Recent surveys and reports suggest that many athletes and bodybuilders abuse anabolic-androgenic steroids (AAS). However, scientific data on the cardiac and metabolic complications of AAS abuse are divergent and often conflicting. A total of 49 studies describing 1,467 athletes were reviewed to investigate the cardiovascular effects of the abuse of AAS. Although studies were typically small and retrospective, some associated AAS abuse with unfavorable effects. Otherwise healthy young athletes abusing AAS may show elevated levels of low-density lipoprotein and low levels of high-density lipoprotein. Although data are conflicting, AAS have also been linked with elevated systolic and diastolic blood pressure and with left ventricular hypertrophy that may persist after AAS cessation. Finally, in small case studies, AAS abuse has been linked with acute myocardial infarction and fatal ventricular arrhythmias. In conclusion, recognition of these adverse effects may improve the education of athletes and increase vigilance when evaluating young athletes with cardiovascular abnormalities.
Anabolic-androgenic steroids (AAS) are synthetic derivatives of testosterone that were originally developed in the late 1930s. At present, the United States Food and Drug Administration has approved a variety of AAS to treat wasting syndrome in human immunodeficiency virus infection, hypogonadism, anemia accompanying renal and bone marrow failure, endometriosis, and cancer. Unfortunately, AAS are frequently abused and have recently been linked to the tragic deaths of celebrated professional athletes in the United States. Indeed, recent estimates suggest that >3 million individuals in the United States abuse AAS, including nandrolone decanoate, methandienone, stanozolol, androsterone, and androstane. This rampant abuse led Congress to enact the Anabolic Steroids Control Act in 1990, requiring that anabolic steroids be added to Schedule 3 of the Controlled Substances Act. All major professional sports organizations ban the use of AAS. Regardless, a recent report by Mitchell et al showed that >29 major league baseball players tested positive for AAS abuse within the past 4 years. Many effects of AAS abuse are unclear. Although side effects are rare at therapeutic doses, abusers typically use 5 to 15 times the recommended clinical doses of AAS. At such doses, general adverse effects include dose-dependent suppression of testicular function, gynecomastia, hepatotoxicity, and psychologic disorders. Cardiac and metabolic effects of AAS abuse are particularly unclear, although there are alarming reports of cardiac morbidity and mortality. Moreover, athletes often abuse AAS for years, prolonging the potential for harm. The purpose of this review is to synthesize the recent published reports on the cardiac and metabolic effects of AAS abuse in athletes.
Methods
We reviewed human studies retrieved from the PubMed, eMedicine, Heart Online, and Cochrane Databases in the English language. Inclusion terms were “anabolic steroid,” “body builder,” “athlete,” and “steroid user,” used alone or in combination with the terms “ventricular hypertrophy,” “hypertension,” “lipoprotein,” “sudden death,” “myocardial infarction” (MI), “cardiac,” “arrhythmia,” “tachycardia,” and “fibrillation.” The only exclusion term was “animal.” In turn, a review of primary sources for each report was also conducted to find additional sources pertaining to their parent topics. Review of published reports was limited to the period from January 1, 1987, to December 31, 2009, because widespread testing became available in the United States and Europe at the end of 1986.
Results
We retrieved a total of 49 reports describing a total of 1,467 athletes (median 15 subjects/study). In aggregate, studies evaluated lipoprotein concentrations in 643 subjects, blood pressure in 348, left ventricular (LV) dimensions in 561, and sudden death in 102. We also report 4 key animal studies whose results shed insights into potential mechanisms linking AAS abuse with cardiovascular disease.
Clinical pharmacology of AAS
AAS include many agents with chemical structures derived from cholesterol that are synthesized in the liver and then metabolized in the adrenal glands and testes to AAS. Their structure resembles that of corticosteroids, explaining some similarities in actions in terms of renal sodium retention and hypertension.
