Abstract
Background: Deficiencies of anabolic hormones are common in men with heart failure (HF). It remains unclear whether the deranged metabolism of these hormones is the pathophysiological element of HF itself or is the consequence of co-morbidities or/and treatment in HF.
Methods: We examined 382 men with systolic HF. Serum hormones (i.e. total testosterone [TT], DHEAS, IGF-1) were assessed using immunoassays, serum free testosterone (eFT) – using the Vermeulen equation.
Results: Prevalence of TT and eFT deficiencies was similar in men with HF aged < versus ≥60 years (23% and 32% for TT and eFT deficiencies). Deficiencies in DHEAS and IGF-1 were more common in younger (63% and 92%) than older patients (48% and 73%). In men <60 years, TT deficiency was accompanied by the therapy with digoxin, eFT deficiency – the therapy with digoxin and the presence of diabetes, DHEAS deficiency – the therapy with loop diuretic (all p < 0.05). In men ≥60 years, TT deficiency – the therapy with loop diuretic, DHEAS deficiency – the therapy with spironolactone and digoxin, and hsCRP, IGF-1 deficiency – the high hsCRP (all p < 0.05).
Conclusions: Deficiencies in anabolic hormones are common in younger and older men with HF. Some therapies (but not major co-morbidities) may contribute to anabolic deficiencies.
Introduction
The fundamental feature of male aging is a gradual age-related decline in circulating major anabolic hormones, i.e. testosterone, dehydroepiandrosterone sulphate (DHEAS) and insulin-like growth factor 1 (IGF-1) [Citation1–4]. There is enormous evidence indicating that these age-related hormone derangements have several unfavorable consequences for male health, including the structure and functioning of cardiovascular system [Citation5,Citation6].
Currently, heart failure (HF) is the only cardiovascular pathology of increasing occurrence and prevalence in contemporary populations [Citation7]. Importantly, it is mainly the consequence of worldwide aging of modern societies, as HF occurs commonly particularly in elderly people, being often described as a cardiogeriatric syndrome [Citation8].
Anabolic deficiencies accompanying male aging are particularly common in men with systolic HF and have serious disadvantageous clinical and prognostic consequences [Citation6,Citation9–12]. Previously, we have demonstrated that testosterone deficiency is associated with impaired exercise capacity [Citation13], deficiencies in testosterone and IGF-1 are accompanied by low haemoglobin [Citation14], whereas deficiencies in testosterone and DHEAS are related to more severe depressive symptoms in men with systolic HF [Citation15]. Most importantly, deficiencies in these three anabolic hormones independently of each other and of other established prognosticators constitute the strong predictors of increased 3-year mortality in men with systolic HF [Citation6].
The origin of the aforementioned hormone derangements in men with HF remains unclear, however, several pathological mechanisms triggering the development of anabolic deficiencies during the progression of HF have been proposed. According to some experts, it is suggested that deficiencies in anabolic hormones seen in men with HF may just be the consequence of concomitant co-morbidities (e.g. chronic obstructive pulmonary disease [COPD] [Citation16], diabetes [Citation17]) and/or applied therapies recommended in HF (e.g. treatment with non-selective aldosterone antagonist [Citation18–21], digoxin [Citation22,Citation23]). However, the available evidence in this field remains equivocal [Citation18,Citation20,Citation24].
Therefore, we have performed the study in order to establish the prevalence of anabolic deficiencies in a broad cohort of men with stable systolic HF, and to investigate the potential associations between these hormone abnormalities and the presence of major co-morbidities or/and applied treatment recommended in HF.
Methods
Study population
We examined male patients with systolic HF who were electively hospitalized or attended the outpatient clinic in Center for Heart Diseases, Military Hospital (Wroclaw, Poland). There were the following inclusion criteria: (1) a > 6 month documented history of HF; (2) left ventricular ejection fraction (LVEF) ≤45% assessed by echocardiography indicating systolic dysfunction; (3) clinical stability and unchanged medications within ≥1 month preceding the study. There were the following exclusion criteria: (1) acute coronary syndrome or/and coronary revascularization within ≥6 months preceding the study; (2) HF decompensation within ≥3 months preceding the study; (3) any hormonal treatment (at the time of the study or in the past).
