by Ed Barillas, Staff Writer
In this article, we will review the cardiovascular and neuro-hormonal actions of testosterone, and how androgen therapy may be of benefit to men with chronic heart failure. Chronic congestive heart failure (CHF) remains a significant cause of mortality and morbidity, which accounts for 5% of acute hospital admissions. Hypertension and coronary artery disease are the most commonly associated conditions. The condition is characterized by left ventricular dysfunction, skeletal muscle abnormalities and impaired vascular tone, which produce breathlessness and fatigue. Neuro-hormonal and cytokine activation are self-perpetuating maladaptive responses to the failing heart, which cause further deterioration in cardiac function and increased catabolism. The most common current therapies include diuretics and neuro-hormonal manipulation; ACE inhibitors are well established as the most important intervention for improving prognosis, and angiotensin II receptor antagonists offer a positive alternative. Reduced mortality has been demonstrated from the use of both beta-blockers and the aldosterone receptor antagonist spironolactone. Vasodilators also provide symptomatic and prognostic benefit. However, the only therapy offering long-term survival is cardiac transplantation, which remains limited by lack of donors and recipient suitability.
A need for therapies that alleviate the suffering associated with CHF, as well as reducing mortality are needed as there are potential strategies under evaluation including anti-cytokine therapy and inhibitors of neutral endo-peptidases, which prevent breakdown of natriuretic peptides.
Testosterone therapy has also been proposed as a useful add-on treatment for men with CHF, although there are currently no conclusive clinical data to support this. As far as the Gonadal function in men with CHF there have been no studies that have determined gonadal function in men with heart failure. However, several small studies suggest that these patients may have relatively low androgen levels. A study of 53 men with CHF found that dehydroepiandrosterone (DHEA) levels were significantly lower than in healthy controls. In 20 men with non-ischaemic cardiomyopathy, testosterone levels correlated with cardiac index, and five men with severe left ventricular dysfunction had markedly reduced plasma testosterone, which normalized 2 months after implantation of a ventricular assist device. In an animal model of heart failure, hamsters with cardiomyopathy were found to have very low testosterone levels.
These findings are perhaps to be expected given the effect of chronic disease on gonadal function. However, there is also a link between hypotestosteronaemia and stable CAD. There is epidemiological data that suggest that men with ischaemic heart disease have low androgen levels, and men with proven coronary atheroma have lower testosterone levels than healthy controls. In animals, castration promotes atherosclerosis while androgen therapy retards it. Similarly, hypertensive men have relatively low androgen levels, which show an inverse correlation with blood pressure. Men with CHF, therefore, are likely to have low testosterone levels, potentially exacerbating the catabolic imbalance.
When it pertains to the effects on cardiovascular function there is no clinical trial data concerning the effects of testosterone on left ventricular functions. In rats for example, androgen therapy improves coronary blood flow and increases both fractional shortening and peak myocardial oxygen consumption, thereby improving cardiac function. Castration results in reduced ejection fraction and diastolic dysfunction, with alteration of the isoenzyme composition of the myosin heavy chain.
Testosterone therapy has also been used to treat men with angina; the beneficial effects on both ischaemia and exercise tolerance have been demonstrated in several studies.
Numerous reports from animal studies have demonstrated the vasodilator properties of androgens in several vascular beds, both in vitro and in vivo. In humans, testosterone reduces blood pressure and enhances relaxation of brachial arteries; direct injection into coronary arteries results in a dilatation and increased coronary blood flow. Low circulating levels of testosterone may therefore contribute to the generalized increase in vascular tone found in patients with CHF. A vasodilator effect could be important in relieving pulmonary congestion and improving peripheral perfusion. Androgen therapy could therefore also improve cardiac function by reducing pre-load and after-load and by increasing coronary blood flow.
As far as skeletal muscle and strength, fatigue and poor exercise tolerance are central features of the symptoms of heart failure, and may be out of proportion to the degree of left ventricular dysfunction. Patients with CHF suffer loss of skeletal muscle mass with reduced muscle strength and endurance. Muscle fiber type and mitochondrial structure are altered, with reduction in the enzymes of the Krebs cycle and oxidative chain. These features may arise from the catabolic effects of neuro-hormonal and cytokine activity. In as such, endothelial function is impaired in CHF, resulting in reduced peripheral vasodilator capacity and muscle hypo-perfusion.
Testosterone may counter these deleterious effects both by its vasodilator action and by promoting protein synthesis and blocking the catabolic action of glucocorticoids. The anabolic effects of androgens are well described in healthy men, producing skeletal muscle hypertrophy and increased muscle bulk and strength. There have been no studies of the effects of androgen therapy on strength and endurance in heart failure. However, several small studies have evaluated testosterone therapy in elderly men. These showed improvement in grip and leg strength as well as an increase in lean body mass.
Testosterone deficiency is likely to contribute to the weakness and fatigue of CHF which constitute a major aspect of the morbidity. Androgen therapy could potentially improve patient well-being by combating this.