THEEFFICACY OF ERGOGENIC AGENTS IN ATHLETIC COMPETITION PART I:ANDROGENIC-ANABOLIC STEROIDS Daniel A. Smith and Paul J. Perry
OBJECTIVE: To summarize the literature describing the epidemiology, pharmacology, efficacy, and adverse effects associated with androgenic-anabolic steroid (AAS) use among athletes . DATA SOURCES: Relevant articles were identified from a MEDLINE search using the search terms " Doping in Sports," "Anabolic Steroid s (exploded)," and "Androgens (exploded)." Additional references were found in the bibliographies of these articles.
We reviewed studies of AAS use among professional athlete s. Interpretation of these studies is difficult because of poor research design. The efficacy studies lacked adequate placebo control. Much of the literature describing adverse effects consists of anecdotal reports . All of this literature was considered for review .
STIJDY SELECTIONIDATA EXTRAl.Il0N:
Of all ergogenic drugs, AASs are the most widely abused . Abuse of AASs among high school students is estimated at five to ten percent. AASs are hypothesized to produce ergogenic effects during periods of concomitant positive nitrogen balance via antagonism of the catabolic effect of glucocorticoids released during intense exercise. Despite years of study, the extent of the ergogenic effects associated with AASs remains unclear. This may be because most studies have failed to approximate athletes ' AAS usage patterns. The primary toxic effects of AAS s are divided into four areas: hepatic, reproductive, cardiovascular, and psychiatric. Athletes do not consider these effects severe enough to refrain from using these drugs. DATA SYNTHESIS:
CONCLUSIONS: Athletes view AASs as an essential component for success. Without adequate intervention measures, AAS abuse is likely to continue unchecked.
Ann Pharmacother 1992;26:520-8. ATHLETIC COMPETITION has intensified to the point that increasing numbers of athletes are striving to upgrade their performances by whatever means necessary to reach the pinnacle of success. Many players and coaches believe that no price is too great to pay in order to win. Thus, significant numbers are employing pharmacologic shortcuts in their training programs. More and more athletes are relying upon ergogenic drugs to enhance their strength, endurance,
DANIEL A. SMITH, Pharm.D.. is a Clinical Pharmacy Fellow; and PAUL J. PERRY, Ph.D.. is a Professor of Pharmac y. Division of Clinical Pharmacy. College of Pharmacy . and an Adjunct Professor of Psychiatry . Department of Psychiatry . College of Medicine . University of Iowa. Iowa City. IA. Reprints: Paul J. Perry. Ph.D.• College of Pharmacy. University of Iowa. 2271 Quadrangle. Iowa City . fA 52242 .
This article is approved for continuing education credit.
520
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•
and performance. The combination of the use of these drugs and more intensive training has opened a pharmacologic "Pandora's Box" for the athletes of the world. Drugs used by athletes fall into three general categories. Ergogenic drugs (performance-enhancing agents) represent those agents used to gain an athletic advantage in either strength (e.g. , androgenic-anabolic steroids [AASs]) or endurance (e.g., amphetamines, epoetin). Therapeutic drugs represent those used for specific medical indications under standards of good medical practice (e.g., nonsteroidal antiinflammatory drugs). The third category, mood-altering agents, represents those drugs taken to alter mood and affect (e.g., marijuana, cocaine). We will restrict our discussion to the rationale for the use of these agents by today's athletes. Only the AASs will be discussed in part I of this report. Other ergogenic agents will be reviewed in next month's issue of The Annals. Of all the ergogenic agents, it is the abuse of AASs that is most widely reported. Although the ergogenic potential of AASs is still widely argued among experts,'? to most casual observers, any doubts regarding the beneficial effects of AASs on athletic performance were dispelled in the Seoul Olympics by Ben Johnson's performance in the lOO-meter dash. The primary reason that athletes use AASs is a strong belief that they are an essential component for becoming a champion.' Among the athletic community, studies challenging the ergogenic potential of AASs are routinely dismissed simply because these drugs are banned by organizations such as the National Collegiate Athletic Association and the International Olympic Committee.' The rationale is: If these drugs do not work, why spend up to $100 per sample testing for them? Furthermore, the overwhelming majority of published studies have failed to evaluate dosages of AASs similar to those used when they are abused.v Athletes also challenge efficacy studies because in the years following the institution of urine testing for AASs at amateur bodybuilding contests, the overall rate of weightlifting improvement has gradually decreased.P In a study of weightlifting improvement at the Junior World Championships in the three years before and after the institution of urine testing, it was noted that significant improvements in various lifts (e.g., snatch, clean and jerk, and total) occurred in the years before, but not following, the institution of urine testing," These data suggest that AASs may have been essential in producing improvements from year to year.
