CSF-1-Induced DC-SIGN+ Macrophages Work In The Ovarian Endometriosis

CSF-1-Induced DC-SIGN+ Macrophages Work In The Ovarian Endometriosis | 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 Research Article CSF-1-Induced DC-SIGN + Macrophages Work In The Ovarian Endometriosis Xiaocui Li, Wei Hong, Yunlang Cai, Zhenzhen Zheng, Min An This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-814415/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Background CSF-1 was found to be accumulated in the lesions and peritoneal fluid of endometriosis patients, and CSF-1 induced THP-1-derived macrophages to polarize toward a suppressive phenotype. Researchers found that macrophages were the predominant cells in the peritoneal fluid (PF) of endometriosis patients, and the primary consensus is that the immune status in the PF of endometriosis patients exhibits a depressed state. Does the cytokine CSF-1 induce monocytes to differentiate into macrophages with a DC-SIGN + suppressive phenotype in endometriosis? Methods The level of CSF-1 in control endometrium (N=11), eutopic endometrium (N=17), and ectopic (N=39) endometrium of endometriosis patients was evaluated by real-time polymerase chain reaction and in the PF of control (N=25) and endometriosis (N=35) patients by enzyme-linked immunosorbent assay. CSF-1 was examined by a MILLIPLEX MAP Mouse Cytokine/Chemokine Magnetic Bead Panel in an in vivo study. DC-SIGN+ suppressive macrophages were detected by immunohistochemical staining of tissues and flow cytometric analysis of the PF of control (N=25) and endometriosis (N=35) patients. The phenotypes and biological activities of the resulting macrophages derived from THP-1 cells induced by CSF-1 were compared by an in vitro coculture system with peripheral blood lymphocytes from normal subjects. Results In this study, we found the proportion of DC-SIGN + suppressive macrophages was larger in the abdominal immune microenvironment of endometriosis patients. CSF-1 was primarily secreted from the ectopic lesions and peritoneum of mice with endometriosis. And, CSF-1 induced the polarization of macrophages toward a DC-SIGN + suppressive phenotype; this effect was abolished by the addition of anti-CSF-1R. CSF-1 induced DC-SIGN + macrophages, leading to a depressed status of peripheral blood lymphocytes, including a high percentage of Treg cells and a low percentage of CD8 + T cells. Similarly, blockade with anti-CSF-1R abrogated this biological effect. This is the first study on the predominant role of DC-SIGN + suppressive macrophages in the depressed immune status of endometriosis patients. Conclusions This is the first study on the predominant role of DC-SIGN+ suppressive macrophages in the depressed immune status of endometriosis patients. Further study of the mechanism and biological activities of CSF-1-induced DC-SIGN+ suppressive macrophages will enhance our understanding of the physiology of endometriosis and indicate new directions for further study. Endocrinology & Metabolism Endometriosis/DC-SIGN+ suppressive macrophages/CSF-56 1/Treg cells Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Full Text Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 24 Sep, 2021 Review # 2 received at journal 20 Sep, 2021 Review # 1 received at journal 16 Sep, 2021 Review # 3 received at journal 13 Sep, 2021 Reviewer # 3 agreed at journal 06 Sep, 2021 Reviewer # 2 agreed at journal 06 Sep, 2021 Reviews received at journal 04 Sep, 2021 Reviewer # 1 agreed at journal 03 Sep, 2021 Reviewers invited by journal 17 Aug, 2021 Editor assigned by journal 16 Aug, 2021 Submission checks completed at journal 15 Aug, 2021 Editor invited by journal 15 Aug, 2021 First submitted to journal 14 Aug, 2021 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-814415","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":46557994,"identity":"4b04247e-2b31-49c3-a6b9-a61dd11582bc","order_by":0,"name":"Xiaocui Li","email":"","orcid":"","institution":"Tongji University Shanghai First Maternal and Infant Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaocui","middleName":"","lastName":"Li","suffix":""},{"id":46557995,"identity":"598c4778-7218-4844-aeec-7854f77eb17e","order_by":1,"name":"Wei Hong","email":"","orcid":"","institution":"Tongji University Shanghai First Maternal and Infant Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Hong","suffix":""},{"id":46557996,"identity":"215d845a-cd86-4bd7-9cde-2deb4576d07b","order_by":2,"name":"Yunlang Cai","email":"","orcid":"","institution":"Southeast University Zhongda Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yunlang","middleName":"","lastName":"Cai","suffix":""},{"id":46557997,"identity":"4202acfd-1abd-4602-a7ad-922bed08d2b0","order_by":3,"name":"Zhenzhen