{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T01:35:59Z","timestamp":1768959359328,"version":"3.49.0"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"International Exchange and Cooperation Program of Sichuan Province","award":["2024YFHZ0296"],"award-info":[{"award-number":["2024YFHZ0296"]}]},{"name":"Student Innovation Training Program","award":["S202410626046"],"award-info":[{"award-number":["S202410626046"]}]},{"name":"Undergraduate Research Interest Cultivation Program of Sichuan Agricultural University","award":["20251797"],"award-info":[{"award-number":["20251797"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Age-related thymic atrophy, a hallmark of immunosenescence linked to age-related diseases, involves gonadal and adrenal steroid hormones, but their distinct roles and mechanisms in this process remain unclear. Through biochemical, histological, and RNA-seq analyses, we comprehensively explored the mechanisms underpinning age-related thymic atrophy in response to ovariectomy (OVX) versus adrenalectomy (ADX) in female mice. Compared to the sham controls, OVX overtly ameliorated age-related thymic atrophy, as evidenced by increased thymus mass, a larger gross thymus area, and denser cortex cellularity. In contrast, ADX evidently accelerated age-related thymic atrophy, characterized by increased adipose infiltration and decreased cortex\/medulla ratio, obscure cortico-medullary junctions, and sparser thymic cortical cells. Unexpectedly, combined OVX and ADX displayed a more pronounced effect than OVX alone in ameliorating age-related thymic atrophy. Mechanistically, OVX decreased while ADX increased the circulating 17\u03b2-estradiol levels in female mice, which drove these opposing outcomes potentially by promoting Pparg-mediated thymic fat deposition and blocking Cdk1-dependent thymocyte cell cycle progression. Although OVX eliminated gonadal 17\u03b2-estradiol production, it appeared to trigger a compensatory adrenal-dependent estrogen biosynthesis, whereas combined OVX and ADX nearly eliminated all estrogen sources, thus leading to a more pronounced effect than OVX alone in ameliorating age-related thymic atrophy in female mice. Notably, OVX increased while ADX decreased serum corticosterone levels, but these alterations exerted minimal impacts on age-related thymic atrophy, highlighting a pivotal role of estrogens over glucocorticoids in accelerating age-related thymic atrophy in females. Undesirably, although OVX ameliorated age-related thymic atrophy, it appeared to simultaneously increase autoimmune susceptibility by downregulating thymic Cd74 expression. Taken together, our results indicate that OVX ameliorates while ADX accelerates age-related thymic atrophy in females. Estrogens rather than glucocorticoids act as the predominant regulator of this process, potentially via promoting Pparg-dependent fat deposition and blocking Cdk1-dependent thymocyte cycle progression. However, OVX-induced estrogen depletion also elevated autoimmune risk, emphasizing the need to balance benefits and risks in regulating thymic aging.<\/jats:p>","DOI":"10.3390\/ijms27021022","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T13:02:07Z","timestamp":1768914127000},"page":"1022","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanical Insights into the Distinct Effects of Ovariectomy Versus Adrenalectomy on Age-Related Thymic Atrophy in Female Mice"],"prefix":"10.3390","volume":"27","author":[{"given":"Junan","family":"Chen","sequence":"first","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xudong","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Wei","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zixuan","family":"Tian","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haozhe","family":"Zeng","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Yan","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junhua","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianyin","family":"Zeng","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengyan","family":"Meng","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohan","family":"Cao","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haozhou","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingfa","family":"Han","sequence":"additional","affiliation":[{"name":"College of Life Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.thorsurg.2018.12.001","article-title":"The Role of the Thymus in the Immune Response","volume":"29","author":"Thapa","year":"2019","journal-title":"Thorac. Surg. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e13671","DOI":"10.1111\/acel.13671","article-title":"Age-related thymic involution: Mechanisms and functional impact","volume":"21","author":"Liang","year":"2022","journal-title":"Aging Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/s41590-021-00927-z","article-title":"Hallmarks of T cell aging","volume":"22","author":"Mittelbrunn","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1073\/pnas.1714478115","article-title":"Thymic involution and rising disease incidence with age","volume":"115","author":"Palmer","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.celrep.2018.01.015","article-title":"Age-Associated Decline in Thymic B Cell Expression of Aire and Aire-Dependent Self-Antigens","volume":"22","author":"Cepeda","year":"2018","journal-title":"Cell Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"110363","DOI":"10.1016\/j.celrep.2022.110363","article-title":"Redox regulation of age-associated defects in generation and maintenance of T cell self-tolerance and immunity to foreign antigens","volume":"38","author":"Hester","year":"2022","journal-title":"Cell Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2494","DOI":"10.1038\/s43587-025-00990-3","article-title":"Single-cell analysis of human thymus and peripheral blood unveils the dynamics of T cell development and aging","volume":"5","author":"Deng","year":"2025","journal-title":"Nat. Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.cellimm.2007.10.007","article-title":"The role of sex steroids and gonadectomy in the control of thymic involution","volume":"252","author":"Hince","year":"2008","journal-title":"Cell Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.bbrc.2010.11.002","article-title":"The role of endogenous glucocorticoids in lymphocyte development in melanocortin receptor 2-deficient mice","volume":"403","author":"Sato","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/S0040-8166(98)80011-6","article-title":"Effects of castration on the lymphocytes of the thymus, spleen and lymph nodes","volume":"30","author":"Windmill","year":"1998","journal-title":"Tissue Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/j.1749-6632.2012.06601.x","article-title":"Thymic atrophy in acute experimental Chagas disease is associated with an imbalance of stress hormones","volume":"1262","author":"Lepletier","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.smim.2012.04.002","article-title":"Impact of immune-metabolic interactions on age-related thymic demise and T cell senescence","volume":"24","author":"Dixit","year":"2012","journal-title":"Semin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.2353\/ajpath.2007.060804","article-title":"Enhanced glucocorticoid receptor signaling in T cells impacts thymocyte apoptosis and adaptive immune responses","volume":"170","author":"McPherson","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1093\/humrep\/17.3.620","article-title":"Ovarian and adrenal steroid production: Regulatory role of LH\/HCG","volume":"17","author":"Piltonen","year":"2002","journal-title":"Hum. Reprod."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1016\/j.celrep.2018.02.041","article-title":"Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor-Dependent Mechanism in Mice","volume":"22","author":"Quinn","year":"2018","journal-title":"Cell Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7371","DOI":"10.4049\/jimmunol.176.12.7371","article-title":"Estrogen induces thymic atrophy by eliminating early thymic progenitors and inhibiting proliferation of beta-selected thymocytes","volume":"176","author":"Zoller","year":"2006","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"H533","DOI":"10.1152\/ajpheart.00195.2024","article-title":"Glucocorticoids impair T lymphopoiesis after myocardial infarction","volume":"327","author":"Shane","year":"2024","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.ajhg.2019.03.025","article-title":"Cell-Type Heterogeneity in Adipose Tissue Is Associated with Complex Traits and Reveals Disease-Relevant Cell-Specific eQTLs","volume":"104","author":"Glastonbury","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eaay3224","DOI":"10.1126\/science.aay3224","article-title":"A cell atlas of human thymic development defines T cell repertoire formation","volume":"367","author":"Park","year":"2020","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"Newman","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"133","DOI":"10.3892\/ijmm.2015.2392","article-title":"Adipocyte and leptin accumulation in tumor-induced thymic involution","volume":"37","author":"Lamas","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/s41580-018-0093-z","article-title":"Adipogenesis and metabolic health","volume":"20","author":"Ghaben","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s10456-022-09848-3","article-title":"Angiogenesis in adipose tissue and obesity","volume":"25","author":"Corvera","year":"2022","journal-title":"Angiogenesis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.canlet.2018.11.019","article-title":"Cyclin B1\/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance","volume":"443","author":"Xie","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gearing, L.J., Cumming, H.E., Chapman, R., Finkel, A.M., Woodhouse, I.B., Luu, K., Gould, J.A., Forster, S.C., and Hertzog, P.J. (2019). CiiiDER: A tool for predicting and analysing transcription factor binding sites. PLoS ONE, 14.","DOI":"10.1101\/599621"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s00011-016-0995-1","article-title":"The biological function and significance of CD74 in immune diseases","volume":"66","author":"Su","year":"2017","journal-title":"Inflamm. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1677\/joe.0.0220177","article-title":"Comparison of the effect of ovariectomy and adrenalectomy on the thymus in young female rats, and a study of the part played by the thymus in body growth","volume":"22","author":"Sirsi","year":"1961","journal-title":"J. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101837","DOI":"10.1016\/j.smim.2023.101837","article-title":"Thymus aging and immune reconstitution, progresses and challenges","volume":"70","author":"Li","year":"2023","journal-title":"Semin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1474-9726.2011.00773.x","article-title":"Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth","volume":"11","author":"Griffith","year":"2012","journal-title":"Aging Cell."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Taves, M.D., and Ashwell, J.D. (2022). Effects of sex steroids on thymic epithelium and thymocyte development. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.975858"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S0031-9384(01)00622-9","article-title":"Effect of 17beta-estradiol and voluntary exercise on lymphocyte apoptosis in mice","volume":"74","author":"Fietsch","year":"2001","journal-title":"Physiol. Behav."