REVIEW URRENT C OPINION
Hormone replacement therapy in heart failure Michele Arcopinto a, Andrea Salzano b, Jorgen Isgaard c,, and Antonio Cittadini b,d,
Purpose of review Despite major advances in medical treatments, survival rates of chronic heart failure (CHF) have not significantly changed in the past 50 years, making it imperative to search for novel pathophysiological mechanisms and therapeutic targets. In this article, we summarize the current knowledge regarding the possibility to treat such anabolic deficiencies with hormone replacement therapy (HRT). Recent findings Mounting evidence supports the concept that CHF is a disease characterized not only by excessive neurohormonal activation but also by a reduced anabolic drive that carries functional and prognostic significance. The recent demonstration of overall beneficial effects of HRT in CHF may pave the way to slow the disease progression in patients with coexisting CHF and hormone deficiencies. The hypothesis is to identify a considerable subset of CHF patients also affected with hormone deficiency and to treat them with HRT. Summary Single or multiple HRT may in theory be performed in CHF. Such a novel approach may improve left ventricular architecture, function, and physical capacity as well as quality of life. Larger randomized, controlled trials are needed to confirm this working hypothesis. Keywords anabolism, heart failure, hormone deficiency, hormone therapy
INTRODUCTION The classic model of chronic heart failure (CHF) is rooted in the overexpression of neurohormonal molecules [1,2]. The neurohormonal model – consisting in the hyperactivation of renin–angiotensin–aldosterone system and adrenergic drive – provided the pathophysiological underpinnings of the successful megatrials in the 1990s [3–6]. In the last 20 years, the implementation of therapies aimed at blocking such detrimental pathways [angiotensin converting enzyme (ACE) inhibitors, b-blockers, and aldosterone receptor antagonists] led to remarkable prognostic advantage in CHF patients [1,7]. However, despite such outstanding results, several limitations of the neurohormonal model have clearly emerged. Indeed, CHF is a notable exception to the overall decrease of mortality rates associated with cardiovascular diseases and, nowadays, the 5year mortality is still approximately 50%, worse than that of many cancers [8]. First, because of the dose-limiting effects of many cardiovascular drugs, it is not possible to totally antagonize the renin–angiotensin–aldosterone system and the adrenergic system; alternative metabolic pathways may be at play, such as myocardial chimases.
Importantly, it appears that CHF progresses, at a certain point, independently of neurohormonal status. The quest for alternative biological systems involved is very active. In this regard, there is increasing evidence that anabolic hormones are downregulated in CHF patients, thus pointing to a multiple hormonal deficiency syndrome that represents a reverse model characterized by downregulation rather than upregulation of biologically active molecules [9]. The list includes growth hormone (GH) and its tissue effector insulin-like a Department of Cardiac Surgery, IRCCS Policlinico San Donato Milanese, Milan, bDepartment of Translational Medical Sciences, Federico II University, cInterdisciplinary Research Centre in Biomedical Materials (CRIB), University of Naples, Naples, Italy and dDepartment of Internal Medicine, Sahlgrenska Academy, University of Go¨thenborg, Go¨thenborg, Sweden
Correspondence to Antonio Cittadini, MD, Department of Translational Medical Sciences, Federico II University, Via Sergio Pansini, 5 80131 Naples, Italy. Tel: +39 081 7464375; fax: +39 081 7464375; e-mail: [email protected] Jorgen Isgaard and Antonio Cittadini contributed equally to the writing of this article.
Curr Opin Cardiol 2015, 30:277–284 DOI:10.1097/HCO.0000000000000166
0268-4705 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-cardiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cardiac failure
KEY POINTS CHF is associated with a wide array of anabolic derangements, including GH and testosterone deficiency, L-T3 syndrome, and insulin resistance, which carry prognostic significance. Testosterone therapy was demonstrated to increase the exercise tolerance and well being in both male and female CHF patients. GH replacement therapy appears to be associated with left ventricular reverse remodeling and increased exercise capacity. L-T3 syndrome is observed particularly in advanced CHF, but despite short-term benefits, no long-term data with thyroid hormone therapy are available. Insulin resistance represents a promising therapeutic target in CHF, and studies with sensitizing therapies are at the start.
growth factor-1 (IGF-1), androgens, thyroid hormones, and insulin axis [9,10]. Importantly, deficiency of anabolic axes in CHF is consistently associated with impaired functional capacity and poor outcome [11]. The pathophysiological links between anabolic hormonal axes and the various features of heart failure are far from being fully elucidated. Notwithstanding, in particular with regard to GH and testosterone, encouraging studies addressing safety and efficacy of hormonal therapies have been carried out [12]. In this article, we describe the current literature in the field, with a special focus on the articles published in the last few years.
