madman
Super Moderator
Abstract
Sarcopenia, cachexia, and atrophy due to inactivity and disease states are characterized by a loss of skeletal muscle mass, often accompanied by reduced levels of anabolic hormones (e.g. testosterone). These conditions are associated with an increase in mortality, hospitalization, and worsening of quality of life. Both physical exercise (EX) and anabolic–androgenic steroid (AAS) administration can improve the prognosis of patients as they increase physical functionality. However, there is a gap in the literature as to the impact of these therapies on the gains in strength and muscle mass and their implications for patient safety. Accordingly, we performed a random-effects meta-analysis to elucidate the effects of AAS and/or EX interventions on lean body mass (LBM) and muscle strength in conditions involving muscle loss. A systematic search for relevant clinical trials was conducted in MEDLINE, EMBASE, SCOPUS, Web of Science, and SPORTDiscus. Comparisons included AAS vs. Control, EX vs. Control, AAS vs. EX, AAS+EX vs. AAS and AAS+EX vs. EX. A total of 1114 individuals were analyzed. AAS increased LBM (effect size [ES]: 0.46; 95% CI: 0.25, 0.68, P=0.00) and muscle strength (ES: 0.31; 95% CI: 0.08, 0.53, P=0.01) when compared to a control group. EX promoted an increase in muscular strength (ES: 0.89; 95% CI: 0.53, 1.25, P=0.00), with no effect on LBM when compared to the control group (ES: 0.15; 95% CI: -0.07, 0.38, P=0.17). AAS did not demonstrate statistically significant differences when compared to EX for LBM and muscle strength. The combination of EX+AAS promoted a greater increase in LBM and muscular strength when compared to AAS or EX in isolation. Qualitatively, AAS administration had relatively few side effects. Significant heterogeneity was found in some analyses, which may be explained by the use of different AAS types and EX protocols. Our findings suggest that AAS administration in cachectic and sarcopenic conditions may be a viable interventional strategy to enhance muscle function when exercise is not a possible approach. Moreover, combining AAS with exercise may enhance positive outcomes in this population.
1 Introduction
Sarcopenia, cachexia, and atrophy due to inactivity are characterized by a loss of skeletal muscle mass. Each of these conditions results in a metabolic adaptation that leads to an increased protein degradation decreased rate of muscle protein synthesis or an alteration in both [1]. It is now recognized that the loss of skeletal muscle mass and strength is associated with an increase in mortality [2, 3], hospitalization [4–6], and worsening in the quality of life [7, 8]; hence, conditions that lead to muscle dysfunction have become an important public health issue [9].
Sarcopenia is broadly defined as an age-related loss of skeletal muscle mass and function; its progression is multifactorial and complex [10]. From 20 to 70 years of age, there is an approximately 30% reduction in muscle mass. This loss results in a decrease in strength, metabolic rate, and aerobic capacity, and, consequently, in functional capacity [11]. Newman et al. [12] reported that a loss of muscle function (strength), rather than a loss of mass, is most associated with mortality risk; however, the two variables are interrelated [13]. As a testament to its clinical importance, sarcopenia is now recognized as an independently reportable medical condition [14].
Cachexia is a complex metabolic syndrome associated with several chronic diseases and acute medical conditions [15]. The main clinical feature of cachexia is weight loss in adults, which can be attributed to skeletal muscle loss with or without fat loss [15]. Clinical studies have shown that the preservation of body fatness and skeletal muscle in cachectic patients can decrease mortality risk [16–18].
Exercise (EX) and physical activity are nonpharmacological treatments shown to improve indices of muscle strength and metabolic function in healthy and diseased individuals [19, 20]. EX is the safest and most effective intervention to attenuate or recover some of the lost muscle mass and strength associated with aging [21]. In contrast, limited clinical trials have investigated the impact of exercise training on cachexia. Although the beneficial effects of EX go beyond increasing muscle strength, some patients or even elderly individuals may not benefit from these adaptations due to exercise intolerance (e.g.: frailty, bed rest conditions, cardiorespiratory disability, etc.) [22–25]. Therefore, alternative approaches should be explored to help these individuals achieve a better prognosis.