Zheng","email":"","orcid":"","institution":"Tongji University Shanghai First Maternal and Infant Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhenzhen","middleName":"","lastName":"Zheng","suffix":""},{"id":46557998,"identity":"81bf0632-aa2e-4b65-8fa7-eeafa25e73f2","order_by":4,"name":"Min An","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIie3RsWrDMBCAYRnBZVGTVcbBeQUbg+njSAloaksgi4cMNgRriEpX9S0yZouDwZOyu5v7BvWWKUkzt9ju1kHffD/ccQhZ1j8Es2PWtBfwHfnWNixZ9ydjistQwzjCqoiCxlT9iU9BeAR8PtIsdj83eMBinopdTWL2oAqR8BTQRG5ZdzI10eMXFS+uTKua76eImtOuO0FP4YcOqlWojnnNDaCAPvcmgUfYlR/qBSx5jgckVMw9UgDPtAA0LCFlGb6nEDnKYMpMRXpvmcns+5Xp/ZXKac/J2p/I1+7kB/K3ccuyLOtXNyfXTFQEh4eWAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-6075-7166","institution":"Southeast University Zhongda Hospital","correspondingAuthor":true,"prefix":"","firstName":"Min","middleName":"","lastName":"An","suffix":""}],"badges":[],"createdAt":"2021-08-15 04:17:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-814415/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-814415/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":12591125,"identity":"8d264841-c8d4-4748-9a21-f4a61bb4e5ca","added_by":"auto","created_at":"2021-08-19 21:18:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1808886,"visible":true,"origin":"","legend":"Suppressive macrophages express high levels of CD169, CD115, and CD209 in the PF of endometriosis patients. (A) Morphological cytograms of FSC (forward scatter) and SSC (side scatter) parameters of peritoneal cells in the PF. (B) The monocyte/macrophage population gated by CD45 and SSC. (C) Gating CD169+ macrophages in the PF of the controls. (D) Gating CD169+ macrophages in the PF of the endometriosis patients. (E) Gating CD115+ macrophages in the PF of the controls. (F) Gating CD115+ macrophages in the PF of the endometriosis patients. (G) Gating CD209+ macrophages in the PF of the controls. (H) Gating CD209+ macrophages in the PF of the endometriosis patients. (I) Differences between groups were analysed by Student’s t test (controls n=25; endometriosis patients n=35). The values are expressed as the mean SD. **P ≤0.01, ***P≤0.001.","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-814415/v1/3a6a19ed89b4bcf0334c4596.png"},{"id":12591123,"identity":"de4d4df3-e2a7-4941-98fd-8676ad738035","added_by":"auto","created_at":"2021-08-19 21:18:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1185574,"visible":true,"origin":"","legend":"There were more CD169+ CD115+ macrophages and CD169+ CD209+ macrophages in the PF of endometriosis patients than in the control. (A) Morphological cytograms of FSC (forward scatter) and SSC (side scatter) parameters of peritoneal cells in PF. (B) The monocyte/macrophage population gated by CD45 and SSC. (C) Gating CD169+ CD209+ macrophages in the PF of the controls. (D) Gating CD169+ CD209+ macrophages in the PF of the endometriosis patients. (E) Gating CD169+ CD115+ macrophages in the PF of the controls. (F) Gating CD169+ CD115+ macrophages in the PF of the endometriosis patients. (G) Differences between groups were analysed by Student’s t test (controls, n=25; endometriosis patients, n=35). The values are expressed as the mean ± SD. ***P≤0.001.","description":"","filename":"fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-814415/v1/c1c9b77b5fc63635211680e4.png"},{"id":12591124,"identity":"2c1d8e75-ec5c-4a1b-bbaf-539e81b23fac","added_by":"auto","created_at":"2021-08-19 21:18:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":7055431,"visible":true,"origin":"","legend":"Macrophages and Treg cells in the ectopic and eutopic endometrium of endometriosis patients and normal endometrium. (A) Macrophages expressed CD68, CD169, CSF-1R, and DC-SIGN, and Treg cells expressed FOXP3 in all the tissues of the normal endometrium, eutopic endometrium, and ectopic endometrium of endometriosis patients. Representative images are shown at 200× magnification. (B) The comparison between the proportion of macrophages and Treg cells in tissues of the normal endometrium, eutopic endometrium, and ectopic endometrium of the endometriosis patients. The data are presented as the mean±SD. Statistical analyses were performed by one-way analysis of variance (eutopic=17; ectopic=17; normal=11), and significant differences are indicated as *P≤0.05, ***P≤0.001.","description":"","filename":"fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-814415/v1/0dabd6cbc1a2d6f4166cb7ea.png"},{"id":12591121,"identity":"d33c83e9-0e7e-4635-a5ee-3a04ad86453a","added_by":"auto","created_at":"2021-08-19 21:18:19","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1245237,"visible":true,"origin":"","legend":"CSF-1 levels are elevated in peritoneal fluid and ectopic endometrium