Pediatric Clinics Aug 2007

Pediatr Clin N Am 54 (2007) xv–xvi
Preface
Peter D. Rogers, MD, MPH, FAAP Brian H. Hardin, MD

Guest Editors
The use of performance enhancing drugs (PEDs) has become a bur-

geoning issue over the past few years. The use of these substances among
both professional and Olympic athletes has filled the sports pages and
incited the curiosity of our youth. Just how much these PEDs can im-
prove athletic performance is not clear. And because there are so many
PEDs on the open and black markets, those of us who take care of chil-
dren, adolescents, and young adults have to be alert to the probability
that our patients are exposed to these substances and may be using
them.
Unfortunately there is a dearth of information in the pediatric and ado-
lescent medicine literature on the use of PEDs in children and adolescents.
Much of the information in this issue, therefore, is gleaned from the adult
literature. The editors of this issue have tried to make the information as
immediate and practical for those of us who deal with children and
adolescents.
The articles in this issue of Pediatric Clinics of North America include (1)
the prevalence of the use of PEDs among United States adolescents, (2) the
office assessment of the adolescent who may be using these substances, (3)
a history of the development of androgenic anabolic steroids, (4) conse-
quences of the use of anabolic androgenic steroids, (5) the science of labo-
ratory testing for PEDs, (6) the use of creatine by adolescents, (7)
testosterone precursor use by adolescents, and (8) gene doping and the
use of erythropoietin and growth hormone by adolescents.
0031-3955/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.pcl.2007.07.005 pediatric.theclinics.com
xvi PREFACE
What we have included in this isssue is the state of the art of perfor-
mance-enhancing drugs as it pertains to adolescents. We admit that our
knowledge of these drugs and the effects they have on adolescent stands only
on the threshold. Some of the information at this time is speculative, but
some of it is frightening and, clearly, dangerous.
Acknowledgment
Dr. Rogers would like to thank Lisa S. Blackwell, MLS, Serials/Research
Librarian, Children’s Hospital Library, Columbus, Ohio for her help in the
preparation of this manuscript.
Peter D. Rogers, MD, MPH, FAAP

Adolescent Health
Children’s Hospital
700 Children’s Drive
Columbus, OH 43205, USA
E-mail address: [email protected]
Brian H. Hardin, MD
University of Arkansas Medical School
Department of Pediatrics
Arkansas Children’s Hospital
800 Marshall Street, Slot 900
Little Rock, AR 72202, USA
Pediatr Clin N Am 54 (2007) 651–662
Performance-Enhancing Substances:
Is Your Adolescent Patient Using?
Cynthia Holland-Hall, MD, MPHa,b,*
a
The Ohio State University College of Medicine, Columbus, OH, USA
b
Adolescent Medicine, Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA
Participation in athletic activities can benefit adolescents in numerous

ways. In addition to keeping adolescents physically active, sports participa-
tion may enhance self-esteem, decrease stress, and encourage individuals to
learn to work as a team; however, for some adolescents, the aim is not sim-
ply to enjoy sports participation but to win at all costs. They are not inter-
ested only in excelling as a team, but in striving to be the best as individuals
as well. These adolescents may be at risk for using performance-enhancing
substances to help them achieve their goals.
It is not only the high-level or ‘‘elite’’ athlete who may be attracted to
these substances. For many, adolescence is a time of intense preoccupation
with one’s own body and body image. As puberty progresses, insecurities
about a changing and growing body may lead an adolescent to consider us-
ing whatever means are available to attempt to alter his or her physical ap-
pearance. Coupled with the common perception among adolescents that
they are unlikely to suffer negative consequences of their actions, this may
lead adolescents to experiment with these substances.
The American Academy of Pediatrics defines a performance-enhancing
substance as ‘‘any substance taken in nonpharmacologic doses specifically
for the purposes of improving sports performance.’’ This may include pre-
scription medications, nutritional supplements, or illicit substances that in-
dividuals use to increase their strength, speed, or endurance or to control
weight or alter body composition [1]. Several performance-enhancing sub-
stances are summarized in Table 1, along with selected positive and negative
effects associated with their use. Virtually no research has been published on
the effects or the risks of these substances in adolescents; therefore, this
* Adolescent Medicine, Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205.

652 HOLLAND-HALL
Table 1
Potential effects of selected performance-enhancing substances
Potential risks and side
Substance Potential benefits effects
Anabolic-androgenic Increased strength Acne
steroids Increased lean body mass Hirsutism
Less muscle breakdown Gynecomastia
Male pattern baldness
Liver tumors
Agitation/psychosis
Virilization in girls
Testicular atrophy
Hypertension
Premature closure of
epiphyseal growth plates
Infertility
Ligamentous injury
Precocious puberty in
younger adolescents
Steroid hormone precursors None proven Increased estrogen levels
(androstenedione, in boys
DHEA) Possible androgenic effects,
as above
Creatine Increased strength Dehydration
Improved performance in Muscle cramps
short, anaerobic efforts Gastrointestinal symptoms
Weight gain Potential risk for renal
toxicity
Human growth hormone No proven effects on Coarsening facial features
performance Hypertension
Decreases subcutaneous fat Cardiovascular disease
Impaired glucose tolerance
Diuretics Weight loss Acute symptomatic
Enhanced muscle definition dehydration
Electrolyte imbalances
Nutritional supplements None proven Unregulated substances
Potential side effects vary
Abbreviation: DHEA, dehydroepiandrosterone.
information is derived from adult studies. More extensive descriptions of the

individual substances may be found elsewhere in this issue.
A large national survey of adolescent children of nurses revealed that
4.7% of boys and 1.6% of girls reported the weekly use of some kind of
product to build muscles or improve the body’s shape [2]. Substances
used included protein powders and amino acid supplements, creatine,
growth hormone, steroids, and steroid precursors. Five to 8% of adolescents
stated that they have used creatine [3,4]. In a survey of high school football
players in several Wisconsin schools, 30% reported that they used creatine
[5]. Ongoing studies that assess substance use and other risky behaviors in
nationally representative samples of high school students suggest that
PERFORMANCE-ENHANCING SUBSTANCES 653
approximately 3% of high school seniors have used anabolic-androgenic

steroids [6,7]. Reported use is higher among boys than girls. Younger teens,
including middle school and junior high school students, are nearly as likely
as older adolescents to report having used steroids [8]. About 40% of high
school seniors did not perceive a significant risk associated with the occa-
sional use of anabolic steroids [7]; although it has not been studied, it is rea-
sonable to hypothesize that younger teens are even less likely to understand
the associated risks.
Therefore, those providing medical care for adolescents must be comfort-
able assessing adolescents for the use of performance-enhancing substances
during sports physicals, at visits for sports-related injuries, and during rou-
tine health encounters. To be perceived as a credible source of information
on this topic, providers must be knowledgeable about the specific substances
in question and must acknowledge the potential benefits of using these sub-
stances in addition to the inherent risks. A ‘‘just say no’’ approach to coun-
seling is unlikely to have the desired impact on an adolescent who is
considering using these substances. By understanding the adolescent’s goals
and desired outcomes, it may be possible to help him or her achieve these
outcomes by way of safer, more appropriate means.
Identifying the at-risk adolescent

Certainly, performance-enhancing substance use is most prevalent among
athletes. The ‘‘typical’’ adolescent user of performance-enhancing sub-
stances is a male athlete who participates in a sport that demands high de-
grees of strength, power, size, or speed. He is more likely to use tobacco,
alcohol, and other illicit substances as well [9,10]. The practice is more prev-
alent among football, baseball, wrestling, and gymnastics participants and
those who engage in weight training and bodybuilding. Athletes who have
reached a plateau in their training may turn to these substances to ‘‘break
through’’ to a higher level of performance. Elite athletes, including those
hoping for a college athletic scholarship or a career in professional sports,
may use these substances to gain an ‘‘edge’’ over the competition. Young ad-
olescents who already have specialized in a single sport year round, rather
than engaging in a variety of athletic activities, may be on this pathway
as well. Wrestlers and other athletes who need to meet certain weight re-
quirements may use diuretics to achieve acute weight loss through dehydra-
tion; bodybuilders also may use such practices to achieve greater muscle
definition before a competition.
Not every adolescent user of performance-enhancing substances fits this
stereotype. More casual athletes, perhaps less informed about these sub-
stances, may believe that these substances are a quick fix or short cut to im-
proved performance or muscle building. Those who are frustrated or
unsatisfied with the results of the efforts they have made with their training
may be tempted to try these products. Even nonathletes desiring an
654 HOLLAND-HALL
improved physique may try using exogenous substances as a means of

changing their bodies. Those who are particularly body conscious, who
look at ‘‘muscle magazines’’ and related media, and who express an interest
in becoming more muscular are at increased risk [2]. Adolescents who are
being bullied may feel the need to ‘‘bulk up’’ to defend themselves or to in-
timidate others and may turn to these substances to help achieve that goal.
Use is not confined to older adolescents; it is well documented among ado-
lescents in middle school as well [8].
Adolescents are likely to do that which they perceive as normative.
Therefore, knowing teammates, competitors, or other athletes who use these
substances or believing that use is widespread may increase an individual’s
likelihood of using [8]. There may be a general feeling of acceptability of the
practice among fellow athletes, rather than any stigma associated with use.
Many athletes may believe that they are well educated about the substances
that they are using (perhaps better educated than their health care pro-
viders), that they understand the risks and benefits, and that they are mak-
ing appropriately informed decisions about using them. Those who believe
that there is little risk for getting caught or reprimanded for the use of per-
formance-enhancing substances may have less hesitation about trying them.
Adolescents with any of the above risk factors should be asked about
their use of performance-enhancing substances. Those who are under pres-
sure from their parents, teammates, or coaches to succeed in their athletic
endeavors or whose identity and self-worth are largely defined by their
sports participation and performance may be at particularly high risk. Re-
cent documented changes in weight or body composition also should
prompt the clinician to inquire about use.
Interviewing the adolescent

Before discussing this or any other sensitive topic with an adolescent, the
provider should clarify his or her confidentiality policies with the patient
and parent. It is reasonable to assure the patient that information regarding
the use of performance-enhancing substances will be kept confidential unless
that use is putting the patient’s life or health in immediate danger. Adoles-
cents have a right to know what their providers intend to do with informa-
tion obtained in confidence, and they are more likely to answer questions
honestly if they believe that their privacy will be protected [11,12].
Depth of interviewing necessarily depends on the amount of time that the
provider has to spend with a patient. In brief encounters, such as during
a visit for an acute sports-related injury, a single, directed screening ques-
tion, ‘‘Are you using any substances to improve your sports performance?’’
may be used. In longer encounters, a more prolonged conversation about
sports participation may naturally lead into a discussion of performance-
enhancing substance use. This may include an assessment of hours per week
spent training and playing sports, specific training practices, and how
important the adolescent feels it is to participate in and excel at his or her

sport. The provider should inquire specifically about the adolescent’s goals
with regard to physique/body composition and sports performance, in the
current season and in the long term (ie, are they anticipating a college or
professional career in sports). Explore what, if anything, the adolescent
sees as limitations or barriers to achieving these goals and what they
have done or considered doing to try to overcome these obstacles.
A technique of ‘‘indirect questioning’’ may put an adolescent at ease when
approaching sensitive topics. Using this technique, the provider begins by
asking the adolescent his or her thoughts on a topic in general or as it applies
to other people. Gradually, the questioning becomes more and more per-
sonal, ultimately culminating in a discussion of the adolescent’s individual
beliefs and experiences. For example, one may begin by asking adolescents
how they feel about the practice of ‘‘doping’’ in professional sports and if
they think that it is acceptable for younger, amateur athletes to use any or
all of these substances as well. One may then ask if the adolescent is aware
of any people their own age, perhaps even their own teammates, who engage
in this practice. Finally, one can ask whether the adolescent has used any of
these substances. This indirect technique gives the provider the opportunity
to demonstrate an open, nonjudgmental consideration of this information,
thereby making it more likely that the adolescent patient will feel comfort-
able disclosing his or her own beliefs and behaviors honestly.
When patients disclose that they have used substances to enhance their
performance or physique, the provider must ask appropriate follow-up
questions to clarify the extent of use and assess the degree of risk associated
with these behaviors. This line of questioning should include what doses of
substances the adolescent is using and how this dosing regimen was chosen.
If a nutritional supplement is labeled for use at a specific dose, an adolescent
may take a ‘‘more is better’’ approach and use even higher doses. Adoles-
cents’ use of the jargon common to the world of doping may be a clue
that they are at particularly high risk for engaging in more dangerous pat-
terns of use. These patients may report ‘‘cycling’’ (using a substance for
a specific period of time and then discontinuing use for a time, perhaps
when anticipating drug testing), ‘‘pyramiding’’ (using a regimen of increas-
ing and decreasing dosing), or ‘‘stacking’’ (using multiple performance-en-
hancing substances simultaneously). Patients should be asked where they
get information about these substances (eg, teammates, coaches, Internet,
nutrition supplement shops). The provider should ask about the presence
of side effects and if the adolescent uses any additional substances to mini-
mize side effects or mask detection of the substances they use, should they be
tested for drugs. Patients who admit to using injection drugs should be
asked about needle-sharing practices. Because adolescents who use ana-
bolic-androgenic steroids are more likely to engage in other risky behaviors,
they should be asked about the use of tobacco, alcohol, and other illicit sub-
stances as well [13,14]. Specific questions that may be used when
656 HOLLAND-HALL
interviewing an adolescent about performance-enhancing substance use, in-

cluding indirect questions and follow-up questions, are listed in Box 1.
The physical examination

Most adolescents who use performance-enhancing substances have no
distinguishing physical findings suggesting their use; however, a thorough
physical examination may be useful in several regards. Height, weight,
and body mass index should be obtained and compared with previous mea-
surements. Body composition and degree of muscularity should be noted.
Elevated blood pressure may suggest stimulant, human growth hormone,
or anabolic-androgenic steroid use. In boys, anabolic-androgenic steroid
use may lead to acne, male pattern baldness, gynecomastia, testicular atro-
phy, and severe striae. In addition to several of the above findings, girls may
develop hirsutism, clitoral hypertrophy, and deepening of the voice. Injec-
tion drug users may have needle marks or evidence of skin abscesses. Crea-
tine and other nutritional supplements are unlikely to have visible
manifestations on physical examination.
Additional testing
Drug testing for exogenous substances may be performed, most com-
monly using gas chromatography with mass spectrometry; however, this
testing may be of limited value. Availability of testing is limited, and
some substances may not be detectable in a urine test. If urine testing is per-
formed, the specimen ideally should be obtained under the direct observa-
tion of a same-gender member of the medical staff. If this is impossible,
other measures to prevent dilution or contamination of the specimen should
be considered, such as coloring the toilet water and disabling the sink in the
restroom where the specimen is obtained. Although the threat or practice of
routine drug screening may deter the ‘‘casual’’ user, a highly motivated ath-
lete is likely to be one step ahead of the primary care provider with regard to
techniques for hiding or masking his or her use. Furthermore, although such
testing may limit the undesirable behavior, it is unlikely to lead the adoles-
cent to give careful consideration to the issues of winning at all costs versus
doing what he or she believes is morally right and justified. An open and
honest discussion of the risks, benefits, and moral implications of doping
may be more effective in this regard. A more extensive discussion of drug
testing is contained elsewhere in this issue.
Patients who use injection drugs, particularly if they admit to any needle
sharing, should be tested for hepatitis B, hepatitis C, and HIV. An electro-
cardiogram and metabolic profile, including glucose, a cholesterol and lipid
panel, and liver function testing, may be considered in persons using hu-
man growth hormone and anabolic-androgenic steroids and their precur-
sors. Electrolytes may be obtained in athletes who use diuretics or
Box 1. Questioning the adolescent patient about the use

of performance-enhancing substances
Brief screening questions
Are you using any substances to improve your sports
performance?
Are you using any substances to improve your body’s
appearance or strength?
Questions about sports participation and performance
Are you satisfied with how well you do at your sport?
What, if anything, do you think keeps you from being even
better at your sport?
Do you put a lot of pressure on yourself to improve your sports
performance?
Do other people in your life, like your parents, coaches, or
teammates, put pressure on you to improve your
performance?
What are your short-term and long-term goals for sports
participation (eg, plans to obtain an athletic scholarship)?
Questions about body image and satisfaction
Are you happy with your current weight and body
composition?
Have you had any recent changes in your weight or body
composition? How did you achieve this?
Do you read magazines or visit Internet sites focused
on bodybuilding or fitness?
Questions about performance enhancing substances
How do you feel about professional athletes who engage
in doping?
Do you think it’s okay for people your age to use substances
to improve their sports performance? What kind of substances
do you think it’s okay to use?
Do you think it’s okay for schools to perform drug testing
on their student athletes?
Do you know any athletes at your school or on your team
who use these substances? Which ones do they use?
Has anyone ever encouraged you to use these substances?
Have you ever used anything to improve your strength,
physique, or performance?
Follow-up questions for positive screens
Which substances have you tried? Which are you using
currently?
658 HOLLAND-HALL
What dose do you use? Is this the recommended dose for this
substance?
Where do you get your information about using these
substances?
How did you determine the dosing regimen you use?
Where do you get these substances?
What changes have you seen in your body or performance
since you started using this?
Are you experiencing any side effects?
Do you use any additional substances to help lessen these side
effects or to avoid having a positive drug screen?
Where do you get your needles? Do you share needles (if
applicable)?
Do you understand that it is illegal to use certain substances
without a doctor’s prescription?
Do you use tobacco, alcohol, or any other drugs?
excessive quantities of creatine. Keep in mind that these laboratory values

are normal in most athletes who use performance-enhancing substances;
normal values should not provide reassurance that the adolescent is not
using.
Prevention
Perhaps the most important role of the primary care provider is to discuss
performance-enhancing substance use with adolescents before they consider
or initiate use. Athletes should be encouraged to consider how they feel
about competition, the importance of winning, and the importance of
achieving their personal best performance. What constitutes fair versus un-
fair competition? How do performance-enhancing substances fit into this
model of fair competition? Does the adolescent make a distinction between
‘‘legal’’ and banned substances in this regard? Patients who voice opposition
to the use of these substances should be supported and their decisions rein-
forced. Skills to resist peer pressure to consider using should be taught, per-
haps by way of role playing.
A categorical ‘‘just say no’’ approach to counseling is unlikely to be
effective and may be detrimental. Recent media attention to doping in
professional sports has contributed to widespread acceptance that the
use of some substances does confer an advantage to the user. Some
patients already may have seen beneficial effects in themselves or peers
who are users. To be seen by the athlete as a credible source of health infor-
mation, a provider must acknowledge that some substances, particularly
anabolic-androgenic steroids, clearly have been shown to increase muscle

mass and potentially improve performance. Creatine also has been associ-
ated with improved performance in some studies. The provider may pro-
ceed, however, by providing additional information about which some
adolescents may not be aware. These two substances are only effective
when used in conjunction with intense resistance training; they do not pro-
vide an effortless ‘‘short cut’’ to bigger muscles. Furthermore, they offer only
a small benefit over a healthy diet and a rigorous training regimen. For the
elite athlete, this may be the tiny edge that one needs over the competition,
but the typical middle school or high school athlete may not perceive a sig-
nificant difference in one’s performance. The provider may point out that
simple measures, such as getting enough sleep, maintaining adequate hydra-
tion, and quitting smoking, may have a greater positive impact on sports
performance than using supplements. When discussing creatine use, adoles-
cents need to be aware that approximately 20% to 30% of the population
seem to be ‘‘nonresponders’’ who will not see beneficial effects [15]. Further-
more, the American College of Sports Medicine, while acknowledging the
positive effects of creatine, does not recommend its use in persons younger
than 18 years of age [16]. It is speculated, but not proven, that creatine may
serve as a ‘‘gateway’’ drug, the use of which may lead to the use of more
dangerous performance-enhancing substances.
Adolescents considering the use of anabolic-androgenic steroids need to
know the potential medical risks and side effects associated with the use
of these substances, including acne, striae, psychiatric symptoms, the devel-
opment of liver tumors, and adverse cardiovascular effects. Female users
may develop hirsutism, deepening of the voice, male pattern baldness, clito-
ral enlargement, and menstrual irregularities. They need to understand that
some of the virilizing features may be irreversible. Boys may experience gy-
necomastia, hair loss, and testicular atrophy. Although the cosmetic effects
may not be the most concerning risks from the provider’s perspective, these
concrete images, such as irreversible gynecomastia for a boy or hirsutism for
a girl, may have a greater psychologic impact than more dangerous but
more abstract risks, such as liver disease. Adolescents who are considering
using steroids or other injection drugs should be educated regarding the in-
fectious risks associated with sharing needles.
Many advertisements for performing-enhancing nutritional supplements
are aimed specifically at the adolescent and young adult demographic. Some
adolescents are becoming more media savvy and may respond well to the
idea that those running the multimillion dollar industry of nutritional sup-
plements are counting on young people to be vulnerable to their marketing
claims. Remind them that these substances are not regulated by the US
Food and Drug Administration in the same manner as prescription medica-
tions and that the claims made by advertisers often are not substantiated.
Furthermore, quality control during the processing and packaging of these
products is variable, and there is no guarantee that the contents of the
660 HOLLAND-HALL
container are reflected accurately on the label. Some products that are mar-
keted as legal nutritional supplements conceivably may contain substances
that are banned or dangerous to enhance their perceived efficacy. This could
result in a positive drug screen or other adverse medical effects in an athlete
who believes that he or she is using a safe substance. Of course, this also
makes it impossible for the provider to counsel on the safety of these prod-
ucts with any degree of certainty.
Counseling a patient not to take a particular course of action (eg, not to
use performance-enhancing substances) is likely to be more effective if the
provider can offer the patient alternative means of achieving the desired out-
comes. Therefore, a broader discussion of an adolescent’s motivation for
considering the use of these substances is warranted. Ask the adolescent
to describe his or her performance goals or goals for physical appearance.
Help the adolescent to explore alternative ways to achieve these goals. Point
out some of the adolescent’s modifiable lifestyle choices that may be impair-
ing performance, such as smoking cigarettes or marijuana, using alcohol,
poor sleep habits, or poor conditioning. Become knowledgeable about local
referral resources that may assist patients in making appropriate changes.
Most adolescents have room for improvement in their diets; a sports nutri-
tionist can help them to make better food choices to optimize their health
and performance. The American College of Sports Medicine endorses the
safety of strength training, even in preteenagers [17]; a qualified trainer
can help them develop a safe and effective training regimen. Sensible weight
control programs, such as Weight Watchers, are widely available in many
communities and are appropriate for adolescents who wish to lose weight
in a healthful manner. For adolescents with symptoms of a mood or anxiety
disorder or who are experiencing stressful psychosocial situations, getting
help from a mental health provider may enhance their overall well-being,
which may be reflected by better performance in sports and other extracur-
ricular activities.
Lastly, parents of adolescent athletes should be educated as well. Some
may not appreciate the potential dangers of using certain performance-en-
hancing substances; others may know that they can be harmful but may
not realize how widespread their use is, even at the middle school level. Par-
ents should know that the American Academy of Pediatrics strongly con-
demns the use of performance-enhancing substances [1]. They should be
encouraged to have ongoing discussions with their children, particularly
those who are athletes, about this issue. These discussions become even
more important as athletes aspire to higher and higher levels of performance
in their sport. Parents should make their own views on the subject clear and
communicate their expectations explicitly and repeatedly to their children.
They should remind their children of all of the positive aspects of sports par-
ticipation and encourage them to focus on these aspects and not solely on
winning. They should attempt not to let their child’s self-esteem be tied
too closely to winning or performance and should encourage them instead
to take pride in being fair and honest in their approach to sports participa-
tion. Parents should be aware of the side effects of dangerous substances and
what to look for in their own child.
Summary
Adolescents have variable knowledge about performance-enhancing sub-
stances, but many athletes and nonathletes may be considering their use.
Young adolescents are as likely as older adolescents to use these substances.
Although most nutritional supplements are not likely to cause serious harm,
they are largely unregulated and their safety cannot be assured. Anabolic-
androgenic steroids, although illegal, are readily available to athletes who
seek them out. Although the potential adverse effects of steroid use are un-
equivocal and should be emphasized, their positive effects must be acknowl-
edged as well if a provider is to have a meaningful discussion with an athlete
regarding their use. While discouraging the use of performance-enhancing
substances, providers should be prepared to assist their patients in achieving
their performance and appearance goals in alternative, healthful ways.
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Prevalence of Use
of Performance-Enhancing Substances
Among United States Adolescents
Edward M. Castillo, PhD, MPHa,
R. Dawn Comstock, PhDb,c,*
a
Department of Emergency Medicine, University of California, San Diego Medical Center,
200 West Arbor Drive, #8676, San Diego, CA 92103, USA
b
College of Medicine, Department of Pediatrics and College of Public Health, Division
of Epidemiology, The Ohio State University, Columbus, OH 43210, USA
c
Columbus Children’s Hospital, Center for Injury Research and Policy, 700 Children’s Drive,
Undoubtedly, athletes always have striven, and will continue to strive, to

improve their performance through means such as physical training, im-
proved nutrition, and skills training. For thousands of years, the use of ex-
ogenous substances has accompanied efforts to improve performance by at
least some competitive athletes [1]. In the past decade, the use of perfor-
mance-enhancing substances by Olympic athletes and United States profes-
sional athletes has sparked a highly publicized discussion of the potential
negative health effects and ethical implications of the use of such substances.
The use of performance-enhancing substances has spread beyond the sport-
ing arena, with increased popularity among individualsdnonathletes as well
as athletesdseeking to improve their physical appearance. Annual sales of
nutritional supplements (a broad term inclusive of some performance-
enhancing substances) have been estimated at up to $12 billion in the United
States [2].
Adolescents, who in the normal course of development become intensely
concerned about peer acceptance, body image, and athletic prowess, may re-
gard the use of performance-enhancing substances as an easy means to gain
self-esteem through improved body appearance and athletic performance
[3]. Additionally, normally experienced feelings of invulnerability can lead
* Corresponding author. Columbus Children’s Hospital, Center for Injury Research and
Policy, 700 Children’s Drive, Columbus, OH 43205.
E-mail address: [email protected] (R.D. Comstock).
664 CASTILLO & COMSTOCK
adolescents to use performance-enhancing substances with disregard to po-

tential negative health effects and long-term consequences [3]. These are not
new phenomena; the use of anabolic steroids by United States adolescent
athletes reportedly occurred first in 1959 [4].
The use of performance-enhancing substances by adolescents is parti-
cularly troubling because safety data associated with the use of such
substances by this population is largely lacking [5]. Most reports on perfor-
mance-enhancing substances have focused on efficacy [6–9]. Few studies
have focused on the use of these substances among adolescents; studies
that have tended to focus on a single supplement. Additionally, published
studies are difficult to compare because of the focus on varying ages, athletic
backgrounds, selection variations, and analysis stratification. This poses
a dilemma for the pediatrician who needs correct information, including
the potential efficacy and negative health effects of such substances as well
as the prevalence of use among adolescents and risk factors for use, to iden-
tify patients in need of counseling and to find the best way to help adolescent
patients make informed decisions to promote healthy behaviors. This article
is intended to assist pediatricians by providing a summary of the current
state of knowledge regarding the prevalence of use of performance-enhanc-
ing substances by United States adolescents.
Overview of performance-enhancing substances

