Accepted Manuscript

Adverse health effects of androgen use

Anna Goldman, Shehzad Basaria

PII: S0303-7207(17)30336-2
DOI: 10.1016/j.mce.2017.06.009
Reference: MCE 9981

To appear in: Molecular and Cellular Endocrinology

Received Date: 8 June 2017

Accepted Date: 8 June 2017

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 ACCEPTED MANUSCRIPT

Adverse Health Effects of Androgen Use

Anna Goldman, MD1 and Shehzad Basaria, MD1

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Research Program in Men's Health: Aging and Metabolism, Brigham and Women’s Hospital,

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Harvard Medical School, Boston, MA

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Corresponding author:

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Shehzad Basaria, M.D.

221 Longwood Ave

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BLI – 541

Boston, MA 02115
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Telephone: 617-525-9144
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Fax: 617-525-9148
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Email: sbasaria@partners.org
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Disclosures:
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Dr. Goldman has no commercial or financial conflicts of interest to disclose.

Dr. Basaria has served as a consultant to AbbVie Pharmaceuticals and Regeneron.

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Abbreviations:

AAS: Anabolic androgenic steroids

ALS: Amyotrophic Lateral Sclerosis

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CMR: Cardiovascular magnetic resonance

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ECW: Extracellular weight

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hCG: Human chorionic gonadotropin

HPG: Hypothalamic-pituitary-gonadal

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HDL: High-density lipoprotein

LDL: Low-density lipoprotein

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LVH: Left ventricular hypertrophy

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rhGH: Recombinant human growth hormone

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SERM: Selective estrogen receptor modulator

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Abstract:

Anabolic androgenic steroids (AAS) are performance enhancing drugs commonly used by

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athletes and bodybuilders to improve appearance and athletic capability. Unfortunately, these

testosterone derivatives can be associated with serious and potentially irreversible side effects,

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and can impact multiple organ systems. It is important that physicians be familiar with these

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adverse consequences so that they can appropriately counsel patients whom they suspect of

AAS-abuse. In this chapter, we will review the negative effects of these compounds on various

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organ systems in men using AAS.
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Introduction:

Anabolic androgenic steroids (AAS) are synthetic androgens derived from testosterone

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that are used by both elite professional athletes and amateur athletes participating in recreational

sports, and also by non-athletes (for body image enhancement) because of their trophic effect on

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muscles and potential improvement in athletic performance. However, their use is associated

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with a number of adverse effects, some potentially fatal 1-3.

Testosterone was first synthesized in the 1930’s 4, 5, and during World War II, Nazi

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physicians administered androgens to German soldiers to promote aggressiveness6. John Ziegler,
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an American physician from York, PA, and a physician member of the U.S. weight-lifting team,
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is credited with pioneering the use of AAS among bodybuilders in the United States after

observing the ergogenic effects of androgens on the Soviet weightlifting team at the World
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Weightlifting Championships in Vienna, Austria in 1954. Upon his return from the
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Championships, Dr. Ziegler started experimenting with testosterone on weight lifters at the York

Babel Club in Pennsylvania. However; he noted that the gains in muscle strength were modest,
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and the subjects experienced undesirable side effects. He collaborated with Ciba

Pharmaceuticals to synthesize the anabolic steroid methandrostenolone, which the company later
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marketed as Dianabol (DBOL) in the late 1950’s; subsequently its use became widespread
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among bodybuilders. The marked gains in muscle mass and strength achieved with DBOL came

at a price as its use was associated with side-effects such as serious hepatotoxicity and sterility.

Observation of these adverse effects made Ziegler very remorseful, and upon his deathbed in

1983, he reportedly said, “All those young kids... what a terrible price they’ll pay. If only I’d

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known it would come to this” 6. Indeed, in a 2006 survey, nearly 100% of AAS users reported

side effects including acne, testicular atrophy, insomnia, sexual dysfunction, injection site pain,

striae, fluid retention, mood alterations, and gynecomastia 7. Additionally, there have been

reports of serious cardiovascular side effects related to AAS-use including reports of sudden

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cardiac death in apparently healthy bodybuilders 8-11.

