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Physical Effects of Anabolic-androgenic Steroids in Healthy Exercising Adults

A Systematic Review and Meta-analysis

Andrews, Mary A. MD, MPH1; Magee, Charles D. MD, MPH1; Combest, Travis M. MS, MPH, ACSM-RCEP®, CDE2; Allard, Rhonda J. MLIS1; Douglas, Kevin M. MD, MPH1

Current Sports Medicine Reports: July 2018 - Volume 17 - Issue 7 - p 232–241
doi: 10.1249/JSR.0000000000000500
Nutrition and Ergogenic Aids: Section Articles
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Many athletes use anabolic-androgenic steroids (AAS) for physical enhancement but the magnitude of these gains and associated adverse effects has not been rigorously quantified. MEDLINE, EMBASE, Cochrane, SPORTDiscus, and PsycINFO were searched to identify randomized placebo-controlled trials of AAS in healthy exercising adults that reported one of the following outcomes: muscular strength, body composition, cardiovascular endurance, or power. Two authors appraised abstracts to identify studies for full-text retrieval; these were reviewed in duplicate to identify included studies. Study quality was assessed using the Cochrane method. Data were extracted in duplicate and pooled using the DerSimonian and Laird random effects model and to calculate the ratio of mean outcome improvement where possible. Pooled standardized mean difference (SMD) in muscle strength between AAS and placebo was 0.27 (95% confidence interval, 0.07-0.47; I2 = 12.7%; 21 studies). Change in strength was 52% greater in the AAS group compared to placebo. The SMD for change in lean mass between AAS and placebo was 0.62 (95% confidence interval, 0.35-0.89; I2 = 26%; 14 studies). Due to missing data, fat mass, cardiovascular endurance, power, and adverse effects were summarized qualitatively. Only 13 of 25 studies reported adverse effects including increased low density lipoprotein (LDL), decreased high density lipoprotein (HDL), irritability, and acne. In healthy exercising adults, AAS use is associated with a small absolute increase in muscle strength and moderate increase in lean mass. However, the transparency and completeness of adverse effect reporting varied, most studies were of short duration, and doses studied may not reflect actual use by athletes.

1Uniformed Services University of the Health Sciences, Bethesda, MD; and

2Walter Reed National Military Medical Center, Bethesda, MD

Address for correspondence: Mary A. Andrews, MD, MPH, Department of Medicine, 4301 Jones Bridge Road, Bethesda, MD 20814; E-mail: mary.andrews@usuhs.edu.

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Introduction

Shortly after the isolation and synthesis of testosterone in the 1930s, athletes began to experiment with this and other anabolic-androgenic steroids (AAS) to improve athletic performance and physical appearance, including increased muscle mass and decreased body fat (1). In the past two decades, the sports medicine community has seen AAS use extend beyond competitive athletes to include even casual exercisers, who sought the beneficial effects of these substances on muscle size and body composition (2). The estimated prevalence of AAS use varies depending on the population studied, from 0.8% to 3.6% in adolescents, 14% to 22% of adults attending fitness centers, 1.1% of UK soldiers in training, and more than half of male bodybuilders (3–9). Lifetime prevalence rates of nonmedical AAS use among males worldwide has been estimated at 6.4% (10). Anabolic-androgenic steroids also have been studied as medical therapy in a variety of conditions including human immunodeficiency virus (HIV)-associated wasting, chronic obstructive pulmonary disease (COPD), osteoporosis, and postoperative recovery from hip fracture (11–14).

While the physiologic basis for increased muscle strength associated with AAS use is well established, the magnitude of this effect has not been precisely defined. A prior systematic review and meta-analysis examined the increase in muscle strength in previously trained athletes and found that the median difference in improvement in strength was 5% greater with AAS compared with placebo (15). However, the estimation of effect size was imprecise given the small number of studies, and the review was further limited by heterogeneous study design, poor methodological quality of the included studies, relatively low AAS dosage, and inclusion of only muscle strength as an outcome. Subsequent studies have used a variety of types and doses of AAS and have measured body composition and power in addition to strength and other important athletic performance outcomes (16–19). Furthermore, while a number of adverse effects have been reportedly associated with AAS use, the prevalence of these effects has not been well defined (20). In the present study, we aimed to systematically review the available literature to answer the following question: What is the best estimate of the effect of AAS on muscular strength, body composition, power, endurance, and adverse outcomes in healthy adult subjects?