The term ‘‘performance-enhancing substance’’ is used commonly to refer to
a broad array of agents that can be segregated into three main categories: ille-
gal substances/substances not available without a prescription that are
banned by some or all sports (eg, anabolic steroids and the hormone precursor
androstenedione); legally available substances that are banned by some or all
sports, in general or in competition only (eg, diuretics and caffeine); and legally
available substances that are not banned (eg, dietary supplements). Determin-
ing the category into which a substance falls can be difficult because the lists of
substances that are banned by the various sporting governing bodies are
amended frequently. Also, although less frequent, a substance’s legal status
can change (eg, the US Food and Drug Administration’s banning of the
sale of supplements containing ephedrine alkaloids in 2004).
As detailed in the Dietary Supplement Health and Education Act of 1994
[10], ‘‘The term ‘dietary supplement’ means a product (other than tobacco)
intended to supplement the diet that bears or contains one or more of the
following dietary ingredients: a vitamin; a mineral; an herb or other botan-
ical; an amino acid; a dietary substance for use by man to supplement the
diet by increasing the total dietary intake; a concentrate metabolite, constit-
uent, extract, or combination of any ingredient described above; is intended
for ingestion in the form of a capsule, powder, softgel, or gelcap; or is la-
beled as a dietary supplement.’’ The United States federal government
allows for the manufacturing and marketing of these supplements with
PREVALENCE OF USE OF PERFORMANCE-ENHANCING SUBSTANCES 665
minimal requirements or regulation, and they are readily available at local

markets and health food stores and from online retailers. Dietary supple-
ments are consumed for a variety of reasons, including general health main-
tenance, increased muscle mass, and athletic performance enhancement. As
with most behaviors, several factors contribute to the use of dietary supple-
ments, including age and various health behaviors, such as smoking, alcohol
use, and physical activity. In adolescents and adults, dietary supplements are
becoming increasingly popular among individuals who are attempting to en-
hance athletic performance, improve body appearance, and achieve health-
ier lifestyles. This increase continues, despite the limited information on
efficacy and safety for most products.
According to the US Anti-Doping Agency, a performance-enhancing
substance gets placed on the prohibited list (ie, is banned by some or all
sports) if it meets two of three criteria: it has the potential to enhance or en-
hances sport performance, it represents an actual or potential health risk to
the athlete, or it violates the spirit of sport [11]. To aid athletes, the US Anti-
Doping Agency annually publishes a Guide to Prohibited Substances that
provides a list of substances banned in competition and out-of-competition
by different sports’ governing bodies. The US Food and Drug Administra-
tion determines the legal status of substances. Although these two categories
of performance-enhancing substances traditionally have been used by ath-
letes to improve performance, a growing number of individuals have adop-
ted the use of such substances to improve body appearance.
In an effort to best serve the needs of the pediatrician, the review pre-
sented here has been limited to peer-reviewed publications that focused
on performance-enhancing substances included in the US Anti-Doping
Agency’s Guide to Prohibited Substances [11] and performance-enhancing
substances that are commonly available for purchase (eg, creatine), and
large, unpublished surveys that assessed the prevalence of use of such sub-
stances by adolescents. In an effort to ensure the generalizability of results,
the presentation of information not published in the peer-review literature is
limited to national surveys. Thus, several state-based surveys capturing in-
formation on the prevalence of performance-enhancing substance use
among adolescents were excluded [12–17].
Prevalence of use of performance-enhancing substances

Performance-enhancing supplement use in adolescents has not been stud-
ied adequately. Although there is a growing number of reports in the peer-
review scientific literature on the prevalence of anabolic steroid and creatine
use among adolescents, few reports provide information on the prevalence
of use of other supplements. To provide an overview of the prevalence
and patterns of performance-enhancing supplements in United States ado-
lescents, pertinent peer-review publications focusing on these substances,
rather than general supplement use, are summarized here (Tables 1 and 2).
Table 1
Anabolic steroid use among United States adolescents: reports in the peer-review literature
Investigators Sample population Overall prevalence
Buckley et al [18] 3403 male 12th graders 6.6%
Krowchuk et al [19] 295 high school athletes 1.0%
Johnson et al [21] 853 11th graders 11.1%
Whitehead et al [20] 3,900 10th–12th graders 5.3%
Radakovich et al [29] 810 7th graders 3.8%
Tanner et al [22] 6930 high school students 2.7%
Scott et al [23] 4722 middle/high school students 2.5%
Faigenbaum et al [24] 965 middle school students 2.7%
Stilger and Yesalis [25] 1325 high school football players 6.3%
Additionally, several national surveys that have not been published or have
not been published in their entirety in the peer-review literature, but which
have assessed the prevalence of performance-enhancing substance use among
United States adolescents, also are presented (Table 3).
Anabolic steroids
Anabolic steroids are synthetic substances that mimic testosterone and are
used for increasing fat-free muscle mass and strength, with potentially severe
adverse effects. Before their classification as a banned substance with the An-
abolic Steroid Control Act of 1990, anabolic steroids were popular perfor-
mance-enhancing supplements among elite and recreational athletes. These
drugs are only available legally by prescription, but they continue to be used
illegally by adults and adolescents aiming to gain a physical edge. The preva-
lence of use depends on several factors and includes participant demographics,
such as age, athletic background, and type of sport participation.
Several studies investigated anabolic steroid use among adolescents be-
fore and around the time of the implementation of the Anabolic Steroid
Control Act of 1990. Buckley and colleagues [18] surveyed male twelfth-
grade students from 46 high schools across the country. Results indicated
Table 2
Creatine use among United States adolescents: reports in the peer-review literature
Investigators Sample population Overall prevalence
Smith and Dahm [30] 328 high school students 8.2%
Metzl et al [31] 1103 middle/high school athletes 5.6%
Ray et al [32] 674 high school athletes 16.0%
McGuine et al [33] 1349 high school football players 30.0%
McGuine et al [34] 4011 high school athletes 16.7%
Reeder et al [35] 475 high school students 11.0%
Kayton et al [36] 270 high school athletes 13.0%
that 6.6% of the 3403 participants used or had used anabolic steroids. Those
who reported use were more likely to participate in sports (67%), the most
common of which was football (44%). Reports with similar study popula-
tions from around the same time period reported the prevalence of use
from 1% to 11% [19–21]. These reports also noted a lack of understanding
about the benefits and adverse effects of these substances. Table 1 summa-
rizes peer-review articles reporting anabolic steroid use among adolescents.
Studies that focused on prevalence after the Anabolic Steroid Control
Act of 1990 reported a slight decrease in steroid use; however, comparing
reports is difficult because of differences in ages and other characteristics.
Tanner and colleagues [22] reported overall steroid use of 3% among
6930 high school students in Denver, with boys reporting more use than girls
(4% and 1%, respectively). Scott and colleagues [23] reported similar use
from their survey of 4722 students from 62 secondary schools; 117 (3%) re-
spondents reported anabolic steroid use in the preceding 30 days, and boys
reported use (5%) more than girls (1%). Faigenbaum and colleagues [24] fo-
cused on steroid use among 965 middle school students between 9 and 13
years of age. In this population, steroid use was reported by 2.6% of boys
and 2.8% of girls, with an overall prevalence of 2.7%. In a survey of
1325 varsity football players from 27 Indiana high schools, Stilger and Yes-
alis [25] reported the prevalence of use to be 6%.
In addition to the peer-review studies summarized above, three multiyear
national surveys have evaluated the prevalence of anabolic steroid use among
adolescents (see Table 3) [26–28]. The longest running survey, the Monitoring
the Future Study [26], assessed the prevalence of anabolic steroid use among
ninth to twelfth graders from 1989 through 2006 in three categories: lifetime
use, use over the previous 12 months, and use over the previous 30 days. Be-
cause variance in this age group is small, and the prevalence of use is low, only
the information for lifetime use by twelfth graders is presented here. This
study, which surveyed between 2533 and 7100 twelfth-grade students from
across the United States annually, reported prevalence rates of lifetime use
of anabolic steroids ranging from a low of 1.9% in 1996 to a high of 4.0%
in 2002. The next-longest running survey, the Youth Risk and Behavior Sur-
veillance System [28], evaluated the prevalence of anabolic steroid use among
ninth to twelfth graders from 1991 through 2005. This study, which surveyed
between 10,904 and 16,262 students from across the United States annually,
reported prevalence rates for the lifetime use of anabolic steroids ranging
from a low of 2.2% in 1993 to a high of 6.1% in 2003. Across the study period,
prevalence rates were consistently higher among boys than among girls, al-
though the gap between genders decreased in 2003 and 2005. The third study,
the National Household Survey on Drug Abuse [27], also assessed lifetime use
of anabolic steroids. This study, which surveyed between 4678 and 8005 ad-
olescents aged 12 to 17 years from across the United States, only collected in-
formation on steroid use from 1991 through 1994. Reported prevalence rates
of the lifetime use of anabolic steroids ranged from a low of 0.2% in 1993 to
668
Table 3
Prevalence of performance-enhancing substance use among United States adolescents: results of national surveys not reported or not fully reported in the
peer-review literature
Sample Overall
Study Year population Substance prevalence
Blue Cross and Blue Shield Association’s Healthy 2001 785 ‘‘Performance-enhancing drugs 5%
Competition Foundation National Survey (survey or sports supplements’’
of 10- to 17-year-olds)
Monitoring the Future Study (survey of 1989 2783 Anabolic steroids (used at least once 3.0%
CASTILLO & COMSTOCK

12th graders) in lifetime)
1990 2533 2.9%
1991 5000 2.1%
1992 5267 2.1%
1993 5433 2.0%
1994 5133 2.4%
1995 5133 2.3%
1996 4767 1.9%
1997 5133 2.4%
1998 5067 2.7%
1999 4533 2.9%
2000 4267 2.5%
2001 4267 3.7%
2002 4300 4.0%
2003 4867 3.5%
2004 4867 3.4%
2005 4900 2.6%
2006 7100 2.7%
National Household Survey on Drug Abuse 1991 8005 Anabolic steroids (used at least once 0.6% (1.0% boys
(survey of 12- to 17-year-olds) in lifetime) and 0.2% girls)
1992 7254 0.3% (0.4% boys
and 0.1% girls)
1993 6978 0.2% (0.3% boys
and 0.1% girls)
1994 4678 0.7% (0.7% boys
and 0.6% girls)
PREVALENCE OF USE OF PERFORMANCE-ENHANCING SUBSTANCES

Youth Athlete Surveys – The Josephson 2004 4200 ‘‘Performance-enhancing drugs’’ 12% boys and 3%
Institute’s Report Card Survey Reports (used at least once in past year) girls
(survey of high school athletes)
2005 and 2006 5275 6% boys and 2%
girls
Youth Risk and Behavior Surveillance 1991 12,272 Anabolic steroids 2.7% (4.1% boys
System (survey of 9th to 12th graders) (used at least once in lifetime) and 1.2% girls)
1993 16,296 2.2% (3.1% boys
and 1.2% girls)
1995 10,904 3.7% (4.9% boys
and 2.4% girls)
1997 16,262 3.1% (4.1% boys
and 2.0% girls)
1999 15,028 3.7% (5.2% boys
and 2.2% girls)
2001 13,627 5.0% (6.0% boys
and 3.9% girls)
2003 15,240 6.1% (6.8% boys
and 5.3% girls)
2005 13,917 4.0% (4.8% boys
and 3.2% girls)
669
a high of 0.6% in 1991. Again, across the study period, prevalence rates were
consistently higher among boys than among girls, although the gap was small
in 1994. The lower prevalence rates reported in this study compared with the
two other national studies likely is due to the broader age range of the sample;
published reports consistently have indicated that the use of performance-
enhancing substances increases with age throughout adolescence.
The reasons for using anabolic steroids have remained consistent in most
studies. Adolescents involved in sports used steroids more often than those
who were not, but use was noted among individuals who were not athletes
[18,20,23]. Among those who participated in sports activities, use varied by
sport. Participating in football was common among users, but so was par-
ticipation in other sports, such as gymnastics, weight training, basketball,
and baseball [18,20,29]. Reasons for using steroids also varied and ranged
from improving athletic performance and improving strength among ath-
letes to improving appearance or building self-esteem among those who
did not participate in sports activities [18,23,29].
Creatine
Creatine may be the most popular performance-enhancing substance used
by adolescents. Creatine is a naturally occurring compound in the body that
supplies energy to muscle and is used to enhance recovery after a workout,
build muscle mass, and improve strength. There are several recent reports
about the prevalence of use of creatine among adolescents (see Table 2).
Smith and Dahm [30] surveyed 328 high school athletes (182 boys and
146 girls) between the ages of 14 and 18 years. Creatine use was reported
by 8.2% of boys and 1 girl, use increased with age, and 78% of users
were male football players. Additionally, 79% of users reported that crea-
tine improved strength. Most creatine users reported learning about creatine
from friends (74%), and most purchased the product from health food
stores (89%). Metzl and colleagues [31] surveyed 1103 middle and high
school athletes (55% boys, 45% girls) between the ages of 10 and 18 years;
62 (5.6%) respondents reported taking creatine. More boys (8.8%) than
girls (1.8%) reported the use of creatine, with use reported by respondents
from every grade. Ray and colleagues [32] surveyed 674 athletes from 11
high schools. About 16% of respondents reported using creatine to enhance
athletic performance and percentages increased with age. Among those sur-
veyed, 75% had knowledge of creatine supplements.
Two of the largest studies investigating creatine use in adolescents were re-
ported from surveys administered to students in 37 public high schools in Wis-
consin [33,34]. McGuine and colleagues [33] reported the results from surveys
administered to 1349 high school football players. Creatine use was reported
by 10.4% of ninth graders, 23.8% of tenth graders, 41.1% of eleventh graders,
and 50.5% of twelfth graders. A subsequent article describing creatine use
among 4011 high school athletes reported overall use among 16.7% of
respondents (25.3% boys, 3.9% girls). Grade-specific rates included 8.4% of

ninth graders, 12.6% of tenth graders, 23.1% of eleventh graders, and 24.6%
of twelfth graders [34].
Studies by Reeder and colleagues [35] and Kayton and colleagues [36]
evaluated creatine use while investigating a variety of dietary supplements.
Reeder and colleagues [35] surveyed 475 high school students and found
that creatine was the most popular supplement, with 11.0% of respondents
reporting use in the past 12 months. Kayton and colleagues [36] surveyed
270 athletes (55% girls, 45% boys) competing in a winter or spring sport
from four different high schools. Creatine use was reported by 13% of stu-
dents (21% of boys and 3% of girls).
The use of creatine among athletes who participate in different sports is
common. Metzl and colleagues [31] reported that the use of creatine varied
by sports participation, with a higher percentage of users participating in gym-
nastics (36%), hockey (20%), wrestling (14.3%), and football (13.4%).
McGuine and colleagues [34] reported the distribution of use in sports by gen-
der. Among girls, creatine use was most frequent among athletes who partic-
ipated in track (5.4%), gymnastics (4.7%), tennis (4.6%), and volleyball
(3.8%). Among boys, creatine use was most frequent among athletes who par-
ticipated in football (30.1%), swimming (28.4%), hockey (28.0%), and base-
ball (26.5%).
Other performance-enhancing substances

There are many types and formulas of performance-enhancing substances
availabledlegally and illegallydto adolescents today. The prevalence for the
use of most performance-enhancing substances among adolescents is largely
unknown. A few reports have described the prevalence of use of a few addi-
tional types of performance-enhancing substances. Human growth hormone
is used to increase muscle mass and strength and has received an increase in
media attention and advertising in the past few years; however, little is known
about the prevalence of its use as a performance-enhancing supplement. In
1992, Rickert and colleagues [37] reported that use among tenth-grade boys
was about 5%.
More recently, Reeder and colleagues [35] surveyed 475 high school stu-
dents regarding their use of common dietary supplements. Of those surveyed,
20.4% (97 students) reported using at least one supplement in the past 12
months. The most common supplements used were creatine (11.0%), andros-
tenedione (4.0%), and Xenadrine (3%).
Kayton and colleagues [36] surveyed 270 athletes (55% girls, 45% boys)
competing in a winter or spring sport from four high schools. Questions about
the use of 21 dietary supplements or ergogenic aids were included in the survey.
About 22% of respondents reported using dietary supplements to enhance
performance, but 58% reported using at least one of the 21 listed dietary sup-
plements for other than ergogenic benefits. Amino acids were used by 8% of
boys and 1% of girls, weight gain formula was used by 10% of boys and 2% of
girls, and ephedrine was used by 12% of boys and 26% of girls.
General performance-enhancing substance use

Not all reports of the prevalence of performance-enhancing substance use
differentiated between the types of such substances. For example, in one na-
tional survey [38], high school athletes were asked if they had used ‘‘perfor-
mance-enhancing drugs’’ in the past year. In this study, there was a much
wider range of prevalence of use within genders than between genders, and
the reported prevalence was lower in 2005/2006 than in 2004. Although 6%
of all male athletes surveyed in 2005/2006 reported the use of performance-en-
hancing substances, the prevalence of use ranged from a low of 0% among
track or volleyball participants to a high of 9%, 10%, and 13% among base-
ball, hockey, and gymnastics participants, respectively. Similarly, although
2% of all female athletes surveyed in 2005/2006 reported the use of perfor-
mance-enhancing substances, the prevalence of use ranged from a low of
0% among cross-country, gymnastics, or swimming participants to a high
of 3%, 3%, and 4% among cheerleading, softball, and tennis participants, re-
spectively. A national survey of 10- to 17-year-olds [39] reported a prevalence
of use of ‘‘performance enhancing drugs or sports supplements’’ of 5%.
Knowledge, attitudes, and beliefs about the use

of performance-enhancing substances
Understanding trends over time in the knowledge, attitudes, and beliefs
held by adolescent athletes regarding the use of performance-enhancing sub-
stances is important to evaluate trends in the prevalence of use in this pop-
ulation and is an essential element of efforts to develop effective preventive
interventions. Questions included on national surveys provide insight into
this issue. For example, it seems that adolescent athletes may not under-
stand, or at least may not acknowledge, the potential negative health effects
of performance-enhancing substances. One national survey [38] indicated
that 17% of boys and 10% of girls disagreed with the statement, ‘‘No athlete
should use performance-enhancing drugs because it’s unhealthy.’’ In an-
other national survey [26], when asked how much people risked harming
themselves if they took steroids, the percentage of twelfth graders respond-
ing that the use of steroids posed ‘‘great risk’’ ranged from a high of 70.7%
in 1992 to a low of 55.0% in 2003.
Similarly, adolescent athletes may not hold negative beliefs about the ap-
propriateness of the use of such substances. In one national survey [38],
15% of boys and 11% of girls disagreed with the statement, ‘‘No athlete
should use performance-enhancing drugs because it’s cheating.’’ Also, the
proportion of twelfth graders who disapproved of people who took steroids
ranged from a high of 92.1% in 1992 to a low of 86.0% in 2003 [26].
Although adolescents seem to have difficulty understanding, or at least ac-

knowledging, the potential negative health effects of performance-enhancing
substances and they may fail to attach a negative connotation to the use of
such substances, at least one survey indicated that adolescents are knowledge-
able about methods of obtaining performance-enhancing substances. In the
Monitoring the Future Study [26], from 1991 through 2006, twelfth graders
were asked how difficult they believed it would be to get steroids. The propor-
tion of adolescents responding that steroids were ‘‘fairly easy’’ or ‘‘very easy’’
to get remained fairly consistent, ranging from a high of 46.8% in 1992 to
a low of 39.7% in 2005.
Summary
Although the reports summarized here demonstrate a wide variance in
the prevalence of the use of performance-enhancing substances by gender,
age, athlete status, and type of substance, the use of performance-enhancing
substances is not uncommon among adolescent athletes who wish to im-
prove their athletic performance as well as among athletic and nonathletic
adolescents who wish to improve their appearance. More importantly, there
is no evidence to show a consistent decline in the prevalence of the use of
performance-enhancing substances in this population. Because adolescents
must interpret mixed messages posed by the medical community’s opposi-
tion to the use of performance enhancing-substances and competing societal
rewards for athletic prowess coupled with mass media’s body image market-
ing, there is a clear need for educational information that adolescents will
find objective, rational, and readily available.
As eloquently stated by the American Academy of Pediatrics Committee
on Sports Medicine and Fitness, pediatricians and other pediatric health
care advocates can serve as this much needed ‘‘voice of reason’’ [40]. Pedi-
atric practitioners cannot depend on a passive approach of community ed-
ucation programs or drug testing to curb the use of performance-enhancing
substances among adolescents. Rather, pediatric health care providers have
an opportunity to fulfill a positive role by gaining knowledge about the
recognition and management of performance-enhancing substance use
among adolescents and by inquiring about their use during routine health
maintenance visits.
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February 28, 2007.
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Consequences of Use of Anabolic

Androgenic Steroids
Marcel J. Casavant, MDa,b,c,*, Kathleen Blake, MDa,
Jill Griffith, PharmDc,d, Andrew Yates, MDa,e,
LaRae M. Copley, RPh, MD, PhDa,f
a
Department of Pediatrics, The Ohio State University College of Medicine,
370 West 9th Ave., Columbus, OH 43210, USA
b
Department of Emergency Medicine, The Ohio State University College of Medicine,
1654 Upham Drive Columbus, OH 43210, USA
c
Central Ohio Poison Center at Children’s Hospital, 700 Children’s Drive,
d
The Ohio State University College of Pharmacy, 500 West 12th Ave., Columbus,
OH 43210, USA
e
Division of Cardiology, Children’s Hospital, 700 Children’s Drive,
f
Department of Psychiatry, The Ohio State University Hospitals, 140 Neurosciences Facility,
1670 Upham Drive, Columbus, OH 43210, USA
Whether providing anticipatory guidance to the young adolescent

patient, conducting a preparticipation examination on a young athlete, or
treating a sick user of anabolic androgenic steroids (AASs), the primary
care physician must be familiar with the adverse consequences of the use
of these compounds. This article reviews the endocrine, cardiovascular, neu-
ropsychiatric, musculoskeletal, hematologic, hepatic, and miscellaneous
effects of AASs, highlighting effects reported in children and adolescents
and relying on consequences in adults when pediatric data are unavailable.
We rely heavily on case reports and series; prospective studies are rare for
technical and ethical reasons and are of questionable generalizability, given
the number of AASs and the variety of dose ranges and patterns of use. The
available data may underestimate the actual untoward effects because doses
* Corresponding author. Central Ohio Poison Center at Children’s Hospital, 700

Children’s Drive, E-265, Columbus, OH 43205.
E-mail address: [email protected] (M.J. Casavant).
678 CASAVANT et al
administered in clinical studies do not approximate the supraphysiologic

