Testosterone and All-cause Mortality in Older Men

The Role of Metabolic Syndrome

Nasser Laouali; Sylvie Brailly-Tabard; Catherine Helmer; Marie-Laure Ancelin; Christophe Tzourio; Archana Singh-Manoux; Aline Dugravot; Alexis Elbaz; Anne Guiochon-Mantel; Marianne Canonico


J Endo Soc. 2018;2(4):322-335. 

In This Article

Abstract and Introduction


Previous studies have shown controversial results about the role of testosterone in all-cause mortality in elderly men. We hypothesized that metabolic syndrome (MetS) could partly explain this discrepancy. We therefore examined the association of all-cause mortality with total and bioavailable testosterone, taking into account the MetS. We used data from the Three-City Cohort (3C) study with 12-year follow-up. The 3C study included 3650 men aged >65 years in three French cities. Hormone was measured in a random subsample of 444 men, and MetS was determined as stated by the International Diabetes Federation criteria. We used inverse-probability–weighted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). Of 444 men included in the analysis, 106 (23.9%) had MetS at baseline, and 166 died over the follow-up. There was a significant interaction between testosterone level and MetS for all-cause mortality (P = 0.002 and P = 0.008 for total and bioavailable testosterone, respectively). Among men with MetS, a decrease in one standard deviation of testosterone was associated with higher mortality risk [HR 1.78 (95% CI 1.13 to 2.78) and HR 1.83 (95% CI 1.17 to 2.86) for total and bioavailable testosterone, respectively]. By contrast, there was no association of testosterone with mortality risk among men without MetS. Our results suggest that MetS modifies the association between testosterone and mortality in older men. If confirmed, these findings could contribute to improve risk stratification and better manage the health of older men.


Testosterone is the principal male sex hormone, mainly secreted by the testes and, to a lesser extent, by adrenal glands.[1] Total testosterone consists of sex hormone-binding globulin– and cortisol-binding globulin–bound steroid, and a bioavailable component that includes free testosterone and an albumin-bound fraction. The bioavailable form of testosterone represents 30% to 50% of total testosterone and is primarily responsible for its biological effects.

Testosterone is an important anabolic hormone that controls the expression and maintenance of male sexual characteristics and promotes muscle mass, strength, and bone density.[2] Testosterone levels decline gradually with age, and low levels have been associated with sexual dysfunction. Low levels of testosterone are also linked to a range of physiological disorders, including reduced insulin sensitivity, diabetes, abdominal obesity, hypertension, and dyslipidemia, which can be grouped under the metabolic syndrome (MetS).[3–6]

Several epidemiological studies have examined the association of low plasma total and bioavailable testosterone with all-cause mortality in elderly men. Their results, reviewed by Araujo et al.[7] in a meta-analysis, are inconsistent. Although some studies show an increased risk of death among men with the lowest testosterone levels,[8–12] others found no association.[13–16] More recent studies also yielded inconsistent findings.[7,17–19]

Studies that reported a noteworthy association of low testosterone with mortality were usually performed in older men who are more likely than younger men to have low high-density lipoprotein (HDL) cholesterol levels, dyslipidemia, or abdominal obesity, three important components of MetS.[8–10,12] In addition, a previous study[20] suggested that the association of low plasma testosterone and mortality could be restricted to men with MetS.

Based on these observations, we hypothesized that the association of testosterone and mortality in men may be modified by MetS. In a random subsample of elderly men aged ≥65 years from the French Three-City Cohort (3C) study,[21] we examined the association between the plasma level of total and bioavailable testosterone and the risk of 12-year all-cause mortality, while taking into account the presence of MetS status and its individual components.