madman
Super Moderator
* Chronic exposure to supraphysiologic doses of AAS induces a variety of pathophysiological changes in the cardiovascular system. The mechanisms are multifactorial, involving direct androgen receptor-mediated effects on cardiac and vascular tissues as well as indirect metabolic and hemodynamic effects. Key pathways include endothelial dysfunction, adverse lipid profile changes, prothrombotic and vasospastic effects, myocardial hypertrophy with fibrosis, and electrical remodeling contributing to arrhythmias.
* Additionally, AR are found in cardiomyocytes as well as in vascular endothelial and smooth-muscle cells, where they regulate nitric oxide (NO) synthesis and vascular tone. Under physiological conditions, activation of endothelial AR by testosterone or DHT may have a protective effect by increasing nitric oxide (NO) synthesis in endothelial cells via the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathways [14–18]. Furthermore, activation of AR in the vascular endothelium may increase prostacyclin (PGI2) production by inducing cyclooxygenase-2 and enhance the release of endothelium-derived hyperpolarizing factor (EDHF), which together promote vasodilation [18,19]. However, excessive AR stimulation by supraphysiological AAS doses disrupts endothelial homeostasis, leading to decreased NO bioavailability, increased oxidative stress, and RAAS overactivation [15–19].
Figure 1. Baseline pathophysiological mechanisms of anabolic–androgenic steroids (AAS) on the cardiovascular system. Abbreviations: AAS, anabolic-androgenic steroids; ANP, atrial natriuretic peptide; DNA, deoxyribonucleic acid; EDHF, endothelium-derived hyperpolarizing factor; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NF-κB, nuclear factor-κB; NLRP3, NOD-like receptor family pyrin domain containing 3; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; TLR4, Toll-like receptor 4. ↑—increase, ↓—decrease.
Abstract
Anabolic–androgenic steroids (AAS) are synthetic derivatives of testosterone that are used therapeutically but are frequently abused by athletes and individuals seeking to increase muscle mass. Their anabolic (promoting muscle growth) and androgenic (inducing masculine characteristics) effects result from androgen receptor activation in target tissues. However, chronic supraphysiological AAS exposure is associated with serious cardiovascular consequences, ranging from hypertension and lipid disorders to cardiomyopathy, atherosclerosis, and sudden cardiac death. This review provides an updated and integrative perspective on both the molecular and clinical aspects of AAS-induced cardiovascular toxicity, highlighting recent advances in understanding endothelial injury, oxidative stress, fibrosis, and arrhythmogenesis. Importantly, it emphasizes the emerging recognition of AAS abuse as a modifiable cardiovascular risk factor and discusses potential preventive and therapeutic strategies, including early cardiovascular screening and risk stratification. Understanding these mechanisms is essential for recognizing the clinical manifestations of AAS misuse and for improving cardiovascular risk assessment in affected individuals. These insights underscore the clinical significance of AAS abuse as a cardiovascular risk factor and the need for vigilant cardiac monitoring and early intervention in this population.
Introduction
From the pathological point of view, supratherapeutic androgen exposure affects the cardiovascular system both directly (via cardiac and vascular androgen receptors) and indirectly (via lipid abnormalities, coagulation changes, and neurohormonal shifts), ultimately promoting atherosclerosis, myocardial fibrosis, and electrical instability. [1–4]. This review summarizes the current knowledge about the cardiovascular effects of AAS, with particular emphasis on molecular mechanisms and clinical implications.
2. Epidemiology of AAS Use
3. Molecular Mechanisms of AAS Cardiovascular Toxicity
Chronic exposure to supraphysiologic doses of AAS induces a variety of pathophysiological changes in the cardiovascular system. The mechanisms are multifactorial, involving direct androgen receptor-mediated effects on cardiac and vascular tissues as well as indirect metabolic and hemodynamic effects. Key pathways include endothelial dysfunction, adverse lipid profile changes, prothrombotic and vasospastic effects, myocardial hypertrophy with fibrosis, and electrical remodeling contributing to arrhythmias. The pathophysiological mechanisms of AAS and their potential cardiovascular consequences are presented in Table 1 and Figure 1.
3.1. Effect of AAS on Androgen Receptors in the Heart and Endothelium
In summary, AAS abuse directly affects both cardiac and vascular cells through androgen receptor-mediated pathways, initiating a cascade of molecular events that culminate in cardiac hypertrophy and endothelial dysfunction [23–26].
