Low testosterone is associated with elevated cardiovascular disease biomarkers

15 December 2017

Pastuszak AW, Kohn TP, Estis J, Lipshultz LI. Low Plasma Testosterone Is Associated With Elevated Cardiovascular Disease Biomarkers. The journal of sexual medicine. 2017;14(9):1095-1103.

The heightened fear of increased risk of heart attack and stroke with testosterone therapy was mainly caused by two high profile but flawed studies.1,2 Even though many new studies have refuted these alleged cardiovascular risks and even demonstrated that testosterone therapy is associated with a reduced cardiovascular risk3-16, concern still remains among both physicians and the general population alike.

Other lines of research have also countered the alleged cardiovascular risks. Compelling data suggest that declining testosterone levels in men can be a signal of deteriorating health17,18, and untreated hypogonadal men have an increased risk of cardiovascular events.16,19,20 Hypogonadism discovered during hospitalization (regardless of cause) is associated with in-hospital and long-term mortality in elderly male patients; it is a strong independent predictor for both all-cause and cardiovascular mortality.21 Specifically, hypogonadism in hospitalized men has been significantly associated with a 3.3-fold increased risk of all-cause mortality and a 2.1-fold increased risk of cardiovascular mortality.21

To gain a better understanding of the relation between testosterone and cardiovascular health and disease, it is useful to look at studies that have investigated mechanisms underlying heart attack and stroke. Here we summarize the results of a study published in the Journal of Sexual Medicine. It examined the relation between testosterone levels and cardiovascular risk using a large panel of 10 objective biomarkers that have been linked to cardiovascular health.22

KEY POINTS

  • Cardiovascular biomarkers can be used as surrogate endpoints to evaluate treatment more efficiently and quickly than to wait for clinical events (hard endpoints) such as heart attacks and strokes to happen.
  • Low testosterone levels are associated with harmful elevations in 9 of 10 cardiovascular biomarkers: cardiac troponin I (cTnI), endothelin-1 (ET-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), N-terminal proB-type natriuretic peptide (NTproBNP), high-density lipoprotein (HDL) cholesterol, high-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), and leptin.
  • Previous studies have shown that testosterone treatment improves several cardiovascular biomarkers; CRP, interleukin-1beta, TNF-α, interleukin-1beta, and leptin.
  • The ability of testosterone treatment to improve leptin sensitivity is especially notable considering that leptin resistance may play a causative role in the metabolic decline seen with aging.

What is known about testosterone and cardiovascular risk factors

Most previous studies investigating the relation between testosterone and cardiovascular risk have looked at “hard clinical endpoints” such as myocardial infarction and stroke to determine risk. While effects on hard clinical endpoints is the gold standard outcome in medical research, it is not resource intensive to conduct such studies. Therefore, analyzing effects on risk factors and biomarkers that contribute to the development of heart disease and stroke, or signal presence of cardiovascular pathology, is a more feasible study approach. Analyzing the effects of testosterone deficiency and testosterone therapy on risk factors and biomarkers will also help discard the conclusions from the flawed studies that alleged cardiovascular risks, and support the growing number of studies which demonstrated cardiovascular safety – and even benefits – of testosterone therapy.3-13,15,16,23

The Institute of Medicine (IOM) defines biomarkers as “indicators of normal biological processes, pathogenic processes or pharmacologic responses to an intervention”.24 When biomarkers are used as proxies for clinical endpoints, they are referred to as surrogate endpoints and provide the utility of evaluating interventions more efficiently and quickly. They are particularly important when the effect of a drug is expected to take extensive time to become manifest. This is the case with testosterone therapy.

Besides traditional risk factors such as high-density lipoprotein cholesterol (HDL), high-sensitivity C-reactive protein (hs-CRP), glycated hemoglobin (HbA1c), several new biomarkers have been linked to cardiovascular disease mechanisms, as outlined in the table.

 

Table: Overview of new biomarkers linked to cardiovascular risk.

Biomarker
(abbreviation)
Description and Significance
Cardiac troponin I
(cTnI)
Troponin I (TnI) is a key regulatory protein of striated muscle. TnI originating from the myocardium (cardiac TnI) differs from skeletal muscle TnI.

