{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T18:09:17Z","timestamp":1788804557800,"version":"build-2803163510"},"reference-count":70,"publisher":"American Society for Clinical Investigation","issue":"17","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":47,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HD090151,DK133760,HD099084,U54 AG062322"],"award-info":[{"award-number":["HD090151,DK133760,HD099084,U54 AG062322"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Brit Jepson d\u2019Arbeloff Center on Women\u2019s Health","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,8]]},"abstract":"<jats:p>The hypothalamic changes that occur after the loss of ovarian estrogen remain poorly characterized. Here, we performed a comprehensive temporal characterization of the mouse hypothalamus after ovariectomy (OVX), combining physiological measurements with bulk RNA-seq of the posterior hypothalamus (PH) and preoptic area at 14 days and 4 months after OVX. Serum luteinizing hormone levels rose progressively and then declined, and core temperature peaked early and subsequently normalized, recapitulating the endocrine and thermoregulatory dynamics of reproductive aging in humans. Transcriptomic analysis revealed time-dependent activation of inflammatory pathways, glial markers, and KNDy neuron-related gene networks, with the most pronounced changes emerging at 4 months after OVX, particularly in the PH. Immunofluorescence confirmed increased neurokinin B release, declining KNDy neuronal activity, and heightened astrocytic reactivity in the arcuate nucleus after prolonged estrogen withdrawal. To contextualize these findings, we analyzed publicly available human hypothalamic RNA-seq data across chronological age. Age-related transcriptomic patterns, including progressive inflammatory signaling, glial activation, and altered KNDy gene expression, showed significant correlation with the OVX mouse model, particularly at the pathway level. These findings establish a temporal framework for hypothalamic molecular changes after estrogen withdrawal, identify conserved neuroinflammatory signatures across species, and provide a preclinical platform for testing interventions targeting menopause-associated hypothalamic dysfunction.<\/jats:p>","DOI":"10.1172\/jci.insight.207270","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:00:27Z","timestamp":1784822427000},"source":"Crossref","is-referenced-by-count":0,"title":["Progressive hypothalamic neuroinflammation in ovariectomized mice parallels aging-related transcriptomic changes in the female human hypothalamus"],"prefix":"10.1172","volume":"11","author":[{"given":"Jordana C.B.","family":"Bloom","sequence":"first","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA."},{"name":"Division of Endocrinology, Mass General Brigham, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Encarnaci\u00f3n","family":"Torres","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Mass General Brigham, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7937-2952","authenticated-orcid":true,"given":"Sidney A.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Mass General Brigham, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Arvizu-Sanchez","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Mass General Brigham, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey N.","family":"Fontes","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Mass General Brigham, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadine","family":"Joffe","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Page","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA."},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA."},{"name":"Howard Hughes Medical Institute, Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5799-219X","authenticated-orcid":true,"given":"Victor M.","family":"Navarro","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Mass General Brigham, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Harvard Graduate Program in Neuroscience, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.25"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2015.82"},{"key":"B3"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.81.10.8855798"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1445-5994.2012.02723.x"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.5114\/pm.2019.86835"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgac447"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgad285"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.1757"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ogc.2011.06.002"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cnur.2003.11.006"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2007.03.008"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0b013e318214f0de"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2023.101774"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)30823-1"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.15965"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.maturitas.2016.01.015"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2014.8063"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-77871-9"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-022-00246-4"},{"key":"B21","doi-asserted-by":"crossref","unstructured":"Korotkevich G et al. Fast gene set enrichment analysis. https:\/\/doi.org\/10.1101\/060012 Posted on bioRxiv February 1, 2021","DOI":"10.1101\/060012"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1074"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1177\/1073858418760481"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2122562119"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0488"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/jne.13094"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-017-3808-1"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08504-8"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1097\/GME.0000000000001424"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2008.05.016"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-0553"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-17315-8"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-025-03177-9"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1042"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1202753"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.nurx.2005.12.010"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.01.028"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.06.026"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21197344"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.23.1.0456"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1097\/GME.0000000000000763"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1111098109"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2025.09.023"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add5463"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/s10863-011-9325-z"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/nature12143"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116715"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fnsyn.2024.1384625"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1177\/1073858410384740"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010325"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-00988-z"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2014.09.018"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3390\/cells11121966"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-022-00450-9"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2004.08.002"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.85.5.6612"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1097\/01.gme.0000191883.59799.2e"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.103.016113"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.12.064"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118543"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00587"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1159\/000502978"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.04.007"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3519"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.7563.1"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky955"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.019"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15816-6"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/207270\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T18:02:21Z","timestamp":1788804141000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/207270"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":70,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,7,23]]},"published-print":{"date-parts":[[2026,9,8]]}},"alternative-id":["10.1172\/jci.insight.207270"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.207270","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]},"article-number":"e207270"}}