The study protocol was approved by the local ethics committee, and all subjects gave written informed consent. The study was conducted in accordance with the Helsinki Declaration.
Study protocol
Each patient underwent a physical examination with routine laboratory tests and standard transthoracic echocardiography. In all patients venous blood samples were taken in the morning after an overnight fast. After centrifugation serum was collected and frozen at −70 °C until being further analyzed.
Serum levels of anabolic hormones and other laboratory measurements
Serum levels of total testosterone (TT) and DHEAS were measured using electrochemiluminescence (Elecsys 2010, Roche Diagnostics GmbH, Mannheim, Germany) and expressed in ng/mL. Serum IGF-1 (ng/mL) was assessed using immunochemiluminescence (Immulite 2000/2500, Diagnostic Products Corporation, San Francisco, CA). Serum level of free testosterone was estimated (eFT) using the validated equation of Vermeulen et al. [Citation25].
Anabolic deficiency with regard to TT, eFT (gonadal androgen deficiency), DHEAS (adrenal androgen deficiency) and IGF-1 was defined as a serum hormone level ≤ the 10th percentile calculated for the equivalent age categories of healthy Polish men, as previously described [Citation13,Citation15]. There were the following values of the 10th percentile of hormone levels in subsequent age categories (≤45, 46–55, 56–65 and ≥66 years, respectively): 3.2, 3.0, 2.7 and 2.6 ng/mL for serum TT, 77, 64, 59 and 52 pg/mL for serum eFT, 1411, 1048, 709 and 310 ng/mL for serum DHEAS, and 258, 227, 216 and 168 ng/mL for serum IGF-1 [Citation6].
Plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) was measured using electrochemiluminescene (Elecsys 1010/2010 System, Roche Diagnostics GmbH, Mannheim, Germany).
Renal function was assessed using the estimated glomerular filtration rate (GFR, mL/min/1.73 m2), calculated from the Modification of Diet in Renal Disease equation [Citation26].
Serum high-sensitive C-reactive protein (hsCRP, mg/L) was assessed using immunonephelometry (Dade Behring, Marburg GmbH, Germany).
Statistical analysis
Normally distributed continuous variables were presented as means ± standard deviations. The intergroup differences were tested using the Student t-test. Variables with a skewed distribution were expressed as medians with lower and upper quartiles. They were log transformed in order to normalize their distribution. The categorical variables were expressed as numbers with percentages. The intergroup differences were tested using the χ2 test.
The associations between the presence of hormone deficiency and clinical variables were assessed using the univariable and multivariable logistic regressions, separately in younger (aged <60 years) and older men with systolic HF (aged ≥ 60 years). For the univariable logistic regression models as the potential associates with the presence of particular anabolic deficiency, we included the following variables: body mass index (BMI) (≥versus <30 kg/m2, i.e. the presence of obesity), ischaemic HF aetiology (yes versus no), NYHA (New York Heart Association) functional class (III-IV versus I-II), LVEF (≤versus >35%, a lower quartile), plasma NT-proBNP (≥versus <2000 pg/mL, a cut-off indicating significantly increased plasma NT-proBNP in HF), serum hsCRP (≥versus <7.78 mg/L, an upper quartile), eGFR (≤versus >60 mL/min/1.73 m2, a cut-off for the diagnosis of impaired renal function), the presence of anemia (defined as haemoglobin <13 g/dL), diabetes, atrial fibrillation, hypertension, COPD, the history of stroke and/or transient ischaemic attack [TIA], therapy with angiotensin converting enzyme inhibitor (ACEI) or/and angiotensin receptor blocker (ARB), β-blocker, non-selective aldosterone antagonist (spironolactone), digoxin, loop diuretic (furosemide), cardiac resynchronization therapy (CRT) (all dichotomized variables: yes versus no).
