The cardiac toxicity of anabolic steroids.Tren e dosage steroids are synthetic derivatives of testosterone that were developed as adjunct therapy for a variety of medical conditions. Today they are most commonly used to enhance athletic performance and muscular development. Both illicit and anabolid indicated anabolic toxic anabolic steroids use toxic anabolic steroids been temporally associated with many subsequent defects within each of the body systems. Testosterone is the preferred ligand of the human androgen receptor in the myocardium and directly modulates transcription, translation, and enzyme function. Consequent alterations of cellular pathology and anbolic physiology are similar to those seen with sgeroids failure and cardiomyopathy. Hypertension, ventricular remodeling, myocardial ischemia, and sudden cardiac death have each been temporally and causally associated with anabolic steroid use in humans. These toxic anabolic steroids persist long after use has been discontinued and have significant impact on subsequent morbidity and mortality.
The cardiac toxicity of anabolic steroids - ScienceDirect
Millions of individuals have used illicit anabolic-androgenic steroids AAS , but the long-term cardiovascular associations of these drugs remain incompletely understood. Using transthoracic echocardiography and coronary computed tomography angiography, we assessed 3 primary outcome measures: Long-term AAS use appears to be associated with myocardial dysfunction and accelerated coronary atherosclerosis.
These forms of AAS-associated adverse cardiovascular phenotypes may represent a previously underrecognized public-health problem. Therefore, these effects remain incompletely understood. Previous studies have suggested an association between AAS use and cardiovascular disease, with a pathophysiologic link first proposed by early case reports of sudden cardiac death or ischemic stroke among young AAS-using men. In aggregate, data from these earlier studies suggest that illicit AAS use may cause a form of cardiomyopathy characterized by decreased left ventricular LV function 18 , 19 , 21 — 23 , 25 , 26 and may increase the risk of atherosclerotic disease.
To address this issue, we conducted comprehensive cardiovascular evaluations of 86 long-term AAS users and 54 nonusers. We conducted an observational study using a cross-sectional cohort design. We have previously presented the formal properties of this design, 27 which has been used both explicitly 28 — 31 and implicitly 32 , 33 in many earlier studies. This method identifies a dynamic cohort of individuals drawn from a given source population who in principle could have been enumerated in the past and followed to the present termed the conceptual cohort.
Instead of sampling from the conceptual cohort, one samples in the present from those currently available the study cohort. With this design, estimates of effects derived from the study cohort are valid with respect to the conceptual cohort, subject to similar conditions for validity as other retrospective designs eg, retrospective cohort and case-control studies.
For the present study, we sampled from a source population of men who lift weights in gymnasiums and then compared exposed ie, AAS-using and nonexposed ie, non-AAS-using men from this group.
We chose this source population because almost all long-term AAS users are male 2 and lift weights regularly. Although this approach minimized the effects of confounding variables inherent to weightlifting, we considered that weightlifting or its associated lifestyle might be associated with specific cardiovascular characteristics.
These 2 groups AAS nonusers and nonweightlifting and non-AAS-using men exhibited no scientifically important or statistically significant differences on measures of cardiovascular physiology or pathology Tables I—III in the online-only Data Supplement , indicating that weightlifting per se, of the duration and intensity selected by our recruitment techniques, was associated with little or no cardiovascular adaptation or pathology.
As described in our previous cross-sectional cohort studies involving AAS, 28 , 29 we advertised in gymnasiums for men 34 to 54 years of age who could bench-press pounds for at least one repetition, currently or in the past to recruit AAS users and nonusers. On telephone screening, advertisement respondents were invited to participate without inquiring about AAS use to minimize selection bias that might arise if they knew in advance the exposure variable of interest.
It is notable that AAS are typically ingested in courses or cycles, with deliberate intervening off-drug intervals. We imposed no specific exclusions for medical or psychiatric history.
Qualifying participants were evaluated at a screening interview, where they provided written informed consent for the study as approved by the McLean Hospital Institutional Review Board. We then obtained demographic data, lifetime exercise history ie, exercise modalities, duration, intensity, and consistency , and fat-free mass index, a validated measure of muscularity. We also assessed use of other performance-enhancing substances, including over-the-counter substances eg, creatine and illicit drugs eg, human growth hormone, clenbuterol.
Participants then provided urine samples to be tested for AAS 29 , 38 and head or axillary hair to be tested for opiates, cannabis, phencyclidine, amphetamines, and cocaine. Men found to qualify after the screening interviews were then referred for a cardiovascular evaluation performed by investigators blinded to AAS status to characterize LV structure, LV function, and coronary atherosclerosis. Two-dimensional transthoracic echocardiography iE33, Philips Medical Systems was used to develop profiles of LV structure and function as previously detailed by our group.
