madman
Super Moderator
Cachexia is a complex wasting syndrome, accompanying a variety of end-stage chronic diseases, such as cancer, heart failure, and human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS). It significantly affects patients’ quality of life and survival. Multiple therapeutic approaches have been studied over time. However, despite promising results, no drug has been approved to date. In this review, we examine and discuss the available data on the therapeutic effects of androgens and selective androgen receptor modulators (SARMs) for cachexia.
Introduction
Cachexia is a complex wasting syndrome, characterized by unintentional progressive weight loss (greater than 5% in 12 months or less) and severe wasting involving all somatic compartments; particularly skeletal muscle and adipose tissue, although bone can also be affected [1,2]. Whether cachexia should be viewed as a disease-specific complication or a common final catabolic process remains a matter of ongoing debate [3].
Its estimated prevalence ranges widely between 15 and 90%, depending on the underlying pathological condition [4] and potentially also the era in which data were collected. Although historically a ubiquitous finding in a variety of end-stage chronic diseases including cancer, heart failure (HF), human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, chronic liver, and kidney disease it now appears less prevalent in the developed world due to the secular obesity epidemic. As affected patients now start from a far higher median BMI at the onset of wasting, it takes that much longer for clinically discernible cachexia to become apparent, even though the rate of wasting is no different.
Cachexia greatly affects patients’ quality of life (QoL) and survival [5,6]. In particular, sarcopenia, or loss of lean body mass (LBM), plays a key role in increasing frailty, hospitalization rate, and mortality by reducing muscular strength and physical capacity [3]. Its pathogenesis is multifactorial, comprising anorexia, inflammation, increased protein catabolism, and other metabolic alterations [7] [Fig. 1]. Since these mechanisms arise early on during the natural history of the underlying disease, an early diagnosis followed by timely intervention might be effective in preventing or delaying the onset of severe wasting.
Ageing strongly contributes to the decline in physical performance, especially in relation to sarcopenia [8], whose prevalence is substantial in most geriatric settings [9]. Indeed, sarcopenia can be considered the biological substrate of physical frailty, which is defined as an age-related decrease in homeostatic reserve [10] and, despite some shared common features, should be distinguished from cachexia. Ageing can exacerbate the muscle wasting associated with chronic illnesses and vice-versa. The relationship between the ageing process and skeletal muscle atrophy and dysfunction - mostly affecting fast fibres - is mediated via several phenomena, comprising DNA mutations, mitochondrial remodelling, lower antioxidant capacity and decline in male serum testosterone (T) - this latter principally arising from impairment of gonadotropin-releasing hormone (GnRH)-stimulated secretion of luteinizing hormone (LH), a reduction in Leydig cell numbers and responsiveness, an increase in sex hormone-binding globulin (SHBG) levels and, potentially, greater aromatase activity [11,12].
Both research and everyday clinical practice in cachexia have largely focused on nutritional support, based on dietary supplementation with proteins, vitamins and minerals, which is not sufficient to delay or prevent progression of muscle wasting due to its multifactorial nature. Therefore, beyond the treatment of the underlying disease, management of cachexia should be based on multimodal interventions, with physical exercise training currently appearing to offer the most promising approach to be deployed in parallel to nutritional interventions [13].
Focusing on the two main pathogenic processes, anorexia and catabolism, multiple attempts have been made to identify and validate medical therapies. These have included appetite stimulants, antiinflammatory drugs, anabolic agents such as androgens and selective androgen receptor modulators (SARMs), and ghrelin (and its agonist anamorelin), which combines anabolic with orexigenic actions [Fig. 2]. Both the European Society for Clinical Nutrition and Metabolism (ESPEN) in 2016 and the American Society of Clinical Oncology (ASCO) in 2020 have suggested pharmacological interventions to improve clinical outcomes in cachectic patients [14,15], but no drug is currently recommended for this purpose.
Overall, cachexia remains a great challenge in clinical practice despite secular changes in body mass index, and the development of preventive and therapeutic strategies and related clinical guidelines is considered to be an urgent healthcare need. As stated during the 11th Cachexia Conference (Maastricht, 2018), “we need personalized medicine to provide the right care to the right patient at the right time” [16]. The aim of this review is to summarize and discuss the available data on the therapeutic effects of androgens and SARMs for cachexia.
