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How the love of muscle can break a heart: Impact of anabolic androgenic steroids on skeletal muscle hypertrophy, metabolic and cardiovascular health
Deaglan McCullough & Richard Webb & Kevin J. Enright & Katie E. Lane & Jim McVeigh & Claire E. Stewart & Ian G. Davies
Abstract
It is estimated 6.4% of males and 1.6% of females globally use anabolic-androgenic steroids (AAS), mostly for appearance and performance-enhancing reasons. In combination with resistance exercise, AAS use increases muscle protein synthesis resulting in skeletal muscle hypertrophy and increased performance. Primarily through binding to the androgen receptor, AAS exerts their hypertrophic effects via genomic, non-genomic, and anti-catabolic mechanisms. However, chronic AAS use also has a detrimental effect on metabolism ultimately increasing the risk of cardiovascular disease (CVD). Much research has focused on AAS effects on blood lipids and lipoproteins, with abnormal concentrations of these associated with insulin resistance, hypertension, and increased visceral adipose tissue (VAT). This clustering of interconnected abnormalities is often referred to as metabolic syndrome (MetS). Therefore, the aim of this review is to explore the impact of AAS use on mechanisms of muscle hypertrophy and markers of MetS. AAS use markedly decreases high-density lipoprotein cholesterol (HDL-C) and increases low-density lipoprotein cholesterol (LDL-C). Chronic AAS use also appears to cause higher fasting insulin levels and impaired glucose tolerance and possibly higher levels of VAT; however, research is currently lacking on the effects of AAS use on glucose metabolism. While cessation of AAS use can restore normal lipid levels, it may lead to withdrawal symptoms such as depression and hypogonadism that can increase CVD risk. Research is currently lacking on effective treatments for withdrawal symptoms and further long-term research is warranted on the effects of AAS use on metabolic health in males and females.
1 Introduction
The fine margins of winning and losing in athletic competitions have always encouraged innovative techniques to help athletes gain a competitive advantage with little regard to the potential negative consequences. Although research into sex hormones existed in the early 19th century, it was only in the 1930s when the anabolic effects of testosterone were demonstrated [1]. Shortly thereafter, the hormone started to be used by competitive athletes to increase muscle mass and performance, however, the British Association of Sports Medicine and the American College of Sports Medicine continued to deny its potential benefits until the 1970s [2, 3]. The use of testosterone and its derivatives were later banned by the International Olympics Committee in 1974 [4]. Due to advancements in technology and pharmacology, a range of anabolic androgenic steroids (AAS) (Table 1, [5, 6]) began to be commonly used by the recreational gym-user in the 1980s, primarily by young men to improve body image [1, 7]. Due to this rise in use and the associated adverse effects of AAS, many countries changed their legislation to incorporate AAS to regulate its use and distribution in the 1990s [8–10]. The world anti-doping agency was created in 1999 to protect athletes from the detrimental health risks of AAS use and to ensure the maintenance of the integrity of sport globally [4, 11].
It is currently estimated that 6.4% of males and 1.6% of females use AAS globally, with recreational sportspeople being the highest users [12]. Although it is common for individuals to use AAS for multiple reasons, the greatest motivation to use AAS is primarily to improve body image, while competitive bodybuilding and athletic performance (non bodybuilding) are secondary and tertiary respectively [12–15]. The Middle East has relatively significantly high levels of AAS use while use in South America, Europe, North America, Oceania, and Africa ranges from 5–2% of the population, highlighting the global issue at hand [12]. However, the significantly higher prevalence rates in the Middle East may be due to the majority of studies relying on self-reports from athletes rather than general populations [12].