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Short-term physiologic adaptations to exercise (increased heart rate and cardiac output,

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and improved pulmonary ventilation) and long-term adaptations (structural changes in skeletal

muscles and tendons, and cardiovascular remodeling) enhance the body’s ability to exercise

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through facilitation of oxygen delivery and efficient utilization by the muscles. These
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adaptations improve fitness and enable a person to achieve a higher level of exercise

performance. Doping potentially augments these adaptations further by stimulating

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hematopoiesis, promoting muscle protein synthesis, which in turn results in an increase in

muscle mass and strength 12. Recent data suggests that genetic variation has an impact on
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androgen metabolism, not only confounding interpretation of doping test results but also
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predisposing individuals to develop drug-related adverse events 13. In this chapter, we will

review the adverse effects of AAS on various physiologic systems in humans. Where applicable,
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we also report data of AAS administration in animal models.

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Types of AAS

AAS represent a large group of synthetic derivatives of testosterone and can be divided

broadly into two categories: aromatizable and non-aromatizable androgens. Aromatizable AAS

like nandrolone are direct derivatives of testosterone and a substrate for aromatase, which

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removes the methyl group from the 19th position of the androgen ring. Non-aromatizable AAS

such as winstrol or trenbolone are modified such that the 19th carbon is not recognized as a

substrate by aromatase, and therefore, they are not aromatized to estrogen. Non-aromatizable

AAS are generally preferred by body builders to minimize estrogenic side effects such as

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gynecomastia. Many AAS are 5-α reduced to dihydrotestosterone, a potent metabolite of

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testosterone, by the enzyme 5-α reductase. Certain side effects of AAS use such as androgenetic

alopecia have been attributed to the action of dihydrotestosterone. Similarly, AAS that are taken

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orally are 17-α alkylated to improve bioavailability with their major adverse effect being

hepatotoxicity. Desirable effects of AAS among athletes include an increase in muscle mass and

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strength, and erythropoiesis, allowing them to train longer and harder, and potentially recover
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faster from an injury 14-16. Unlike ‘anabolic’ effects that are desirable, ‘androgenic’

(“masculinizing”) effects such as male pattern baldness, oily skin and acne are undesirable for
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the users of AAS. Table 1 summarizes the metabolism of various AAS, and the active
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metabolites serve as a guide to the potential side effects of these androgens.

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Administration of AAS

AAS can be administered orally or parenterally. The majority of athletes use

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intramuscular AAS in supraphysiologic doses equivalent to at least 1000 mg of testosterone per

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week (10 times the replacement dose) 7. Many athletes administer AAS in 2-3 cycles per year,

with each cycle generally lasting 6-18 weeks, the recovery periods between the cycles are meant

to allow the recovery of the hypothalamic-pituitary-gonadal (HPG) axis. In a typical cycle, 2-3

different AAS are used in combination (for example combination of intramuscular nandrolone

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decanoate with an oral AAS); a practice known as “stacking” 17. This strategy is used by the

athletes to potentially minimize development of tolerance to any single agent. Additionally,

AAS are often taken with an aromatase inhibitor or a selective estrogen receptor modulator

(SERM) to minimize estrogenic adverse effects of aromatizable AAS such as gynecomastia and

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suppression of the HPG axis 18. In men using AAS, an average steroid regimen consists of

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approximately 3 different agents in doses that are 5-29 times higher than physiologic

replacement doses 19.

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Adverse Effects of AAS:
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AAS have been associated with a variety of adverse effects that impact many organ

systems (Figure 1). These adverse effects are summarized below.

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Cardiovascular
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As prospective, randomized trials evaluating long-term adverse cardiovascular effects of

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AAS use do not exist, information regarding AAS-related cardiovascular harm is limited to case

reports and case series. Androgen receptors are present in the myocardium and in major arteries
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. Although a few small mechanistic studies have shown that administration of physiologic
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doses of testosterone might have some beneficial effects on the cardiovascular system

(improvement in endothelial function, coronary vasodilation, reduction in vascular smooth

muscle tone) 21, use of supraphysiologic doses of AAS by athletes (both professional and

recreational) have been associated with a number of adverse effects including dyslipidemia,

arrhythmias, cardiovascular remodeling, hypertension and thrombosis.

