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Cardiovascular disease and testosterone therapy: Dangerous or protective?
Testosterone deficiency is common in men with cardiovascular disease, and randomized placebo‑controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise‑induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO2max) and muscle strength in chronic heart failure, shortening of the Q‑T interval, and improvement of some cardiovascular risk factors.1 Testosterone deficiency is associated with an adverse cardiovascular disease risk profile and mortality.
Experimental and clinical studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid‑onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance. Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L‑calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra‑rapid potassium channel‑operated current. Testosterone improves cardiac output, functional exercise capacity, VO2max and vagally mediated arterial baroreceptor cardiac reflex sensitivity in chronic heart failure. Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, which could contribute to the improvement in functional exercise capacity. Testosterone improves metabolic cardiovascular disease risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism.1
All-cause mortality, cardiovascular mortality and prevalence of testosterone deficiency was investigated in men with coronary disease referred for diagnostic angiography who were followed up for nearly 7 years. The overall prevalence of biochemical testosterone deficiency was 24%. It as found that men with low bioavailable testosterone had a 2.3-fold higher all-cause and cardiovascular mortality than men with normal bioavailable testosterone.2
Between 1939 and 1946 several studies were published showing beneficial effects of testosterone treatment in angina patients, with consistent improvement in chest pain. In 2000 a randomized placebo controlled trial showed that testosterone treatment in men with chronic stable angina significantly reduces exercise-induced myocardial ischemia.3 The likely explanation for this comes from another study, which demonstrated that intracoronary administration of testosterone, at physiological concentrations, induces coronary artery dilatation and increases coronary blood flow in men with established coronary artery disease.4
Chronic heart failure is associated with maladaptive and prolonged neurohormonal and proinflammatory cytokine activation, causing a metabolic shift favouring catabolism, vasodilator incapacity, and loss of skeletal muscle bulk and function. Testosterone therapy improves functional capacity and symptoms in men with moderately severe heart failure.5
Low testosterone causes long EKG QT-intervals and testosterone therapy shortens the QT-interval. Short QT-interval is associated with reduced risk of atrial fibrillation. In accordance with this, it has been shown that effective testosterone therapy, which results in normalization of testosterone levels, is associated with a significant decrease in the incidence of atrial fibrillation.6
T. Hugh Jones Centre for Diabetes & Endocrinology, Barnsley Hospital NHS Foundation Trust Academic Unit of Diabetes, Endocrinology & Metabolism, University of Sheffield UK
Jones TH, Kelly DM. Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system. Asian J Androl. 2018 Mar-Apr;20(2):120-130.Return to content
Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS. Low serum testosterone and increased mortality in men with coronary heart disease. Heart. 2010 Nov;96(22):1821-5.Return to content
English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: A randomized, double-blind, placebo-controlled study. Circulation. 2000 Oct 17;102(16):1906-11.Return to content
Webb CM, McNeill JG, Hayward CS, et al. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation. 1999;100:1690 –1696.Return to content
Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J. 2006 Jan;27(1):57-64.Return to content
Sharma R, Oni OA, Gupta K, Sharma M, Sharma R, Singh V, Parashara D, Kamalakar S, Dawn B, Chen G, Ambrose JA, Barua RS. Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. J Am Heart Assoc. 2017 May 9;6(5).Return to content