{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:29:42Z","timestamp":1787066982212,"version":"build-2736575974"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:00:00Z","timestamp":1623456000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:00:00Z","timestamp":1623456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2020R1I1A2061281"],"award-info":[{"award-number":["NRF-2020R1I1A2061281"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Chronic stress has a negative impact on many fertility-related functions; thus, the recent decline in female fertility seems to be at least partially associated with increased stress. The secretion of glucocorticoids is a typical endocrine response to chronic stress and indirectly reduces uterine receptivity through the hypothalamus-pituitary-gonadal (HPG) axis. However, in addition to its well-known canonical role, the direct effects of chronic stress-induced glucocorticoids on various uterine functions and their underlying molecular mechanisms are complex and have not yet been revealed. Recent studies have found that resident stem cell deficiency is responsible for the limited regenerative potential of the endometrium (the innermost lining of the uterine cavity) during each menstrual cycle, which subsequently increases infertility rates. In this context, we hypothesized that stress-induced glucocorticoids directly damage endometrial stem cells and consequently negatively affect endometrial reconstruction, which is important for uterine receptivity. In addition to its well-known canonical roles, we identified for the first time that cortisol, the most abundant and potent glucocorticoid in humans, directly suppresses the multiple beneficial functions (self-renewal, transdifferentiation, and migratory potential) of human endometrial stem cells through its functional receptor, glucocorticoid receptor (GR). Glucocorticoids inhibit well-known survival signals, such as the PI3K\/Akt and FAK\/ERK1\/2 pathways. More importantly, we also found that immobilization of stress-induced glucocorticoids suppresses the various beneficial functions of tissue resident stem cells in vivo. To the best of our knowledge, this is the first study to investigate the direct effects of glucocorticoids on the regenerative capacity of endometrial stem cells, and the findings will facilitate the development of more promising therapeutic approaches to increase female fertility.<\/jats:p>","DOI":"10.1038\/s41419-021-03893-4","type":"journal-article","created":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T14:02:27Z","timestamp":1623506547000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells"],"prefix":"10.1038","volume":"12","author":[{"given":"Se-Ra","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Kwan","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo-Rim","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doojin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun-Woo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3267-0127","authenticated-orcid":false,"given":"In-Sun","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwa-Yong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,12]]},"reference":[{"key":"3893_CR1","first-page":"109","volume":"35","author":"S Whirledge","year":"2010","unstructured":"Whirledge S, Cidlowski JA. Glucocorticoids, stress, and fertility. Minerva Endocrinol. 2010;35:109\u201325.","journal-title":"Minerva Endocrinol"},{"key":"3893_CR2","doi-asserted-by":"publisher","first-page":"e0226753","DOI":"10.1371\/journal.pone.0226753","volume":"14","author":"K Van Looveren","year":"2019","unstructured":"Van Looveren K, Van Boxelaere M, Callaerts-Vegh Z, Libert C. Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization. PLoS ONE. 2019;14:e0226753.","journal-title":"PLoS ONE"},{"key":"3893_CR3","doi-asserted-by":"crossref","unstructured":"Kawakami-Mori F, Nishimoto M, Reheman L, Kawarazaki W, Ayuzawa N, Ueda K, et al. Aberrant DNA methylation of hypothalamic angiotensin receptor in prenatal programmed hypertension. JCI Insight 2018, 3.","DOI":"10.1172\/jci.insight.95625"},{"key":"3893_CR4","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1038\/s41590-018-0185-0","volume":"19","author":"L Quatrini","year":"2018","unstructured":"Quatrini L, Wieduwild E, Escaliere B, Filtjens J, Chasson L, Laprie C, et al. Endogenous glucocorticoids control host resistance to viral infection through the tissue-specific regulation of PD-1 expression on NK cells. Nat Immunol. 2018;19:954\u201362.","journal-title":"Nat Immunol"},{"key":"3893_CR5","doi-asserted-by":"publisher","first-page":"4450","DOI":"10.1210\/en.2013-1652","volume":"154","author":"S Whirledge","year":"2013","unstructured":"Whirledge S, Cidlowski JA. A role for glucocorticoids in stress-impaired reproduction: beyond the hypothalamus and pituitary. Endocrinology. 2013;154:4450\u201368.","journal-title":"Endocrinology"},{"key":"3893_CR6","doi-asserted-by":"crossref","unstructured":"Joseph DN, Whirledge S Stress and the HPA Axis: Balancing Homeostasis and Fertility. Int J Mol Sci. 2017, 18(10).","DOI":"10.3390\/ijms18102224"},{"key":"3893_CR7","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/j.ygyno.2017.09.013","volume":"147","author":"IL Tangen","year":"2017","unstructured":"Tangen IL, Veneris JT, Halle MK, Werner HM, Trovik J, Akslen LA, et al. Expression of glucocorticoid receptor is associated with aggressive primary endometrial cancer and increases from primary to metastatic lesions. Gynecol Oncol. 2017;147:672\u20137.","journal-title":"Gynecol Oncol"},{"key":"3893_CR8","doi-asserted-by":"publisher","first-page":"15166","DOI":"10.1073\/pnas.1508056112","volume":"112","author":"SD Whirledge","year":"2015","unstructured":"Whirledge SD, Oakley RH, Myers PH, Lydon JP, DeMayo F, Cidlowski JA. Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization. Proc Natl Acad Sci USA. 2015;112:15166\u201371.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3893_CR9","doi-asserted-by":"publisher","first-page":"2995","DOI":"10.1016\/j.celrep.2018.02.076","volume":"22","author":"JM Vahrenkamp","year":"2018","unstructured":"Vahrenkamp JM, Yang CH, Rodriguez AC, Almomen A, Berrett KC, Trujillo AN, et al. Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor alpha in endometrial cancer. Cell Rep. 2018;22:2995\u20133005.","journal-title":"Cell Rep"},{"key":"3893_CR10","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1262\/jrd.2012-185","volume":"59","author":"M Kuse","year":"2013","unstructured":"Kuse M, Lee HY, Acosta TJ, Hojo T, Okuda K. Expression of glucocorticoid receptor alpha and its regulation in the bovine endometrium: possible role in cyclic prostaglandin F2alpha production. J Reprod Dev. 2013;59:346\u201352.","journal-title":"J Reprod Dev"},{"key":"3893_CR11","doi-asserted-by":"publisher","first-page":"5071","DOI":"10.1210\/jcem.86.10.8101","volume":"86","author":"AM Bamberger","year":"2001","unstructured":"Bamberger AM, Milde-Langosch K, Loning T, Bamberger CM. The glucocorticoid receptor is specifically expressed in the stromal compartment of the human endometrium. J Clin Endocrinol Metab. 2001;86:5071\u20134.","journal-title":"J Clin Endocrinol Metab"},{"key":"3893_CR12","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.rbmo.2013.06.012","volume":"27","author":"ES Lucas","year":"2013","unstructured":"Lucas ES, Salker MS, Brosens JJ. Uterine plasticity and reproductive fitness. Reprod Biomed Online. 2013;27:506\u201314.","journal-title":"Reprod Biomed Online"},{"key":"3893_CR13","first-page":"605","volume":"26","author":"CE McLennan","year":"1965","unstructured":"McLennan CE, Rydell AH. Extent of endometrial shedding during normal menstruation. Obstet Gynecol. 