Review Article

Anabolic-androgenic steroids and cardiovascular risk

Jian-Di Liu, Yan-Qing Wu

Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.

Abstract
Objective: Anabolic-androgenic steroids (AAS) represents a group of synthetic testosterone derivatives that play an important role in
clinical treatment. These drugs are widely abused among the general public to increase lean weight and improve athletic
performance. It has been reported that AAS use can produce many adverse effects, especially the occurrence of cardiovascular risk.
Although there are many related studies, there has been no consensus on AAS use and cardiovascular risk. The present study was to
review the effect of AAS on the cardiovascular system.
Data sources: The data in this review were obtained from articles included in PubMed and the National Center for Biotechnology
Information database.
Study selection: Original articles, case reports, and systematic reviews about AAS were selected for the article.
Results: The use/abuse of AAS is correlated with higher cardiovascular risks, and many AAS users/abusers had cardiovascular
diseases. However, there are many confounding factors in the studies that explored the causality between AAS intake and disease
development, and additional studies are required to determine AAS toxicity.
Conclusion: AAS produces toxic effects on the cardiovascular system, and it is necessary to ensure that more people know this about
AAS, including medical personnel.
Keywords: Anabolic-androgenic steroid; Cardiovascular risk; Toxicity effects

Introduction count. Thus, it makes sense to prolong the life-span of these

mice by designing a mouse model of aplastic anemia that was
Anabolic-androgenic steroids (AAS), including testoster- induced by short telomeres in the bone marrow compart-
one and its numerous derivatives that have been modified ment. Additionally, androgens can promote growth by
to improve anabolism, are usually used to boost protein stimulating growth hormone synthesis to treat some diseases
synthesis, muscle growth, and erythropoiesis.[1] Common that result in short stature and stunted development, such as
preparations are Nandrolone, Stanozolol (STZ), Oxan- Turners syndrome.[10] Ongoing progress in medical research
drolone, Methandrostenolone, and Trenbolone, and some has shown that AAS can be used in the treatment of breast
are parenteral or oral formulations.[2] cancer.[11] Appropriate doses of testosterone (T) or T
combined with anastrozole (A) in women with hormone
Since the 1940s, these drugs have been used in rehabilita- deficiency caused a reduced incidence of breast cancer, and T
tion from burns, trauma, and surgery.[3] Following in- + A implants placed in breast tissue surrounding malignant
depth research, AAS began to be used to treat diseases that tumors significantly reduced breast tumor size, indicating
are associated with aging such as physiological or that T has a direct anti-proliferative and protective effect that
pathological hypogonadism and osteoporosis.[4,5] More- was delivered by the sub-cutaneous implants for breast cancer
over, high doses of AAS can treat cachexia, which is caused treatment. Many medical studies on AAS have shown that
by human immunodeficiency virus and cancer, by AAS play an important role in the treatment of an increasing
promoting protein synthesis and maintaining and increas- number of diseases.
ing lean mass.[6,7] Many prospective randomized studies
have shown that androgens can be used to treat leukemia However, in the 1950s, AAS started to be used by elite
by stimulating bone marrow proliferation and hematopoi- athletes as a stimulant to enhance athletic performance and
esis.[8] Bar et al[9] found that androgen therapy resulted in increase muscle mass.[2] Use/abuse of AAS occurs
telomerase up-regulation and improvement in the blood worldwide, and the most common motives for using

Access this article online Correspondence to: Prof. Yan-Qing Wu, Department of Cardiology, The Second
Affiliated Hospital of Nanchang University, Minde Road No.1, Nanchang, Jiangxi
Quick Response Code: Website: 330006, China
www.cmj.org E-Mail: [email protected]
Copyright © 2019 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the
CC-BY-NC-ND license. This is an open access article distributed under the terms of the Creative
DOI: Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is
10.1097/CM9.0000000000000407 permissible to download and share the work provided it is properly cited. The work cannot be
changed in any way or used commercially without permission from the journal.
Chinese Medical Journal 2019;132(18)
Received: 19-04-2019 Edited by: Yi Cui

