{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T12:15:55Z","timestamp":1784117755859,"version":"3.55.0"},"reference-count":54,"publisher":"The Endocrine Society","issue":"3","funder":[{"DOI":"10.13039\/100017540","name":"Division of Intramural Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017540","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000092","name":"National Library of Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000092","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Concerns about potential prostate-related complications associated with testosterone replacement therapy (TRT) often lead hypogonadal men to remain untreated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This large-scale retrospective cohort study aimed to address these concerns by analyzing Medicare enrollment and claims data (Parts A\/B\/C\/D) from 2007 to 2020 for men aged \u226565 with diagnosed primary or secondary hypogonadism. Cox regression analysis and 1:1 propensity score matching, both stratified by age group, were employed to evaluate the association between prostate outcomes and TRT use. TRT use was further categorized by treatment duration, administration route, and aromatase inhibitor (AI) coadministration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Following propensity score matching, the prostate cancer (PCa) and benign prostatic hyperplasia (BPH) risk analyses included 546 964 and 412 782 hypogonadal men, respectively, with comparable baseline characteristics at the time of hypogonadism diagnosis. TRT use was linked to a significant 16% reduction in the hazard of PCa (HR = 0.84; 95% CI: 0.82-0.86), including reductions observed across long-term (15%), short-term (16%), parenteral (12%), and topical (13%) use. Sensitivity analyses excluding individuals with elevated prostate-specific antigen and family history of PCa similarly demonstrated a 18% reduction in the hazard of PCa among TRT users. Conversely, TRT use exhibited a 13% increase in the hazard of BPH (HR = 1.13; 95% CI: 1.11-1.14), with a larger increase for parenteral (19%) vs topical TRT (12%). Notably, long-term topical use was linked to a modest 9% increase.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TRT use was associated with reduction in PCa hazard and modest increase in BPH hazard. These associations varied by treatment duration, route, and AI coadministration. These findings may inform clinical decision-making regarding TRT use in hypogonadal men and support a more individualized approach to care.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgaf504","type":"journal-article","created":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T11:44:46Z","timestamp":1757159086000},"page":"e794-e810","source":"Crossref","is-referenced-by-count":1,"title":["Association Between Testosterone Replacement Therapy and Prostatic Disorders in Elderly Hypogonadal Men"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2077-4316","authenticated-orcid":false,"given":"Seo Hyon","family":"Baik","sequence":"first","affiliation":[{"name":"Division of Intramural Research, National Library of Medicine, National Institutes of Health , Bethesda, MD 20894 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fitsum","family":"Baye","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Library of Medicine, National Institutes of Health , Bethesda, MD 20894 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kin Wah","family":"Fung","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Library of Medicine, National Institutes of Health , Bethesda, MD 20894 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Xian","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Library of Medicine, National Institutes of Health , Bethesda, MD 20894 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clement J","family":"McDonald","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Library of Medicine, National Institutes of Health , Bethesda, MD 20894 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"issue":"1","key":"2026021918515261600_dgaf504-B1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1093\/emph\/eoac044","article-title":"Lower testosterone levels are associated with higher risk of death in men","volume":"11","author":"Muehlenbein","year":"2023","journal-title":"Evol Med Public Health"},{"issue":"11","key":"2026021918515261600_dgaf504-B2","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1007\/BF03350341","article-title":"Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome","volume":"33","author":"Aversa","year":"2010","journal-title":"J Endocrinol Invest"},{"issue":"11","key":"2026021918515261600_dgaf504-B3","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1056\/NEJMoa1206168","article-title":"Gonadal steroids and body composition, strength, and sexual function in men","volume":"369","author":"Finkelstein","year":"2013","journal-title":"N Engl J Med"},{"issue":"5","key":"2026021918515261600_dgaf504-B4","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1210\/jc.2018-00229","article-title":"Testosterone