*Testosterone and its derivatives are anabolic-androgenic steroids (AAS) hormones that lead to an increase in muscle mass [26]. Testosterone effects on skeletal muscle mass are dose-dependent, with the administration of supraphysiological doses leading to a substantial increase in muscle strength, which seems to be closely associated with an increase in muscle mass [27].
In several clinical conditions as well as aging, a decline in levels of anabolic hormones, particularly testosterone, can lead to a worse clinical prognosis [28, 29]. Given the role of AAS in improving muscle function, it, therefore, is speculated that the use of these anabolic agents may increase muscle mass and strength, especially when administered in combination with exercise. It is possible that the increased survival rate in individuals observed with higher levels of blood testosterone is due to better maintenance of muscle mass and strength, which enhances patients’ resilience to adverse clinical situations.
Several studies have reported the use of AAS or EX in clinical conditions and sarcopenic states; however, to the best of our knowledge, no meta-analysis has endeavored to compare the effects of AAS and/or EX interventions in conditions where skeletal muscle loss is seen. Thus, the purpose of this meta-analysis is to evaluate the effects of AAS interventions alone or in combination with EX on lean body mass (LBM) (an indicator of muscle mass) and skeletal muscle strength in conditions involving muscle loss.
3 Results
3.1 Effect on lean body mass
3.2 Effect on muscle strength
3.3 Meta‑regression
3.4 Testosterone blood levels
3.5 Side effects and adverse experiences
4 Discussion
*Regarding the combination of AAS + EX, the studies included in this review indicate that any additional increase in testosterone plasma between the range of 2.5th—97.5th percentile induced by AAS intervention is capable of promoting an increase in LBM and muscle strength when compared to EX or AAS alone. Therefore, our results do not support the need to attain supraphysiological blood testosterone levels to increase muscle mass and strength in this population.
4.1 Side effects of AAS
The duration of the AAS regimens in the studies included herein ranged from 3 to 12 months. Overall, the controlled use of AAS for this period did not appear to cause adverse effects that would contraindicate its use to combat muscle loss in a clinical population. It should be noted that the use of AAS in sports has been associated with liver, heart, and kidney damage [93–95]. However, these athletes often abuse anabolic agents, taking supraphysiological doses that result in testosterone levels values as high as 2,000 ng/dL.
[96]. Long-term supraphysiological testosterone levels produce toxicity in several tissues, although the mechanism underlying these effects is not fully elucidated. In this review, only two studies reported an increase in testosterone levels above the normal physiological range [32, 36], and these studies did not observe any severe adverse effects.
4.2 From hypogonadism to eugonadal: a viewpoint beyond consensus
5 Conclusion: can conditions of skeletal muscle loss be improved by combining exercise with anabolic–androgenic steroids?
Our study analyzed the effects of AAS and AAS+EX interventions on LBM and muscle strength in clinical conditions associated with muscle loss. Short-term AAS administration exhibits a positive effect on LBM and muscle strength, with few adverse effects reported. The combination of AAS+EX was superior to EX or AAS interventions alone for increasing muscle mass and strength (Fig. 5). To our knowledge, this is the first meta-analysis to assess AAS interventions and exercise in clinical conditions. Our analyses indicate that individuals with an impaired capacity for physical activity may achieve a clinical benefit from AAS interventions. Also, EX, in combination with short-term AAS intervention, helps to maximize results in the studied population.
Given the evidence that muscle loss conditions (sarcopenia and cachexia) lead to a worsened clinical prognosis, and added to the fact that the EX [116, 117] and the use of AAS [91, 92] may increase survival in some clinical conditions, our findings provide promising evidence that affected patients may obtain positive benefits from EX+AAS therapy or only AAS, if exercise is not a viable option (Fig. 6). In addition, AAS therapy appears to be relatively safe to use in a controlled clinical setting, whereby biomarkers and adverse reactions are monitored by a clinician. The benefits of restoring muscle mass, and strength and, consequently, improving the patient's prognosis and survival can outweigh the associated risks. However, the long-term effects of clinical AAS administration remain undetermined, and the potential for adverse responses with continued use cannot be ruled out.