1965;26:605\u201321.","journal-title":"Obstet Gynecol"},{"key":"3893_CR14","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1007\/s11154-012-9221-9","volume":"13","author":"CE Gargett","year":"2012","unstructured":"Gargett CE, Nguyen HP, Ye L. Endometrial regeneration and endometrial stem\/progenitor cells. Rev Endocr Metab Disord. 2012;13:235\u201351.","journal-title":"Rev Endocr Metab Disord."},{"key":"3893_CR15","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.fertnstert.2012.05.004","volume":"98","author":"CE Gargett","year":"2012","unstructured":"Gargett CE, Ye L. Endometrial reconstruction from stem cells. Fertil Steril. 2012;98:11\u201320.","journal-title":"Fertil Steril."},{"key":"3893_CR16","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1002\/stem.2222","volume":"34","author":"ES Lucas","year":"2016","unstructured":"Lucas ES, Dyer NP, Murakami K, Lee YH, Chan YW, Grimaldi G, et al. Loss of endometrial plasticity in recurrent pregnancy loss. Stem Cells. 2016;34:346\u201356.","journal-title":"Stem Cells"},{"key":"3893_CR17","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1634\/stemcells.2004-0176","volume":"24","author":"G Forte","year":"2006","unstructured":"Forte G, Minieri M, Cossa P, Antenucci D, Sala M, Gnocchi V, et al. Hepatocyte growth factor effects on mesenchymal stem cells: proliferation, migration, and differentiation. Stem Cells. 2006;24:23\u201333.","journal-title":"Stem Cells"},{"key":"3893_CR18","doi-asserted-by":"publisher","first-page":"2789","DOI":"10.1111\/j.1582-4934.2012.01602.x","volume":"16","author":"B Gharibi","year":"2012","unstructured":"Gharibi B, Ghuman MS, Hughes FJ. Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRbeta-induced MSC self-renewal. J Cell Mol Med. 2012;16:2789\u2013801.","journal-title":"J Cell Mol Med"},{"key":"3893_CR19","doi-asserted-by":"publisher","first-page":"2704","DOI":"10.1002\/jcb.24148","volume":"113","author":"JM Tang","year":"2012","unstructured":"Tang JM, Yuan J, Li Q, Wang JN, Kong X, Zheng F, et al. Acetylcholine induces mesenchymal stem cell migration via Ca2+\/PKC\/ERK1\/2 signal pathway. J Cell Biochem. 2012;113:2704\u201313.","journal-title":"J Cell Biochem"},{"key":"3893_CR20","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1002\/jcp.24114","volume":"228","author":"B Zheng","year":"2013","unstructured":"Zheng B, Wang C, He L, Xu X, Qu J, Hu J, et al. Neural differentiation of mesenchymal stem cells influences chemotactic responses to HGF. J Cell Physiol. 2013;228:149\u201362.","journal-title":"J Cell Physiol"},{"key":"3893_CR21","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1159\/000430167","volume":"36","author":"BQ Song","year":"2015","unstructured":"Song BQ, Chi Y, Li X, Du WJ, Han ZB, Tian JJ, et al. Inhibition of notch signaling promotes the adipogenic differentiation of mesenchymal stem cells through autophagy activation and PTEN-PI3K\/AKT\/mTOR pathway. Cell Physiol Biochem. 2015;36:1991\u20132002.","journal-title":"Cell Physiol Biochem"},{"key":"3893_CR22","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1016\/j.ymthe.2019.04.019","volume":"27","author":"A Cho","year":"2019","unstructured":"Cho A, Park SR, Kim SR, Nam S, Lim S, Park CH, et al. An endogenous anti-aging factor, sonic hedgehog, suppresses endometrial stem cell aging through SERPINB2. Mol Ther. 2019;27:1286\u201398.","journal-title":"Mol Ther"},{"key":"3893_CR23","doi-asserted-by":"publisher","first-page":"9363","DOI":"10.1073\/pnas.92.20.9363","volume":"92","author":"GP Dimri","year":"1995","unstructured":"Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA. 1995;92:9363\u20137.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3893_CR24","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/nature09595","volume":"468","author":"B Gan","year":"2010","unstructured":"Gan B, Hu J, Jiang S, Liu Y, Sahin E, Zhuang L, et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature. 2010;468:701\u20134.","journal-title":"Nature"},{"key":"3893_CR25","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/nature09572","volume":"468","author":"S Gurumurthy","year":"2010","unstructured":"Gurumurthy S, Xie SZ, Alagesan B, Kim J, Yusuf RZ, Saez B, et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature. 