Second, coronary computerized tomography angiography CTA was performed using a dual-source slice CT scanner Definition Flash, Siemens Medical Systems , with a primary outcome variable of total coronary artery plaque volume. Based on our pilot data 18 and those of others, 1 , 24 our primary hypotheses were that AAS users would exhibit: We further hypothesized that within the AAS-user group, greater pathology on these variables would be associated with currency of AAS use ie, on-drug versus off-drug status at the time of evaluation and with cumulative lifetime duration of AAS exposure.
Using linear regression, we estimated the mean difference between groups on the outcome measures technically, the estimated mean difference was the estimated beta coefficient corresponding to group status in a linear model that also included a set of covariates and was fitted using ordinary least-squares linear regression. To control for confounding, our primary analysis adjusted for a set of plausible confounding variables including: For echocardiographic measures, we additionally adjusted for body surface area as calculated by the Mosteller formula.
Also, because resting heart rate could influence cardiac functional outcomes, we performed additional analyses of the primary cardiac functional outcomes by adding resting heart rate as a covariate. Note that heart rate may influence functional outcomes and also might be affected by current AAS use. In the latter eventuality, the estimated mean difference between groups adjusted for resting heart rate would likely be biased toward the null ie, would potentially represent an overadjustment , thus producing an underestimate of the effect of AAS use.
In subsequent sensitivity analyses assessing the influence of adjustments using alternative sets of potential confounders, we repeated all comparisons 1 with no adjustment for any covariates, 2 with the adjustment covariates reduced to only age and race plus body surface area for echocardiographic measures , and 3 with the adjustment covariates augmented to include hypertension and dyslipidemia as defined in Tables X-X in the online-only Data Supplement. It is important to note that the augmented set of covariates would be expected to yield underestimates of the effect of AAS use because hypertension and dyslipidemia are often effects of AAS use, 1 , 7 , 9 , 47 and adjustment for these variables would consequently adjust out effects of AAS mediated by these variables.
Because the distributions of coronary CTA measures contained many zero values ie, no measurable coronary artery disease , we used ranked data for these analyses. Within the AAS-user group, we evaluated the association of all outcome measures with duration of use and currency of use ie, on-drug versus off-drug using linear regression with adjustment for the same set of covariates. To aid in interpretation of comparisons between groups and associations within groups involving rank-transformed data, we used standard deviation SD units to express the estimated difference in ranks for binary predictor variables and the estimated change in ranks for each 1-unit increase in continuous predictor variables.
The SD units were calculated by dividing the estimated beta coefficient for the predictor variable from the linear regression model by the SD of the ranks for the entire sample used for a given model.
All models were fitted using Stata We did not perform corrections for multiple comparisons, so that the statistical significance of P -values for secondary outcomes, particularly those between 0. We screened men, of whom 25 were excluded from medical evaluation as follows: The remaining sample comprised 86 AAS users and 54 nonusers.
The off-drug users had last used AAS a median interquartile range of 15 5, 70 months before evaluation. AAS users and nonusers were similar on most characteristics Table 1 , but users showed higher body mass index and fat-free mass index, consistent with known effects of AAS.
On subsequent analyses examining the association of outcomes with duration and currency of AAS use, currency of use was strongly associated with greater pathology Figure 1 and Table IV in the online-only Data Supplement. Left ventricular systolic and diastolic function in anabolic-androgenic steroid users and comparison nonusers.
B , Left ventricular early relaxation velocity in the same 4 groups. Therefore, we assessed the associations separately for AAS users and nonusers. AAS users showed significantly higher coronary plaque volume than nonusers Table 3 and Figure 2.
On examining the association of CTA measures with currency and duration of AAS use, we found strong associations between lifetime duration of use on all angiographic measures of coronary pathology Table 4 and Figure 3. However, we found no significant association between currency of use and plaque volume estimated mean difference between on-drug and off-drug users in ranks: In addition, 1 AAS user had presented at 42 years of age after 20 years of cumulative lifetime AAS exposure with congestive heart failure and underwent stenting of the left circumflex and first obtuse marginal arteries.
None of the 54 nonusers had a history of myocardial infarction or stenting. Distribution of computed tomography coronary angiography measures in anabolic-androgenic steroid users and nonusers. The histograms for plaque volume and calcium score include for men with imputed values, as described in the footnote to Table 3. Relationship between coronary artery plaque volume and cumulative lifetime duration of anabolic-androgenic steroid exposure. Scatter plot displaying coronary artery plaque volume and cumulative years of lifetime anabolic-androgenic steroid AAS exposure, with a median spline red line fitted to the data to aid in the visualization of the relationship between these variables.
Because of the highly right-skewed distributions, the data are presented on a transformed scale square root transformation for coronary artery plaque volume; logarithmic transformation for cumulative years of AAS use.