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METHODS

Approach to the Research Question

Systematic reviews and meta-analysis involve comprehensive and transparent searching of the literature to identify all studies relevant to the research question and pooling results where appropriate to generate a summary estimate of the effect of an intervention that is more precise and reliable than the results of any single study (21). We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to inform the design and reporting of this study (22). We have no external funding or conflicts of interest. This study was deemed exempt from institutional review (USUHS IRB #1, FWA 00001628, DoD Assurance P60001).

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Data Sources and Searches

With the assistance of a reference librarian with experience in systematic reviews, we developed a comprehensive search strategy to identify candidate studies for inclusion (see Description of Search Strategy, Supplemental Digital Content 1, http://links.lww.com/CSMR/A21). Prior research describing different synthetic modifications to testosterone, lists compiled by international sport monitoring bodies, and expert opinion informed the search strategy (23,24). We searched MEDLINE, EMBASE, Cochrane CENTRAL, SPORTDiscus, and PsycINFO without date restrictions. Searches were carried out between April 13, 2015 and April 15 , 2015.

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Study Selection

Two investigators independently and in duplicate evaluated the titles and abstracts of a random 10% sample of the references to determine whether a full-text review was warranted. The results were compared with ensure adequate interrater agreement, after which the same two investigators each evaluated one half of all titles and abstracts generated by the electronic database searches. In addition, each investigator manually searched reference lists for studies warranting review. If either investigator believed a full-text review was warranted, the full-text was retrieved and evaluated. Full text review was performed by one investigator (K.D.) and then verified by the other (C.M.). All discrepancies were resolved by discussion and consensus. We included published, randomized, placebo-controlled trials reporting the effects of anabolic-androgenic steroids on athletic performance and/or body composition among healthy, exercising adults. We included studies that quantified an effect on any of the primary endpoints, to include muscular strength, anaerobic power, cardiovascular endurance, lean mass, or fat mass. Studies reporting strength outcomes were included if the outcome was a true measure of muscular strength (e.g., single repetition maximal load or maximum voluntary isometric contraction). We excluded animal studies, studies not involving exercise, and studies in which a disease or medical condition was a prerequisite for enrollment. In addition, we excluded studies with duplicate data sets, unquantifiable results, or a cointervention that confounded the results.

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Data Extraction and Quality Assessment

Study characteristics (authorship, year, country of origin, study design, risks of bias, subject characteristics, type of AAS along with dosage and duration of use, form and frequency of exercise, any additional cointerventions such as diet or supplements, methods of outcome measurement, and outcome data) were determined a priori and extracted into an evidence table independently and in duplicate by two investigators. If a study employed a cross-over design, we extracted data from only the first period to avoid carryover effects. If a study reported more than one strength exercise (e.g., biceps curl and bench press), aggregate data (if reported) or data for the exercise involving the greatest weight was extracted. Discrepancies were resolved by discussion. Risk of bias was assessed independently by two investigators using the Cochrane method which includes the following criteria: sequence generation, allocation concealment, blinding, attrition, selective outcome reporting, and industry support. Differences were resolved by discussion (25).

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Data Synthesis and Analysis

Pooled standardized mean differences (SMDs) and 95% confidence intervals were calculated using a random-effects model according to the method of DerSimonian and Laird (26). A small effect was interpreted as an SMD of 0.2 to 0.5; medium, 0.5 to 0.8; and large, >0.8 (27). To describe the relative effects of AAS on physical enhancement compared to placebo, a pooled ratio of the mean improvement in the outcome in the AAS group compared to the mean improvement in the placebo group was calculated according to methods previously described (28,29). Heterogeneity was assessed visually and using the I2 statistic (30). Missing SD were calculated from reported data where possible and otherwise imputed by using an average of SD from comparable studies or substituting when only one comparable study was available. Preplanned sensitivity analyses included doubling the value of any substituted SD and using the largest SD instead of the average to determine whether this meaningfully changed the results (25). If data imputation was required for more than half the studies of particular outcome, these outcomes were not pooled due to the increased risk of bias. Risk of publication bias was assessed by visual inspection of funnel plots and using Egger's test. To evaluate for the effects of study characteristics on the primary outcome, metaregression was performed on key variables where heterogeneity was at least moderate (I2 > 25%). Ratio of means analyses was conducted in WINPEPI; all other analyses were conducted in Stata/IC 13.1 (StataCorp, College Station, TX).

