P.J. Pugh, K.M. English, T.H. Jones1 and K.S. Channer
From the Department of Cardiology, Royal Hallamshire Hospital 1 Department of
Human Metabolism and Clinical Biochemistry, University of Sheffield, Sheffield,
UK
Introduction
Chronic congestive heart failure (CHF) remains a significant cause of mortality
and morbidity in the UK, accounting for 5% of acute hospital admissions and 1%
of the total NHS budget.1 Coronary artery disease (CAD) and hypertension are
the most commonly associated conditions. The condition is characterized by left
ventricular dysfunction, impaired vascular tone and skeletal muscle
abnormalities, producing 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 mainstay of current therapy includes 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 good alternative.2 More recently, reduced mortality has been
demonstrated from the use of both beta-blockers and the aldosterone receptor
antagonist spironolactone.3,4 Vasodilators may 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.
There remains, therefore, a need for therapies which alleviate the suffering
associated with CHF, as well as reducing mortality. Potential strategies under
evaluation include anti-cytokine therapy and inhibitors of neutral
endopeptidases, 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 clinical data to support this.6 In this
article, we review the cardiovascular and neuro-hormonal actions of
testosterone, and discuss how androgen therapy may be of benefit to men with
chronic heart failure.
Gonadal function in men with CHF
No studies have sought specifically to determine 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.7 In 17 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.8,9 In an animal model of
heart failure, hamsters with cardiomyopathy were found to have very low
testosterone levels.10
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. Epidemiological data suggest that men with ischaemic heart
disease have low androgen levels, and men with proven coronary atheroma have
lower testosterone levels than healthy controls.11,12 In animals, castration
promotes atherosclerosis while androgen therapy retards it.13 Similarly,
hypertensive men have relatively low androgen levels, which show an inverse
correlation with blood pressure.11 Men with CHF, therefore, are likely to have
low testosterone levels, potentially exacerbating the catabolic imbalance.
Effects on cardiovascular function
There are no clinical trial data concerning the effects of testosterone on left
ventricular function. In rats, androgen therapy improves coronary blood flow
and increases both fractional shortening and peak myocardial oxygen
consumption, thereby improving cardiac function.14 Castration results in
reduced ejection fraction and diastolic dysfunction, with alteration of the
isoenzyme composition of the myosin heavy chain.14
Testosterone therapy has been used to treat men with angina; the beneficial
effects on both ischaemia and exercise tolerance have been demonstrated in
several studies (see Table 1).
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Table 1 Studies of testosterone therapy for men with angina
Numerous reports from animal studies have demonstrated the vasodilator
properties of androgens in several vascular beds, both in vitro and in vivo
(see Table 2). In humans, testosterone reduces blood pressure and enhances
relaxation of brachial arteries; direct injection into coronary arteries
produces dilatation and increased coronary blood flow.3941 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.
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Table 2 Animal studies of effects of androgens on vascular tone
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 fibre type and mitochondrial structure
are altered, with reduction in the enzymes of the Krebs cycle and oxidative
chain.42 These features may arise from the catabolic effects of neuro-hormonal
and cytokine activity. Also, endothelial function is impaired in CHF, resulting
in reduced peripheral vasodilator capacity and muscle hypoperfusion.
Testosterone may counter these deleterious effects both by its vasodilator
action and by promoting protein synthesis and blocking the catabolic action of
glucocorticoids.6 The anabolic effects of androgens are well described in
healthy men, producing skeletal muscle hypertrophy and increased muscle bulk
and strength.43
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.4446
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.
Neuro-hormonal activity
In recent years, advances in our understanding of the role hormones play in the
progression, morbidity and mortality of CHF have directed modern therapy at
reducing hormonal activity. Patients have varying degrees of hormonal
activation which results in a catabolic/anabolic imbalance, ranging from a rise
in the cortisol/DHEA ratio to elevation of circulating catecholamines, cortisol,
aldosterone and plasma renin activity.7 Levels of anabolic factors, including
testosterone and insulin-like growth factor-1 (IGF-1), are depressed, and
insulin resistance may develop.47,48
Although the effects of androgens on hormonal activation in CHF have not been
studied, it would seem logical to oppose excess catabolism with anabolism.
Testosterone has been found to increase IGF-1 levels and reduce
hyperinsulinaemia and insulin resistance.39,49 In addition, in animal
experiments, the increased release of atrial natriuretic peptide (ANP) which
results from cardiac overload is reduced by testosterone, an effect which may
have positive prognostic implications.50
Cytokine activation
It is now recognized that cytokine activation is likely to play an important
role in the progression of cardiac failure. The cytokine hypothesis of
heart failure is perhaps a natural progression of the neurohumoral theory and
is based on the known actions of several cytokines.51 Circulating levels of
tumour necrosis factor (TNF) and interleukin-6 (Il-6) are elevated in CHF and
independently predict mortality.52 The levels correlate adversely with several
prognostic markers, including NYHA class, exercise tolerance and myocardial
oxygen consumption, as well as plasma levels of ANP, catecholamines,
endothelin-1 and angiotensin II.5254
TNF is produced mainly by macrophages, but also by the myocardium in CHF. It
impairs synthesis and promotes catabolism of skeletal muscle, and reduces
testosterone production. It causes endothelial dysfunction and impairs
production of NO by endothelium.55 Administration causes left ventricular
dysfunction and heart failure in humans; anti-TNF therapy may improve cardiac
function.56,57 Cytokines therefore appear to mediate many of the
pathophysiological processes of heart failure.
The immune-modulatory properties of androgens have been well described. In
various disease models (though not in heart failure), androgens have been found
to significantly suppress macrophage production of cytokines both in vitro and
in vivo (see Table 3). In man, androgen levels correlate negatively with plasma
cytokine levels and gonadotropin therapy suppresses the high level seen in
hypogonadal men.72
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Table 3 Effects of androgens on cytokine activity
These findings suggest another important mechanism by which androgen therapy
could improve outcome in men with CHF.
Conclusion
Patients with chronic heart failure suffer considerable morbidity as well as
early mortality. They exhibit altered structure and function of cardiac and
skeletal muscle and excessive activation of catabolic hormones and inflammatory
cytokines. Men with CHF have relatively low androgen levels, which may
contribute to the pathophysiological process. Androgen replacement therapy
could potentially ameliorate symptoms by improving cardiac and vascular
function and increasing strength and endurance. It may also redress the
catabolic/anabolic imbalance of chronic CHF and suppress the cytokine
activation which leads to progression of the disease. Clinical trials are
needed to evaluate the effects of androgen therapy for chronic congestive heart
failure.
Notes
Address correspondence to Dr K.S. Channer, Room 131, M Floor, Royal Hallamshire
Hospital, Glossop Road, Sheffield S10 2JF. e-mail:
kevin.channer@csuh.nhs.uk
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