title":"Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish","volume":"70","author":"de Oliveira","year":"2019","journal-title":"J Hepatol."},{"issue":"4","key":"2021122205213257100_CIT0079","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.rbmo.2009.05.010","article-title":"Adipose tissue, metabolic syndrome and polycystic ovary syndrome: from pathophysiology to treatment","volume":"19","author":"Garruti","year":"2009","journal-title":"Reprod Biomed Online."},{"issue":"11","key":"2021122205213257100_CIT0080","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1016\/j.metabol.2013.07.004","article-title":"Inflammatory cytokines and chemokines, skeletal muscle and polycystic ovary syndrome: effects of pioglitazone and metformin treatment","volume":"62","author":"Ciaraldi","year":"2013","journal-title":"Metabolism."}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgaa951\/35878258\/dgaa951.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/106\/4\/e1022\/41848680\/dgaa951.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/106\/4\/e1022\/41848680\/dgaa951.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:23:11Z","timestamp":1640132591000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/106\/4\/e1022\/6056640"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,31]]},"references-count":80,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,12,31]]},"published-print":{"date-parts":[[2021,3,25]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgaa951","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,4,1]]},"published":{"date-parts":[[2020,12,31]]}}}