1992 April , Volume 26
The athletes who use AASs today possess sophisticated pharmacologic knowledge about these agents that surpasses that of the vast majority of physicians and pharmacists," For this reason, traditional warnings regarding their lack of efficacy and potential dangers are universally held in ridicule. The experts on AAS use in athletic competition are not medical clinicians, but rather, the athletes who have personally used them for years," Prevalence ofAndrogenic-Anabolic Steroid Abuse The prevalence of AAS abuse is summarized in Table I. A 1970 survey of nonmedical drug use conducted at five major universities found that 15 percent of intercollegiate athletes were taking AASs. This figure increased to 20 percent according to surveys conducted in 1976, 1980, and 1984. The prevalence of AAS use was not reported for specific sports. In the 1984 survey, it was also estimated that only 1 percent of nonathletic university students were using AASs.' One survey of competitive bodybuilders suggests an even higher prevalence of AAS use in this population than in college athletes. Of 380 bodybuilders who were mailed a survey, 176 responded. Of these, 54.6 percent of the men and 10.3 percent of the women admitted to using AASS.4 In another report of 138 male bodybuilders who attended a gym regularly for two months, 53 (38.4 percent) reported using AASs for 1-12 years (median 2) at some point in their lives. 10 These figures are conservative when compared with more recent data on junior and senior high school students. Current estimates indicate that 5-10 percent of high school students are AAS users.P:" In 1986, the Hazelden Foundation of Minneapolis calculated the rate of previous or current AAS use at 5 percent for male and 1 percent for female students. II In a more recent national survey of 12thgrade male students conducted by Buckley et al., it was estimated that 6.6 percent have used or are still using AASs. Even more disturbing is the fact that 4.4 percent of male high school seniors started abusing AASs at the age of 16 or younger," In a follow-up report, these same investigators noted a pattern of habituation and addictive attitudes similar to that found with "harder" drugs among the subset of AAS users classified as "heavy users." Members of this group are much more likely to continue using AASs even when presented with evidence demonstrating a definitive high risk of associated liver cancer, myocardial infarction, and permanent sterility." Johnson et al. reported AAS use in 95 of 853 11th-grade male students (1Ll percent) enrolled in six Arkansas high schools." These investigators speculated that the lower prevalence of AAS use reported by Buckley et al." was a result of the low sampling of high schools in the Sunbelt region." Windsor and Dumitru, however, compared adolescent AAS use among students of five relatively affluent high schools with that of five less affluent high schools in the southwestern US. For all of the schools combined, 3 percent of the students reported AAS use. At the affluent schools, 7.3 percent of the male and 1.7 percent of the female students were users; 10.2 percent of the male athletes were users. At the less affluent schools, 2.6 and 1.0 percent of the male and female students were AAS users, respectively. Only 2.8 percent of the male athletes at the less affluent schools were users." Terney and McLain surveyed AAS use in a suburban Chicago high
Table 1. Prevalence of Androgenic-Anabolic Steroid Abuse POPULATION
n
Bodybuilders men women College students athletes: 1970 1976 1980 1984 nonathletes: 1984 Male bodybuilders High school students male female l Zth-grade male students l lth-grade male students High school students male female High school students male female
PREVALENCE (%)"
REF.
4
380 59/108 (54.6) 7/68 (10.3) NA
9 (15) (20) (20) (20) (I)
138 NA
53 (38.4)
10 II
(5) (I)
3403 853 1010
226 (6.6) 95 (I1.1)
12 13 14
23/462 (5.0) 6/439 (1.4) 3047
15 67/1028 (6.5) 27/1085 (2.5)
"Includes only those subjects who completed the survey. NA = not available.
school of 3047 students. Of the 2113 students who completed the survey, 6.5 percent of the male and 2.5 percent of the female students admitted to AAS use. IS Mechanism ofAction AASs have been theorized to have several effects that may enhance performance. These include antagonism of the catabolic effect of glucocorticoids, direct stimulation of protein synthesis, increased red blood cell production, and central nervous system effects that increase motivation and decrease fatigue.!" The relative significance of each of these effects is controversial and not well documented. During stress (i.e., vigorous athletic training), the catabolic effect of glucocorticoids generates a negative nitrogen balance. Under these circumstances, the body uses its own nitrogen stores to counteract the effects of the stress. It has been suggested that during heavy training the protein intake requirement of a weightlifter should be 2.0-2.2 g/kg of body weight to maintain a positive nitrogen balance.'? AASs are anticatabolic and act on skeletal muscle by first reversing the catabolic effect of corticosteroids released during stress.' In vitro and in vivo studies of rat skeletal muscle have shown that this anticatabolic effect results from competition of testosterone and other AAS with cortisol, dexamethasone, and triamcinolone for glucocorticoid binding sites. IS This may reverse the negative nitrogen balance induced by the glucocorticoids as long as adequate protein intake is maintained, including all of the essential amino acids.' In the first edition of the Underground Steroid Handbook it is suggested that AASs will not cause individuals to gain size or strength unless they eat a high-protein diet containing 6000-8000 (men) or 4000 (women) calories per day. One example given is to quickly consume 2000 calories of the daily requirement by eating a dozen eggs at breakfast and again at dinner. I' Obviously, this would be a difficult diet to maintain.