TESTOSTERONE THERAPY Although several clinical practice recommendations exist regarding evaluation and treatment of androgen deficiency, there is a lack of robust evidence guiding replacement therapy due to low-quality evidence. Due to the nonspecific signs and symptoms of testosterone deficiency overlapping with comorbidities and to uncertain reference ranges for testosterone levels in older men, definition of testosterone deficiency itself is not widely accepted, although it is often considered when morning total testosterone level is below 300 mg/dl on two or more occasions in the presence of consistent symptoms and signs [13]. Low testosterone status is estimated to be around 25% in CHF patients [14], is associated with impaired exercise tolerance in CHF, reduced skeletal muscle mass, and fatigue [15], and may contribute to a reduced survival [11]. Mechanisms underlying the beneficial effects mediated by testosterone therapy in CHF include 278
www.co-cardiology.com
changes in body composition, increase in skeletal muscle strength, anti-inflammatory effects, peripheral insulin sensitization, and improvement of ischemic risk profile [16]. As detailed below, improved cardiac output, exercise tolerance, and general well being have been observed with testosterone therapy. In 2003, for the first time, the acute hemodynamic effects of testosterone were described in 12 stable, male CHF patients. Sixty milligrams of testosterone per os increased cardiac output by approximately 10% after 180 min, likely via a reduction of left ventricular afterload, and with no significant side-effects. These changes were even more pronounced in patients with baseline bioavailable testosterone levels below the median value [17]. The same research group subsequently administered intramuscular testosterone therapy (100 mg every 2 weeks for 12 weeks) in 20 male CHF patients independently of basal testosterone values in a doubleblind, placebo-controlled trial [18]. The authors found a significant increase in the 6-min walked distance (mean þ 91 m) associated with lower scores in the Minnesota Living With Heart Failure Questionnaire over the placebo group at the end of the follow-up. The last study conducted by the same group was a randomized, double-blind, and placebocontrolled parallel trial of testosterone replacement therapy (5 mg of Androderm, Watson Laboratories, Salt Lake City, USA) at physiological doses in 76 unselected CHF patients [19]. Exercise capacity significantly improved with testosterone therapy compared with placebo, despite no significant changes in handgrip strength, skeletal muscle bulk by crosssectional computed tomography, or tumor necrosis factor (TNF)-a levels. Moreover, testosterone therapy was well tolerated, although the patch preparation was not well tolerated by some patients because of local reactions. The beneficial effects of testosterone therapy were recently confirmed by a 12-week study involving 70 elderly patients. Muscle performance, functional capacity as well as insulin resistance, and baroreflex sensitivity were all significantly improved in testosterone-treated patients compared with the placebo-treated group [20]. One year later, the same group published a proof-of-concept study involving 36 female patients, who also are known to experience age-related androgen decline, randomized to transdermal patch of testosterone (300 mg patch, applied twice/week) or placebo. For a 6-month period, patients in the active treatment arm displayed an increase in 6-min walked distance and peak oxygen consumption, and a reduction of insulin resistance. Of note, few adverse effects were recorded, mostly related to the site of patch application [21]. The most Volume 30 Number 3 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Hormone replacement therapy in heart failure Arcopinto et al.
