{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:21:43Z","timestamp":1791408103400,"version":"4.3.3"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T00:00:00Z","timestamp":1689811200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T00:00:00Z","timestamp":1689811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Preterm birth (PTB) is the leading cause of neonatal mortality, and reducing the PTB rate is one of the most critical issues in perinatal medicine. Cervical insufficiency (CI), a\u00a0major\u00a0cause of PTB, is characterised by premature cervical ripening in the second trimester,\u00a0followed by recurrent pregnancy loss. Although multiple clinical trials have suggested that progesterone inhibits cervical ripening, no studies have focused on\u00a0progesterone-induced molecular signalling\u00a0in CI. Here, we established a primary culture system for human uterine cervical fibroblasts using a sample of patients with refractory innate CI\u00a0who underwent transabdominal cervical cerclage and patients with low Bishop scores who underwent elective caesarean section as controls.\u00a0RNA sequencing showed that the progesterone response\u00a0observed\u00a0in the control group was impaired in the CI group.\u00a0This was consistent with the finding that progesterone receptor expression was markedly downregulated in CI.\u00a0Furthermore, the inhibitory effect of progesterone on lipopolysaccharide-induced inflammatory stimuli was also impaired in CI. These results suggest that abnormal cervical ripening in CI is caused by the downregulation of progesterone signalling at the receptor level, and provide a novel insight into the molecular mechanism of PTB.<\/jats:p>","DOI":"10.1038\/s41598-023-37732-7","type":"journal-article","created":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T10:02:28Z","timestamp":1689847348000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Characteristic impairment of progesterone response in cultured cervical fibroblasts obtained from patients with refractory cervical insufficiency"],"prefix":"10.1038","volume":"13","author":[{"given":"Yosuke","family":"Sugita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimitsu","family":"Kuwabara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Katayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Matsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Manabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunji","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Oishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,20]]},"reference":[{"key":"37732_CR1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1251816","author":"R Romero","year":"2014","unstructured":"Romero, R., Sudhansu, K. D. & Fisher, S. J. Preterm labor: One syndrome, many causes. Science https:\/\/doi.org\/10.1126\/science.1251816 (2014).","journal-title":"Science"},{"key":"37732_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/s0165-0378(97)00065-x","author":"DJ Dudley","year":"1997","unstructured":"Dudley, D. J. Pre-term labor: An intra-uterine inflammatory response syndrome?. J. Reprod. Immunol. https:\/\/doi.org\/10.1016\/s0165-0378(97)00065-x (1997).","journal-title":"J. Reprod. Immunol."},{"key":"37732_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2008.04.002","author":"I Christiaens","year":"2008","unstructured":"Christiaens, I. et al. Inflammatory processes in preterm and term parturition. J. Reprod. Immunol. https:\/\/doi.org\/10.1016\/j.jri.2008.04.002 (2008).","journal-title":"J. Reprod. Immunol."},{"key":"37732_CR4","doi-asserted-by":"publisher","DOI":"10.1016\/s0143-4004(96)90052-1","author":"CA Van Meir","year":"1996","unstructured":"Van Meir, C. A. et al. Immunoreactive 15-hydroxyprostaglandin dehydrogenase (PGDH) is reduced in fetal membranes from patients at preterm delivery in the presence of infection. Placenta https:\/\/doi.org\/10.1016\/s0143-4004(96)90052-1 (1996).","journal-title":"Placenta"},{"key":"37732_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/S1071-5576(97)00104-4","author":"CM Salafia","year":"1998","unstructured":"Salafia, C. M., Ghidini, A., Lop\u00e8z-Zeno, J. A. & Pezzullo, J. C. Uteroplacental pathology and maternal arterial mean blood pressure in spontaneous prematurity. J. Soc. Gynecol. Investig. https:\/\/doi.org\/10.1016\/S1071-5576(97)00104-4 (1998).","journal-title":"J. Soc. Gynecol. Investig."