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ygcen.2005.04.016","article-title":"Mechanism of androgen-induced thymic atrophy in the wall lizard, Hemidactylus flaviviridis: An in vitro study","volume":"144","author":"Hareramadas","year":"2005","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/0024-3205(92)90204-3","article-title":"Adrenal glands of mouse and rat do not synthesize androgens","volume":"50","author":"Bierings","year":"1992","journal-title":"Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1677\/joe.0.1710373","article-title":"Immunoelectron microscopic localization of three key steroidogenic enzymes (cytochrome P450(scc), 3 beta-hydroxysteroid dehydrogenase and cytochrome P450(c17)) in rat adrenal cortex and gonads","volume":"171","author":"Pelletier","year":"2001","journal-title":"J. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Li, H., Liu, Y., Meng, F., Chen, J., and Han, X. (2024). Adrenarche-accompanied rise of adrenal sex steroid precursors prevents NAFLD in Young Female rats by converting into active androgens and inactivating hepatic Srebf1 signaling. BMC Genom., 25.","DOI":"10.1186\/s12864-024-10107-6"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1677\/joe.1.06972","article-title":"Adrenarche in the rat","volume":"191","author":"Pignatelli","year":"2006","journal-title":"J. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1136\/vr.c3303","article-title":"Thymus atrophy and regeneration following dexamethasone administration to beef cattle","volume":"167","author":"Cannizzo","year":"2010","journal-title":"Vet. Rec."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1172\/JCI63067","article-title":"Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness","volume":"122","author":"Mittelstadt","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1210\/en.2003-1660","article-title":"Glucocorticoids delay age-associated thymic involution through directly affecting the thymocytes","volume":"145","author":"Pazirandeh","year":"2004","journal-title":"Endocrinology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.coi.2010.06.010","article-title":"Thymic fatness and approaches to enhance thymopoietic fitness in aging","volume":"22","author":"Dixit","year":"2010","journal-title":"Curr. Opin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e2303774120","DOI":"10.1073\/pnas.2303774120","article-title":"Loss of PPAR\u03b3 activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity","volume":"120","author":"Caruso","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","first-page":"2023:4481354","article-title":"PPARG: A Promising Therapeutic Target in Breast Cancer and Regulation by Natural Drugs","volume":"8","author":"Li","year":"2023","journal-title":"PPAR Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1046\/j.1365-2567.1998.00595.x","article-title":"The Ii41 isoform of invariant chain mediates both positive and negative selection events in T-cell receptor transgenic mice","volume":"95","author":"Wright","year":"1998","journal-title":"Immunology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3749","DOI":"10.1038\/s41467-024-47981-3","article-title":"CD74 supports accumulation and function of regulatory T cells in tumors","volume":"15","author":"Bonnin","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e710","DOI":"10.1016\/S2665-9913(22)00198-9","article-title":"Investigating sex differences in T regulatory cells from cisgender and transgender healthy individuals and patients with autoimmune inflammatory disease: A cross-sectional study","volume":"4","author":"Robinson","year":"2022","journal-title":"Lancet Rheumatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/978-1-61779-415-5_34","article-title":"Ovariectomy\/orchidectomy in rodents","volume":"816","author":"Idris","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1210\/en.2014-1890","article-title":"Measurement of a Comprehensive Sex Steroid Profile in Rodent Serum by High-Sensitive Gas Chromatography-Tandem Mass Spectrometry","volume":"156","author":"Nilsson","year":"2015","journal-title":"Endocrinology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1021\/acs.chemrestox.4c00060","article-title":"Induction of Thymus Atrophy and Disruption of Thymocyte Development by Fipronil through Dysregulation of IL-7-Associated Genes","volume":"37","author":"Kuo","year":"2024","journal-title":"Chem. Res. Toxicol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/j.1439-0264.2006.00695.x","article-title":"Morphometrical characteristics of age-associated changes in the thymus of old male Wistar rats","volume":"35","year":"2006","journal-title":"Anat. Histol. Embryol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"101563","DOI":"10.1016\/j.isci.2020.101563","article-title":"Hypothalamic and Cell-Specific Transcriptomes Unravel a Dynamic Neuropil Remodeling in Leptin-Induced and Typical Pubertal Transition in Female Mice","volume":"23","author":"Han","year":"2020","journal-title":"iScience"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1172\/JCI90350","article-title":"Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4\/LTB4R1 signaling","volume":"127","author":"Ying","year":"2017","journal-title":"J. Clin. Investig."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/2\/1022\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T13:02:52Z","timestamp":1768914172000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/2\/1022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,20]]},"references-count":52,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27021022"],"URL":"https:\/\/doi.org\/10.3390\/ijms27021022","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,20]]}}}