recent published study dwelling upon testosterone therapy in CHF was performed in an Iranian population of 50 male CHF patients followed up for 12 weeks in a placebo-controlled trial (1 ml of intramuscular long-acting testosterone enanthate, 250 mg/ml every 4 weeks), and led to similar results, including improved 6-min walked distance and quality-of-life (QoL) indexes [22]. (A total of 50 male CHF patients were recruited in a double-blind, placebocontrolled trial, and randomized to receive an intramuscular long-acting androgen injection once every 4 weeks for 12 weeks or intramuscular injections of isotonic saline. This study strengthens insights into the beneficial role of testosterone in the improvement of functional capacity and QoL in heart failure patients.) Overall, these studies reported no significant change in heart chambers’ dimension and function following testosterone therapy, supporting the hypothesis of peripheral rather than central mechanism(s) of action of testosterone in CHF, mostly centered on improvement of skeletal muscle. In this regard, the effect of testosterone supplementation has also been tested on top of a rehabilitation program in male patients with CHF with a low testosterone status (defined in this study as
Hormone replacement therapy in heart failure Michele Arcopinto a, Andrea Salzano b, Jorgen Isgaard c,, and Antonio Cittadini b,d,
Purpose of review Despite major advances in medical treatments, survival rates of chronic heart failure (CHF) have not significantly changed in the past 50 years, making it imperative to search for novel pathophysiological mechanisms and therapeutic targets. In this article, we summarize the current knowledge regarding the possibility to treat such anabolic deficiencies with hormone replacement therapy (HRT). Recent findings Mounting evidence supports the concept that CHF is a disease characterized not only by excessive neurohormonal activation but also by a reduced anabolic drive that carries functional and prognostic significance. The recent demonstration of overall beneficial effects of HRT in CHF may pave the way to slow the disease progression in patients with coexisting CHF and hormone deficiencies. The hypothesis is to identify a considerable subset of CHF patients also affected with hormone deficiency and to treat them with HRT. Summary Single or multiple HRT may in theory be performed in CHF. Such a novel approach may improve left ventricular architecture, function, and physical capacity as well as quality of life. Larger randomized, controlled trials are needed to confirm this working hypothesis. Keywords anabolism, heart failure, hormone deficiency, hormone therapy
INTRODUCTION The classic model of chronic heart failure (CHF) is rooted in the overexpression of neurohormonal molecules [1,2]. The neurohormonal model – consisting in the hyperactivation of renin–angiotensin–aldosterone system and adrenergic drive – provided the pathophysiological underpinnings of the successful megatrials in the 1990s [3–6]. In the last 20 years, the implementation of therapies aimed at blocking such detrimental pathways [angiotensin converting enzyme (ACE) inhibitors, b-blockers, and aldosterone receptor antagonists] led to remarkable prognostic advantage in CHF patients [1,7]. However, despite such outstanding results, several limitations of the neurohormonal model have clearly emerged. Indeed, CHF is a notable exception to the overall decrease of mortality rates associated with cardiovascular diseases and, nowadays, the 5year mortality is still approximately 50%, worse than that of many cancers [8]. First, because of the dose-limiting effects of many cardiovascular drugs, it is not possible to totally antagonize the renin–angiotensin–aldosterone system and the adrenergic system; alternative metabolic pathways may be at play, such as myocardial chimases.
Importantly, it appears that CHF progresses, at a certain point, independently of neurohormonal status. The quest for alternative biological systems involved is very active. In this regard, there is increasing evidence that anabolic hormones are downregulated in CHF patients, thus pointing to a multiple hormonal deficiency syndrome that represents a reverse model characterized by downregulation rather than upregulation of biologically active molecules [9]. The list includes growth hormone (GH) and its tissue effector insulin-like a Department of Cardiac Surgery, IRCCS Policlinico San Donato Milanese, Milan, bDepartment of Translational Medical Sciences, Federico II University, cInterdisciplinary Research Centre in Biomedical Materials (CRIB), University of Naples, Naples, Italy and dDepartment of Internal Medicine, Sahlgrenska Academy, University of Go¨thenborg, Go¨thenborg, Sweden
Correspondence to Antonio Cittadini, MD, Department of Translational Medical Sciences, Federico II University, Via Sergio Pansini, 5 80131 Naples, Italy. Tel: +39 081 7464375; fax: +39 081 7464375; e-mail: [email protected] Jorgen Isgaard and Antonio Cittadini contributed equally to the writing of this article.
Curr Opin Cardiol 2015, 30:277–284 DOI:10.1097/HCO.0000000000000166
0268-4705 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-cardiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cardiac failure
KEY POINTS CHF is associated with a wide array of anabolic derangements, including GH and testosterone deficiency, L-T3 syndrome, and insulin resistance, which carry prognostic significance. Testosterone therapy was demonstrated to increase the exercise tolerance and well being in both male and female CHF patients. GH replacement therapy appears to be associated with left ventricular reverse remodeling and increased exercise capacity. L-T3 syndrome is observed particularly in advanced CHF, but despite short-term benefits, no long-term data with thyroid hormone therapy are available. Insulin resistance represents a promising therapeutic target in CHF, and studies with sensitizing therapies are at the start.
growth factor-1 (IGF-1), androgens, thyroid hormones, and insulin axis [9,10]. Importantly, deficiency of anabolic axes in CHF is consistently associated with impaired functional capacity and poor outcome [11]. The pathophysiological links between anabolic hormonal axes and the various features of heart failure are far from being fully elucidated. Notwithstanding, in particular with regard to GH and testosterone, encouraging studies addressing safety and efficacy of hormonal therapies have been carried out [12]. In this article, we describe the current literature in the field, with a special focus on the articles published in the last few years.