doses used by illicit steroid users.
Endocrine consequences
The adverse endocrine effects of AASs are best understood if one first
looks at the native effects of testosterone. Testosterone is responsible for
the in utero masculinization of internal genitalia, postnatal skeletal muscle
development, and the development of male secondary sexual characteristics.
In addition, testosterone is converted in peripheral tissues by 5-alpha-reduc-
tase to dihydrotestosterone (DHT), which contributes to fetal development
of external genitalia, prostate, and seminal vesicles. DHT acts in the cell
nucleus of target tissues, such as skin, male accessory glands, and the pros-
tate, exerting predominantly androgenic, but also anabolic, effects. Testos-
terone is converted by the enzyme aromatase to estradiol and estrone,
which are involved in the sexual differentiation of the brain, bone mass ac-
cretion, and fusion of the epiphyses at the conclusion of puberty, in addition
to feminizing effects [1]. Under normal physiologic circumstances, aroma-
tase has a limited role; however, with high-dose AAS use, this role increases,
and, therefore, so does the level of estrogens [2]. An antiestrogen effect may
be present as well with supraphysiologic doses of AASs. Excess AASs lead
to a down-regulation of androgen receptors and AASs then compete with
estrogens for the estrogen receptor. The net outcome of these two different
pathways is difficult to predict [3]. With this information, it is easier to un-
derstand the adverse outcomes of AAS use because many of the effects are
amplifications of physiologic effects.
Testosterone acts at the androgen receptor to increase protein synthesis;
it also has effects through conversion to DHT and estrogens. At normal
physiologic levels of testosterone, androgen receptors are saturated, and it
is believed that some of the effects of AASs may be through one or more
different mechanisms. Research has shown an antagonist effect at the gluco-
corticoid receptor at supraphysiologic levels that leads to an anticatabolic
effect [4]. Glucocorticoids influence glucose synthesis and protein catabo-
lism. The stimulation of glucocorticoid receptors by glucocorticoids leads
to increased protein breakdown in muscle. High-dose AASs may displace
glucocorticoids from the glucocorticoid receptor and inhibit muscle protein
breakdown that leads to an overall anabolic or muscle-building effect [5]. By
competing with glucocorticoids for the glucocorticoid receptor, AASs block
the depressed protein synthesis that usually occurs during stressful training.
AASs also exert some effect on the growth hormone (GH)–insulin-like
growth factor (IGF)-1 axis. There seems to be an androgen-induced stimu-
lation of GH secretion and a direct stimulation of hepatic IGF-1 synthesis.
IGF-l stimulates skeletal muscle formation, and GH exhibits anabolic
effects [6,7]. AASs act on osteoblasts to stimulate proliferation and differen-
tiation that may inhibit bone breakdown. There also may be some degree of
CONSEQUENCES OF USE OF ANABOLIC STEROIDS 679
‘‘placebo effect’’ that allows AAS users to train harder and increase muscle
mass as a result of the increased aggression, euphoria, and decreased fatigue
and recovery time that many AAS users report [2,4].
In men, chronic AAS use can lead to decreased endogenous testosterone
production and hypogonadotropic hypogonadism associated with testicular
atrophy. Chronic AAS abuse causes a decrease in gonadotropins, luteinizing
hormone (LH), and follicle-stimulating hormone (FSH) as part of the neg-
ative feedback system of the hypothalamic-pituitary-gonadal axis. LH and
FSH are needed for spermatogenesis so when these hormones are decreased,
there is a decrease in sperm count and mobility as well as an increase in the
number of morphologically abnormal sperm [2,3,8–10]. One study found
a 73% overall decrease in sperm count; three individuals had azoospermia
with chronic use of high-dose AASs. In individuals who did not experience
azoospermia, there was a 10% increase in the number of immotile sperm
and a 30% decrease in the number of motile sperm. Overall, fertility was
severely reduced [11]. Decreases in gonadotropins can be seen within 24
hours of beginning AASs. Infertility may result within months [2]. After
cessation of use, gonadotropin and testosterone secretion are suppressed
for months to years. Usually, the infertility is spontaneously reversible,
typically within 1 year of cessation of AAS abuse, but it may take longer
in long-term users [10]. At least one user of multiple AASs did not recover
fertility spontaneously and required treatment with LH-releasing hormone
to regain normal levels of testosterone and fertility [12]. Men also may ex-
perience priapism, impotence, prostatic hypertrophy, difficulty/pain with
urination, and a possible increased risk for prostate cancer [13]. The risk
for these consequences increases with dose and duration of use [6].
Testosterone is converted to estrogens by aromatase and to DHT by way
of 5-alpha reductase. The estrogens lead to feminizing effects in men, such as
gynecomastia and an increase in voice pitch. Although the breast tissue that
develops becomes softer and less prominent after cessation of AAS use, this
effect may be irreversible and require surgical correction [8,10]. Men experi-
ence male-pattern baldness, acne (mostly on the trunk), and altered libido
[9], which likely is due to the effects of DHT. Acne is the result of androgenic
stimulation of sebaceous glands [1].
The sexual and reproductive effects of AAS are more dramatic in women
[14]. Although AASs have been developed to try to minimize androgen
effects, all AASs exert some degree of virilizing effects if given for long
enough and in sufficiently large doses. Virilization occurs with AAS use
by women, regardless of the type used. Early effects include acne, deepening
of the voice, and changes in libido. Deepening of the voice occurs as a result
of laryngeal hypertrophy. Long-term use can lead to clitoral enlargement,
male-pattern baldness, and alterations in pubic hair. Other virilizing effects
include decreased body fat, breast atrophy, amenorrhea or oligomenorrhea,
uterine atrophy, and hirsutism [1,13]. The changes in menses are due to
suppression of the hypothalamic-pituitary-gonadal axis [1]. Some of these
680 CASAVANT et al
effects may be irreversible with chronic use [1,2,6,9,10,13,15]. AASs may act
as a teratogen [13].
Children seem to be the most susceptible to the adverse effects of AAS
use [15]. Children and adolescents experience accelerated maturation associ-
ated with changes in physique and earlier development of secondary sexual
characteristics [13]. An additional concern with adolescents is premature
closure of growth plates in long bones, leading to a decrease in final height;
this likely is due to aromatization to estrogens [1,2,9]. Precocious puberty in
boys and contrasexual precocity in girls also can occur [15]. With
adolescents, some of the effects may become irreversible with chronic use,
particularly the virilizing effects in young women [6,14,15].
Thyroid cells have androgen receptors, and AASs may directly influence
thyroid function [16]. Some studies have shown effects on thyroid function,
including a decrease in total triiodothyronine, thyroxine (T4), and thyroid-
binding globulin. Some studies have shown an increase in thyrotropin and
free T4, whereas others have shown no change in these concentrations. It is
unclear if this relative impairment in thyroid function leads to a clinical
effect. These changes may be due to direct block of thyroid hormone
release or synthesis or some other mechanism [16–18]. AASs decrease
glucose tolerance and increase insulin resistance, which lead to hyperin-
sulinism and secondary diabetes mellitus with type II symptoms
[2,3,9,11,13].
Many AAS users take additional drugs or supplements to counteract the
adverse effects of AASs [19]. Among 500 users of AASs, more than 50%
reported taking clomiphene, antiaromatases (eg, anastrozole), or the anties-
trogen tamoxifen; 40% admitted to using human chorionic gonadotropin
[4]. Human chorionic gonadotropin and clomiphene are taken at the end
of or after an AAS cycle to reduce hypogonadotropic hypogonadism and
reverse testicular atrophy and infertility. Some studies have shown mainte-
nance of spermatogenesis with the concurrent use of human chorionic
gonadotropin, but there are still significantly more abnormal and hypoki-
netic spermatozoa. The maintenance of spermatogenesis by human cho-
rionic gonadotropin occurs without an increase in FSH. The low FSH
concentration explains why sperm quality remains abnormal [4]. The effect
on offspring is unknown [20]. The side effects of human chorionic gonado-
tropin include hyperglycemia, insulin resistance, decreased thyroid function,
adrenal insufficiency, carpal tunnel syndrome, arthralgia, myopathy, pan-
creatitis, hepatotoxicity, and an increased risk for certain malignancies
[21]. Clomiphene stimulates the release of gonadotropins and is used in
women with infertility; however, clomiphene may not increase serum gonad-
otropins when taken by power athletes during an AAS cycle [20]. Antiaro-
matase or antiestrogen drugs, such as anastrozole and tamoxifen, are taken
to counteract the effects of aromatization of the AAS to estrogens (eg,
gynecomastia). There is no data to support their effectiveness, and they
also have side effects [2].
Cardiovascular consequences
The most common cardiovascular consequences of AAS include athero-
sclerosis (secondary to changes in cholesterol metabolism and platelet func-
tion), hypertension, cardiac hypertrophy, impaired cardiac function, and
sudden death [22–24].
AAS use causes metabolic derangements that increase the risk for athero-
sclerosis and thrombus formation. Studies using animal models and various
steroid regimens have demonstrated changes in serum cholesterol levels with
decreased high-density lipoprotein and increased low-density lipoprotein,
both promoting atherosclerotic and peripheral vascular disease [2,25,26].
Cholesterol alterations vary among different AASs; alkylated agents (eg,
stanozolol) cause greater changes than testosterone [27].
AAS use also increases platelet reactivity without an associated thrombo-
cytosis; this has been proposed as an etiology for some of the myocardial
infarctions, strokes, and peripheral vascular disease events reported in
otherwise healthy individuals [28,29]. AAS use also increases serum C-reac-
tive protein (CRP), reflecting an inflammatory state that may contribute to
atheroma formation and peripheral vascular disease [30]. Conversely,
changes in lipid metabolism may be protective from atheroma formation
because of a reduction in lipoprotein A [25]. Many studies show that
AASs cause abnormal cholesterol profiles, increased CRP, and increased
platelet reactivity. It is difficult to quantify the change in risk, but one study
estimates AASs triple the cardiovascular risk [31].
Systemic hypertension is a side effect of medical steroid administration
and may require antihypertensive therapy; therefore, high-dose ASA use
also should result in systemic hypertension. This is found in some reports
[23,32], but not consistently [33]. AAS-induced hypertension may be related
to vascular endothelial response [34], increased responsiveness to catechol-
amines [35], and increased renin production [36]. The magnitude and inci-
dence of hypertension likely are related to dosage and to the specific AAS.
Recent echocardiographic studies of AAS users demonstrate an increase
in septal and left ventricular posterior wall thickness. This hypertrophy is
greater in weight-trained individuals using AASs than in weight-trained
individuals provided placebo or not using AASs [34,37–41] and persists
for years among former AAS users [40]. Cardiac wall hypertrophy may
not occur after short-term ASA use [26,42,43].
AAS use impairs measures of diastolic function (eg, isovolumetric relax-
ation time [37] and altered tissue Doppler imaging of the left ventricle
[44,45]) that reflect impaired relaxation and altered filling during diastole.
Possible etiologies for impaired diastolic function include increased collagen
content [46] or areas of focal necrosis, seen at autopsy of AAS users [47,48].
Cardiovascular performance also can be assessed by way of formal exer-
cise testing; although AASs may increase bulk and strength, they do not im-
prove endurance. Despite having similar aerobic and weight-training
682 CASAVANT et al
schedules as control subjects, AAS users had a significantly decreased max-

imum oxygen consumption (VO2max; an index of metabolic and cardiovas-
cular endurance ability) [38]. Impaired diastolic function could contribute to
decreased VO2max.
Sudden death is the most frightening consequence of AAS use. The
etiology of these events likely is multifactorial, with AAS use contributing
to the observed pathology. There are case reports of myocardial infarctions
[49], stroke, and peripheral vascular obstruction [50] from thrombus that
likely are related to the changes in platelet function, inflammation, and cho-
lesterol metabolism discussed above. Autopsies of 34 users of AASs found
chronic cardiac changes consisting of cardiac hypertrophy, myocardial
fibrosis, and coronary artery atheromatous changes in 12 victims, although
these were believed to contribute to the deaths of only 2 victims [48].
Many sudden death events among AAS users have been due to ischemia
secondary to coronary artery disease; however, there is a report of ventric-
ular tachycardia during exercise testing of an AAS user who had myocardial
fibrosis on biopsy [51]. Other case reports of sudden death demonstrate
diffuse, patchy fibrotic changes in the myocardium of AAS users without
coronary artery atherosclerosis [47]. The presence of scar or infiltrative pro-
cesses is commonly believed to be a cause for arrhythmia. The exact cause of
sudden death in AAS users is unclear but likely is due to ischemia or
arrhythmia.
Neurologic and psychiatric consequences

In a recent study in middle and high school students, 5.4% of boys and
2.9% of girls had used steroids in the previous year [52]. Use in boys was
associated with higher rates of depressed mood, prior suicide attempts,
greater substance abuse, and lower self-esteem. Another study of adoles-
cents suggested that steroid use was associated with other high-risk behav-
iors and was less likely to be an isolated behavior [53]. Although pediatric
data are scarce, psychiatric, behavioral, and neurologic consequences of
AAS use are well described [54–58].
Many case reports describe psychiatric symptoms in patients using AASs
[48,59–63]. Reports of suicide include at least one patient who did not have
a personal or family history of depression or suicidal behaviors [59]. In one
series of eight suicides in AAS users from Sweden, collateral information
was sought, and when possible, psychologic autopsies were performed
[60]. Retrospectively, psychiatric symptoms, such as irritability, aggressive-
ness (‘‘roid rage’’), mood swings, decreased impulse control, and increased
energy were noted during AAS use; however, the series included men who
had prior psychiatric syndromes, personality disorders, and other substance
abuse. Another report showed homicidal or near homicidal behavior in
three men during AAS use [61]. None had a history of psychiatric illness
or violence before AAS use, and all met the Diagnostic and Statistical
Manual of Mental Disorders, Revised Third Edition criteria for manic epi-
sode during use. Two of the three men experienced depression and suicidal
ideation upon the abrupt discontinuation of use. Although it is tempting to
attribute this behavior to AAS use, this is a small set of case studies and as
the investigators note, legal ramifications for the patients may have led to
exaggeration in their reports. A series of 34 deaths of AAS users revealed
nine victims of homicide, 11 suicides, 12 accidental deaths, and 2 deaths
of indeterminate cause [48]. The homicide victims showed high levels of
aggression; in most of the suicide and accidental deaths, impulsive and vi-
olent behaviors had been noted by family or physicians. Most of the cases
of accidental death were related to polysubstance overdose; four of the vic-
tims were heroin addicts who had histories of only sporadic or moderate
AAS use.
One study identified seven AAS users and evaluated them every 2 weeks for
as long as 44 weeks [62]. During clinic visits, subjects reported their AAS use,
and assessments, including the Beck Depression Inventory (BDI), Profile of
Mood States Questionnaire, and Buss-Durkee Hostility Scale, were adminis-
tered. Scores fluctuated over time, but the fluctuations were not associated
with AAS use. Additionally, most of the subjects had a history of major de-
pression, and five reported abusing other substances. A larger study (n ¼ 160)
comparing AAS-using athletes with nonusing athletes revealed that far more
AAS users displayed mood disorders compared with nonusers and AAS users
during periods of no use [64]. Another study describing 41 AAS-using athletes
reported that 22% displayed mood syndromes during use, which was signif-
icantly higher than the rate observed during periods of no exposure [65]. Ad-
ditionally, this study reported that 12.2% displayed psychotic symptoms
during use compared with 0% during AAS-free periods. Another naturalistic
study comparing weight-lifting AAS users with nonusers correlated supranor-
mal testosterone levels with subjective and objective measures of aggression
[66]. Cluster B personality traits, including antisocial, borderline, and histri-
onic, were more prominent in AAS users.
Attempts have been made to study the effects of AASs in humans in
prospective laboratory-controlled settings. One double-blind study adminis-
tered placebo followed by low-dose (40 mg/d) and then high-dose (240 mg/d)
methyltestosterone to 20 normal healthy men without psychiatric disease
or history of AAS use [67]. During the high-dose period (3 days), distract-
ibility, irritability, and energy level increased significantly, and there was
a trend for an increase in anger and violent feelings. One subject developed
acute mania, and another developed hypomania. Subtle, but significant,
elevations in the BDI, Hamilton Depression Rating Scale, Brief Psychiatric
Rating Scale, and hostility, anxiety and somatization on the Symptom
Checklist (SCL-90) were observed. In follow-up studies, an increase in
aggressiveness correlated with an increase in free T4, an increase in forget-
fulness and distractibility correlated with total testosterone levels, and an
increase in activation symptoms (energy, sexual arousal, and diminished
684 CASAVANT et al
sleep) correlated with cerebrospinal fluid 5-hydroxyindole acetic acid levels

[18,68]. In another placebo-controlled cross-over study of 50 men free of
substance abuse or psychiatric illness, increasing levels of testosterone cy-
pionate were administered over 6 weeks [69]. Aggressive responses on the
Point Subtraction Aggression Paradigm and increased manic scores on the
Young Mania Rating Scale were demonstrated; 84% showed minimal psy-
chiatric symptoms, 12% became mildly hypomanic, and 4% became mark-
edly hypomanic. An additional study evaluated testosterone cypionate
over 14 weeks at levels up to 500 mg/wk in healthy men free of psychiatric
illnesses and personality disorders; it found minimal psychologic effects in
most men, but one adverse psychiatric effect resembled mania [70]. Addi-
tionally, some studies showed no changes in psychometric measures in
healthy men who were administered AASs [71]. All of these studies used
doses lower than those typical in AAS use, so they likely underestimated
the psychiatric consequences of AAS.
Musculoskeletal consequences
Muscle mass seems to be affected greatly by AAS dosing. Higher doses
have been shown to garner increases in muscle mass [2]. Muscle mass gains
are larger when AAS use is combined with strength training compared with
AAS use alone. AASs increase the number of myonuclei. Strenuous exercise
seems to increase the number of androgen receptor sites on the muscle. Body
weight increases can be in the range of 2 to 5 kg after 10 weeks of AAS use.
With more androgen receptors present in the upper regions of the body, the
neck, shoulders, thorax, and upper arms gain the most new bulk [2]. The
thigh muscles require higher doses to show measurable increases in mass
and are not as likely to show increases in the number of androgen receptors
[72,73]. Upon discontinuation, muscles shrink and strength declines over
a period of 6 to 12 weeks.
Androgens stimulate osteoblast proliferation and differentiation and
inhibit the osteoclast. At the start of puberty, androgens stimulate bone
formation. At the end of puberty, they induce epiphyseal closure. In adult-
hood, the sex hormones slow the rate of bone remodeling, protect against
bone loss, encourage bone formation, and increase bone density [2].
The adolescent AAS user risks an increased rate of muscle strains or
ruptures [3,74]. Unlike muscles, tendons do not increase in strength so
with more intense training, they have a greater risk for rupture [75–77]. In
a developing adolescent, the growth plate cartilage is considered the ‘‘weak-
est link,’’ and generally is more prone to injury compared with ligaments
[78]. A rapid increase in the intensity, frequency, or volume of training is
noted consistently in athletes who present with overuse injuries. Injury to
the growth plate from weight training has long been a subject of contro-
versy; power lifting may increase the risk for injury, even in adolescents
not taking AASs [79,80]. Of particular concern in this age group is

premature physeal closure resulting in decreased adult height [3].
AAS users also are at risk for rhabdomyolysis or acute skeletal muscle
destruction. Rhabdomyolysis has been reported after vigorous weight lifting
and may be more likely in patients escalating and supplementing weight train-
ing with AASs [81,82]. Physicians should consider the creatine phosphokinase
and gamma-glutamyl transpeptidase levels as essential elements in distin-
guishing muscle damage from liver damage when evaluating enzyme eleva-
tions in patients who use anabolic steroids [83].
Hematologic consequences
Before the introduction of recombinant human erythropoietin, AASs
were used in the treatment of anemias. AASs increase renal synthesis of
erythropoietin. They also promote erythropoietic stem cell differentiation.
Subsequently, hemoglobin and hematocrit may become elevated, which
could result in erythrocytosis or sludging [13].
Two adult cases of intramuscular testosterone–induced polycythemia
were reportedly reversed by switching to transdermal testosterone [84];
however a 65-year-old man developed hypertension and polycythemia dur-
ing daily testosterone application to his scrotum for 5 years (estimated dose
10 mg/d). Polycythemia and hypertension resolved when testosterone was
discontinued [85].
Mild, but significant, increases in mean red blood cell, hematocrit, hemo-
globin, and white blood cell concentrations in 33 men were reported follow-
ing intramuscular testosterone enanthate, 200 mg every 3 or four weeks for
24 weeks [86]. The men remained asymptomatic.
Increased platelet count and aggregation also may occur. AASs may
potentiate platelet aggregation and be thrombogenic in humans [30,87];
however, another study found only nonsignificant trends, including throm-
bocytosis and increased aggregation [28].
Suppression of clotting factors II, V, VII, and X and bleeding in patients
receiving concomitant anticoagulant therapy have been reported with
testosterone [88,89]. Case reports demonstrated that coadministration of
oral anticoagulants and 17-alkylated androgens (fluoxymesterone, oxandro-
lone, oxymetholone, methyltestosterone, methandrostenolone, stanozolol)
resulted in a prolonged prothrombin time and hemorrhages; AASs may
reduce the need for therapeutic anticoagulants by 25% [90].
Hepatic consequences
Multiple hepatic consequences of AAS use are reported, ranging from
benign and reversible to permanent and life threatening. None is universal;
the incidence of each may vary with dosage, length of use, and specific AAS
chosen; alkylated AASs are particularly hepatotoxic [27]. Cholestasis is
686 CASAVANT et al
common, but often is asymptomatic or associated with subclinical elevation of

hepatic transaminases [91]. Hepatocellular hyperplasia and elevations of
transaminases, conjugated bilirubin, alkaline phosphatase, and lactate dehy-
drogenase occur [27]. Early elevation of transaminases without increasing
gamma-glutamyl transpeptidase may represent muscle damage; serum
creatine phosphokinase should be measured [2]. Dose-dependent jaundice is
common after several months of AAS use and usually resolves after
discontinuing AAS use [10]. Steroid ‘‘cycling’’ is believed to reduce cholestasis
and jaundice. Benign hepatic adenomas and rarer hepatocellular carcinoma
have been reported in association with AAS use [2,3,10,27]. Regression of ad-
enomas after avoidance of AAS has occurred; death from carcinoma also has
occurred [27,91]. Peliosis hepatis is the presence of blood-filled cavities in the
liver; this has occurred with iatrogenic AAS use and with AAS abuse. Some-
times reversible, peliosis hepatis can cause liver failure, and the rupture of
these cysts can cause fatal internal hemorrhage [15,27,91].
Miscellaneous consequences
Acutely, injections of AAS may lead to bacterial or viral infections from
use of contaminated needles or lack of sterile technique. Of concern with
deep intramuscular administration are local tissue reactions to the oil dilu-
ent, cellulitis, as well as bacterial and fungal abscesses. These infections are
related primarily to nonsterile injection technique and shared injection
equipment; they are avoidable [92]. Other skin findings may include in-
creased keloid formation and injection track marks.
Users of high-dose AAS regimens report a withdrawal syndrome, includ-
ing steroid craving, depression, suicidality, irritability, muscle aches, and
autonomic instability including hot flashes, nausea and vomiting, tachycar-
dia, and hypertension [3,27].
Adolescent users could be susceptible to all of the above adverse effects.
There exists a great division between the conviction of athletes that AASs
are effective and the conviction of clinicians that they are harmful. Rather
than teaching that these products are ineffective, which will only convince
the patient of the clinician’s unreliability, it may be more prudent first to ac-
knowledge the common increase in muscle mass that accompanies AAS use,
and then to teach about the common, manageable, and minor side effects
and the more severe, often irreversible, unpredictable toxicities. It is hoped
that coaches, trainers, and clinicians share the same goal of a drug-free sports
experience for young athletes; showing role models who achieve their physical
goals without AAS use can be helpful in providing realistic alternatives to drug
use [3].
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Erythropoietin and Other

Blood-Boosting Methods
Thomas L. Pommering, DOa,b,c,*
a
Departments of Pediatrics and Family Medicine, The Ohio State University
College of Medicine, Columbus, OH, USA
b
Sports Medicine Program, Columbus Children’s Hospital, Columbus, OH, USA
c
Tour de Grandview Professional Cycling Race, Columbus, OH, USA
Why do athletes use performance-enhancing substances (PESs)? It is not

a new phenomenon. PESs have been a part of sports competition since as early
as 776 BC when Olympians used substances, such as mushrooms, dried figs,
and strychnine, to gain an advantage [1]. Later, heroin, cocaine, and morphine
were added and probably did more harm than enhancement [2,3]. Yet, modern
athletes are still willing to risk their health, reputation, and even their team or
country’s honor to gain an athletic advantage.
Nothing illustrates this better than an often-referenced survey published in
1997 in which Olympic hopefuls were asked two simple questions: The first, ‘‘If
you were offered a banned performance-enhancing substance that guaranteed
that you would win an Olympic medal and you would not be caught, would
you take it?’’. Remarkably, 98% of the 198 athletes surveyed reported
‘‘yes.’’ But even more remarkable was the answer to the second question,
‘‘Would you take a banned performance-enhancing drug that guaranteed
you would win an Olympic medal and you will not be caught, you win every
competition for the next 5 years, but then will die from adverse effects of the
substance?’’ More than 50% of the athletes still reported ‘‘yes’’ [1,4–6].
The word ‘‘doping’’ was used in the 1860s to describe a drug used for horse
racing that consisted of opium and narcotics [7]. With human athletes, ‘‘blood
doping’’ originally referred to a process whereby athletes increased their oxy-
gen-carrying capacity by receiving blood transfusions from previously do-
nated blood to increase their hematocrits a few days before competition [5].
The first report of blood doping in a controlled experiment was reported in
* Children’s Sports Medicine Center, 584 County Line Road West, Westerville, OH
43082.
692 POMMERING
1947 [8,9]. Today, ‘‘blood doping’’ is used more synonymously with cheating
of any kind, including any of the various blood-boosting methods or classes of
ergogenic aids that are available to athletes. Advances in genetic medicine
have allowed athletes to raise their level of sophistication significantly by using
PESs that are virtually undetectable. The most ubiquitous illegal method of
increasing oxygen-carrying capacity in athletes is by the use of recombinant
human erythropoietin (rHuEPO). If athletes are caught using rHuEPO, sanc-
tions can range from 2-year suspensions to lifetime bans from competition.
The role of oxygen transport in athletic performance

The body’s oxygen transport system brings oxygen to working muscle
through a cooperative effort of the circulatory and respiratory systems.
There are two ways to improve oxygen transport. The first is to stimulate
the natural oxygen carrier, hemoglobin (Hb). The second way is to use other
types of oxygen carriers to fill the role of Hb [10]. Athletic endurance is
determined by an athlete’s maximum oxygen uptake (VO2max); by the
1930s, it was clear that champion endurance athletes had extremely high
measurements of VO2max [11,12]. By the 1970s, it also was evident to the
scientific world that maneuvers that increased total body Hb also increased
VO2max [12]. The athletic world had been exploiting this fact for at least
a decade through the practice of blood doping [5,13]. Hence, the modern
era of scientifically based performance enhancement for athletes was born.
Physiology of erythropoietin
Structure and function
Erythropoietin (EPO) is a naturally occurring glycoprotein hormone that
regulates red blood cell (RBC) production. The peritubular fibroblast cells
of the renal cortex produce 90% of the body’s EPO, whereas mainly the
liver, but also the brain, uterus, and lung account for the remaining 10%
[9,14,15]. Within the bone marrow, EPO binds various receptor sites, of
which colony-forming unit erythroid cells seem to be most sensitive
[16,17]. Subsequently, progenitor cells proliferate into normoblasts and
eventually, reticulocytes. Regulation of EPO is controlled by a gene on chro-
mosome 7 (band7q21). The transcription of this gene is controlled by hyp-
oxic inducible factor, which responds to tissue hypoxia [15,18]. Strenuous
exercise alone does not seem to affect EPO levels significantly [16]. New
circulating erythrocytes are seen within 1 to 2 days after plasma EPO levels
increase [14].
Clinical applications
In June 1989, the first rHuEPO product was marketed in the United States.
It was isolated and purified from Chinese hamster ovaries and reproduced
ERYTHROPOIETIN AND OTHER BLOOD BOOSTING 693
using DNA recombinant techniques [18]. Until recently, there were two forms
of rHuEPO commercially available in the United States: epoetin alfa and
epoetin beta. Now, there are at least four erythropoietic isoforms available
worldwide that are synthesized by modifying the rHuEPO molecule.
rHuEPO is used to treat anemias related to renal failure, chemotherapy,
HIV infection, prematurity, hemoglobinopathies, autoimmune disease, and
malignancies, and it is used in patients who undergo surgery who are not can-
didates for blood transfusion (eg, Jehovah’s Witness). It can be administered
intravenously (IV) or subcutaneously (SQ). IV dosing results in a shorter
half-life and shorter duration of peak plasma levels, which makes SQ admin-
istration easier, more effective, and less expensive. The therapeutic range for
epoetin alfa is 50 to 300 units/kg given two to three times weekly. Therapeutic
increases in hematocrit occur after 2 to 6 weeks, depending on baseline levels
and existing iron stores [15,18].
Adverse effects
The most common side effects are headache, fever, nausea, anxiety, and
lethargy. Hypertension and hyperkalemia are seen in up to half of patients
who are on dialysis [18]. More concerning side effects are associated with hy-
perviscosity syndromes related to high hematocrits and include myocardial
infarction, seizure, stroke and other thromboembolic events, and sudden
death [18–21]. When combined with dehydration, athletes are especially at
risk for this potentially lethal scenario (see later discussion). Finally, another
rare, but serious, side effect is an autoimmune form of pure red cell aplasia
that has been linked with SQ administration of rHuEPO [18,22].
Recombinant human erythropoietin

Tainted history
The popularity and effectiveness of rHuEPO in elite endurance athletes is
demonstrated by a long list of anecdotes associated with its misuse during
international competition. When the average speed of the cyclists racing
in the Tour de France began to increase suddenly during the 1990s, rumors
of rHuEPO use began to circulate. The gene that produces EPO was cloned
in 1985, and rHuEPO was available in Europe by 1987 [23]. Between 1987
and 1991, more than 20 Dutch and Belgian cyclists died at restdsome of
them while sleepingdas a result of unexplainable cardiac arrest [13,14,24].
Between 1997 and 2000, 18 more cyclists died from pulmonary embolisms,
stroke, and myocardial infraction [5]. Finally, suspicions of rHuEPO use in
professional cyclists competing in Europe were confirmed during the 1998
Tour de France; boxes of ampules containing rHuEPO were found in
team vehicles and the personal rooms of riders from many of the biggest
and most successful teams [14]. It became embarrassingly clear that
694 POMMERING
rHuEPO use in elite professional cyclists was organized, widespread, and

sophisticated.
Ergogenic effectiveness of recombinant human erythropoietin

The ability of rHuEPO to enhance endurance is impressive. Athletes can
improve their overall performance by as much as 10% to 15% [25]. Al-
though there is a paucity of literature documenting the ergogenic potential
of rHuEPO in elite athletes, what has been published using moderately
trained subjects shows similarly effective results when comparing rHuEPO
with RBC infusion [5]. Specifically, Ekblom and Berglund [26] showed
similar increases in VO2max and time to exhaustion on a treadmill run after
several weeks of rHuEPO administration compared with an acute infusion
of RBCs. In addition, Audran and colleagues [27] demonstrated a significant
increase in VO2max, ventilatory threshold, and a decrease in maximal heart
rate after only 25 days of rHuEPO administration.
Detection of recombinant human erythropoietin