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a. Dyslipidemia

Use of AAS has been associated with dyslipidemia, elevation in inflammatory markers

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and endothelial dysfunction, each potentially impacting vascular function 22, 23. Elevations in

low-density lipoprotein (LDL) cholesterol, reduction in high-density lipoprotein (HDL)

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cholesterol, and an increase in triglyceride concentrations have been observed 22, 24-26. These

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lipid abnormalities may become evident within a few months of AAS-use 27. Steroid hormones

stimulate hepatic lipase, which catabolizes HDL, reducing its concentration while increasing

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serum concentration of LDL as the final product of VLDL catabolism 28, 29. Accelerated
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atherosclerosis from these lipoprotein abnormalities is thought to precipitate cardiac ischemia in

athletes during peak exercise. For example, in 1988, a 22 year-old weightlifter who was using
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AAS and had no past personal or family history of cardiac disease presented with an acute
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myocardial infarction and was found to have impressive dyslipidemia (total cholesterol 596

mg/dL, LDL 513 mg/dL, HDL 14 mg/dL) 30. Twenty-four days after discontinuation of AAS,
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his total and LDL cholesterol decreased to 283 mg/dL and 220 mg/dL, respectively, and his HDL
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levels increased to 35 mg/dL. Although the lipoprotein abnormalities of this athlete improved

within weeks, some reports suggest that it may take up to 5 months after discontinuation of AAS
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for the lipid profile to completely normalize 27.

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b. Arrhythmia

There have been reports of potentially lethal ventricular arrhythmias in men using AAS,

mainly during physical exertion 9, 31. These arrhythmias include atrial fibrillation, ventricular

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and supraventricular tachycardia and ventricular ectopic beats 32. Indeed, there are reports of

sudden cardiac death in men taking AAS where post-mortem autopsies have not demonstrated a

culpable thrombus or an atheroma 9, 31. In other autopsy studies, varying degrees of myocardial

fibrosis have been described; fibrosis being a known risk factor for lethal arrhythmias 33. In

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contrast, some studies that have used cardiovascular magnetic resonance imaging have shown

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left ventricular hypertrophy but no fibrosis 34. Di Bello and colleagues used video densitometry

to identify changes in myocardial texture as an early potential sign of myocardial damage in

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weight-lifters using AAS 35. Ten weightlifters who used AAS (mean age 32 +/- 6 years) were

compared with 10 counterparts who did not use AAS and with 10 healthy, sedentary controls.

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They found that the 'cyclic variation index' of the interventricular septum and the left ventricular
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posterior wall was significantly lower in the AAS-users compared with the other groups,

suggesting structural alterations. The authors hypothesized that these findings reflect a focal
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increase in myocardial collagen in AAS-users, which could predispose them to these

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arrhythmias.
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Animal studies have provided further mechanistic insights on the effects of AAS on the

cardiac conduction system. Administration of supraphysiological doses of AAS to rats results in

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changes in left ventricular repolarization by influencing the potassium channel 36, leading to
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prolongation of the corrected QT interval. To the contrary, one study showed that administration
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of high-dose AAS for 17 days to male rats had no effect on cardiac conduction in the absence of

ischemia 37, however, nandrolone did potentiate arrhythmogenic effects during ischemia.

Additionally, laboratory studies have shown that testosterone stimulates intracellular calcium

release via a G-protein coupled receptor in the myocardium, suggesting that calcium overload

could be another mechanism that increases susceptibility to arhythmias 38.

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c. Anatomic remodeling

Use of AAS is associated with a dose-dependent increase in left ventricular mass in

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athletes, which may result in diastolic dysfunction 39, 40. However; as left ventricular

hypertrophy (LVH) is considered a physiologic aspect of cardiac adaptation to graded isometric

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exercises 40, it has been difficult to tease out the direct impact of AAS on anatomic remodeling
41-43

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. Clinical studies have shown distinct anatomical changes in the myocardium (on

echocardiogram) in AAS-users that are subtle and occur before the onset of overt LVH 44-46.