For the multivariable logistic regression models as the potential associates with the presence of particular anabolic deficiency, we included the variables which occurred to be significant associates in the univariable models, and the final construction of the multivariable models was based on the stepwise approach.
p < 0.05 was considered statistically significant.
Results
Clinical characteristics of younger and older men with systolic HF
We prospectively identified 382 men with systolic HF (mean age: 60 ± 11 years), who were suitable for the study and agreed to participate. The baseline clinical characteristics of 382 male patients included in the study were given in .
Table 1. Baseline characteristics of the studied men with systolic HF.
Men with systolic HF aged ≥ 60 years (n = 203, 53%) had a more prevalent ischemic HF etiology, higher LVEF, and lower eGFR and hemoglobin as compared to those aged <60 years (all p < 0.05). Moreover, the prevalence of diabetes, hypertension and COPD was higher in older male patients with HF (all p < 0.05) ().
Prevalence of anabolic deficiencies in younger and older men with systolic HF
Prevalence of TT and eFT deficiencies was similar in men with systolic HF aged < versus. ≥60 years (23% and 32% for TT and eFT deficiencies, respectively, in a whole cohort) (). Deficiencies in circulating DHEAS and IGF-1 were more common in younger (63% and 92%, respectively) than older male patients with systolic HF (48% and 73%, both p < 0.01) ().
Table 2. Mean serum hormone levels and the prevalence of hormone deficiencies in the studied men with systolic HF.
Risk factors of anabolic deficiencies in younger men with systolic HF
In univariate logistic regression models, in men aged <60 years with systolic HF, the following variables were associated with the presence of TT deficiency: advanced NYHA class, lower LVEF, the therapies with loop diuretic and digoxin (all p < 0.05) (). The presence of eFT deficiency was accompanied by the presence of diabetes, and the therapy with digoxin (both p < 0.05) (). The presence of DHEAS deficiency was related to high plasma NT-proBNP, reduced hemoglobin, and the therapy with loop diuretic (all p < 0.05) (). There was no association between the presence of IGF-1 deficiency and any assessed clinical variable ().
Table 3. Risk factors predisposing to the prevalence of total testosterone deficiency in younger versus older men with systolic HF.
Table 4. Risk factors predisposing to the prevalence of estimated free testosterone deficiency in younger versus. older men with systolic HF.
Table 5. Risk factors predisposing to the prevalence of DHEAS deficiency in younger versus older men with systolic HF.
Table 6. Risk factors predisposing to the prevalence of IGF-1 deficiency in younger versus older men with systolic HF.
In multiple stepwise logistic regression models, there were only few and weak relationships between the presence of anabolic deficiencies, and co-morbidities and applied therapies in men with systolic HF aged <60 years. In this group, TT deficiency was associated with therapy with digoxin (odd ratio [OR] = 2.14, 95% confidence interval [CI]: 1.03–4.42, χ2 = 4.24, p = 0.04), eFT deficiency – the therapy with digoxin (OR = 2.25, 95% CI: 1.14–4.44, χ2 = 5.55, p = 0.02) and the presence of diabetes (OR = 2.59, 95% CI: 1.19–5.63, χ2 = 5.89, p = 0.02), DHEAS deficiency – therapy with loop diuretic (OR = 2.12, 95% CI: 1.14–3.95, χ2 = 5.74, p = 0.02).
In men with systolic HF aged <60 years, TT deficiency was found in 35% versus 18% of those treated versus not treated with digoxin (p = 0.01), eFT deficiency – in 45% versus 23% of those treated versus not treated with digoxin (p = 0.004), and in 47% versus 25% of those with versus without diabetes (p = 0.01), whereas DHEAS deficiency – in 71% versus 53% of those treated versus not treated with loop diuretic (p = 0.01).