2010;468:659\u201363.","journal-title":"Nature"},{"key":"3893_CR26","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.stem.2007.07.017","volume":"1","author":"Z Tothova","year":"2007","unstructured":"Tothova Z, Gilliland DG. FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell. 2007;1:140\u201352.","journal-title":"Cell Stem Cell"},{"key":"3893_CR27","first-page":"1819209","volume":"2016","author":"W Haylett","year":"2016","unstructured":"Haylett W, Swart C, van der Westhuizen F, van Dyk H, van der Merwe L, van der Merwe C, et al. Altered mitochondrial respiration and other features of mitochondrial function in Parkin-mutant fibroblasts from Parkinson\u2019s disease patients. Parkinsons Dis. 2016;2016:1819209.","journal-title":"Parkinsons Dis."},{"key":"3893_CR28","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.drudis.2007.12.008","volume":"13","author":"DA Ferrick","year":"2008","unstructured":"Ferrick DA, Neilson A, Beeson C. Advances in measuring cellular bioenergetics using extracellular flux. Drug Disco Today. 2008;13:268\u201374.","journal-title":"Drug Disco Today"},{"key":"3893_CR29","doi-asserted-by":"publisher","first-page":"192503","DOI":"10.1155\/2012\/192503","volume":"2012","author":"C Desler","year":"2012","unstructured":"Desler C, Hansen TL, Frederiksen JB, Marcker ML, Singh KK, Juel Rasmussen L. Is there a link between mitochondrial reserve respiratory capacity and aging? J Aging Res. 2012;2012:192503.","journal-title":"J Aging Res"},{"key":"3893_CR30","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1038\/nrc1478","volume":"4","author":"RA Gatenby","year":"2004","unstructured":"Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4:891\u20139.","journal-title":"Nat Rev Cancer"},{"key":"3893_CR31","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/1475-2867-13-89","volume":"13","author":"Y Kato","year":"2013","unstructured":"Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T. et al. Acidic extracellular microenvironment and cancer. Cancer Cell Int. 2013;13:89.","journal-title":"Cancer Cell Int"},{"key":"3893_CR32","doi-asserted-by":"crossref","unstructured":"Pajak B, Siwiak E, Soltyka M, Priebe A, Zielinski R, Fokt I, et al. 2-Deoxy-d-glucose and its analogs: from diagnostic to therapeutic agents. Int J Mol Sci. 2019, 21.","DOI":"10.3390\/ijms21010234"},{"key":"3893_CR33","doi-asserted-by":"publisher","first-page":"11727","DOI":"10.1074\/jbc.M117.786442","volume":"292","author":"AP Trotta","year":"2017","unstructured":"Trotta AP, Gelles JD, Serasinghe MN, Loi P, Arbiser JL, Chipuk JE. Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition. J Biol Chem. 2017;292:11727\u201339.","journal-title":"J Biol Chem"},{"key":"3893_CR34","doi-asserted-by":"crossref","unstructured":"Zhang H, Menzies KJ, Auwerx J. The role of mitochondria in stem cell fate and aging. Development 2018, 145.","DOI":"10.1242\/dev.143420"},{"key":"3893_CR35","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1016\/j.bbabio.2015.05.014","volume":"1847","author":"KJ Ahlqvist","year":"2015","unstructured":"Ahlqvist KJ, Suomalainen A, Hamalainen RH. Stem cells, mitochondria and aging. Biochim Biophys Acta. 2015;1847:1380\u20136.","journal-title":"Biochim Biophys Acta"},{"key":"3893_CR36","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1101\/gad.293167.116","volume":"31","author":"N Shyh-Chang","year":"2017","unstructured":"Shyh-Chang N, Ng HH. The metabolic programming of stem cells. Genes Dev. 2017;31:336\u201346.","journal-title":"Genes Dev"},{"key":"3893_CR37","doi-asserted-by":"publisher","first-page":"662","DOI":"10.14336\/AD.2017.0713","volume":"8","author":"TR Tidwell","year":"2017","unstructured":"Tidwell TR, Soreide K, Hagland HRAging. Metabolism, and cancer development: from Peto\u2019s paradox to the Warburg effect. Aging Dis. 2017;8:662\u201376.","journal-title":"Aging Dis"},{"key":"3893_CR38","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1093\/hmg\/ddl112","volume":"15","author":"L Armstrong","year":"2006","unstructured":"Armstrong L, Hughes O, Yung S, Hyslop L, Stewart R, Wappler I, et al. The role of PI3K\/AKT, MAPK\/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Hum Mol Genet. 