Role of androgens and SARMs in cachexia
T, the dominant male sex steroid, binds to the nuclear androgen receptor (AR) and, thereby, promotes a signaling pathway that ultimately results in the clinical features that define androgenicity, comprising anabolic effects on muscle, bone and bone marrow as well as the better known virilizing effects on sexual function and reproduction [17].
Notably, any systemic chronic disease of sufficient severity can potentially suppress gonadotropin levels; a form of functional hypogonadism or “non-gonadal illness” (NGI), which is reversible once the underlying cause remits or is cured. However, it remains unknown whether this phenomenon is adaptive, maladaptive, or neutral in its biological effects [18].
Based on these foundations, androgens have been identified and studied as a potential treatment for chronic disorders-associated muscle wasting.
*Mechanisms of action on key tissues
-Muscle
-Bone
-Bone marrow
-Testosterone supplementation
-Synthetic androgens
-SARMs
*Role of other anabolic agents in cachexia Recombinant
-human growth hormone (rhGH)/recombinant human IGF-1 (rhIGF-1)
-Ghrelin/anamorelin
-Insulin
-Bimagrumab
*Cancer cachexia
-General considerations
-Role of androgens and SARMs in cancer cachexia
*Cardiac cachexia
General considerations
Role of androgens in cardiac cachexia
HIV/AIDS-associated cachexia
-General considerations
-Role of androgens in HIV/AIDS-associated cachexia
*Glucocorticoid-associated cachexia
Conclusions
Cachexia represents a major health and social burden, accompanying a variety of end-stage chronic diseases and greatly affecting patients' QoL and survival. It remains to date a great challenge in clinical practice, with progress required in terms of achieving timely diagnosis and developing evidence-based treatments. Apart from addressing the underlying disease, the management of cachexia should be based on multimodal strategies. Indeed, although multiple medical therapies have been suggested, no drug is currently recommended. Among these, androgens and SARMs have been quite extensively studied with promising results. In this setting, the whole reason d’^etre of using synthetic androgens or SARMs in men is predicated on the basis that native T has undesirable or potentially dangerous effects. However, the more we learn about T therapy in men, the safer it appears, albeit its efficacy outside the core indication of organic hypogonadism remains elusive. On balance, despite a current standstill on the clinical application of SARMs, there remains considerable confidence about their potential, but standardized hard endpoints are required for future clinical trials. Moreover, a greater understanding of the mechanisms involved in tissue wasting - especially in cancer patients - might encourage the development of more targeted therapies, with a view to counteracting or even reverse the progression of cachexia.
Introduction
Cachexia is a complex wasting syndrome, characterized by unintentional progressive weight loss (greater than 5% in 12 months or less) and severe wasting involving all somatic compartments; particularly skeletal muscle and adipose tissue, although bone can also be affected [1,2]. Whether cachexia should be viewed as a disease-specific complication or a common final catabolic process remains a matter of ongoing debate [3].
Its estimated prevalence ranges widely between 15 and 90%, depending on the underlying pathological condition [4] and potentially also the era in which data were collected. Although historically a ubiquitous finding in a variety of end-stage chronic diseases including cancer, heart failure (HF), human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, chronic liver, and kidney disease it now appears less prevalent in the developed world due to the secular obesity epidemic. As affected patients now start from a far higher median BMI at the onset of wasting, it takes that much longer for clinically discernible cachexia to become apparent, even though the rate of wasting is no different.
Cachexia greatly affects patients’ quality of life (QoL) and survival [5,6]. In particular, sarcopenia, or loss of lean body mass (LBM), plays a key role in increasing frailty, hospitalization rate, and mortality by reducing muscular strength and physical capacity [3]. Its pathogenesis is multifactorial, comprising anorexia, inflammation, increased protein catabolism, and other metabolic alterations [7] [Fig. 1]. Since these mechanisms arise early on during the natural history of the underlying disease, an early diagnosis followed by timely intervention might be effective in preventing or delaying the onset of severe wasting.
Ageing strongly contributes to the decline in physical performance, especially in relation to sarcopenia [8], whose prevalence is substantial in most geriatric settings [9]. Indeed, sarcopenia can be considered the biological substrate of physical frailty, which is defined as an age-related decrease in homeostatic reserve [10] and, despite some shared common features, should be distinguished from cachexia. Ageing can exacerbate the muscle wasting associated with chronic illnesses and vice-versa. The relationship between the ageing process and skeletal muscle atrophy and dysfunction - mostly affecting fast fibres - is mediated via several phenomena, comprising DNA mutations, mitochondrial remodelling, lower antioxidant capacity and decline in male serum testosterone (T) - this latter principally arising from impairment of gonadotropin-releasing hormone (GnRH)-stimulated secretion of luteinizing hormone (LH), a reduction in Leydig cell numbers and responsiveness, an increase in sex hormone-binding globulin (SHBG) levels and, potentially, greater aromatase activity [11,12].