Risk factors of anabolic deficiencies in older men with systolic HF
In univariate logistic regression models, in men aged ≥60 years with systolic HF, the presence of TT deficiency was accompanied by the therapies with aldosterone antagonist and loop diuretic (both p < 0.05) (). There was no association between the presence of eFT deficiency and any assessed clinical variable (). The following variables were associated with the presence of DHEAS deficiency: advanced NYHA class, high serum hsCRP, the history of previous stroke and/or TIA, the therapies with loop diuretic, aldosterone antagonist and digoxin (all p < 0.05) (). The presence of IGF-1 deficiency was related to high serum hsCRP (p < 0.05) ().
In multiple stepwise logistic regression models, there were only few and weak associations between the presence of anabolic deficiencies, and co-morbidities and applied therapies in men with systolic HF aged ≥60 years. In this group, TT deficiency was associated with therapy with loop diuretic (OR = 2.42, 95% CI: 1.18–4.96, χ2 = 5.92, p = 0.02), DHEAS deficiency – with high serum hsCRP (OR = 2.02, 95% CI: 1.02–4.01, χ2 = 4.07, p = 0.045), and the therapies with aldosterone antagonist (OR = 2.02, 95% CI: 1.09–3.74, χ2 = 5.01, p = 0.03) and digoxin (OR = 2.41, 95% CI: 1.24–4.68, χ2 = 6.79, p = 0.009), whereas IGF-1 deficiency – with high serum hsCRP (OR = 2.69, 95% CI: 1.32–5.47, χ2 = 7.59, p = 0.006).
In men with systolic HF aged ≥60 years, TT deficiency was found in 29% versus 15% of those treated versus not treated with loop diuretic (p = 0.01), DHEAS deficiency – in 61% versus 44% of those with serum hsCRP ≥versus <7.78 mg/L (median) (p = 0.04), in 60% versus 43% of those treated versus not treated with aldosterone antagonist (p = 0.02), in 64% versus 42% of those treated versus not treated with digoxin (p = 0.008), whereas IGF-1 deficiency – in 77% versus 57% of those with serum hsCRP ≥versus <7.78 mg/L (median) (p = 0.005).
Disscusion
In the present study, we have clearly shown that deficiencies in circulating testosterone, DHEAS and IGF-1 are very common in both younger and older men with systolic HF. We have demonstrated that the clinical features associated with the presence of particular anabolic deficiencies markedly differ between younger and older male subjects. Importantly, the administration of some therapies in HF (but rather not co-morbidities) may favor the development of these hormone abnormalities in men with systolic HF.
Prevalence of anabolic deficiencies
To the best of our knowledge, the reported cohort of unselected men with systolic HF is the greatest published report on circulating major anabolic hormones in such a type of patients. We have confirmed that HF is characterized by multiple anabolic hormonal deficiency. In our report, the deficiencies in TT and eFT have been found in approximately 20% and 30% of men with systolic HF, regardless of the analyzed age group. Interestingly, the deficiencies in DHEAS and IGF-1 have been demonstrated to be even more prevalent in men with systolic HF as compared to the occurrence of testosterone deficiency. Deficiencies in DHEAS and IGF-1 have been found in 48% and 73% of men aged ≥60 years and have been more frequent in younger men (aged <60 years, i.e. 62.5% and 92%, respectively). Our findings are in an agreement with our previous studies [Citation6] and most of the reports of the other authors [Citation9,Citation11,Citation12,Citation27].
