Testosterone: a promising adjuvant for a failing heart?

Among the chronic diseases which occur with advancing age, chronic heart failure (CHF) remains one of the leading causes of morbidity and mortality worldwide. In patients with nonedematous cachetic heart failure, the neuroendocrine activation creates an imbalance between the anabolism/catabolism and that explains the pathophysiology and symptomatology of CHF. Therefore cardiac cachexia has been identified as an independent prognostic factor in HF. There is overall anabolic hormone deficiency including testosterone which explains the inflammatory cytokine activation and ventricular remodelling in HF. Replacement of physiological doses of testosterone as an immune modulating therapeutic modality has shown promising results. Although, the evidence to demonstrate that the level of testosterone as an independent prognostic marker in these patients are conflicting.


Introduction
Chronic heart failure (CHF) is a major public health problem causing significant morbidity and mortality 1 .Despite current optimal therapy, patients still experience debilitating symptoms and poor quality of life.
Chronic congestive heart failure is characterized by poor exercise intolerance and dyspnoea and is associated by prolonged neurohormonal activation and proinflammatory cytokine activation which contributes to further deterioration.These mechanisms leads to ananabolic/catabolic imbalance, favouring catabolism, affecting vasodilator capacity and muscle bulk and function 2 .Cachexia is often an unrecognised sign of heart failure and is associated with a poor outcome with no therapy options.
Androgens are an important factor in anabolic function and contribute to muscle strength and function.The imbalance is related to activation of the Vol.42, Nos. 1 & 2, 2011   Testosterone: a promising adjuvant for a failing heart?neuroendocrine and inflammatory systems.The anabolic impairment is a multifaceted phenomenon and is related to abnormalities in at least three key anabolic endocrine axes: gonadal, adrenal, and somatotropic.Patients with CHF develop GH resistance, which results in depletion of IGF-1 in peripheral tissues, thereby promoting skeletal muscle apoptosis 3,4 .A number of different mediators have been implicated in the wasting process, including activation of pro-inflammatory cytokines: tumour necrosis factor, secretion of neurohormones and peptides, including ghrelin, leptin, growth hormone, cortisol, adrenaline, noradrenaline and insulin, and a relative deficiency of micronutrients and macronutrients 4,5,6,7 .Cachexia is more closely associated with hormonal changes in congestive heart failure than symptoms, exercise capacity and left ventricular function 8 .

Role of androgens on heart failure
With aging, there is progressive decline of the secretion of anabolic hormones including testosterone which may play a role in increasing the risk of chronic disease 9 .The rate of decline is estimated at 1% per year after the age of 30 years and further lowers in persons with comorbidities and on medications such as steroids.In chronic heart failure, renin-angiotensinaldosterone (RAA) axis is the most affected endocrinal system.It is often accompanied by disturbances in other endocrinal gland secretions.Some studies have shown deficiencies of testosterone, DHEA-S 3,4,10 and IGF-1 5,11,12 , whereas others have not 4,12,13 .It has been hypothesized that these deficiencies are associated with catabolism and aggravate the symptoms of heart failure and possibly has an impact on the disease progression 14,15 .The occurrence of these disorders depends on the degree of heart failure, increasing with the severity of CHF 16 .Some studies had revealed that patients with HF have marked deficiencies in all three main anabolic hormonal axes TT, DHEAS, and IGF-1.Testosterone deficiency was most evident in the youngest group of men with CHF (<45 years old).The deficiency of total blood testosterone or free testosterone is an independent marker of poor prognosis in HF and significant reduction in blood testosterone identifies groups with a higher mortality 17 .A Chinese study reinforces this fact and they have found that the androgen levels in elderly male patients with chronic heart failure were decreased significantly and the level of FT was negatively correlated with degree of heart failure 18 .Another study showed that levels of TT and eFT are decreased in elderly patients with systolic CHF and related to disease severity, but they are not independent predictors for mortality 19 .
One study revealed that, DHEAS and free testosterone were found to be inversely associated with NYHA class (p<0.01 for both).Adjustment for age and NYHA class slightly diminished the prognostic value of the androgens and SHBG, whereas when variables were identified that were associated with both the respective hormone and the outcome and when the level of adjustment was expanded to the full list of those confounders, any prognostic significance of free testosterone, DHEAS or SHBG vanished.Confounders included renal function, the presence of atrial fibrillation, the systolic blood pressure, C-reactive protein, NTproBNP, cortisol, total cholesterol and medication including the use of statins, diuretics and ACE inhibitors 20 .
It has been suggested that a low testosterone level may represent one of the factors contributing to the anabolic/catabolic imbalance characteristically present in many patients with advanced CHF 21 .However, this causal contribution of testosterone deficiency to worsening outcome in heart failure is still not proven completely as studies on the prognostic significance of serum levels of androgens in chronic heart failure have yielded conflicting results 22 .

Effect of immune mediators on heart failure
The role of cytokine network in the pathogenesis of CHF has been gathering research interest.Serum levels of proinflammatory cytokines such as serum tumor necrosis factor (TNF-a) are increased in CHF patients, whereas anti-inflammatory cytokines such as interleukin-10 (IL-10) are decreased.This imbalance in the inflammation and anti-inflammation pathways may result in decreased myocardial contractility, ventricular dilatation, myocardial remodelling, increased cardiac myocyte apoptosis, and cardiac cachexia.TNF-levels are independent predictors of mortality in patients with advanced heart failure 23 .Moreover, TNF-α is one of the most important stimulus of matrix metalloproteinase (MMP), which are the most important proteolysis system in the process of extracellular matrix degradation.Activation of MMP that induces extracellular matrix fibrosis is an important character of ventricular remodelling 24 .
Therefore morphological and functional muscle abnormalities are present in patients with CHF, including fibre atrophy and a prevalence of type II fibres with a predominance of glycolytic over oxidative metabolism.The 'muscle hypothesis' in heart failure proposes that muscle alterations in CHF trigger prolonged neurohumoral and inflammatory activation and abnormal haemodynamic, autonomic and ventilatory responses to exercise; these may contribute C M Wickramatilake, M R Mohideen, C Pathirana to heart failure symptomatology and also be involved in the pathophysiology of the heart failure syndrome 25 .

