Abstract: Testosterone deficiency syndrome (TDS) induces several negative effects that generally involve different organs such as testis, bone, skeletal muscle, and heart, leading to reduction in testis function, causing osteoporosis, strongly reducing muscle mass, decreasing exercise capacity and strength and facilitating heart failure. Approximately 25% of patients affected by chronic heart failure (CHF) is characterized by plasma Testosterone (T) levels below normal ranges also related to disease progression. In addition, reduction of circulating testosterone levels may contribute to some specific features of CHF, such as abnormal energy handling, weakness, dyspnoea and cachexia in particular. According to some recent evidence it has emerged that testosterone replacement therapy (TRT) may improve muscle strength and functional pulmonary capacity in CHF men with TDS. This review will place emphasis on the pathophysiological role of testosterone deficiency in CHF men as well as the effects of the testosterone replacement therapy.

Introduction

Chronic heart failure (CHF) is a growing health problem throughout the world, especially as a consequence of the evident ageing of western populations [1]. CHF is a syndrome characterized by an anabolic-catabolic imbalance of both the peripheral skeletal muscles and the heart which might involve the neurohumoral, the endocrine and the metabolic systems. The impairment of major anabolic systems (somatotropic, adrenal and gonadal) may be thought of as widely involved in the CHF pathophysiology and especially low serum Testosterone (T) levels have been correlated to the symptoms severity and the adverse outcomes in men suffering from CHF [2, 3]. This latest assumption was related to the rise in cardiovascular disease (CVD) in men affected by testosterone deficiency syndrome (TDS) and was put forward by various prospective studies carried out for decades [4-23]. On the other hand, it is noteworthy that heart failure (HF) as an illness can affect sex steroid metabolism [24]. Furthermore, patients affected by metabolic diseases, such as diabetes [25], metabolic syndrome [26] and especially obesity [27], which per se may favor the onset and progression of CHF, often present low circulating T levels or overt hypogonadism. Elderly men may experience a prolonged mild or severe hypotestosteronemia which can affect metabolic diseases and over the time worsen heart failure outcomes too. Furthermore, the reduction in T levels is a main predictor of decreased peak of oxygen consumption (VO2), an independent risk marker for impaired exercise capacity and a poor prognostic factor in men with CHF [28-30].

The purpose of this review is to sum up the available evidence on the role of the T deficiency syndrome (TDS) as a modifiable pathogenic factor in HF as well as to highlight both the positive and the potential side effects of T replacement therapy (TRT) in men suffering from CHF.

Androgen Deficiency Syndrome and it's treatment in men

Male hypogonadism is very often a chronic syndrome characterized by low total testosterone (T) levels and its free fractions (FT), being clinical signs dependent on the age of onset. Indeed, if it begins at a very early age, at birth, or at prepuberty, it can easily be diagnosed as most of its symptoms are typical (female or intersexual internal and external genitalia, hypospadias, absent or incomplete pubertal development, eunuchoid body proportions, persistence of prepubertal external genitalia, cryptorchidism, etc). By contrast, the late-onset form is characterized by symptoms and signs that are often unspecific and mimic the natural men ageing (weakness, obesity, fatigue, low libido, depression, mild anemia, sleep disturbances and osteoporosis, type 2 diabetes mellitus, etc) and cannot be easily diagnosed [31].

Hypogonadism is classified according to the level of the hypothalamus-pituitary-testis axis involved. We can define a condition of primary hypogonadism when the main problem involves the testis. In this case the Luteinizing Hormone (LH) and the Follicle Stimulating Hormone (FSH) levels are usually elevated (hypergonadotropic hypogonadism). Hypogonadism is defined as secondary when the hypothalamus and/or the pituitary are involved and low circulating T levels are commonly associated with low or inadequately normal levels of LH and FSH (hypogonadotropic hypogonadism) [32].

According to the Endocrine Society [33] and recent consensus statements of major Societies in the field [34], a diagnosis of androgen deficiency or hypogonadism requires the presence of typical symptoms besides the establishment of low T levels (< 280 ng/dl) by laboratory assessment. Indeed, it is recommended that serum T should only be assessed in those patients who are affected by clinical disorders at high risk for low serum T, whilst a widespread evaluation of serum T is strongly discouraged (Table 1). The determination of serum FT is only recommended in the presence of total T levels within the “grey zone” (250-350 ng/dl) or in the presence of remarkable modifications of Sex Hormone Binding Globulin (SHBG) levels such as in obese men [27] or in those who suffer from metabolic syndrome or overt diabetes mellitus [35]. Since the method considered as the gold standard (dialysis method) for the FT measurement is extremely complicated, time consuming and not routinely available in laboratories, the FT evaluation can be calculated by Vermeulen’s formula, knowing in advance the circulating levels of SHBG and the total T fraction [36]: FT levels lower than 65 pg/ml (0,225 nmol/l) are suggestive of overt hypogonadism and require TRT [37]. Finally, if low serum total testosterone levels are found (< 150 ng/dl), it is advisable to measure the gonadotrophins and the serum PRL in order to exclude any serious problems at the hypothalamus-pituitary level and/or at the testicular level [33].