2006;15:1894\u2013913.","journal-title":"Hum Mol Genet"},{"key":"3893_CR39","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1007\/s12013-014-0228-6","volume":"71","author":"F Gao","year":"2015","unstructured":"Gao F, Hu X, Xie X, Liu X, Wang J. Heat shock protein 90 stimulates rat mesenchymal stem cell migration via PI3K\/Akt and ERK1\/2 pathways. Cell Biochem Biophys. 2015;71:481\u20139.","journal-title":"Cell Biochem Biophys"},{"key":"3893_CR40","doi-asserted-by":"publisher","first-page":"e71283","DOI":"10.1371\/journal.pone.0071283","volume":"8","author":"P Muller","year":"2013","unstructured":"Muller P, Langenbach A, Kaminski A, Rychly J. Modulating the actin cytoskeleton affects mechanically induced signal transduction and differentiation in mesenchymal stem cells. PLoS ONE. 2013;8:e71283.","journal-title":"PLoS ONE"},{"key":"3893_CR41","doi-asserted-by":"publisher","first-page":"851367","DOI":"10.1155\/2012\/851367","volume":"2012","author":"SS Morelli","year":"2012","unstructured":"Morelli SS, Yi P, Goldsmith LT. Endometrial stem cells and reproduction. Obstet Gynecol Int. 2012;2012:851367.","journal-title":"Obstet Gynecol Int"},{"key":"3893_CR42","doi-asserted-by":"publisher","first-page":"R159","DOI":"10.1530\/REP-16-0306","volume":"152","author":"ES Lucas","year":"2016","unstructured":"Lucas ES, Dyer NP, Fishwick K, Ott S, Brosens JJ. Success after failure: the role of endometrial stem cells in recurrent miscarriage. Reproduction. 2016;152:R159\u2013166.","journal-title":"Reproduction"},{"key":"3893_CR43","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.nlm.2013.09.017","volume":"112","author":"C Finsterwald","year":"2014","unstructured":"Finsterwald C, Alberini CM. Stress and glucocorticoid receptor-dependent mechanisms in long-term memory: from adaptive responses to psychopathologies. Neurobiol Learn Mem. 2014;112:17\u201329.","journal-title":"Neurobiol Learn Mem"},{"key":"3893_CR44","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1080\/10253890.2018.1470238","volume":"21","author":"JK Gjerstad","year":"2018","unstructured":"Gjerstad JK, Lightman SL, Spiga F. Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility. Stress. 2018;21:403\u201316.","journal-title":"Stress"},{"key":"3893_CR45","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1111\/jne.12179","volume":"26","author":"D Toufexis","year":"2014","unstructured":"Toufexis D, Rivarola MA, Lara H, Viau V. Stress and the reproductive axis. J Neuroendocrinol. 2014;26:573\u201386.","journal-title":"J Neuroendocrinol"},{"key":"3893_CR46","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1007\/BF03343627","volume":"22","author":"AE Calogero","year":"1999","unstructured":"Calogero AE, Burrello N, Bosboom AM, Garofalo MR, Weber RF, D\u2019Agata R. Glucocorticoids inhibit gonadotropin-releasing hormone by acting directly at the hypothalamic level. J Endocrinol Invest. 1999;22:666\u201370.","journal-title":"J Endocrinol Invest"},{"key":"3893_CR47","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1210\/en.2005-1523","volume":"147","author":"K Maeda","year":"2006","unstructured":"Maeda K, Tsukamura H. The impact of stress on reproduction: are glucocorticoids inhibitory or protective to gonadotropin secretion? Endocrinology. 