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AAS are increased athletic performance, building muscles, metabolism disorder, which leads to decreased high-
improved physical appearance, strengthened libido, and an density lipoprotein (HDL) and increased low-density
enhanced self-confidence.[12] The adverse effects of AAS lipoprotein (LDL) levels, which increase the risk of CAD
abuse have been gradually recognized, and using AAS is and cerebrovascular disease.[26] It has been shown that
associated with non-negligible toxic effects on the body. physical exercise increases the HDL level and has a
Long-term AAS use can induce abnormal endogenous remarkable effect on the reduction of LDL and triglyceride
hormone secretion, producing reversible or irreversible levels, thereby reducing the harmful effects of AAS in the
damage. The most common side effect of AAS is increased body.[27] Lipoprotein levels will return to their normal
secretion of oil from sebaceous glands, which causes range after AAS is discontinued for weeks to months.[28]
dermatological diseases such as acne vulgaris, androgenic Additionally, Peoples et al[29] reported that long-term AAS
alopecia, and hypertrichosis.[13] AAS can also induce some abuse leads to a continuous increase in homocysteine levels
sex problems, such as testicular atrophy, impotence, in the blood, resulting in hyperhomocysteinemia, which is
azoospermia, and infertility in men.[14,15] In women, a risk factor for coronary atherosclerosis, and this
AAS abuse can produce voice changes, amenorrhea, increases the incidence of CAD.
uterine atrophy, and clitoral enlargement.[15] In athletes,
AAS abusers are at a significantly increased risk of tendon Thromboembolism
ruptures, which is a crushing blow for the athlete’s
career.[16] Additionally, long-term AAS users are prone to AAS can directly affect the coagulation/fibrinolysis sys-
psychobehavioral disorders such as headache, irritability, tem,[30] and abusers have an increased risk of arterial and
depression, and AAS dependence syndrome,[17] leading to intra-cardiac embolism and a higher incidence of deep vein
violence and suicide in some cases.[13] An excessive oral thrombosis and pulmonary embolism.[31] These drugs
AAS burden is metabolized by the hepatorenal system, enhance platelet generation and aggregation, which expand
which aggravates hepatorenal damage, and it could also the range of thrombus embolism[32] and promote the
cause liver or kidney diseases, such as coagulation generation of thrombin[33] and thromboxane A2 (TXA2),
dysfunction, liver fibrosis, renal hypertrophy, and renal which inhibit the production of prostacyclin (prostaglandin
failure.[18,19] AAS abuse also increases the cardiovascular I2, an inhibitor of platelet aggregation) and results in hyper-
risk and seriously threatens the safety of its users.[13,20] coagulability.[26,34] Additionally, testosterone directly reg-
ulates TXA2 receptor density on platelets and vascular cells,
Effects of AAS on the Cardiovascular System thus affecting the coagulation/fibrinolysis function.[35]
However, prospective studies are required to clarify whether
Cardiovascular diseases are considered to be the largest this pathological state increases the thrombotic risk in AAS
threat to human life, and it is a main public health issue abusers even after cessation.
worldwide.[21,22] Diseases that involve the heart and blood
vessels include coronary artery disease (CAD), hyperten- Hypertension
sion, cardiac arrhythmia, cardiomyopathy, and thrombo-
embolism. The underlying pathogenic mechanisms vary The link between AAS and blood pressure (BP) is unclear.
depending on the type of disease. However, the cardiovas- A correlation between AAS use and higher BP has been
cular system in most AAS abusers is always unhealthy, and found in some studies,[26,36] whereas other studies have
the cardiovascular lesions in AAS abusers vary because shown no association.[37-39] Junior et al[40] found that,
