[Controversy] Mendelian Randomization Suggests NonCausal Associations Of Testosterone With Cardiometabolic Risk Factors And Mortality “Although testosterone assessment might improve risk prediction, implementation of testosterone replacement therapy requires further evidence of a direct effect on cardiometabolic outcomes from double-blinded randomized controlled trials and large-scale Mendelian randomization meta-analyses.” This is the first Mendelian randomization study to investigate whether serum testosterone concentrations in men have a direct unconfounded effect on cardiometabolic risk factors and mortality using recently identified polymorphisms as genetic instruments. On the basis of previous observational findings, low serum testosterone concentrations were recently postulated as a cardiometabolic risk factor in men. In contrast, the principal findings of the present study suggest that the associations of serum testosterone concentrations with cardiometabolic risk factors and mortality might largely result from imperfect adjustment for confounding or measurement error that induces spurious findings. In addition, reverse causation might have taken place where subclinical CVD influence testosterone concentrations, which in turn affects CVD risk factor burden. As expected, the standard regression analyses confirmed the associations of serum testosterone concentrations with different cardiometabolic risk factors showing inverse associations with obesity, lipid parameters, blood pressure, glucose, HbA1c and subclinical inflammation. However, when we used genetic instruments in subsequent IV analyses to represent lifetime serum testosterone concentrations free of residual confounding or reverse causation, none of these previous associations were proved to be causal. The metabolic syndrome consists of a cluster of cardiometabolic risk factors, including visceral obesity, glucose intolerance, dyslipidaemia and hypertension; which strongly predict subsequent CVD and mortality. However, although previous prospective studies showed that low testosterone concentration precede the development of metabolic syndrome, reverse causality remains a possibility, as it remains still unclear whether low testosterone concentrations contributes to or are a very early consequence of mechanisms finally leading to overt metabolic syndrome. Similarly, also for the reported associations of low testosterone concentrations with obesity, hypertension, or type 2 diabetes, the possibility exist that there is a vicious cycle between low testosterone concentration and metabolic alterations finally leading to clinical CVD and premature death. Researchers also found that the association between low serum testosterone concentrations and increased all-cause mortality risk is subject to residual confounding, reverse causation, or regression dilution bias. This finding is in agreement with a recent systematic review and meta-analysis concluding that the association between serum testosterone concentrations and mortality is seriously challenged by considerable between-study heterogeneity with regard to age structure, baseline testosterone concentration, length of follow-up period and day time of blood sampling. In a recent systematic review and meta-analysis of 51 testosterone trials, testosterone therapy showed no significant effects on all-cause mortality, prostatic outcomes, cardiovascular events, or cardiovascular risk factors. In addition, a recent testosterone replacement trial among 209 community-dwelling men, 65 years of age or older, and with limitations in mobility and a high prevalence of chronic disease was discontinued after the application of a testosterone gel was associated with adverse cardiovascular events. Although this finding provides some new caution about testosterone therapy, its generalizability is limited by an elderly study population, higher cardiovascular risk burden in the intervention group, and a sample composition designed to assess frailty as the primary endpoint. However, results from existing interventional trials provide only limited evidence for causal mechanisms between exogenous testosterone, cardiometabolic risk factors and clinical CVD. Thus, more rigorously conducted double-blinded randomized controlled trials in metabolically healthy men are strongly needed. In conclusion, this study provided further insights into the causal role of testosterone concentrations in men with CVD and mortality. The triangulation of the associations between genetic instruments, serum testosterone and cardiometabolic risk factors suggests a non-causal effect of serum testosterone on cardiometabolic risk burden and mortality. This result adds to previous findings suggesting low serum testosterone concentrations in men as a secondary marker of subclinical disease progression rather than a causal risk factor. Thus, establishing statistically significant associations is necessary, but not sufficient to prove causality. To date, assessment of serum testosterone concentrations improves our ability to predict risk and provides a marker of good health and overall well-being in men. However, before issuing any firm clinical recommendations, additional insights into the causal role of testosterone as a CVD risk factor require further research from double-blinded randomized controlled trials, as well as large-scale Mendelian randomization meta-analyses. Haring R, Teumer A, Völker U, et al. Mendelian randomization suggests non-causal associations of testosterone with cardiometabolic risk factors and mortality. Andrology 2013;1(1):17-23. onlinelibrary.wiley/doi/10.1111/j.2047-2927.2012.00002.x/abstract
Posted on: Mon, 10 Jun 2013 14:18:54 +0000
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