The public health problem: prevalence of AAS abuse
AAS are abused by athletes primarily to increase lean muscle mass, enhance appearance, and improve performance. Self-reported rates of abuse in bodybuilders range from 29% to 67%. In a 1996 British survey of steroid abuse in competitive gymnasiums (albeit with few women), 29% of respondents admitted using AAS. In an American study of 380 competitive bodybuilders in 1989, 54% of men and 10% of women admitted using AAS on a regular basis, while 10 of 15 bodybuilders from an American power-lifting team admitted to taking AAS in a more recent study.
Mortality in AAS abuse: the importance of cardiovascular causes
Mortality appears to be significantly higher in AAS abusers than in nonabusing athletes. In a retrospective case-cohort study of 248 AAS users and 1,215 controls (average age 23 years), 12 AAS users died during the study period, providing a standard mortality ratio of 20.43 (95% confidence interval 10.56 to 35.70). Of the 1,215 athletes who did not abuse AAS, 22 died during the study period, resulting in a standard mortality ratio of 6.02 (95% confidence interval 3.77 to 9.12). Although the exact causes of death were difficult to ascertain, a postmortem study of male Caucasian AAS abusers (aged 20 to 45 years) suggested primary cardiac pathology in 1/3, while a recent case-control study suggested cardiac causes in 2/3 of deaths, with others being attributed to suicide, hepatic coma, and malignancy. Many mechanisms have been proposed to explain potential adverse cardiovascular events of AAS.
Potential mechanisms
The physiologic and pharmacologic mechanisms of action of AAS on vascular structure and function are incompletely understood. AAS bind to androgen receptors in the heart and major arteries, and physiologic levels (e.g., of testosterone) may have a beneficial effect on coronary arteries via endothelial release of nitric oxide and inhibition of vascular smooth muscle tone. Conversely, animal studies show that abused AAS such as nandrolone at appropriately high doses may reverse this vasodilator response and lead to growth-promoting effects on cardiac tissue, as seen in hypertrophic cardiomyopathy, followed by apoptotic cell death. These effects are likely mediated by membrane receptor–second messenger cascades that increase intracellular Ca 2+ influx and Ca 2+ mobilization from the sarcoplasmic reticulum. Increases in Ca 2+ affect mitochondrial permeability, leading to the release of apoptogenic factors such as holocytochrome c, apoptosis-inducing factor, and caspase-9. Notably, AAS dosing associated with sudden cardiac death, MI, ventricular remodeling, and cardiomyopathy is related to apoptosis. These findings may explain clinical observations that AAS can lead to myocardial death without coronary thrombosis or atherosclerosis.
AAS and abnormal plasma lipoproteins
AAS abuse has been linked with abnormal plasma lipoproteins ( Table 1 ). Several studies suggest that AAS abuse in athletes increase low-density lipoprotein (LDL) levels by >20% and decrease high-density lipoprotein (HDL) levels by 20% to 70%. More generally, steroid hormones alter serum lipoprotein levels via the lipolytic degradation of lipoproteins and their removal by receptors through modification of apolipoprotein A-I and B synthesis. Although some studies have shown an association between AAS and elevated LDL, no definitive mechanism has been established. Baldo-Enzi et al suggested that serum LDL levels may increase through the induction of the enzyme hepatic triglyceride lipase and catabolism of very low density lipoprotein. Hepatic triglyceride lipase induction may also catabolize HDL and reduce its serum levels. By some estimates, these lipoprotein abnormalities increase the risk for coronary artery disease by three- to sixfold.