2006;147:1085\u20136.","journal-title":"Endocrinology"},{"key":"3893_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0892-3","volume":"9","author":"SR Park","year":"2018","unstructured":"Park SR, Cho A, Park ST, Park CH, Lim S, Jin M, et al. Double-edged sword of gonadotropin-releasing hormone (GnRH): A novel role of GnRH in the multiple beneficial functions of endometrial stem cells. Cell Death Dis. 2018;9:828.","journal-title":"Cell Death Dis"},{"key":"3893_CR49","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-1-125","volume":"1","author":"X Luo","year":"2003","unstructured":"Luo X, Xu J, Chegini N. Gonadotropin releasing hormone analogue (GnRHa) alters the expression and activation of Smad in human endometrial epithelial and stromal cells. Reprod Biol Endocrinol. 2003;1:125.","journal-title":"Reprod Biol Endocrinol"},{"key":"3893_CR50","doi-asserted-by":"publisher","first-page":"19629","DOI":"10.1002\/jcp.28562","volume":"234","author":"MBH Shariati","year":"2019","unstructured":"Shariati MBH, Niknafs B, Seghinsara AM, Shokrzadeh N, Alivand MR. Administration of dexamethasone disrupts endometrial receptivity by alteration of expression of miRNA 223, 200a, LIF, Muc1, SGK1, and ENaC via the ERK1\/2-mTOR pathway. J Cell Physiol. 2019;234:19629\u201339.","journal-title":"J Cell Physiol"},{"key":"3893_CR51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jri.2018.10.001","volume":"131","author":"S Cooper","year":"2019","unstructured":"Cooper S, Laird SM, Mariee N, Li TC, Metwally M. The effect of prednisolone on endometrial uterine NK cell concentrations and pregnancy outcome in women with reproductive failure. A retrospective cohort study. J Reprod Immunol. 2019;131:1\u20136.","journal-title":"J Reprod Immunol"},{"key":"3893_CR52","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1095\/biolreprod.114.123463","volume":"92","author":"MK Nanjappa","year":"2015","unstructured":"Nanjappa MK, Medrano TI, Lydon JP, Bigsby RM, Cooke PS. Maximal dexamethasone inhibition of luminal epithelial proliferation involves progesterone receptor (PR)- and non-PR-mediated mechanisms in neonatal mouse uterus. Biol Reprod. 2015;92:122.","journal-title":"Biol Reprod."},{"key":"3893_CR53","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1097\/GCO.0000000000000457","volume":"30","author":"M Simoni","year":"2018","unstructured":"Simoni M, Taylor HS. Therapeutic strategies involving uterine stem cells in reproductive medicine. Curr Opin Obstet Gynecol. 2018;30:209\u201316.","journal-title":"Curr Opin Obstet Gynecol."},{"key":"3893_CR54","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1186\/s13287-019-1313-y","volume":"10","author":"X Lu","year":"2019","unstructured":"Lu X, Cui J, Cui L, Luo Q, Cao Q, Yuan W, et al. The effects of human umbilical cord-derived mesenchymal stem cell transplantation on endometrial receptivity are associated with Th1\/Th2 balance change and uNK cell expression of uterine in autoimmune premature ovarian failure mice. Stem Cell Res Ther. 2019;10:214.","journal-title":"Stem Cell Res Ther"},{"key":"3893_CR55","doi-asserted-by":"crossref","unstructured":"Tomari H, Kawamura T, Asanoma K, Egashira K, Kawamura K, Honjo K, et al. Contribution of senescence in human endometrial stromal cells during proliferative phase to embryo receptivity. Biol Reprod. 2020.","DOI":"10.1093\/biolre\/ioaa044"},{"key":"3893_CR56","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1167\/iovs.06-0889","volume":"48","author":"V Gupta","year":"2007","unstructured":"Gupta V, Awasthi N, Wagner BJ. Specific activation of the glucocorticoid receptor and modulation of signal transduction pathways in human lens epithelial cells. Invest Ophthalmol Vis Sci. 2007;48:1724\u201334.","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"3893_CR57","doi-asserted-by":"publisher","first-page":"3224","DOI":"10.1016\/j.febslet.2011.09.010","volume":"585","author":"E Kumamaru","year":"2011","unstructured":"Kumamaru E, Numakawa T, Adachi N, Kunugi H. Glucocorticoid suppresses BDNF-stimulated MAPK\/ERK pathway via inhibiting interaction of Shp2 with TrkB. FEBS Lett. 2011;585:3224\u20138.","journal-title":"FEBS Lett."