The Annals ofPharmacotherapy
•
1992 April, Volume 26 • 521
In nonathletic healthy adults, the anticatabolic effect of AASs is short-lived because of the readjustment of homeostatic mechanisms to normalize nitrogen balance. Athletes who maintain an adequate diet and who are in chronic catabolic state and negative nitrogen balance through heavy training may continue to experience the anticatabolic effect of AASs in performance beyond the point where a plateau is normally reached. AASs exploit a nitrogen surplus by binding to androgen receptors in the cytoplasm of skeletal muscles, the prostate, and other sites. This steroid-receptor complex results in increased protein synthesis via messenger and ribosomal RNA in skeletal muscle cells. I The process continues only as long as the athlete is stressed (i.e., is in a negative nitrogen balance). This explains why AAS users maintain that the more they take, train, and eat, the more they grow,' Athletic performance may also be enhanced in athletes taking AASs because of increased erythropoietin synthesis and subsequent increases in hematocrit and blood oxygencarrying capacity.'> Because of this effect, AASs have been used in the treatment of anemia. I It is postulated that increased erythropoietin synthesis may enhance performance because healthy women and hypogonadal men achieve elevations in hematocrit concentrations similar to those of normal men. Furthermore, AASs increase the hematocrit of healthy men at high dosages.' This increase, however, usually amounts to only 10 gIL and is not consistent among users. Increased hematocrit in conjunction with AAS-induced sodium retention can increase blood volume by as much as 15 percent and contribute to any weight gain an athlete may experience while using AASs.I,3 More reliable methods of increasing hematocrit that are currently being used in the athletic community include either blood doping or the administration of epoetin, which has become widely available." The central effects of AASs on athletic performance are not well established. Anecdotal reports suggest that athletes may experience euphoria, decreased fatigue, and shortened recovery time following workouts while taking AASs.I.2.21 Although athletes may claim to feel euphoric and stronger while taking AASs (effects that have unblinded some double-blind studies"), these effects have never been objectively demonstrated to improve athletic performance.
Efficacy Research on the efficacy of AASs in enhancing athletic performance has been hampered by poor study design. The greatest difficulty in designing these studies is the lack of adequate placebo control. This problem is best exemplified by the double-blind, crossover study conducted by Freed et al. in which all 13 of their subjects correctly determined the order in which they received placebo and the active drug methandrostenolone." The development of such adverse effects as acne and testicular atrophy often compromises the blinding of these studies.P'" As a result, Haupt and Rovere downplayed the need for double-blind studies in their analysis of AAS efficacy.' The placebo effect in athletic performance is also well documented. In a report by Ariel and Saville, 15 well-trained college athletes were recruited and informed that the 8 with the best performance over an eight-week period would be given methandrostenolone 10 mg/d when, in fact, they were slated to re522
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The Annals ofPharmacotherapy •
ceive placebo. Of the 8 who were chosen for the study, 6 passed the screening tests and were given placebo daily for five weeks. The rate of improvement in performance in these subjects was significantly greater during the placebo phase than during the baseline training phase." This information clearly indicates a problem: double-blind methods are needed in situations where there is a lack of satisfactory placebo control. Further difficulties in analyzing data are caused by differences among studies. Wilson noted that variables in study design include the specific AAS and dosage studied, the training schedule, training experience, criteria for improvement, diet, and statistical analysis.' The biggest problem, however, is that in many published studies of AAS use, the drugs are not administered in the same large dosages used by athletes when they "stack the pyramid." "Stacking" is the term used by athletes to describe AAS administration during a cycle of drug use when they gradually increase the dose and add a new AAS to the regimen. Ethical considerations currently forbid investigators from administering AASs in this manner, thus making the evaluation of published reports very difficult.tv Given these variables, it is almost impossible to demonstrate a very small drug effect in members of the upper echelon of athletes for whom a small improvement in performance may be very beneficial. For example, although a one percent improvement would be difficult to demonstrate statistically, this improvement could be the difference between a world-class sprinter placing first versus last in a particular race. The effect of AASs on athletic capacity has been extensively reviewed.I" The conclusions of these reviews are not consistent. The most definitive conclusion that can be derived from these reports is that AASs are clearly not effective in improving aerobic performance and that if they do have any ergogenic effect, it is to increase strength. The problem with the design of aerobic performance studies is that endurance athletes such as runners and cyclists use AASs not to increase strength, but rather, to increase muscular recovery rate so that they can work out six or seven days per week instead of only three. These athletes are convinced that AASs allow them to be able to train more often than normal. If their observation is indeed true, controlling for the duration of training in efficacy studies would bias the study design against AASs. The most common explanation for inconsistencies in response among strength studies is that there is considerable variability in response to AASs (i.e., some subjects may respond with increases in strength whereas others may not).I.3 Wilson analyzed only those studies involving blind placebo control as motivation and innate ability could not otherwise be controlled for. He reasoned that if nonblind studies were included, the placebo effect noted in Ariel and Saville's report" would confound the results.' Many of the studies analyzed, however, may have been nonblind because of adverse effects, as reported by Freed et al." In the 16 studies of AAS use by athletes judged by Wilson to be adequately blinded and controlled, only 7 reported increases in strength. Moreover, in 2 of these studies, the differences were small and variances were not reported.' Factors such as androgen-mediated weight gain, previous history of weight training, and protein supplementation failed to distinguish those studies likely to report a positive result.