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RESULTS

Description of Studies

The electronic search strategy yielded 7179 references. Seven thousand sixty-three references were excluded after title/abstract review and 94 after full text review. Three references were added after hand-searching reference lists for a total of 25 included studies (see Study Flow Diagram, Supplemental Digital Content 2, http://links.lww.com/CSMR/A22) (16–19,31–51). The interrater agreement for title/abstract review was substantial (κ = 0.71, see Interrater Agreement, Supplemental Digital Content 3, http://links.lww.com/CSMR/A23). Most of the studies were small (median, n = 20), conducted in the United States, and involved male participants (Table 1). Twelve studies required resistance training for >1 yr before enrollment. The most common AAS used were testosterone (n = 6 studies) followed by forms of androstenedione (n = 5 studies), methandrostenolone (n = 4 studies), and dehydroepiandrosterone (DHEA, n = 4 studies). Most studies (n = 23) followed up the participants for 12 wk or fewer and required resistance training (n = 21) as the form of exercise. Five studies included a protein supplement. Thirteen of 25 studies included statements about the presence or absence of adverse effects; the remainder did not address adverse effects in any way.

Table 1

Table 1

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Study Quality Assessment

The quality and risk of bias in included studies varied (see Risk of Bias for Included Studies by Cochrane Method, Supplemental Digital Content 4, http://links.lww.com/CSMR/A24). Risk of attrition bias was generally low, with only one study reporting more than 20% differential attrition between AAS and placebo groups (46). While all included studies randomized participants to treatment or placebo, the methods of random sequence generation and allocation concealment were clearly reported for only one and two studies, respectively. Twenty studies blinded both participants and outcome assessors, whereas five had clear statements about the absence of support from the pharmaceutical industry.

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Physically Enhancing Effects

The pooled SMD for the increase in muscle strength in the AAS group versus placebo was 0.27 (95% confidence interval [CI], 0.07-0.47, I2 = 12.7%, 21 studies; Fig. 1). The pooled ratio of mean increase in strength for the AAS group compared to placebo was 1.52 (95% CI, 1.28-1.79), indicating that the increase in strength in the AAS group was 52% greater than the increase in strength in the placebo group. The pooled SMD for the change in lean mass between AAS and placebo was 0.62 (95% CI, 0.35-0.89, I2 = 26%, 14 studies; Fig. 2), indicating an increase in lean mass in the AAS group. Some studies reported a decrease in lean mass in the placebo group. Since the pooled ratio of means formula requires all means to be of the same sign (either all positive or all negative), calculating a pooled ratio of means was not mathematically feasible for this outcome (28). Change in fat mass was assessed in 13 studies, cardiovascular endurance in six, and power in five; however, these studies were not pooled due to missing data for more than half the studies. Results for change in fat mass, cardiovascular endurance, and power are summarized individually and reported in Supplemental Digital Content 5–7 (see Table 3, Supplemental Digital Content 5, http://links.lww.com/CSMR/A25; Table 4, Supplemental Digital Content 6, http://links.lww.com/CSMR/A26; Table 5, Supplemental Digital Content 7, http://links.lww.com/CSMR/A27). For methods of strength assessment see Supplemental Digital Content 8, http://links.lww.com/CSMR/A28.

Figure 2

Figure 2

Figure 1

Figure 1

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Adverse Effects

Monitoring and reporting of adverse effects varied across studies (Table 2). Twelve studies did not address adverse effects in any way. The most commonly assessed adverse effects included lipids (five studies), mood (five studies), and liver-associated enzymes (four studies). Three of the five studies that monitored lipids found a statistically significant decrease in high density lipoprotein (HDL) (41,42,50) and one also found significantly increased low density lipoprotein (LDL) (50). Two of the five studies that monitored mood found more irritability and mood changes in the AAS group compared to placebo, although the role of chance in these findings was not clear (40,46). One of the four studies that monitored liver-associated enzymes found significant elevations in aspartate aminotransferase in the AAS group compared to placebo but this was of uncertain clinical significance (50). Other reported adverse effects included injection site reactions, alopecia, acne, increased hematocrit, and decreased testicular size (Table 2).