| Study | Abused Agent | Dosage of AAS (mg/week) | Subjects, Age (years) | |||
|---|---|---|---|---|---|---|
| Users Ex-Users Controls | Users LDL (mg/dl) HDL (mg/dl) | Ex-users LDL (mg/dl) HDL (mg/dl) | Controls LDL (mg/dl) HDL (mg/dl) | |||
| Baldo-Enzi et al ¶ | Methenolone enanthate | 100–300 | 14, 27 ± 5 | 129 ± 37 | — | 119 ± 17 |
| Testosterone cypionate | 200–300 | 17, 25 ± 4 | 27 ± 11 ∥ | — | 48 ± 6 | |
| Fröhlich et al | — | — | 13, 27 ± 4 | 154 ± 58 | — | 121 ± 22 |
| 11, 27 ± 7 | 23 ± 16 ‡ | — | 34 ± 7 | |||
| Hartgens et al ¶ | Stanozolol | 30–140 | 19, 31 ± 7 | — | — | — |
| Nandrolone decanoate | 8–250 | — | 17 ± 9 ∥ | — | 47 ± 22 | |
| 16, 33 ± 5 | ||||||
| Lajarin et al | Stanozolol | 50–100 | 2, 27 ± 3 | 238 ± 8 | — | — |
| Methenolone enanthate | 100 | — | 14 ± 0.4 | — | — | |
| — | ||||||
| Lane et al | Testosterone | — | 10, 26 ± 7 | 113 ± 27 | 86 ± 23 | 82 ± 12 |
| Nandrolone | 8, 32 ± 7 | 27 ± 16 † , ∥ | 51 ± 16 | 51 ± 12 | ||
| Stanozolol | 10, 24 ± 4 | |||||
| Lenders et al ¶ | Methenolone | 385–690 | 20, 26 ± 8 | 206 ± 21 ⁎ , ‡ | 156 ± 9 | 130 ± 13 |
| Testosterone | 310–355 | 42, 28 ± 7 | 27 ± 3 † , ∥ | 42 ± 2 | 46 ± 2 | |
| Oxymetholone | 580–650 | 13, 28 ± 5 | ||||
| McKillop and Ballantyne | Stanozolol | 280 | 8, 25 ± 4 | 243 ± 50 ∥ | — | 122 ± 27 |
| Nandrolone decanoate | 200 | — | 16 ± 11 ∥ | — | 43 ± 12 | |
| 8, 25 ± 3 | ||||||
| Palatini et al ¶ | Testosterone enanthate and propionate | 50–1,500 | 10, 27 ± 8 | 153 ± 34 § | — | 107 ± 41 |
| Stanozolol | 50–150 | — | 30 ± 10 | — | 57 ± 13 | |
| 14, 28 ± 5 | ||||||
| Sader et al | Stanozolol | — | 10, 37 ± 3 | — | — | — |
| Nandrolone | — | 23 ± 4 ∥ | — | 55 ± 4 | ||
| Creatine | 10, 34 ± 3 | |||||
| Urhausen et al | Oral (i.e., mesterolone) and intramuscular AAS (i.e., stanozolol, nandrolone) | 1,030 |
|
|
|
|
| Zuliani et al | Testosterone enanthate and propionate | 750–1,500 | 6, 28 ± 2 | — | — | — |
| — | 19 ± 8 ∥ | — | 49 ± 6 | |||
| Human growth hormone | 8, 26 ± 2 | |||||
In a study of 88 bodybuilders who tested positive for AAS, Lenders et al showed that AAS abusers had significantly higher LDL and lower HDL levels than nonabusers. Other studies have confirmed these effects ( Table 1 ). Although actual lipoprotein levels vary among studies, LDL levels as high as 596 mg/dl and HDL levels as low as 14 mg/dl have been noted in otherwise healthy athletes who abuse AAS. We have observed a markedly low HDL level of 5 mg/dl in a bodybuilder who admitted to AAS abuse (unpublished observations). Abnormalities of HDL and LDL may arise within 9 weeks of AAS self-administration ( Table 1 ). This time of onset and duration is supported in numerous studies. Fortunately, lipid effects seem to be reversible ( Table 1 ) and may normalize 5 months after discontinuation. Nevertheless, further studies are warranted, because the duration of effect is longer than would be expected from the terminal half-lives of these agents (typically 7 to 12 days).
