How Dangerous is Testosterone Supplementation?

Recently, significant media attention has been focused on testosterone supplementation therapy (TST) and increased cardiovascular (CV) risk. Treatment for testosterone deficiency syndrome (TDS) has been on the rise in the past several years. US Food & Drug Administration (FDA) drug utilization data showed sales increased 65% between 2009 and 2013 (1). The true prevalence of TDS varies based on the source, definition of the condition and age of population studied, however, it is believed to range from 2-39% (2, 3). Patients suffering from TDS are at an irrefutably increased risk for bone density loss, development of type 2 diabetes (T2DM), anemia, sarcopenia, cognitive deficits, and premature death (4). Shores et al, have shown increased mortality rates in men with low testosterone (mortality rates with normal, equivocal, and low testosterone levels were 20%, 25%, 35% respectively) (5). Patients should be made aware of possible adverse events associated with TST in particular as polycythemia and hyperestrogenism (6). Polycythemia is believed to be a dose-dependent effect and hematocrit levels should be maintained below 54% to prevent hyperviscosity-related events. Hyperestrogenism is a response of testosterone conversion to estrogen via aromatase in adipose tissue and may be associated with gynecomastia. Two recent meta-analyses have shown that prostate related events (rates of prostate cancer, PSA >4 ng/mL, prostate biopsies) were not statistically significantly higher in the testosterone supplementation group compared to the placebo group (6, 7). Also these meta-analyses demonstrated no significant elevation in CV risk. In a meta-analysis by Aruajo et al., the authors reported that testosterone levels ≥2.18 standard deviations below normal range were associated with 35% and 25% elevated risk in all-cause mortality and CV disease mortality, respectively (8). However, the authors note that their analysis showed considerable between-study heterogeneity limiting the clinical extrapolation of the data. Some of the difficulty addressing research in TST relates to the methodological challenges related to studying patients with TDS, including: population heterogeneity, circadian rhythm of testosterone secretion, use of total vs. free testosterone, number of pre-treatment testosterone levels, covariate analysis, duration and follow-up of TST. There is often significant heterogeneity in the populations being studied therefore limiting the validity of comparative analyses. Ideally, populations should be matched in patient demographics, and baseline TDS parameters (symptoms and severity). Trial design should account for testosterone level variance based on circadian rhythm and consistently use total (by LCMS analysis) or free testosterone (by equilibrium dialysis) level measurement. Also, important for trial design are standardized minimum number of pre-treatment testosterone levels, standardized duration of treatment and follow-up How Dangerous is Testosterone Supplementation? Volume 41 | number 2 | March . April, 2015 | INT BRAZ J UROL