therapy in men with hypogonadism: an endocrine society* clinical practice guideline","volume":"103","author":"Bhasin","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2026021918515261600_dgaf504-B5","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.juro.2015.10.083","article-title":"Effect of testosterone solution 2% on testosterone concentration, sex drive and energy in hypogonadal men: results of a placebo controlled study","volume":"195","author":"Brock","year":"2016","journal-title":"J Urol"},{"issue":"3","key":"2026021918515261600_dgaf504-B6","doi-asserted-by":"crossref","first-page":"e1096","DOI":"10.1210\/clinem\/dgaa917","article-title":"Testosterone replacement therapy added to intensive lifestyle intervention in older men with obesity and hypogonadism","volume":"106","author":"Barnouin","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2026021918515261600_dgaf504-B7","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1056\/NEJMoa1000485","article-title":"Adverse events associated with testosterone administration","volume":"363","author":"Basaria","year":"2010","journal-title":"N Engl J Med"},{"issue":"4","key":"2026021918515261600_dgaf504-B8","doi-asserted-by":"crossref","first-page":"198","DOI":"10.3109\/13685538.2012.699562","article-title":"A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 mo","volume":"15","author":"Behre","year":"2012","journal-title":"Aging Male"},{"issue":"40","key":"2026021918515261600_dgaf504-B9","doi-asserted-by":"crossref","first-page":"2706","DOI":"10.1093\/eurheartj\/ehv346","article-title":"Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men","volume":"36","author":"Sharma","year":"2015","journal-title":"Eur Heart J"},{"issue":"6","key":"2026021918515261600_dgaf504-B10","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1001\/jama.2014.17334","article-title":"Testosterone replacement therapy faces FDA scrutiny","volume":"313","author":"Garnick","year":"2015","journal-title":"JAMA"},{"key":"2026021918515261600_dgaf504-B11","author":"U.S. Food & Drug Administration","year":"2015"},{"issue":"4","key":"2026021918515261600_dgaf504-B12","first-page":"293","article-title":"Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate*","volume":"1","author":"Huggins","year":"1941","journal-title":"Cancer Res"},{"key":"2026021918515261600_dgaf504-B13","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.15585\/mmwr.mm6941a1","article-title":"Prostate cancer incidence and survival, by stage and race\/ethnicity\u2014United States, 2001\u20132017","author":"Siegel","year":"2020","journal-title":"Morb Mortal Wkly Rep"},{"issue":"6","key":"2026021918515261600_dgaf504-B14","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1210\/er.2004-0013","article-title":"The decline of androgen levels in elderly men and its clinical and therapeutic implications","volume":"26","author":"Kaufman","year":"2005","journal-title":"Endocr Rev"},{"key":"2026021918515261600_dgaf504-B15","author":"Centers for Medicare & Medicaid Services (CMS)","year":"2013"},{"key":"2026021918515261600_dgaf504-B16","doi-asserted-by":"crossref","first-page":"012087","DOI":"10.1088\/1742-6596\/979\/1\/012087","article-title":"The application of extended cox proportional hazard method for estimating survival time of breast cancer","volume":"979","author":"Husain","year":"2018","journal-title":"J Phys Conf Ser"},{"issue":"11","key":"2026021918515261600_dgaf504-B17","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1097\/CCM.0b013e3181b7fbbb","article-title":"Immortal time bias in critical care research: application of time-varying cox regression for observational cohort studies*","volume":"37","author":"Shintani","year":"2009","journal-title":"Crit Care Med"},{"key":"2026021918515261600_dgaf504-B18","author":"WHO Collaborating Center for Drug Statistics Methodology","year":"2023"},{"issue":"12","key":"2026021918515261600_dgaf504-B19","doi-asserted-by":"crossref","first-page":"4785","DOI":"10.1210\/jc.2009-0739","article-title":"Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels","volume":"94","author":"Burnett-Bowie","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"2026021918515261600_dgaf504-B20","author":"The Chronic Conditions Data Warehouse","year":"2024"},{"issue":"1","key":"2026021918515261600_dgaf504-B21","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/biomet\/70.1.41","article-title":"The central role of the propensity score in observational studies for causal effects","volume":"70","author":"Rosenbaum","year":"1983","journal-title":"Biometrika"},{"issue":"3","key":"2026021918515261600_dgaf504-B22","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1080\/00273171.2011.568786","article-title":"An introduction to propensity score methods for reducing the effects of confounding in observational studies","volume":"46","author":"Austin","year":"2011","journal-title":"Multivariate Behav Res"},{"issue":"3-4","key":"2026021918515261600_dgaf504-B23","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1023\/A:1020363010465","article-title":"Using