AAS may elevate blood pressure
The relation between AAS abuse and blood pressure is controversial. A link between AAS abuse and elevated blood pressure has been observed in some studies, whereas others have shown no association. When hypertension is observed, it likely follows renal retention of sodium from AAS. Blood pressure response to AAS abuse typically shows a dose-response relation. In a retrospective study, Urhausen et al reported that mean arterial pressure in AAS users was elevated, in the prehypertensive and stage I hypertensive range as defined in the “Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,” compared to former users or nonusers. Other studies support these data ( Table 2 ). Although actual elevations vary ( Table 2 ), blood pressures as high as 195/110 mm Hg have been recorded in otherwise healthy athletes with no other identifiable cause. Again, the effects of AAS abuse on blood pressure may persist for long periods; some studies have shown persistent elevations for 5 to 12 months after discontinuing AAS. Although this may reflect the prolonged half-lives of depot AAS preparations, it may also reflect the fact that self-reporting of discontinuation is unreliable. In some studies, AAS remain detectable after self-reported discontinuation. Furthermore, there is variability in dosing regimens and supplemental substance use in numerous studies.
| Study | Abused Agent | Dosage (mg/week) | Subjects, Age (years) Users Ex-Users Controls | Blood Pressure (mm Hg) | ||
|---|---|---|---|---|---|---|
| Users Systolic Diastolic | Ex-Users Systolic Diastolic | Controls Systolic Diastolic | ||||
| D’Andrea et al ∥ | — | 525 (90) | 20, 35 ± 3 | 140 ± 7 | — | 131 ± 9 |
| — | 84 ± 4 | — | 81 ± 5 | |||
| 25, 34 ± 3 | ||||||
| De Piccoli et al | — | — | 14, 26 ± 5 | 142 ± 11 | 140 ± 10 | 136 ± 12 |
| 9, 26 ± 5 | 83 ± 5 | 83 ± 5 | 87 ± 9 | |||
| 14, 26 ± 4 | ||||||
| Di Bello et al | Testosterone propionate | 300–500 | 10, 33 ± 3 | 135 ± 19 | — | 138 ± 8 |
| Methenolone enanthate | 300–600 | — | 89 ± 12 ‡ | — | 87 ± 8 | |
| Testosterone cypionate | 200–350 | 10, 30 ± 7 | ||||
| Hartgens et al ∥ | Nandrolone decanoate | 20–250 | 17, 32 ± 7 | 139 ± 13 | — | 134 ± 8 |
| Stanozolol | 30–140 | — | 85 ± 12 | — | 81 ± 7 | |
| 15, 33 ± 5 | ||||||
| Karila et al ∥ | — | 770 (310) | 16, 30 ± 5 | 131 ± 13 | — | 131 ± 13 |
| — | 76 ± 10 | — | 77 ± 9 | |||
| 15, 26 ± 3 | ||||||
| Krieg et al ∥ | — | 820 (620) | 14, 36 ± 7 | 135 ± 10 | — | 130 ± 5 |
| — | 85 ± 5 | — | 85 ± 5 | |||
| 11, 36 ± 11 | ||||||
| Kuipers et al | Nandrolone decanoate | 200–400 | 7 | 134 ± 14 | — | 127 ± 11 |
| Testosterone | 2000 | — | 86 ± 14 | — | 74 ± 8 | |
| Stanozolol | 150–300 | 6 | ||||
| Lane et al | Testosterone | 10, 27 ± 7 | 119 ± 7 | 121 ± 7 | 125 ± 13 | |
| Nandrolone | 8, 32 ± 7 | 81 ± 4 | 67 ± 18 | 72 ± 14 | ||
| Stanozolol | 10, 24 ± 4 | |||||
| Lenders et al ∥ | Methenolone | 385–690 | 20, 26 ± 8 | 121 ± 2 † | 119 ± 2 † | 114 ± 2 |
| Testosterone | 310–360 | 42, 28 ± 7 | 74 ± 2 | 72 ± 1 | 71 ± 2 | |
| Oxymetholone | 580–650 | 13, 28 ± 5 | ||||