3.2. Effects of AAS on Oxidative Stress and Mitochondrial Dysfunction
These findings underscore oxidative stress as a one of the central mediators of AAS-induced cardiotoxicity, suggesting that mitigating oxidative damage may help protect the heart against the long-term consequences of steroid abuse.
3.3. Effects of AAS on Apoptosis and Autophagy
Impaired autophagy contributes to impaired clearance of damaged mitochondria and protein aggregates, promoting further cell damage and the development of cardiac dysfunction [35–37]. Although conclusive experimental data on autophagy in the context of AAS are lacking, numerous pathological phenomena observed in the hearts of steroid users such as the accumulation of abnormal structures in cardiomyocytes may result from autophagy disorders [40]. It is worth emphasizing the need for further research on this aspect, as the balance between autophagy and apoptosis is crucial for cardiac cell survival during stress.
4. Myocardial Remodeling and Fibrosis in AAS Users
Chronic AAS abuse thus promotes a mixed hypertrophic–fibrosing phenotype of cardiomyopathy, substantially increasing the risk of premature heart failure and sudden cardiac death [42,43].
5. Effects of Anabolic–Androgenic Steroids on the Coagulation System
Collectively, the hemostatic phenotype in AAS users is modulated by the specific compound, cumulative dose, way of administration, and duration of exposure. Importantly, a proportion of coagulation-system abnormalities appears at least partially reversible following cessation of AAS.
6. Effect of AAS on Lipid Metabolism and Blood Pressure Regulation
Chronic adrenergic stimulation and excessive activation of the RAA by AAS contribute to cardiac pressure overload, the development of pathological cardiac hypertrophy, endothelial dysfunction, and myocardial fibrosis [27,28,63]. Changes caused by AAS are not always reversible, and high blood pressure and dyslipidemia may persist in some users even after AAS discontinuation [27,28].
7. Other Neurohormonal Effects of AAS Use and Their Cardiovascular Implications
Altogether, neurohormonal alterations induced by AAS, including gonadal suppression and thyroid imbalance, act synergistically with direct metabolic and vascular effects of steroids. These disturbances aggravate dyslipidemia, vascular stiffness, and insulin resistance, thereby accelerating atherosclerosis, promoting left ventricular hypertrophy, and increasing susceptibility to arrhythmias and sudden cardiac death [62,67,74]. In this way, neuroendocrine disruption constitutes a crucial and often underestimated component of the overall cardiovascular toxicity of AAS.
8. Arrhythmias and Electrical Remodeling in AAS Users
Four main mechanisms appear to underlie arrhythmias and sudden cardiac death in AAS users: the atherogenic, thrombosis, vasospasm (due to impaired nitric oxide signaling), and direct myocardial injury models. Hypertrophy, fibrosis, and necrosis create an arrhythmogenic substrate, and AAS use transforms physiological remodeling in athletes into pathological hypertrophy, increasing the risk of fatal arrhythmias [40].
9. Conclusions
Abuse of AAS at high doses exerts negative effects on the cardiovascular system. Through a combination of endothelial damage, adverse metabolic changes, and direct toxic effects on the myocardium, the effects of AAS provide a substrate for premature cardiovascular disease. Numerous studies indicate that inappropriate AAS use can lead to accelerated coronary atherosclerosis, thrombosis, hypertension, pathological cardiac hypertrophy, and electrical instability, which consequently contribute to myocardial infarction, heart failure, arrhythmias, and sudden cardiac death. Due to society’s changing lifestyle, AAS abuse is an emerging cardiovascular risk factor that clinicians should consider in the differential diagnosis of cardiovascular disease. Unfortunately, many cases of AAS-related cardiomyopathy or myocardial infarction may remain undiagnosed if the patient’s history of drug use is not properly assessed. Therefore, cardiologists and primary care physicians should consider the use of AAS in young patients with unexplained left ventricular dysfunction, early coronary artery disease, or arrhythmias, especially if there are physical or laboratory findings. In addition, AAS users should undergo cardiovascular risk evaluation, including blood pressure monitoring, lipid panels, and possibly echocardiography. Studies in the last decade have demonstrated the mechanisms how AAS affect the cardiovascular system—dyslipidemia, endothelial dysfunction, prothrombotic changes, myocardial fibrosis, and arrhythmogenesis—and confirmed long-suspected clinical links with heart disease However, the long-term cardiovascular prognosis of former AAS users remains uncertain, as some steroid-induced changes may persist even after cessation. Future research should focus on quantifying the dose-dependent risk threshold for irreversible cardiovascular damage, developing strategies for early detection of AAS-induced cardiac injury, and implementing effective educational and rehabilitation programs to reduce AAS use in society.