1992 April, Volume26
Androgenic-Anabolic Steroids
In 1984, Haupt and Rovere reviewed 24 "well-documented" studies of the effect of AASs on strength and found several factors that statistically predicted which studies were likely to report a significant effect. Of the 14 positive studies, 7 were double-blind, as were 9 of the 10 negative studies. The positive studies were statistically more likely than the negative ones to have evaluated athletes already trained in weightlifting prior to enrollment in the study. Furthermore, 13 of the positive studies and 3 of the negative studies measured increases in strength using the maximal weight lifted in a single repetition; the remaining studies measured strength via devices such as a cable tensiometer, dynamometer, hydraulic machines, and strain gauges.' The movements measured by these other techniques differ significantly from those of athletes during normal training. For example, in a study conducted by Hervey et aI., a significant increase in strength among male athletes was demonstrated using a one-repetition maximal lift; however, in the same subjects, no increase in strength was measured via a dynamometer." Although the postulated mechanism by which AASs may increase strength requires a concomitant high-protein diet, Haupt and Rovere's review did not demonstrate this to be the case.' However, this conclusion was biased because of a lack of dietary histories in many of the studies they evaluated. The value of past efficacy studies published in the medical literature is questionable by today's standards. All of these studies were conducted using either a single oral or intermuscular AAS formulation. A case-series analysis of 20 AAS users found that during cycles typically lasting between 7 and 14 weeks, athletes commonly used two or three oral agents and two long-acting injectable AASs. The dosages of oral preparations were similar to those used in past efficacy studies, although the dosages of injectable formulations were approximately three to eight times greater than those used in controlled studies," Injectable preparations are favored by athletes because they are less hepatotoxic than oral preparations.' The rationale for this "stacking" administration technique is to increase the drugs' anabolic effects, to decrease health risk by allowing the body to recover between cycles, and to decrease the likelihood of detection at athletic events." Despite claims to the contrary by AAS users," there is no evidence that this technique is safer or more effective. These findings lead one to conclude that past efficacy and toxicology studies are of limited value in delineating the benefits and hazards of AASS.6 Thus, currently available data regarding AASs do not provide sports medicine specialists with the information necessary to professionally counsel athletes. Commonly used AASs are listed in Table 2. This table was constructed from the Underground Steroid Handbook IF as opposed to traditional texts because of the many foreign, "black-market", and counterfeit AASs currently being used by athletes. Adverse Effects The toxic effects of AASs are divided into four general areas: hepatic, reproductive, cardiovascular, and psychiatric. HEPATIC EFFECTS
Published efficacy studies have reported elevations in four liver enzymes associated with AAS use. These en-
Table 2. Anabolic Steroids Currently in Uses FORMULATION
AGENT
25-, 50-mg/mL injections 50-, 100-, 200-mg tablets 50-mg/mL injection 2-mg tablet 2, 5, IO-mg tablets 5-mg tablet or capsule; 25-mg/mL injection 5-, 25-, 50-mg tablets 20-mg/mL injection 20-mg/mL injection 5-mg buccal; 10-, 25-mg tablets loo-llg/mL injection 50-, 100-, 200-mg/mL injections 25-mg/mL injection 2.5-mg tablet 50-mg tablet IO-mg capsule 2-mg tablet; 50-mg/mL injection 25-mg/mL injection 2oo-mg/mL injection 200-, 250-mg/mL injections 50-mg/mL injection 2oo-mg/mL injection 40-mg capsule 30-, 76-mg/mL injections
Boldenon undecyclenate" Danazol Dromostanolone propionate" Ethylestrenol Fluoxyrnesterone" Methandrostenolone" Methenolone Methenolone acetate Methenolone enanthate Methyltestosterone" Mibolerone" Nandrolone decanoate" Nandrolone phenpropionate" Oxandrolone" Oxyrnetholone Quinbolone Stanozolol" Stenbolone acetate Testosterone cypionate" Testosterone enanthate" Testosterone nicotinate Testosterone propionate" Testosterone undecanoate Trenbolone acetate
"Generically available. bNot available commercially (i.e., "black-market" drug).