from women with endometriosis and ectopic lesions and peritoneum of mice with endometriosis. (A) The gene expression of CSF-1 in the normal endometrium, eutopic endometrium and ectopic endometrium of endometriosis patients detected by RT-PCR. (B) The percentage of the cytokine CSF-1 in the total protein detected by ELISA in the PF of the control and endometriosis groups. (C) The model of EMS and ectopic lesions of the EMS model. (D) The cytokine CSF-1 in the PF, the peritoneal cells of PF, the peritoneum, the normal endometrium, the eutopic endometrium, and the ectopic endometrium of the control and the EMS models was analysed by the MILLIPLEX MAP Mouse Cytokine/Chemokine Magnetic Bead Panel. The data are presented as the mean±SD. Statistical analyses were performed by Student’s t test (control, n=25, endometriosis patients, n=35; normal mouse, n=9; EMS mouse, n=9) and one-way analysis of variance (eutopic=17; ectopic=17; normal=11). Significant differences are indicated as *P≤0.05, **P≤0.01.","description":"","filename":"fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-814415/v1/026ef99f3dce37352c466f2a.png"},{"id":12591282,"identity":"edf12031-63db-490b-8078-9c1ab39d6aa9","added_by":"auto","created_at":"2021-08-19 21:21:19","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2141859,"visible":true,"origin":"","legend":"CSF-1 induces macrophages to differentiated into a DC-SIGN+ suppressive phenotype, and this effect can be abolished by the addition of anti-CSF-1R. (A) CD169 expression in the original macrophages, macrophages induced by CSF-1 (MCSF) and macrophages induced by CSF-1 (MCSF) after blockade with anti-CSF-1R. (B) DC-SIGN expression in the original macrophages, macrophages induced by CSF-1 (MCSF) and macrophages induced by CSF-1 (MCSF) after blockade with anti-CSF-1R. Representative images are shown at 200× magnification (n=5).","description":"","filename":"fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-814415/v1/b2c767f5d7e8c18b31a21634.png"},{"id":12591120,"identity":"4e33bae4-f1ef-4201-98c3-0fbe4f3eb6e0","added_by":"auto","created_at":"2021-08-19 21:18:19","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":2347551,"visible":true,"origin":"","legend":"CSF-1-induced DC-SIGN+ macrophages, leading to a suppressive phenotype of peripheral blood lymphocytes, while anti-CSF-1R could abrogate this effect. (A) The coculture system of treated macrophages and PBMCs. (B) The percentages of CD8+ T cells and Treg cells in the PBMCs of the coculture system. (C) The experiment was repeated nine times, and the differences between the groups were analysed by two-way analysis of variance. The values are expressed as the mean±SD. *P≤0.05. NC: PBMC without coculture; CO1: PBMCs were cocultured with untreated macrophages; CO2: PBMCs were cocultured with CSF-1-induced macrophages; CO3: PBMCs were cocultured with CSF-1-induced macrophages, which were first treated with anti-CSF-1R; and CO4: PBMCs were cocultured with CSF-1-induced macrophages, which were first treated with anti-DC-SIGN.","description":"","filename":"fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-814415/v1/507d56c29571713aaa5ae2e0.png"},{"id":13670137,"identity":"13a4087e-e44f-4306-a656-7c9245b8cb0d","added_by":"auto","created_at":"2021-09-17 11:04:06","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":834456,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-814415/v1_covered.pdf"},{"id":12591284,"identity":"ef76c037-7b55-4fce-b010-49ba334f0dd3","added_by":"auto","created_at":"2021-08-19 21:21:35","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":732542,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-814415/v1_covered.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eCSF-1-Induced DC-SIGN\u003csup\u003e+\u003c/sup\u003e Macrophages Work In The Ovarian Endometriosis\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-814415/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"reproductive-biology-and-endocrinology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rbej","sideBox":"Learn more about [Reproductive Biology and Endocrinology](http://rbej.biomedcentral.com)","snPcode":"12958","submissionUrl":"https://submission.nature.com/new-submission/12958/3","title":"Reproductive Biology and Endocrinology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Endometriosis/DC-SIGN+, suppressive macrophages/CSF-56 1/Treg cells","lastPublishedDoi":"10.21203/rs.3.rs-814415/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-814415/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eCSF-1 was found to be accumulated in the lesions and peritoneal fluid of endometriosis patients, and CSF-1 induced THP-1-derived macrophages to polarize toward a suppressive phenotype. Researchers found that macrophages were the predominant cells in the peritoneal fluid (PF) of endometriosis patients, and the primary consensus is that the immune status in the PF of endometriosis patients exhibits a depressed state. Does the cytokine CSF-1 induce monocytes to differentiate into macrophages with a DC-SIGN\u003csup\u003e+\u003c/sup\u003e suppressive phenotype in endometriosis?