There have been 2 recently published articles ^(1-2) that have captured the attention of the news media and class action attorneys – the “if it bleeds, it leads” crowd – and therefore the attention of the public. The authors of the 2 papers have concluded that Testosterone hormone replacement therapy increases the risk of heart attack. What you are not as likely to have heard from the news media and certainly not at the time they published news stories about these 2 papers, is that there is a large body of evidence ^(3-37) that indicates otherwise: that low Testosterone is associated with increased risk of heart disease and Testosterone replacement therapy decreases the risk of heart disease. The weight of evidence is clear.

The design of the 2 studies suggesting risk of Testosterone therapy will be discussed after a brief review of the extensive literature indicating increased risk in men with low Testosterone and decreased risk with Testosterone therapy.

Low Testosterone Levels and Increased Risk of Heart & Carotid Artery Disease

Men with Coronary Heart Disease had a significantly lower total Testosterone, free Testosterone, and bioavailable Testosterone. ⁽³⁾

Low testosterone levels in men are associated with increased Mortality due to Cardiovascular Disease and other causes. ^{(4, 5)}

Study showed a possible correlation between lower Testosterone levels, Erectile Dysfunction and conditions associated with higher Cardiovascular risk. ⁽⁶⁾

Men under the age of 45 with Coronary Heart Disease had significantly lower Testosterone levels than same age men with normal hearts. ⁽⁷⁾

Testosterone levels were found to be lower in men with greater levels of Carotid Artery Disease. ⁽⁸⁾ 

Low testosterone levels are associated with Atherosclerosis in men. ⁽⁹⁾

Low Testosterone Levels and Increase Risk of Diabetes Type II and Metabolic Syndrome– both of which increase the risk of Atherosclerosis, High Blood Pressure, Heart Disease, Coronary Artery Disease and Obesity

Low Testosterone levels are associated with an increased risk for the development of Type 2 Diabetes and Metabolic Syndrome. ^{(10, 11, 12, 13, 14)}

Since low Testosterone has been shown to lower Blood Sugar levels, the Endocrine Society now recommends measurement of Testosterone in all male patients with Type 2 Diabetes. ⁽¹⁵⁾

Low Testosterone Levels Are Associated with an Increased Risk of Mortality

Low Testosterone level in men predicts Mortality from Cardiovascular Disease. ⁽¹⁶⁾

Low Testosterone levels are associated with an increased risk of Death from Cardiovascular Disease, Cancer and all-causes. ⁽¹⁷⁾

Low Testosterone levels are associated with an increased risk of Death from all causes and Cardiovascular Disease. ⁽¹⁸⁾

For all-cause Mortality, each increase of six nanomoles of Testosterone was associated with an almost fourteen percent drop in the risk of Death. And low Testosterone was associated with increased death from Cardiovascular Disease and Cancer. ⁽¹⁹⁾

Low Testosterone Levels and Increased Risk of Hypertension

Low total Testosterone concentrations are predictive of Hypertension, suggesting total Testosterone as a potential biomarker for increased Cardiovascular risk. ⁽²⁰⁾

Low Testosterone and Congestive Heart Failure

In males with Heart Failure, low serum Androgens were associated with an adverse prognosis. ⁽²¹⁾

In men with Chronic Heart Failure, Anabolic hormone depletion is common and deficiency of each Anabolic hormone is an independent marker of poor prognosis. ⁽²²⁾

Testosterone Replacement and Heart Disease

Testosterone replacement was associated with an improvement in serum Lipid levels. ⁽²³⁾

The mechanism by which Testosterone replacement decreases Lipid levels may be due to Testosterone’s positive effects on Abdominal Fat and Insulin Resistance. ⁽²⁴⁾

Short-term administration of Testosterone induces a beneficial effect on exercise-induced Myocardial Ischemia in men with Coronary Heart Disease. This effect may be related to a direct coronary-relaxing effect of Testosterone. ⁽²⁵⁾

Short-term intracoronary administration of Testosterone, at physiological concentrations, induces Coronary Artery Dilatation and an increase in Coronary Blood Flow in men with established Coronary Heart disease. ⁽²⁶⁾

Low-dose supplementation with Testosterone in men with Chronic Stable Angina reduced exercise-induced Myocardial Ischemia. ⁽²⁷⁾

Testosterone replacement has been shown to increase Coronary Blood Flow in patients with Coronary Heart Disease. ^{(28, 29)}

Transdermal Testosterone replacement has been shown to improve Chronic Stable Angina by increasing the Angina-Free Exercise Tolerance vs. controls that were getting placebos. ⁽³⁰⁾