OBJECTIVE: To summarize the literature describing the epidemiology, pharmacology, efficacy, and adverse effects associated with androgenic-anabolic steroid (AAS) use among athletes . DATA SOURCES: Relevant articles were identified from a MEDLINE search using the search terms " Doping in Sports," "Anabolic Steroid s (exploded)," and "Androgens (exploded)." Additional references were found in the bibliographies of these articles.
We reviewed studies of AAS use among professional athlete s. Interpretation of these studies is difficult because of poor research design. The efficacy studies lacked adequate placebo control. Much of the literature describing adverse effects consists of anecdotal reports . All of this literature was considered for review .
STIJDY SELECTIONIDATA EXTRAl.Il0N:
Of all ergogenic drugs, AASs are the most widely abused . Abuse of AASs among high school students is estimated at five to ten percent. AASs are hypothesized to produce ergogenic effects during periods of concomitant positive nitrogen balance via antagonism of the catabolic effect of glucocorticoids released during intense exercise. Despite years of study, the extent of the ergogenic effects associated with AASs remains unclear. This may be because most studies have failed to approximate athletes ' AAS usage patterns. The primary toxic effects of AAS s are divided into four areas: hepatic, reproductive, cardiovascular, and psychiatric. Athletes do not consider these effects severe enough to refrain from using these drugs. DATA SYNTHESIS:
CONCLUSIONS: Athletes view AASs as an essential component for success. Without adequate intervention measures, AAS abuse is likely to continue unchecked.
Ann Pharmacother 1992;26:520-8. ATHLETIC COMPETITION has intensified to the point that increasing numbers of athletes are striving to upgrade their performances by whatever means necessary to reach the pinnacle of success. Many players and coaches believe that no price is too great to pay in order to win. Thus, significant numbers are employing pharmacologic shortcuts in their training programs. More and more athletes are relying upon ergogenic drugs to enhance their strength, endurance,
DANIEL A. SMITH, Pharm.D.. is a Clinical Pharmacy Fellow; and PAUL J. PERRY, Ph.D.. is a Professor of Pharmac y. Division of Clinical Pharmacy. College of Pharmacy . and an Adjunct Professor of Psychiatry . Department of Psychiatry . College of Medicine . University of Iowa. Iowa City. IA. Reprints: Paul J. Perry. Ph.D.• College of Pharmacy. University of Iowa. 2271 Quadrangle. Iowa City . fA 52242 .
This article is approved for continuing education credit.
520
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•
and performance. The combination of the use of these drugs and more intensive training has opened a pharmacologic "Pandora's Box" for the athletes of the world. Drugs used by athletes fall into three general categories. Ergogenic drugs (performance-enhancing agents) represent those agents used to gain an athletic advantage in either strength (e.g. , androgenic-anabolic steroids [AASs]) or endurance (e.g., amphetamines, epoetin). Therapeutic drugs represent those used for specific medical indications under standards of good medical practice (e.g., nonsteroidal antiinflammatory drugs). The third category, mood-altering agents, represents those drugs taken to alter mood and affect (e.g., marijuana, cocaine). We will restrict our discussion to the rationale for the use of these agents by today's athletes. Only the AASs will be discussed in part I of this report. Other ergogenic agents will be reviewed in next month's issue of The Annals. Of all the ergogenic agents, it is the abuse of AASs that is most widely reported. Although the ergogenic potential of AASs is still widely argued among experts,'? to most casual observers, any doubts regarding the beneficial effects of AASs on athletic performance were dispelled in the Seoul Olympics by Ben Johnson's performance in the lOO-meter dash. The primary reason that athletes use AASs is a strong belief that they are an essential component for becoming a champion.' Among the athletic community, studies challenging the ergogenic potential of AASs are routinely dismissed simply because these drugs are banned by organizations such as the National Collegiate Athletic Association and the International Olympic Committee.' The rationale is: If these drugs do not work, why spend up to $100 per sample testing for them? Furthermore, the overwhelming majority of published studies have failed to evaluate dosages of AASs similar to those used when they are abused.v Athletes also challenge efficacy studies because in the years following the institution of urine testing for AASs at amateur bodybuilding contests, the overall rate of weightlifting improvement has gradually decreased.P In a study of weightlifting improvement at the Junior World Championships in the three years before and after the institution of urine testing, it was noted that significant improvements in various lifts (e.g., snatch, clean and jerk, and total) occurred in the years before, but not following, the institution of urine testing," These data suggest that AASs may have been essential in producing improvements from year to year.
