{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:17:47Z","timestamp":1791454667976,"version":"4.3.3"},"reference-count":71,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"15","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,4,11]]},"abstract":"<jats:p>Neurodegenerative disorders such as Alzheimer\u2019s disease and macular degeneration represent major sources of human suffering, yet factors influencing disease severity remain poorly understood. Sex has been implicated as one modifying factor. Here, we show that female sex is a risk factor for worsened outcomes in a model of retinal degeneration and that this susceptibility is caused by the presence of female-specific sex hormones. The adverse effect of female sex hormones was specific to diseased retinal neurons, and depletion of these hormones ameliorated this phenotypic effect, while reintroduction worsened rates of disease in females. Transcriptional analysis of retinas showed significant differences between genes involved in pyroptosis, inflammatory responses, and endoplasmic reticulum stress\u2013induced apoptosis between males and females with retinal degeneration. These findings provide crucial insights into the pathogenesis of neurodegenerative diseases and how sex hormones can affect disease severity. These findings have far-reaching implications for clinical trial design and the use of hormonal therapy in females with certain neurodegenerative disorders.<\/jats:p>","DOI":"10.1126\/sciadv.adr6211","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T13:59:46Z","timestamp":1744379986000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":18,"title":["Female sex hormones exacerbate retinal neurodegeneration"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4202-7079","authenticated-orcid":true,"given":"Ashley A.","family":"Rowe","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio J.","family":"Velasquez","sequence":"additional","affiliation":[{"name":"Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob W.","family":"Aumeier","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2381-2094","authenticated-orcid":true,"given":"Sofia","family":"Reyes","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8709-8017","authenticated-orcid":true,"given":"Tiffany","family":"Yee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8581-1205","authenticated-orcid":true,"given":"Emily R.","family":"Nettesheim","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1570-4142","authenticated-orcid":true,"given":"Jeffrey G.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA."},{"name":"Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8430-2916","authenticated-orcid":true,"given":"Katherine J.","family":"Wert","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA."},{"name":"Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA."},{"name":"Peter O\u2019Donnell, Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA."},{"name":"Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.01.024"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1167\/tvst.11.5.22"},{"key":"e_1_3_2_4_2","first-page":"14","article-title":"Sex and gender differences in Alzheimer's disease dementia","volume":"35","author":"Mielke M. M.","year":"2018","unstructured":"M. M. Mielke, Sex and gender differences in Alzheimer's disease dementia. Psychiatr. Times 35, 14\u201317 (2018).","journal-title":"Psychiatr. Times"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00066"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-18487-4"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31561-0"},{"key":"e_1_3_2_8_2","unstructured":"S. R. Daiger J. Greenberg A. Christoffels W. Hide RetNet (1998); https:\/\/RetNet.org\/."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12203"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0960-0760(93)90257-W"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.05.008"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-14-0349"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-005-0102-8"},{"key":"e_1_3_2_14_2","first-page":"1906","article-title":"Estrogen receptor in the human eye: Influence of gender and age on gene expression","volume":"40","author":"Ogueta S. B.","year":"1999","unstructured":"S. B. Ogueta, S. D. Schwartz, C. K. Yamashita, D. B. Farber, Estrogen receptor in the human eye: Influence of gender and age on gene expression. Invest. Ophthalmol. Vis. Sci. 40, 1906\u20131911 (1999).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1638"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106943"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00188-4"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aau5956"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.08.036"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M300029-MCP200"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0693-130"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2019.107773"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-53731-8"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.66.1.28"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.64.3.18"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-27681-1_49"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-22316-8"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50033-5"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45748-4"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add5479"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06970-6"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20231011"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-27681-1_62"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69740-7"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.209759"},{"key":"e_1_3_2_36_2","unstructured":"K. Daniels J. C. Amba in Current Contraceptive Status Among Women Aged 15\u201349: United States 2017\u20132019 National Center for Health Statistics Eds. (NCHS 2020)."},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.291.1.47"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/0047-6374(90)90125-Y"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glt046"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.30577"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2015.08.002"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1994.63010086.x"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R016675"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.049336"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.3390\/ph15030328"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2011.07354.x"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13388"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2019.107826"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.02-1204"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.19-27246"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2020.11.010"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.09-3628"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.10.141"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200310015"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2018.01.032"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-19351-w"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2023.109474"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.015779"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1440309"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2024.04.012"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2023.109462"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-73279-x"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2013.12.043"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104314"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.150898"},{"key":"e_1_3_2_66_2","first-page":"e64379","article-title":"Murine orchiectomy and ovariectomy to reduce sex hormone production","author":"Rowe A. A.","year":"2023","unstructured":"A. A. Rowe, Y. Issioui, B. Johnny, K. J. Wert, Murine orchiectomy and ovariectomy to reduce sex hormone production. J. Vis. Exp. e64379 (2023).","journal-title":"J. Vis. Exp."},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035538"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232314691"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2014.10.006"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.7150\/jca.10890"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-0930"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2004.10.010"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adr6211","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T14:01:44Z","timestamp":1744380104000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adr6211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,11]]},"references-count":71,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2025,4,11]]}},"alternative-id":["10.1126\/sciadv.adr6211"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adr6211","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.07.11.603104","asserted-by":"object"}]},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,11]]},"assertion":[{"value":"2024-07-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadr6211"}}