Testosterone replacement reduced exercise induced Myocardial Ischemia. ⁽³¹⁾

Testosterone is a Coronary Vasodilator by functioning as a Calcium Antagonistic agent. ⁽³²⁾

Testosterone replacement therapy in patients with low Testosterone improves the metabolic derangements associated with Cardiovascular risk. ⁽³³⁾

Testosterone replacement has been shown to decrease Inflammation and lower Total Cholesterol. ⁽³⁴⁾

Testosterone replacement in patients with Congestive Heart Failure has been shown to improve Exercise Capacity, improve Insulin Resistance, and improve Muscle Performance. ⁽³⁵⁾

Testosterone replacement therapy improves Functional Capacity and symptoms in men with moderately severe Heart Failure. ⁽³⁶⁾

Testosterone replacement has been shown to be helpful in patients with severe Heart Failure. ⁽³⁷⁾

As you can see there is a big discrepancy between these 2 studies that show an increased risk of Heart Disease and Testosterone and the 35 studies that show Testosterone is associated with a decreased risk of Heart Disease. Let’s take a look at study characteristics and conclusions of the 2 studies discrepant from the rest of the literature.

The Following Study Flaws Contribute to this Obvious Discrepancy

1.  In neither of these studies, ^(1-2) was Estrogen measured. This is tremendously important because Testosterone is converted to Estrogen by the aromatase enzyme. This occurs at a greater rate in men with larger waist sizes because the more abdominal fat there is, the more aromatase there is to convert Testosterone to Estrogen. It is most often the case that men who need Testosterone replacement have larger waist size because, as seen in multiple studies, ^{(10-15 & 24)} low Testosterone is highly associated with Metabolic Syndrome and Type 2 Diabetes. And both of these are associated with increased waist size. It is important therefore to prescribe an aromatase inhibitor along with prescribing testosterone to prevent this conversion of testosterone to estrogen. So, two flaws in this study include not drawing estrogen levels and not identifying whether an aromatase inhibitor was prescribed at the same time as the Testosterone. Why this is important is because high Estrogen levels in men have definitively been shown to increase Heart Disease and Stroke, as can be seen from the studies below.

High Estrogens are Associated with an Increased Risk of Heart Disease and Stroke

High Estradiol in males is associated with an increased risk of Stroke. ⁽³⁸⁾

Elevated Estradiol levels predict progression of Carotid Artery Disease in middle age men. ⁽³⁹⁾

Elevated levels of Estradiol in men were associated with an increase incidence of Strokes, Peripheral Vascular Disease, and Carotid Artery Stenosis compared to subjects with lower Estradiol levels. ⁽⁴⁰⁾

High Estrone and low Testosterone levels are associated with worse Lipid levels in men with Coronary Heart Disease. ⁽⁴¹⁾

Low Testosterone and elevated Estradiol is associated with increased lower extremity Peripheral Artery Disease in older men. ⁽⁴²⁾

Men with Myocardial Infarction had high Estradiol and low Testosterone levels. ⁽⁴³⁾

High Estradiol levels in men were associated with Acute Myocardial Infarctions. ⁽⁴⁴⁾

Elevated levels of Estrogen in men are associated with an increased risk of Heart Disease. ⁽⁴⁵⁾

2.  Neither study looked at red blood cell numbers. It is well known that Testosterone can increase the number of red blood cells. This increases blood viscosity, which increases the risk of Heart Disease and Thrombosis. ⁽⁴⁶⁾ It is important, when prescribing Testosterone, to monitor red blood cell counts and reduce the dose if red cell counts get too high. If the hematocrit is more than fifty-four percent then testosterone therapy should be stopped until the hematocrit is at a safe level. ⁽⁴⁷⁾

3.  Neither study measured all patients for Testosterone levels at follow-up. For this reason we have no idea if participants had supraphysiologic or higher than normal levels of Testosterone. And supraphysiologic levels of Testosterone can cause oxidative stress which induces endothelial dysfunction, ⁽⁴⁸⁾ which is the biggest contributor to Heart and Vascular Disease.

4.  Some men in these studies were using testosterone injections. Injectable Testosterone often creates supraphysiologic levels when injected, which can then diminish to subtherapeutic levels before the next dose. This can create fluctuations in metabolic state and could contribute to increased risk. This is discussed in Coppola’s review ⁽⁴⁹⁾ of the Vigen study.

