madman
Super Moderator
Abstract: Anabolic-androgenic steroids (AASs) are a large group of molecules including endogenously produced androgens, such as testosterone, as well as synthetically manufactured derivatives. AAS use is widespread due to its ability to improve muscle growth for aesthetic purposes and athletes’ performance, minimizing androgenic effects. AAS use is very popular and 1–3% of US inhabitants have been estimated to be AAS users. However, AASs have side effects, involving all organs, tissues, and body functions, especially long-term toxicity involving the cardiovascular system and the reproductive system, thereby, their abuse is considered a public health issue. The aim of the proposed review is to highlight the most recent evidence regarding the mechanisms of action of AASs and their unwanted effects on organs and lifestyle, as well as suggesting that AAS misuse and abuse lead to adverse effects in all body tissues and organs.
Oxidative stress, apoptosis, and protein synthesis alteration are common mechanisms involved in AAS-related damage in the whole body. The cardiovascular system and the reproductive system are the most frequently involved apparatuses. Epidemiology, as well as the molecular and pathological mechanisms involved in the neuropsychiatric side-effects of AAS abuse, are still unclear, further research is needed in this field. In addition, diagnostically reliable tests for AAS abuse should be standardized. In this regard, to prevent the use of AASs, public health measures in all settings are crucial. These measures consist of improved knowledge among healthcare workers, proper doping screening tests, educational interventions, and updated legislation.
1. Introduction
Anabolic-androgenic steroids (AASs), commonly known as anabolic steroids, are a large group of molecules including endogenously produced androgens, such as testosterone, as well as synthetically manufactured derivatives [1]. Testosterone, Nandrolone Decanoate (ND), methandienone, and methenolone are the most commonly abused androgens [2]. AAS use is widespread due to its ability to improve muscle growth for esthetic purposes and athletes’ performance, minimizing androgenic effects [3]. Indeed, androgens are able to increase the size of muscle fibers as well as muscle strength, and while their use was initially restricted to professional bodybuilders, nowadays it has become more popular among recreational athletes [4,5]. AAS anabolic properties have been widely used for therapeutic purposes. Indeed, AASs had a role in the treatment of chronic kidney disease and osteoporosis in postmenopausal women, as well as inoperable breast cancer, and for diseases characterized by a negative nitrogen balance [2]. However, the use of AASs is forbidden by the World Anti-Doping Agency (WADA). However, AAS use is still very popular and 1–3% of US inhabitants have been estimated to be AAS users [6]. Moreover, in younger subjects’ higher estimates have been reported [7,8]. However, AASs have side effects involving all organs, tissues, and body functions, especially long-term toxicity involving the cardiovascular system and the reproductive system, therefore, their abuse is considered a public health issue [9,10]. In this regard, increased awareness is needed among the population and healthcare workers, both for diagnostic, therapeutic, and prevention purposes. The aim of the proposed review is to highlight the state of the art regarding the mechanisms of action of AASs and the adverse effects related to AAS use/abuse.
2. Physiology of AASs
The anabolic-androgenic effects are related to the androgen receptor (AR)-signaling action. Androgen receptors are widespread in human tissues and organs. There are three main action mechanisms: (i) direct binding to androgen receptor; (ii) via dihydrotestosterone (DHT) produced by the action of 5- a-reductase, and (iii) via estrogen receptors by means of estradiol produced by CYP19 aromatase. In particular, free testosterone is transported into target tissue cell cytoplasm; binding to the AR takes place either directly or after conversion to 5αdihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha reductase. Into the cell nucleus, both free or bound, testosterone binds specific nucleotide sequences of the chromosomal DNA. The produced DNA activates the transcription of specific responsive genes, with significant influence on protein synthesis [11–13]. After dimerization, the complex binds to specific promoter areas of target genes called androgen response elements (AREs), influencing the transcription process [14]. Furthermore, non-genomic pathways, by interfering with the G-protein coupled receptor, a transmembrane receptor located inside the cell, can lead to rapid steroid hormone activation [6,15]. In this regard, sex steroids might influence thyroid function as a consequence of the expression of androgen receptors in this tissue, leading to thyrocyte proliferation in culture independently from TSH [16]. The same mechanism has been described in other tissues [17].