\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe level of CSF-1 in control endometrium (N=11), eutopic endometrium (N=17), and ectopic (N=39) endometrium of endometriosis patients was evaluated by real-time polymerase chain reaction and in the PF of control (N=25) and endometriosis (N=35) patients by enzyme-linked immunosorbent assay. CSF-1 was examined by a MILLIPLEX MAP Mouse Cytokine/Chemokine Magnetic Bead Panel in an in vivo study. DC-SIGN+ suppressive macrophages were detected by immunohistochemical staining of tissues and flow cytometric analysis of the PF of control (N=25) and endometriosis (N=35) patients. The phenotypes and biological activities of the resulting macrophages derived from THP-1 cells induced by CSF-1 were compared by an in vitro coculture system with peripheral blood lymphocytes from normal subjects.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eIn this study, we found the proportion of DC-SIGN\u003csup\u003e+\u003c/sup\u003e suppressive macrophages was larger in the abdominal immune microenvironment of endometriosis patients. CSF-1 was primarily secreted from the ectopic lesions and peritoneum of mice with endometriosis. And, CSF-1 induced the polarization of macrophages toward a DC-SIGN\u003csup\u003e+\u003c/sup\u003e suppressive phenotype; this effect was abolished by the addition of anti-CSF-1R. CSF-1 induced DC-SIGN\u003csup\u003e+\u003c/sup\u003e macrophages, leading to a depressed status of peripheral blood lymphocytes, including a high percentage of Treg cells and a low percentage of CD8\u003csup\u003e+\u003c/sup\u003e T cells. Similarly, blockade with anti-CSF-1R abrogated this biological effect. This is the first study on the predominant role of DC-SIGN\u003csup\u003e+\u003c/sup\u003e suppressive macrophages in the depressed immune status of endometriosis patients.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e This is the first study on the predominant role of DC-SIGN+ suppressive macrophages in the depressed immune status of endometriosis patients. Further study of the mechanism and biological activities of CSF-1-induced DC-SIGN+ suppressive macrophages will enhance our understanding of the physiology of endometriosis and indicate new directions for further study.\u003c/p\u003e","manuscriptTitle":"CSF-1-Induced DC-SIGN+ Macrophages Work In The Ovarian Endometriosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-08-19 21:18:17","doi":"10.21203/rs.3.rs-814415/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-09-25T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-09-21T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2021-09-17T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2021-09-14T00:00:00+00:00","index":3,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2021-09-07T01:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-09-07T00:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-09-04T10:59:20+00:00","index":0,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-09-04T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-08-17T11:56:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-08-16T04:04:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-08-15T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-08-15T23:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Reproductive Biology and Endocrinology","date":"2021-08-14T08:02:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"reproductive-biology-and-endocrinology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rbej","sideBox":"Learn more about [Reproductive Biology and Endocrinology](http://rbej.biomedcentral.com)","snPcode":"12958","submissionUrl":"https://submission.nature.com/new-submission/12958/3","title":"Reproductive Biology and Endocrinology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a79f8472-55ab-4f41-9851-fb34c4ebecf4","owner":[],"postedDate":"August 19th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":6568620,"name":"Endocrinology \u0026 Metabolism"}],"tags":[],"updatedAt":"2022-01-26T05:27:02+00:00","versionOfRecord":[],"versionCreatedAt":"2021-08-19 21:18:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-814415","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-814415","identity":"rs-814415","version":["v1"]},"buildId":"WvIrzKhiLBfengagbw6Ux","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}