1.1 Effects on skeletal muscle
1.2 Effects on metabolic health
Regular exercise is undoubtedly beneficial for mental, physical, and metabolic health [22]. However, the potential benefits acquired from regular exercise may be reduced with chronic AAS use as AAS users are at a higher risk of developing cardiovascular disease (CVD), psychological disorders, neuroendocrine disorders, sex-specific disorders (aromatization and hypogonadism in males and virilization in females) and a range of other disorders (Table 2) [7, 23–26]. Long term AAS use has been shown to result in premature death due to cardiovascular events; however, due to AAS use only being prevalent since the 1980s, long term longitudinal studies, on their impact, are scarce [27]. Furthermore, the direct impact of AAS use on health is difficult to determine as users reportedly use other substances to complement their AAS use while also using a variety of AAS types, doses, and cycles [13, 28]. AAS-related polysubstance use also includes other anabolic agents such as insulin-like growth factor-I (IGF-I) and growth hormone (hGH); drugs to prevent AAS-related adverse effects, other image enhancing drugs (clenbuterol, diuretics, and thyroid hormones), and psychoactive drugs [13, 28]. The chemical interactions of AAS-related polysubstance use may also elicit additional adverse health outcomes. Quantifying the adverse effects of these drugs is further complicated by the prevalence of adulterated products, an inevitable consequence of the illicit market [29].
Metabolic syndrome (MetS) is the constellation of the often interrelated metabolic abnormalities that lead to increased risk of CVD, which are the number one cause of death globally [30, 31]. It is most commonly associated with sedentary/obese populations and is defined by having a combination of some, but not all, of high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), elevated blood glucose, hypertension, and elevated waist circumference [30, 32]. Insulin resistance (IR), visceral adipose tissue (VAT), and small dense low-density lipoprotein cholesterol (sdLDL-C) also highly correlate with MetS [30]. Although AAS users are highly active, they are also at risk of CVD as AAS use has been reported to increase the risk of sudden cardiac arrest as a result of cardiac remodelling and abnormal cardiac function [33–35]. The use of AAS reportedly results in polycythemia, reduced left ventricular and diastolic function and accelerated atherosclerosis compared to non-use [24, 36]. AAS use may affect blood pressure (BP) and metabolism which ultimately increases CVD risk in addition to altered cardiac function [33]. Furthermore, AAS use can increase low-density lipoprotein cholesterol (LDL-C) and decrease high-density lipoprotein cholesterol (HDL-C) increasing the risk of developing atherosclerosis and hence CVD [33], particularly given that AAS use could result in lower insulin sensitivity and higher levels of VAT compared to matched controls [37]. Therefore, although most AAS users have high levels of activity and low adiposity, they can also share similar metabolic characteristics of obese/sedentary populations such as the MetS, thereby increasing the risk of CVD.
1.3 AAS withdrawal
2 Aim and scope
3.1 Genomic-mediated mechanisms
3.2 Non-genomic mediated adaptations
3.3 Anti-catabolic effects of AAS
3.4 Resulting effect on muscle mass and/or performance
4 Impact on metabolic health
4.1 Lipid metabolism
4.2 Glucose metabolism and VAT
4.3 Hypertension
5 Reducing CVD risk
6 Conclusion
CVD is the number one cause of death globally, with the obesity epidemic being a major contributor. The increasing prevalence of AAS use, particularly in young males, will exacerbate the current CVD rates. Chronic use of AAS leads to increased skeletal muscle hypertrophy and improved performance by binding to the AR. Activation of the AR by AAS leads to enhanced gene transcription, second messenger signaling, and satellite cell activation leading to increased muscle protein accretion and synthesis and possibly decreased catabolism. However, chronic AAS use not only leads to impaired cardiac function but also MetS and associated dysregulated metabolic health (IR, dyslipidemia, VAT, and BP) which is more commonly related to the sedentary/obese population. Effective management of AAS and AAS-related polypharmacy use in the first place, together with appropriate guidance on AAS cessation is key, both of which may be managed by education and psychological interventions to ultimately improve health. Therefore, further research is warranted on the long-term effects of AAS use and cessation on markers of metabolic health to provide accurate information on the potential harms in males and females. Further research is also required for treatments to aid AAS cessation and combat adverse metabolic health in this population.
