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Endogenous testosterone may influence cardiovascular health in men
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Thromboembolism, heart failure and myocardial infarction may be linked to high levels of endogenous testosterone in men, according to findings from a genome-wide association study published in BMJ.
“Observational studies of the association of measured endogenous testosterone with overall and specific cardiovascular diseases, including thromboembolism, myocardial infarction and heart failure, are difficult to interpret,” C. Mary Schooling, PhD, MSC, professor and department chair of environmental, occupational and geospatial health sciences at the School of Public Health and Health Policy at the City University of New York, and colleagues wrote. “Therefore, it is unclear from observational studies whether testosterone has a role or is an indicator of poor general health, particularly because testosterone might be affected by some cardioprotective treatments.”
Schooling and colleagues found a genome-wide significant association between testosterone and the gene regions of JMJD1C and SHBG. These genetic predictors were then assessed via a two-sample Mendelian randomization in 3,225 men from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) randomized controlled trial and 171,875 men and women from the UK Biobank. Validation was accomplished via a sample of 171,875 participants in the CARDIoGRAMplusC4D 1000 Genomes study. In total, there were 392,038 participants (mean age, 57.2 years in men and 56.7 years in women).
The researchers identified 13,691 instances of thromboembolism, 1,688 of heart failure and 12,882 of MI. For each unit change in serum log testosterone, there was a 1.24 increase in odds for thromboembolism, a 1.65 increase in odds for heart failure and a 1.24 increase in odds for MI, although the latter measure decreased to 1.15 based on the validation study.
Of the 661 variants of the JMJD1C gene region, 234 predicted testosterone level while 286 of the 325 SHBG variants did the same. The researchers wrote that there was a positive association between JMD1C-predicted testosterone level and thromboembolism (OR = 2.09; 95% CI, 1.27-3.46) and heart failure (OR = 7.81; 95% CI, 2.56-23.81) in men. A similar association was not found for MI (OR = 1.17; 95% CI, 0.78-1.75), even in the validation study (OR = 1.37; 95% CI, 1.03-1.82). SHBG gene region-predicted testosterone level did not share similarly positive associations with thromboembolism (OR = 1.08; 95% CI, 0.83-1.42), heart failure (OR = 1.78; 95% CI, 0.82-3.87) or MI (OR = 0.79; 95% CI, 0.59-1.04). However, the researchers noted a positive association of thromboembolism with SHBG-gene predicted sex hormone-binding globulin (OR = 1.35; 95% CI, 1.02-1.79). Using the same measure, there was a negative association with MI in men (OR = 0.69; 95% CI, 0.49-0.97).
“These results extend and complement previous findings of an association between endogenous testosterone and a higher risk of ischemic heart disease and ischemic stroke, particularly in men,” the researchers wrote. “Taken together, these findings suggest a common factor could underlie thromboembolism, heart failure and myocardial infarction, and explain higher rates of these conditions in men than in women.” – by Phil Neuffer
Disclosures: The authors report no relevant financial disclosures.
Perspective
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Adrian Sandra Dobs, MD, MHS
Recent Endocrine Society clinical practice guidelines recommended against using testosterone replacement therapy in men with stroke, MI or thrombophilia. The data in favor or against this is still hotly debated. The variability of type of study designs, ages and comorbidities all contribute to the difficulty in documenting the risk of testosterone therapy on CVD.
The goal of this study was to assess the effect of endogenous serum testosterone on CVD using the UK biobank participants. To do this they evaluated the genetic predictors of serum testosterone in their population of men and women. The final sample size consisted of 392,038 participants (46% men), 88% of whom were white and British. The investigators found an association between the genetic markers that predicted endogenous testosterone levels in a previous study, called REDUCE, and a higher risk of thromboembolism, heart failure and MI, particularly in men. The investigators concluded that this supports an association between endogenous testosterone and the higher risk of CVD, especially in men.
This study has important significance. Many would agree that men are more likely to have CVD compared with women. This might be due to the observation that men have poor health habits (eg, smoking) or are less likely to engage in the health care system. However, it has long been hypothesized that estrogen has the major impact on lowering CVD rates. Yet studies of estrogen treatment in men and women were found to be detrimental. This may explain the shift to testing the hypothesis that serum testosterone may be an important biologic modulator of CVD.
The detrimental effect of testosterone could act via its conversion to estradiol and result in thromboembolism. Alternatively, testosterone may act directly to impact CVD by increasing platelet aggregation through thromboxane A2, or increase endothelin, which causes ischemic heart disease.
The study is tantalizing since it suggests that the genetic variants in the JMJD1C region that predict endogenous serum testosterone are detrimental for thromboembolism, heart failure and MI. However, the excitement has to be minimized. First, the population was mainly white and British, with slightly more women. This limits its generalizability, and in fact, analyzing men and women together is challenging, since women may have very different responses to hyperandrogenism (eg, the PCOS model with increased CVD). Also, in general, GWAS studies can be limiting since the variants studied explain only 1.1% (JMJD1C) and 1.4% (SHBG) of the variance of serum testosterone. There are many other factors besides the genetics of serum hormone levels that can predict CVD in this population. Yet it is exciting to start looking at novel ways to evaluate the relationships between serum testosterone and CVD.
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