The role of testosterone in cardiovascular health

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Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. Mesbah Oskui P, French W, Herring M, et al. J Am Heart Assoc 2013; 2: e000272

This summary gives an overview of a comprehensive review of studies that have examined the association between testosterone levels and cardiovascular health.1 The review focuses on the role of testosterone in cardiovascular diseases, including the incidence of coronary artery disease (CAD), congestive heart failure (CHF), and heart-rate-corrected QT (QTc) length prolongation. The role of testosterone on risk factors for atherosclerosis, including type 2 diabetes mellitus (T2DM), obesity, and inflammation, are also reviewed. Findings from studies that investigated the use of testosterone replacement therapy (TRT) on cardiovascular diseases in men with testosterone deficiency (TD) are summarized and possible mechanisms of action (MoA) for testosterone with respect to these outcomes are discussed.

Key Points

  • Testosterone levels are inversely associated with severity of CAD,2,3 which may be improved by TRT

    • In men with CAD, both acute and chronic TRT improved myocardial ischemia by prolonging time to exercise-induced 1-mm ST-segment depression (by 68–108 seconds)4,5
    • Stepwise administration of testosterone in eugonadal men with CAD increased angina threshold by increasing vasodilation and coronary artery blood flow by 4.5% and 17.4% versus baseline6
    • The exact MoA is unknown, but testosterone may cause vasodilation via potassium channel opening7 and/or inactivation of L-type voltage-operated calcium8 channels in smooth muscle cells, or by modulation of nitric oxide release9
    • Animal studies suggest that the MoA may be non-genomic and endothelium independent10
  • Testosterone levels are significantly associated with CHF, which often presents as progressive worsening of exercise capacity in patients

    • In a study of 208 men with CHF and left ventricular ejection fraction of 33%, there was a statistically significant prevalence of TD in men aged ≤45 or ≥66 years, and worsening severity of CHF was associated with a stepwise decrease in levels of both total and free testosterone11
    • A meta-analysis of studies investigating exercise capacity in men with CHF showed that TRT improved 6-minute walk test, isometric walk test, and peak VO2 by 16.7%, 15.9%, and 22.7%, respectively12
    • Based on findings from investigative models, TRT may improve exercise capacity in men with CHF via a peripheral mechanism, such as increasing type I muscle fiber proliferation13
  • T2DM, a risk factor for atherosclerosis and CAD, is associated with significantly lower levels of total14 and free15 testosterone versus nondiabetics

    • The risk of developing T2DM significantly decreased with higher endogenous total testosterone levels, but no significant association was seen for bioavailable testosterone16
    • In clinical studies, TRT has improved levels of HbA1c (0.37–1.5%), homeostatic model of insulin resistance (HOMA-IR), and fasting plasma glucose (0.61–1.9 mmol/L) in hypogonadal men with diabetes15,17-21
    • The bidirectional relationship between T2DM and TD is complex and requires further study
    • A pilot study in three hypogonadal men showed that TRT altered the lipid composition of erythrocyte membranes, suggesting that TRT can influence erythrocyte flexibility and improve diabetic microvascular complications22
  • Total testosterone levels are inversely related to BMI, a risk factor for atherosclerosis

    • The Swedish MrOS study in 2416 men showed a significant decrease in BMI with increasing quartiles of total testosterone: 28.1 and 24.9 kg/m2 for the first and fourth quartile, respectively23
    • TRT has been shown to improve obesity, with significant reductions in BMI (–1.3 kg/m2 at 30 weeks)20 and fat mass (–2.19%)15
    • It is proposed that testosterone may reduce obesity through increased lipolysis and decreased fat accumulation in visceral adipose tissue1
  • Testosterone may exert protective effects against cardiovascular events such as atherosclerosis by suppressing the systemic inflammatory response and leukocyte activation in the vasculature

    • Evidence shows that testosterone levels are inversely correlated to carotid intima-media thickness,24,25 a marker for preclinical atherosclerosis
    • Data for the MoA of this anti-inflammatory effect are conflicting; in-vitro studies propose antagonism of the androgen26,27 and estrogen receptors28 in human umbilical vein endothelial cells, as well as androgen and estrogen receptor-independent mechanisms29
  • Testosterone levels are significantly negatively associated with QTc length, a risk factor for CAD and torsades de pointes,30,31 suggesting that testosterone has a role in regulating ventricular polarization

    • In 26 hypogonadal men, TRT normalized QTc length (average decrease 66 ms) in all subjects with prolonged QTc length32
    • Animal study results suggest that testosterone reduces the QTc length by increasing the activity of potassium channels and simultaneously slowing the activity of L-type calcium channels33

What is known

Despite an increasing incidence of hypogonadism in the USA,34 the relationship between testosterone levels and cardiovascular health is not fully understood. Low levels of testosterone are associated with comorbidities known to increase cardiovascular mortality, such as T2DM and obesity.23 In a meta-analysis of seven population-based studies, low levels of testosterone showed a trend towards an association with increased cardiovascular mortality.35 Although statistical significance was not attained, the study showed that a decrease of 2.1 standard deviations in total testosterone levels was associated with a 25% increase in cardiovascular mortality risk. Two further studies have analyzed the association between testosterone and cardiovascular mortality.36,37 Menke et al. showed that a reduction of testosterone levels from the 90th to the 10th percentile correlated with a significant increase in cardiovascular mortality.36 In agreement with Menke et al., Malkin et al. demonstrated that levels of bioavailable testosterone > 2.6 nmol/L were associated with improved survival from vascular mortality (death from atherosclerosis, heart failure, or cardiac arrest) in 930 men with CAD.37 The association between testosterone and cardiovascular diseases is well documented; however, the exact mechanisms behind this are currently unknown. Further investigation is required to fully elucidate the MoA of testosterone in the cardiovascular system and develop further treatment targets.

What this study adds

A comprehensive review of the clinical literature shows that patients with CAD,2,3 CHF,11 T2DM,14,15 and obesity23 have low testosterone levels. Furthermore, levels of testosterone in hypogonadal men were associated with the severity of CAD2,3 and CHF.11 TRT in hypogonadal men improves a number of cardiovascular health factors. In hypogonadal men with CAD, TRT improved exercise-induced 1-mm ST-segment depression,4,5 a measure of myocardial ischemia, and vasodilation and coronary artery blood flow.6 In patients with CHF, TRT significantly improved components of exercise capacity, a fundamental feature of CHF.12 Furthermore, TRT improved a number of risk factors for atherosclerosis, including T2DM,15,17-21 obesity,15,20 and QTc length.32 Overall, these findings suggest that testosterone plays an important role in the cardiovascular system and maintaining cardiovascular health.

The exact mechanisms of testosterone that influence the cardiovascular system are not yet fully elucidated. Conflicting evidence for possible underlying mechanisms are from experimental in-vitro, animal, and pilot studies, such as Angelova et al.22 This highlights how in-vitro studies play a key role in determining the positive effects of testosterone on the cardiovascular system. Despite the growing evidence for the important role of testosterone on the cardiovascular system, the Endocrine Society guidelines make no recommendations for screening of hypogonadism in patients with heart disease.38 Furthermore, using TRT in patients with heart disease to improve survival is not recommended. As such, longitudinal, placebo-controlled, randomized trials of TRT in hypogonadal men are warranted to understand the role of testosterone in cardiovascular diseases.

References

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Last updated: 2018
G.MKT.GM.MH.01.2018.0500