TESTOSTERONE THERAPY Although several clinical practice recommendations exist regarding evaluation and treatment of androgen deficiency, there is a lack of robust evidence guiding replacement therapy due to low-quality evidence. Due to the nonspecific signs and symptoms of testosterone deficiency overlapping with comorbidities and to uncertain reference ranges for testosterone levels in older men, definition of testosterone deficiency itself is not widely accepted, although it is often considered when morning total testosterone level is below 300 mg/dl on two or more occasions in the presence of consistent symptoms and signs [13]. Low testosterone status is estimated to be around 25% in CHF patients [14], is associated with impaired exercise tolerance in CHF, reduced skeletal muscle mass, and fatigue [15], and may contribute to a reduced survival [11]. Mechanisms underlying the beneficial effects mediated by testosterone therapy in CHF include 278
www.co-cardiology.com
changes in body composition, increase in skeletal muscle strength, anti-inflammatory effects, peripheral insulin sensitization, and improvement of ischemic risk profile [16]. As detailed below, improved cardiac output, exercise tolerance, and general well being have been observed with testosterone therapy. In 2003, for the first time, the acute hemodynamic effects of testosterone were described in 12 stable, male CHF patients. Sixty milligrams of testosterone per os increased cardiac output by approximately 10% after 180 min, likely via a reduction of left ventricular afterload, and with no significant side-effects. These changes were even more pronounced in patients with baseline bioavailable testosterone levels below the median value [17]. The same research group subsequently administered intramuscular testosterone therapy (100 mg every 2 weeks for 12 weeks) in 20 male CHF patients independently of basal testosterone values in a doubleblind, placebo-controlled trial [18]. The authors found a significant increase in the 6-min walked distance (mean þ 91 m) associated with lower scores in the Minnesota Living With Heart Failure Questionnaire over the placebo group at the end of the follow-up. The last study conducted by the same group was a randomized, double-blind, and placebocontrolled parallel trial of testosterone replacement therapy (5 mg of Androderm, Watson Laboratories, Salt Lake City, USA) at physiological doses in 76 unselected CHF patients [19]. Exercise capacity significantly improved with testosterone therapy compared with placebo, despite no significant changes in handgrip strength, skeletal muscle bulk by crosssectional computed tomography, or tumor necrosis factor (TNF)-a levels. Moreover, testosterone therapy was well tolerated, although the patch preparation was not well tolerated by some patients because of local reactions. The beneficial effects of testosterone therapy were recently confirmed by a 12-week study involving 70 elderly patients. Muscle performance, functional capacity as well as insulin resistance, and baroreflex sensitivity were all significantly improved in testosterone-treated patients compared with the placebo-treated group [20]. One year later, the same group published a proof-of-concept study involving 36 female patients, who also are known to experience age-related androgen decline, randomized to transdermal patch of testosterone (300 mg patch, applied twice/week) or placebo. For a 6-month period, patients in the active treatment arm displayed an increase in 6-min walked distance and peak oxygen consumption, and a reduction of insulin resistance. Of note, few adverse effects were recorded, mostly related to the site of patch application [21]. The most Volume 30 Number 3 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Hormone replacement therapy in heart failure Arcopinto et al.
recent published study dwelling upon testosterone therapy in CHF was performed in an Iranian population of 50 male CHF patients followed up for 12 weeks in a placebo-controlled trial (1 ml of intramuscular long-acting testosterone enanthate, 250 mg/ml every 4 weeks), and led to similar results, including improved 6-min walked distance and quality-of-life (QoL) indexes [22]. (A total of 50 male CHF patients were recruited in a double-blind, placebocontrolled trial, and randomized to receive an intramuscular long-acting androgen injection once every 4 weeks for 12 weeks or intramuscular injections of isotonic saline. This study strengthens insights into the beneficial role of testosterone in the improvement of functional capacity and QoL in heart failure patients.) Overall, these studies reported no significant change in heart chambers’ dimension and function following testosterone therapy, supporting the hypothesis of peripheral rather than central mechanism(s) of action of testosterone in CHF, mostly centered on improvement of skeletal muscle. In this regard, the effect of testosterone supplementation has also been tested on top of a rehabilitation program in male patients with CHF with a low testosterone status (defined in this study as