1992 April , Volume 26
The athletes who use AASs today possess sophisticated pharmacologic knowledge about these agents that surpasses that of the vast majority of physicians and pharmacists," For this reason, traditional warnings regarding their lack of efficacy and potential dangers are universally held in ridicule. The experts on AAS use in athletic competition are not medical clinicians, but rather, the athletes who have personally used them for years," Prevalence ofAndrogenic-Anabolic Steroid Abuse The prevalence of AAS abuse is summarized in Table I. A 1970 survey of nonmedical drug use conducted at five major universities found that 15 percent of intercollegiate athletes were taking AASs. This figure increased to 20 percent according to surveys conducted in 1976, 1980, and 1984. The prevalence of AAS use was not reported for specific sports. In the 1984 survey, it was also estimated that only 1 percent of nonathletic university students were using AASs.' One survey of competitive bodybuilders suggests an even higher prevalence of AAS use in this population than in college athletes. Of 380 bodybuilders who were mailed a survey, 176 responded. Of these, 54.6 percent of the men and 10.3 percent of the women admitted to using AASS.4 In another report of 138 male bodybuilders who attended a gym regularly for two months, 53 (38.4 percent) reported using AASs for 1-12 years (median 2) at some point in their lives. 10 These figures are conservative when compared with more recent data on junior and senior high school students. Current estimates indicate that 5-10 percent of high school students are AAS users.P:" In 1986, the Hazelden Foundation of Minneapolis calculated the rate of previous or current AAS use at 5 percent for male and 1 percent for female students. II In a more recent national survey of 12thgrade male students conducted by Buckley et al., it was estimated that 6.6 percent have used or are still using AASs. Even more disturbing is the fact that 4.4 percent of male high school seniors started abusing AASs at the age of 16 or younger," In a follow-up report, these same investigators noted a pattern of habituation and addictive attitudes similar to that found with "harder" drugs among the subset of AAS users classified as "heavy users." Members of this group are much more likely to continue using AASs even when presented with evidence demonstrating a definitive high risk of associated liver cancer, myocardial infarction, and permanent sterility." Johnson et al. reported AAS use in 95 of 853 11th-grade male students (1Ll percent) enrolled in six Arkansas high schools." These investigators speculated that the lower prevalence of AAS use reported by Buckley et al." was a result of the low sampling of high schools in the Sunbelt region." Windsor and Dumitru, however, compared adolescent AAS use among students of five relatively affluent high schools with that of five less affluent high schools in the southwestern US. For all of the schools combined, 3 percent of the students reported AAS use. At the affluent schools, 7.3 percent of the male and 1.7 percent of the female students were users; 10.2 percent of the male athletes were users. At the less affluent schools, 2.6 and 1.0 percent of the male and female students were AAS users, respectively. Only 2.8 percent of the male athletes at the less affluent schools were users." Terney and McLain surveyed AAS use in a suburban Chicago high
Table 1. Prevalence of Androgenic-Anabolic Steroid Abuse POPULATION
n
Bodybuilders men women College students athletes: 1970 1976 1980 1984 nonathletes: 1984 Male bodybuilders High school students male female l Zth-grade male students l lth-grade male students High school students male female High school students male female
PREVALENCE (%)"
REF.
4
380 59/108 (54.6) 7/68 (10.3) NA
9 (15) (20) (20) (20) (I)
138 NA
53 (38.4)
10 II
(5) (I)
3403 853 1010
226 (6.6) 95 (I1.1)
12 13 14
23/462 (5.0) 6/439 (1.4) 3047
15 67/1028 (6.5) 27/1085 (2.5)
"Includes only those subjects who completed the survey. NA = not available.
school of 3047 students. Of the 2113 students who completed the survey, 6.5 percent of the male and 2.5 percent of the female students admitted to AAS use. IS Mechanism ofAction AASs have been theorized to have several effects that may enhance performance. These include antagonism of the catabolic effect of glucocorticoids, direct stimulation of protein synthesis, increased red blood cell production, and central nervous system effects that increase motivation and decrease fatigue.!" The relative significance of each of these effects is controversial and not well documented. During stress (i.e., vigorous athletic training), the catabolic effect of glucocorticoids generates a negative nitrogen balance. Under these circumstances, the body uses its own nitrogen stores to counteract the effects of the stress. It has been suggested that during heavy training the protein intake requirement of a weightlifter should be 2.0-2.2 g/kg of body weight to maintain a positive nitrogen balance.'? AASs are anticatabolic and act on skeletal muscle by first reversing the catabolic effect of corticosteroids released during stress.' In vitro and in vivo studies of rat skeletal muscle have shown that this anticatabolic effect results from competition of testosterone and other AAS with cortisol, dexamethasone, and triamcinolone for glucocorticoid binding sites. IS This may reverse the negative nitrogen balance induced by the glucocorticoids as long as adequate protein intake is maintained, including all of the essential amino acids.' In the first edition of the Underground Steroid Handbook it is suggested that AASs will not cause individuals to gain size or strength unless they eat a high-protein diet containing 6000-8000 (men) or 4000 (women) calories per day. One example given is to quickly consume 2000 calories of the daily requirement by eating a dozen eggs at breakfast and again at dinner. I' Obviously, this would be a difficult diet to maintain.