3. Pathophysiology of AASs
The most relevant mechanisms that lead to the increase of AASs in circulation are: administration of testosterone or its synthetic derivatives or administration of drugs that raise endogenous testosterone production [11]. The mechanism of action of AASs in supraphysiological doses are characterized by the impairment of testosterone biosynthesis in tissues (Figure 1).
AASs exert their effects by activating androgen receptor (AR) signaling. Several parts of the body are involved because of the presence of ARs in many tissues [12]. At normal physiologic levels of testosterone, androgen receptors are saturated and the AASs effects may be a consequence of other mechanisms rather than androgen receptor activation. High testosterone levels may have an antagonist effect on glucocorticoid receptors, leading to inhibition of glucose synthesis and protein catabolism. Indeed, high dose AASs may displace glucocorticoids from their receptors, decrease protein breakdown in muscles, leading to an increase in muscle mass and muscle strength [18]. The inhibition of glucocorticoid action is also due to the stimulation of growth hormone (GH) and insulin-like growth factor (IGF)-1 axis. In this regard, AASs induce an androgen-mediated stimulation of GH and the hepatic synthesis of IGF-1, leading to muscle protein formation and anabolic effects [5]. Moreover, testosterone is converted by aromatase action to estradiol and estrone, influencing the brain and sexual differentiation, bone and muscle mass increase, puberty, and sexual functions. High doses of AASs exert an antiestrogenic effect due to a down-regulation of androgen receptors and competition with estrogens with their receptors [18]
4. AAS Use and Adverse Effects
4.1. Autopsy Findings
4.2. Brain and Behavior
4.3. Cardiovascular System
4.4. Liver
4.5. Urinary System
4.6. Musculoskeletal System
4.7. Reproductive System
4.8. Hematologic Consequences
4.9. AASs and Cancer
5. Conclusions
This review suggests that AAS misuse and abuse lead to adverse effects in all body tissues and organs. Oxidative stress, apoptosis, and protein synthesis alteration are common mechanisms involved in AAS-related damage in the whole body. This review shows that long-term administration of high doses of AASs may lead to serious consequences, such as hypogonadism, cardiac impairment, neurodegeneration, coronary artery disease, and sudden cardiac death. The most-reported long-term side effects affect the cardiovascular system, such as cardiomyopathy and atherosclerotic disease. Hypogonadism is a frequent finding in AAS abusers and needs to be taken into consideration when AAS use is suspected in order to undertake aggressive treatment [8,120].
Several experimental studies focused on the mechanisms involved in the neuropsychiatric effects of AASs. The pathways and the molecular processes are still unclear and need to be clarified [121–124]. In this regard, further studies are needed to assess the epidemiology of antisocial behavior related to AAS assumption and the relationship with other drug consumption.
Moreover, considering that most of the customers are young sportsman and that most of these drugs are easily obtained online, AAS abuse is a considerable public health issue [3].
Clinicians and family doctors should be aware of AAS adverse effects, in order to investigate AAS use in high-risk patients, especially in young athletes [121]. In this regard, cardiac imaging may be a helpful tool to assess the presence of subclinical morphological cardiac alterations in AAS abusers. In addition, recent studies reported that miRNAs may play a role in multiple human diseases including AAS adverse effects, suggesting a possible role of these markers in identifying serum or tissue biomarkers with anti-doping potential. However, further studies are needed in this field, given that there is no reliable test to diagnose AAS abuse.
Given the high mortality of the atherosclerotic disease and AAS-induced cardiomyopathy, as well as the risk of sudden cardiac death reported in the literature, primary and secondary prevention are crucial in AAS users in order to avoid serious consequences. The scientific community should intensify its efforts to assess the pathophysiology of behavior and cognitive impairment due to long term AAS exposure. Moreover, the evidence is urgently required to support the development of a reliable diagnostic tool to identify precociously AAS abuse as well as evidence-based therapy [57,125–131].
