{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T16:49:30Z","timestamp":1773334170044,"version":"3.50.1"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100007128","name":"Natural Science Foundation of Shaanxi Province","doi-asserted-by":"publisher","award":["2025JC-YBMS-854"],"award-info":[{"award-number":["2025JC-YBMS-854"]}],"id":[{"id":"10.13039\/501100007128","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hypertensive disorders of pregnancy (HDP) substantially increase maternal and fetal morbidity and mortality. Although reduced circulating bioavailable testosterone (BT) has been observed in women with HDP, the causal relationship and underlying mechanisms remain unresolved. Based on previous clinical and experimental evidence, we hypothesized a potential causal relationship between BT levels and HDP, with subsequent analyses designed to explore the possible metabolic and anti-inflammatory pathways involved.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Summary statistics for BT and HDP were obtained from the Integrative Epidemiology Unit OpenGWAS database. A 2-sample Mendelian randomization (MR) framework was implemented to evaluate causality, complemented by extensive sensitivity analyses to strengthen robustness. To explore potential mechanisms, expression quantitative trait loci integration, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes enrichment, and protein-protein interaction (PPI) network analyses were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Mendelian randomization analyses provided evidence of a protective causal effect of BT on HDP (inverse variance weighted OR\u2009=\u20090.81; 95% confidential interval, 0.68-0.97; P\u2009=\u2009.023), with no indication of reverse causality. Sensitivity tests consistently confirmed the reliability of these findings. Genes associated with BT-related single nucleotide polymorphisms were enriched in metabolic and immune pathways, notably the NOD-like receptor and interleukin-17 (IL-17) pathways. Within the PPI network, nuclear factor kappa B inhibitor alpha (NFKBIA) emerged as a pivotal regulator of nuclear factor kappa B (NF-\u03baB) signaling, thereby supporting a role for testosterone-mediated modulation of inflammation in HDP protection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>From a genetic standpoint, BT appears to act as a protective factor against HDP, potentially safeguarding cardiovascular function through interconnected metabolic and anti-inflammatory mechanisms.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ajh\/hpaf208","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T12:21:45Z","timestamp":1760617305000},"page":"595-604","source":"Crossref","is-referenced-by-count":1,"title":["Bidirectional Mendelian Randomization Analysis Reveals Protective Effects of Bioavailable Testosterone Against Hypertensive Disorders of Pregnancy"],"prefix":"10.1093","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1374-0097","authenticated-orcid":false,"given":"Hua","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Second Affiliated Hospital of Xi\u2019an Jiaotong University , Xi\u2019an, Shaanxi,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Second Affiliated Hospital of Xi\u2019an Jiaotong University , Xi\u2019an, Shaanxi,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pan","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pathology, Second Affiliated Hospital of Xi\u2019an Jiaotong University , Xi\u2019an, Shaanxi,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Second Affiliated Hospital of Xi\u2019an Jiaotong University , Xi\u2019an, Shaanxi,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Second Affiliated Hospital of Xi\u2019an Jiaotong University , Xi\u2019an, Shaanxi,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Second Affiliated Hospital of Xi\u2019an Jiaotong University , Xi\u2019an, Shaanxi,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"2026031200563594000_hpaf208-B1","doi-asserted-by":"crossref","first-page":"2050312119843700","DOI":"10.1177\/2050312119843700","article-title":"Hypertension in pregnancy: pathophysiology and treatment","volume":"7","author":"Braunthal","year":"2019","journal-title":"SAGE Open Med."},{"key":"2026031200563594000_hpaf208-B2","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1161\/HYPERTENSIONAHA.114.04850","article-title":"Cardiovascular disease risk factors after early-onset preeclampsia, late-onset preeclampsia, and pregnancy-induced hypertension","volume":"65","author":"Veerbeek","year":"2015","journal-title":"Hypertension."},{"key":"2026031200563594000_hpaf208-B3","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1136\/bmj.39335.385301.BE","article-title":"Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis","volume":"335","author":"Bellamy","year":"2007","journal-title":"BMJ."