Effect of age and severity of HF on prevalence of anabolic deficiencies
It is worthy to emphasize that the risk of developing testosterone deficiency in younger men with systolic HF is similar as in older subjects, whereas the risk of developing deficiencies in DHEAS and IGF-1 is even higher in the younger age group. Hence, the pattern of age-related changes in circulating aforementioned hormones in men with systolic HF differ from the analogous pattern seen in a general male population [Citation1]. In other words, both younger and older men with systolic HF are at a substantial risk to suffer from clinical and prognostic unfavorable consequences of these anabolic deficiencies, and therefore it is reasonable to recommend the hormone screening in all age groups of male patients with systolic HF. One may anticipate that the deficiencies in anabolic hormones would be particularly prominent in advanced stages of HF, which has been demonstrated by some authors [Citation9–12,Citation28]. In our analyses, we have found only few associations between circulating anabolic hormones and measures of HF severity (NYHA class, LVEF, plasma NT-proBNP) in univariable models, which did not remain as the most important clinical determinants in multivariable models. It suggests that deficiencies in anabolic hormones are not the reflection of just an advanced stage of severe chronic disease (when virtually all systems are compromised), but occur also in men with asymptomatic and mild HF (at the early stages of HF progression). Moreover, the prevalence of anabolic hormones did not differ between men with systolic HF of ischemic versus non-ischemic etiology. The aforementioned hormone derangements occurred equally frequent also in men with heart dysfunction but without accompanying coronary artery disease (i.e. without clinically overt atherosclerosis in coronary arteries). Therefore, such patients should also undergo the hormone screening.
Therapies applied in HF and prevalence of anabolic deficiencies
Hormone abnormalities seen in HF are suggested to result from some therapies applied in HF which are known to interfere with hormone metabolism, e.g. the therapies with non-specific aldosterone antagonist (spironolactone) [Citation18–21], digoxin [Citation22,Citation23,Citation29] and loop diuretic [Citation30]. According to the European Society of Cardiology (ESC) guidelines, patients with symptomatic systolic HF should be treated with aldosterone antagonists to improve survival and lessen HF symptoms (e.g. spironolactone or recently introduced eplerenone) [Citation7]. Spironolactone is a non-specific mineralocorticoid receptor antagonist, which also reveals anti-androgenic effects [Citation18–21] (e.g. in the RALES study, spironolactone therapy dramatically reduced all-cause mortality in patients with systolic severe HF, but also caused gynecomastia in 10% of treated subjects [Citation31]). Spironolactone diminishes the secretion of testosterone from Leydig cells, reducing circulating levels of testosterone [Citation19], inhibits an activity of 5α-reductase in peripheral tissues [Citation21], and acts as an antagonist of androgen receptors [Citation18,Citation20]. As a consequence of all these aforementioned mechanisms men treated with spironolactone are most likely to develop the clinical features of hypogonadism [Citation32,Citation33], particularly when the daily doses of spironolactone are high [Citation33]. Based on the reported data, we have demonstrated that the therapy with spironolactone is associated with the more common deficiencies only in TT and DHEAS (adrenal androgen) in men aged ≥60 years. However, still the prevalence of TT and DHEAS deficiencies in older men with systolic HF not treated with spironolactone were also clinically relevant (18% and 43%, respectively).
Digoxin is another drug recommended for patients with systolic HF patients, mainly to lessen HF symptoms [Citation7], and indeed is commonly used mainly in elderly subjects with HF with accompanying atrial fibrillation to control the heart rate. Digoxin inhibits the adrenal and gonadal synthesis of steroid hormones [Citation22,Citation29] and the secretion of testosterone [Citation23]. We have shown that the therapy with digoxin is accompanied by reduced circulating levels of both TT and eFT in men with systolic HF aged <60 years and reduced circulating DHEAS in those aged ≥60 years. However, we need to emphasize that the prevalence of TT (18%) and eFT (23%) deficiencies in younger men not treated with digoxin and the prevalence of DHEAS deficiency (42%) in older male patients again not treated with digoxin is not low enough to be neglected in clinical practice.