Information and education are fundamental tools for AAS misuse prevention. As long as anabolic steroid misuse is popular among young athletes, information campaigns regarding AASs and other doping agents should be encouraged in high schools. In this regard, to prevent the use of AASs public health measures in all settings are crucial. These measures consist of improved knowledge among healthcare workers, proper doping screening tests, educational interventions, and updated legislation. Although the use of AASs appears to increase the risk of premature death in various categories of patients, further research about this problem is urgently needed [132–139].
Oxidative stress, apoptosis, and protein synthesis alteration are common mechanisms involved in AAS-related damage in the whole body. The cardiovascular system and the reproductive system are the most frequently involved apparatuses. Epidemiology, as well as the molecular and pathological mechanisms involved in the neuropsychiatric side-effects of AAS abuse, are still unclear, further research is needed in this field. In addition, diagnostically reliable tests for AAS abuse should be standardized. In this regard, to prevent the use of AASs, public health measures in all settings are crucial. These measures consist of improved knowledge among healthcare workers, proper doping screening tests, educational interventions, and updated legislation.
1. Introduction
Anabolic-androgenic steroids (AASs), commonly known as anabolic steroids, are a large group of molecules including endogenously produced androgens, such as testosterone, as well as synthetically manufactured derivatives [1]. Testosterone, Nandrolone Decanoate (ND), methandienone, and methenolone are the most commonly abused androgens [2]. AAS use is widespread due to its ability to improve muscle growth for esthetic purposes and athletes’ performance, minimizing androgenic effects [3]. Indeed, androgens are able to increase the size of muscle fibers as well as muscle strength, and while their use was initially restricted to professional bodybuilders, nowadays it has become more popular among recreational athletes [4,5]. AAS anabolic properties have been widely used for therapeutic purposes. Indeed, AASs had a role in the treatment of chronic kidney disease and osteoporosis in postmenopausal women, as well as inoperable breast cancer, and for diseases characterized by a negative nitrogen balance [2]. However, the use of AASs is forbidden by the World Anti-Doping Agency (WADA). However, AAS use is still very popular and 1–3% of US inhabitants have been estimated to be AAS users [6]. Moreover, in younger subjects’ higher estimates have been reported [7,8]. However, AASs have side effects involving all organs, tissues, and body functions, especially long-term toxicity involving the cardiovascular system and the reproductive system, therefore, their abuse is considered a public health issue [9,10]. In this regard, increased awareness is needed among the population and healthcare workers, both for diagnostic, therapeutic, and prevention purposes. The aim of the proposed review is to highlight the state of the art regarding the mechanisms of action of AASs and the adverse effects related to AAS use/abuse.
2. Physiology of AASs
The anabolic-androgenic effects are related to the androgen receptor (AR)-signaling action. Androgen receptors are widespread in human tissues and organs. There are three main action mechanisms: (i) direct binding to androgen receptor; (ii) via dihydrotestosterone (DHT) produced by the action of 5- a-reductase, and (iii) via estrogen receptors by means of estradiol produced by CYP19 aromatase. In particular, free testosterone is transported into target tissue cell cytoplasm; binding to the AR takes place either directly or after conversion to 5αdihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha reductase. Into the cell nucleus, both free or bound, testosterone binds specific nucleotide sequences of the chromosomal DNA. The produced DNA activates the transcription of specific responsive genes, with significant influence on protein synthesis [11–13]. After dimerization, the complex binds to specific promoter areas of target genes called androgen response elements (AREs), influencing the transcription process [14]. Furthermore, non-genomic pathways, by interfering with the G-protein coupled receptor, a transmembrane receptor located inside the cell, can lead to rapid steroid hormone activation [6,15]. In this regard, sex steroids might influence thyroid function as a consequence of the expression of androgen receptors in this tissue, leading to thyrocyte proliferation in culture independently from TSH [16]. The same mechanism has been described in other tissues [17].
3. Pathophysiology of AASs
The most relevant mechanisms that lead to the increase of AASs in circulation are: administration of testosterone or its synthetic derivatives or administration of drugs that raise endogenous testosterone production [11]. The mechanism of action of AASs in supraphysiological doses are characterized by the impairment of testosterone biosynthesis in tissues (Figure 1).