The International Olympic Committee (IOC) added rHuEPO to its list of
banned substances in 1990, even though all forms of blood doping had been
officially prohibited since 1984 [17,28,29]. The use of rHuEPO also is banned
by the US Olympic Committee and the National Collegiate Athletic Asso-
ciation [18]. The challenges associated with detecting rHuEPO lie in the
fact that it is almost identical in structure and metabolism to endogenous
erythropoietin and it has a rapid half-life (4–9 hours for IV administration
and 24 hours for SQ administration), allowing it to clear the body within 2
to 3 days [18,29,30].
Despite justified suspicions of rHuEPO use in cycling and the inability of
current methods to detect its use [31], in 1997, the governing body of the
International Cycling Union (UCI) enacted hematocrit cutoffs for male
(50%) and female (47%) cyclists while more reliable methods of detection
could be developed [14,18]. The hematocrit cutoffs were based on existing
normative data on elite athletes, taking into consideration the expected effect
of dehydration, in an attempt not to exclude athletes with normal variations
but to protect athletes from danger [32]. Anyone over that limit would be
considered ‘‘unfit to race’’ and could not compete for 2 weeks, although
they were not subjected to official sanctions.
To circumvent this, an athlete could inject rHuEPO every 2 to 3 days
over 3 to 4 weeks, along with some form of iron supplementation, to get
a desired effect and then reduce the dose to match the basal rate of endog-
enous EPO production to maintain one’s hematocrit just below the ‘‘legal
limit.’’
During the 2000 Sydney Olympics, the IOC approved the use of a test
developed by the Australian Institute of Sport to detect rHuEPO users.
The test relied on mathematical models applied to the measurements of in-

direct blood markers associated with rHuEPO use, such as soluble transfer-
rin, reticulocyte percentage, and EPO or Hb levels. This test produced an
‘‘ON-model’’ that was designed to identify current or recent users and an
‘‘OFF-model’’ for users weeks after stopping treatment [14,17,33,34,35].
Although this method was quick, inexpensive, and could use existing tech-
nology, it had some major drawbacks, one of which was the fact that a re-
quired ‘‘B’’ blood sample could not be preserved reliably for confirmatory
testing at a later date because of the instability of whole blood, even with
freezing. Thus, it was used only as a screen to decide when to apply a
new testdthe Lasne test, developed earlier that yeardthat specifically could
detect rHuEPO in the urine [36].
Just before the 2000 Sydney Olympics, the National Anti-Doping
Laboratory in France developed a direct test for rHuEPO that is based
on the fact that the exogenous isoforms of rHuEPO are slightly more acidic
than endogenous EPO [36]. Using two techniquesdisoelectric focusing and
immunoblottingdit was possible to distinguish between natural EPO and
the four current isoforms of synthetic EPO plus a newer analog, darbopoie-
tin. Disadvantages of the test are that it is labor intensive, taking 3 days to
obtain a final result [35], and expensive, at least $130 per test [31]. Also,
because of the short half-life of rHuEPO, the urine sample has to be
collected within 2 to 3 days of rHuEPO use to be accurate [18,31]. More re-
cently, researchers reported on a false positive detection in a postexercise,
protein-rich urine sample [37]. To the author’s current knowledge, this is still
the test of choice for detecting rHuEPO use in elite athletes.
Other blood-boosting methods

High-altitude training and altitude tents
Oxygen binding to Hb is determined by the partial pressure of oxygen in
the plasma (pO2). Additionally, in environments of low pO2, Hb modifies
itself to bind oxygen more efficiently [9]. Using this concept, altitude is used
as a natural stimulus for erythropoiesis. It requires 3 to 4 weeks before a re-
sponse is seen [10] and is ‘‘legal.’’ Despite a paucity of randomized, controlled
studies, some form of this technique (‘‘sleep high and train low’’ or vice versa)
is practiced often by elite endurance athletes. For those athletes who are
geographically challenged, hypobaric chambers or tents that simulate alti-
tudes of 9000 to 13,000 feet can be purchased for about $5000 to $10,000.
Blood doping
During the 1967 Olympics in Mexico, an elite cyclist broke the outdoor
1-hour cycling record. He was reported to have been accompanied by an
entourage of two cardiologists and eight men aged 18 to 20 years, chosen
several months before the games because of their blood type compatibility
696 POMMERING
[9]. Autologous or heterologous blood transfusions were used most preva-

lently by athletes during the 1970s and 1980s, until the risk for blood-borne
infections became more apparent. The IOC banned this practice in 1976
[10]. With the Lasne test now available, this practice has resurfaced as an
option for some athletes. Currently, only heterologous blood transfusions
are detectable.
Novel erythropoiesis-stimulating protein (darbepoietin)

Novel erythropoiesis-stimulating protein was developed by increasing
the carbohydrate content of EPO, giving it a longer half-life and enhanced
biologic activity, and, thus, allowing less frequent injections [9,10]. The re-
sult is an EPO analog named darbepoietin. Three athletes were excluded
from the Olympic Games at Salt Lake City for darbepoietin use [10].
Artificial oxygen carriers

Artificial oxygen carriers or blood substitutes were designed to serve as
a temporary replacement for transfused RBCs. Their potential clinical appli-
cations include RBC replacement during surgery and emergency resuscitation
and as a therapeutic adjunct treatment for chemotherapy [38]. Although
banned in international competition, these agents are not tested for routinely,
except during exceptional circumstances [10]. Elite cyclists are notorious for
their abuse. They are classified into two general categories: hemoglobin
oxygen carriers (HBOCs) and perfluorocarbon emulsions (PFCs).
Hemoglobin oxygen carriers

Several HBOCs are available for human and veterinary use. There is little
published data on the human ergogenic potential of HBOCs [38]. One recent
study did not find a significantly positive effect on endurance performance
or VO2max with one particular form of HBOC, but it did describe hyperten-
sion as a significant side effect [39]. Other known adverse affects include gas-
trointestinal hypertonicity and potentially fatal renal toxicity [38].
Perfluorocarbon emulsions
Chemically related to the commercial product, Teflon, this chemically
inert synthetic liquid can dissolve oxygen more than 100 times per equal vol-
ume of plasma [38]. This was demonstrated spectacularly in 1966 when a rat
was able to survive for hours while totally immersed in an oxygen-saturated
PFC solution [38,40]. Without concomitant oxygen supplementation, PFCs
likely would not benefit endurance athletes [10]. Side effects include flu-like
symptoms, thrombocytopenia, allergic reactionsdand more seriouslydhep-
atosplenomegaly, organ failure, and immune compromise (because PFCs
are inert and can only be removed by the reticuloendothelial system) [38].
Gene doping
Gene doping was added to the prohibited list by the World Anti-Doping
Agency in 2005 and was defined as the ‘‘non-therapeutic use of cells, genes,
genetic elements, or modulation of gene expression, having the capacity to
enhance human performance’’ [41,42]. This can be accomplished with the
use of biologic vectors (viruses), chemical sources (liposomes), or physical
methods (direct injection of gene) [41]. As with all forms of gene doping,
the potential problem with EPO gene therapy is with gene overexpression
leading to excessive erythropoiesis and its deadly consequences. Gene dop-
ing is expected to be seen by the 2008 Beijing Olympic Games [29,41,43].
There are no effective ways to identify or prevent gene doping.
The reality
Current testing for rHuEPO or other advanced blood-boosting tech-
niques is inadequate and easy for athletes to ‘‘beat.’’ The ‘‘dopers’’ continue
to stay a few steps ahead of the ‘‘testers.’’ Drug testing is extremely expen-
sive, and its methods are subject to the rigors of scientific validation to pro-
tect the athletes who are competing fairly. Funding challenges for new tests
and barriers to testing still exist [26,44]. Perhaps a more reasonable ap-
proach is for elite athletes to have a type of ‘‘hematologic passport’’ [34],
coupled with longitudinal laboratory monitoring, to document where
athletes’ normal or ‘‘clean’’ baseline hematologic parameters should be
[17,45]. As this article was being written, professional cycling teams are
adopting this policy in a first sincere attempt by a team owner in profes-
sional cycling to clean up the sport. Although there remains the tremendous
financial incentives attached to success in sports competition, there will
always dangle the ‘‘doping carrot.’’
Final thoughts
For now, the use of rHuEPO in young athletes is not believed to be nearly
as prevalent as with their adult counterparts; however, it is known that young
users typically minimize the known health risks associated with using ergo-
genic aids, which puts them at particular risk for future use and subsequent
harm [46]. Early recognition by physicians, parents, and coaches followed
by honest education and ‘‘thoughtful discouragement’’ has been recommen-
ded as a strategy to dissuade adolescents away from ergogenic aids [46–48].
Some investigators have advocated a position that by allowing and moni-
toring PESs, the athlete’s health and safety would be improved [3]. This phi-
losophy should be denounced; it would give young athletes and their
supporters a new, unparalleled, and seemingly legitimate incentive to risk their
health in their quest for the opportunity of future sporting success. As physi-
cians, parents, and coaches, how would we then counsel our young athletes?
698 POMMERING
Summary
The use of rHuEPO to illegally enhance performance and its health risks
are well documented. Testing methods exist, but they can easily be outwit-
ted. Today’s athletes also can choose from other blood-boosting methods
and often use these concomitantly with rHuEPO. Most notable is the emerg-
ing genetic technology, which may, as soon as the 2008 Olympic Games, an-
tiquate all other ‘‘doping’’ methods as athletes continue to place themselves
at the ultimate risk in search of success and glory.
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The World Anti-Doping Program

and the Primary Care Physician
Richard L. Hilderbrand, PhD
United States Anti-Doping Agency, 1330 Quail Lake Loop,
Suite 260, Colorado Springs, CO 80906, USA
Over the past 4 decades, the role of the physician in the treatment of athletes
has changed significantly. The traditional role of the physician in sport was the
immediate protection of the health of the athlete, including treatment of in-
juries and illness. Unfortunately, some physicians have crossed the line
from legitimately restoring health to the improper use of medications to en-
hance performance. This may happen because the line is not always clear, es-
pecially in the presence of the growth of preventive and wellness medicine, or it
may be the result of a rogue physician working with an athlete to achieve im-
proper objectives. In any case, the role of physicians in aiding athletes who
want to dope has expanded [1,2]. With the pharmaceutical and technological
developments of the recent past, the athletes who are doping (Box 1) have be-
come dependent on physicians and other medical professionals to achieve
their maximum results. This is a matter of grave concern, and the US Anti-
Doping Agency (USADA) is working with medical professionals and others
to establish ethical standards on the treatment of athletes.
Conversely, the role of the physician in anti-doping efforts has increased
remarkably, as well. The greatest change has taken place in the last few
years, with primary care physicians and specialists having a formalized
role in submitting documentation to support an athlete’s request to use med-
ications that may be prohibited in sport [3]. The International Standard for
Therapeutic Use Exemptions (TUEs) [4] is a part of the World Anti-Doping
Code (the Code) [5] and allows an athlete who has a legitimate medical need
for the use of an otherwise prohibited substance to submit a request to use
that particular medication. There are two types of TUEs that are used for
two different purposes: the Abbreviated TUE and the Standard TUE. If
filled out properly and completely, the Abbreviated TUE, which is a notifi-
cation only, is effective upon receipt at the responsible anti-doping
702 HILDERBRAND
Box 1. Definition of doping as defined in the Code

The presence of a prohibited substance, or its metabolites or
markers, in an athlete’s bodily specimen (the athlete is
responsible for any prohibited substance that is in his/her
system, irrespective of how the substance got into the body).
Use or attempted use of a prohibited substance or a prohibited
method. The use does not have to be successful to be a doping
violation.
Refusing, or failing without compelling justification, to submit to
sample collection after appropriate notification.
Not being available for testing as a result of failure to provide
location information or by missing a test.
Tampering, or attempting to tamper, with any part of doping
control.
Possession of prohibited substances. This includes possession
by athletes or support personnel.
Trafficking in any prohibited substance or prohibited method.
Administration, or attempted administration, or assisting,
encouraging, aiding, abetting, covering up, or any other
complicity in an antidoping rule violation.
organization. The Abbreviated TUE applies only to corticosteroids admin-

istered by inhalation or local injection and certain b-2 agonists that are per-
mitted by inhalation for respiratory conditions. The Abbreviated TUE relies
on the signature of the physician and only rarely requires medical record
documentation. The Standard TUE, which applies to all other prohibited
substances and methods, must be supported by complete medical documen-
tation. The Standard TUE must be submitted and approved before the use
of the prohibited medication or method in sport. These two exemption re-
quest forms are covered in detail in the next section. Because the procedures
and documentation that are required by sport authorities are complex, this
article is intended to provide explanatory information and specific assistance
to pediatricians and primary care providers, in general, on how to comply
with the rules that apply under the Code. Now, more than in the past, phy-
sicians must be involved in the process of doping control.
Anti-Doping organizations
The World Anti-Doping Agency (WADA) was established by the Inter-
national Olympic Committee (IOC) in November of 1999 as a foundation
with the support and participation of intergovernmental organizations,
governments, public authorities, and other public and private bodies [6].
WADA’s mission is to work with the IOC, national anti-doping
THERAPEUTIC USE EXEMPTIONS 703
organizations (NADO), sports federations, and athletes with the common

objective of controlling doping in sport.
USADA is the United States-based NADO; it began operations on Oc-
tober 1, 2000 with full authority for testing, education, research, and results
management for US Olympic, Pan American, and Paralympic athletes [7].
WADA and USADA are independent of the bodies responsible as advo-
cates for the advancement of sport.
The World Anti-Doping Program

The objective of the World Anti-Doping Program (the Program) [8] is to
preserve what is intrinsically valuable about sport or ‘‘the spirit of sport.’’
The spirit of sport is characterized by development of ethics, fair play, hon-
esty, a healthy lifestyle, character, and an ability to participate on a team.
An inherent part of character is for the athlete to develop respect for rules,
laws, self, and other participants.
The Program consists of the Code, International Standards, and Models of
Best Practice. All organizations that are signatories to the Code must follow
the Code and the International Standards; the procedures in the Models of
Best Practice are recommended. Of particular interest here are the Prohibited
List International Standard (2007) [9] and TUEs [4]. The other International
Standards are for Laboratories [10] and for Testing [11] of athletes.
The International Standards

Prohibited list
The Prohibited List (the List) is a list of categories of substances and
methods that are controlled by WADA. The prohibition may be at all times
or only in competition. The List is not exhaustive in that several categories
of substances are ‘‘open’’ and include ‘‘other substances with a similar chem-
ical structure or similar biological effect(s).’’ The placement of a substance
or method on the List is not subject to appeal by the athlete in the case
of a doping violation. The List is compiled by a committee convened by
WADA and is updated annually, or more frequently, as needed. Sport-
specific prohibitions occur as well (Box 2).
Therapeutic Use Exemptions

The Code permits an athlete to apply for a TUE to use an otherwise
prohibited substance or method for a documented therapeutic purpose.
The International Standard includes the criteria for allowing the exemp-
tion, the application process, and a procedure for appeals to decisions.
The ultimate objective is to harmonize this exemption process across the
world.
704 HILDERBRAND
Box 2. Prohibited list of pharmaceuticals, substances,

and methods
Substances and methods prohibited at all times (in and out of
competition)
Prohibited substances
Anabolic agents
Hormones and related substances
b-2 Agonists
Agents with antiestrogenic activity
Diuretics and other masking agents
Prohibited methods
Enhancement of oxygen transfer
Chemical and physical manipulation
Gene doping
Substances prohibited in competition (must be cleared from
the body at the competition)
Stimulants
Narcotics
Cannabinoids
Glucocorticosteroids
Substances prohibited in particular sports
Alcohol
b-Blockers
Testing
The testing standard is to plan for effective testing (sample collections)
and to maintain the integrity and identity of the samples from the notifica-
tion of the athlete to receipt of the sample at the laboratory. The topics in-
cluded are test distribution planning, notification of athletes, processes for
collection, security, and transport of samples.
Laboratories
This standard is intended to harmonize the laboratories across the world
that are accredited by WADA. The standard, including all annexes and
technical documents, is intended to ensure that quality results are produced
by all accredited laboratories and that evidentiary data are appropriate for
the intended use. The standard also describes the application and accredita-
tion process for the laboratories and the process for accreditation of satellite
laboratories created for a specific purpose.
Models of best practice

Models of best practice are based on the Code and are developed to pro-
vide the best available information on various areas of anti-doping program
operation. These best practices are recommended but not mandatory.
History of medical exemptions to use prohibited medications

With the addition of commonly used pharmaceuticals to the list of pro-
hibited substances that was established by the IOC came the need for elite ath-
letes to use those medications for legitimate medical purposes. In the late
1980s, Sweden and Australia began a process to approve such use of pro-
hibited medications for national athletes. At the 1988 Olympic Games, the
IOC Medical Commission allowed the use of oral glucocorticosteroids by
a hockey player in Calgary and the use of furosemide by a female heavyweight
rower in Seoul. In October of 1991, the IOC established a committee consist-
ing of Drs. Ken Fitch (Chair), Don Catlin, and Arne Ljungvist to prepare cri-
teria by which medical exemptions would be granted. Subsequently, the
committee became the Medication Advisory Committee (MAC) of the IOC
and continued to make decisions for various Olympic Games and sports until
2002. Following a series of meetings of the MAC with the IOC legal staff, the
concept of TUEs was included in the Olympic Movement Anti-Doping Code
in 2000. Also in 2000, the concept of TUEs was included in the Olympic Games
Doping Control Guide for the Sydney Olympic Games. After the Games, the
Australian TUE Committee prepared a protocol for TUEs. This was the basis
for the TUE process that was adopted at the World Conference on Doping
in Sport in Copenhagen, Denmark on March 5, 2003 and promulgated as
an International Standard in 2004 [12].
Therapeutic Use Exemptions

The authority to review and accept an Abbreviated or Standard TUE [5]
is established by the Code [6]. An International Federation (IF) is estab-
lished for each sport (eg, the International Ski Federation is the IF for ski-
ing) and writes and updates the rules of competition for elite national,
international, and Olympic sport competitions. The Code gives the IFs re-
sponsibility for receiving and approving TUEs for international-level ath-
letes or those athletes who compete at international events. USADA is
given responsibility for receiving and approving TUEs for American na-
tional-level athletes. The IFs may retain the review of the TUE requests
made by international-level athletes or they may agree with organizations
(eg, USADA) to have the decisions made at the national level. Unless there
is an agreement in place that an IF will recognize the decision of a national-
level anti-doping body (such as USADA), any national-level athletes who
move to international competition must ensure that the TUE request to
706 HILDERBRAND
the appropriate IF for their sport is completed in a timely manner and be-
fore they might be subject to doping control.
There are several salient points related to the TUE process that med-
ical care providers need to be aware of. First, USADA does not provide
advice on medical matters or treatments. Treatment for routine or emer-
gency medical conditions is between the athlete and his/her physician.
The athlete is responsible for managing his/her own care and for using
medications in a manner consistent with the Code [5]. The anti-doping
rules do not deny or recommend the use of medications, they only con-
trol how the medications may be used in sport. USADA provides infor-
mation on the status of medications solely for athletes’ information, in
accordance with the Code. Second, anti-doping rules, like competition
rules, are rules governing conditions under which sport is played and
must be complied with in the same manner as rules on the field of
play, equipment, time, and so forth. Please remember that prohibited
substances (eg, methylphenidate, oral methylprednisolone, insulin, or ox-
androlone) used to treat a legitimate medical condition (without a TUE)
are prohibited even if prescribed properly by a medical professional.
Abbreviated Therapeutic Use Exemptions

The Abbreviated TUE only applies to in-competition and out-of-
competition use of four b-2 agonists (formoterol, salbutamol [also known
as albuterol or levalbuterol], salmeterol, and terbutaline) by inhalation
and the in-competition use of glucocorticosteroids by inhalation and local
or intra-articular injection. An Abbreviated TUE for use of any of the
four listed b-2 agonists must be received prior to the athlete being tested
in- or out-of-competition (Box 3).
Standard Therapeutic Use Exemptions

A Standard TUE may be requested for the use of an otherwise prohibited
substance and for which an Abbreviated TUE is not allowed [4]. Interna-
tional-level athletes may send the completed application to USADA for for-
warding to the appropriate IF. National-level athletes must submit the
Standard TUE to USADA. In cases in which IF approval is needed,
USADA forwards the request. USADA has established the required pro-
cesses for reviewing the Standard TUEs, including a Therapeutic Use Ex-
emption Committee (TUEC) for review and an appeal process for
national-level athletes.
The Standard TUE application must include a comprehensive medical
history and the results of all examinations, laboratory investigations,
and imaging studies relevant to the diagnosis that is the basis for the re-
quest. Any additional relevant investigations, examinations, or imaging
studies requested by the TUEC will be at the expense of the athlete
Box 3. Summary of requirements for an acceptable Abbreviated

Therapeutic Use Exemption
The correct Abbreviated TUE form must be completed fully. For
example, certain IFs require the use of their own form.
All information written on the form must be legible (to allow
faxing and understanding by the international medical
community). Typed or block letters are preferred.
The generic name, rather than the brand name (for example,
salbutamol rather than Ventolin), is needed. These forms will
be faxed to IFs and WADA, and brand names differ from
country to country.
All signatures (parent/guardian as applicable) and address
information for the athlete and physician must be included.
All medical information on the b-2 agonists or
glucocorticosteroids including, but not limited to, diagnosis,
medical examinations performed (including dates), dose, route
of administration, frequency of use, and duration of treatment
with the prohibited substances must be included.
Failure to follow these instructions will delay the processing of
the request.
making the request. The application must be legible, signed by an appro-

priately qualified physician, and describe the necessity of the otherwise
prohibited substance or prohibited method. In particular, the need for
the prohibited substance must be justified, and the reasons why alterna-
tive permitted medications cannot, or could not, be used also must be
cited. The dose, frequency, route, and duration of administration of the
otherwise prohibited substance or prohibited method must be specified.
If a TUE has been granted to an athlete by USADA, the athlete and
WADA are promptly provided with a notification of approval and infor-
mation pertaining to the duration and any conditions associated with the
TUE. Standard TUEs may be considered for renewal by submission of
a new form with medical information to update the record from the
last submission. Some IFs may require a complete resubmission for
a renewal.
Emergency Therapeutic Use Exemptions

In certain emergency situations in which a prohibited substance or
method is required to protect the health of the athlete and there is insuffi-
cient time to file the appropriate Standard or Abbreviated TUE, an Emer-
gency TUE may be filed. The Emergency TUE, in all cases, requires the
708 HILDERBRAND
Standard TUE form with medical documentation supporting the emergency

request. An example of an emergency situation is an oral glucocorticoste-
roid to treat anaphylactic shock. The decision on the Emergency TUE is,
of necessity, made after the fact.
Therapeutic Use Exemption Committee review factors

The TUEC considers the request and the medical information submitted.
The Committee is not convened to complete a diagnosis or to recommend
any treatment plan. The committee is solely tasked with evaluating the ap-
plication with the existing medical information and to make a determination
if the use of the prohibited medications or method falls within the rules of
sport. In this process, the Committee first determines that the diagnosis is
appropriate and well documented. Several factors are considered; however,
the key items are the credentials of the physician completing the request, the
types of examination or evaluation used in making the diagnosis, and the
acceptability of the documentation. Specialty training of the submitting
physician in the area of the diagnosis is a positive factor in the consideration
(Boxes 4 and 5).
Appeal of decisions
In the case of the denial of a request for a TUE, international-level
United States athletes, those who enter an international competition, or na-
tional-level athletes included in the national antidoping organization’s Reg-
istered Testing Pool may submit a request for a review of the decision.
WADA has established a fee that applies to the review of appeals. For in-
formation on how to request a review or file an appeal, see Section 7 of
the WADA International Standard for Therapeutic Use Exemptions.
In the case of the denial of a request for a TUE by athletes other than
those listed above, the athlete may request a review of the decision from
Box 4. Criteria used by the Therapeutic Use Exemption

