Anabolic-Androgenic Steroids and Cardiovascular Risk

Anabolic-androgenic steroids (AAS) are synthetic derivatives of testosterone originally developed for clinical use in treating conditions such as hypogonadism, osteoporosis, and muscle-wasting diseases. Over time, their misuse has expanded into non-medical contexts, particularly among athletes and bodybuilders seeking enhanced physical performance and muscle growth. While AAS have legitimate therapeutic applications, their abuse is associated with significant cardiovascular risks, including hypertension, atherosclerosis, arrhythmias, and cardiomyopathy. This article explores the multifaceted cardiovascular effects of AAS, synthesizing evidence from clinical studies, animal models, and case reports to elucidate the mechanisms and consequences of their misuse.

Clinical Applications and Patterns of Abuse

AAS were first introduced in the 1940s for rehabilitation purposes, such as recovery from burns, trauma, and surgery. Their therapeutic scope later expanded to include age-related conditions like hypogonadism, osteoporosis, and cachexia associated with HIV or cancer. In oncology, AAS have been used to stimulate bone marrow proliferation in leukemia patients and to reduce tumor size in breast cancer cases. Testosterone and its analogs also promote growth hormone synthesis, aiding in the treatment of growth disorders such as Turner syndrome.

Despite these benefits, the non-medical use of AAS surged in the 1950s, driven by their anabolic effects. Users often consume supraphysiological doses—10 to 100 times higher than therapeutic levels—through oral, injectable, or transdermal formulations. Common motives include muscle hypertrophy, improved athletic performance, and aesthetic enhancement. Polypharmacy is prevalent, with users combining multiple AAS, growth hormones, insulin, thyroid hormones, and diuretics to amplify effects. This practice exacerbates toxicity, complicating the assessment of individual drug contributions to adverse outcomes.

Cardiovascular Toxicity Mechanisms

AAS exert cardiovascular toxicity through genomic and non-genomic pathways. The genomic mechanism involves binding to intracellular androgen receptors (AR), which translocate to the nucleus and modulate gene transcription. This process enhances protein synthesis and collagen production, contributing to pathological cardiac hypertrophy and fibrosis. Non-genomic effects occur when AAS interact with membrane-associated receptors or ion channels, rapidly altering cellular functions such as calcium flux and platelet aggregation.

Vascular Calcification and Atherosclerosis

Chronic AAS exposure promotes vascular calcification, a precursor to arterial stiffness and cardiovascular events. Immunohistochemical studies reveal AR expression in calcified human femoral arteries and heart valves. In vitro, testosterone and dihydrotestosterone increase calcium deposition in vascular smooth muscle cells by upregulating osteogenic markers. AAS also disrupt lipid metabolism, reducing high-density lipoprotein (HDL) by 20–50% and elevating low-density lipoprotein (LDL) by 30–40%. These changes persist for weeks to months post-cessation, accelerating atherosclerotic plaque formation. Hyperhomocysteinemia, observed in long-term users, further exacerbates coronary and cerebrovascular atherosclerosis.

Thrombosis and Coagulopathy

AAS induce a prothrombotic state by enhancing platelet aggregation, thrombin generation, and thromboxane A2 (TXA2) production while suppressing prostacyclin. Users exhibit a 2- to 3-fold increased risk of deep vein thrombosis, pulmonary embolism, and intracardiac thrombi. Testosterone upregulates TXA2 receptors on platelets and vascular cells, amplifying thrombotic responses. Case reports document fatal thromboembolic events in otherwise healthy young athletes, highlighting the acute risks of hypercoagulability.

Hypertension and Autonomic Dysfunction

The relationship between AAS and hypertension remains contentious. Some studies report systolic blood pressure elevations of 10–20 mmHg in users, attributed to renal sodium retention and increased blood volume. Others find no significant association, suggesting confounding factors like concurrent exercise. AAS impair post-exercise hypotension, delaying blood pressure normalization by 30–60 minutes. Autonomic dysfunction, evidenced by reduced heart rate variability, increases susceptibility to arrhythmias and sudden cardiac death.

Coronary Vasospasm and Myocardial Ischemia

Supraphysiological AAS doses paradoxically induce coronary vasospasm despite testosterone’s vasodilatory effects at physiological levels. A case study of a 32-year-old bodybuilder revealed normal coronary angiography despite elevated cardiac biomarkers and ECG changes, consistent with vasospastic angina. Reduced AR expression in atherosclerotic coronary arteries may enhance vasoreactivity, precipitating plaque rupture and myocardial infarction.

Myocardial Structural and Functional Abnormalities

Apoptosis and Fibrosis

AAS induce dose-dependent cardiomyocyte apoptosis via mitochondrial pathways. In rabbit ventricular myocytes, stanozolol and testosterone enanthate increase caspase-3 activity by 40–60% at 100 μM concentrations. Norethandrolone-treated animals exhibit adrenergic myocarditis-like lesions with interstitial fibrosis. Human autopsies of AAS abusers show patchy myocardial scarring and replacement fibrosis, indicative of chronic subclinical injury.

Pathological Hypertrophy and Cardiomyopathy

Echocardiographic studies demonstrate left ventricular hypertrophy (LVH) in 50–70% of long-term AAS users, characterized by wall thickening ≥13 mm and reduced ejection fraction. Unlike exercise-induced physiological hypertrophy, AAS-related LVH impairs diastolic relaxation and increases myocardial stiffness. Case series describe dilated cardiomyopathy in bodybuilders with normal coronaries, suggesting direct toxic effects or unmasking genetic predispositions.

Arrhythmias and Sudden Cardiac Death

AAS alter cardiac electrophysiology, prolonging QRS duration and QT intervals. Ventricular fibrillation (VF) latency decreases by 30% in animal models exposed to nandrolone and exercise. Users exhibit a 4-fold higher incidence of ventricular ectopy and supraventricular tachycardia. Sudden cardiac death, often attributed to catecholamine surges during exertion, occurs via VF triggered by ion channel remodeling or coronary spasm.

Challenges in Establishing Causality

Confounding factors complicate the assessment of AAS-related cardiovascular risk. Self-reported dosing data are often unreliable, and polydrug use obscures individual drug effects. Ethical constraints limit controlled human trials, necessitating reliance on observational studies and animal models. Murine experiments, while informative, may not fully replicate human pharmacokinetics or disease phenotypes.

Clinical Implications and Public Health Considerations

AAS cessation remains the cornerstone of management, though gradual tapering is advised to avoid withdrawal symptoms (e.g., depression, fatigue). Public health initiatives must address knowledge gaps among users and clinicians. Surveys indicate that 60–80% of users perceive AAS as low-risk, underscoring the need for targeted education. Medical training should emphasize recognition of AAS toxicity, particularly in young males presenting with unexplained cardiovascular abnormalities.

Conclusion

Anabolic-androgenic steroids pose significant cardiovascular risks through diverse mechanisms, including dyslipidemia, thrombogenesis, vasomotor dysfunction, and direct myocardial injury. While therapeutic doses remain valuable in clinical contexts, supraphysiological abuse disrupts cardiovascular homeostasis, culminating in life-threatening conditions. Multidisciplinary efforts—encompassing research, education, and harm reduction—are essential to mitigate this growing public health burden.

doi.org/10.1097/CM9.0000000000000407

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