| Nottin et al | — | 6, 41 ± 6 | 132 ± 10 | — | 122 ± 11 | |
| — | 87 ± 8 | — | 77 ± 12 | |||
| 9, 38 ± 6 | ||||||
| Palatini et al ∥ | Testosterone enanthate and propionate | 50–1,500 | 10, 27 ± 8 | 124 ± 14 | — | 128 ± 11 |
| Stanozolol | 50–150 | — | 80 ± 14 | — | 74 ± 7 | |
| 14, 28 ± 5 | ||||||
| Riebe et al ∥ | Stanozolol | 110–200 | 9, 25 ± 4 | 133 ± 8 † | — | |
| Testosterone | 250–400 | — | 83 ± 7 | — | 123 ± 10 | |
| Nandrolone decanoate | 200–400 | 10, 28 ± 4 | 77 ± 7 | |||
| Sader et al | Stanozolol | 10, 37 ± 3 | 127 ± 3 | — | 119 ± 4 | |
| Nandrolone | — | 74 ± 5 | — | 71 ± 5 | ||
| Creatine | 10, 34 ± 3 | |||||
| Urhausen et al ∥ | — | 1,030 | 17, 31 ± 5 | 140 ± 10 ⁎ , § | 130 ± 5 | 125 ± 10 |
| 15, 38 ± 7 | 85 ± 10 | 85 ± 5 | 80 ± 10 | |||
| 15, 28 ± 5 | ||||||
Importantly, the link between AAS abuse and elevated blood pressure is not seen in all studies. In a small cross-sectional study, Palatini et al did not find any difference in blood pressure between 10 AAS users and 14 age-matched controls. Measurements were made when users were taking AAS and during the withdrawal stage of cycling. Misclassification of athletes was minimized by measuring gonadratropin levels, follicle-stimulating hormone, and luteinizing hormone, which decreased significantly in users. In another cross-sectional study by D’Andrea et al, blinded blood pressure measurements in 20 AAS-abusing athletes did not differ significantly from those in 25 age-matched AAS-free bodybuilders using the same exercise protocol, although blood pressure was nonsignificantly elevated (p >0.05). Moreover, Lenders et al did not show elevated blood pressure in AAS users compared with nonusers in a larger population. Possible explanations include lower AAS doses in those abusers or, speculatively, undeclared abuse in the “control” population in whom occult AAS abuse was not tested for. Another confounding variable that some investigators neglect to report relates to cuff size. In athletes with larger arms, regular sized blood pressure cuffs could overestimate blood pressure. Analysis is complicated further by variability in exercise regimens, variability in dosing and duration of AAS use, and potential biases in unblended studies. Clearly, additional studies are necessary to definitively reveal a link between AAS and blood pressure.
AAS and LV hypertrophy (LVH)
Athletes abusing AAS often exhibit LVH ( Table 3 ). However, because the hypertrophy may relate to increased afterload from isometric exercise, the interpretation of LVH in elite athletes who admit to AAS abuse is complex. Possible associations between AAS and LVH may be explained as secondary to hypertension or as a direct effect on the myocardium. Notably, studies in isolated human myocytes have shown that AAS bind to androgen receptors and may directly cause hypertrophy, potentially via tissue upregulation of the renin-angiotensin system. Indeed, clinical studies suggest a distinct form of LVH in AAS abusers, suggested by textural changes in the myocardium on echocardiography before the onset of overt LVH.