Small increases in hs-cTnI levels, even in the absence of clinical symptoms, are a sign of underlying cardiomyocyte injury and cardiac disease.25

Studies have shown that asymptomatic men and women with cTnI levels above the 99th percentile of the reference range have a significantly increased risk of CVD, coronary heart disease, and all causes of death.26
Interleukin-6
(IL-6)
Interleukin-6 is a cytokine that is involved in a wide range of chronic disease conditions associated with inflammation.

Increased plasma IL-6 levels are observed in men with atherosclerosis and are associated with a threefold increased risk of death from cardiovascular causes.27

Elevated circulating interleukin-6 levels are independently associated with greater risk of cardiovascular and all-cause mortality in the general elderly population.28
Tumor necrosis factor-
α (TNF- α)
Tumor necrosis factor- α is a cytokine which is produced mainly by immune cells and mediates inflammation.

Increased levels of TNF-α in asymptomatic men are associated with clinical and subclinical CVD and heart failure.29
Interleukin-17A
(IL-17A)
Interleukin-17A is a cytokine which mediates immune and inflammatory responses.

High levels in asymptomatic men are associated with worse atherosclerosis and vessel wall plaque instability.27,30,31
Endothelin-1
(ET-1)
Endothelin-1 is a vasoconstrictor that has been implicated in the development and progression of vascular disorders such as atherosclerosis and hypertension.

Increased levels of ET-1 accelerate development of atherosclerotic disease by inducing smooth muscle cell hyperplasia32  and are a predictor of increased 10-year mortality in otherwise asymptomatic individuals.33
LeptinLeptin is a satiety hormone that is produced by the body's fat cells.

In obese people, plasma leptin levels are elevated due to leptin resistance. In this scenario, leptin may act as a pathophysiological trigger and/or marker for cardiovascular diseases.34

High leptin levels are associated with high waist circumference, BMI, subcutaneous fat, visceral fat, total abdominal fat, and resistin.35
N-terminal pro-B-type
natriuretic peptide
(NTproBNP)
N-terminal pro-B-type natriuretic peptide is a hormone produced by the heart.

Increased NTproBNP, a peptide released with myocardial stretching, can predict up to six-fold higher mortality and hospitalization for cardiovascular reasons in asymptomatic patients.36

What this study adds

10,041 male patients were identified in the database of a commercial clinical laboratory performing biomarker testing.22 Patients were grouped by total testosterone levels and associations with the following 10 biomarkers – also known as cardiovascular risk markers - were determined: cardiac troponin I (cTnI), endothelin-1 (ET-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-17A (IL-17A), N-terminal pro-B-type natriuretic peptide (NTproBNP), HDL, hs-CRP, HbA1c, and leptin.

The median age was 58 years (range = 48-68), and the median plasma testosterone level was 14.6 nmol/L (420 ng/dL) (range = 10.5 – 19.6 nmol/L, 304-565 ng/dL). An inverse relation between testosterone levels and cardiovascular risk was seen for 9 of 10 biomarkers: cTnI, ET-1, IL-6, TNF-α, NTproBNP, HDL cholesterol, hs-CRP, HbA1c, and leptin.

Even after adjusting for age, body mass index, HbA1c, hs-CRP, and HDL cholesterol levels, the biomarkers IL-6, ET-1, NTproBNP, and leptin were significantly associated with a testosterone level lower than 250 ng/dL.

Figure 1: Relation between low testosterone and increased cardiovascular risk.

Figure 1: Relation between low testosterone and increased cardiovascular risk.

Note: Odds ratio indicates increased likelihood of cardiovascular risk for each biomarker when their respective levels are above normal range.
Data from Pastuszak AW, Kohn TP, Estis J, Lipshultz LI. Low Plasma Testosterone Is Associated With Elevated Cardiovascular Disease Biomarkers. The journal of sexual medicine. 2017;14(9):1095-1103

The clinical implication of these results is that men with low testosterone levels could be at increased risk for cardiovascular disease as seen by deleterious changes in cardiovascular risk markers.22 This is consistent with previous studies showing that men with testosterone deficiency are at increased risk of cardiovascular disease and mortality.16,19,20

Commentary

This is the first study to examine cardiovascular risk associated with testosterone levels using a large panel of 10 biomarkers that have been linked to cardiovascular health.22 It should be noted that this was a cross-sectional study looking at the relation between testosterone levels and deleterious changes in cardiovascular risk markers (biomarkers). It did not investigate the effect of testosterone therapy on changes in these risk markers, it merely demonstrated that low testosterone levels are associated with deleterious changes in risk markers for cardiovascular disease. Considering the multiple studies showing that testosterone therapy reduces cardiovascular and all-cause mortality3-13,15,16,23,37, testosterone therapy should lead to improvement in cardiovascular risk markers.

