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.
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.
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