{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:37:19Z","timestamp":1791607039424,"version":"4.3.4"},"reference-count":83,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T00:00:00Z","timestamp":1644192000000},"content-version":"vor","delay-in-days":37,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["2017ZZ01016"],"award-info":[{"award-number":["2017ZZ01016"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008750","name":"Shanghai Hospital Development Center","doi-asserted-by":"publisher","award":["SHDC2020CR2062B"],"award-info":[{"award-number":["SHDC2020CR2062B"]}],"id":[{"id":"10.13039\/501100008750","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N022556\/1"],"award-info":[{"award-number":["MR\/N022556\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771553"],"award-info":[{"award-number":["81771553"]}],"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":["81871144"],"award-info":[{"award-number":["81871144"]}],"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":["82071623"],"award-info":[{"award-number":["82071623"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Reprod Medicine &amp; Biology"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>To investigate how the extent of fibrosis in adenomyosis lesions contributes to heavy menstrual bleeding (HMB).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We recruited 57 women with histologically confirmed adenomyosis, 29 of whom reported moderate\/heavy bleeding (MHB) (menstrual blood loss (MBL) \u226520 but &lt;100\u00a0mL) and the remaining 28, excessive MBL (EXB; \u2265100\u00a0mL). Lesional stiffness was measured by transvaginal elastosonography. Full\u2010thickness uterine tissue columns containing the lesion and its neighboring endometrial\u2010myometrial interface (EMI) and endometrial tissues were evaluated for tissue fibrosis and immunohistochemical analysis of HIF\u20101\u03b1, COX\u20102, EP2, and EP4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The lesional stiffness in the EXB group was significantly higher than that of MHB, and consistently, the extent of lesional fibrosis and the extent of tissue fibrosis in both EMI and eutopic endometrium were also significantly higher. In adenomyotic lesions and their neighboring EMI and eutopic endometrial tissues, the immunostaining of HIF\u20101\u03b1, COX\u20102, EP2, and EP4 was significantly reduced. The extent of fibrosis and the immunostaining levels of HIF\u20101\u03b1, COX\u20102, EP2, and EP4 were negatively correlated in all tissues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Lesional fibrosis begets stiffening matrix, propagating fibrosis to neighboring EMI and eutopic endometrium, resulting in reduced PGE<jats:sub>2<\/jats:sub> and HIF\u20101\u03b1 signaling, and thus likely reduced hypoxia necessary for endometrial repair, leading to HMB.<\/jats:p><\/jats:sec>","DOI":"10.1002\/rmb2.12442","type":"journal-article","created":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T16:36:09Z","timestamp":1644251769000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["How does the extent of fibrosis in adenomyosis lesions contribute to heavy menstrual bleeding?"],"prefix":"10.1002","volume":"21","author":[{"given":"Qingqing","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Gynecology The Third Affiliated Hospital of Guangzhou Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xishi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gynecology Shanghai OB\/GYN Hospital Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine\u2010Related Diseases Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary","family":"Critchley","sequence":"additional","affiliation":[{"name":"MRC Centre for Reproductive Health University of Edinburgh The Queen's Medical Research Institute  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongpeng","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Imaging Shanghai OB\/GYN Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8511-7624","authenticated-orcid":false,"given":"Sun\u2010Wei","family":"Guo","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine\u2010Related Diseases Fudan University  Shanghai China"},{"name":"Research Institute Shanghai OB\/GYN Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3109\/00016346609158455"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-2115(98)00224-3"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","unstructured":"(RCOG).RCoOaG. National heavy menstrual bleeding audit first. Annual Report.2011.","DOI":"10.12968\/indn.2011.23.5.84090"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2019.02.048"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/aogs.12394"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.whi.2008.07.002"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.2217\/whe.15.100"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijgo.12666"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2019"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dew018"},{"issue":"2","key":"e_1_2_9_12_1","first-page":"355","article-title":"Transforming growth factor beta1 signaling coincides with epithelial\u2010mesenchymal transition and fibroblast\u2010to\u2010myofibroblast transdifferentiation in the development of adenomyosis in mice","volume":"31","author":"Shen M","year":"2016","journal-title":"Hum Reprod"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2016.03.015"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dey015"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/0284185120948489"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/1933719117750752"},{"issue":"1","key":"e_1_2_9_17_1","first-page":"240","article-title":"Role of inflammatory mediators in human endometrium during progesterone withdrawal and early pregnancy","volume":"84","author":"Critchley HO","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1262\/jrd.50.215"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-1153"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2010.11.070"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02375-6"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00232.2006"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-128801"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.558130"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2014-0468OC"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2020.07.023"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2020.11.002"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201004082"},{"issue":"1","key":"e_1_2_9_29_1","doi-asserted-by":"crossref","first-page":"e12423","DOI":"10.1002\/rmb2.12423","article-title":"Higher fibrotic content of endometriotic lesions is associated with diminished prostaglandin E2 (PGE2) signaling","volume":"21","author":"Huang Q","year":"2021","journal-title":"Reprod Med Biol"},{"issue":"1","key":"e_1_2_9_30_1","doi-asserted-by":"crossref","first-page":"e12426","DOI":"10.1002\/rmb2.12426","article-title":"Changing prostaglandin E2 (PGE2) signaling during lesional progression and exacerbation of endometriosis by inhibition of PGE2 receptor EP2 and EP4","volume":"21","author":"Huang Q","year":"2021","journal-title":"Reprod Med Biol"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(97)70482-4"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102258"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2013.10.051"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.3109\/00365516409060511"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2003.11.015"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.17242.1"},{"issue":"1","key":"e_1_2_9_37_1","first-page":"15","article-title":"Adenomyosis: Back to the future?","volume":"9","author":"Ferraz Z","year":"2017","journal-title":"Facts Views vis Obgyn"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.14806"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1159\/000252789"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1159\/000122602"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1159\/000345883"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dey392"},{"key":"e_1_2_9_43_1","volume-title":"R: A language and environment for statistical computing","author":"R Core Team a","year":"2021"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0050OC"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00108.2012"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18112431"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2020-0227OC"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0335OC"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.11.032"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086378"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(72)90781-8"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deaa307"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf7533"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1450"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-2971"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dev156"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2008-0080OC"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.22242"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00403.2018"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1080\/09513590601005375"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.9.5644"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200706-963OC"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.100446"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1177\/1933719115607978"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1177\/1933719117718275"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/16.3.561"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2013.04.028"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1097\/PGP.0b013e318182c2be"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00404-020-05742-9"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/del503"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmv038"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.9.7856"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63653-X"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dep036"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2007.03.028"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5314"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2214-z"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1040-z"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00972-2"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00001.2004"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dex378"},{"key":"e_1_2_9_82_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmz024"},{"key":"e_1_2_9_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0039-128X(03)00139-9"},{"key":"e_1_2_9_84_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.13888"}],"container-title":["Reproductive Medicine and Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rmb2.12442","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/rmb2.12442","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rmb2.12442","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T22:20:29Z","timestamp":1692483629000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/rmb2.12442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":83,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["10.1002\/rmb2.12442"],"URL":"https:\/\/doi.org\/10.1002\/rmb2.12442","archive":["Portico"],"relation":{},"ISSN":["1445-5781","1447-0578"],"issn-type":[{"value":"1445-5781","type":"print"},{"value":"1447-0578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1]]},"assertion":[{"value":"2021-11-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-16","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12442"}}