},{"key":"37732_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9378(96)70042-x","author":"RL Copper","year":"1996","unstructured":"Copper, R. L. et al. The preterm prediction study: Maternal stress is associated with spontaneous preterm birth at less than thirty-five weeks\u2019 gestation. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am. J. Obstet. Gynecol. https:\/\/doi.org\/10.1016\/s0002-9378(96)70042-x (1996).","journal-title":"Am. J. Obstet. Gynecol."},{"key":"37732_CR7","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.83.5.4804","author":"C Korebrits","year":"1998","unstructured":"Korebrits, C. et al. Maternal corticotropin-releasing hormone is increased with impending preterm birth. J. Clin. Endocrinol. Metab. https:\/\/doi.org\/10.1210\/jcem.83.5.4804 (1998).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"37732_CR8","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a116535","author":"MS Kramer","year":"1992","unstructured":"Kramer, M. S., McLean, F. H., Eason, E. L. & Usher, R. H. Maternal nutrition and spontaneous preterm birth. Am. J. Epidemiol. https:\/\/doi.org\/10.1093\/oxfordjournals.aje.a116535 (1992).","journal-title":"Am. J. Epidemiol."},{"key":"37732_CR9","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2001.117638","author":"MA Elovitz","year":"2001","unstructured":"Elovitz, M. A., Baron, J. & Phillippe, M. The role of thrombin in preterm parturition. Am. J. Obstet. Gynecol. https:\/\/doi.org\/10.1067\/mob.2001.117638 (2001).","journal-title":"Am. J. Obstet. Gynecol."},{"key":"37732_CR10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.550541","author":"H Mogami","year":"2014","unstructured":"Mogami, H., Keller, P. W., Haolin, S. & Word, R. A. Effect of thrombin on human amnion mesenchymal cells, mouse fetal membranes, and preterm birth. J. Biol. Chem. https:\/\/doi.org\/10.1074\/jbc.M114.550541 (2014).","journal-title":"J. Biol. Chem."},{"key":"37732_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2011.01.006","author":"D Kumar","year":"2011","unstructured":"Kumar, D. et al. The effects of thrombin and cytokines upon the biomechanics and remodeling of isolated amnion membrane, in vitro. Placenta https:\/\/doi.org\/10.1016\/j.placenta.2011.01.006 (2011).","journal-title":"Placenta"},{"key":"37732_CR12","doi-asserted-by":"publisher","DOI":"10.1210\/endo.138.12.5624","author":"CW Ou","year":"1997","unstructured":"Ou, C. W., Orsino, A. & Lye, S. J. Expression of connexin-43 and connexin-26 in the rat myometrium during pregnancy and labor is differentially regulated by mechanical and hormonal signals. Endocrinology https:\/\/doi.org\/10.1210\/endo.138.12.5624 (1997).","journal-title":"Endocrinology"},{"key":"37732_CR13","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-1289","author":"AR Mohan","year":"2007","unstructured":"Mohan, A. R., Sooranna, S. R., Lindstrom, T. M., Johnson, M. R. & Bennett, P. R. The effect of mechanical stretch on cyclooxygenase type 2 expression and activator protein-1 and nuclear factor-kappaB activity in human amnion cells. Endocrinology https:\/\/doi.org\/10.1210\/en.2006-1289 (2007).","journal-title":"Endocrinology"},{"key":"37732_CR14","doi-asserted-by":"publisher","first-page":"e81340","DOI":"10.1371\/journal.pone.0081340","volume":"8","author":"SM Yellon","year":"2013","unstructured":"Yellon, S. M. et al. Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth. PLoS ONE 8, e81340. https:\/\/doi.org\/10.1371\/journal.pone.0081340 (2013).","journal-title":"PLoS ONE"},{"key":"37732_CR15","doi-asserted-by":"publisher","DOI":"10.1530\/REP-11-0466","author":"M Mahendroo","year":"2012","unstructured":"Mahendroo, M. Cervical remodeling in term and preterm birth: insights from an animal model. Reproduction https:\/\/doi.org\/10.1530\/REP-11-0466 (2012).","journal-title":"Reproduction"},{"key":"37732_CR16","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1210\/en.2010-1105","volume":"152","author":"R Holt","year":"2011","unstructured":"Holt, R., Timmons, B. C., Akgul, Y., Akins, M. L. & Mahendroo, M. The molecular mechanisms of cervical ripening differ between term and preterm birth. Endocrinology 152, 1036\u20131046. https:\/\/doi.org\/10.1210\/en.2010-1105 (2011).","journal-title":"Endocrinology"},{"key":"37732_CR17","doi-asserted-by":"publisher","DOI":"10.1097\/01.AOG.0000443276.68274.cc","author":"ACOG Practice Bulletin No.142","year":"2014","unstructured":"ACOG Practice Bulletin No.142. Cerclage for the management of cervical insufficiency. Obstet. Gynaecol. https:\/\/doi.org\/10.1097\/01.AOG.0000443276.68274.cc (2014).","journal-title":"Obstet. Gynaecol."