The Annals ofPharmacotherapy
•
1992 April, Volume 26 • 521
In nonathletic healthy adults, the anticatabolic effect of AASs is short-lived because of the readjustment of homeostatic mechanisms to normalize nitrogen balance. Athletes who maintain an adequate diet and who are in chronic catabolic state and negative nitrogen balance through heavy training may continue to experience the anticatabolic effect of AASs in performance beyond the point where a plateau is normally reached. AASs exploit a nitrogen surplus by binding to androgen receptors in the cytoplasm of skeletal muscles, the prostate, and other sites. This steroid-receptor complex results in increased protein synthesis via messenger and ribosomal RNA in skeletal muscle cells. I The process continues only as long as the athlete is stressed (i.e., is in a negative nitrogen balance). This explains why AAS users maintain that the more they take, train, and eat, the more they grow,' Athletic performance may also be enhanced in athletes taking AASs because of increased erythropoietin synthesis and subsequent increases in hematocrit and blood oxygencarrying capacity.'> Because of this effect, AASs have been used in the treatment of anemia. I It is postulated that increased erythropoietin synthesis may enhance performance because healthy women and hypogonadal men achieve elevations in hematocrit concentrations similar to those of normal men. Furthermore, AASs increase the hematocrit of healthy men at high dosages.' This increase, however, usually amounts to only 10 gIL and is not consistent among users. Increased hematocrit in conjunction with AAS-induced sodium retention can increase blood volume by as much as 15 percent and contribute to any weight gain an athlete may experience while using AASs.I,3 More reliable methods of increasing hematocrit that are currently being used in the athletic community include either blood doping or the administration of epoetin, which has become widely available." The central effects of AASs on athletic performance are not well established. Anecdotal reports suggest that athletes may experience euphoria, decreased fatigue, and shortened recovery time following workouts while taking AASs.I.2.21 Although athletes may claim to feel euphoric and stronger while taking AASs (effects that have unblinded some double-blind studies"), these effects have never been objectively demonstrated to improve athletic performance.
Efficacy Research on the efficacy of AASs in enhancing athletic performance has been hampered by poor study design. The greatest difficulty in designing these studies is the lack of adequate placebo control. This problem is best exemplified by the double-blind, crossover study conducted by Freed et al. in which all 13 of their subjects correctly determined the order in which they received placebo and the active drug methandrostenolone." The development of such adverse effects as acne and testicular atrophy often compromises the blinding of these studies.P'" As a result, Haupt and Rovere downplayed the need for double-blind studies in their analysis of AAS efficacy.' The placebo effect in athletic performance is also well documented. In a report by Ariel and Saville, 15 well-trained college athletes were recruited and informed that the 8 with the best performance over an eight-week period would be given methandrostenolone 10 mg/d when, in fact, they were slated to re522
•
The Annals ofPharmacotherapy •
ceive placebo. Of the 8 who were chosen for the study, 6 passed the screening tests and were given placebo daily for five weeks. The rate of improvement in performance in these subjects was significantly greater during the placebo phase than during the baseline training phase." This information clearly indicates a problem: double-blind methods are needed in situations where there is a lack of satisfactory placebo control. Further difficulties in analyzing data are caused by differences among studies. Wilson noted that variables in study design include the specific AAS and dosage studied, the training schedule, training experience, criteria for improvement, diet, and statistical analysis.' The biggest problem, however, is that in many published studies of AAS use, the drugs are not administered in the same large dosages used by athletes when they "stack the pyramid." "Stacking" is the term used by athletes to describe AAS administration during a cycle of drug use when they gradually increase the dose and add a new AAS to the regimen. Ethical considerations currently forbid investigators from administering AASs in this manner, thus making the evaluation of published reports very difficult.tv Given these variables, it is almost impossible to demonstrate a very small drug effect in members of the upper echelon of athletes for whom a small improvement in performance may be very beneficial. For example, although a one percent improvement would be difficult to demonstrate statistically, this improvement could be the difference between a world-class sprinter placing first versus last in a particular race. The effect of AASs on athletic capacity has been extensively reviewed.I" The conclusions of these reviews are not consistent. The most definitive conclusion that can be derived from these reports is that AASs are clearly not effective in improving aerobic performance and that if they do have any ergogenic effect, it is to increase strength. The problem with the design of aerobic performance studies is that endurance athletes such as runners and cyclists use AASs not to increase strength, but rather, to increase muscular recovery rate so that they can work out six or seven days per week instead of only three. These athletes are convinced that AASs allow them to be able to train more often than normal. If their observation is indeed true, controlling for the duration of training in efficacy studies would bias the study design against AASs. The most common explanation for inconsistencies in response among strength studies is that there is considerable variability in response to AASs (i.e., some subjects may respond with increases in strength whereas others may not).I.3 Wilson analyzed only those studies involving blind placebo control as motivation and innate ability could not otherwise be controlled for. He reasoned that if nonblind studies were included, the placebo effect noted in Ariel and Saville's report" would confound the results.' Many of the studies analyzed, however, may have been nonblind because of adverse effects, as reported by Freed et al." In the 16 studies of AAS use by athletes judged by Wilson to be adequately blinded and controlled, only 7 reported increases in strength. Moreover, in 2 of these studies, the differences were small and variances were not reported.' Factors such as androgen-mediated weight gain, previous history of weight training, and protein supplementation failed to distinguish those studies likely to report a positive result.