},{"key":"3893_CR58","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.1093\/humrep\/dew186","volume":"31","author":"SA Robertson","year":"2016","unstructured":"Robertson SA, Jin M, Yu D, Moldenhauer LM, Davies MJ, Hull ML, et al. Corticosteroid therapy in assisted reproduction - immune suppression is a faulty premise. Hum Reprod. 2016;31:2164\u201373.","journal-title":"Hum Reprod."},{"key":"3893_CR59","doi-asserted-by":"publisher","first-page":"518","DOI":"10.3109\/01443615.2012.693988","volume":"32","author":"M Krigstein","year":"2012","unstructured":"Krigstein M, Sacks G. Prednisolone for repeated implantation failure associated with high natural killer cell levels. J Obstet Gynaecol. 2012;32:518\u20139.","journal-title":"J Obstet Gynaecol."},{"key":"3893_CR60","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1016\/j.fertnstert.2005.05.012","volume":"84","author":"S Quenby","year":"2005","unstructured":"Quenby S, Kalumbi C, Bates M, Farquharson R, Vince G. Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Fertil Steril. 2005;84:980\u20134.","journal-title":"Fertil Steril."},{"key":"3893_CR61","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.canlet.2012.09.009","volume":"328","author":"ES Choi","year":"2013","unstructured":"Choi ES, Jung JY, Lee JS, Park JH, Cho NP, Cho SD. Myeloid cell leukemia-1 is a key molecular target for mithramycin A-induced apoptosis in androgen-independent prostate cancer cells and a tumor xenograft animal model. Cancer Lett. 2013;328:65\u201372.","journal-title":"Cancer Lett."},{"key":"3893_CR62","doi-asserted-by":"publisher","first-page":"D562","DOI":"10.1093\/nar\/gki022","volume":"33","author":"T Barrett","year":"2005","unstructured":"Barrett T, Suzek TO, Troup DB, Wilhite SE, Ngau WC, Ledoux P, et al. NCBI GEO: mining millions of expression profiles-database and tools. Nucleic Acids Res. 2005;33:D562\u2013566. (Database issue)","journal-title":"Nucleic Acids Res"},{"key":"3893_CR63","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/nar\/30.1.207","volume":"30","author":"R Edgar","year":"2002","unstructured":"Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30:207\u201310.","journal-title":"Nucleic Acids Res"},{"key":"3893_CR64","first-page":"175","volume":"338","author":"T Barrett","year":"2006","unstructured":"Barrett T, Edgar R. Mining microarray data at NCBI\u2019s Gene Expression Omnibus (GEO)*. Methods Mol Biol. 2006;338:175\u201390.","journal-title":"Methods Mol Biol."}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03893-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03893-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03893-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T18:04:01Z","timestamp":1675447441000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03893-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,12]]},"references-count":64,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["3893"],"URL":"https:\/\/doi.org\/10.1038\/s41419-021-03893-4","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,12]]},"assertion":[{"value":"22 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 May 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 May 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 June 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors have no competing interests as defined by Cell Death & Disease or other interests that might be perceived to influence the results and\/or discussion reported in this article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Human endometrial stem cells were obtained from endometrial tissues of uterine fibroid patients with written informed consent from the patients and approval from the Gachon University Institutional Review Board (IRB No: GAIRB2018-134). All of the animal experiments were approved and conducted in accordance with the Institutional Animal Care and Use Committee (IACUC) (LCDI-2019-0008) of the Gachon University.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"612"}}