},{"key":"2026031200563594000_hpaf208-B4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10654-013-9762-6","article-title":"Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis","volume":"28","author":"Brown","year":"2013","journal-title":"Eur J Epidemiol."},{"key":"2026031200563594000_hpaf208-B5","doi-asserted-by":"crossref","first-page":"834","DOI":"10.3109\/09513590.2012.683061","article-title":"A comparison of serum androgens in pre-eclamptic and normotensive pregnant women during the third trimester of pregnancy","volume":"28","author":"Sharifzadeh","year":"2012","journal-title":"Gynecol Endocrinol."},{"key":"2026031200563594000_hpaf208-B6","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/S1028-4559(09)60301-6","article-title":"Expression of androgen receptor in human placentas from normal and preeclamptic pregnancies","volume":"48","author":"Hsu","year":"2009","journal-title":"Taiwan J Obstet Gynecol."},{"key":"2026031200563594000_hpaf208-B7","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1080\/0144361031000074637","article-title":"The role of androgens in the aetiology and pathology of pre-eclampsia","volume":"23","author":"Fi\u00e7icio\u011flu","year":"2003","journal-title":"J Obstet Gynaecol."},{"key":"2026031200563594000_hpaf208-B8","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1210\/er.2017-00025","article-title":"A reappraisal of testosterone\u2019s binding in circulation: physiological and clinical implications","volume":"38","author":"Goldman","year":"2017","journal-title":"Endocr Rev."},{"key":"2026031200563594000_hpaf208-B9","first-page":"105","article-title":"Testosterone deficiency\u2014establishing a biochemical diagnosis","volume":"26","author":"Krakowsky","year":"2015","journal-title":"EJIFCC."},{"key":"2026031200563594000_hpaf208-B10","first-page":"344","article-title":"Evidence of high circulating testosterone in women with prior \u00adpreeclampsia","volume":"83","author":"Laivuori","year":"1998","journal-title":"J Clin Endocrinol Metab."},{"key":"2026031200563594000_hpaf208-B11","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ecl.2021.11.002","article-title":"Accurate measurement and harmonized reference ranges for total and free testosterone levels","volume":"51","author":"Jasuja","year":"2022","journal-title":"Endocrinol Metab Clin North Am."},{"key":"2026031200563594000_hpaf208-B12","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1373\/49.8.1381","article-title":"Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children","volume":"49","author":"Taieb","year":"2003","journal-title":"Clin Chem."},{"key":"2026031200563594000_hpaf208-B13","doi-asserted-by":"crossref","first-page":"105496","DOI":"10.1016\/j.jsbmb.2019.105496","article-title":"Vascular mechanisms of testosterone: the non-genomic point of view","volume":"196","author":"Lorigo","year":"2020","journal-title":"J Steroid Biochem Mol Biol."},{"key":"2026031200563594000_hpaf208-B14","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/0002-9378(75)90468-8","article-title":"On the regulation of fetal and maternal 16 alpha- hydroxydehydroepiandrosterone and its sulfate by cortisol and ACTH in human pregnancy at term","volume":"121","author":"Simmer","year":"1975","journal-title":"Am J Obstet Gynecol."},{"key":"2026031200563594000_hpaf208-B15","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1161\/HYPERTENSIONAHA.114.03283","article-title":"Elevated testosterone levels during rat pregnancy cause hypersensitivity to angiotensin II and attenuation of endothelium-dependent vasodilation in uterine arteries","volume":"64","author":"Chinnathambi","year":"2014","journal-title":"Hypertension."},{"key":"2026031200563594000_hpaf208-B16","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.jsxm.2018.04.641","article-title":"Testosterone and cardiovascular risk: meta-analysis of interventional studies","volume":"15","author":"Corona","year":"2018","journal-title":"J Sex Med."},{"key":"2026031200563594000_hpaf208-B17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1874192401610010001","article-title":"Testosterone and cardiovascular disease","volume":"10","author":"Tambo","year":"2016","journal-title":"Open Cardiovasc Med J."},{"key":"2026031200563594000_hpaf208-B18","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.1161\/CIRCULATIONAHA.107.719005","article-title":"Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) prospective population study","volume":"116","author":"Khaw","year":"2007","journal-title":"Circulation."},{"key":"2026031200563594000_hpaf208-B19","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1007\/s11255-021-02876-w","article-title":"Efficacy of testosterone replacement therapy for treating metabolic disturbances in late-onset hypogonadism: a systematic review and meta-analysis","volume":"53","author":"Kim","year":"2021","journal-title":"Int Urol Nephrol."