propensity scores to help design observational studies: application to the tobacco litigation","volume":"2","author":"Rubin","year":"2001","journal-title":"Health Serv Outcomes Res Methodol"},{"issue":"1","key":"2026021918515261600_dgaf504-B24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1214\/09-STS313","article-title":"Matching methods for causal inference: a review and a look forward","volume":"25","author":"Stuart","year":"2010","journal-title":"Stat Sci"},{"issue":"7497","key":"2026021918515261600_dgaf504-B25","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1136\/bmj.330.7497.960","article-title":"Reader's guide to critical appraisal of cohort studies: 2. Assessing potential for confounding","volume":"330","author":"Mamdani","year":"2005","journal-title":"BMJ"},{"issue":"4","key":"2026021918515261600_dgaf504-B26","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0895-4356(00)00321-8","article-title":"Validating recommendations for coronary angiography following acute myocardial infarction in the elderly: a matched analysis using propensity scores","volume":"54","author":"Normand","year":"2001","journal-title":"J Clin Epidemiol"},{"issue":"25","key":"2026021918515261600_dgaf504-B27","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1002\/sim.3697","article-title":"Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples","volume":"28","author":"Austin","year":"2009","journal-title":"Stat Med"},{"issue":"7","key":"2026021918515261600_dgaf504-B28","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1093\/aje\/kwq439","article-title":"Doubly robust estimation of causal effects","volume":"173","author":"Funk","year":"2011","journal-title":"Am J Epidemiol"},{"issue":"10","key":"2026021918515261600_dgaf504-B29","doi-asserted-by":"crossref","first-page":"e2340030","DOI":"10.1001\/jamanetworkopen.2023.40030","article-title":"Efficacy of testosterone replacement therapy in correcting anemia in men with hypogonadism","volume":"6","author":"Pencina","year":"2023","journal-title":"JAMA Netw Open"},{"issue":"3","key":"2026021918515261600_dgaf504-B30","doi-asserted-by":"crossref","first-page":"194","DOI":"10.5534\/wjmh.2016.34.3.194","article-title":"Effect of testosterone replacement therapy on cognitive performance and depression in men with testosterone deficiency syndrome","volume":"34","author":"Jung","year":"2016","journal-title":"World J Men's Health"},{"key":"2026021918515261600_dgaf504-B31","first-page":"1","article-title":"Metabolic effects of testosterone replacement therapy in patients with type 2 diabetes mellitus or metabolic syndrome: a meta-analysis","volume":"2020","author":"Li","year":"2020","journal-title":"Int J Endocrinol"},{"issue":"3","key":"2026021918515261600_dgaf504-B32","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1111\/ijcp.12319","article-title":"Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study","volume":"68","author":"Traish","year":"2014","journal-title":"Int J Clin Pract"},{"issue":"6","key":"2026021918515261600_dgaf504-B33","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1210\/jc.2009-2354","article-title":"Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline","volume":"95","author":"Bhasin","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2026021918515261600_dgaf504-B34","author":"National Institute of Diabetes and Digestive and Kidney Diseases","year":"2024"},{"key":"2026021918515261600_dgaf504-B35","author":"Centers for Disease Control and Prevention"},{"issue":"2","key":"2026021918515261600_dgaf504-B36","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/luts.12150","article-title":"Serum testosterone levels are negatively correlated with international prostate symptom score and transitional prostate volume","volume":"10","author":"Shim","year":"2018","journal-title":"Low Urin Tract Symptoms"},{"issue":"5","key":"2026021918515261600_dgaf504-B37","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1177\/1557988316652843","article-title":"Improved lower urinary tract symptoms associated with testosterone replacement therapy in Japanese men with late-onset hypogonadism","volume":"12","author":"Okada","year":"2018","journal-title":"AM J Mens Health"},{"issue":"1","key":"2026021918515261600_dgaf504-B38","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1158\/1055-9965.EPI-19-0619","article-title":"Testosterone therapy in relation to prostate cancer in a U.S. commercial insurance claims database","volume":"29","author":"Cook","year":"2020","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"1","key":"2026021918515261600_dgaf504-B39","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.juro.2014.06.071","article-title":"Incidence of prostate cancer in hypogonadal men receiving testosterone therapy: observations from 5-year median followup of 3 registries","volume":"193","author":"Haider","year":"2015","journal-title":"J Urol"},{"issue":"1","key":"2026021918515261600_dgaf504-B40","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1080\/13685538.2019.1575354","article-title":"Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality","volume":"23","author":"Saad","year":"2020","journal-title":"Aging