| Study | Abused Agent | Dosage (mg/week) | Subjects, Age (years) Users Ex-Users Controls | IVS (mm) | PW (mm) | ||||
|---|---|---|---|---|---|---|---|---|---|
| Users | Ex-Users | Controls | Users | Ex-Users | Controls | ||||
| D’Andrea et al ∥ | — | 525 (91) | 20, 35 (3) | 12.3 (1.3) | — | 11.2 (2.1) | 11.8 (1.4) | — | 10.4 (2.1) |
| — | |||||||||
| 25, 34 (3) | |||||||||
| De Piccoli et al | — | — | 14, 26 (5) | 11 (0.8) | 10.6 (1.0) | 10.5 (0.8) | 10.3 (0.8) | 9.8 (0.9) | 9.8 (0.7) |
| 9, 26 (5) | |||||||||
| 14, 26 (4) | |||||||||
| Di Bello et al | Testosterone propionate | 300–500 | 10, 33 (3) | 12.3 (0.7) | — | 12.2 (0.4) | 11.6 (0.5) | — | 11.7 (0.4) |
| Methenolone enanthate | 300–600 | — | |||||||
| Testosterone cypionate | 200–350 | 10, 30 (7) | |||||||
| Dickerman et al | — | — | 8 | 11.27 (0.2) † | — | 8.74 (2.5) | 12.1 (1.0) † | — | 10.3 (2.0) |
| — | |||||||||
| 8 | |||||||||
| Hartgens et al ∥ | Nandrolone decanoate | 20–250 | 17, 32 (7) | 8.8 (1.1) | — | 8.3 (1.0) | 8.9 (0.7) | — | 8.6 (0.8) |
| Stanozolol | 30–140 | — | |||||||
| 15, 33 (5) | |||||||||
| Karila et al ∥ | — | 770 (310) | 16, 30 (5) | 11.2 (1.0) ‡ | — | 8.9 (1.1) | 11.3 (1.1) ‡ | — | 9.1 (1.0) |
| — | |||||||||
| 15, 26 (3) | |||||||||
| Krieg et al ∥ | — | 820 (620) | 36 (7) | 12 (1.5) † | — | 10.5 (1.0) | 10.5 (1.5) | — | 10 (0.5) |
| — | |||||||||
| 36 (11) | |||||||||
| Nieminen et al ∥ | Testosterone | 2,860 ¶ | 4, 30 (3) | 12.75 (1.5) | — | — | 13.75 (1.3) | — | — |
| Testosterone undecanoate | 2,660 ¶ |
| |||||||
| Nottin et al | — | — | 6, 41 (6) | 10.8 (1.3) | — | 9.7 (1.7) | 10.0 (1.4) | — | 10.3 (0.9) |
| — | |||||||||
| 9, 38 (6) | |||||||||
| Palatini et al ∥ | Testosterone enanthate and propionate | 50–1,500 | 10, 27 (8) | 10.8 (2.3) | — | 9.6 (0.8) | 10.4 (2.3) | — | 10.1 (1.3) |
| Stanozolol | 50–150 | — | |||||||
| 14, 28 (5) | |||||||||
| Sachtleben et al | Stanozolol | — | 11, 27 (6) | 11.1 (1.2) ⁎ | — | 9.3 (1.2) | 11.2 (1.5) ⁎ | — | 9.5 (1.6) |
| Methandrostenolone nandrolone | — | ||||||||
| Testosterone cypionate | 13, 27 (6) | ||||||||
| Sader et al | Stanozolol | — | 10, 37 (3) | 10 (0.3) ‡ | — | 8.7 (0.2) | 9/8 (0.4) † | — | 8.7 (0.3) |
| Nandrolone | — | ||||||||
| Creatine | 10, 34 (3) | ||||||||
| Thompson et al ∥ | Nandrolone decanoate | — | 12, 23 (4) | 10 (2.0) | — | 9.0 (1.0) | 8.0 (1.0) | — | 8 (1.0) |
| Testosterone cypionate | — | ||||||||
| Stanozolol | 11, 26 (7) | ||||||||
| Urhausen et al ∥ | — | 1,030 | 17, 31 (5) | 12.3 (1.4) § | 11.5 (1.2) † | 10.3 (1.0) | 11.4 (1.3) ⁎ , § | 10.2 (0.8) | 9.4 (1.5) |
| 15, 38 (7) | |||||||||
| 15, 28 (5) | |||||||||
| Urhausen et al | Methandione, stanozolol | 630 | 14, 28 (6) | 12.6 (1.7) | — | 11.6 (0.9) | 12.5 (1.2) ‡ | — | 10.3 (1.8) |
| Testosterone depot | — | ||||||||
| 7, 26 (5) | |||||||||
| Zuliani et al ∥ | Testosterone enanthate and propionate | 750–1,500 | 6, 28 (2) | 11.8 (0.8) | — | 11.2 (0.7) | 10.8 (0.7) | — | 10.3 (0.5) |
| Human growth hormone |
| ||||||||
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