},{"key":"2026031200563594000_hpaf208-B20","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1093\/ije\/dyq158","article-title":"Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies","volume":"40","author":"Brand","year":"2011","journal-title":"Int J Epidemiol."},{"key":"2026031200563594000_hpaf208-B21","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.bbrc.2012.06.151","article-title":"Src kinase-mediates androgen receptor-dependent non-genomic activation of signaling Cascade leading to endothelial nitric oxide synthase","volume":"424","author":"Yu","year":"2012","journal-title":"Biochem Biophys Res Commun."},{"key":"2026031200563594000_hpaf208-B22","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.it.2017.04.005","article-title":"Evolutionary convergence and divergence in NLR function and structure","volume":"38","author":"Meunier","year":"2017","journal-title":"Trends Immunol."},{"key":"2026031200563594000_hpaf208-B23","doi-asserted-by":"crossref","first-page":"104173","DOI":"10.1016\/j.jri.2023.104173","article-title":"NLRP3 inflammasome pathway, the hidden balance in pregnancy: a comprehensive review","volume":"161","author":"Balci","year":"2024","journal-title":"J Reprod Immunol."},{"key":"2026031200563594000_hpaf208-B24","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nri910","article-title":"NF-kappaB regulation in the immune system","volume":"2","author":"Li","year":"2002","journal-title":"Nat Rev Immunol."},{"key":"2026031200563594000_hpaf208-B25","doi-asserted-by":"crossref","first-page":"156058","DOI":"10.1016\/j.metabol.2024.156058","article-title":"1,25-Dihydroxyvitamin D(3) protects against placental inflammation by suppressing NLRP3-mediated IL-1\u03b2 production via Nrf2 signaling pathway in preeclampsia","volume":"162","author":"Liu","year":"2025","journal-title":"Metabolism."},{"key":"2026031200563594000_hpaf208-B26","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1158\/0008-5472.CAN-22-2405","article-title":"Androgen signaling contributes to sex differences in cancer by inhibiting NF-\u03baB activation in T cells and suppressing antitumor immunity","volume":"83","author":"Zhang","year":"2023","journal-title":"Cancer Res."},{"key":"2026031200563594000_hpaf208-B27","doi-asserted-by":"crossref","first-page":"26267","DOI":"10.1074\/jbc.271.42.26267","article-title":"Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter","volume":"271","author":"Keller","year":"1996","journal-title":"J Biol Chem."},{"key":"2026031200563594000_hpaf208-B28","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/S0006-291X(81)80034-4","article-title":"Enzymatic inactivation of SRS-Cys-Gly (leukotriene D)","volume":"101","author":"Sok","year":"1981","journal-title":"Biochem Biophys Res Commun."},{"key":"2026031200563594000_hpaf208-B29","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jsbmb.2017.11.001","article-title":"Antihypertensive responses of vasoactive androgens in an in vivo experimental model of preeclampsia","volume":"178","author":"Perusqu\u00eda","year":"2018","journal-title":"J Steroid Biochem Mol Biol."},{"key":"2026031200563594000_hpaf208-B30","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/aja.2008.12","article-title":"Testosterone alleviates tumor necrosis factor-alpha-mediated tissue factor pathway inhibitor downregulation via suppression of nuclear factor-kappa B in endothelial cells","volume":"11","author":"Jin","year":"2009","journal-title":"Asian J Androl."},{"key":"2026031200563594000_hpaf208-B31","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jri.2017.09.002","article-title":"Increased expression of NLRP3 inflammasome in placentas from pregnant women with severe preeclampsia","volume":"123","author":"Cw","year":"2017","journal-title":"J Reprod Immunol"}],"container-title":["American Journal of Hypertension"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajh\/advance-article-pdf\/doi\/10.1093\/ajh\/hpaf208\/64828966\/hpaf208.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajh\/article-pdf\/39\/4\/595\/64828966\/hpaf208.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajh\/article-pdf\/39\/4\/595\/64828966\/hpaf208.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T04:56:46Z","timestamp":1773291406000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajh\/article\/39\/4\/595\/8294114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,21]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,10,21]]},"published-print":{"date-parts":[[2026,4,1]]}},"URL":"https:\/\/doi.org\/10.1093\/ajh\/hpaf208","relation":{},"ISSN":["0895-7061","1941-7225"],"issn-type":[{"value":"0895-7061","type":"print"},{"value":"1941-7225","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,4]]},"published":{"date-parts":[[2025,10,21]]}}}