Treatment modalities for CHF
The traditional approaches of heart failure therapy from symptoms relief through diuretics, vasodilators and inotropic agents have contributed to mortality improvement strategy through use of angiotensin converting enzyme inhibitors, beta-blockers and aldosterone receptor antagonists.However, despite optimal pharmacological therapy, mortality of heart failure remains high suggesting that there could be other pathogenic mechanisms that remain unexplained and thereby unmodified by current therapy.Persistent immune activation and inflammation may represent such 'unmodified mechanisms'.
Immunomodulatory therapy has been applied to restore the inflammatory imbalance in patients with CHF as a new mode of therapy.The immunomodulatory regimens include some broad-spectrum antiinflammatory agents such as testosterone, immunoglobulin, growth hormone and statins, which have been shown to improve the symptoms and prognosis of CHF by modulating inflammatory cytokine network 26,27 .
Correcting sex steroid axes in chronic heart failure has largely concentrated on testosterone replacement.Several animal studies and small clinical trials have suggested that testosterone treatment may increase cardiac output, reduce peripheral vascular resistance and improve exercise capacity, but the mechanism of benefit of therapy was unclear; the functional improvement was thought to be due to an effect of testosterone on skeletal muscle rather than on myocardium 28,29,30,31,32 .The beneficial effect appears to be at doses that correct the deficiency as supraphysiological doses have produced unwanted cardiac effects.
Effect of testosterone therapy on ventricular remodelling in HF is explained by different mechanisms.Testosterone receptors are present in endothelial cells, vascular smooth muscle cells and cardiomyocytes.On the vascular arterial wall, testosterone induces vasodilation; in cardiomyocytes, it induces protein synthesis and hypertrophy 21 .
An important character of ventricular remodelling during heart failure is extracellular matrix fibrosis or over degradations.MMP is the most important proteolysis system in the process of extracellular matrix degradation and play a vital role in ventricular remodelling in chronic heart failure.TNF-α is one of the most important stimulus of MMP 33 .Some studies found that the expression of MMP-9-mRNA in myocardial tissue of the placebo group is increased significantly, whilst testosterone therapy diminishes the myocardial expression of MMP-9-mRNA (34).
Hydroxyproline mainly resides in collagen protein.
The hydroxyproline contents in the myocardium reflect the extent of collagen deposition.One study shows that the myocardial hydroxyproline contents are increased following heart failure.Testosterone therapy reduces the myocardial hydroxyproline contents, diminishing excessive proliferation of collagen protein, thus preventing ventricular remodelling.These beneficial effects of testosterone are likely to be mediated by suppressing TNF-α or by down-regulating MMP-9 directly as described above 33,34,35 .

Clinical implications and conclusions
This review summarises the evidence from epidemiological studies and some clinical trials showing the relationship of testosterone levels to severity and prognosis of heart failure.Although some studies have demonstrated that low serum levels of testosterone relationship to prognosis is confounded by comorbid condition and medication, there are others that indicate androgen deficiency aggravate heart failure symptoms and accelerate disease progression.
The studies reviewed in this article suggest that cardiac cachexia is directly related to the prognosis of heart failure and the symptomatology and the pathophysiology is related to the neuroendocrine activation and the inflammatory process which seemed to be modulated by restoring the anabolic hormones such as testosterone which possess immune modulatory effects.The lack of long-term studies with testosterone replacement makes it difficult to recommend this treatment as yet, but its value as a therapy for augmenting skeletal muscle strength in patients with congestive heart failure is promising.
Although different mechanisms have been described the impact of low testosterone on the outcome of HF and effect of replacement, further studies are required in establishing the mechanism completely.There are also certain issues to resolve: such as a defining cut off values for the deficiency status of testosterone which may lead to underestimate or overestimate the prevalenceof androgen deficiency.Similarly the cause of this high prevalence of biochemical hypogonadism and its significance remains unclear.
In conclusion, in men with heart failure, testosterone was found to be closely associated with disease severity.The prognostic utility of testosterone Vol.42, Nos. 1 & 2, 2011   Testosterone: a promising adjuvant for a failing heart?depended on other factors that confounded the relation between testosterone and mortality risk, questioning a causal role of androgens in the pathophysiology and clinical course of heart failure.
To date, testosterone therapy has shown some positive benefits, although there are some concerns over adverse effects.However, large randomized controlled trials are still needed to assess the longterm safety and efficacy.Until such time, testosterone will remain an exciting novel therapy for heart failure that will have to wait its turn to fulfil the rigors of testing.

Testosterone: a promising
AbbreviationsHF -Heart failure SHBG -Sex hormone binding globulin CHF -Chronic heart failure NTproBNP -N-terminal fragment of prohormone Btype natriuretic peptide RHF -Right heart failure MMP -Matrix metalloproteinase NYHA -New York Heart Association TNF -Tumour necrosis factor GH -Growth hormone IL -Interleukin IGF -Insulin like growth factor mRNA -Messenger ribonucleic acid TT -Total testosterone LVEF -Left ventricular ejection fraction FT -Free testosterone