Committee
If the athlete would suffer significant impairment without the use
of the prohibited medication.
If the medication will produce significant performance.
enhancement above what would be obtained with a return to
normal health.
If there are reasonable therapeutic alternatives.
If the need is a result of a prior nontherapeutic use of an
otherwise prohibited medication or method.
Box 5. Therapeutic Use Exemption Committee requirements for

attention deficit disorder/attention-deficit/hyperactivity
disorder medications
A thorough clinical history, including the initial reports that led to
the diagnosis of attention deficit disorder/attention-deficit/
hyperactivity disorder, discussion of the measures used and
their interpretation, age of onset, and family history of related
diagnoses.
A description of the deficit in performance, physical or mental,
exhibited by the athlete and the description of how the
proposed medication will affect performance at the doses
used.
The results of any laboratory testing completed during diagnosis.
Any observations and consequences of discontinuance of the
medication for a brief period of time.
Evidence that permitted medications have been considered or
tried and that the outcome of use of the allowed medications is
such that the prohibited medication must be used.
Any clinical, educational, psychologic, or consultative reports
with comments on related performance issues, such as anxiety
or depression.
A statement provided by the athlete outlining how he/she feels
when the medication is being taken and not taken. This
statement is helpful to the physicians and should, in fact, be
written by the athlete. Statements written by parents over the
athlete’s signature are not helpful and should not be submitted.
USADA. The review is conducted by an independent physician and is based

on the material included in the initial submission of the athlete. There is
a fee associated with this request for review. The request must be made
within 30 days of the receipt of the decision from the initial TUEC.
Summary
The presence of a prohibited substance in an athlete’s urine (or blood, when
applicable) or the use of a prohibited method constitutes a doping offense. The
presence of a prohibited substance is a violation irrespective of the manner in
which the prohibited substance came to be in the athlete’s system. It is the per-
sonal responsibility of an athlete to ensure that no prohibited substance is al-
lowed to enter his or her body or use, or allow the use of, any prohibited
method (in other words, the concept of ‘‘strict liability’’ applies). For the ther-
apeutic use of a prohibited substance or method, the TUE rules must be fol-
lowed. The TUE must be obtained according to WADA guidelines and
710 HILDERBRAND
before testing or conditions where the substance is prohibited. Ultimately, the

most powerful deterrent to doping may be the proactive maintenance of a sup-
portive, open, and trusting professional relationship between athletes and
medical personnel. The medical personnel must be perfectly clear that doping
practices are seen as ethically unacceptable.
In the past few years, anti-doping programs have been established to have
independence from the sport organizations that are expected to be advocates
of sport. The World Anti-Doping Program has established International
Standards for a Prohibited List (substances and methods) and for Therapeu-
tic Use Exemptions to allow athletes who have essential medical needs to use
a prohibited substance or method. In addition, WADA has established In-
ternational Standards for Testing and for Laboratories and is working to
harmonize these programs worldwide. The procedures for requesting
TUEs have been developed carefully. These procedures and the criteria
for evaluation were presented here in some detail. At this time, the Code
is being reviewed and revised and will be formalized at a World Conference
in the fall of 2007. Certain minor aspects of the Code and requirements for
TUEs may be modified; however, the changes are expected to be minimal.
Updated information on the Code, including any revisions to the Interna-
tional Standard for TUEs, may be found on the WADA Web site. In addi-
tion, USADA provides information on prohibited substances and the TUE
process in a variety of ways. Information on prohibited substances and
TUEs is available online at the USADA Drug Reference Online (DRO)
[13], by telephone at the Drug Reference Line (DRL) (800-233-0393), and
in the USADA Guide to Prohibited Substances and Prohibited Methods of
Doping, which is available online [14] or in printed format [15]. Given the
growing complexity of sports medicine and doping methods, physicians
and other support personnel must play an important role in influencing
the decisions of athletes that effect long-term health.
Acknowledgments
The author thanks Drs. Larry Bowers and Caroline Hatton for their con-
structive comments on this article, and Ms. Carla O’Connell and Ms. Ca-
mila Zardo for editorial and preparation assistance. Despite the
assistance, the author accepts responsibility for any factual errors or misrep-
resentations that may be included in the writing.
References
[1] Pipe A, Best T. Editorial. Drugs, sport, and medical practice. Clin J Sport Med 2002;12:
201–2.
[2] Hoberman J. Sports physicians and the doping crisis in elite sport. Clin J Sport Med 2002;12:
203–8.
[3] Green G. Doping control for the team physician: a review of drug testing procedures in sport.
Am J Sports Med 2006;34:1690–8.
[4] World Anti-Doping Agency. The World Anti-Doping Code. International standard for
therapeutic use exemptions. Available at: http://www.wada-ama.org/rtecontent/
document/international_standard.pdf. Accessed January 12, 2007.
[5] World Anti-Doping Agency. The World Anti-Doping Code, Version 3. 2003. Available at:
http://www.wada-ama.org/rtecontent/document/code_v3.pdf. Accessed January 12, 2007.
[6] Lausanne Declaration on doping in sport. Adopted at the World conference on doping in
sport. Lausanne (Switzerland), February 2–4, 1999.
[7] Report of the U.S. Olympic Committee select task force on externalization. Presented at
the U.S. Anti-Doping Agency 2001 Annual Report. USADA. Colorado Springs (CO),
December 3, 1999.
[8] World Anti-Doping Agency. The World Anti-Doping Agency Mission. Available at: http://
www.wada-ama.org/en/dynamic.ch2?pageCategory.id¼255. Accessed January 12, 2007.
[9] World Anti-Doping Agency. The World Anti-Doping Code. 2007 Prohibited List, Interna-
tional Standard. Available at: http://www.wada-ama.org/rtecontent/document/2007_
List_En.pdf. Accessed January 12, 2007.
[10] World Anti-Doping Agency. International Standard for Laboratories. Available at: http://
www.wada-ama.org/rtecontent/document/lab_aug_04.pdf. Accessed January 12, 2007.
[11] World Anti-Doping Agency. The World Anti-Doping Code. International standard for
testing. Available at: http://www.wada-ama.org/rtecontent/document/testing_v3_a.pdf.
Accessed January 12, 2007.
[12] Fitch K. History of therapeutic use exemptions. Presented at World Anti-Doping Agency/
National Anti-Doping Agency Meeting On Therapeutic Use Exemptions. Bonn (Germany),
December 13, 2006.
[13] United States Anti-Doping Agency. Drug reference online (DRO). Available at: www.
usantidoping.org/dro. Accessed June 12, 2007.
[14] United States Anti-Doping Agency. 2007 Guide to Prohibited Substances and Prohibited
Methods of Doping. 7th edition. Available at: http://www.usantidoping.org/files/active/
what/usada_guide.pdf. Accessed February 1, 2007.
[15] United States Anti-Doping Agency. Guide to prohibited substances and prohibited methods
of doping. 7th edition. Colorado Springs (CO): USADA; 2006.
Beyond Sports-Doping Headlines:

The Science of Laboratory Tests
for Performance-Enhancing Drugs
Caroline K. Hatton, PhD
UCLA Olympic Laboratory, University of California at Los Angeles,
2122 Granville Avenue, Los Angeles, CA 90025, USA
Young athletes breaking into the elite level can look forward to giving in-
terviews, autographs. and urine samples. This article shows what happens
when the latter are tested for prohibited doping agents at the laboratoryd
how roomfuls of regulations and teams of specialized professionals ensure
that the laboratory work is conducted accurately and that the test results
are handled properly. Drug testing, along with drug education, research,
and results management, is how an antidoping program enforces the rules,
protects fair play, and defends the clean athletes’ freedom to compete with-
out drugs.
Regulatory framework
The fight against drug abuse in sports has grown and improved since
doping control began in the 1960s. Worldwide antidoping efforts are better
organized, harmonized, and structured than ever. This is true not only of the
rules, prohibited substances and methods, sanctions, and appeals, but also
of laboratory accreditation and reporting criteria. A positive test result, or
laboratory report that a prohibited drug was found in a sample, is referred
to in antidoping jargon as an adverse analytical finding. It is the antidoping
organization that determines whether the case is positive.
The World Anti-Doping Agency (WADA, see Box 1 for common acro-
nyms) has the support and participation of World Anti-Doping Code signa-
tories, such as governments and private entities, to work with the
International Olympic Committee (IOC), national antidoping organizations
(NADOs), sports federations, and athletes to control doping in sport.
714 HATTON
Box 1. List of acronyms

CIR: carbon isotope ratio (same as carbon IRMS)
DAD: diode array detector
EPO: erythropoietin
ERC: endogenous reference compound
GC: gas chromatography
GC-C-IRMS: gas chromatography-combustion-isotope ratio mass
spectrometry
GC-MS: gas chromatography-mass spectrometry
GC-MS-MS: gas chromatography-tandem mass spectrometry
GH: growth hormone
HBOC: hemoglobin-based oxygen carrier
hCG: human chorionic gonadotropin
HES: hydroxyethylstarch
HPLC: high-performance liquid chromatography
IA: immunoassay
IEC: International Electrochemical Commission
IEF: isoelectric focusing
IOC: International Olympic Committee
IRMS: isotope ratio mass spectrometry (when applied to carbon,
same as CIR)
ISL: International Standard for Laboratories (WADA)
ISO: the symbolic name of the International Organization for
Standardization
LC-MS: liquid chromatography-mass spectrometry
LC-MS-MS: liquid chromatography-tandem mass spectrometry
LH: luteinizing hormone
MRM: multiple reaction monitoring
MS: mass spectrometry
NADO: national antidoping organization
NCAA: National Collegiate Athletic Association
RSR-13: a pharmaceutical hemoglobin modifier
SIM: selected ion monitoring
SOP: standard operating procedure
SRM: selected reaction monitoring
TD: technical document (WADA)
THG: tetrahydrogestrinone
TMS: trimethylsilyl
TUE: Therapeutic Use Exemption
USADA: United States Anti-Doping Agency
WADA: World Anti-Doping Agency
DOPING CONTROL LABORATORY TESTS 715
NADOs testing programs, such as that of the US Anti-Doping Agency

(USADA), fall under WADA regulations, but those of United States profes-
sional sports, the National Collegiate Athletic Association (NCAA), and
United States high schools do not.
The WADA 2007 List of Prohibited Substances and Methods [1] includes
prohibitions effective at all times or only in competition. Among them are
anabolic agents (eg, anabolic steroids), hormones (eg, erythropoietin
[EPO]), diuretics, and other masking agents, chemical and physical manip-
ulation, stimulants, and more. The list gives examples in each class and in-
cludes ‘‘other substances with a similar chemical structure or similar
biological effect(s).’’ Therefore, athletes cannot claim innocence merely be-
cause the drug that they used was not listed by name. Only nine of several
hundred prohibited drugs have a cut-off [2]; for all the others, any detectable
amount constitutes an adverse analytical finding. In the United States, pro-
fessional sports, the NCAA [3], and high schools have their own prohibited
lists, which overlap with those of WADA.
National antidoping agencies, such as USADA, must use WADA-
accredited laboratories to test the samples that they collect. A prerequisite
to WADA accreditation is ISO accreditation (ie, the laboratory must meet
the requirements of ISO/IEC 17025) [4]. These include a quality assurance
program, standard operating procedure (SOP) for assays; instrument opera-
tion and maintenance; personnel qualifications; restricted access to premises,
computers, and electronic records; internal audit trails; and traceability of re-
sults to reference standards.
The WADA requirements for laboratories reflect those of ISO and are
stated in the International Standard for Laboratories [4] and WADA tech-
nical documents. Generally, WADA does not require laboratories to follow
prescribed SOPs; instead, laboratories are required to meet performance cri-
teria. For example, laboratories must be able to detect 2 ng/mL of clenbu-
terol in urine [2]; the sample preparation procedure and analytical
techniques are up to each laboratory. WADA requires laboratories to
have research activities to optimize tests performance and to keep up with
cheaters. WADA accreditation is up for renewal annually.
Sample identity and integrity

The first step in a doping-control urine test is getting an authentic urine
sample from the correct person and getting it sealed and documented for
shipment to the laboratory. Thus, the first crucial link in the doping-control
process is the Doping Control Officer or Sports Drug Testing Collector and
his or her staff.
Athletes who enter sports competitions agree to follow the rulesdincluding
antidoping rulesdfrom being subjected to doping-control tests to accepting
the consequences of a positive test. Athletes selected for a test identify
716 HATTON
themselves before they urinate in a cup, under direct observation by an official

of the same gender. Next, the urine is poured into a pair of bottles, A and B,
labeled only with numbers (eg, 963852A and 963852B), and the bottles are
sealed. Only the sport organizationdnot the laboratorydknows which num-
ber corresponds to which athlete. Chain of custody paperwork documents
who has custody of the samples or where they are locked up, from the moment
the bottles are sealed, to their receipt at the laboratory, to the day when they
are finally discarded.
Blood is rarely collected in the major United States sports drug-testing
programs. At the Olympics, blood is collected, but not as often as urine.
For example, at the 2004 Athens Olympics, the laboratory received 2926
urine samples and 691 blood samples [5]. Some federations, such as Union
Cycliste Internationale, collect blood before races for health tests (not dop-
ing-control tests), and athletes with atypical values deemed medically unsafe
(eg, high hematocrit) are not allowed to compete [6].
Testing urine is better than testing blood for most prohibited substances
(small molecules, molecular weight less than w800 atomic mass units).
Urine collection is noninvasive and yields a large volume of sample, with
higher drug concentrations than in blood and with far fewer cells and pro-
teins to complicate extraction.
Is it possible to tamper with the sample containers? Not without leaving
evidence of it. Sample integrity is checked and documented upon receipt at
the laboratory, by technicians who inspect containers and tamper-evident
seals visually, then record whether the chain of custody was intact. The bot-
tles used at the Olympics are sealed with a thick plastic cap over the stopper,
and the only way to access the sample is to destroy the cap.
To deter urine substitution, urination is observed. This led to the discovery
at the Athens Olympics of a contraption consisting of a bag of clean urine up
the rectum and plastic tubing running along the underside of the penis [7].
High school drug-testing programs may test only for street drugs or only
for anabolic steroids. In some programs, samples are not split and adverse
analytical findings are not reported by individual bottle number, but only in
an aggregate fashion, reporting the finding of a drug with no further detail
than ‘‘in one sample in the batch.’’
A doping-control laboratory test consists of more than one test

At the laboratory (Fig. 1), all ‘‘A’’ samples (a portion or ‘‘aliquot’’ of
each) undergo screening for all of the drugs on the relevant (in- or out-of-
competition) list (menu). The goal of screening is to rapidly sort samples
into two categories: certainly negative and maybe containing a target com-
pound. A well-designed screen is quick, detects a broad variety of substances,
and provides a mere indication, not full proof, that the compound is present.
Because drugs tend to be chemically similar within each class (eg, stimulants,
Fig. 1. Typical antidoping laboratory procedure.
steroids), but chemically different between classes, the best conditions for ex-
traction and detection tend to be the same within a class, but different between
classes. Typically, laboratories conduct one stimulant screen, one or two ste-
roid screens, one diuretic screen, and so forth on each sample in a batch of test
tubes; each test tube represents one athlete. The batch also includes quality-
control test tubes.
If the screening data contain any indication that a drug might be present,
a fresh portion (aliquot) of the ‘‘A’’ sample undergoes a confirmation at-
tempt. Although a screen collects a little bit of data on each of numerous
target compounds, to see if any might be present, a confirmation collects
a lot of data on only the suspected compound.
Typically, the time elapsed between receiving the samples at the labora-
tory and reporting results on the ‘‘A’’ samples (turn-around time) is 1 to
2 weeks for year-round testing, and it can be as short as 24 hours for neg-
ative ‘‘A’’ results during major events. ‘‘A’’ confirmations take longer. Re-
sults are needed as soon as possible when the world is watching and
athletes compete more than once, because if they used drugs, they should
be removed from competition.
If the ‘‘A’’ sample analysis confirms the presence of a drug, the labora-
tory reports to the antidoping program its finding in the sample, identified
only by code numberdthe only identification known to the laboratory.
The athlete is notified and has the right to come to the laboratory or send
a representative of his or her choice to witness the ‘‘B’’ confirmation. After
verification of identity, the witness examines the ‘‘B’’ sample exactly as it
was last seen by the athlete when it originally was sealed for shipment to
718 HATTON
the laboratory; paperwork is filled out and signed. The witness may then ob-
serve the ‘‘B’’ confirmation, which takes 2 to 3 days, depending on the drug.
Some witnesses choose to watch the process; others choose to leave before
the laboratory work begins. After completion and conclusion, the labora-
tory reports the result of the ‘‘B’’ confirmation to the antidoping program.
What remains of positive samples is securely frozen for the length of time
that meets applicable regulatory and contractual requirements. Typically,
negative samples are disposed of sooner. Disposal is the last entry for
each sample’s chain of custody documentation.
Main analytical techniques

The goal of this article is to cover key points without being exhaustive
and to focus on urine analysis and data interpretation. The laboratories’
job is to detect hundreds of substances. Table 1 shows common technolo-
gies. The choice of technology is determined primarily by chemical charac-
teristics (eg, solubility in water or organic solvents, volatility, thermolability,
polarity) and secondarily by logistics (eg, resident expertise, staff or instru-
mentation, capacity and throughput in different laboratory sections). Many
substances are detected routinely by more than one approach [5,8].
Sample preparation
The work-up ranges from 1 hour to 1 day, depending on the screen. Be-
cause metabolism attaches sugars (conjugates) to some drugs (eg, anabolic
steroids), the sugars need to be cleaved (deconjugated) using an enzyme
(eg, b-glucuronidase) or an acid for some incubation time. The freed drugs
that are still too polar and involatile to be vaporized for analysis need to be
derivatized, or reacted with chemicals that will ‘‘cap’’ their polar functional
groups (eg, to convert hydroxyl groups into trimethylsilyl ether groups in
the case of anabolic steroid screening).
Analysis
Chromatography
Chromatography is an analytical chemistry technique used to separate
(resolve) the chemical compounds in a mixture. Gas chromatography
(GC) is done in the gas phase. A gas chromatograph has three parts: a sam-
ple introduction system (injector), an oven containing a chromatography
column to achieve separation, and a detector. Typically, a microliter of liq-
uid urine extract is automatically injected into the injector, a chamber at
a high temperature. The sample is vaporized and swept along a hair-thin
glass tube (capillary column, many meters long, flexible enough to be rolled
up in a coil) by a carrier gas (mobile phase), such as helium. Different com-
pounds travel at different speeds because of the differences in boiling point,
Table 1
Screening technologies for classes of prohibited substances and methods
From WADA 2007
prohibited list Urine screening technology
Substances and methods IA GC GC-MS LC-MS or LC-MS-MS Miscellaneous IEF
prohibited at all times (in
and out of competition)
Prohibited substances
Anabolic agents X X
DOPING CONTROL LABORATORY TESTS

(anabolic steroids)
Hormones hCG, LH EPO
b-2-agonists X
Antiestrogens X
Diuretics and other X X
masking agents
Prohibited methods
Enhancement of oxygen HES, RSR-13 HES dextran by HBOCs
transfer biochemical analyzer
Chemical and physical
manipulation
Gene doping No urine test
Substances and methods prohibited in competition
Stimulants X X
Narcotics X X
Cannabinoids X X
Glucocorticosteroids X
Substances prohibited in particular sports
Alcohol Dipstick or GC
Beta-blockers X X
719
720 HATTON
polarity, and relative solubility in the carrier gas versus the coating of the
inner wall of the column (stationary phase). The compounds emerge from
the column outlet at different times after injection (the chromatographic re-
tention time)dseparated from each other. Under identical operating condi-
tions, the retention time is characteristic of each chemical compound. If two
compounds have the same retention time, they may be identical (eg, testos-
terone). If two compounds have different retention times, they certainly are
different (eg, testosterone and methyltestosterone). Matching retention
times between an unknown and a reference standard is one element of
identification.
A graph of the amount of substance as a function of the retention time is
a chromatogram (Fig. 2A) [9]. Two common GC detectors in antidoping
laboratories are the nitrogen-phosphorus detector (NPD) and the mass
spectrometer. The NPD detector is ideal for detecting nitrogen-containing
compounds, such as stimulants.
Mass spectrometry
Mass spectrometry (MS) is an analytical chemistry technique used for
structure elucidation of unknowns or identification of known compounds.
A mass spectrometer has three parts: an ion source where the compound
is ionized to form a molecular ion and fragmented into smaller ions;
a mass filter that separates ions by mass-to-charge ratio (m/z); and a detec-
tor. The graph of ion abundance as a function of m/z is a mass spectrum. In
Figure 2B, the molecular ion is 360 and significant ions are 345 and 143
(largest ¼ base peak ¼ 100%). The fragmentation pattern is determined
by weak bonds and other physicochemical characteristics; therefore, frag-
mentation is reproducible and characteristic of the molecular structure,
and the mass spectrum is like a fingerprint of the compound. Matching
mass spectra between an unknown and a reference standard is another ele-
ment of identification. Significant ions are so characteristic that matching
only three ions (eg, 143, 345, 360) and their percent abundance relative to
the most intense of the three (eg, 143) has long been widely accepted as
proof of chemical identification.
Gas chromatography-mass spectrometry

Gas chromatography-mass spectrometry (GC-MS) is the technique that is
used most widely in antidoping labs. The GC effluent enters the mass spec-
trometer continuously, and the mass spectrometer continuously records
roughly one mass spectrum (scan) per second. There are two main modes
of MS operation: the full-scan mode and the selected ion monitoring (SIM)
mode (see Fig. 2). In the full-scan mode, the mass spectrometer records the
whole mass spectrum (from m/z 70 to 400), monitoring hundreds of ions.
In the SIM mode, only selected ions are monitored (eg, 143, 345, 360); there-
fore, a longer time is spent recording each ion. In physics, signal strength (sig-
nal-to-noise ratio) increases with the time spent collecting data. Therefore, on
Fig. 2. GC-MS data for designer steroid madol. (A) Chromatogram; the isomer differs only by
the position of the double bond. (B) Full scan. (C) SIM scan.
the same instrument SIM is more sensitive than full scan; it can detect smaller
amounts of drug. Other types of MS that are more sensitive include high-res-
olution MS, tandem MS, and ion traps. High-resolution MS is designed to
measure m/z not only to the nearest unit or decimal, but out to several
more decimals. This makes it possible to mathematically deduce the molecu-
lar formula (how many carbon, hydrogen, oxygen, and other atoms it con-
tains); the more decimals, the fewer combinations of atoms fit, the
narrower the possibilities. High-resolution MS instruments happen to be
722 HATTON
inherently more sensitive. Tandem MS instruments have two mass spectrom-

eters back to back. The first one can be used to select only one ion, the precur-
sor ion, which can be the molecular ion. The second mass spectrometer
monitors only one (or at most a few) characteristic fragmentations (transi-
tions to product ions). This is called the multiple reaction monitoring or se-
lected reaction monitoring mode. (Alternatively, the first mass spectrometer
can be used to select only the molecular ion and the second mass spectrometer
can be used to record a full scan.) Tandem MS is more sensitive because it is
blind to interferences. Unlike all of the above MS types, which let all ions
formed continually escape from the ion source, ion traps trap all ions until
they are released, one m/z at a time, to determine their abundance.
Liquid chromatography
Whereas GC is done in the gas phase, liquid chromatography (LC) is
done in the liquid phase. This is a crucial difference because it works for
thermolabile compounds (destroyed by GC) and polar compounds (cannot
be vaporized). The separation principles are the same. A typical high-pres-
sure or high-performance LC (HPLC) column is a steel tube the size of a fat
marker pen, packed with microbeads on the surface of which is the station-
ary phase. The mobile phase is a liquid solvent, often a mixture whose com-
position is programmed to change during the run (gradient elution).
Two common HPLC detectors are the diode-array detector (DAD) and
the mass spectrometer. The DAD monitors UV absorption over a range
of wavelengths or at selected wavelengths; it detects only those compounds
that absorb UV light. When the HPLC is connected to an MS, the instru-
ment is called LC-MS. The most advanced type of LC-MS can do tandem
MS by one of several choices of conceptual and hardware approaches. It
is called LC-MS-MS or LC-tandem MS.
For a given class of drugs, such as diuretics (Fig. 3), the LC-tandem MS
screen is far superior to the GC-MS screen. Sample preparation time can be
well less than 1 hour, down from a full day’s work, because unlike GC, LC
does not require the removal of water or salts, deconjugation or derivatiza-
tion. Typically, the instrumental analysis run-time is two to three times
shorter, well under 10 minutes per sample, because LC-MS-MS is blind to
interferences; therefore, chromatographic resolution is not required, and
LC run times can be shortened.
Drug identification
Except for proteins, such as EPO, most prohibited drugs are identified by
GC-MS, the workhorse of doping-control laboratories. LC-MS is used in-
creasingly for diuretics, some anabolic steroids, and corticosteroids. Dop-
ing-control scientists identify a substance, in the laboratory and in court,
by matching chromatographic retention time and mass spectra between un-
known and standard. They need an authentic reference standardda sample
of the substance, certified to be correct. The standard may be a white
Fig. 3. Example of diuretic screen LC-MS-MS data. Top row: positive quality control (QC)
urine spiked with diuretics chlorothiazide, hydrochlorothiazide, and spironolactone. Middle
row: negative quality control urine. Bottom row: unknown urine sample. The internal standard
(etebenecid) is added to each sample and control during work-up; detecting it shows that the
assay performed as expected. Detecting the diuretics spiked into the positive control confirms
this. The sample screens positive for hydrochlorothiazide.
powder or an excretion urine from a volunteer who took the drug. Chroma-
tography coupled with MS makes it possible to identify not just drug clas-
ses, but specific chemicals, with absolute certainty.
Pharmaceuticals include some synthetic compounds that do not occur nat-
urally (eg, the anabolic steroid stanozolol) and some that do (eg, testosterone).
Unfortunately, GC-MS and LC-MS cannot distinguish natural, endogenous
testosterone from pharmaceutical, exogenous testosterone; however, normal
human urine samples contain a testosterone isomer with no known function,
epitestosterone. The urinary ratio of testosterone to epitestosterone (T/E ra-
tio) is roughly 1:1 in most normal men, and it increases upon testosterone ad-
ministration. Since the 1984 Olympics, the T/E ratio has been used to screen
for testosterone use. Adverse analytical findings are defined by a T/E cut-
off, which currently is 4. The two problems with any cut-off are that rare,
drug-free individuals might have a naturally elevated T/E and that T/E may
never exceed the cut-off in some users, either because their T/E is not respon-
sive to administration or because they use small doses and titrate themselves.
To distinguish users from nonusers, longitudinal profiling consists of plotting
T/E and other urinary androgen parameters over time, expecting stability for
nonusers and a spike for users. In the 1990s a new approach was introduced:
isotope ratio MS (IRMS) [10].
Isotope ratio mass spectrometry or carbon isotope ratio