* Additionally, AR are found in cardiomyocytes as well as in vascular endothelial and smooth-muscle cells, where they regulate nitric oxide (NO) synthesis and vascular tone. Under physiological conditions, activation of endothelial AR by testosterone or DHT may have a protective effect by increasing nitric oxide (NO) synthesis in endothelial cells via the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathways [14–18]. Furthermore, activation of AR in the vascular endothelium may increase prostacyclin (PGI2) production by inducing cyclooxygenase-2 and enhance the release of endothelium-derived hyperpolarizing factor (EDHF), which together promote vasodilation [18,19]. However, excessive AR stimulation by supraphysiological AAS doses disrupts endothelial homeostasis, leading to decreased NO bioavailability, increased oxidative stress, and RAAS overactivation [15–19].
Figure 1. Baseline pathophysiological mechanisms of anabolic–androgenic steroids (AAS) on the cardiovascular system. Abbreviations: AAS, anabolic-androgenic steroids; ANP, atrial natriuretic peptide; DNA, deoxyribonucleic acid; EDHF, endothelium-derived hyperpolarizing factor; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NF-κB, nuclear factor-κB; NLRP3, NOD-like receptor family pyrin domain containing 3; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; TLR4, Toll-like receptor 4. ↑—increase, ↓—decrease.
Abstract
Anabolic–androgenic steroids (AAS) are synthetic derivatives of testosterone that are used therapeutically but are frequently abused by athletes and individuals seeking to increase muscle mass. Their anabolic (promoting muscle growth) and androgenic (inducing masculine characteristics) effects result from androgen receptor activation in target tissues. However, chronic supraphysiological AAS exposure is associated with serious cardiovascular consequences, ranging from hypertension and lipid disorders to cardiomyopathy, atherosclerosis, and sudden cardiac death. This review provides an updated and integrative perspective on both the molecular and clinical aspects of AAS-induced cardiovascular toxicity, highlighting recent advances in understanding endothelial injury, oxidative stress, fibrosis, and arrhythmogenesis. Importantly, it emphasizes the emerging recognition of AAS abuse as a modifiable cardiovascular risk factor and discusses potential preventive and therapeutic strategies, including early cardiovascular screening and risk stratification. Understanding these mechanisms is essential for recognizing the clinical manifestations of AAS misuse and for improving cardiovascular risk assessment in affected individuals. These insights underscore the clinical significance of AAS abuse as a cardiovascular risk factor and the need for vigilant cardiac monitoring and early intervention in this population.
Introduction
From the pathological point of view, supratherapeutic androgen exposure affects the cardiovascular system both directly (via cardiac and vascular androgen receptors) and indirectly (via lipid abnormalities, coagulation changes, and neurohormonal shifts), ultimately promoting atherosclerosis, myocardial fibrosis, and electrical instability. [1–4]. This review summarizes the current knowledge about the cardiovascular effects of AAS, with particular emphasis on molecular mechanisms and clinical implications.
2. Epidemiology of AAS Use
3. Molecular Mechanisms of AAS Cardiovascular Toxicity
Chronic exposure to supraphysiologic doses of AAS induces a variety of pathophysiological changes in the cardiovascular system. The mechanisms are multifactorial, involving direct androgen receptor-mediated effects on cardiac and vascular tissues as well as indirect metabolic and hemodynamic effects. Key pathways include endothelial dysfunction, adverse lipid profile changes, prothrombotic and vasospastic effects, myocardial hypertrophy with fibrosis, and electrical remodeling contributing to arrhythmias. The pathophysiological mechanisms of AAS and their potential cardiovascular consequences are presented in Table 1 and Figure 1.
3.1. Effect of AAS on Androgen Receptors in the Heart and Endothelium
In summary, AAS abuse directly affects both cardiac and vascular cells through androgen receptor-mediated pathways, initiating a cascade of molecular events that culminate in cardiac hypertrophy and endothelial dysfunction [23–26].
3.2. Effects of AAS on Oxidative Stress and Mitochondrial Dysfunction
These findings underscore oxidative stress as a one of the central mediators of AAS-induced cardiotoxicity, suggesting that mitigating oxidative damage may help protect the heart against the long-term consequences of steroid abuse.