One of the highly publicized flawed studies alleged increased risk of myocardial infarction following initiation of testosterone therapy prescription.38 If one accepts the hypothesis that testosterone therapy leads to early cardiovascular complications, there must be a mechanism that would lead to myocardial infarction in as early as 3 months, as alleged to in the flawed study by Finkle et al.2 Since testosterone therapy does not cause progression of atherosclerotic plaque 39 - in men not taking statins, one marker of atherosclerosis (coronary artery calcium) was actually significantly lower in the testosterone group than in the placebo group 39 - a more likely mechanism in this short timeframe would be through worsening of endothelial function.40 Endothelial dysfunction is a marker of atherosclerotic risk 41, and is a well-established response to cardiovascular risk factors that precedes the development of atherosclerosis.42,43

A recent study specifically looked at the effect of testosterone therapy on endothelial (dys)function.44 The aim was to evaluate arterial endothelial function in hypogonadal men prior to and at least 3 months after initiation of testosterone therapy.44 23 male patients with symptoms of hypogonadism, a total testosterone level of <350 ng/dL, and who planned to begin testosterone therapy, were included in the study. Endothelial function was non-invasively assessed using the EndoPAT-2000 machine. Notably, endothelial function assessment with the EndoPAT method is not limited by methodological variability, as is the case with the flow-mediated dilation method.45 Recordings were made of the augmentation index (AI) (normal <3%), a measure of arterial stiffness, and reactive hyperemia index (RHI), a measure of endothelial vasodilation (normal >1.69). Endothelial function was reassessed at the next clinic visit, between 3 and 6 months if the patients were compliant with therapy.

Mean age of subjects was 53 years (range, 34–68 years) and starting testosterone level 197 ng/dL (range, 35-339 ng/dL). There was a history of diabetes in four, hypertension in ten and coronary artery disease in five subjects. Mean RHI was 1.67 (70% were abnormal) and mean AI was 2.57% (39% were abnormal). There were no cardiac events. At follow-up, 20 patients were compliant with therapy and retested. Mean testosterone had significantly increased to 511 ng/dL. Mean RHI significantly improved from 1.0 to 2.14 and AI significantly improved from 2.9% to −1.75%. There was no significant worsening of reactive hyperemia index, and no subjects had worsened augmentation index.44 It was concluded that men with symptomatic hypogonadism often have abnormal endothelial function, and that testosterone therapy improves endothelial function in the majority of men, and remains unchanged only in a minority.44 Importantly, no subject in this study experienced a significant worsening of endothelial function after testosterone therapy. In accordance with the improvement in endothelial function, testosterone therapy also reduces levels of endothelin-146, which is one of the most potent vasoconstrictors, which contributes to development of endothelial dysfunction.47 These studies clearly refute the flawed study by Finkle et al. and supports the growing number of studies showing cardiovascular benefits with testosterone therapy16,48-50, and the position by the European Medicine Agency that testosterone therapy is safe.51 Interestingly, it has been suggested that drugs that improve endothelial dysfunction are preferable in the treatment of cardiovascular risk factors.52

Regarding the other biomarkers, two high quality randomized controlled trials showed that testosterone treatment results in a significant reduction in circulating levels of CRP, TNF-α, interleukin-1beta53, and leptin.54,55 Other studies have confirmed that testosterone treatment reduces levels of CRP56, TNF-α53 and leptin.57-59

The reduction in leptin levels, which suggest a reduction in leptin resistance (or improved leptin sensitivity), is especially notable. Currently there is no established treatment for leptin resistance, a condition for which treatment is needed.60 Considering that leptin resistance may play a causative role in the metabolic decline seen with aging61, the improvement of leptin sensitivity with testosterone treatment is especially notable.

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