Androgen deficiency affects approximately 9% of elderly males in the United States and the prevalence is projected to increase with the overall aging of the population. The diagnosis of androgen deficiency is made when clinical symptoms such as decreased libido, erectile dysfunction, fatigue and depression are found in conjunction with low levels of serum testosterone. Testosterone replacement therapy is a widespread and growing practice for treating androgen deficiency. Known or suspected risks of testosterone therapy include cardiovascular diseases and adverse prostate outcomes. The proposed study is a retrospective cohort analysis of testosterone users in a large integrated healthcare delivery system (health-plan) that has extensive electronic health record and clinical data so that complete utilization and exposure data can be captured. The specific aims are to: 1) to determine the risk of cardiovascular events associated with the use of testosterone replacement therapy, and 2) to test the hypothesis that the risk of benign and malignant prostate disease associated with the use of testosterone replacement therapy is greater than expected for men with similar underlying risk. The unique and comprehensive data resources available from the health-plan will allow linkage of all inpatient and outpatient care with prescriptions, laboratory testing results, procedures and diagnostic tests. The cohort will be created by inclusion of any man with a diagnosed indication (androgen deficiency) for exogenous testosterone therapy as well as those with low serum testosterone levels. Exposure to exogenously administered testosterone will be directly ascertained from electronic pharmacy data that exists within the health-plan. Comparisons will be made between androgen deficient males treated and not treated with exogenous testosterone. Standard survival analysis techniques will be used to examine testosterone replacement therapy in relation to each event of interest (cardiovascular diseases and prostate outcomes). Comorbidities that are potentially related to exogenous testosterone exposure, cardiovascular and prostate-related disease will be determined, categorized and controlled for in the multivariate analysis. In addition to conventional proportional hazards models a Propensity Score Analysis and/or an Instrumental Variable Analysis will be used to identify and control for unobserved confounding. These additional approaches will allow for a more robust and fuller understanding of the risks associated with testosterone replacement therapy. Completion of the aims will provided important information about the potential adverse effects of testosterone therapy in men, adding insight into the risk side of the risk-benefit evaluation to help guide current thinking about the appropriate use of thi therapy. PUBLIC HEALTH RELEVANCE: As outlined in RFA-AG-12-007 [Analysis of Databases from Health Care Systems or Large Epidemiologic Studies to Evaluate Safety of Testosterone Administration in Older Men (R01)] studies evaluating the safety of testosterone administration in aging males are urgently needed. There is a growing trend toward using testosterone replacement therapy in elderly males but recently concerns have been raised about the cardiovascular and prostate safety of this treatment. In an effort to provide insight into this question the proposed study will evaluate these two issues in an integrated healthcare delivery system where complete patient health care and exposure information is readily captured.