Deaglan McCullough & Richard Webb & Kevin J. Enright & Katie E. Lane & Jim McVeigh & Claire E. Stewart & Ian G. Davies
Abstract
It is estimated 6.4% of males and 1.6% of females globally use anabolic-androgenic steroids (AAS), mostly for appearance and performance-enhancing reasons. In combination with resistance exercise, AAS use increases muscle protein synthesis resulting in skeletal muscle hypertrophy and increased performance. Primarily through binding to the androgen receptor, AAS exerts their hypertrophic effects via genomic, non-genomic, and anti-catabolic mechanisms. However, chronic AAS use also has a detrimental effect on metabolism ultimately increasing the risk of cardiovascular disease (CVD). Much research has focused on AAS effects on blood lipids and lipoproteins, with abnormal concentrations of these associated with insulin resistance, hypertension, and increased visceral adipose tissue (VAT). This clustering of interconnected abnormalities is often referred to as metabolic syndrome (MetS). Therefore, the aim of this review is to explore the impact of AAS use on mechanisms of muscle hypertrophy and markers of MetS. AAS use markedly decreases high-density lipoprotein cholesterol (HDL-C) and increases low-density lipoprotein cholesterol (LDL-C). Chronic AAS use also appears to cause higher fasting insulin levels and impaired glucose tolerance and possibly higher levels of VAT; however, research is currently lacking on the effects of AAS use on glucose metabolism. While cessation of AAS use can restore normal lipid levels, it may lead to withdrawal symptoms such as depression and hypogonadism that can increase CVD risk. Research is currently lacking on effective treatments for withdrawal symptoms and further long-term research is warranted on the effects of AAS use on metabolic health in males and females.
1 Introduction
The fine margins of winning and losing in athletic competitions have always encouraged innovative techniques to help athletes gain a competitive advantage with little regard to the potential negative consequences. Although research into sex hormones existed in the early 19th century, it was only in the 1930s when the anabolic effects of testosterone were demonstrated [1]. Shortly thereafter, the hormone started to be used by competitive athletes to increase muscle mass and performance, however, the British Association of Sports Medicine and the American College of Sports Medicine continued to deny its potential benefits until the 1970s [2, 3]. The use of testosterone and its derivatives were later banned by the International Olympics Committee in 1974 [4]. Due to advancements in technology and pharmacology, a range of anabolic androgenic steroids (AAS) (Table 1, [5, 6]) began to be commonly used by the recreational gym-user in the 1980s, primarily by young men to improve body image [1, 7]. Due to this rise in use and the associated adverse effects of AAS, many countries changed their legislation to incorporate AAS to regulate its use and distribution in the 1990s [8–10]. The world anti-doping agency was created in 1999 to protect athletes from the detrimental health risks of AAS use and to ensure the maintenance of the integrity of sport globally [4, 11].
It is currently estimated that 6.4% of males and 1.6% of females use AAS globally, with recreational sportspeople being the highest users [12]. Although it is common for individuals to use AAS for multiple reasons, the greatest motivation to use AAS is primarily to improve body image, while competitive bodybuilding and athletic performance (non bodybuilding) are secondary and tertiary respectively [12–15]. The Middle East has relatively significantly high levels of AAS use while use in South America, Europe, North America, Oceania, and Africa ranges from 5–2% of the population, highlighting the global issue at hand [12]. However, the significantly higher prevalence rates in the Middle East may be due to the majority of studies relying on self-reports from athletes rather than general populations [12].
