Testosterone Replacement Therapy and the Risk of Prostate Cancer in men With Late-Onset Hypogonadism

Christina Santella; Christel Renoux; Hui Yin; Oriana H. Y. Yu; Laurent Azoulay


Am J Epidemiol. 2019;188(9):1666-1673. 

In This Article

Abstract and Introduction


The association between the use of testosterone replacement therapy (TRT) and prostate cancer remains uncertain. Thus, we investigated whether TRT is associated with an increased risk of prostate cancer in men with late-onset hypogonadism. We used the UK Clinical Practice Research Datalink to assemble a cohort of 12,779 men who were newly diagnosed with hypogonadism between January 1, 1995, and August 31, 2016, with follow-up until August 31, 2017. Exposure to TRT was treated as a time-varying variable and lagged by 1 year to account for cancer latency, with nonuse as the reference category. During 58,224 person-years of follow-up, a total of 215 patients were newly diagnosed with prostate cancer, generating an incidence rate of 3.7 per 1,000 person-years. In time-dependent Cox proportional hazards models, use of TRT was not associated with an overall increased risk of prostate cancer (hazard ratio = 0.97; 95% confidence interval: 0.71, 1.32) compared with nonuse. Results remained consistent in secondary and sensitivity analyses, as well as in a propensity score–matched cohort analysis that further assessed the impact of residual confounding. Overall, the use of TRT was not associated with an increased risk of prostate cancer in men with late-onset hypogonadism.


Testosterone replacement therapy (TRT) is indicated for men with pathologic testosterone deficiency, namely hypogonadism.[1,2] While this treatment has been approved and shown to be effective in men with pathologic hypogonadism, the benefit of replacing testosterone in aging men with late-onset hypogonadism is less certain.[2–4] Nonetheless, TRT is increasingly being prescribed off-label in this population,[2,5] despite concerns about its cardiovascular safety and its potential to increase the risk of prostate cancer.[1,4,6]

Current treatment guidelines recommend against the initiation of TRT in patients with a history of or known risk factors for prostate cancer.[1,7] This recommendation is based on the well-established role of androgens on the incidence of prostate cancer.[8–10] However, to date, the evidence supporting an association between TRT and prostate cancer incidence is inconclusive. Indeed, meta-analyses of randomized clinical trials designed to assess the efficacy of TRT have reported null associations with respect to prostate cancer.[11,12] It is important to note that trials included in these meta-analyses were neither designed nor powered to assess prostate cancer as a safety outcome.[11,12] Similarly, the few observational studies that have been conducted have also reported null associations,[13–20] but these had several methodological limitations, including short durations of follow-up, potential confounding by indication, immortal time bias, and potential detection bias.[13–20]

Given the increasing use of TRT in aging men and the limitations of the available evidence, additional studies are needed to assess the long-term safety of this therapy. The objective of this population-based study was to determine whether the use of TRT is associated with an increased risk of prostate cancer in men with late-onset hypogonadism.