1992 April, Volume26
Androgenic-Anabolic Steroids
In 1984, Haupt and Rovere reviewed 24 "well-documented" studies of the effect of AASs on strength and found several factors that statistically predicted which studies were likely to report a significant effect. Of the 14 positive studies, 7 were double-blind, as were 9 of the 10 negative studies. The positive studies were statistically more likely than the negative ones to have evaluated athletes already trained in weightlifting prior to enrollment in the study. Furthermore, 13 of the positive studies and 3 of the negative studies measured increases in strength using the maximal weight lifted in a single repetition; the remaining studies measured strength via devices such as a cable tensiometer, dynamometer, hydraulic machines, and strain gauges.' The movements measured by these other techniques differ significantly from those of athletes during normal training. For example, in a study conducted by Hervey et aI., a significant increase in strength among male athletes was demonstrated using a one-repetition maximal lift; however, in the same subjects, no increase in strength was measured via a dynamometer." Although the postulated mechanism by which AASs may increase strength requires a concomitant high-protein diet, Haupt and Rovere's review did not demonstrate this to be the case.' However, this conclusion was biased because of a lack of dietary histories in many of the studies they evaluated. The value of past efficacy studies published in the medical literature is questionable by today's standards. All of these studies were conducted using either a single oral or intermuscular AAS formulation. A case-series analysis of 20 AAS users found that during cycles typically lasting between 7 and 14 weeks, athletes commonly used two or three oral agents and two long-acting injectable AASs. The dosages of oral preparations were similar to those used in past efficacy studies, although the dosages of injectable formulations were approximately three to eight times greater than those used in controlled studies," Injectable preparations are favored by athletes because they are less hepatotoxic than oral preparations.' The rationale for this "stacking" administration technique is to increase the drugs' anabolic effects, to decrease health risk by allowing the body to recover between cycles, and to decrease the likelihood of detection at athletic events." Despite claims to the contrary by AAS users," there is no evidence that this technique is safer or more effective. These findings lead one to conclude that past efficacy and toxicology studies are of limited value in delineating the benefits and hazards of AASS.6 Thus, currently available data regarding AASs do not provide sports medicine specialists with the information necessary to professionally counsel athletes. Commonly used AASs are listed in Table 2. This table was constructed from the Underground Steroid Handbook IF as opposed to traditional texts because of the many foreign, "black-market", and counterfeit AASs currently being used by athletes. Adverse Effects The toxic effects of AASs are divided into four general areas: hepatic, reproductive, cardiovascular, and psychiatric. HEPATIC EFFECTS
Published efficacy studies have reported elevations in four liver enzymes associated with AAS use. These en-
Table 2. Anabolic Steroids Currently in Uses FORMULATION
AGENT
25-, 50-mg/mL injections 50-, 100-, 200-mg tablets 50-mg/mL injection 2-mg tablet 2, 5, IO-mg tablets 5-mg tablet or capsule; 25-mg/mL injection 5-, 25-, 50-mg tablets 20-mg/mL injection 20-mg/mL injection 5-mg buccal; 10-, 25-mg tablets loo-llg/mL injection 50-, 100-, 200-mg/mL injections 25-mg/mL injection 2.5-mg tablet 50-mg tablet IO-mg capsule 2-mg tablet; 50-mg/mL injection 25-mg/mL injection 2oo-mg/mL injection 200-, 250-mg/mL injections 50-mg/mL injection 2oo-mg/mL injection 40-mg capsule 30-, 76-mg/mL injections
Boldenon undecyclenate" Danazol Dromostanolone propionate" Ethylestrenol Fluoxyrnesterone" Methandrostenolone" Methenolone Methenolone acetate Methenolone enanthate Methyltestosterone" Mibolerone" Nandrolone decanoate" Nandrolone phenpropionate" Oxandrolone" Oxyrnetholone Quinbolone Stanozolol" Stenbolone acetate Testosterone cypionate" Testosterone enanthate" Testosterone nicotinate Testosterone propionate" Testosterone undecanoate Trenbolone acetate
"Generically available. bNot available commercially (i.e., "black-market" drug).