Different formulations for TRT have been commercialized so far (Table 2), although those more recently launched on market (trans-cutaneous T gel and long-acting intramuscular compounds) have documented a greater capability to reproduce the T circadian rhythm and to keep the circulating T levels within the normal range than the older ones [32]. The absolute contraindications to testosterone treatment include prostate and breast cancer as well as erythrocytosis, although severe liver, kidney or pulmonary diseases, uncontrolled hypertension, limitation in mobility and frailty seem to be important factors that one should take into consideration whenever starting the T therapy [32, 33, 52].

Pathophysiological role of T Deficiency in CHF men

Heart failure (HF) is a common, costly, disabling, and potentially deadly condition in western countries, affecting about 2% of adults and up to 6-10 % of people over the age of 65. The most frequent causes and risk factors which can lead to HF are hypertension, atherosclerosis, obesity, diabetes mellitus, hypercholesterolemia, ischemic heart disease [38]. As hypogonadism in men may favor the onset of abdominal obesity [27] and type 2 diabetes mellitus [35], as well as lead to an unfavorable lipid profile, hypertension [39], atherosclerosis [40] and aortic aneurysm [41], it has been hypothesized that it might be instrumental in the onset and progression of cadiovascular diseases (CVD) and HF.

Concerning low serum T levels and mortality in men, current evidence has been conflicting until now. As a matter of fact, some studies carried out in elderly men in particular, showed increased mortality rate [22, 42-46]. Furthermore, in men with coronary heart disease or CHF, low serum T levels resulted to be related to higher mortality [47] and disease severity [48]. On the other hand, several other studies have reported no correlation between low T levels and mortality [49, 50] most likely because the examined population was younger than in previous studies. A recent meta-analysis and a cross-sectional study, both conducted by Ruige et al., [51, 52], have provided no association between endogenous T and CVD risk in middle-aged men, whilst in elderly men it is unclear whether low T may have a direct negative effect on CVD or should it be considered as a poor general health parameter. In addition, this issue remains rather conflicting in the light of recent results from a randomized controlled trial (RCT) which reported a high rate of testosterone replacement therapy-associated cardiovascular adverse events in those elderly men suffering from hypogonadism (serum T below 12 nmol/l) and chronic diseases with important limitations in mobility [53]. In men with CHF, low serum T and low calculated T/ Estradiol (E2) ratio can be also due to an increased peripheral aromatization of T to E2 [24], even more in those suffering from metabolic diseases such as obesity and overt type 2 diabetes mellitus [24-25]. A recent meta-analysis [54] has led to the conclusion that there are no evident harmful or beneficial effects of augmented serum E2 in men at risk for incidental CVD and an increased level of E2, if present, might be correlated with Body Mass Index (BMI). Therefore, these results focus our attention on alterations of gonadic sex steroids pattern as a parameter of poor general health in men [26] which can negatively influence different risk factors (hyperlipemia, hypertension, hyperglycemia etc). In turn, this might contribute to worsen the metabolic syndrome, obesity and diabetes mellitus [27, 55-57] that often lead to complications such as CVD and HF. As a result, in men with diabetes mellitus and hypogonadism the TRT might be aimed at improving metabolic control and reducing CV risk and microvascular complications eventually [32, 35].

It is commonly accepted that anabolic/catabolic imbalance which facilitates catabolism, is the main pathophysiological factor that can impair heart compensation in patients with advanced CHF [58, 59]. Different studies showed a significant reduction in serum concentrations of anabolic hormones, including testosterone, in men affected by CHF as well as a direct and independent relationship between serum T reduction and both the peak oxygen consumption and the peak oxygen pulse in men with CHF. This may indicate that low T might be a marker of poor prognosis, independent of conventional risk predictors and of the underlying cause of CHF [28, 30]. Moreover, low T levels seem to account for the magnitude of deterioration in peak VO2 over time, whilst other indices related to the progression of heart disease, did not predict the deterioration of exercise capacity, thus indicating that T deficit plays a crucial role in the progressive deterioration of functional capacity in male affected by CHF. Anabolic hormones are determinants of exercise capacity and the age-related decline in circulating T and in other anabolic hormones such as weak androgens (dehydroepiandrosterone and its sulphate) and insulin-like growth factor 1 (IGF-1) may contribute to gradually impaired exercise tolerance in elderly men [60, 61]. Androgen receptors are present in myocytes from multiple species including humans [62] and, in this context, they can modulate both ventricular structure and function [63, 64]. Testosterone can stimulate hypertrophy of both type I (oxidative ‘‘slow twitch’’) and type II (glycolityc ‘‘fast twitch’’) muscle fibers, although the former may be quite sensitive to anabolic agents than the latter, given that type II muscle fibers are able to enlarge only in response to the administration of high testosterone doses [65, 66]. Furthermore, T effects on muscle fibers might involve modifications in the expression of many muscle growth regulators such as IGF-I, IGF-binding protein-3, and myostatin [67]. Testosterone also seems to have positive effects on the cardiomyocyte function as documented by different researches in rats and in humans [68, 69]. This protective effect consists of a reduction in QT interval and arrhythmia susceptibility, modulating the early phase of ventricular repolarization by increasing NO production, channel K+ kinetics [68] and intracellular calcium [69]. Moreover, it may inhibit the cardiomyocyte apoptosis and the damage of both ventricles during HF and/or myocardial injury modulating local cytokine production such as the Tumor Necrosis Factor-alpha (TNF-

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