Low Testosterone and Risk of Premature Death in Older Men: Analytical and Preanalytical Issues in Measuring Circulating Testosterone

Abstract

Two recent papers in Circulation (1) and Journal of Clinical Endocrinology and Metabolism (2) reported that older men with lower serum testosterone concentrations had a greater risk of dying than did men with higher testosterone. This potentially clinically important finding was not observed in 2 other prospective cohort studies (3)(4), and another cohort study reported that low concentrations of a combination of hormones, but not of bioavailable testosterone alone, were associated with death (5). These studies raise important issues related to measuring testosterone for etiologic and clinical use. An important question in clinical epidemiology is whether low testosterone concentrations are causally associated with premature death in older men. At least 3 scenarios (Fig. 1 ) may underlie the observation that older men with low testosterone are more likely to die (1)(2). Scenario 1: Disease states cause low testosterone, which in turn causes premature death, although disease states also may cause death via other mechanisms. In this scenario, either preventing disease states or intervening to increase low testosterone secondary to disease states could, in theory, reduce risk of death. Scenario 2: Disease states cause both premature death and low testosterone. If low testosterone does not cause death, it will nevertheless appear to be a risk factor for death if disease states are not taken into account. In this scenario, only intervention on disease states, their risk factors, a…