Caveat emptor: does testosterone treatment reduce mortality in men?

Much interest and controversy surround the clinical implications of the age-related decline in circulating testosterone (T) in aging men (1) and the decision to treat symptomatic men with androgen replacement (2, 3). There is a seductive simplicity to the conceptualization of low T in the elderly man as a straightforward problem of an age-related deficiency state—boosting the hormone level with treatment will remedy multiple problems of senescence whether they are sexual dysfunction, mobility limitation, diabetes, or cardiovascular disease. But the apparent relationships between T and various physiological deficits and adverse clinical outcomes are likely to be the result of complex interactions (bidirectional, nonlinear, and multilevel) between many coexisting factors, some of which are known but others not. Low T may also be considered as a normal (adaptive) response to an abnormal environment (e.g. starvation, obesity) or pathological conditions (e.g. diabetes, cardiovascular diseases, organ failure, or cancer) common in the elderly (4, 5). If this is the case, T treatment is not only unphysiological and inappropriate but may also potentially cause adverse effects (6). Further debate has been fueled by several epidemiological studies, some but not others reporting an inconsistent association between low endogenous T and increased allcause and cardiovascular mortality (7–10). This raises the stakes regarding the importance of T beyond symptomatic and quality of life improvements to broader issues of general health and longevity, positing important questions such as: is T a risk marker for poor health and mortality; does T treatment reduce mortality in men; and what might be the mechanisms that link variations in T with risks/ causes of death? Invoking the cardiometabolic risks that commonly coexist with low T does not provide definitive answers (11, 12), especially to all-cause mortality. Randomized controlled trials of T treatment to prolong life or reduce cardiovascular events are highly challenging and costly and thus unlikely to be supported. Against this background, the question addressed in the study by Shores et al. (13) in this issue of the JCEM, the first to specifically investigate the relationships between T treatment and mortality in middle-aged and elderly men with low T, is therefore highly topical and timely, given that the longterm risk-benefit ratio of T treatment in older men is presently unknown. But the publication of this work should come with a prominent “health warning. ” Using the database from seven U.S. Veterans Administration (VA) medical centers, the authors performed a retrospective observational study comparing all-cause mortality in T-treated (n 398) vs. untreated (n 633) hypogonadal men [mean age, 62.1 yr; with an average 6.7 comorbid conditions and T 250 ng/dl (8.7 nmol/liter)] followed for 40.5 months. Shores et al. (13) report a significantly lower mortality rate of 10.3% in the treated men compared with 20.7% in the untreated men, with a hazard ratio of 0.61 (95% confidence interval, 0.42–0.88; P 0.008). It is important to highlight the limitations of this study to amplify the concerns expressed in the paper. (The discussion on the study limitations is more than twice as long as the discussion on the actual results of the study.)