of individual differences, presenting diverse signs and compared with the pre-exercise baseline, there was no
symptoms. significant decrease in arterial pressure from 30 to 60 min
after exercise in AAS users, indicating that AAS inhibited
Vascular calcification post-exercise hypotension. The effect of AAS use/abuse on
BP may persist for long periods, and some studies have
One study addressed the hypothesis of exogenous andro- reported a persistent BP elevation for 5 to 12 months after
gen-induced vascular calcification. Immunohistochemical cessation.[41] When reversible hypertension is observed, it
analysis showed expression of the androgen receptor (AR) may follow water–sodium retention in the kidney that is
in the calcified tissue of human femoral artery and in induced by AAS, which results in an increase in blood
calcified human valves, and in vitro studies revealed that 9 volume and BP.[42] If such hypertension is irreversible,
days of treatments with testosterone or dihydrotestosterone AAS-induced atherosclerosis will likely be the main cause.
resulted in increased calcification of phosphate-induced Because the analysis is complicated by many factors, such
mouse vascular smooth muscle cells.[23] These experimental as dose and duration of AAS use, additional studies are
data suggest that androgens increase the degree of vascular necessary to further reveal the link between AAS and BP.
calcification through binding to AR, then directly inducing
cell damage, resulting in loss of tissue elasticity and Coronary spasm
ultimately fibrotic hyperplasia.[24]
A physiological dose of AAS directly binds to the AR on the
Atherosclerosis arteries, which promotes the release of nitric oxide to inhibit
vascular smooth muscle tension by activating the smooth
Atherosclerosis is a disease in which the artery narrows muscle ion channels such as L-type voltage-gated Ca2+
because of plaque formation, and lipid metabolism channels, voltage-gated K+ channel, and Ca2+-activated K+
disorder is the pathological basis of atherosclerosis. channels, which induce vasodilatation.[43,44] However,
Samieinasab et al[25] found that AAS can induce lipid supraphysiological doses cause coronary spasm. Sonmez
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et al[45] reported a clinical case of a 32-year-old male have shown pathological cardiac hypertrophy in AAS
who had severe chest pain and was admitted to the local users.[38,54] AAS-induced cardiac hypertrophy should be
hospital. He had been taking AAS (200 mg weekly) for 3 distinguished from physiological hypertrophy, which
years for bodybuilding. Medical examination showed that causes a reduction in ventricular compliance and degrada-
his cardiac markers were elevated remarkably, but his tion of cardiac inotropes.[55-57] Liu et al[58] have found that
electrocardiogram (ECG) did not show ST elevation or 5a-reductase, aromatase, and AR expression levels were
depression in each derivation, only showing peaked T significantly elevated in hypertrophic hearts in both
waves. The diagnostic coronary angiogram showed humans and mice, and it was suggested that AAS increased
completely normal states in both the right and left coronary protein synthesis,[59] which was a vital stage in the process
artery systems. Ferrer et al[46] showed that constriction of of cardiac growth[60] in myocardial cells by activating
the thoracic aorta was correlated with lower concentrations intra-cellular AR. Additionally, AASs can strongly stimu-
of arterial endothelial cyclic guanosine monophosphate, late collagen production and myocardial fibroblastic
which is inhibited by androgens. However, Liu et al[47] growth.[61] Many patients with cardiac hypertrophy are
reported that patients with CAD had a decreased AR professional athletes who have been using AAS for a long
expression in the coronary arteries and they were more time, especially bodybuilders and powerlifters,[20] and
likely to have coronary spasm because of the favorable effect high-intensity training and AAS have a cumulative effect
