Low testosterone is associated with elevated cardiovascular disease biomarkers
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 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.
Other lines of research have also countered the alleged cardiovascular risks. For example it has been shown that declining testosterone levels in men can be a signal of deteriorating health17,18, and men with testosterone deficiency hypogonadism) who remain untreated have an increased risk of heart attack and stroke.16,19,20 This is contrary to what the few flawed studies concluded. Furthermore, testosterone deficiency discovered during hospitalization (regardless of cause) is associated with in-hospital and long-term mortality in elderly male patients.21 Specifically, testosterone deficiency 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 get 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 biomarkers
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 biomarkers 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.
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 10 biomarkers – also known as cardiovascular risk markers - were determined. Included in this panel of biomarkers were HDL (the “good cholesterol”), glycated hemoglobin (an index of average blood sugar levels over the past 3 months), CRP (an inflammatory marker) and leptin (a satiety hormone that is produced by the body's fat cells).
The men’s age was 58 years (range = 48-68), and testosterone level of 14.6 nmol/L (range = 10.5 – 19.6 nmol/L). An inverse relation between testosterone levels and cardiovascular risk was seen for 9 of 10 biomarkers, including the ones just mentioned; in other words, the lower the testosterone level, the worse the biomarker profile.
The practical 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 “snap-shot” 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 mortality 3-13,15,16,23,25, testosterone therapy should lead to improvement in cardiovascular risk markers.
One of the highly publicized flawed studies alleged increased risk of heart attack following start of testosterone therapy prescription.26 If one accepts the idea that testosterone therapy leads to early heart disease complications, there must be a mechanism that would lead to heart attack in as early as 3 months, as alleged to in one of the flawed studies.2 Since testosterone therapy does not cause progression of atherosclerosis27 - in men not taking statins, one marker of atherosclerosis (calcium score) was actually significantly lower in the testosterone group than in the placebo group27 - a more likely mechanism in this short timeframe would be through worsening of endothelial function.28 Endothelial dysfunction means that blood vessels in the body have become dysfunctional and tend to constrict excessively as well as release substances that contribute to development of atherosclerosis and inflammation. Endothelial dysfunction is a marker of atherosclerosis29, and a well-established response to cardiovascular risk factors that precedes the development of atherosclerosis.30,31
A recent study specifically looked at the effect of testosterone therapy on endothelial dysfunction.32 Endothelial function was measured in hypogonadal men prior to and at least 3 months after initiation of testosterone therapy.32 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. It was found 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.32 Importantly, no subject in this study experienced a significant worsening of endothelial function after testosterone therapy. These study clearly refute the flawed study by Finkle et al. and supports the growing number of studies showing cardiovascular benefits with testosterone therapy16,33-35, and the position by the European Medicine Agency that testosterone therapy is safe.36
Regarding leptin, other studies have confirmed that testosterone treatment reduces leptin levels.37-39
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.40 Considering that leptin resistance may play a causative role in the metabolic decline seen with aging41, the improvement of leptin sensitivity with testosterone treatment is especially notable.
References
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- Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS one. 2014;9(1):e85805. Return to content
- Baillargeon J, Urban RJ, Kuo YF, et al. Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy. Ann Pharmacother. 2014;48(9):1138-1144. Return to content
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- Ramasamy R, Scovell J, Mederos M, Ren R, Jain L, Lipshultz L. Association Between Testosterone Supplementation Therapy and Thrombotic Events in Elderly Men. Urology. 2015;86(2):283−285. Return to content
- Haider A, Yassin A, Haider KS, Doros G, Saad F, Rosano GM. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study. Vascular health and risk management. 2016;12:251-261. Return to content
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- Traish AM, Haider A, Haider KS, Doros G, Saad F. Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups. J Cardiovasc Pharmacol Ther. 2017;22(5):414-433. Return to content
- Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc. 2015;90(2):224-251. Return to content
- Saad F. Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? Diabetes Metab Res Rev. 2012;28 Suppl 2:52-59. Return to content
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- 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. Return to content
- Saad F, Haider A, Haider KS, Doros G, Traish AM. Obese Hypogonadal Men with Cardiovascular Diseases (CVD) Benefit from Long-Term Treatment with Testosterone Undecanoate (TU): Observational, Real-Life Data from a Registry Study. Male Hypogonadism - Causes and Treatments. Vol March 72015:SAT-135-SAT-135. Return to content
- Institute of Medicine I. Evaluation of biomarkers and surrogate endpoints in chronic disease. 2010. https://www.ncbi.nlm.nih.gov/books/NBK220297/pdf/Bookshelf_NBK220297.pdf (accessed December 2nd, 2017). Return to content
- Cheetham T, An J, Jacobsen SJ, et al. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA internal medicine. 2017. Return to content
- Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, al. e. Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. PLoS ONE 9(1): e85805 doi:101371/journalpone0085805. 2014. Return to content
- Basaria S, Harman SM, Travison TG, et al. Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. JAMA. 2015;314(6):570-581. Return to content
- Tabata N, Hokimoto S, Akasaka T, et al. Differential impact of peripheral endothelial dysfunction on subsequent cardiovascular events following percutaneous coronary intervention between chronic kidney disease (CKD) and non-CKD patients. Heart Vessels. 2016;31(7):1038-1044. Return to content
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- Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study. Andrologia. 2016;48(7):793-799. Return to content
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- Yassin A, Almehmadi Y, Saad F, Doros G, Gooren L. Effects of intermission and resumption of long-term testosterone therapy on body weight and metabolic parameters in hypogonadal in middle-aged and elderly men. Clin Endocrinol (Oxf). 2016;84(1):107-114. Return to content
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