DO THE BENEFITS OF TESTOSTERONE REPLACEMENT THERAPY OUTWEIGH THE HARMS? A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS

Purpose: Testosterone replacement products are generally touted as a way to restore youth and vitality, improve sexual health, and elevate mood and quality of life. However, regulators in Canada and the US have warned of an increased risk of adverse cardiovascular events associated with testosterone use, and patients and providers must decide whether the potential benefits outweigh the harms. This decision is complicated by contradictory findings of placebo-controlled meta-analyses. The choice between products is further complicated because most products have not been compared in head-to-head trials, and their relative benefits and harms are unknown. In this study, we asked “What are the relative benefits and harms of individual testosterone products in hypogonadal men?” 

Method: We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature for randomized controlled trials (RCTs) and non-randomized studies (NRS) of at least 3 months’ duration that involved adult hypogonadal men. Outcomes included benefits (quality of life, depression, libido, erectile function, activities of daily living) and harms (cardiovascular death, myocardial infarction, stroke, prostate cancer, serious adverse events, withdrawals due to adverse events, erythrocytosis, heart disease, diabetes). Risk of bias was assessed using Cochrane’s risk of bias tool (RCTs) and SIGN50 (NRS). We pooled the results of RCTs using Bayesian network meta-analyses and pair-wise meta-analyses. 

Result: We identified 73 RCTs and 41 NRS. Most were at high or unclear risk of bias. Testosterone levels were increased by most products to the normal range (20/25 products); however, few improved quality of life (1/14) or depression (3/11) relative to placebo, and there were few differences between products. No product improved libido or erectile function. No studies addressed activities of daily living. There was no increased risk of any harm, including cardiovascular-related adverse events, with the exception of withdrawals due to adverse events.

Conclusion: Although most testosterone replacement products increase testosterone levels into the normal range, major benefits are not being observed for the outcomes studied. Although we found no increased risk of major harms, we cannot rule out this possibility because of the low quality of the evidence, the rare nature of such events, and short treatment duration. Patients and providers should carefully weigh the evidence when choosing whether testosterone replacement therapy is right for them. Registration: PROSPERO (CRD42014009963)