of AR. Therefore, we hypothesize that the vasospasm effect on cardiac hypertrophy, causing cardiac dysfunction and
may be enhanced in AAS abusers with CAD, even inducing even heart failure.[55]
myocardial infarction. The sudden vasoconstriction causes
detachment of atherosclerotic plaques and thrombosis Dilated cardiomyopathy
forms, which obstructs coronary artery lumens, resulting
in ischemic myocardial necrosis. Some case reports suggested that dilated cardiomyopathy
in bodybuilders was directly related to AAS abuse.[32,62,63]
Myocardial apoptosis However, further studies suggested that dilated cardiomy-
opathy is mainly related to an individual’s genetic
AAS is associated with myocardial apoptosis.[48] In an background.[64,65] Dilated cardiomyopathy is an autoso-
animal model, ventricular myocytes were isolated from mal dominant disease in most clinical cases, and it rarely
adult male rabbits and treated in vitro for 20 h using shows autosomal recessive or X chromosome inheritance.
different doses of STZ, Testosterone Enanthate (TE), and Some dilated cardiomyopathy cases may be caused by
Testosterone (T) (0.1, 1, 10, and 100 mmol/L). These results infection or immune and environmental factors.[66]
showed, for the first time, that AASs induce significant
myocardial apoptosis in a dose-dependent manner.[49] Arrhythmia
Similar apoptosis in myocardial cells was observed by
Fanton et al[50] after norethandrolone therapy. Most of the AAS can induce abnormal electrical activity of the heart in
histopathological examination of hearts from treated abusers, and ECGs often show irregular electrical activity
rabbits showed that these myocardial lesions were similar during physical exertion, such as QRS-wave delay,
to adrenergic or toxic myocarditis, and caspase-3 activity ventricular fibrillation (VF), supraventricular, and ventric-
was increased in the hearts of treated animals, indicating ular ectopic beat.[26] Barbosa et al[67] showed that long-
that apoptosis was involved in the process of norethan- term use of a supraphysiological AAS dose would induce
drolone-induced cardiac lesions. Hassan et al[51] designed a cardiac autonomic disorders, suggesting that AASs induce
controlled experiment using rats to explore the effects of autonomic nervous dysfunction by affecting a variety of
AAS on apoptosis and histology of cardiac muscle. The neurotransmitter systems, such as the dopaminergic
results showed that cardiac caspase-3 activity was signifi- system, the 5-hydroxytryptophan system, and the GABA
cantly elevated in rats treated with nandrolone decanoate, system.[68,69] Ghorbani et al[70] have reported in a
and histological examination showed apoptosis and controlled experiment that the combination of exercise
hypertrophy of cardiac myocytes. Additionally, a clinical and nandrolone remarkably increased the incidence of VF
case report showed that AAS abusers with normal coronary and reduced the VF latency. Medei et al[71] investigated the
arteries were diagnosed with left ventricular hypertrophy mechanism of ventricular repolarization with AAS treat-
with myocardial scarring.[52] It was also suggested that ment at the cellular, ionic, and molecular levels, and they
AAS induces myocardial apoptosis. These studies indicated found that supraphysiological doses of AAS caused
that AAS had a pro-apoptotic effect on cardiac myocytes. morphological remodeling in bilateral ventricles as well
Vicencio et al[53] suggested that androgens promoted as electrical remodeling, especially in the left ventricle, and
Ca2+ influx and Ca2+ mobilization in the sarcoplasmic it was suggested that a supraphysiological dose of AAS
reticulum to increase mitochondrial permeability, which induced a disorder of electrical activity, resulting in cardiac
led to the release of apoptosis factors, such as cytochrome autonomic dysfunction.
C, apoptosis-inducing factor, and caspase, resulting in
apoptosis. Sudden cardiac arrest

