Testosterone and Cardiovascular Disease

Kloner RA, Carson C, Dobs A, Kopecky S, Mohler ER III.
Testosterone and Cardiovascular Disease. J Am Coll Cardiol 2016;67:545-557.

The following are key points to remember from this review of testosterone (T) and cardiovascular disease (CVD), hypogonadism, and testosterone replacement therapy (TRT):

  1. Testosterone (T) is the principal male sex hormone whose androgenic effects are responsible for development of male sex organs and maturing characteristics including sex drive, muscle mass, strength, and bone density. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates luteinizing hormone (LH), which stimulates T synthesis and follicle stimulating hormone (FSH) that stimulates spermatogenesis. The majority of circulating T is bound to sex hormone-binding globulin (SHBG) or albumin. Active free T binds to cell receptors and migrates to the nucleus where it stimulates gene transcription.
  2. Male hypogonadism is defined as a deficiency of T, which can be primary (testicular from radiation, trauma, infection, or ischemia) or central from the hypothalamus or pituitary (opioids, steroids) and simply related to age or chronic diseases. Low T is defined based upon two samples of free T or total T obtained prior to 10:00 a.m. A total T <300 ng/dl is considered low, but it is best to use the laboratory normal ranges. Total T may be high because of elevated SHBG that occurs with age. About 25% of men over 65 years have a low T primarily related to a reduced central response to GnRH, and 50% will have low levels of free T as the diagnostic criteria. Low T occurs in diabetes and the metabolic syndrome (about 50% of each), hypothyroid, and obesity. LH and FSH levels should be obtained to separate primary from centrally mediated hypogonadism.
  3. Symptoms associated with low T include hot flashes, decreased libido, decrease in erectile function, gynecomastia, decreased bone density, decrease in lean body mass and strength, fatigue, and depression. T decreases with age, which is associated with an increase in atherosclerosis and CV risk, and those with higher levels have lower risk. CVD is associated with lower T and higher estrogen levels in men. The baseline T was lower in those with CV mortality and in men with premature coronary artery disease. Low total T is also inversely associated with the Framingham Risk Score and high-sensitivity C-reactive protein. It is not clear whether the association of CVD with low T is causal or simply a biomarker reflection of poor health.
  4. The goal of testosterone replacement therapy (TRT) is to restore T to physiologic ranges and reverse symptoms of hypogonadism. However, clinical trials have not provided clear evidence of the value of treating low T for any of the indications or symptoms. The trials have been underpowered, and have had poorly defined selection criteria and endpoints. Nevertheless, guidelines recommend that men with low T and symptoms of hypogonadism should be given treatment with target to the low to mid normal range of T. The complete blood cell count and prostate-specific antigen should be monitored. Polycythemia is a potential complication of TRT, which may lead to venous thrombosis. Whether deep-venous thrombosis occurs in the absence of polycythemia is not clear. Levels of free or total T should be monitored to assure goal levels are met.
  5. TRT does improve sexual dysfunction associated with low T, but numerous other causes of decreased libido or vascular supply to the genitals reduce the response. Combination TRT with phosphodiesterase type 5 inhibitors has an additive effect. There is less evidence for improvement in depression, cognition, or fatigue. TRT for low T reduces fasting blood sugar, glycated hemoglobin, and triglycerides, but does not affect other lipids. Most trials have shown TRT to increase muscle mass and reduce fat mass in men with low T, particularly in combination with resistance training. Similarly, there is an improvement in bone mineral density with longer duration of TRT.
  6. There are small studies and some biologic plausibilities that support the potential value of TRT in heart failure with reduced ejection fraction, angina, and ischemia/reperfusion. None of these have been tested with appropriate trials.
  7. In a recent male veteran observational study of men with low T not receiving TRT, those on T failing to achieve a normal T, and those on TRT who achieved a normal T, those with normal levels had significantly lower all-cause mortality, and lower risk of myocardial infarction and stroke compared to the other two groups.
  8. Experts have called for a large, prospective, randomized placebo-controlled trial lasting at least 1 year in men with validated symptomatic hypogonadism by two blood samples. Treatment tested should be both intramuscular and gel formulation. Endpoints should be CV, sexual health, glycemic control, and insulin resistance.
  9. Over the past 2 years, the Food and Drug Administration concluded that there was no evidence of a significant CV risk for any given group treated with TRT, but the safety in high CV risk including the elderly and diabetic men needs further study. The most recent recommendations are that TRT should be limited to men with documented low T caused by specific medical conditions, and that the benefits and safety are not clear for the aging male with low T, even if symptomatic. It should be avoided in men with a recent myocardial infarction, revascularization, poorly controlled heart failure, and stroke within the previous 6 months.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Sports and Exercise Cardiology, Vascular Medicine, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Exercise

Keywords: Atherosclerosis, Blood Glucose, Bone Density, Cardiovascular Diseases, C-Reactive Protein, Depression, Diabetes Mellitus, Follicle Stimulating Hormone, Gonadotropin-Releasing Hormone, Heart Failure, Hemoglobin A, Glycosylated, Hot Flashes, Hypogonadism, Libido, Metabolic Syndrome X, Myocardial Infarction, Myocardial Ischemia, Obesity, Phosphodiesterase 5 Inhibitors, Pituitary Diseases, Polycythemia, Primary Prevention, Spermatogenesis, Resistance Training, Stroke, Testosterone, Triglycerides, Venous Thrombosis

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