Table 2

Table 2

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Additional Analyses

Eggers’ test of small study effects (to include publication bias) was negative for all pooled outcomes (P > 0.1) and visual inspection of funnel plots of the effect size against standard error showed symmetry around the pooled estimate of effect. Varying the value of imputed standard deviations as described in the methods did not significantly alter the effect size or statistical significance of the results.

Statistical heterogeneity in the results for change in lean mass (I2 = 26.0%) was explored using meta-regression on type of AAS and type of body composition measurement. There was a trend toward decreased effect sizes for DHEA and androstenedione compared to other types of AAS but this did not attain statistical significance. We also explored whether the method of body composition measurement (e.g., hydrodensitometry, dual x-ray absorptiometry, etc.) had an effect on study results but found none. Given the clinical heterogeneity in type of study participant (trained vs. untrained/sedentary), an exploratory subgroup analysis by participant type was performed (see Subgroup Analyses, Supplemental Digital Content 9, http://links.lww.com/CSMR/A29). We found that in general those studies of participants with a resistance training background showed greater gains in muscle strength and lean mass than studies in untrained participants (e.g., sedentary adults). In the case of muscle strength, the SMD in trained participants was 0.55 (0.17–0.92) while the SMD for untrained participants was smaller and no longer statistically significant (0.15; 95% CI, −0.064 to 0.37). For change in lean mass, the SMD for trained participants was 0.81 (95% CI, 0.25–1.36) while for untrained it was 0.56 (95% CI, 0.24-0.88). Given the differences across studies in attrition, blinding, and industry support, we undertook subgroup analyses of studies at low risk of these types of bias. Pooling of studies deemed low risk for bias yielded similar effect sizes to the primary analysis including all studies (see Subgroup Analyses, Supplemental Digital Content 9, http://links.lww.com/CSMR/A29).

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DISCUSSION

In this systematic review of the physical and performance-enhancing effects of AAS in healthy exercising adults, we found a small absolute increase in strength attributed to AAS which represents a 52% increase in strength compared to placebo alone. Furthermore, we found that AAS use was associated with a moderate increase in lean mass. Quantitative synthesis of the effect of AAS on fat mass, cardiovascular endurance, and power was limited by missing data in more than half the studies. These results were robust to sensitivity analyses undertaken to examine the effects of data imputation, type of AAS studied, and type of outcome measurement. Although the analysis was exploratory and other important between-study differences may exist, our findings suggest that AAS use in participants with a resistance training background may yield greater gains in strength and lean mass than in sedentary subjects. Some studies were high risk for bias but subgroup analyses showed that results from only low risk of bias studies yielded effect sizes similar to the primary analysis, providing reassurance against inflated results from the inclusion of potentially biased studies. The presence or absence of adverse effects was explicitly addressed in only 13 of 25 studies. Furthermore, studies varied widely in which adverse effects were assessed and how they were assessed. In many cases, it was difficult to ascertain the clinical and statistical significance of these effects.

Our results are consistent with a prior meta-analysis on this topic which found that AAS may slightly increase muscle strength in trained athletes (15). The biological plausibility of the increase in muscle strength associated with AAS used is further supported by many studies showing a dose-dependent increase in muscle mass resulting from AAS administration (52,53). Indeed, the many studies of AAS as a potential treatment for low muscle mass in variety of disease states such as COPD, liver disease, and HIV shows the strength of the scientific consensus about the physiologic effects of these agents on muscle mass (11,13,54). Given that the effect of AAS plus exercise on muscle strength in this meta-analysis is 52% greater than the increase in strength attributable to exercise alone, it is no wonder that professional athletes, elite military members, and others with high performance expectations may experiment with AAS to gain a competitive advantage.

The magnitude of the impact of AAS on body composition also is compelling and may help clinicians and sports medicine professionals understand the motivation of recreational and casual exercisers to use these substances. Weight loss through diet and exercise alone is difficult to initiate and maintain, usually requiring comprehensive lifestyle interventions (55). With increasing attention in mainstream media to the ideal muscular male body and the rise of muscle dysmorphia (a subtype of body dysmorphic disorder which consists of a pathologic belief that one’s body lacks sufficient muscle mass), both competitive athletes and casual exercisers may turn to AAS as a way to improve their physical appearance (2). With this meta-analysis showing that AAS use when coupled with regular exercise yields a moderate increase in lean mass of 0.62 standard deviations above what would be gained from exercise alone, the advantages of AAS use to even the untrained individual become readily apparent.