Both research and everyday clinical practice in cachexia have largely focused on nutritional support, based on dietary supplementation with proteins, vitamins and minerals, which is not sufficient to delay or prevent progression of muscle wasting due to its multifactorial nature. Therefore, beyond the treatment of the underlying disease, management of cachexia should be based on multimodal interventions, with physical exercise training currently appearing to offer the most promising approach to be deployed in parallel to nutritional interventions [13].
Focusing on the two main pathogenic processes, anorexia and catabolism, multiple attempts have been made to identify and validate medical therapies. These have included appetite stimulants, antiinflammatory drugs, anabolic agents such as androgens and selective androgen receptor modulators (SARMs), and ghrelin (and its agonist anamorelin), which combines anabolic with orexigenic actions [Fig. 2]. Both the European Society for Clinical Nutrition and Metabolism (ESPEN) in 2016 and the American Society of Clinical Oncology (ASCO) in 2020 have suggested pharmacological interventions to improve clinical outcomes in cachectic patients [14,15], but no drug is currently recommended for this purpose.
Overall, cachexia remains a great challenge in clinical practice despite secular changes in body mass index, and the development of preventive and therapeutic strategies and related clinical guidelines is considered to be an urgent healthcare need. As stated during the 11th Cachexia Conference (Maastricht, 2018), “we need personalized medicine to provide the right care to the right patient at the right time” [16]. The aim of this review is to summarize and discuss the available data on the therapeutic effects of androgens and SARMs for cachexia.
Role of androgens and SARMs in cachexia
T, the dominant male sex steroid, binds to the nuclear androgen receptor (AR) and, thereby, promotes a signaling pathway that ultimately results in the clinical features that define androgenicity, comprising anabolic effects on muscle, bone and bone marrow as well as the better known virilizing effects on sexual function and reproduction [17].
Notably, any systemic chronic disease of sufficient severity can potentially suppress gonadotropin levels; a form of functional hypogonadism or “non-gonadal illness” (NGI), which is reversible once the underlying cause remits or is cured. However, it remains unknown whether this phenomenon is adaptive, maladaptive, or neutral in its biological effects [18].
Based on these foundations, androgens have been identified and studied as a potential treatment for chronic disorders-associated muscle wasting.
*Mechanisms of action on key tissues
-Muscle
-Bone
-Bone marrow
-Testosterone supplementation
-Synthetic androgens
-SARMs
*Role of other anabolic agents in cachexia Recombinant
-human growth hormone (rhGH)/recombinant human IGF-1 (rhIGF-1)
-Ghrelin/anamorelin
-Insulin
-Bimagrumab
*Cancer cachexia
-General considerations
-Role of androgens and SARMs in cancer cachexia
*Cardiac cachexia
General considerations
Role of androgens in cardiac cachexia
HIV/AIDS-associated cachexia
-General considerations
-Role of androgens in HIV/AIDS-associated cachexia
*Glucocorticoid-associated cachexia
Conclusions
Cachexia represents a major health and social burden, accompanying a variety of end-stage chronic diseases and greatly affecting patients' QoL and survival. It remains to date a great challenge in clinical practice, with progress required in terms of achieving timely diagnosis and developing evidence-based treatments. Apart from addressing the underlying disease, the management of cachexia should be based on multimodal strategies. Indeed, although multiple medical therapies have been suggested, no drug is currently recommended. Among these, androgens and SARMs have been quite extensively studied with promising results. In this setting, the whole reason d’^etre of using synthetic androgens or SARMs in men is predicated on the basis that native T has undesirable or potentially dangerous effects. However, the more we learn about T therapy in men, the safer it appears, albeit its efficacy outside the core indication of organic hypogonadism remains elusive. On balance, despite a current standstill on the clinical application of SARMs, there remains considerable confidence about their potential, but standardized hard endpoints are required for future clinical trials. Moreover, a greater understanding of the mechanisms involved in tissue wasting - especially in cancer patients - might encourage the development of more targeted therapies, with a view to counteracting or even reverse the progression of cachexia.
