Increased use of testosterone supplementation among older men in recent years has caused concern about the safety of exogenous testosterone administration. New formulations and delivery mechanisms, increased direct-to-consumer marketing, and wider recognition of natural declines in testosterone levels in older age and chronic disease have all contributed to wider use of testosterone therapy, without strong evidence of benefit or assurance of safety in older men who are already at risk for morbidity and mortality. Recent randomized trials have suggested an increased risk of cardiovascular events, but the body of literature is still without conclusive evidence. Additional analyses of large populations are needed to better describe how testosterone therapy is used in real-world practice and assess the possibility that use of testosterone may increase risk of serious adverse events. We propose a large retrospective cohort study using healthcare and laboratory testing data from a large population of older men in the United States with Medicare or commercial insurance. We will also create a second cohort using clinical data from the United Kingdom's General Practice Research Database. We will study patterns of initiation relative to testosterone testing, and how prescribing has changed over time. We will use propensity score techniques to compare rates of cardiovascular events in testosterone users to those of non-users with comparable testosterone levels. We will examine the risk of bone fractures and prostate cancer as secondary outcomes. These effects will also be investigated in vulnerable subgroups (e.g. older age, chronic disease, varying levels of testosterone deficiency). We will study transient risk of acute events using a self-controlled case-crossover analysis. And finally, different testosterone delivery mechanisms (e.g. patch, gel, injections) will be compared to determine if there are differential risks among the different formulations. The results of this stuy will contribute important evidence to the growing, but yet inconclusive, body of literature surrounding the safety of exogenous testosterone use among older men.

Public Health Relevance

Testosterone supplementation is increasingly used in older men, although the benefits and safety have not been well-established. This study will use insurance billing information and laboratory test results from the United States and medical records from the United Kingdom to determine if taking testosterone supplementation increases older men's risk of serious events such as heart attack, stroke, other cardiovascular diseases, bone fractures, and prostate cancer. This study will use modern statistical methods and novel study designs to provide accurate measures of the risk of these events in men supplementing testosterone.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8 (M1))
Program Officer
Joseph, Lyndon
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Public Health & Prev Medicine
Schools of Public Health
Chapel Hill
United States
Zip Code
Akizawa, Tadao; Kurita, Noriaki; Mizobuchi, Masahide et al. (2016) PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism. Sci Rep 6:19612
Gokhale, Mugdha; Buse, John B; Pate, Virginia et al. (2016) More realistic power estimation for new user, active comparator studies: an empirical example. Pharmacoepidemiol Drug Saf 25:462-6
Jirón, Marcela; Pate, Virginia; Hanson, Laura C et al. (2016) Trends in Prevalence and Determinants of Potentially Inappropriate Prescribing in the United States: 2007 to 2012. J Am Geriatr Soc 64:788-97
Brookhart, M Alan; Freburger, Janet K; Ellis, Alan R et al. (2016) Comparative Short-term Safety of Sodium Ferric Gluconate Versus Iron Sucrose in Hemodialysis Patients. Am J Kidney Dis 67:119-27
Jensen, Elizabeth T; Cook, Suzanne F; Allen, Jeffery K et al. (2015) Enrollment factors and bias of disease prevalence estimates in administrative claims data. Ann Epidemiol 25:519-525.e2
McGrath, Leah J; Ellis, Alan R; Brookhart, M Alan (2015) Controlling Time-Dependent Confounding by Health Status and Frailty: Restriction Versus Statistical Adjustment. Am J Epidemiol 182:17-25
Cai, Mona; Kappelman, Michael D; Girman, Cynthia J et al. (2015) Trends and Determinants of Oral Anti-Diabetic Initiation in Youth with Suspected Type 2 Diabetes. PLoS One 10:e0140611
Butler, Anne M; Kshirsagar, Abhijit V; Olshan, Andrew F et al. (2015) Trends in Anemia Management in Hemodialysis Patients with Cancer. Am J Nephrol 42:206-15
Layton, J Bradley; Meier, Christoph R; Sharpless, Julie L et al. (2015) Comparative Safety of Testosterone Dosage Forms. JAMA Intern Med 175:1187-96
Lauffenburger, Julie C; Farley, Joel F; Gehi, Anil K et al. (2015) Effectiveness and safety of dabigatran and warfarin in real-world US patients with non-valvular atrial fibrillation: a retrospective cohort study. J Am Heart Assoc 4:

Showing the most recent 10 out of 28 publications