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Indeed, echocardiograms of athletes using AAS have shown abnormal ventricular wall
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waveforms compared with non-users 47. This AAS-induced cardiac remodeling is mediated via

androgen receptors in the myocardium 45, 46, 48. The use of AAS likely also results in direct
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toxicity to the myocardium; autopsy studies show myocytolysis, eosinophilic infiltration,

collagen deposition, fibrosis and changes in the cardiac microcirculation 49. Data from
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cardiovascular magnetic resonance imaging in bodybuilders using AAS show significant LVH
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and a specific pattern of myocardial scarring, which appears as enhancement of the septal and

posterolateral wall of the left ventricle, and is different from the enhancement pattern typically
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seen in patients with ischemic heart disease (subendocardial involvement in the vicinity of a
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coronary artery 50. As discussed above, this cardiac remodelling might form the basis for
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arrhythmias and diastolic dysfunction seen in some men using AAS.

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d. Hypertension

There are conflicting data regarding the use of AAS and hypertension; some studies have

shown an association 27, 35, 51, 52 while others have not 35, 39, 42, 53-60. These discrepant results may

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be attributable in part to the small number of subjects enrolled in these studies. Limited data

suggest that AAS-use is associated with both systolic and diastolic hypertension, and the

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association is stronger with longer duration of AAS-use 61. Although the exact mechanism

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remains unclear, inhibition of 11β-hydroxylation by AAS, resulting in cortisol-induced

activation of the mineralocorticoid receptor, has been implicated 62, 63.

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Androgens have also been shown to inhibit extraneuronal uptake of catecholamines 64, 65;
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and stimulate salt and water retention 59. In a study of men with panhypopituitarism, testosterone

administration was associated with increased extracellular weight (ECW), which further
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increased when growth hormone was added to the regimen (Figure 2) 66. In another trial that
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included community-dwelling men aged 65-90 years, replacement with testosterone was
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associated with an increase in both systolic and diastolic blood pressure (though the absolute

levels remained within the normal range) (Figure 3), with one-third of the participants reporting
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new lower extremity edema 67.

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e. Thrombosis and Erythrocytosis

There is some evidence that androgen use is associated with thrombosis 68. It has been

posited that aromatization of testosterone to estrogen might be the mechanism behind this risk;

similar to the risk of thromboembolism in postmenopausal women on hormone replacement

therapy 69, 70. However; an independent effect of testosterone in promoting thrombosis has also

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been suggested. Indeed, dihydrotestosterone, an active metabolite of testosterone, stimulates

monocyte activation in endothelial cells 71, a process implicated in acute coronary events 72.

Androgens also increase collagen and other fibrous proteins in the arterial wall 73.

Administration of testosterone to individuals with familial and acquired thrombophilia has been

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associated with thrombotic events that can occur as early as 4-6 months after initiation of

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treatment 74, 75; these events have been seen in the absence of erythrocytosis, suggesting that

other mechanisms might be involved 74-79. Erythrocytosis (an independent risk factor for

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cardiovascular disease) occurs in approximately 40% of men using AAS 80. Intramuscular

injectable formulations are more likely to result in erythrocytosis compared with transdermal

preparations 81,82

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. Androgens also stimulate synthesis of coagulation factors; indeed, Danazol, a
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synthetic androgen, is used in patients with haemophilia to increase factors VIII and IX 83.

Testosterone also increases thromboxane A2 receptor density on human platelets, promoting

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their aggregation, which may further increase risk of thrombosis 84. Oral androgens are also
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associated with reduction in the levels of prostacyclin (an inhibitor of platelet aggregation) and
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increase fibrinogen levels 85. Indeed, men using AAS have experienced stroke, some associated

with left ventricular thrombus 86, 87.

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Hyperhomocysteinemia is an independent risk factor for acute myocardial infarction and

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multi-vessel coronary artery disease 88, 89 and has been associated with endothelial dysfunction,
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reduced bioavailability of nitric oxide, increased oxidative stress, vascular smooth muscle

proliferation and activation of the coagulation cascade 90-92. Use of AAS in body builders has

been associated with hyperhomocysteinemia 93. Hence, use of AAS can predispose to

thrombosis via multiple mechanisms.