Male"},{"issue":"6","key":"2026021918515261600_dgaf504-B41","doi-asserted-by":"crossref","first-page":"878","DOI":"10.4103\/1008-682X.150841","article-title":"Testosterone replacement therapy and the risk of prostate cancer","volume":"17","author":"Warburton","year":"2015","journal-title":"Asian J Androl"},{"issue":"4","key":"2026021918515261600_dgaf504-B42","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1016\/j.juro.2010.11.084","article-title":"Testosterone therapy in men with untreated prostate cancer","volume":"185","author":"Morgentaler","year":"2011","journal-title":"J Urol"},{"issue":"2","key":"2026021918515261600_dgaf504-B43","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.eururo.2008.09.024","article-title":"Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth","volume":"55","author":"Morgentaler","year":"2009","journal-title":"Eur Urol"},{"issue":"1","key":"2026021918515261600_dgaf504-B44","doi-asserted-by":"crossref","first-page":"44","DOI":"10.14218\/ERHM.2022.00120","article-title":"The origin of BPH and prostate cancer in different prostate zones and the impact on the incidence of prostate cancer: a systematic review and update of the literature for urologists and clinicians","volume":"9","author":"Sellers","year":"2024","journal-title":"Explor Res Hypothesis Med"},{"issue":"11","key":"2026021918515261600_dgaf504-B45","doi-asserted-by":"crossref","first-page":"3793","DOI":"10.1210\/jcem.82.11.4387","article-title":"Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis","volume":"82","author":"Hajjar","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2026021918515261600_dgaf504-B46","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/S2213-8587(16)00112-1","article-title":"Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study","volume":"4","author":"Wallis","year":"2016","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"7","key":"2026021918515261600_dgaf504-B47","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1001\/jamainternmed.2015.1573","article-title":"Comparative safety of testosterone dosage forms","volume":"175","author":"Layton","year":"2015","journal-title":"JAMA Intern Med"},{"issue":"1","key":"2026021918515261600_dgaf504-B48","doi-asserted-by":"crossref","first-page":"83","DOI":"10.5534\/wjmh.190166","article-title":"A national analysis of temporal changes in prescribing of testosterone replacement therapy considering methods of delivery and government regulation","volume":"39","author":"Morton","year":"2021","journal-title":"World J Men's Health"},{"issue":"1","key":"2026021918515261600_dgaf504-B49","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/1477-7827-9-93","article-title":"Aromatase inhibitors in men: effects and therapeutic options","volume":"9","author":"de Ronde","year":"2011","journal-title":"Reprod Biol Endocrinol"},{"key":"2026021918515261600_dgaf504-B50","volume-title":"StatPearls [Internet]","author":"Peters","year":"2023"},{"issue":"4S","key":"2026021918515261600_dgaf504-B51","doi-asserted-by":"crossref","first-page":"e226","DOI":"10.1016\/j.juro.2016.02.2812","article-title":"PD07-09 effect of anastrozole on prostate specific antigen values in hypogonadal, subfertile men","volume":"195","author":"Digiorgio","year":"2016","journal-title":"J Urol"},{"issue":"9","key":"2026021918515261600_dgaf504-B52","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1002\/cncr.10844","article-title":"Selective aromatase inhibition for patients with androgen-independent prostate carcinoma","volume":"95","author":"Smith","year":"2002","journal-title":"Cancer"},{"issue":"8","key":"2026021918515261600_dgaf504-B53","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1002\/1097-0142(20011015)92:8<2095::AID-CNCR1550>3.0.CO;2-Y","article-title":"Use of the aromatase inhibitor anastrozole in the treatment of patients with advanced prostate carcinoma","volume":"92","author":"Santen","year":"2001","journal-title":"Cancer"},{"issue":"3","key":"2026021918515261600_dgaf504-B54","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.eururo.2011.11.013","article-title":"The correlation between metabolic syndrome and prostatic diseases","volume":"61","author":"De Nunzio","year":"2012","journal-title":"Eur Urol"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgaf504\/64225581\/dgaf504.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/111\/3\/e794\/64225581\/dgaf504.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/111\/3\/e794\/64225581\/dgaf504.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T23:52:09Z","timestamp":1771545129000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/111\/3\/e794\/8249697"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,9]]},"references-count":54,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,9,9]]},"published-print":{"date-parts":[[2026,2,20]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgaf504","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,3]]},"published":{"date-parts":[[2025,9,9]]}}}