5.  Dihydrotestosterone (DHT) was not measured in either study. Testosterone converts to Dihydrotestosterone by the enzyme 5-alpha-reductase. There is a high concentration of 5-alpha-reductase at the base of hair follicles.  Higher Testosterone dosing and topical application to hairy skin increase the conversion of Testosterone to DHT. Higher levels of DHT have been shown to enhance early atherosclerosis. ⁽⁵⁰⁾ High levels of DHT are also associated with hair loss and growth of prostate cells. When prescribing Testosterone, it is important to measure DHT levels and if elevated decrease testosterone dose or prescribe a 5-alpha-reductase inhibitor. In neither study do we know what DHT levels were, where the testosterone was applied or whether patients were placed on 5-alpha-reductase inhibitors.

6.  In the paper by Finkle, the control group consisted of patients prescribed Erectile Dysfunction (ED) medication. ED medications as a group are called Phosphodiesterase inhibitors. What these medications do is to cause vasodilation, which produces the desired effect of attaining and maintaining an erection. They also dilate blood vessels in other parts of the body and are considered potential therapy for many forms of Heart Disease. ⁽⁵¹⁾ These are the patients that were used as comparisons to the patients put on Testosterone. So, they compared patients put on Testosterone to patients put on medication that shows benefits in reducing Cardiovascular Risk to look at the occurrence of Heart Attack. If you are comparing one group of patients to patients whose risk of Heart Attack is being reduced, then, by comparison, their risk of Heart Attack is going to look increased.

 

Conclusion

The conclusion of the authors, Vigen and Finkle, that Testosterone increases risk of Heart Attack and Death, is very misleading when you look at the way in which their studies were done. And then there is the great volume of prior research that shows that Testosterone is associated with Heart and Vascular Health. These two sets of information contradict each other. The poor quality of these two studies, which has been hyped by the news media and some class-action lawyers, makes these authors conclusions invalid. The vast majority of evidence shows that Testosterone is Healthy for Heart and Blood Vessels. Dosage, application (route of delivery), application site, and follow-up and monitoring are all extremely important aspects of prescribing for all hormone replacement therapy treatments.

 

I would like to thank Pamela Smith, MD for her white paper on this topic, from which I drew heavily for this article.

 