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Neuropsychiatric and Behavioral

The most common behavioral effects associated with AAS-use include reduced inhibitory

control, impulsive behavior, aggression, anxiety, hypomania and occasionally, frank mania 17, 94-

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. Not all men use AAS for performance enhancement, and may use them for image

enhancement. Many men experience muscle dysmorphia (a form of body dysmorphic disorder)

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, a pathologic state in which there is preoccupation with muscularity. These men are also

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more likely to have attempted suicide, have a poorer quality of life, and have a higher frequency

of substance abuse other than AAS 101.

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Alterations in the GABAergic system are thought to mediate many of the behavioral
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effects of AAS 94. In a controlled study of 160 athletes, a quarter of AAS-users reported major

mood disorders such as mania, hypomania, or major depression 17; there was a direct correlation
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between the dose of AAS and psychopathologic symptoms. In a randomized, placebo-controlled,

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crossover trial, supraphysiologic dose of testosterone cypionate of 500 mg per week or higher for

6 weeks was associated with symptoms of mania in otherwise normal men 102. In addition to
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experiencing neuropsychiatric symptoms during AAS use, withdrawal from AAS is also
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associated with major depressive episodes, including suicidal ideation 103-105. Previous use of

AAS has long-lasting effects on mood as former AAS-users have a significantly higher lifetime
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prevalence of mental-health problems compared with non-users 106.

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In addition to changes in neurotransmitters (such as GABA), AAS use influences the

brain via other mechanisms. These include formation of β-amyloid, increased oxidative stress,

and adverse effects on cerebral circulation 107, 108. Studies using high-resolution magnetic

resonance imaging show that weightlifters using AAS experience structural changes in the brain

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including reduced gray matter, reduced volume of the putamen, and thinner cerebral cortex

compared with age-matched weightlifters who have not used AAS 109. Although these findings

do not establish causality, there is a concern that long-term use of AAS might lead to cerebral

atrophy. Indeed, pre-clinical studies have shown that AAS administration can induce neuronal

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apoptosis 110-112 and altered expression of nerve growth factor (NGF), which is essential for

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neuronal differentiation and survival 113.

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Reproductive

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Androgens play a key role in the development and maintenance of male reproductive
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function and endogenous testosterone is the key regulator of the HPG axis 114, 115. Therefore,

administration of exogenous androgens result in suppression of gonadotropins, which in turn

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leads to reduction in intratesticular testosterone production (essential for spermatogenesis),

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resulting in suppression of spermatogenesis. This leads to testicular atrophy, androgen deficiency

and impaired fertility 116-118. The adverse effects of AAS on reproductive system are mediated
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both via androgen receptors and via aromatization of androgens to estradiol, which potently
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inhibits the HPG axis and is responsible for gynecomastia seen in some men using aromatizable

AAS.
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Prolonged androgen deficiency as a result of previous AAS is a growing cause of

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hypogonadotropic hypogonadism; approximately 20% of men seeking testosterone therapy

report previous AAS exposure 80, 119, 120 and mainly complain of sexual dysfunction, fatigue and

depression 80. Many men take selective estrogen receptor modulators (SERMs) and aromatase

inhibitors to hasten the recovery of the HPG axis; and also use human chorionic gonadotropin

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(hCG) to stimulate Leydig cells, hoping to increase testicular size 80, 121, 122. Though both SERMs

and aromatase inhibitors activate the HPG axis by directly acting at the hypothalamus; the use of

hCG might further delay the recovery of the gonadal axis due to the negative feedback on the

hypothalamus/pituitary by the hCG-stimulated testosterone production by the Leydig cells.

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Animal studies show that AAS have a profound impact on reproductive organs of

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immature male rats that include decreased testosterone production, reduced spermatogenesis, and

decreases in the weight of the testes, prostate and seminal vesicles 123, 124. Male contraception

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studies that used exogenous testosterone (some in combination with a progestin) show that

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resumption of normal spermatogenesis (semen sperm concentration >20 million/ml) is usually
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seen within 6 months of cessation of hormonal contraception in 67% of men; successful recovery

is seen in 100% of the participants within 24 months of discontinuation of these medications 125-
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. Although men abusing AAS do not follow a structured regimen contrary to those used in

male contraception trials, one can posit that recovery of spermatogenesis in these men might be
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expected within a 6-24 month time frame. This variability depends on the duration and intensity
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of preceding use. Some AAS have active metabolites that are cleared slowly over a period of 6-

