Dienogest interrupts the chemokine signalling axis in endometriotic lesions with resistant signatures providing novel opportunities for personalised treatment.

Dienogest interrupts the chemokine signalling axis in endometriotic lesions with resistant signatures providing novel opportunities for personalised treatment. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Dienogest interrupts the chemokine signalling axis in endometriotic lesions with resistant signatures providing novel opportunities for personalised treatment. Brett McKinnon, Lea Duempelmann, Jitka Skrabalova, Sugarniya Subramaniam, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8096027/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Progestins are important first line and adjuvant medications for endometriosis, yet their efficacy varies among patients. Dienogest (DNG), a 4th generation progestin, is one of the most prescribed and successful progestins, although a subset of patients remain refractory to treatment. A prospective method to match patients to DNG, or other treatments could significantly improve patient outcomes. We employed a multidisciplinary approach using archival patient samples, clinical data, single nuclei sequencing, in silico prediction and high-content organoid drug screening to investigate DNG's impact on endometriotic lesions, signatures of non-response, and treatment options for refractory patients. We found DNG represses the inflammatory phenotype of deeply infiltrating endometriotic lesions by disrupting the chemokine signalling axis. Refractory patients displayed altered epithelial and stromal cell composition, aberrant progesterone receptor co-repressor signalling and enhanced TGF-B mediated fibrosis. Computational drug predictions identified potential therapies for refractory cases, including glucocorticoid receptor agonists for stroma- and immune-rich lesions, and HSP90 or NF-κB inhibitors for epithelial-dominant lesions, the activity of which were validated in high content screening of patient derived organoids. Notably some progestins already approved for endometriosis management possess off-target glucocorticoid activity, providing immediate potential for personalized treatment selection. Biological sciences/Molecular biology/Transcriptomics Health sciences/Diseases/Reproductive disorders/Endocrine reproductive disorders Biological sciences/Cell biology/Mechanisms of disease Endometriosis Dienogest single nuclei organoids CMAP glucocorticoids HSP90 NF- κB High content screening drug screening Luminespib Triptolide Parthenolide Full Text Additional Declarations All patients provided written informed consent for the collection and use of their samples for research purposes, in accordance with approved institutional ethics protocols. Yes there is potential Competing Interest. I am on the scientific advisory board for Maipl Therapeutics. I have received no compensation or input from Maipl for the conduct of this study. I have a project with Bayer. I receive no compensation from Bayer for this project. Supplementary Files sTable1.xlsx Supplementary Table 1: sTable3.xlsx Supplementary Table 3: sTable9.xlsx Supplementary Table 9: sTable7.xlsx Supplementary Table 7: sTable6.xlsx Supplementary Table 6: sTable11.xlsx Supplementary Table 11: sTable10.xlsx Supplementary Table 10: sTable2.xlsx Supplementary Table 2: sTable5.xlsx Supplementary Table 5: sTable8.xlsx Supplementary Table 8: sTable4.xlsx Supplementary Table 4: Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8096027","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":570402304,"identity":"cc637a19-c9f5-4472-9648-9e0987793456","order_by":0,"name":"Brett 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I am on the scientific advisory board for Maipl Therapeutics. I have received no compensation or input from Maipl for the conduct of this study. I have a project with Bayer. I receive no compensation from Bayer for this project.\u003c/p\u003e","formattedTitle":"Dienogest interrupts the chemokine signalling axis in endometriotic lesions with resistant signatures providing novel opportunities for personalised treatment.","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Endometriosis, Dienogest, single nuclei, organoids, CMAP, glucocorticoids, HSP90, NF- κB, High content screening, drug screening, Luminespib, Triptolide, Parthenolide","lastPublishedDoi":"10.21203/rs.3.rs-8096027/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8096027/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Progestins are important first line and adjuvant medications for endometriosis, yet their efficacy varies among patients. Dienogest (DNG), a 4th generation progestin, is one of the most prescribed and successful progestins, although a subset of patients remain refractory to treatment. A prospective method to match patients to DNG, or other treatments could significantly improve patient outcomes. We employed a multidisciplinary approach using archival patient samples, clinical data, single nuclei sequencing, in silico prediction and high-content organoid drug screening to investigate DNG's impact on endometriotic lesions, signatures of non-response, and treatment options for refractory patients. We found DNG represses the inflammatory phenotype of deeply infiltrating endometriotic lesions by disrupting the chemokine signalling axis. Refractory patients displayed altered epithelial and stromal cell composition, aberrant progesterone receptor co-repressor signalling and enhanced TGF-B mediated fibrosis. Computational drug predictions identified potential therapies for refractory cases, including glucocorticoid receptor agonists for stroma- and immune-rich lesions, and HSP90 or NF-κB inhibitors for epithelial-dominant lesions, the activity of which were validated in high content screening of patient derived organoids. Notably some progestins already approved for endometriosis management possess off-target glucocorticoid activity, providing immediate potential for personalized treatment selection.","manuscriptTitle":"Dienogest interrupts the chemokine signalling axis in endometriotic lesions with resistant signatures providing novel opportunities for personalised treatment.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-13 12:09:41","doi":"10.21203/rs.3.rs-8096027/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fef02f00-bee2-4ff1-9af7-de7f6256596a","owner":[],"postedDate":"January 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":60697151,"name":"Biological sciences/Molecular biology/Transcriptomics"},{"id":60697152,"name":"Health sciences/Diseases/Reproductive disorders/Endocrine reproductive disorders"},{"id":60697153,"name":"Biological sciences/Cell biology/Mechanisms of disease"}],"tags":[],"updatedAt":"2026-03-20T13:31:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-13 12:09:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8096027","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8096027","identity":"rs-8096027","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}