},{"key":"37732_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2011.01.003","author":"KS Bevis","year":"2011","unstructured":"Bevis, K. S. & Biggio, J. R. Cervical conization and the risk of preterm delivery. Am. J. Obstet. Gynecol. https:\/\/doi.org\/10.1016\/j.ajog.2011.01.003 (2011).","journal-title":"Am. J. Obstet. Gynecol."},{"key":"37732_CR19","doi-asserted-by":"publisher","DOI":"10.1097\/00003081-199506000-00009","author":"PC Leppert","year":"1995","unstructured":"Leppert, P. C. Anatomy and physiology of cervical ripening. Clin. Obstet. Gynaecol. https:\/\/doi.org\/10.1097\/00003081-199506000-00009 (1995).","journal-title":"Clin. Obstet. Gynaecol."},{"key":"37732_CR20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0232463","author":"GH Son","year":"2020","unstructured":"Son, G. H. et al. Outcomes after transabdominal cerclage in twin pregnancy with previous unsuccessful transvaginal cerclage. PLoS ONE https:\/\/doi.org\/10.1371\/journal.pone.0232463 (2020).","journal-title":"PLoS ONE"},{"key":"37732_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2007.06.060","author":"RH Debbs","year":"2007","unstructured":"Debbs, R. H. et al. Transabdominal cerclage after comprehensive evaluation of women with previous unsuccessful transvaginal cerclage. Am. J. Obstet. Gynecol. https:\/\/doi.org\/10.1016\/j.ajog.2007.06.060 (2007).","journal-title":"Am. J. Obstet. Gynecol."},{"key":"37732_CR22","doi-asserted-by":"publisher","DOI":"10.1345\/aph.10397","author":"RM Dehart","year":"2001","unstructured":"Dehart, R. M. & Morehead, M. S. Mifepristone. Ann. Pharmacother. https:\/\/doi.org\/10.1345\/aph.10397 (2001).","journal-title":"Ann. Pharmacother."},{"key":"37732_CR23","doi-asserted-by":"publisher","first-page":"3156","DOI":"10.3389\/fimmu.2019.03156","volume":"10","author":"SM Yellon","year":"2019","unstructured":"Yellon, S. M. Immunobiology of cervix ripening. Front. Immunol. 10, 3156. https:\/\/doi.org\/10.3389\/fimmu.2019.03156 (2019).","journal-title":"Front. Immunol."},{"key":"37732_CR24","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12731","author":"Y Kuwabara","year":"2017","unstructured":"Kuwabara, Y. et al. Diversity of progesterone action on lipopolysaccharide-induced expression changes in cultured human cervical fibroblasts according to inflammation and treatment timing. Am. J. Reprod. Immunol. https:\/\/doi.org\/10.1111\/aji.12731 (2017).","journal-title":"Am. J. Reprod. Immunol."},{"key":"37732_CR25","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1095\/biolreprod.111.091983","volume":"85","author":"SM Yellon","year":"2011","unstructured":"Yellon, S. M. et al. Remodeling of the cervix and parturition in mice lacking the progesterone receptor B isoform. Biol. Reprod. 85, 498\u2013502. https:\/\/doi.org\/10.1095\/biolreprod.111.091983 (2011).","journal-title":"Biol. Reprod."},{"key":"37732_CR26","doi-asserted-by":"publisher","DOI":"10.1089\/ten.TEA.2018.0036","author":"M House","year":"2018","unstructured":"House, M. et al. Mechanical and biochemical effects of progesterone on engineered cervical tissue. Tissue Eng. Part A https:\/\/doi.org\/10.1089\/ten.TEA.2018.0036 (2018).","journal-title":"Tissue Eng. Part A"},{"key":"37732_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-5793(96)01538-4","author":"K Tanaka","year":"1997","unstructured":"Tanaka, K. et al. Regulation of hyaluronate metabolism by progesterone in cultured fibroblasts from the human uterine cervix. FEBS Lett. https:\/\/doi.org\/10.1016\/s0014-5793(96)01538-4 (1997).","journal-title":"FEBS Lett."