It so happens that there is a measurable difference in carbon-13 content
between endogenous and pharmaceutical testosterone. Most carbon atoms
724 HATTON
in nature are carbon-12, with a nucleus containing six protons and six neu-
trons. Radiocarbon dating relies on the rare carbon-14, an unstable, radio-
active isotope, with a nucleus containing six protons and eight neutrons,
which decays over time. Between the two is carbon-13, a stable isotope
with six protons and seven neutrons. Roughly 1.1% of carbon in nature
is carbon-13. Pharmaceutical testosterone contains a few parts per thousand
less carbon-13 than does natural testosterone. This is because they arise
from biosynthetic pathways that are sufficiently different. Humans make en-
dogenous testosterone from cholesterol, itself made from acetate or coming
from the diet. Pharmaceutical companies make testosterone by semisynthe-
sis from plant sterols. All carbon in living beings is ultimately derived from
atmospheric carbon dioxide (CO2), fixed in plants by photosynthesis. Differ-
ent plants make the first multicarbon intermediates and downstream biosyn-
thetic compounds differently. Animals eat plants, humans eat plants and
animals, and we are what we eat. At every biosynthetic step, carbon-13 is
left behind. This is because of the isotopic effect: chemical reactions go faster
with lighter compounds; the molecule with a carbon-12 reacts sooner than
the molecule with a carbon-13 instead. Because the pathways from atmo-
spheric CO2 to endogenous or pharmaceutical testosterone are different
enough, carbon-13 is depleted to different extents; the difference happens
to be measurable.
The technique used to make the measurement is GC-combustion-IRMS
(GC-C-IRMS). Before application to doping control, it had long been
used to detect the fraudulent substitution of synthetic compounds in place
of natural compounds in the food, flavor, and fragrance industries. The an-
abolic steroids are extracted from urine and separated by GC. The separated
testosterone enters the pencil-size combustion oven where it is pyrolyzed.
Every carbon atom in the molecule is converted to CO2, and every hydrogen
atom is converted to water (H2O). The water is scrubbed out and only the
CO2 enters the IRMS. This type of MS measures only three m/z: 44 for
12 16
C O2, and 45 and 46 for variants containing carbon-13, oxygen-17, or ox-
ygen-18. From the relative abundances, the instrument software calculates
the d13C (delta) value. It reflects the 13C/12C ratio, but it actually is the dif-
ference between the 13C/12C ratio of the sample and that of an international
standard. The units are & (per mil). By definition, the delta value of the in-
ternational standard is 0&. Examples of values are 24& for natural testos-
terone and 29& for pharmaceutical testosterone. The values are negative
because both compounds contain less carbon-13 than the international stan-
dard: 29 fewer parts per thousand for the pharmaceutical testosterone.
After exogenous testosterone administration, the delta values of urinary
testosterone metabolites become more negative (Fig. 4). In contrast, the delta
values of testosterone precursors, or of endogenous steroids not involved in
testosterone metabolism, remain unchanged; therefore, they can be used as en-
dogenous reference compounds. A gap in delta value between testosterone or
its metabolites and an endogenous reference compound indicates the use of
Fig. 4. (A, B) How an IRMS test detects doping. A testosterone (T) precursor is metabolized to
another T precursor, which is metabolized to T, which undergoes one or more metabolism steps
to a T metabolite. Endogenous reference compound (ERC), is a steroid not involved in T me-
tabolism; therefore, it remains unaffected by the administration of pharmaceutical, exogenous
T, or of its precursors.
testosterone or of any steroid in its metabolism. If the difference between the

delta values of one metabolite and the endogenous reference compound is
three delta units or more, the WADA requirement for reporting an adverse an-
alytical finding has been met [11]. The power of this approach is that it can de-
tect the use of not only testosterone itself, but also of any one of many
testosterone precursors and metabolites. The second advantage is that it is
not affected by factors that might influence baseline delta values. For example,
diet influences the carbon-13 content of endogenous steroidsdall of them to
a similar extent. Although interpreting vastly different delta values from one
individual to the next might be difficult, a difference in delta values between
a testosterone metabolite and an endogenous reference compound clearly re-
veals drug use. In short, the approach compensates for individual variability.
The third advantage is that it does not require identifying or even knowing
what exact compound was taken.
IRMS testing has been applied to various testosterone precursors, testos-
terone metabolites, and endogenous reference compounds. It is currently
done for samples with T/E greater than 4 or on request by the sports
authority.
726 HATTON
Isoelectric focusing
Isoelectric focusing (IEF) is used to detect recombinant EPO in the urine
EPO test [12–14]. Historically, the EPO test at the Olympics (2000 to 2006)
was done on paired blood and urine samples collected simultaneously. The
blood test is an indirect test because it does not detect the presence of re-
combinant EPO. Instead, it measures multiple parameters (eg, hemoglobin,
hematocrit, percentage of reticulocytes) and calculates a score that indicates
whether the individual is on or recently off recombinant EPO [15]. Since
2002, EPO tests done by United States sports authorities have included
only the urine test, a direct test that identifies recombinant EPO. EPO tests
are done on only some of all of the urine samples, upon request by the sports
authority.
Endogenous human EPO is a glycoprotein with a known amino acid se-
quence and glycosylation pattern. More precisely, it consists of a family of
isoforms (molecules that differ only by their degrees of glycosylation). As
a result, the pH at which each isoform bears as many negative charges as
positive charges (isoelectric point or PI) is different.
Recombinant human EPO differs from endogenous human EPO only by
its overall glycosylation pattern (ie, it consists of a different family of iso-
forms). The difference in overall pattern of isoforms allows differentiation
between recombinant and endogenous human EPO.
The urine EPO test, also known as the French test or the IEF test, con-
sists of four steps: sample preparation, IEF, double blotting, and visualiza-
tion. Sample preparation concentrates EPO by multiple ultrafiltrations that
leave the proteins of desired molecular weight in the filtration ‘‘retentate.’’
Next, the retentate is deposited on a gel with an embedded pH gradient,
and a current is applied to achieve electrophoretic separation of the isoforms
(IEF). Unknown samples, reference standards, and known positive and neg-
ative quality controls are normally run on each gel. Each sample, standard,
or control spreads out in its own ‘‘lane.’’ Each isoform is charged; therefore,
it migrates in the electrical field until it reaches the distance on the gel at
which the pH is equal to its PI. There the isoform is electrically neutral so
it stops migrating. Its position or distance up the gel is key, and the goal
of the remaining steps is to visualize it.
The first blotting step transfers all proteins (erythropoietic and other) to
a first membrane. The membrane is incubated with antibodies specific to
erythropoietic proteins. The second blot transfers only these specific anti-
bodies to the second membrane, thus transferring the isoform pattern, but
leaving behind all proteins, including some that otherwise would obscure
the final image.
Visualization is based on chemiluminescence; it involves incubation with
a second antibody that binds to the first antibody and a chemical reaction
that emits light. The image (electropherogram) is captured with a special
digital camera. All steps use commonplace molecular biology techniques.
The electropherogram contains one lane per sample, standard, or quality
control sample (Fig. 5). In each lane, the isoform pattern consists of bands.
The pattern (number of bands, positions, relative intensities) allows
identification.
In common language, a negative EPO test often is discussed as if it re-
flects the absence of EPO, but of course what it means is that there was
no recombinant erythropoietic protein in the urine sample, which normally
would (hopefully!) contain natural, endogenous EPO.
Blood tests
Blood screening [5] is done at the Olympics, but not in the main United
States sports drug-testing programs. At the 2004 Athens Olympics, whole
blood was tested by cytometry to detect blood transfusions. Serum was
tested by LC-MS-MS to detect hemoglobin-based oxygen carriers and by
immunoassay to detect recombinant human growth hormone (GH). Natu-
ral GH is a family of isoforms, including a major one of 22 kd (22,000
atomic mass units) and some non–22-kd isoforms, whereas recombinant
GH is 100% 22-kd isoforms. Administration of recombinant GH suppresses
endogenous GH production. The current approach to recombinant GH de-
tection in serum is based on estimating the ratio of the 22-kd isoform to
non–22-kd isoforms by immunoassay; it can detect administration for 3
hours after the last dose [16]. The test was conducted at the 2006 Winter
Games in Torino as well. No adverse analytical findings were reported.
This test can be implemented more widely as soon as reagents can be man-
ufactured in sufficient quantities [17].
Fig. 5. EPO test result. Lane number and content: 1 & 4: rEPO ¼ recombinant EPO (rEPO),
pure standard; 2: NQC ¼ negative quality control ¼ research subject urine before rEPO admin-
istration; 3: PQC1 ¼ positive quality control 1 ¼ research subject urine after rEPO administra-
tion; 5 & 7: NESP ¼ darbepoetin ¼ long-lasting rEPO, pure standard; 6: PQC2 ¼ positive
quality control 2 ¼ urine from different research subject after NESP administration.
728 HATTON
Laboratory report interpretation

The laboratory urine drug test can determine what substance is present in
the urine sample, not the brand, formulation, route of administration, dose,
or how long before urine collection the drug was taken. Reasons why a urine
drug test is negative include the drug is not prohibited by this program; the
drug was never used; the drug was used long enough ago to have been elim-
inated completely; the drug is present below the cut-off; the drug is present
below the limit of detection of the test; the drug is a prohibited (designer)
drug that the laboratory does not look for; the sample was manipulated;
and the sample was not real urine. The latter can be revealed by steroid
screen data devoid of natural steroids in cases that would be missed by com-
mercial adulteration tests and dipsticks.
Many factors determine test retrospectivity (Table 2), or how long after
the end of administration the test can detect the drug in urine: among
them are the dose, body burden, elimination pharmacokinetics, and test sen-
sitivity. Anabolic steroids can be detected for as little as only a few days or
as long as many months after the user stops taking them, depending on the
type used (eg, short-acting pill or long-acting oily injection), how much was
used, and for how long. In addition, some steroids are easier to detect than
others because of chemical differences. Individuals who have been in a drug-
testing program for some time are less likely to use long-acting, easy-to-
detect steroids.
The test result on a follow-up sample collected some time after an initial,
positive sample needs to be interpreted in light of the above. If the follow-up
test is positive for the same drug, it may be because the drug was not com-
pletely eliminated yet or because the athlete used the drug again in the mean-
time. Comparing the laboratory data from both tests may or may not
provide an indication of which is the case. The follow-up test is expected
to be negative if the drug was eliminated completely. This is why a negative
follow-up test is not relevant to determining the accuracy or inaccuracy of
a positive result on a sample collected previously. Conversely, a negative
follow-up test is a valid check that the athlete has stopped using the drug.
Table 2
Urine drug test retrospectivity
Prohibited drugs Period of detectability after last dose
Stimulants A few hours to a few days
Anabolic steroids From a few days (short-acting, water
soluble, small doses) to many months
(long-acting oily injection, large doses
for a long time)
Diuretics A few hours to a few days
Marijuana Some weeks
rEPO A few days
Drug users who expect to be tested at events try to time their discontin-
uation to pass the test; this is why no-notice, out-of-competition testing was
implemented in the 1980s. In the early 2000s, United States track and field
athlete Kelli White passed 17 drug tests while on steroids (tetrahydrogestri-
none [THG], testosterone), stimulants (modafinil), and EPO before she was
caught on modafinil, then confessed to having used the whole regimen [18].
THG was not found in her samples because laboratories were still blind to
this designer steroid (used only to beat the test). Testosterone use was not
detected because she masked it by taking epitestosterone as well; because
her T/E never exceeded the cut-off, it never triggered IRMS analysis, which
would have detected exogenous testosterone. Modafinil was first targeted
and found by the French WADA-accredited laboratory; her EPO use was
not detected because sprinters’ samples were not tested for EPO yet.
It is said that the test is blind to designer steroids, because the test is tar-
geted and finds only what it looks for. Typically, WADA-accredited labora-
tories screen for most anabolic steroids by GC-MS in the more sensitive
SIM mode, monitoring only a few ions per target compound (eg, an ion
of 415 atomic mass units). A designer steroid could differ from a known
one by only two extra hydrogens, give an ion of 417 atomic mass units
upon fragmentation, and escape detection because the test monitors 415,
not 417. Or the designer steroid could fragment to ions that happen to be
monitored, in which case data readers would see suspicious signals and in-
vestigate further. The first reported designer steroid (norbolethone) [19] was
a pharmaceutical abandoned decades before, during clinical trials. It resur-
faced upon further investigation of an athlete’s urine sample devoid of nor-
mal endogenous androgens, a telltale sign of endocrine suppression, which is
expected after androgen administration because of negative feedback. The
second designer steroid (THG) [20] was discovered because a coach turned
in a used syringe. THG simply is not detected in the standard steroid screen,
probably because its chemical properties are such that it disintegrates along
the way. Different modifications of the screen now allow its detection.
Are the tests accurate? What are the risks of ‘‘false positive’’ or ‘‘false
negative’’? Both phrases can have widely different meanings in common lan-
guage compared with antidoping jargon. In common language, a ‘‘false pos-
itive’’ might be any adverse analytical finding that does not result in
a sanction, perhaps because the athlete had a therapeutic use exemption, be-
cause a courier’s signature was missing on a shipping document, or because
the prohibited drug was a supplement contaminant. Supplements are not
regulated by the US Food and Drug Administration (FDA); athletes should
not only use them at their own risk but question whether they need them to
win [21]. A case in which on appeal, an arbitrators’ panel had purely legal
reasons to exonerate the athlete, might casually be called a ‘‘false positive.’’
But for the laboratory, a false positive is only the case in which the labora-
tory reports the presence of a drug and it is later proven scientifically that
the drug was not present.
730 HATTON
As for a ‘‘false negative,’’ in common language that might be a case where

the athlete used a drug but passed the test. This could be because the metab-
olite was accurately detected just below the cut-offda perfectly accurate
negative result. Other possible explanations for negative results following
drug use were listed above.
Handling of results by the sports authority

Based on the laboratory ‘‘B’’ report, the sports authority decides whether to
charge the athlete with a doping offense. For USADA, the process includes au-
tomatic consideration by a Review Board and the opportunity for the athlete
to request an arbitration hearing to contest the sanction [22]. The NCAA pro-
tocol includes an appeal process [23]. The laboratory remains involved when
additional documentation (administrative or technical), scientific support for
the legal team, or testimony is requested.
When doping cases lead to legal activities, the laboratories’ decision cri-
teria are reviewed. The WADA criteria for drug identification are not novel;
they have long been widely used. GC-MS, LC-MS, and GC-C-IRMS tech-
nology were not invented for doping control; instead doping control is
merely one of many fields of application.
The days of genuine or alleged inadvertent use being excused are over now
that strict liability is enforced. It has room for refinement (lesser penalties)
when authorities believe that the athlete made an honest mistake. Sanctions
for the athlete’s entourage (eg, team physicians) are meted out in more cases.
Antidoping program administrators and attorneys, such as those of
USADA, are the third key link in the chain that began with the sample col-
lection team and continued with the laboratory team. They take the drug
test result to its final conclusion, carrying the baton over the finish line.
They also have gone beyond drug testing by charging athletes in cases
involving ‘‘non-analytical positives’’ (ie, evidence of doping that does not
include a positive test result).
Testing statistics are available online. In 2000, WADA took over the
IOC’s annual collection of statistics from worldwide accredited laboratories,
including the total number of samples tested per laboratory and number of
adverse analytical findings (total per laboratory, per drug worldwide, and
per sport worldwide) [24]. USADA posts annual testing statistics and the
test history of all United States athletes tested by USADA since its inception
in 2000 [25]. The NCAA results since 2001 are online [26].
Current trends
Will antidoping science ever get ahead of the cheats? (Not that we can
ever catch every last one.) The pace of medical progress makes doping con-
trol an endless escalade in complication and expense. If society wants no
performance-enhancing drugs in sports, the prospects for a technological
fix for values gone out of line might be dim. This is, in part, because crooked
scientists can market new designer drugs overnight with no concern for
FDA approval, and some athletes pay good money to be the ones to dis-
cover safety and efficacy. or the lack thereof. Meanwhile, antidoping sci-
entists need months or years to develop and validate new tests.
Yet major, recent improvements include the increased commitment of
government entities in the United States and in Europe to the fight against
doping, the speed at which sports authorities will add a drug to the pro-
hibited list, and the expansion of profiling as a means to detect drug use.
Physicians have long monitored patient biomarkers (eg, blood cholesterol)
for preventive purposes. Drug use is expected to affect common clinical test re-
sults and additional ones selected for their responsiveness to doping agents.
Two examples are how longitudinal T/E profiling helps to spot users and
how the absence of endogenous urinary steroids led to the discovery of the de-
signer steroid norbolethone. Extending the review of steroid profiles to all ath-
letes undergoing doping-control tests has not been done yetdalthough it has
long been possible technically because urinary steroid profiles are archived at
laboratories, and sports authorities know which bottle numbers represent
each athlete. Now that blood collection is more common in sports, more pa-
rameters could be added. Several programs in different countries are gearing
up to formally and prospectively collect athlete urine and blood profile data.
Some of those programs are voluntary, and although they all look similar at
first glance, only one of them is all carrots and no sticks: envisioned by Don
Catlin [27], it is designed to help clean athletes show the world that they are
drug-free, so that when they win they do not have to suffer suspicion of
drug use. Beyond public recognition, the program might offer free medical
care and nutrition and fitness advice. Deviations from normal variability
would be discussed with a trusted health care team. If a deviation had no ex-
planation other than drug use, the athlete merely would be dropped from the
program. No athlete would be sanctioned or suspended from competition or
kicked off teams or contracts. With no sanctions, the lower risk for legal activ-
ities would lower the cost of the program. The central question would be:
‘‘What if an anti-doping program rewarded drug-free athletes instead of pun-
ishing drug-using athletes?’’ Could it trigger a shift in culture or is that just
a wild hope for a crazy idea?
At the heart of any program is a trusting relationship with health care pro-
fessionals, something that patients can experience at a young age with their pe-
diatricians, who could be among the most influential people in turning around
the culture of drug use in sports.
Summary
Pediatricians or their patients may have to deal with sports-doping con-
trol tests and positive results. A substantial international regulatory frame-
work is in place to harmonize sports rules and drug-testing laboratories. In
732 HATTON
major programs, urine and blood samples are split into an ‘‘A’’ and a ‘‘B’’
sample, and urination is observed directly. Chain of custody paperwork
documents who has custody of the samples or where they are locked up,
from the moment the bottles are sealed, to their receipt at the laboratory,
to the day when they are finally discarded. If an ‘‘A’’ sample screens posi-
tive, the finding is confirmed twice before sanctions are considered: by rean-
alyzing the ‘‘A’’ sample and then analyzing the ‘‘B’’ sample. The main
analytical chemistry technologies in doping-control laboratories are GC-
MS, LC-MS-MS, IRMS detection of exogenous testosterone use, and IEF
detection of recombinant EPO use. The approaches, technologies, and
drug identification criteria are not novel; they have long been widely used
in other fields. Although every medical advance has a potential for abuse
by athletes, overnight and underground, antidoping scientists, who work
above board, are slowed by the requirements of testing research, develop-
ment, and validation. To try to leap ahead of the curve, the newest trend
in doping control is the expansion of all elite athletes’ profiling by monitor-
ing biomarkers and watching for deviations that may be indicative of
drug use.
Acknowledgments
Many thanks to Don Catlin for illuminating discussions, Brian Ahrens
for superb assistance with figures, and to Patrick Do, Charles Do, MD,
Gary Green, MD, and Richard Hilderbrand, PhD, for editorial advice.
References
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Creatine and Other Supplements

Anthony Lattavo, DOa,*, Andrew Kopperud, MDb,c,
Peter D. Rogers, MD, MPH, FAAPc,d
a
Department of Medical Education, Grant Medical Center, 285 East State Street,
Suite 670, Columbus, OH 43215-4354, USA
b
Columbus Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA
c
The Ohio State University College of Medicine, Columbus, OH 43210, USA
d
Section of Adolescent Health, Columbus Children’s Hospital, 700 Children’s Drive,
The dietary supplement industry in the United States is growing rapidly,

with annual sales of approximately $18 billion [1]. Ergogenic supplement use
(ie, for the purpose of enhancing athletic performance) is increasing among
adolescent and collegiate athletes, and the average age of initiation of use is
decreasing [2]. In the adolescent population, use is estimated at 24% to 29%,
and the likelihood of use increases with increasing physical activity [3]. One
large study found that about two thirds of supplement use starts before
college, and 9.2% begins before high school [2]. The most common supple-
ments used by collegiate athletes (all sports combined) are as follows (per-
centage of athletes reporting use in parentheses): protein products
(70.4%), creatine (39.6%), amino acids (20.4%), thermogenics/weight loss
(5.1%), beta-hydroxy-beta-methylbutyrate (HMB) (1.9%), chromium
(1.6%), and others (17.3%) [2]. To provide appropriate recommendations
for or against use by individual athletes, the physician working with adoles-
cent and collegiate athletes should be familiar with these most commonly
used supplements and be able to locate high-quality information about
the multitude of ‘‘others.’’
Athletes obtain information about supplements from a variety of sources,
including friends, teammates, coaches, trainers, family members, physicians,
dietitians, and the media (including the Internet) [3]. The quality of informa-
tion provided by many of these sources is poor and biased; highly motivated
athletes tend to accept information that promises performance gains and re-
ject information that presents a lack of performance benefit or a risk for ad-
verse effects. Therefore, the physician must avoid the ‘‘just say no’’
* Corresponding author.
E-mail address: [email protected] (A. Lattavo).
736 LATTAVO et al
approach and give sound advice based on scientific data (or lack thereof),
educating the athlete in the process [4]. One also must consider that informa-
tion about efficacy and safety of dietary supplement use in adolescents is
scarce compared with such information in adult populations. Pharmacody-
namically and pharmacokinetically, the adolescent body may handle and re-
spond to supplements differently than adults, resulting in less predictable
ergogenic and adverse effects [3]. Also, athletes of all ages use supplements
in an infinite number of combinations. Although the individual agents may
be well studied in isolation, there may not be any good scientific information
to guide the use of them in combination.
Regulation of dietary supplements

To make appropriate recommendations to athletes regarding dietary sup-
plements, one must have a basic understanding of their definition, classifica-
tion, and regulatory environment. An understanding of the dietary
supplement industry’s regulatory environment is enhanced by comparing
and contrasting it with that of the prescription drug industry. The notion
that the dietary supplement industry is unregulated is a common misconcep-
tion among health care professionals. Dietary supplements are regulated pri-
marily by the US Food and Drug Administration (FDA), but also by the
Federal Trade Commission (FTC); however, supplements are regulated
much differently, and much less rigorously, than are the drug products
that physicians prescribe every day. The FDA and the FTC cooperate in
regulating the dietary supplement industry [5]. The FDA is responsible for
product safety and labeling, including label claims and promotional litera-
ture at the point of sale [5]. The FTC regulates the advertising of dietary
supplements, including print and broadcast advertisements, infomercials,
catalogs, and Internet Web sites [5]. The Dietary Supplements Health and
Education Act of 1994 (DSHEA) is the preeminent legislation that compre-
hensively defines and governs dietary supplements in the United States [6].
Originally, the DSHEA was intended to facilitate greater consumer access
to dietary supplements that may have positive health benefits; in the process,
it weakened the FDA’s authority over the supplement market [7].
Definition and classification

Dietary supplements are classified as a subcategory of ‘‘foods’’ and have
a specific definition:
A product (other than tobacco) that is intended to supplement the diet
that bears or contains one or more of the following dietary ingredients:
a vitamin, a mineral, an herb or other botanical, an amino acid, a die-
tary substance for use by man to supplement the diet by increasing the
total daily intake, or a concentrate, metabolite, constituent, extract, or
combinations of these ingredients
CREATINE AND OTHER SUPPLEMENTS 737
Intended for ingestion in pill, capsule, tablet, or liquid form

Not represented for use as a conventional food or as the sole item of
a meal or diet
Labeled as a ‘‘dietary supplement’’ [6]
Product approval and assurance of safety

In contrast to drugs, supplements have much less stringent requirements
for new product approval. For drug products, ‘‘premarket approval’’ is re-
quired, in which the FDA requires extensive research data demonstrating
that a drug’s health benefits outweigh its risks before it approves the product
for sale [8]. In general, there is no premarket approval process for dietary
supplements (the exception being supplements that contain ‘‘new dietary in-
gredients’’; see later discussion). To market a supplement, the manufacturer
does not have to provide the FDA with any efficacy data per se, although
the manufacturer is responsible for the accuracy of claims it makes concern-
ing the product [9]. Regarding safety, if the supplement’s ingredients were
marketed in the United States before the passage of the DSHEA, then the
product is presumed to be safe, and the manufacturer can market the prod-
uct without providing safety data or even notifying the FDA [9,10]. How-
ever, if the supplement contains a ‘‘new dietary ingredient’’ (ie, one not
marketed before passage of the DSHEA), it is presumed to be unsafe, and
the manufacturer must provide the FDA with safety data at least 75 days
before marketing the product [9,11,12]. The FDA reviews this evidence
and decides whether to take action to prevent the product from reaching
the market [11]. The FDA has been stringent with new dietary ingredients,
accepting fewer than 30% of new dietary ingredient submissions [12]. This
process is conceptually similar to the process of premarket approval for
drug products, although there is an important distinction. When considering
a new drug application, the FDA performs a ‘‘risk/benefit’’ analysis to de-
termine whether it is adequately safe for use; however, the FDA is not re-
quired to assess a new dietary ingredient’s efficacy when it decides
whether there is reasonable assurance of safety to permit it to be marketed
[9]. This results in a great degree of subjectivity in this determination. ‘‘Ad-
equate safety’’ can only truly be determined when the degree of potential
benefit is known and considered. For the many dietary supplements that
have little or no evidence of significant benefit, it is difficult to determine
whether there is ‘‘adequate safety’’ to justify use.
Once on the market, the manufacturer (not the FDA) is responsible for
assuring the supplement’s safety, and the lack of diligence by manufacturers
in investigating side effects and safety issues has been criticized [4,10]. At this
point, the FDA can act against a product only if it poses a significant health
threat. In such situations, the FDA has the burden of proving that the use of
a supplement, as recommended on the label, is unsafe [8–10,13]. Then, the
US Secretary of Health and Human Services has the authority to order
738 LATTAVO et al
the supplement removed from the market; however, before doing so, the
government is required to convene hearings to review the evidence for tak-
ing such a measure, potentially delaying necessary action [5]. In recent years,
the FDA has taken action in this manner in removing several supplements
from the market, including ephedra and androstenedione.
Product labeling
Supplement product labeling has specific regulations, including (1) infor-
mation that must be presented on the label (eg, a statement identifying the
product as a dietary supplement with a list of ingredients present in ‘‘signif-
icant amounts’’ and their quantities); (2) information that needs not be pre-
sented (eg, disclosure of ingredients not present in ‘‘significant amounts’’);
and (3) claims that may be made about the product on its label and in its
package [6]. Several types of claims can be made about supplements. With
ergogenic supplements, the most pertinent of these are structure/function
claims, which are statements describing the effect of a supplement on the
structure or function of the body [14]. This type of claim also may describe
a mechanism by which the supplement acts to maintain such structure or
function [8]. Supplements with structure/function claims are not subject to
premarket review by the FDA, and a disclosure must be present on the label,
stating that the FDA has not evaluated the claim and that the product is not
intended to diagnose, treat, cure, or prevent any disease [8,14]. The manu-
facturer is responsible for the truthfulness of its claims, and, although the
DSHEA requires the manufacturer to have evidence to support them, there
is no requirement that such evidence be provided to the FDA for its review
before marketing the product [8,10]. Turner and colleagues [8] questioned
the degree to which the FDA has enforced misleading claims regulations,
stating that because of its limited resources it has made product safety
a higher priority. Their article is an excellent review of label claims for
supplements.
Quality assurance and standardization