12 months after cessation of the drug, resulting in prolonged suppression of the HPG axis and
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spermatogenesis 128. In general, sperm concentrations correlate positively with the period of time
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since discontinuation of AAS (Figure 4) 127. Shorter duration of AAS use, lower doses, younger
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age, and higher baseline testosterone levels may be associated with a quicker recovery of the

HPG axis 80. Serum gonadotropin levels serve as an indicator of the recovery of spermatogenesis

as they negatively correlate with sperm concentration in semen analysis. Similarly, as 95% of the

testicular volume is formed by seminiferous tubules, testicular size is also a crude indicator of

spermatogenesis. If recovery of spermatogenesis does not occur even after 24 months of

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cessation of AAS, possibility of pre-existing defects in spermatogenesis should be considered. In

some circumstances, even after the recovery of spermatogenesis has occurred, some

ultrastructural abnormalities of spermatozoa may persist 129. Indeed, approximately15% of

previous AAS-users report regret because of the impact of AAS on fertility 130. In men with

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persistent AAS-induced azoospermia, fertility may be restored with gonadotropins or anti-

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estrogens 131, 132, the latter strategy is more likely to be efficacious if aromatizable androgens

were used.

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Liver
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Hepatic adverse effects of AAS-use are generally (perhaps exclusively) limited to oral 17

α-alkylated agents. These androgens are synthesized from substitution of 17 α-hydrogen for a
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methyl or ethyl group on the steroid nucleus, thus preventing deactivation during hepatic first-
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pass metabolism and enabling oral administration. Despite hepatic side effects, these compunds
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are popular among the bodybuilder community. Prolonged administration of 17 α-alkylated

agents result in an increase in hepatic lysosomal hydrolases, reduction in the activity of the
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microsomal drug-metabolizing enzyme system and a decrease in the activity of the mitochondrial

respiratory chain complex; these changes occur even in the absence of elevated liver function
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tests 133. Hepatic peliosis (proliferation of sinusoidal hepatic capillaries that result in cystic
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blood-filled cavities), cholestatic jaundice and hepatic neoplasms (rare) are related to the

cumulative dose and duration of use 133. Some data suggests that peliosis and hepatic adenomas

are identified during autopsy and do not become clinically apparent during a subject’s lifetime.

On the other hand, spontaneous hepatic rupture and cholestatic jaundice have been reported 134.

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An increase in reactive-oxygen species and hepatocyte mitochondrial degeneration have been

posited as proposed mechanisms 135.

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Dermatologic

Androgen receptors are present in the skin; conditions like acne vulgaris and folliculitis

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are frequently seen in AAS-users 116, 136. Skin biopsies from these men demonstrate hypertrophy

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of the sebaceous glands, increase in skin surface lipids and increased populations of cutaneous

Propionibacterium acnes and Staphylococcus aureus bacteria 137, 138. Acne generally tends to

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resolve upon cessation of AAS. Intramuscular injections of AAS have also been associated with
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infections; indeed a case of Staphylococcus aureus infection resulting in full thickness skin

necrosis has been reported which resulted from an exaggerated inflammatory reaction around an
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end-artery, probably due to intra or para-arterial injection of the drug 139. Both injectable and
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oral AAS have also been associated with necrotizing myositis, resulting in severe

rhabdomyolysis 140-143.
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Musculoskeletal
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Androgens increase skeletal muscle mass and strength 14, 144. These skeletal muscle
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adaptations occur more rapidly in comparison to adaptations in the connective tissues, therefore,

the tendons may not be prepared to withstand the load of bulkier muscles. The combination of

AAS use with resistance training is associated with a higher risk of injury to the tendons 145.

Limited data suggest that AAS use adversely influences the metabolism of type-1 collagen 146.

Although studies in mice have shown that administration of AAS is associated with degeneration

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of collagen and reduction in tensile strength of the tendons, electron microscopy analysis of

ruptured tendons in AAS-users did not reveal any difference in collagen fibril ultrastructure

compared with non-users 147. Another side effect of AAS use is myositis ossificans, which is

solely seen in men using intramuscular injections 148. Another musculoskeletal side effect of

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AAS, which is limited to aromatizable AAS, is premature closure of the epiphyses in teenage

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users, which may result in reduced final height 149, 150.