References

1. Vigen, R., et al., “Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels,” JAMA 2013; 310(17):1829- 36.
2. Finkle, W., et al., “Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men,” PLOS January 29, 2014.
3. English, K., et al., “Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms,” Eur Heart Jour 2000; 21(11):890-4.
4. Vermeulen, A., “Androgen replacement therapy in the aging male—a critical evaluation,” Jour Clin Endocrinol Metabol 2001; 86:2380-90.
5. Malkin, C., et al., “Low serum testosterone and increased mortality in men with coronary heart disease,” Heart 2010; 96:1821-25.
6. Ma, R., et al., “Erectile dysfunction predicts coronary heart disease in type 2 diabetes,” Jour Amer Coll Cardiol 2008; 51:2045-50
7. Turhan, S., et al., “The association between androgen levels and premature coronary artery disease in men,” Coron Artery Dis 2007; 18(3):159-62.
8. Bhasin, S., et al., “Serum free testosterone is inversely related to carotid intima-media thickness (IMT) and plaque score,” Diabetes Care 2003; 26:1869-73.
9. Svartberg, J., et al., “Low testosterone levels are associated with carotid atherosclerosis in men,” Jour Int Med 2006; 269(6):576-82.
10. Ding, E., et al., “Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis,” JAMA 2006; 295:1288-99.
11. Laaksonen, D., et al., “Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-age men,” Diabetes Care 2004; 27:1036-41.
12. Pasquali, R., et al., “Effects of acute hyperinsulinemia on testosterone serum concentrations in adult obese and normal-weight men,” Metabolism 1997; 46(5):526-9.
13. Rizza, R., et al., “Androgen effect on insulin action and glucose metabolism,” Mayo Clin Proc 2000; 75(Suppl):S61-S64.
14. Stellato, R., et al., “Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study,” Diabetes Care 2000; 23(4):490-94. Rizza, R., et al., “Androgen effect on insulin action and glucose metabolism,” Mayo Clin Proc 2000; 75(Suppl):S61-S64.
15. Dardona, P., et al., “Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity,” Jour Clin Endo and Met 2011; 96(9):2643.
16. Hyde, Z., et al., “Low free testosterone predicts mortality from CVD but not other causes: The Health in Men Study,” Jour of Clin Endocriol and Met 2012; 97(1):179.
17. Haring, R., et al., “Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79,” European Heart Jour 2010; 31(12):1494-1501.
18. Araujo, A., et al., “Endogenous testosterone and mortality in men: a systematic review and meta-analysis,” Jour Clin Endocrinol Metab 2011; 90:3007-19.
19. Khaw, K., et al., “Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) Prospective Population study,” Circulation 2007; December 4th.
20. Torkler, S., et al., “Inverse association between total testosterone concentrations, incident hypertension and blood pressure,” Aging Male 2011; 14(3):176-82.
21. Guder, G., et al., “Low circulating androgens and mortality risk in heart failure,” Heart 2010; 96:504-09.
22. Jankowska, E., et al., “Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival,” Circulation 2006; 114:1829-37.
23. Baum, N., et al., “Testosterone replacement in elderly men,” Geriatrics 207; 62:15-8.
24. Marin, P., et al., “Androgen treatment of abdominally obese men,” Obes Res 1993; 1:245-48.
25. Rosano, G., et al., “Acute anti-ischemic effect of testosterone in men with coronary artery disease,” Circulation 1999; 99:166-70.
26. Webb, C., et al., “Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease,” Circulation 1999 100(16):1690-96.
27. English, K., et al., “Low dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina,” Circulation 2000; 102:1906-11.
28. Haffner, J., et al., “Sex hormones and DHEASO4 in relation to ischemic heart disease in diabetic subjects,” The WESDR Study. Diabetes Care 1996; 19:1045-50.
29. Channer, K., et al., “Cardiovascular effects of testosterone: implications of the “male menopause?” Heart 2003; 89(2):121-22.
30. Whitsel, E., et al., “Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis,” Amer Jour Med 2001; 111:261-69.
31. English, K., et al., “Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: A randomized, double-blind, placebo-controlled study,” Circulation 2000; 102(16):1906-11.
32. English, K., et al., “Testosterone acts as a coronary vasodilator by a calcium antagonistic action,” Jour Endocrinol Invest 2002; 25(5):455-58.
33. Corona, G., et al., “Hypogonadism as a risk factor for CV mortality in men: a meta- analytic study,” Eur Jour Endocrinol 2011; 165:687-701.
34. Malkin, C., et al., “The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men,” Jour Clin Endocrinol Metab 2004; 89(7):3313-18.
35. Carminiti, G., et al., “Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study,” Jour Amer Coll Cardiol 2009; 54(10):919-27.
36. Malkin, C., et al., “Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial,” Eur Hear Jour 2006; 27:57-64.
37. Toma, M., et al., “Testosterone supplementation in heart failure,” Circulation 2012; 5:315-21.
38. Abbott, R., et al., “Serum estradiol and risk of stroke in elderly men,” Neurology 2007; 68(8):563-68.
39. Tivesten, A., et al., “Circulating estradiol is an independent predictor of progression of carotid artery intima-media thickness in middle-aged men,” Jour Clin Endocrinol Met 2006; 91(11):4433-37.
40. Lerchbaum, E., et al., “High estradiol levels are associated with an increase in mortality in older men referred to coronary angiography,” Exp Clin Endocrinol Diabetes 2011; 119(8):490-96.
41. Dunajska, K., et al., “Evaluation of sex hormone levels and some metabolic factors in men with coronary atherosclerosis,” Aging Male 2004; 7(3):197-204.
42. Tivesten, A., et al., “Low serum testosterone and high serum estradiol associated with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden,” Jour Amer Coll Cardiol 2007; 50(11):1070-76.
43. Tripathi, Y., et al., “Serum estradiol and testosterone levels following acute myocardial infarction in men,” Jour Physiol harmacol 1998; 42(2):291-94.
44. Mohamad, M., “Serum levels of sex hormones in men with acute myocardial infarction,” Neuro Endocrinol Lett 2007; 28(2):182-86.
45. Sudhir, K., et al., “Cardiovascular actions of estrogens in men,” Jour Clin Endocrinol Metab 1999; 84(10):3411-15.
46. Merchant, S., et al., Erythrocytosis. In Hematopathology. 2nd Ed. His, E., (Ed.) Philadelphia: Elsevier/Saunders, 2012.
47. Bassil, N., et al., “The benefits and risk of testosterone replacement: a review,” Ther Clin Risk Manag 2009: 5:427-48.
48. Skogastiema, C., et al., “A supraphysiological dose of testosterone induces nitric oxide production and oxidative stress,” Eur Jour Prev Cariol March 7, 2013.
49. Cappola, A., “Testosterone therapy and risk of cardiovascular disease in men,” JAMA 2013; 310(17):1805-06.
50. Death, A., et al., “DHT promotes vascular cell adhesion molecule-1 expression in male human endothelial cells via a nuclear factor-kappa-B-dependent pathway,” Endocrinology 2004; 145(4):1889-97.
51. Kukreja, RC, et.al., “Emerging new uses of phosphodiesterase-5 inhibitors in cardiovascular disease.” Exp Clin Cardiol, 2011 Winter; 16(4): e30-e35.