The issues of quality of the manufacturing process and product standard-
ization raise concern as well. The FDA has the authority to establish current
‘‘good manufacturing practices’’ (GMPs) that are specific for dietary supple-
ments, but it has not done so [15]. The current GMPs for supplements are
the same as those for conventional food products, and the degree of enforce-
ment is questionable [7]. The FDA does not inspect manufacturing facilities,
and it does not routinely perform premarket or after-market testing of die-
tary supplements [11]. Product testing is done only if an adverse event occurs
that triggers concern about safety [10]. The manufacturer is responsible for
ensuring standardization and reliability [16]. Compliance with these require-
ments is clearly suboptimal, as numerous studies have analyzed individual
supplements and found them to contain ingredient quantities inconsistent

with quantities listed on the label (usually less than the stated amount, some-
times containing none of the stated ingredients, and sometimes even con-
taining ingredients not listed on the label, including substances that would
cause positive drug tests for banned substances) [17–21]. In 2001, Green
and colleagues [19] tested 12 different androgen precursor supplement
brands (legal at the time but currently banned by most sporting organiza-
tions) purchased from retail stores in Los Angeles, California; 11 were mis-
labeled according to DSHEA requirements. Most supplements contained
less than the stated amount, but one of them contained 10 mg of testoster-
one, an illegal anabolic steroid. Baume and colleagues [18] tested 103 legal
supplements obtained from Web sites in Europe and in America; 18%
were contaminated with substances not disclosed on the label. Most of
the contaminated supplements were androgen precursors, but one was a cre-
atine supplement contaminated with several androgen precursors that have
been known to cause positive urine tests for metabolites of nandrolone,
a banned anabolic steroid. One ‘‘mental enhancer’’ stated to contain caffeine
was found to contain an androgen precursor. Significant dose-to-dose vari-
ability also has been found within individual supplement packages [22].
Because of these findings, a supplement’s product labeling cannot be relied
upon to ascertain the actual ingredient content, especially when the stakes
are high for elite athletes [18]. From a scientific standpoint, the lack of uni-
formity makes supplements difficult to study [4]. To the athlete, these find-
ings are important for two reasons. First, if a supplement does not contain
the stated amount of an ergogenic ingredient, the athlete may lose the poten-
tial benefit of taking it. Second, athletes subject to drug testing who test pos-
itive for banned substances, aredin most jurisdictionsdjudged according to
the ‘‘strict liability’’ principle, which holds the athlete responsible for what is
found in his/her body, regardless of whether the athlete knowingly ingested
the banned substance [21,23].
Out of the lack of standardization and reliability have emerged several
independent agencies (eg, ConsumerLab.com, National Sanitation Founda-
tion International, and the U.S. Pharmacopeia’s Dietary Supplement Veri-
fication Program) that perform testing of supplements’ quality and integrity
[24–26]. They perform initial supplement analysis and random off-the-shelf
testing of supplements at the manufacturer’s request and expense, in ex-
change providing a seal of approval on the label if the product meets its
standards. ConsumerLab.com provides its findings to paid subscribers on
its Web site. These are several means by which athletes can verify the quality
and integrity of the products that they are considering using.
Commentary
Although the DSHEA established regulations for the marketing of die-
tary supplements, manufacturers’ compliance with regulations and the
740 LATTAVO et al
FDA’s enforcement of them have been seriously questioned [5,16]. Since the
passage of the DSHEA, the regulatory environment has evolved as the leg-
islation has been interpreted, and this process will continue in the future.
There is some evidence that the FDA is trying to regain more control
over the dietary supplement industry [7]. Wollschlaeger [5] contended that
the FDA and FTC have sufficient legislative authority to provide optimal
consumer protection from unsafe products and untruthful claims and adver-
tising, and that rather than establish new rules and regulations, adequate
funding and other resources should be provided to the FDA and FTC for
them to function as legally intended in the dietary supplement arena.
Creatine
Prevalence of use
Although creatine was discovered more than 100 years ago, and its use as
a performance-enhancing supplement has been occurring for some time,
there have been few studies on the frequency of use and patterns of use until
recent years, particularly among adolescents. One of the first large-scale
studies of creatine use was performed by the National Collegiate Athletic
Association (NCAA) in 1997. The study, which surveyed nearly 14,000 ath-
letes from Division I, II, and III, reported that 32% of those surveyed had
used creatine in the last 12 months [27]. Since that time there have been mul-
tiple other studies documenting the prevalence of creatine use among profes-
sional and collegiate athletes.
Given the high frequency of creatine use among professional and colle-
giate athletes, there has been legitimate concern regarding the use of creatine
by adolescent athletes. Smith and Dahm [28] were among the first to report
findings based primarily on adolescent athletes in 2000. Their study, al-
though small, showed that 8.2% of the athletes surveyed had ever used cre-
atine, and 52% of those were using it at the time of the survey. Users in their
sample were composed primarily (89%) of athletes who played football,
hockey, or basketball. Even more concerning, however, was the fact that
the primary source of information on creatine was their friends (74%). Sub-
sequently, 55% of their athletes did not know the dose of creatine they were
taking, and another 23% reported taking a dose higher than the recommen-
ded maintenance dose.
Given the significance of these findings, there has been other research in
this area. A 2001 study of 674 high school athletes in Tennessee and Georgia
reported that 16% of the athletes surveyed used creatine. Twenty-three per-
cent of the boys in the study used creatine, and 2% of the girls used it. The
study also found that creatine use tended to increase with age and grade. In
line with the previous study, 70% of the athletes surveyed reported taking
excessive amounts of creatine as a maintenance dose [29]. Another slightly
larger study at about the same time showed that 5.6% of athletes surveyed
in a suburban New York population admitted to taking creatine (8.8% of

boys and 1.8% of girls). In this study, creatine was used most commonly
by athletes who participated in gymnastics, hockey, wrestling, football, and
lacrosse. This study also showed an increase in creatine use with an increase
in grade in school, although it did show use as early as sixth grade [30]. Finally,
a 2001 study of Wisconsin high school football players showed that 30% were
using creatine, including more than 50% of the seniors surveyed [31].
These first studies were performed primarily using young athletes as
a population; however, more recent studies also showed significant creatine
use among all adolescents. A 2003 study of 333 Canadian adolescents
reported that 5.3% of those surveyed reported using creatine; those who re-
ported using creatine reported an average of 23 hours per week of physical
activity versus 12.2 hours for those who did not report creatine use. The lat-
ter numbers, however, were not significant based on the power of their study
[32]. A subsequent 2005 study of dietary supplement use in adolescents
showed that 4.7% of adolescents reported ever using creatine [33]. A recent
large-scale study of 15,000 adolescents showed that 8% of adolescents re-
ported using a legal performance-enhancing supplement in the past year;
youth participating in sports were about 1.5 times more likely to have
done so [34].
Mechanism of action
Although the use of creatine as a performance-enhancing substance
seems to be a new phenomenon, creatine originally was described in the
1830s by Chevreul; it has undergone extensive study since that time. Crea-
tine is a nonessential amino acid that is formed in the liver by a two-step
process from arginine and glycine; it also is found in varying amounts in dif-
ferent meats [35,36]. Creatine is taken up by muscle cells by way of a so-
dium-dependent transporter [36]. Once in the cells, creatine is believed to
have multiple functions through which supplementation may enhance exer-
cise performance. All of these major functions center around the following
reaction of the enzyme creatine kinase:
MgADP þ PCr2 þ Hþ4 MgATP2 þ Cr
Creatine then gives rise to five major functions within skeletal muscle cells
[37].
The first of these functions of the ‘‘phosphocreatine system’’ is to serve as
a ‘‘temporal energy buffer’’ within the cell. The main purpose is the direct
rephosphorylation of ATP from phosphocreatine as a means of ‘‘buffering’’
against changes in ATP during short-duration exercise [36]. This is corrob-
orated by the fact that there seems to be little difference in total cell ATP in
muscle cells whether they are contracted or relaxed [38]. In addition to being
an acute energy buffer for the regeneration of ATP within the cell, it is
742 LATTAVO et al
generally accepted that the phosphocreatine system serves as a transport sys-

tem for energy between sites of energy production and sites of energy use.
This is supported most significantly by a surprising amount of evidence re-
garding the compartmentation of creatine kinase isoenzymes within the cell
[37].
Not only does the phosphocreatine system give cells a specialized system
of energy buffer and energy transport, it serves three other biochemical func-
tions within the cell. The first of these is to buffer against an increase in in-
tracellular ADP, which prevents inhibition of ATP-dependent processes and
prevents a net loss of adenine nucleotide pools by way of adenylate kinase
[37,39]. The reaction also helps to prevent intracellular acidosis during exer-
cise by consuming hydrogen ions [36]. Finally, the system plays an impor-
tant role in providing an appropriate ATP/ADP ratio in localized areas of
the cell. For example, in muscle cells, the action of creatine kinase allows
for a larger amount of ATP at the myofibril, while providing a higher
amount of ADP at the mitochondria, which can then be rephosphorylated
to ATP by way of oxidative phosphorylation [37].
Although the physiologic effects of creatine within the body are impor-
tant and likely play a vital role in the effectiveness of creatine as a perfor-
mance-enhancing substance, there has been some evidence that ingestion
of exogenous creatine may have other effects within the cell. First of all, it
is believed that ingestion of creatine and uptake into cells increases water in-
take into the cells by osmotic action [40]. Secondary to this, there seems to
be an increase in body mass after ingestion of creatine, especially in young,
healthy men [36]. It also is theorized that the increase in intracellular water
may have the effect of decreasing the breakdown of protein within the cell
and possibly also increasing protein synthesis within the cell [41].
Recommended dosage
One of the major concerns regarding creatine use among adolescents is
that teens are getting much of their information from the wrong sources,
and, subsequently, are not taking creatine correctly. For instance, a recent
Internet search of ‘‘creatine dosage’’ performed by the authors using a pop-
ular search engine resulted in more than 1 million Internet sites. In addition,
there are hundreds of products on the market that contain creatine mono-
hydrate, as well as some of the newer formulations of creatine (eg, creatine
ethyl ester and magnesium-citrate chelate), each of which has its own label
recommendations for dosing. With all of this information, it is surprising
that there have been studies specifically designed to try and elucidate appro-
priate creatine dosing.
Most studies have used and tested creatine supplementation using a load-
ing regimen, usually 20 to 30 g/d for 2 to 10 days. This regimen seems to in-
crease stores of total creatine within the muscle by 15% to 30% [42];
however, Hultman and colleagues [40] showed that taking 3 g/d for 28
days resulted in the same increase in total muscle creatine concentration as

taking 20 g/d for 6 days followed by a 2-g/d maintenance regimen. This
study also showed that after the initial loading phase, muscle creatine con-
centration was maintained with a 2-g/d regimen. This latter fact was corrob-
orated in other studies [42,43].
Longer-term studies of creatine use also showed that there may be a slow
decrease in muscle creatine over time, despite continued supplementation
[44]. This is the primary reason why ‘‘cycling’’ came into being. Currently,
most creatine regimens recommended by manufacturers include three
phases: a loading phase (1 week), a maintenance phase (5–8 weeks), and
an off-cycle phase (2–4 weeks). The belief is that this type of regimen will
help to counteract the slow decrease in muscle creatine over time.
There also has been some research (and even more marketing) with dif-
ferent forms of creatine and creatine mixtures to try to enhance its effect.
Although overall results showed that there is likely little effect of any of
these above the effects of creatine itself, there has been some evidence to
show that ingestion of caffeine with creatine may negate its effects, whereas
ingestion of large carbohydrate loads with creatine may enhance cellular up-
take [36]. The load of carbohydrates required to attain this effect is large,
however, and certainly health effects related to repeated large loads of car-
bohydrates may preclude this regimen’s potential advantage.
Ergogenic value
A major controversy still exists surrounding the question of whether cre-
atine really works as a performance-enhancing supplement. Multiple review
articles in the last 10 years have come to the conclusion that creatine is ef-
fective at increasing power/force in short bouts of near maximal to maximal
exertion and increasing performance with repeated efforts of maximal exer-
tion [36,42,45,46]. In a 2005 review, Bemben and Lamont [43] looked at all
of the literature on creatine as an ergogenic drug since 1999 and categorized
the findings based on the type of outcomes measured. Their findings reiter-
ated previous findings, but more specifically, showed that creatine supple-
mentation seems to be most beneficial if dynamic or isotonic peak force is
assessed as the outcome measure. Conversely, isokinetic studies have had
mixed results, and measures of changes in isometric parameters showed
that there is likely little benefit of creatine supplementation.
There has been significant discussion with regard to the reasons why stud-
ies involving the ergogenic value of creatine have shown mixed results. One
of the most highly discussed reasons for this is the idea of ‘‘responders’’ ver-
sus ‘‘nonresponders.’’ This was highlighted by Lemon [47] in 2002, who
noted that some of the early studies of muscle creatine concentrations after
loading showed that, although the average increase in concentration was
15% to 30%, some study participants had minimal to no increase in muscle
creatine concentration. It seems that this effect is related to preloading
744 LATTAVO et al
muscle creatine concentration; participants with higher levels of creatine be-

fore supplementation seem to have less increase in muscle creatine with
supplementation.
Ergogenic value in adolescents

Although creatine has been studied meticulously in adults, there is signif-
icantly less information regarding the ergogenic value of the substance in ad-
olescents. There are studies, although rare, which showed that creatine is
likely to be effective as a performance enhancer in teenagers as well. The first
study of this type looked at the effect of creatine on competitive swimming.
In this article, Grindstaff and colleagues [48] showed that 9 days of creatine
supplementation improved the athletes’ (mean age, 15.3 years) performance
in a 100-m swim; however, they also showed that creatine decreased swim
times in subsequent 100-m swims. A similar effect of creatine was shown
later in a trial by Theodorou and colleagues [49], which was not placebo
controlled, involving swimmers (mean age, 17.8 years). A later study of soc-
cer players (mean age, 16.6 years) by Ostojic [50] showed that creatine sup-
plementation improved soccer-specific activities, specifically sprint power,
dribbling test, and vertical jump. Although this is far from conclusive evi-
dence, these trends seem to indicate that there may be an ergogenic value
of creatine in adolescents as well.
Adverse effects
At conventional doses, creatine seems to be safe in healthy athletes, al-
though long-term data (beyond 2–3 months of use) are sparse. Numerous
minor adverse effects have been reported, most of which are anecdotal in na-
ture and not supported by scientific data. There have been several case
reports of more serious adverse effects in which creatine was not clearly
causative. Most controlled studies report a complete absence of side effects,
do not address the issue of side effects, or report no difference in the inci-
dence of side effects between creatine and placebo [51]; however, some of
the studies investigating adverse effects have potential bias that is due to
funding by supplement manufacturers [52–54]. Further limiting extrapola-
tion of research findings to the playing field, most studies of adverse effects
have tested conventional doses, and surveys have indicated that most crea-
tine users exceed the recommended maintenance dose; therefore, the actual
incidence of adverse effects may be higher than reported [1,55]. Also, most
of the safety data derives from studies of athletes of collegiate age or older,
although one adolescent study reported no adverse effects [50].
Weight gain is the most well-documented side effect (0.5–2 kg in the first 2
weeks); it probably is due to water retention within muscle, which may be
advantageous or disadvantageous, depending on the particular sport
[52,53,56–58]. In one study, after a standard 5-day creatine load, subjects
gained an average of 1.04 kg, with men gaining 1.6 kg (2.0% of body weight)
and women gaining 0.45 kg (0.8% of body weight) [59].
Frequently, gastrointestinal (GI) side effects are reported anecdotally, in-
cluding nausea, diarrhea, dyspepsia, and abdominal pain, possibly due to mal-
absorption of high doses of creatine [51]; however, most studies do not indicate
an increase in these symptoms compared with placebo. In one study, 3 of 87
subjects taking creatine discontinued use because of intolerable nausea (1 sub-
ject) or diarrhea (2 subjects) [60]. In a retrospective study, several subjects re-
ported GI upset (excessive gas, diarrhea) during the loading phase [53]. The
incidence of GI side effects may be lower with dissolved powder than with cap-
sule forms of creatine [58]. Other adverse effects that have been reported
include rash, dyspnea, anxiety, headache, and fatigue [56].
The greatest safety concern with creatine is renal function; a large body of
research indicates that creatine supplementation has no detrimental effect on
renal function in healthy athletes, including longer-term studies of up to 5.6
years [51–53,59–64]. Creatine may cause reversible elevation of serum
creatinine (up to w30%) in athletes with normal renal function
[52,53,56,59,62,63,65], without causing a decrement in glomerular filtration
rate as measured by creatinine clearance (which remains unchanged because
urine creatinine concentration increases concomitantly) or other methods
[51,61]. There are several possible explanations for this increase: (1) the
increased muscle pool of creatine, which subsequently is converted to creat-
inine [51,65]; (2) creatine and creatinine cross-reactivity in commonly used
laboratory assays [1,60]; and (3) the ability of athletes to maintain a greater
training volume and intensity because of creatine’s ergogenic effect, with
increased creatine turnover [52,53,63]. Proteinuria has not been found to oc-
cur with creatine use [51,60,64,65]. It remains possible that high doses of cre-
atine over long periods of time may cause renal dysfunction [1]. One must
also consider that the trials investigating the renal effects of creatine were
conducted primarily in healthy, active, young men. This is the patient pop-
ulation that is most likely to use creatine; however, it limits the ability to
draw safety conclusions for other populations [61]. Data on the effects of
creatine on renal function and serum creatinine concentrations in patients
who have renal disease or other comorbidities are not available [61]. The
slight increase in creatinine that normally is observed with creatine use
may confound the estimation of renal function in athletes who have renal
disease [61,65], and, as an amino acid by-product, creatine theoretically
may worsen renal function in such patients [58].
Creatine has been studied and found to have no clinically significant ef-
fect on blood pressure [58,59], liver enzymes [51–53,62,63], electrolytes [52],
glucose [52], uric acid [53], hematologic parameters [52,53,59,62], or muscle
enzymes [52,59,62]. Some studies indicated a modest favorable effect on lipid
parameters of uncertain clinical significance [52,53]. There have been anec-
dotal reports of muscle cramps and stiffness, musculotendinous injury, de-
hydration, and heat illness, but the research to date indicates that creatine
746 LATTAVO et al
does not increase the incidence of these effects [4,43,51–54]. The incidence of
musculoskeletal injuries and heat illness actually may be decreased by crea-
tine [54]; however, there is evidence that creatine may increase muscle com-
partmental pressures in the leg [58].
Several case reports of more serious adverse effects are found in the liter-
ature. These include:
New onset of lone atrial fibrillation during the creatine loading phase [66]
Interstitial nephritis and focal tubular injury in a previously healthy
20-year-old man taking creatine, 20 g/d, for 4 weeks, which resolved
with discontinuation of creatine [67].
Worsening renal function (elevated serum creatinine and decline in glo-
merular filtration rate) after initiating a standard-dose regimen of cre-
atine in a 25-year-old man who had focal segmental glomerulosclerosis
and frequently relapsing steroid-responsive nephrotic syndrome, tak-
ing a therapeutic dose of cyclosporine. His renal function normalized
1 month after stopping creatine [68].
Rhabdomyolysis and acute renal failure following arthroscopic anterior
cruciate ligament reconstruction in a 21-year-old, previously healthy
college football player who had been taking creatine preoperatively,
up to 10 g/d for 6 weeks, with full recovery [69].
Acute quadriceps compartment syndrome and rhabdomyolysis in a
24-year-old male bodybuilder taking creatine, 25 g/d, and no other
supplements or anabolic steroids, after a lower extremity resistance
training session. He underwent fasciotomy, had a complicated postop-
erative course, and at 6 months, his quadriceps strength was just 60%
of his baseline strength. The investigators stated that creatine may have
predisposed him to compartment syndrome by increasing water con-
tent in the muscle cells, and, thus, increasing baseline compartment
pressures, a hypothesis that has some scientific support [55,58].
The Physician’s Desk Reference states that contraindications to creatine
use include renal failure and other renal disorders, including nephrotic syn-
drome, and it should be avoided in children, adolescents, pregnant women,
nursing mothers, diabetics, and other persons at risk for renal disease [56].
Because of theoretic concerns of dehydration and heat illness, athletes tak-
ing creatine are recommended to drink six to eight glasses of water per day
[56]. Other sources also recommend that athletes who have known or sus-
pected renal disease or who are taking nephrotoxic medications should
avoid creatine [64,65]. Because of the relative lack of long-term safety
data, some investigators recommend laboratory monitoring of liver, muscle,
and kidney function, including testing for proteinuria under resting condi-
tions (after R20 hours of physical inactivity) [58,61].
Safety is less certain for adolescent and younger athletes, and some au-
thorities, including the American College of Sports Medicine, conclude
that physicians should recommend against creatine use in adolescents
[1,56,57]. Also, its effects on other creatine-containing tissues, such as the

brain, cardiac muscle, and testes, are unknown [4]. There also is concern
that creatine may function as a ‘‘gateway substance’’ that may prompt
a young athlete to consider other ergogenic aids, such as anabolic steroids
[1]. Overall, however, the published literature provides an excellent safety re-
cord for creatine supplementation at standard dosages, with the foregoing
caveats kept in mind.
Beta-hydroxy-beta-methylbutyrate
HMB, a metabolite of the essential branched-chain amino acid (BCAA)
leucine, is produced endogenously in small amounts and contained in foods
such as catfish, citrus fruits, and breast milk [22]. It also is known as hydrox-
ymethylbutyrate, beta-hydroxyisovalerate, and 3-hydroxyisovalerate [70]. It
is promoted as an ‘‘anticatabolic’’ agent that exerts an anabolic effect by
suppressing protein breakdown and cellular damage after intense exercise,
thereby allowing quicker recovery and increased lean body mass and
strength [4,46,57]. HMB also is a cholesterol precursor, and its promotion
of muscle growth may be due to its provision of a larger supply of choles-
terol for cell membrane synthesis to ‘‘patch up’’ local deficiencies of mem-
brane cholesterol that are believed to occur with muscular hypertrophy
[71]. It also may have immunomodulatory properties [70]. HMB may be at-
tractive to adolescents because of its purported ‘‘muscle-building’’ effects
that may positively affect physical appearance, regardless of its effect on
muscle performance [72].
The typical dosage of HMB is 1.5 to 3 g/d. Higher dosages do not seem to
offer additional benefit [71,73,74]. Most of the studies investigating the effect
of HMB on muscle strength and body composition have been 3 to 8 weeks
in duration. In one of the original studies of HMB, a dosage of 1.5 to 3 g/d im-
proved strength and muscle mass gains in untrained subjects undertaking
a resistance-training regimen [75]. Other studies have corroborated these
findings [4,46,57,71,74]; however, studies have found little to no benefit
for trained athletes [4,46,76]. This may be explained by the fact that physical
training itself stimulates adaptation in the athlete, such that subsequent ex-
ercise is accompanied by less protein turnover and breakdown (ie, training
has an anticatabolic effect). Therefore, trained athletes would receive less, if
any, benefit from an anticatabolic agent like HMB [74]. From a muscle
damage standpoint, HMB was shown to reduce levels of markers of muscle
damage (eg, creatine phosphokinase, lactate dehydrogenase) after exercise,
such as distance running and weight training [75,77]. These outcomes, how-
ever, are merely surrogate end points for the athlete who seeks to realize ac-
celerated recovery from exercise sessions, and studies examining the effect of
HMB on real-life outcomes, such as delayed-onset muscle soreness, have
been conflicting [78,79]. One interpretation of the available evidence is
that although it seems that HMB may enhance the untrained athlete’s initial
748 LATTAVO et al
adaptation to resistance training in the short-term (3–8 weeks), nonusers

eventually will ‘‘catch up,’’ such that HMB probably does not enhance
the athlete’s ultimate performance potential that is achieved by optimal
training without supplementation. Although HMB has not been studied
in this manner, it may be useful for a 4- to 8-week period at the beginning
of training, after which it may be discontinued without detrimental effect.
There are no reported adverse effects of HMB in limited short-term stud-
ies, including no changes in blood pressure, liver enzymes, lipid profile, renal
function, electrolytes (except a decrease in bicarbonate level of unclear sig-
nificance), hematologic parameters, urinalysis, testosterone, cortisol, or
male fertility [4,70,80,81]. There are no contraindications, although the Phy-
sician’s Desk References advises to avoid HMB in pregnant and lactating
women [70]. No studies exist in adolescents or in long-term supplementa-
tion, and one investigator advises physicians to recommend against use by
adolescent athletes until more data are accumulated [67].
Protein and amino acids

Athletes use protein supplements to increase body mass and strength and
enhance recovery from exercise. Although athletes, especially strength-
trained athletes, are known to require more dietary protein than nonathletes
to maintain a positive nitrogen balance, intake of excess protein does not pro-
vide additional gains in strength or mass [82]. Although the recommended
protein intake for sedentary individuals is 0.8 to 1.0 g/kg/d, strength-trained
athletes require 1.6 to 1.7 g/kg/d, which is not difficult to achieve from whole
food sources [46,82]. There is no evidence that ingesting protein above recom-
mended levels improves muscle growth; however, protein supplements may be
useful to meet bodily needs for athletes who ingest inadequate amounts in
their diets (eg, vegetarians, athletes following restrictive diets) [46].
There is evidence, however, that the timing and composition of protein/
amino acid intake in relation to exercise sessions may affect the athlete’s
physiologic response to training. For optimal muscle anabolism following
exercise, amino acids must be made available to the muscle, and adequate
insulin must be present to enable muscle to use them. It is known that cer-
tain amino acids stimulate insulin release. Postexercise ingestion of a ‘‘recov-
ery drink’’ containing insulinotropic amino acids with carbohydrate
stimulates increased pancreatic insulin release, which stimulates muscle
anabolism. Of these amino acids, leucine seems to be most important. A
protein supplement that contains amino acids in dipeptide and tripeptide
forms results in the most rapid increase in blood amino acid levels following
exercise, because these forms are absorbed fastest by the GI tract. Protein
hydrolysates, such as whey protein and casein protein, contain amino acids
in these forms and may be advantageous to the strength-trained athlete [83].
There are several particular amino acids that are used by athletes and
merit discussion. Glutamine is known to be used by immune cells, and
some athletes use protein hydrolysate supplements enriched with glutamine

in an attempt to optimize immune function along with the previously men-
tioned anabolic effects [46,82,83]. The BCAAs leucine, isoleucine, and valine
are purported to aid in endurance exercise by counteracting central fatigue,
possibly by interfering with tryptophan kinetics or other mechanisms
[72,84–87]. Supplements containing BCAAs may prove to be helpful for
sports such as tennis, soccer, distance running, cycling, and swimming
[72]. The research has been conflicting, and further study is needed
[84,85]. One recent study of elite outrigger canoeists found that 6 weeks of
leucine supplementation (45 mg/kg/d) significantly increased time to exhaus-
tion and peak upper body power and decreased the rating of perceived
exertion throughout a 55-minute period of rowing [88]. The investigators
noted that most previous studies of leucine in exercise used single or multiple
doses on the day of testing, whereas their study used leucine for a 6-week
period before testing [88]. The catabolism of BCAAs is thiamine dependent,
and the use of them may require increased thiamine intake [72]. Several
other amino acids are known to stimulate growth hormone secretion (argi-
nine, lysine, and ornithine) and increase nitric oxide synthesis (arginine) in
addition to their direct role in protein synthesis [46,86]. Whether they
have any ergogenic effect, however, is unclear [86]. It remains possible
that there exists optimal combinations of amino acids, including those
described above, that will produce significant ergogenic effects, and the con-
coction may vary for different athletic activities.
Stimulants
Caffeine
Caffeine, a trimethylxanthine with stimulant properties, has strong evi-
dence of ergogenicity. Approximately 27% of adolescent athletes in the
United States report caffeine use for performance enhancement [89]. In ath-
letics, it is used mainly for enhancement of submaximal aerobic and endur-
ance activities [46,89]. It may have other applications, such as team sports.
Caffeine has a myriad of physiologic effects, on the central nervous system
and on peripheral body systems, which contribute to its ergogenic effects.
Caffeine’s key physiologic mechanism may be adenosine receptor antago-
nism [90]. Adenosine inhibits central nervous system (CNS) neurotransmis-
sion, decreases catecholamine release, and inhibits lipolysis; caffeine affects
all of these in the opposite manner (CNS stimulation, increased catechol-
amine release and lipolysis) [46,72,90]. Regular caffeine use causes up-regu-
lation of adenosine receptors, which may contribute to tolerance in habitual
users [90]. CNS activity may be affected by caffeine through other mecha-
nisms as well [57,82]. Stimulation of lipolysis functions to mobilize free fatty
acids to be used by exercising muscle, thus sparing glycogen stores [72].
Other mechanisms may include increased contractility of skeletal and
750 LATTAVO et al
cardiac muscle (by way of mobilization of intracellular calcium, sensitiza-

tion of myofibrils to calcium, and other mechanisms) [57,72,82], increased
metabolic rate [23], increased cortisol levels [46], and antioxidant activity
[46]. Caffeine is known to increase heart rate and blood pressure [46]. It is
absorbed rapidly from the GI tract, with 90% cleared from the stomach
within 20 minutes of ingestion, peak plasma concentrations reached in 40
to 60 minutes, and a half-life of 3 to 5 hours [90].
Caffeine may produce ergogenic effects at doses as low as 250 mg (3.0–3.5
mg/kg body weight) [82]; most studies showing benefit used doses around
400 to 600 mg [90], and on a body-weight basis, a reasonable dose would
be 5 mg/kg [72]. In the past, caffeine was banned by the World Anti-Doping
Agency (WADA) above a threshold urinary concentration, but in 2007 it is
legal at any level [91]; however, the NCAA has set an upper legal limit of 15
mg/mL in urine [92]. A 100-mg dose of caffeine increases urine levels by ap-
proximately 1.5 mg/mL; therefore, 800 to 1000 mg would need to be ingested
to approach the legal limit [90]. Because exercise reduces the urinary excre-
tion of caffeine, however, the correlation between oral dose and subsequent
urine concentration is unpredictable [72]. Most studies have used caffeine in
capsule form. In comparison with caffeine ingested in coffee, plasma caffeine
levels are similar, but enhancement of endurance is observed only when caf-
feine is consumed independent of coffee, indicating that there are substances
in coffee that antagonize the ergogenic effects of caffeine [90]. Caffeine also
may be effective in ‘‘defizzed’’ soft drinks, which also provide a source of
simple carbohydrate, although the caffeine concentration is low in this
form. This practice is common among endurance and ultradistance athletes
[90]. Caffeine’s positive effect occurs regardless of whether it is ingested in
single or multiple doses or before or during exercise, and its effect seems
to be prolonged as much as 6 hours postingestion [90]; however, its benefits
may depend on abstinence for several days before use [72], and its effect is
more pronounced in relative nonusers (!50 mg/d) than in regular users
(O300 mg/d) [90].
Caffeine was shown to reduce perception of fatigue and increase time to
exhaustion in submaximal exercise of 30- to 60-minute duration (running
and cycling) [46,89]. It also was shown to reduce times to run a set distance
and to improve 1500-m swim times [90]. Caffeine does not seem to be useful
for sprinting or short-burst activity [46,72], but it may be effective for sports
involving repeated short bursts of activity interspersed in more prolonged
activity, as in tennis and team sports [90,93]. During periods of sleep depri-
vation, caffeine improves alertness, neurocognitive performance, and aero-
bic performance [23,90].
Common adverse effects of caffeine are insomnia, tremors, headache [23],
anxiety [57], flushing [72], palpitations [46], premature ventricular contrac-
tions [90], and supraventricular arrhythmias [23]. Caffeine is believed to
have a diuretic effect, but it seems not to have this effect when used imme-
diately before exercise, and there is no evidence that it causes dehydration
[57,72]. Habitual caffeine use produces physiologic dependence, in which the

body’s ‘‘normal’’ state becomes the caffeinated state, and performance de-
clines in its absence [23]. Withdrawal symptoms, including headache, irrita-
bility, decreased alertness, difficulty concentrating, and increased fatigue,
occur as soon as 12 hours after cessation of use in habituated users [90].
There is concern that caffeine may increase core body temperature [90].
Of greatest concern are the reports of sudden deaths in athletes taking sup-
plements containing caffeine and ephedra. None of these events occurred
with supplements containing only caffeine, however, and the deaths were be-
lieved to be due to ephedra [90]. As with most dietary supplements, there is
much more scientific evidence in adult subjects than in adolescents, and al-
though adult studies indicate safety of use, some investigators contend that
there is not enough evidence to make recommendations regarding the use
and safety of caffeine in adolescents [57].
Ephedra and other stimulants