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Recent data reveals novel mechanisms by which AAS may adversely impact motor

neurons. For instance, AAS-abuse was recently suggested to be a contributory factor in the

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increased prevalence of amyotrophic lateral sclerosis (ALS) in soccer and American football
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players 151-153. Mutation in the superoxide dismutase 1 (SOD1) gene is associated with some

familial forms of ALS and overexpression of mutant human SOD1 (mutSOD1) in mice results
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in alterations in muscle cell signaling pathways 154. Indeed, animal studies have confirmed that

administration of nandrolone exacerbates the deleterious effects of mutSOD1, affecting motor

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neuron survival 155-157.

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Renal

The mechanisms involved in renal injury in the setting of AAS-abuse have not been well-
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delineated. In men who develop cholestasis due to oral AAS use, elevated plasma concentrations
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of bile salts can result in bile acid nephropathy due to deposition of bile acid casts within the

tubules158, 159. In a small case series, AAS use resulted in variable degrees of renal insufficiency,

proteinuria and nephrotic syndrome in body builders160. Renal biopsy in these men revealed focal

segmental glomerulosclerosis,160 while electron microscopy revealed loss of podocytes.

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Prognosis is variable and ranges from improvement in renal function to progression to end stage

renal disease in some men160, 161. Similarly, animal data show that administration of testosterone

exacerbates renal injury by stimulating TNF-α production and increasing pro-apoptotic and pro-

fibrotic signaling162 by activating triggering a caspase-dependent apoptotic pathway 163.

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Furthermore, androgens also increase tubular sodium and water resorption via activation of the

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renin-angiotensin-aldosterone system and by upregulation of endothelin164-167.

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Conclusion

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Despite numerous reports of adverse effects, many AAS-users still lack awareness of
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these consequences and continue to use these drugs 116. In fact, the use of AAS continues to
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grow among both professional and recreational athletes, and among men seeking to improve

body image. Some of these side effects are mild and reversible, but others are irreversible and
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potentially fatal. AAS-users tend to doubt physicians’ knowledge about AAS, compromising the
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physicians’ ability to educate and treat AAS-users168-171. Physicians must continue to educate

their patients and counsel them regarding the deleterious side effects of AAS. The
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implementation of community-based prevention programs targeting AAS-use at the gyms and

other settings169 will be a good step in curtailing this major public health problem.
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Table 1: Metabolism of various AAS

AAS Aromatization 5α-reduction 17α-alkylation

Metandione * * *

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Methandrosteneolone * * *

Testosterone * *

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19-Nortestoterone (Nandrolone) * *

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Boldenone * *

Dihydrotestosterone *

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Mesterolone *
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Methenolone *

Trenbolone *
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17 α-Methyltestosterone * *
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Fluoxymesterone * *
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Dehydrochloromethyl-testosterone * *

Formebolone * *
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Oxandrolone * *

Oxymetholone * *
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Stanozolol (derivative of DHT)

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Clostebol

Drostanelone

Adapted from Nieschlag and Vorona 170, 171

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Figure 1. Summary of Adverse Effects of AAS by Organ System

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Figure 2. Extracellular Water Retention with Testosterone Administration

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Legend: Mean (±SE) changes on ECW (in kilograms) testosterone (T) treatment alone and in

combination with growth hormone (GH). Adapted from Johannson et al.66.

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Figure 3. Systolic and diastolic blood pressure changes on testosterone therapy

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Legend. Systolic and diastolic blood pressure increased (N=112) with mean increases of 12 ±

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Figure 4. Sperm concentrations in 41 bodybuilders either currently using AAS,

discontinued 3-14 weeks ago (upper part) and in 41 non-user volunteers (lower part).

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Legend. The bars represent sperm concentrations from individual body-builders (upper panel) and from

normal volunteers (lower panel). The horizontal lines indicate a concentration of 20  million/ml as lower

limit of normal. Reproduced from Nieschlag and Vorona with permission.127

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