3.3. Effects of AAS on Apoptosis and Autophagy
Impaired autophagy contributes to impaired clearance of damaged mitochondria and protein aggregates, promoting further cell damage and the development of cardiac dysfunction [35–37]. Although conclusive experimental data on autophagy in the context of AAS are lacking, numerous pathological phenomena observed in the hearts of steroid users such as the accumulation of abnormal structures in cardiomyocytes may result from autophagy disorders [40]. It is worth emphasizing the need for further research on this aspect, as the balance between autophagy and apoptosis is crucial for cardiac cell survival during stress.
4. Myocardial Remodeling and Fibrosis in AAS Users
Chronic AAS abuse thus promotes a mixed hypertrophic–fibrosing phenotype of cardiomyopathy, substantially increasing the risk of premature heart failure and sudden cardiac death [42,43].
5. Effects of Anabolic–Androgenic Steroids on the Coagulation System
Collectively, the hemostatic phenotype in AAS users is modulated by the specific compound, cumulative dose, way of administration, and duration of exposure. Importantly, a proportion of coagulation-system abnormalities appears at least partially reversible following cessation of AAS.
6. Effect of AAS on Lipid Metabolism and Blood Pressure Regulation
Chronic adrenergic stimulation and excessive activation of the RAA by AAS contribute to cardiac pressure overload, the development of pathological cardiac hypertrophy, endothelial dysfunction, and myocardial fibrosis [27,28,63]. Changes caused by AAS are not always reversible, and high blood pressure and dyslipidemia may persist in some users even after AAS discontinuation [27,28].
7. Other Neurohormonal Effects of AAS Use and Their Cardiovascular Implications
Altogether, neurohormonal alterations induced by AAS, including gonadal suppression and thyroid imbalance, act synergistically with direct metabolic and vascular effects of steroids. These disturbances aggravate dyslipidemia, vascular stiffness, and insulin resistance, thereby accelerating atherosclerosis, promoting left ventricular hypertrophy, and increasing susceptibility to arrhythmias and sudden cardiac death [62,67,74]. In this way, neuroendocrine disruption constitutes a crucial and often underestimated component of the overall cardiovascular toxicity of AAS.
8. Arrhythmias and Electrical Remodeling in AAS Users
Four main mechanisms appear to underlie arrhythmias and sudden cardiac death in AAS users: the atherogenic, thrombosis, vasospasm (due to impaired nitric oxide signaling), and direct myocardial injury models. Hypertrophy, fibrosis, and necrosis create an arrhythmogenic substrate, and AAS use transforms physiological remodeling in athletes into pathological hypertrophy, increasing the risk of fatal arrhythmias [40].
9. Conclusions
Abuse of AAS at high doses exerts negative effects on the cardiovascular system. Through a combination of endothelial damage, adverse metabolic changes, and direct toxic effects on the myocardium, the effects of AAS provide a substrate for premature cardiovascular disease. Numerous studies indicate that inappropriate AAS use can lead to accelerated coronary atherosclerosis, thrombosis, hypertension, pathological cardiac hypertrophy, and electrical instability, which consequently contribute to myocardial infarction, heart failure, arrhythmias, and sudden cardiac death. Due to society’s changing lifestyle, AAS abuse is an emerging cardiovascular risk factor that clinicians should consider in the differential diagnosis of cardiovascular disease. Unfortunately, many cases of AAS-related cardiomyopathy or myocardial infarction may remain undiagnosed if the patient’s history of drug use is not properly assessed. Therefore, cardiologists and primary care physicians should consider the use of AAS in young patients with unexplained left ventricular dysfunction, early coronary artery disease, or arrhythmias, especially if there are physical or laboratory findings. In addition, AAS users should undergo cardiovascular risk evaluation, including blood pressure monitoring, lipid panels, and possibly echocardiography. Studies in the last decade have demonstrated the mechanisms how AAS affect the cardiovascular system—dyslipidemia, endothelial dysfunction, prothrombotic changes, myocardial fibrosis, and arrhythmogenesis—and confirmed long-suspected clinical links with heart disease However, the long-term cardiovascular prognosis of former AAS users remains uncertain, as some steroid-induced changes may persist even after cessation. Future research should focus on quantifying the dose-dependent risk threshold for irreversible cardiovascular damage, developing strategies for early detection of AAS-induced cardiac injury, and implementing effective educational and rehabilitation programs to reduce AAS use in society.