Finally, loop diuretics are considered as the major element of HF pharmacotherapy in case of the presence of congestion and/or other HF symptoms [Citation7]. Although they allow to relieve symptoms and decongest the patients, their use (particularly in high doses) is followed by a paradoxical increase in mortality [Citation34,Citation35]. The detrimental effects of loop diuretics on outcomes (regardless of their diuretic effects) is explained by several pathophysiological mechanisms, such as the secondary activation of the renin–angiotensin–aldosterone and sympathetic systems [Citation36,Citation37] and the induction of electrolyte imbalances (such as hypokalemia, hyponatremia and hypomagnesemia) that may exacerbate cardiac arrhythmias and increase the risk of sudden cardiac death [Citation38]. We have observed that the therapy with loop diuretic is associated with reduced circulating TT and DHEAS in both younger and older men with systolic HF in univariable analyses, however, the most prominent effect of the loop diuretic therapy revealed in multivariable models, has been seen for the reduction of serum TT in men aged <60 years, and for the reduction of serum DHEAS in men aged ≥60 years of age. There is no clear evidence explaining the development of hypogonadism during the therapy with loop diuretics (e.g. furosemide). One theory is related to the fact that loop diuretics (e.g. furosemide) reveal inhibitory effects on testicular 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta- OHSD type1) [Citation30]. Although this enzyme has both oxidative and reductive activities, its oxidative properties dominate in Leydig cells [Citation39], and in this tissue 11 beta-OHSD type 1 mainly oxidizes corticosterone to its inactive metabolite 11-dehydrocorticosterone [Citation39,Citation40]. Reduced enzymatic activity of 11 beta-OHSD type 1 due to furosemide therapy [Citation30] is followed by an increased plasma corticosterone, which subsequently diminishes the testosterone secretion by testes [Citation41] through a direct inhibition of testosterone biosynthesis in Leydig cells via a receptor-mediated mechanism [Citation30,Citation39–42]. We suggest that the development of androgen deficiencies could be considered as another detrimental effect of loop diuretic therapy, potentially contributing also to poor outcomes in men with HF receiving such a long-term treatment.
Co-morbidities in HF and prevalence of anabolic deficiencies
The prominent feature of HF syndrome is the concomitance of several co-morbidities [Citation43], which are particularly common in elderly patients with HF [Citation44,Citation45]. Many chronic non-cardiovascular diseases have been reported to be associated with anabolic deficiencies in men, e.g. diabetes mellitus [Citation46,Citation47], renal failure [Citation48], hypertension [Citation49], COPD [Citation50,Citation51]. Surprisingly, in our cohort only the presence of diabetes was accompanied by eFT deficiency in men aged <60 years old. Our observation is in accordance with numerous studies indicating diabetes as an independent risk factor of male hypogonadism [Citation46,Citation47]. Importantly, we found no relationships between the presence of anabolic deficiencies and co-morbidities in men aged 60 years and over, but on the other hand, only in this age group high circulating hsCRP was related to low DHEAS and IGF-1 levels, confirming the previous findings that inflammatory stimuli may impede the secretion of these hormones in healthy subjects [Citation52] and in patients with metabolic syndrome [Citation53]. Our study provides additional evidence on the unfavorable (here: endocrine) consequences of inflammation in men with systolic HF.
In conclusion, deficiencies in three major anabolic hormones (testosterone, DHEAS and IGF-1) are common in men with stable systolic HF. These hormone derangements are seen both in younger and older male subjects, in those with mild and severe systolic HF, as well as in those with and without accompanying coronary artery disease (CAD) (as the major etiological factor of HF). Concomitant co-morbidities are of a minor importance as the potential risk factors of the development of anabolic deficiencies (in spite of diabetes mellitus in younger men), however, the therapies with spironolactone, digoxin and loop diuretic may favor the occurrence of anabolic deficiencies in male patients with systolic HF.
Declaration of interest
The authors report no conflict of interest.
The study was funded by the statutory grant of Department of Heart Diseases, Wroclaw Medical University (no. 436).
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