Cardiac hypertrophy Clinical cases have demonstrated that AAS abuse is

associated with sudden cardiac arrest,[72,73] but the
Some controlled experiments that examined the hearts of mechanism of the sudden cardiac arrest remains unknown.
AAS users and non-users using standard Doppler On the one hand, most AAS abusers’ death from sudden
echocardiography or cardiac magnetic resonance imaging, cardiac arrest was observed as cardiomyopathy, such as
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cardiac hypertrophy, ventricle dilatation, and myocardial temporary functional disorder of the sympathetic axon
fibrosis, during an autopsy.[74-76] On the other hand, many terminals, which increases the susceptibility to VF,
AAS abusers use a variety of AASs, and combine multiple resulting in sudden cardiac death.[81] Thus, we guess that
drugs to enhance the anabolic stacking effects. Body- professional athletes with a history of long-term AAS use
builders use oral and injection AASs, and also supra- are more likely to experience sudden death.
physiological doses of recombinant human growth
hormone, insulin, and thyroid hormones (T3, mainly), Discussion
which enhance muscle growth, nutrient absorption, and
metabolism, respectively,[77-79] and diuretics are used to AAS has a protective effect on the cardiovascular system in
minimize sub-cutaneous water to obtain a “hard” look.[80] the physiological dose range. However, supraphysiological
The combination of these drugs may cause a lethal effect, AAS doses produce toxicity in the cardiovascular system,
but more studies are needed to support the suggestion. which significantly increases the cardiovascular risk
AAS can quickly inhibit the re-uptake of catecholamines [Figure 1].
into extra-neuronal tissue, and consequently increase the
concentration of catecholamines at the receptor sites.[31] The mechanism of AAS toxicity has not been fully
Therefore, the combination of AASs and physical exercise elucidated. Studies demonstrated that there were two
over-stimulates the sympathetic nervous system to induce a main mechanisms [Figure 2], one of which is AAS gene

Figure 1: The toxicity effects of AAS on the cardiovascular system. ↑: increase/enhance; ↓: decrease/inhibit. AAS: Anabolic-androgenic steroids; AR: Androgen receptor; cGMP: Cyclic
guanosine monophosphate; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; SR: Sarcoplasmic reticulum; TXA2: Thromboxane A2.

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Figure 2: The two main signaling pathways of AAS toxicity. AAS: Anabolic-androgenic steroids; AR: Androgen receptor; ARE: Androgen reactive element.

regulation where AASs or their metabolites bind to ARs, which did not clarify the causality between AAS intake and
which leads to a conformational change of these receptors. disease development.[55] However, it is unethical to design
AR dimers are then transported from the cytoplasm into control experiments in humans because long-term admin-
the nucleus where the dimers bind to androgen reactive istration of high AAS doses in the experimental group
elements in DNA, thereby regulating gene transcription in would be life-threatening.[72,73] Although the mechanism
cooperation with activation (or inactivation) of co- and toxicity of AAS can be explored using animal model
regulations, which results in toxic effects.[82] Another experiments, there are differences between humans and
non-gene regulatory mechanism (mainly in skeletal muscle animals, and the results may show different effects and
cells and prostate cancer cells) is that AR dimers bind to metabolic pathways for AASs.
cytoplasmic proteins through a variety of signaling
pathways that directly induce toxicity without gene The general therapy for AAS toxicity is drug cessation.[86]
transcription pathways.[82,83] The degree of AAS toxicity However, most case reports have not shown whether AAS
is related to a variety of factors such as dose, cycle, and was discontinued immediately or if the dose was reduced
individual differences. Through medical examinations, gradually.[45,87,88] Immediate discontinuation of high-dose
people taking AASs for a period of time or even a few years AASs after long-term can lead to the withdrawal responses,
may not show any abnormal index results. including mood disorders (depression), anorexia, de-
creased libido, insomnia, fatigue, headache, and the desire
There are some difficulties in studying AAS toxicity in the to take more steroids.[86] These withdrawal reactions
cardiovascular system. First, a general limitation of these would increase the seriousness of the illness in AAS users.
studies results from the information about AAS doses and Therefore, we suggest that causative therapy combined
cycles of use/abuse, which is self-reported, and it is difficult with gradual reduction of AAS doses is a more sensible
to objectively assess the exact data.[84] Additionally, scheme to treat users/abusers.
because of the stacking effect from polydrug abuse, it is
difficult to assess the toxic effects of AAS.[85] These studies Currently, few people really understand the effects of AAS
only demonstrated AAS-related cardiovascular lesions by on health,[89] but the recreational use of such drugs is
observing the morphological and functional differences becoming increasingly popular.[3] The largest group of
between the experimental group and the control group, AAS users are “average people who just want to get
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