Sarcopenia, cachexia, and atrophy due to inactivity and disease states are characterized by a loss of skeletal muscle mass, often accompanied by reduced levels of anabolic hormones (e.g. testosterone). These conditions are associated with an increase in mortality, hospitalization, and worsening of quality of life. Both physical exercise (EX) and anabolic–androgenic steroid (AAS) administration can improve the prognosis of patients as they increase physical functionality. However, there is a gap in the literature as to the impact of these therapies on the gains in strength and muscle mass and their implications for patient safety. Accordingly, we performed a random-effects meta-analysis to elucidate the effects of AAS and/or EX interventions on lean body mass (LBM) and muscle strength in conditions involving muscle loss. A systematic search for relevant clinical trials was conducted in MEDLINE, EMBASE, SCOPUS, Web of Science, and SPORTDiscus. Comparisons included AAS vs. Control, EX vs. Control, AAS vs. EX, AAS+EX vs. AAS and AAS+EX vs. EX. A total of 1114 individuals were analyzed. AAS increased LBM (effect size [ES]: 0.46; 95% CI: 0.25, 0.68, P=0.00) and muscle strength (ES: 0.31; 95% CI: 0.08, 0.53, P=0.01) when compared to a control group. EX promoted an increase in muscular strength (ES: 0.89; 95% CI: 0.53, 1.25, P=0.00), with no effect on LBM when compared to the control group (ES: 0.15; 95% CI: -0.07, 0.38, P=0.17). AAS did not demonstrate statistically significant differences when compared to EX for LBM and muscle strength. The combination of EX+AAS promoted a greater increase in LBM and muscular strength when compared to AAS or EX in isolation. Qualitatively, AAS administration had relatively few side effects. Significant heterogeneity was found in some analyses, which may be explained by the use of different AAS types and EX protocols. Our findings suggest that AAS administration in cachectic and sarcopenic conditions may be a viable interventional strategy to enhance muscle function when exercise is not a possible approach. Moreover, combining AAS with exercise may enhance positive outcomes in this population.
1 Introduction
Sarcopenia, cachexia, and atrophy due to inactivity are characterized by a loss of skeletal muscle mass. Each of these conditions results in a metabolic adaptation that leads to an increased protein degradation decreased rate of muscle protein synthesis or an alteration in both [1]. It is now recognized that the loss of skeletal muscle mass and strength is associated with an increase in mortality [2, 3], hospitalization [4–6], and worsening in the quality of life [7, 8]; hence, conditions that lead to muscle dysfunction have become an important public health issue [9].
Sarcopenia is broadly defined as an age-related loss of skeletal muscle mass and function; its progression is multifactorial and complex [10]. From 20 to 70 years of age, there is an approximately 30% reduction in muscle mass. This loss results in a decrease in strength, metabolic rate, and aerobic capacity, and, consequently, in functional capacity [11]. Newman et al. [12] reported that a loss of muscle function (strength), rather than a loss of mass, is most associated with mortality risk; however, the two variables are interrelated [13]. As a testament to its clinical importance, sarcopenia is now recognized as an independently reportable medical condition [14].
Cachexia is a complex metabolic syndrome associated with several chronic diseases and acute medical conditions [15]. The main clinical feature of cachexia is weight loss in adults, which can be attributed to skeletal muscle loss with or without fat loss [15]. Clinical studies have shown that the preservation of body fatness and skeletal muscle in cachectic patients can decrease mortality risk [16–18].
Exercise (EX) and physical activity are nonpharmacological treatments shown to improve indices of muscle strength and metabolic function in healthy and diseased individuals [19, 20]. EX is the safest and most effective intervention to attenuate or recover some of the lost muscle mass and strength associated with aging [21]. In contrast, limited clinical trials have investigated the impact of exercise training on cachexia. Although the beneficial effects of EX go beyond increasing muscle strength, some patients or even elderly individuals may not benefit from these adaptations due to exercise intolerance (e.g.: frailty, bed rest conditions, cardiorespiratory disability, etc.) [22–25]. Therefore, alternative approaches should be explored to help these individuals achieve a better prognosis.