},{"key":"37732_CR28","doi-asserted-by":"publisher","DOI":"10.3109\/14767050903353216","author":"SS Hassan","year":"2009","unstructured":"Hassan, S. S. et al. The transcriptome of cervical ripening in human pregnancy before the onset of labor at term: Identification of novel molecular functions involved in this process. J. Maternal-fetal Neonatal. Med. Off. J. Eur. Assoc. Perinat. Med. Fed. Asia Ocean. Perinat. Soc. Int. Soc. Perinat. Obstet. https:\/\/doi.org\/10.3109\/14767050903353216 (2009).","journal-title":"J. Maternal-fetal Neonatal. Med. Off. J. Eur. Assoc. Perinat. Med. Fed. Asia Ocean. Perinat. Soc. Int. Soc. Perinat. Obstet."},{"key":"37732_CR29","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18122614","author":"GR Fries","year":"2017","unstructured":"Fries, G. R., Gassen, N. C. & Rein, T. The FKBP51 glucocorticoid receptor co-chaperone: Regulation, function, and implications in health and disease. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms18122614 (2017).","journal-title":"Int. J. Mol. Sci."},{"key":"37732_CR30","doi-asserted-by":"publisher","DOI":"10.3390\/biom9010035","author":"A H\u00e4hle","year":"2019","unstructured":"H\u00e4hle, A., Merz, S., Meyners, C. & Hausch, F. The many faces of FKBP51. Biomolecules https:\/\/doi.org\/10.3390\/biom9010035 (2019).","journal-title":"Biomolecules"},{"key":"37732_CR31","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2004.01.017","author":"MM Sullivan","year":"2004","unstructured":"Sullivan, M. M. & Sage, E. H. Hevin\/SC1, a matricellular glycoprotein and potential tumor-suppressor of the SPARC\/BM-40\/Osteonectin family. Int. J. Biochem. Cell Biol. https:\/\/doi.org\/10.1016\/j.biocel.2004.01.017 (2004).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"37732_CR32","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2016.11.013","author":"F Gagliardi","year":"2017","unstructured":"Gagliardi, F., Narayanan, A. & Mortini, P. SPARCL1 a novel player in cancer biology. Crit. Rev. Oncol. Hematol. https:\/\/doi.org\/10.1016\/j.critrevonc.2016.11.013 (2017).","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"37732_CR33","doi-asserted-by":"publisher","DOI":"10.1080\/09513590310001651777","author":"Y Stjernholm-Vladic","year":"2004","unstructured":"Stjernholm-Vladic, Y., Wang, H., Stygar, D., Ekman, G. & Sahlin, L. Differential regulation of the progesterone receptor A and B in the human uterine cervix at parturition. Gynecol. Endocrinol. https:\/\/doi.org\/10.1080\/09513590310001651777 (2004).","journal-title":"Gynecol. Endocrinol."},{"key":"37732_CR34","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.6.8609","author":"S Mesiano","year":"2002","unstructured":"Mesiano, S. et al. Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. J. Clin. Endocrinol. Metab. https:\/\/doi.org\/10.1210\/jcem.87.6.8609 (2002).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"37732_CR35","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-0077","author":"AA Merlino","year":"2007","unstructured":"Merlino, A. A. et al. Nuclear progesterone receptors in the human pregnancy myometrium: Evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-A. J. Clin. Endocrinol. Metab. https:\/\/doi.org\/10.1210\/jc.2007-0077 (2007).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"37732_CR36","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.00883","author":"DA Kniss","year":"2020","unstructured":"Kniss, D. A. & Summerfield, T. L. Progesterone receptor signaling selectively modulates cytokine-induced global gene expression in human cervical stromal cells. Front. Genet. https:\/\/doi.org\/10.3389\/fgene.2020.00883 (2020).","journal-title":"Front. Genet."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-37732-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-37732-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-37732-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T10:11:19Z","timestamp":1689847879000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-37732-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,20]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["37732"],"URL":"https:\/\/doi.org\/10.1038\/s41598-023-37732-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,20]]},"assertion":[{"value":"20 December 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11709"}}