AASs exert their effects by activating androgen receptor (AR) signaling. Several parts of the body are involved because of the presence of ARs in many tissues [12]. At normal physiologic levels of testosterone, androgen receptors are saturated and the AASs effects may be a consequence of other mechanisms rather than androgen receptor activation. High testosterone levels may have an antagonist effect on glucocorticoid receptors, leading to inhibition of glucose synthesis and protein catabolism. Indeed, high dose AASs may displace glucocorticoids from their receptors, decrease protein breakdown in muscles, leading to an increase in muscle mass and muscle strength [18]. The inhibition of glucocorticoid action is also due to the stimulation of growth hormone (GH) and insulin-like growth factor (IGF)-1 axis. In this regard, AASs induce an androgen-mediated stimulation of GH and the hepatic synthesis of IGF-1, leading to muscle protein formation and anabolic effects [5]. Moreover, testosterone is converted by aromatase action to estradiol and estrone, influencing the brain and sexual differentiation, bone and muscle mass increase, puberty, and sexual functions. High doses of AASs exert an antiestrogenic effect due to a down-regulation of androgen receptors and competition with estrogens with their receptors [18]
4. AAS Use and Adverse Effects
4.1. Autopsy Findings
4.2. Brain and Behavior
4.3. Cardiovascular System
4.4. Liver
4.5. Urinary System
4.6. Musculoskeletal System
4.7. Reproductive System
4.8. Hematologic Consequences
4.9. AASs and Cancer
5. Conclusions
This review suggests that AAS misuse and abuse lead to adverse effects in all body tissues and organs. Oxidative stress, apoptosis, and protein synthesis alteration are common mechanisms involved in AAS-related damage in the whole body. This review shows that long-term administration of high doses of AASs may lead to serious consequences, such as hypogonadism, cardiac impairment, neurodegeneration, coronary artery disease, and sudden cardiac death. The most-reported long-term side effects affect the cardiovascular system, such as cardiomyopathy and atherosclerotic disease. Hypogonadism is a frequent finding in AAS abusers and needs to be taken into consideration when AAS use is suspected in order to undertake aggressive treatment [8,120].
Several experimental studies focused on the mechanisms involved in the neuropsychiatric effects of AASs. The pathways and the molecular processes are still unclear and need to be clarified [121–124]. In this regard, further studies are needed to assess the epidemiology of antisocial behavior related to AAS assumption and the relationship with other drug consumption.
Moreover, considering that most of the customers are young sportsman and that most of these drugs are easily obtained online, AAS abuse is a considerable public health issue [3].
Clinicians and family doctors should be aware of AAS adverse effects, in order to investigate AAS use in high-risk patients, especially in young athletes [121]. In this regard, cardiac imaging may be a helpful tool to assess the presence of subclinical morphological cardiac alterations in AAS abusers. In addition, recent studies reported that miRNAs may play a role in multiple human diseases including AAS adverse effects, suggesting a possible role of these markers in identifying serum or tissue biomarkers with anti-doping potential. However, further studies are needed in this field, given that there is no reliable test to diagnose AAS abuse.
Given the high mortality of the atherosclerotic disease and AAS-induced cardiomyopathy, as well as the risk of sudden cardiac death reported in the literature, primary and secondary prevention are crucial in AAS users in order to avoid serious consequences. The scientific community should intensify its efforts to assess the pathophysiology of behavior and cognitive impairment due to long term AAS exposure. Moreover, the evidence is urgently required to support the development of a reliable diagnostic tool to identify precociously AAS abuse as well as evidence-based therapy [57,125–131].
Information and education are fundamental tools for AAS misuse prevention. As long as anabolic steroid misuse is popular among young athletes, information campaigns regarding AASs and other doping agents should be encouraged in high schools. In this regard, to prevent the use of AASs public health measures in all settings are crucial. These measures consist of improved knowledge among healthcare workers, proper doping screening tests, educational interventions, and updated legislation. Although the use of AASs appears to increase the risk of premature death in various categories of patients, further research about this problem is urgently needed [132–139].
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