*Testosterone and its derivatives are anabolic-androgenic steroids (AAS) hormones that lead to an increase in muscle mass [26]. Testosterone effects on skeletal muscle mass are dose-dependent, with the administration of supraphysiological doses leading to a substantial increase in muscle strength, which seems to be closely associated with an increase in muscle mass [27].
In several clinical conditions as well as aging, a decline in levels of anabolic hormones, particularly testosterone, can lead to a worse clinical prognosis [28, 29]. Given the role of AAS in improving muscle function, it, therefore, is speculated that the use of these anabolic agents may increase muscle mass and strength, especially when administered in combination with exercise. It is possible that the increased survival rate in individuals observed with higher levels of blood testosterone is due to better maintenance of muscle mass and strength, which enhances patients’ resilience to adverse clinical situations.
Several studies have reported the use of AAS or EX in clinical conditions and sarcopenic states; however, to the best of our knowledge, no meta-analysis has endeavored to compare the effects of AAS and/or EX interventions in conditions where skeletal muscle loss is seen. Thus, the purpose of this meta-analysis is to evaluate the effects of AAS interventions alone or in combination with EX on lean body mass (LBM) (an indicator of muscle mass) and skeletal muscle strength in conditions involving muscle loss.
3 Results
3.1 Effect on lean body mass
3.2 Effect on muscle strength
3.3 Meta‑regression
3.4 Testosterone blood levels
3.5 Side effects and adverse experiences
4 Discussion
*Regarding the combination of AAS + EX, the studies included in this review indicate that any additional increase in testosterone plasma between the range of 2.5th—97.5th percentile induced by AAS intervention is capable of promoting an increase in LBM and muscle strength when compared to EX or AAS alone. Therefore, our results do not support the need to attain supraphysiological blood testosterone levels to increase muscle mass and strength in this population.
4.1 Side effects of AAS
The duration of the AAS regimens in the studies included herein ranged from 3 to 12 months. Overall, the controlled use of AAS for this period did not appear to cause adverse effects that would contraindicate its use to combat muscle loss in a clinical population. It should be noted that the use of AAS in sports has been associated with liver, heart, and kidney damage [93–95]. However, these athletes often abuse anabolic agents, taking supraphysiological doses that result in testosterone levels values as high as 2,000 ng/dL.
[96]. Long-term supraphysiological testosterone levels produce toxicity in several tissues, although the mechanism underlying these effects is not fully elucidated. In this review, only two studies reported an increase in testosterone levels above the normal physiological range [32, 36], and these studies did not observe any severe adverse effects.
4.2 From hypogonadism to eugonadal: a viewpoint beyond consensus
5 Conclusion: can conditions of skeletal muscle loss be improved by combining exercise with anabolic–androgenic steroids?
Our study analyzed the effects of AAS and AAS+EX interventions on LBM and muscle strength in clinical conditions associated with muscle loss. Short-term AAS administration exhibits a positive effect on LBM and muscle strength, with few adverse effects reported. The combination of AAS+EX was superior to EX or AAS interventions alone for increasing muscle mass and strength (Fig. 5). To our knowledge, this is the first meta-analysis to assess AAS interventions and exercise in clinical conditions. Our analyses indicate that individuals with an impaired capacity for physical activity may achieve a clinical benefit from AAS interventions. Also, EX, in combination with short-term AAS intervention, helps to maximize results in the studied population.
Given the evidence that muscle loss conditions (sarcopenia and cachexia) lead to a worsened clinical prognosis, and added to the fact that the EX [116, 117] and the use of AAS [91, 92] may increase survival in some clinical conditions, our findings provide promising evidence that affected patients may obtain positive benefits from EX+AAS therapy or only AAS, if exercise is not a viable option (Fig. 6). In addition, AAS therapy appears to be relatively safe to use in a controlled clinical setting, whereby biomarkers and adverse reactions are monitored by a clinician. The benefits of restoring muscle mass, and strength and, consequently, improving the patient's prognosis and survival can outweigh the associated risks. However, the long-term effects of clinical AAS administration remain undetermined, and the potential for adverse responses with continued use cannot be ruled out.