We also reanalyzed the echocardiographic findings while omitting the 3 men with previous myocardial infarctions. Illicit AAS use is widespread, but its long-term adverse effects remain poorly understood. A growing literature, largely comprised of case reports and small observational studies, suggests that AAS use may cause cardiovascular disease.
We undertook the present study to examine cardiovascular health measures among long-term AAS users and otherwise similar nonusers with the following 4 key findings. This finding was driven almost entirely by those AAS users who were on-drug at the time of evaluation, suggesting that LV dysfunction may be a dynamically related to AAS-use patterns. Second, AAS users also showed impaired LV diastolic dysfunction, both relative to nonusers and also as defined by current diagnostic criteria.
Third, AAS users had significantly more LV hypertrophy, as reflected by LV mass index, than nonusers, suggesting an anabolic effect on cardiac muscle mass. In addition, the magnitude of LV hypertrophy among AAS users was directly related to the degrees of both systolic and diastolic function, suggesting a mechanistic link between LV hypertrophy and functional deterioration.
Fourth, AAS use was associated with increased coronary atherosclerosis, and the severity of atherosclerotic disease was strongly associated with cumulative lifetime duration of AAS use. In aggregate, our findings suggest that long-term AAS use is associated with adverse cardiovascular phenotypes characterized by both myocardial pathology and coronary artery pathology, which may represent a clinically substantial and largely unrecognized public health problem. Several scientific and clinical implications emerge from this study.
First, improved identification of the adverse cardiovascular associations of AAS use may deter potential future users. Second, clinicians may be better informed about the potential adverse cardiovascular effects of AAS. Thus, when comparable men are found to have impaired LV function or premature coronary artery disease, it seems prudent for clinicians to now include AAS use on the differential diagnosis of possible causes. Third, data derived from the present cross-sectional study provide a foundation for critical future work.
The hypothesis that some cardiovascular phenotypes associated with AAS use may wax and wane with drug exposure eg, LV systolic dysfunction while others may be more permanent, perhaps irreversible eg, LV diastolic dysfunction and coronary atherosclerosis , deserves rigorous assessment.
Longitudinal studies of illicit AAS users with hard clinical end points, and with interventions to impact drug exposure patterns and treat detected disease, are also of importance. Several threats regarding the internal validity of this study, as previously delineated in general for cross-sectional cohort studies, 27 , 29 deserve consideration.
First, bias might arise through exiting from the underlying conceptual cohort ie, becoming unavailable for study in the present that is differential with respect to exposure status. For example, AAS users might be more likely than nonusers to develop cardiovascular morbidity, stop weightlifting, and hence be unavailable for recruitment.
Any resulting bias, however, would likely underestimate the effects of AAS use. Second, as in all observational studies, we cannot exclude residual confounding. However, given the lack of confounding seen with our measured potential confounders—as evidenced by similar estimates in sensitivity analyses using both reduced and augmented sets of potential confounders—it is unlikely that substantial residual bias remains because of unmeasured confounders.
Third, because both AAS users and nonusers were weightlifters, the effects of AAS might be clouded if weightlifting contributed to cardiovascular pathology. However, our ancillary study comparing non-AAS-using weightlifters with nonweightlifters demonstrated that weightlifting alone of the duration and intensity exhibited by our sample had little effect on cardiac adaptation or pathology.
Fourth, bias could arise from measurement error, particularly in the exposure variables eg, misclassifying surreptitious AAS users as nonusers or inaccurately assessing the type, duration, dose, and currency of use. In particular, AAS users provided retrospective accounts, often spanning many years of time, of the use of illicit drugs of uncertain potency or authenticity. The effect of these various sources of measurement error would be expected to be differential for between-group comparisons because of the potential for inclusion of surreptitious AAS users in the nonuser group and the much less likely inclusion of individuals falsely reporting AAS use in the user group and random for within-group comparisons among AAS users because of the low likelihood of an association between cardiac outcomes and error in the predictor variables.
Both of these sources would likely bias results toward the null, thereby yielding an underestimate of the effects of AAS use. Potential threats to external validity generalizability also require consideration.
First, we recruited AAS users from gymnasiums. Thus, our results might not generalize to other AAS-using groups eg, elite athletes. However, most AAS users are recreational weightlifters, and thus our results likely generalize to the population of AAS users of greatest public health importance.
Overall, however, these potential threats to internal and external validity appear modest. Thus, our findings likely represent reasonably unbiased estimates of the associations of AAS exposure with adverse cardiovascular phenotypes. Our findings suggest that AAS use is associated with LV dysfunction and premature coronary artery disease. These findings may inform public health initiatives to curb drug exposure and provide clinicians with information that will translate into improved patient care.