1.1 Effects on skeletal muscle
1.2 Effects on metabolic health
Regular exercise is undoubtedly beneficial for mental, physical, and metabolic health [22]. However, the potential benefits acquired from regular exercise may be reduced with chronic AAS use as AAS users are at a higher risk of developing cardiovascular disease (CVD), psychological disorders, neuroendocrine disorders, sex-specific disorders (aromatization and hypogonadism in males and virilization in females) and a range of other disorders (Table 2) [7, 23–26]. Long term AAS use has been shown to result in premature death due to cardiovascular events; however, due to AAS use only being prevalent since the 1980s, long term longitudinal studies, on their impact, are scarce [27]. Furthermore, the direct impact of AAS use on health is difficult to determine as users reportedly use other substances to complement their AAS use while also using a variety of AAS types, doses, and cycles [13, 28]. AAS-related polysubstance use also includes other anabolic agents such as insulin-like growth factor-I (IGF-I) and growth hormone (hGH); drugs to prevent AAS-related adverse effects, other image enhancing drugs (clenbuterol, diuretics, and thyroid hormones), and psychoactive drugs [13, 28]. The chemical interactions of AAS-related polysubstance use may also elicit additional adverse health outcomes. Quantifying the adverse effects of these drugs is further complicated by the prevalence of adulterated products, an inevitable consequence of the illicit market [29].
Metabolic syndrome (MetS) is the constellation of the often interrelated metabolic abnormalities that lead to increased risk of CVD, which are the number one cause of death globally [30, 31]. It is most commonly associated with sedentary/obese populations and is defined by having a combination of some, but not all, of high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), elevated blood glucose, hypertension, and elevated waist circumference [30, 32]. Insulin resistance (IR), visceral adipose tissue (VAT), and small dense low-density lipoprotein cholesterol (sdLDL-C) also highly correlate with MetS [30]. Although AAS users are highly active, they are also at risk of CVD as AAS use has been reported to increase the risk of sudden cardiac arrest as a result of cardiac remodelling and abnormal cardiac function [33–35]. The use of AAS reportedly results in polycythemia, reduced left ventricular and diastolic function and accelerated atherosclerosis compared to non-use [24, 36]. AAS use may affect blood pressure (BP) and metabolism which ultimately increases CVD risk in addition to altered cardiac function [33]. Furthermore, AAS use can increase low-density lipoprotein cholesterol (LDL-C) and decrease high-density lipoprotein cholesterol (HDL-C) increasing the risk of developing atherosclerosis and hence CVD [33], particularly given that AAS use could result in lower insulin sensitivity and higher levels of VAT compared to matched controls [37]. Therefore, although most AAS users have high levels of activity and low adiposity, they can also share similar metabolic characteristics of obese/sedentary populations such as the MetS, thereby increasing the risk of CVD.
1.3 AAS withdrawal
2 Aim and scope
3.1 Genomic-mediated mechanisms
3.2 Non-genomic mediated adaptations
3.3 Anti-catabolic effects of AAS
3.4 Resulting effect on muscle mass and/or performance
4 Impact on metabolic health
4.1 Lipid metabolism
4.2 Glucose metabolism and VAT
4.3 Hypertension
5 Reducing CVD risk
6 Conclusion
CVD is the number one cause of death globally, with the obesity epidemic being a major contributor. The increasing prevalence of AAS use, particularly in young males, will exacerbate the current CVD rates. Chronic use of AAS leads to increased skeletal muscle hypertrophy and improved performance by binding to the AR. Activation of the AR by AAS leads to enhanced gene transcription, second messenger signaling, and satellite cell activation leading to increased muscle protein accretion and synthesis and possibly decreased catabolism. However, chronic AAS use not only leads to impaired cardiac function but also MetS and associated dysregulated metabolic health (IR, dyslipidemia, VAT, and BP) which is more commonly related to the sedentary/obese population. Effective management of AAS and AAS-related polypharmacy use in the first place, together with appropriate guidance on AAS cessation is key, both of which may be managed by education and psychological interventions to ultimately improve health. Therefore, further research is warranted on the long-term effects of AAS use and cessation on markers of metabolic health to provide accurate information on the potential harms in males and females. Further research is also required for treatments to aid AAS cessation and combat adverse metabolic health in this population.
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