While the extent of adverse effect reporting varied greatly across studies in this review, many of the adverse effects found here have been previously noted in the literature. These include unfavorable alterations in lipid profiles (56), hypertension (57), and mood changes (58). However, accurate estimates of the prevalence of adverse effects are limited by inconsistent monitoring and reporting across studies. At least 15 different types of adverse effects were assessed in these 25 studies; but no more than five studies assessed the same adverse effect. This may reflect uncertainty in the scientific community about the types of adverse effects that may be expected from AAS use or a lack of consensus as to which adverse effects are the most worrisome. Unfortunately, this limits the sports medicine professional's ability to fully explain the risks of AAS to individuals who are using or considering using these substances. Because cardiovascular and thromboembolic complications carry high morbidity and mortality, and based on the summary of potential adverse effects in a recent review, we recommend that future studies should consistently measure the effect of AAS on blood pressure, lipid profiles, left ventricular size, liver and renal function, and behavior (20).

This systematic review and meta-analysis represents an exhaustive search of multiple medical, psychology, and sports medicine databases using an extensive list of anabolic agents. We minimized bias by using independent duplicate screening of studies for inclusion and data abstraction carried out by experienced systematic reviewers after establishing substantial interrater agreement. Where assumptions were made about the precision of study outcomes, rigorous sensitivity analyses were conducted to assess the durability of our conclusions.

Nevertheless, this study is not without limitations. Study quality was mixed and included studies at risk of selection bias. Support from pharmaceutical industry was common, which also may lead to bias. AAS doses in these studies may be lower than those taken by recreational or professional athletes; thus we may underestimate the true effect of AAS in these populations. Most studies had small numbers of participants leading to imprecise effect estimates and were conducted over a relatively short duration (12 wk or less); longer duration of use may produce larger gains in muscle strength and lean mass. Adverse effects, particularly those related to lipid profiles and atherogenesis, may similarly be time-dependent and underestimated in this review. Incomplete data reporting limited our ability to calculate a reliable pooled estimate for the effect of AAS on the outcomes of change in fat mass, cardiovascular endurance, and power. Data imputation has the potential to introduce bias; therefore, we limited data imputation and conducted sensitivity analyses. The overwhelming majority of participants in these studies are male; the physical enhancements attributable to AAS may differ in women. Finally, adverse effects were inconsistently monitored and reported across studies.

Future research on the physical effects of AAS in healthy exercising adults should use graded doses of AAS for longer periods of time with explicit and uniform monitoring for adverse effects as outlined above. Study design should include explicit statements about random sequence generation and allocation concealment to lower the risk of selection bias. Outcomes should include the physical performance measures of cardiovascular endurance and power, as the effect of AAS on these outcomes is not well described. Lastly, researchers should include a measure of precision (e.g., standard deviation) for the outcomes that they report to allow quantitative synthesis.

Our study shows that AAS use in healthy exercising adults is associated with increases in strength that are 52% greater than exercise plus placebo and a moderate increase in lean body mass. Reliable pooled estimates of the effect of AAS on cardiovascular endurance are impeded by incomplete data reporting. These results will be useful for sports medicine professionals, personal trainers, physicians, and military leaders who counsel recreational and competitive athletes about AAS use. This study also identifies the gaps in existing literature which can inform future directions of research on this topic. While this study advances our understanding of the physiologic effects of AAS in healthy exercising adults, these results must be tempered with the knowledge that adverse effects were not rigorously assessed or reliably reported.

This study was unfunded.

The views expressed here are those of the authors and do not necessarily reflect the policy or position of the Uniformed Services University of the Health Sciences (USUHS), the Department of Defense, or the U.S. Government.

All authors made substantial contributions to the conception and design of the work. M.A., C.M., R.A., K.D. made substantial contributions to the acquisition, analysis and interpretation of data. M.A. drafted the work and M.A., C.M., T.C., R.A., and K.D. revised it critically for important intellectual content. All authors gave final approval of the version published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

This study was deemed an EXEMPT protocol by USUHS IRB #1 (FWA 00001628; DoD Assurance P60001).

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