Free testosterone and cardiometabolic parameters in men: comparison of algorithms

Abstract

Objective: Calculating the free testosterone level has gained increasing interest and different indirect algorithms have been suggested. The objective was to compare free androgen index (FAI), free testosterone estimated using the linear binding model (Vermeulen: cFTV) and the binding framework accounting for allosterically coupled SHBG monomers (Zakharov: cFTZ) in relation to cardiometabolic conditions.

Design: A prospective cohort study including 5350 men, aged 30-70 years, participating in population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with baseline and follow-up information on cardiometabolic parameters and vital status.

Results: Using age-standardized hormone levels, FAI was higher among men with baseline cardiometabolic conditions, whereas cFTV and cFTZ levels were lower compared to men without these conditions as also seen for total testosterone. Men in highest quartiles of cFTV or cFTZ had lower risk of developing type 2 diabetes (cFTV: HR = 0.74 (0.49-1.10), cFTZ: HR = 0.59 (0.39-0.91)) than men in lowest quartile. In contrast, men with highest levels of FAI had a 74% (1.17-2.59) increased risk of developing type 2 diabetes compared to men in lowest quartile.

Conclusion: The association of estimated free testosterone and the studied outcomes differ depending on algorithm used. cFTV and cFTZ showed similar associations to baseline and long-term cardiometabolic parameters. In contrast, an empiric ratio, FAI, showed opposite associations to several of the examined parameters and may reflect limited clinical utility.

Keywords: follow-up study; free testosterone; metabolic syndrome; total testosterone.

Figure 1

(A) Free testosterone according to Vermeulen equation plotted against the level according to Zakharov equation (Pearson coefficient r = 0.9, P < 0.01). The line represents the identity line. (B) Bland–Altman plot of the absolute difference between free testosterone calculated by Zakharov and Vermeulen equation (cFTZ – cFTV) according to mean levels of free testosterone calculated by the two equations.

Figure 2

Hazard ratios and 95% CIs for quartiles of free testosterone stratified according to algorithm (FAI, Vermeulen or Zakharov) in relation to type 2 diabetes, ischemic heart disease, cardiovascular disease mortality and all-cause mortality. All models are stratified according to smoking status and adjusted for study, BMI, alcohol consumption and physical exercise with age as the underlying time scale.