Ephedra sinica, also known as Chinese ephedra or ma huang, is a shrub
native to northern China and Mongolia. It contains ephedrine alkaloids, in-
cluding ephedrine (the primary alkaloid), pseudoephedrine, norephedrine,
and norpseudoephedrine, that mediate its physiologic effects. There is an
ephedra species native to North America, Ephedra americana, which has
no ephedrine alkaloid content [94]. Ephedrine has been used traditionally
as a cold remedy. Other sports-related uses include weight loss, appetite sup-
pression, increased alertness, and improved performance when fatigued
[2,4,23,57]. There is little evidence of any benefit to ephedra use for athletic
purposes [94]. Ephedra was banned by the FDA in 2004 because of numer-
ous severe adverse effects associated with it, including several deaths, and it
is banned by virtually all amateur and professional sports-governing bodies
[94]. It is a sympathomimetic, with CNS, cardiovascular, and metabolic ef-
fects mediated directly and indirectly by way of catecholamine release
[94,95]. It has a myriad of adverse effects, including hypertension, insomnia,
anxiety, tremors, headache, dependence, psychosis, nephrolithiasis, seizures,
arrhythmias, strokes, myocardial infarction, and several deaths
[23,57,94,96]. It may still be available to athletes by way of the Internet.
Ephedra’s risks clearly outweigh its benefits; it is obvious that the physi-
cian’s recommendation must be that ephedra should not be used by any ath-
lete for any purpose.
Since ephedra was banned, many supplement manufacturers have
replaced it with Citrus aurantium. Other names for this botanical are bitter
orange, Seville orange, sour orange, Zhi shi (Chinese), Kijitsu (Japanese),
and Chisil (Korean) [97]. It contains synephrine, also a sympathomimetic,
which has similar effects as other ephedrine alkaloids, although it is a milder
stimulant than ephedrine [23]. Citrus aurantium is banned by the NCAA but
not by the WADA [91,92]. It has been studied for weight loss only in
752 LATTAVO et al
combination with other substances (caffeine, ephedrine, and others), and

even then there is no long-term evidence of efficacy [98]. Elevated blood
pressure has been observed with Citrus aurantium, and drug interactions
are likely because it is a potent inhibitor of the cytochrome p450 enzyme
CYP3A4 [97]. There have been case reports of myocardial infarction, vari-
ant angina, ischemic colitis, seizure, syncope, and stroke associated with its
use [98–101]. Athletes should be strongly advised to avoid these supplements
as well.
Alkalotic agents
The most commonly used agents in this class are sodium bicarbonate
(NaHCO3) and sodium citrate. They are used to delay fatigue and improve
high-intensity anaerobic exercise performance [46]. They are believed to
work by increasing extracellular pH, thus enhancing the extracellular buffer
capacity. During high-intensity exercise, glycolysis produces lactic acid,
which dissociates into hydrogen ions (Hþ) and lactate, which decrease intra-
cellular pH. At lower intracellular pH, glycolytic enzyme activity is inhibited
and fatigue ensues. By increasing the extracellular pH and increasing the pH
gradient across the cell membrane, alkalotic agents delay the decrease in in-
tracellular pH by enhancing efflux of Hþ and lactate out of the myocyte,
hence improving contractile activity and delaying fatigue [102]. Their effect
on performance may involve other mechanisms, including CNS effects and
increased plasma volume [103].
Study results, however, have been conflicting. They may be beneficial
only for exercise activities in which the acidosis of exercise is the limiting fac-
tor in performance. If the exercise task does not use fully the body’s endog-
enous buffer system, then augmenting with buffering agents would not be
expected to improve performance. This may be why studies generally have
not shown alkalotic agents to be beneficial for exercise lasting less than 30
seconds or in strength/resistance exercise [46,102]. Studies failing to show
benefit may be limited by insufficient dosing, the exercise protocol itself (fail-
ure to challenge the body’s buffering capacity), characteristics of study sub-
jects (eg, elite, anaerobically trained athletes familiar with the exercise
protocol may benefit more than less-trained subjects), or other factors
[102,104]. High-intensity exercise (80%–125% of VO2 max for 1–7 minutes)
that involves large muscle groups and recruits fast motor units is most likely
to benefit (eg, mountain bike downhills, track and road cycling, running
[800–3000 m distance, possibly up to 10,000 m], and prolonged intermittent
bouts of intense exercise as in team sports) [46,102,105,106]. Although alka-
lotic agents do not increase time to exhaustion, they have been shown to
decrease rating of perceived exertion at a given intensity and improve
5000-m running time by 30 seconds in trained collegiate runners [103].
Alkalotic agents are legal in all jurisdictions but may cause a problem for
athletes undergoing drug testing. Because they cause urine alkalinization,
which can mask the presence of some banned substances, the athlete may be
withheld at the point of testing until urine pH normalizes [102]. For sodium
bicarbonate, 0.3 g/kg body weight seems to be the minimally effective dose,
and it is unclear whether higher doses provide greater benefit. The increase
in pH peaks at 100 to 120 minutes postingestion. For sodium citrate, 0.5 g/
kg is the most effective dose, and pH peaks at 120 minutes postingestion
[102]. Sodium bicarbonate also has been studied in a chronic dosing regimen
(0.3–0.5 g/kg daily for 5–6 days) and was shown to improve performance
similarly to acute dosing, with the alkalotic effect persisting for up to 2
days after the final dose [104]. Both agents are limited by GI side effects
(nausea, cramps, diarrhea), which may be problematic during the 60 to
120 minutes before exercise [103,104]. Chronic daily dosing offers the poten-
tial advantage of circumventing these side effects [104]. Excessive doses of
alkalotic agents are known to cause severe metabolic alkalosis (with compli-
cations such as arrhythmias and respiratory failure), and there have been
several reports of gastric rupture due to bicarbonate conversion to carbon
dioxide in the stomach, although none of these is known to have occurred
in athletic situations [107].
Glycerol
Glycerol is an osmotically active molecule that is used to optimize hydra-
tion status for the purpose of improving performance in warm conditions
[108]. It acutely (up to 4 hours) increases total body water, but as a prehydra-
tion method it has had conflicting results in studies of exercise performance
[108,109]. Also, when used for ‘‘hyperhydration’’ before exercise, it has had
adverse effects of GI upset, headache, and blurred vision [109]; however,
a recent study showed that rehydration with glycerol after an exercise ses-
sion inducing dehydration (4% body weight) significantly improved time
to exhaustion in a subsequent exercise session 90 minutes later in trained
male cyclists, compared with rehydration with water alone. None of the sub-
jects experienced adverse effects [109]. Glycerol has been shown to be safe in
doses of up to 5 g/kg body weight [109]. It may be useful for athletes who
undertake multiple exercise sessions daily (eg, football players in preseason
practices, all-day tournaments in other team and individual sports).
Vitamins and minerals

The dietary reference intakes for all known vitamins and essential min-
erals are available at http://www.iom.edu/Object.File/Master/21/372/0.pdf.
As a general rule, there is no benefit to supplementation of vitamins and
minerals above the recommended daily amounts. With an adequately bal-
anced diet, the athlete without any medical condition that predisposes to
754 LATTAVO et al
vitamin deficiency will not enhance performance by supplemental intake

[46]; however, athletes who follow restrictive diets may benefit from supple-
mentation if their diet does not provide recommended amounts [23]. It may
be reasonable to recommend that athletes who are at risk for, or concerned
about, micronutrient deficiency take a daily multivitamin supplement. Sev-
eral micronutrients are discussed further.
Iron supplements are used commonly by athletes for performance en-
hancement, a practice that can be helpful or harmful. In the presence of
iron-deficiency anemia, which is more common in young athletes than in
the general population, supplementation is clearly beneficial for perfor-
mance [46,110]; however, the diagnosis can be difficult to establish in ath-
letes. In response to training, hemoglobin concentration decreases
transiently as the plasma volume expands to a greater degree than does
red cell mass, the so-called ‘‘sports anemia.’’ Ferritin levels also decrease,
but this usually does not indicate true iron deficiency. An elevated serum
transferrin receptor level is a more specific indicator of iron deficiency
than is a low ferritin level in athletes, rendering it a useful test in this
case. Studies of iron supplementation showed objective performance im-
provement only in athletes who had iron-deficiency anemia or untrained
individuals with low ferritin levels. Athletes with normal or low ferritin
levels do not benefit from supplementation. The risks for empiric iron sup-
plementation include overlooking a serious medical condition that presents
with anemia (eg, celiac disease, occult gastrointestinal bleeding, gynecologic
disease), as well as the complications of iron overload, including hemochro-
matosis and diabetes mellitus [110].
Chromium is an essential trace element that is used by athletes for mod-
ifying body composition (eg, muscle building, decreasing body fat). It is
most commonly ingested as chromium picolinate in quantities that provide
approximately 100 times the recommended amount because of greater bio-
availability compared with dietary chromium; however, a large body of sci-
entific evidence indicates that chromium has no effect on body composition
when taken in this form, and there are serious concerns for the potential ad-
verse effects of chromium accumulation within the body. Evidence of muta-
genicity has been found in animal studies, and there have been human
reports of anemia, thrombocytopenia, hepatic dysfunction, renal failure,
rhabdomyolysis, dermatitis, neurologic disturbances, hypoglycemia, and
exanthematous pustulosis [111].
The Gateway Theory

In addition to their inherent risks, the adolescent use of dietary supplements
has been linked to an increased risk for using illegal performance-
enhancing substances (eg, anabolic steroids, growth hormone, erythropoietin)
[3]. Dodge and Jaccard [34], in their analysis of the Add Health database
(w15,000 respondents), found that adolescents who report the use of any legal
ergogenic supplement are nearly 26 times more likely to report the use of
anabolic steroids compared with adolescents who do not report the use of legal
supplements. This relationship is concerning, because it indicates that the use
of legal dietary supplements may function as a ‘‘stepping stone’’ or ‘‘gateway’’
to illegal or more harmful types of substance use. Although this relationship
has been observed in other types of substance abuse, such as alcohol, tobacco,
and marijuana, the potential for dietary supplements to function similarly
remains to be clarified [3].
The Gateway Theory is complex and involves three interrelated hypoth-
eses. ‘‘Sequencing’’ implies that there is a fixed relationship between two
substances, such that one substance is regularly initiated before the other.
‘‘Association’’ implies that initiation of one substance increases the likeli-
hood of initiation of the second substance. ‘‘Causation’’ implies that the
use of the first substance actually causes the use of the second substance
[112]. The Gateway Theory predicts a positive, sequential relationship be-
tween the use of legal substances (eg, ergogenic dietary supplements) and
the use of illicit substances (eg, anabolic steroids), in which the use of legal
substances is followed by the use of illegal substances [34]. This relationship
may be causative, such that the use of legal substances causes a person to
proceed to using illicit substances, although such a relationship has never
been proven. Alternatively, it is possible that the use of ergogenic supple-
ments and anabolic steroids is part of a ‘‘problem behavior cluster,’’ a hy-
pothesis that risky behaviors in adolescents often co-occur because
adolescents learn risk behaviors together, learn it is socially appropriate
to engage in such behaviors simultaneously, or the behaviors share some
other underlying cause. Dodge and Jaccard [34] found a low correlation be-
tween performance-enhancing substance use and other ‘‘risky’’ behaviors,
such as binge drinking, drug use, and injectable drug use; hence they con-
cluded that their findings are better explained by the Gateway Theory.
Regardless of whether the relationship between legal supplement use and
anabolic steroid use is causative, or merely sequential or associational, there
is practical application to adolescent medical care. At preparticipation ex-
aminations and routine health maintenance visits, the physician should in-
quire about past and present ergogenic dietary supplement use and
whether the patient is considering using supplements in the future. This
will identify patients who may benefit from education about legal supple-
ments and more extensive counseling about the risks and consequences of
illegal performance-enhancing substance use.
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The History of the Development

of Anabolic-Androgenic Steroids
Jennifer L. Dotson, MDa,*, Robert T. Brown, MDb,c
a
Department of Pediatrics, Columbus Children’s Hospital, 700 Children’s Drive,
b
The Ohio State University College of Medicine, Columbus, OH, USA
c
Section of Adolescent Health, Columbus Children’s Hospital, 700 Children’s Drive,
Anabolic-androgenic steroids (AASs) are synthetic derivatives of testos-

terone. The term ‘‘androgenic’’ indicates masculinizing. Androgens are
responsible for stimulating the growth of the male reproductive tract and
secondary sex characteristics. The term ‘‘anabolic’’ indicates tissue building
and is the component of a steroid which is responsible for thickening of the
vocal cords, enlargement of larynx, increasing libido, linear growth acceler-
ation before epiphyseal plate closure, increasing muscle bulk and strength
through dose-dependent hypertrophy, and decreasing body fat [1–3]. The
anabolic action is mediated by androgen receptors on skeletal muscle [2].
Testosterone increases muscle protein synthesis, thus increasing the cross-
sectional area of the fibers themselves, as well as increasing the myonuclear
number [2,3].
The history of AASs is a tale that has its roots in ancient ‘‘endocrinol-
ogy.’’ More than 6000 years ago, farmers noted an enhanced ability to do-
mesticate animals after castration. Years later, the medical theories of
‘‘humoralism’’ developed. This doctrine was based on a theory that attemp-
ted to explain diseases based on imbalances among the four humors: san-
guine, choleric, melancholic, and phlegmatic [4]. In addition, ancient
Egyptians and Romans believed that testicles and animal penises held spe-
cial healing powers [1]. Ancient Greek athletes used a wide variety of alleged
performance-enhancing drugs, such as plant extracts and testicular extracts.
These early theories and practices marked the beginning of future
discoveries.
E-mail address: [email protected] (J.L. Dotson).
762 DOTSON & BROWN
John Hunter (1728–1793) was a Scottish surgeon who was later ap-
pointed as Surgeon General for the British army. He made many notewor-
thy contributions to science, including contributions to the understanding of
digestion, fetal development, venereal diseases, dentistry, and lymphatics.
He conducted the first testicular transplant in 1786 in which he removed
a testicle from a rooster and implanted it into a hen.
It was not until 1849 that Arnold Adolf Berthold (1803–1861) found ev-
idence of a ‘‘bloodstream substance’’ from roosters that affected their ap-
pearance and behavior. His theory was correct, but it was not widely
accepted by his contemporaries. Berthold was a professor at the University
of Göttingen, and he performed experiments on roosters while he was a cu-
rator at a local zoo. He observed the impacts of castration and the reimplan-
tation of testicular tissues on roosters. Once castrated, the roosters’ combs
decreased in size, they lost interest in the hens, and they lost their aggressive
male behaviors. Those effects were reversed after reimplanting testicular tis-
sues or extract, despite denervation [4,5]. Despite these findings, other re-
searchers did not cite Berthold’s work for nearly 50 years.
Perhaps the most well-known researcher of anatomy and physiology was
Charles Edouard Brown-Sequard (1817–1894). Brown-Sequard, a prominent
French physiologist and Harvard professor, was one of the founders of mod-
ern endocrinology [4]. He had a strong interest in endocrinology, and he
studied adrenal glands, testes, thyroid, pancreas, liver, spleen, and kidneys.
He is probably most famous for his auto-experimentation with testicular
substances (extracted from guinea pigs and dogs), the results of which
were published in 1889 [1,4]. He reported increased strength, mental abil-
ities, and appetite and even claimed that the process relieved constipation
and increased the arc of his urine stream [1]. Although no one is sure why
he experienced these effects [5], his experiment caused others to investigate
the testicular substance as a possible cure for various ailments, such as di-
abetes, tuberculosis, epilepsy, paralysis, gangrene, anemia, influenza, arte-
riosclerosis, Addison’s disease, hysteria, and migraine headaches. He
encouraged testing of his testosterone products by providing free samples
to physicians [1]. Unfortunately, with such widespread use, shoddy re-
searchers subjected animals and humans alike to high risks for infection
and inflammation [4].
Austrian physiologist Oskar Zoth was the first person to propose inject-
ing athletes with a hormonal substance, as published in his 1896 paper de-
scribing how the use of an ‘‘extract’’ improved muscular strength and the
‘‘neuromuscular apparatus,’’ thus potentially improving athletic perfor-
mance [1]. He and his physician partner, Fritz Pregl (1869–1930), self-in-
jected testosterone extracts from bulls and measured the strength of their
middle fingers by plotting them on ‘‘fatigue curves’’ [1]. They won the Nobel
Prize in chemistry in 1923.
Substances referred to as ‘‘chemical messengers’’ were discovered in
1902 by English physiologists and professors, William Maddock Bayliss
DEVELOPMENT OF ANABOLIC-ANDROGENIC STEROIDS 763
(1860–1924) and Ernest Henry Starling (1866–1927), at University College

London. Bayliss’ research team was the focus of an animal rights contro-
versy in 1903dthe Brown Dog Affairdin which Bayliss was alleged to
have performed a live dissection of a brown dog in his laboratory. He, of
course, denied the accusation and won a civil suit, donating the money to
the University for further research; he even wrote articles promoting the hu-
mane treatment of animals. Other accomplishments included contributions
on shock, digestive system, and endocrinology; being knighted in 1922; and
authoring four editions of Principles of General Physiology. Starling offi-
cially coined the term ‘‘hormone’’ in 1905 when giving a Croonian Lecture
(prestigious lectureships) titled ‘‘The Chemical Control of the Functions of
the Body’’ to the Royal College of Physicians [1,4–6]. The term ‘‘hormone’’
means ‘‘to urge on’’ or ‘‘impulse or arouse’’ in the sense of ‘‘to set in mo-
tion’’ in Greek. Years later, reports suggested that a Cambridge physiolo-
gist, William B. Hardy, actually suggested the term ‘‘hormone’’ to Bayliss
and Starling. In 1911, Andre Pezard first noted a direct relationship between
the amount of testicular extract injected into a rooster and the size of his
comb [1].
An Austrian physician, Eugen Steinach (1861–1944), developed the ‘‘Stei-
nach operation,’’ an ‘‘autoplastic’’ treatment for the ‘‘middle-aged and list-
less’’ [4]. The 20-minute operation involved ligation of the vas deferens,
often at the most proximal position to the testicle. This allegedly increased
testosterone production. He believed that the incision produced a ‘‘back
pressure’’ on the testicle, thus increasing testosterone production by the in-
terstitial cells. He also implanted testicular tissue grafts between the perito-
neal muscles. He reported that his patients were able to regrow hair, had
better erections with less premature ejaculation, and had increased libido.
Despite little clinical evidence of his claims on ‘‘rejuvenation,’’ the results
of his operations, at best, likely were due to the power of suggestion; how-
ever, he performed this procedure on some famous patients, including Sig-
mund Freud and William Butler Yeats. He also discovered, by
transplanting male sex glands into females and vice versa, that guinea pigs
developed sexual behaviors of the opposite sex. Later research proved
that sex hormone injections have no effect on sexual orientation but that
high doses of testosterone may increase sexual desire.
In 1913 in Chicago, Victor D. Lespinasse (1878–1923), a urologist,
claimed that he cured a patient who had sexual dysfunction by transplanting
a testicle from a donor. He removed the organ, made three transverse slices,
and inserted them into muscle tissue around the patient’s scrotum. His most
famous patient was Harry F. McCormick (husband of Edith Rockefeller),
whose case was described in The New York Times. Five years later, the first
journal of Endocrinology was published.
In the 1920s, Sergio Voronoff, a Russian-French physician and surgeon,
made a fortune from removing testes from animals (including the controver-
sial monkey and chimpanzee gland transplants by way of vivisection,
764 DOTSON & BROWN
sparking campaigns from animal rights groups and satirical cartoons and
books on the subject) and transplanting them into men. The chimpanzee tis-
sue was not implanted inside the scrotum but instead in the tunica vaginalis.
He concluded that his experiments with testicular transplants helped to re-
lieve pain and provided a sense of well-being [1,5].
It was apparent to researchers that some substance circulating in the
blood was responsible for their findings; however, it was not until 1929,
when a German chemist and professor, Adolf Butenandt (1903–1995), iso-
lated the first sex hormone, that a new path of discovery was initiated. He
isolated estrone from the urine of pregnant women and later isolated 15
mg of androsterone (‘‘andro’’ ¼ male, ‘‘ster’’ ¼ sterol, ‘‘one’’ ¼ ketone)
from 15,000 L of urine from local policemen [4]. Over the next few years,
researchers found that the hormones isolated from the testes were more an-
drogenic than were those isolated from urine [1]. Perhaps the most famous,
and perhaps unethical, research of ‘‘organotherapy’’ occurred in the 1920s
and 1930s at San Quentin prison in California where Leo Stanley trans-
planted the testicles from executed prisoners into impotent prisoners. He
had a limited supply, so he turned to substituting a variety of animal gonads
(from ram, sheep, goat, deer, and boar) to treat men who suffered from se-
nility, epilepsy, and paranoia [1,4]. Over the years he performed hundreds of
operations [1].
During the 1930s, three pharmaceutical companies each hired research
teams to isolate the testicular hormone. The term testosterone (‘‘testo’’ ¼
testes, ‘‘ster’’ ¼ sterol, ‘‘one’’ ¼ ketone) was coined in 1935 by Karoly Da-
vid and his research team [7]. Ernst Laqueur isolated testosterone from bull
testes [5]. The research team was funded by the pharmaceutical company
Organon in Oss, The Netherlands [4]. Later that same year (on a team
funded by Schering Corporation in Berlin, Germany), Butendant and
Gunicr Hanisch published ‘‘A Method for Preparing Testosterone from
Cholesterol’’ in a German journal. Only a week later, Leopold Ruzicka
(who synthesized androsterone in 1934) and A. Wettstein published ‘‘On
the Artificial Preparation of the Testicular Hormone Testosterone (An-
dro-sten-3-one-17-ol)’’ in Helvetica Chimica Acta and applied for a patent.
Butenandt and Ruzicka won the Nobel Prize for chemistry in 1939 [1,4].
Butenandt spent a large part of his career studying the sex hormones and
their relationship with one another. His work laid the foundation for the
production of cortisone.
In the late 1930s, experimentation using humans involved testosterone
propionate (slow-release derivative) and methyl testosterone (oral form
that was slower to metabolize). Most of the research at that time was fo-
cused on treating hypogonadism in men (inducing and maintaining second-
ary sexual characteristics and treating impotence) [1]. Charles D. Kochakian
discovered an increase in protein anabolic processes, thus opening the door
for the treatment of a variety of disorders by restoring tissue and stimulating
growth [1].
In 1939, it was reported that daily topical application of testosterone by

females enlarged the clitoris and increased sexual desire. The use of synthetic
testosterone skyrocketed after publication of the book The Male Hormone
by Paul de Kruif in 1945, which made claims of increasing libido and boost-
ing athletic performance [1,4]. Testosterone was a proposed treatment for
menorrhagia, dysmenorrhea, estrogen-derived breast cancers, and other
breast conditions. It was reported to help relieve pain, increase appetite,
and promote a ‘‘sense of well being.’’ Despite these claims, physicians re-
mained reluctant to begin widespread use among women because of the vir-
ilizing side effects [1]. Most of the profits from sale of this substance were
obtained by way of the black market [1].
Body builders and athletes began using testosterone to increase muscle
mass and to intensify training protocols on the West Coast of the United
States in the late 1940s and early 1950s. The US Food and Drug Adminis-
tration approved methandrostenolone in 1958. In the 1950s, Soviet Union
and East German Olympic athletes were using AASs. They later found their
way into the hands of Olympic competitors, including track and field ath-
letes from many countries [1].
Paul Niehans wrote the 1960 book Introduction to Cellular Therapy, in
which the main emphasis was on testicular secretions. He believed that tes-
ticle cell injections increased testosterone derivative excretion. Some of Paul
Niehans’ famous patients included Pope Pius XII, Bernard Baruch, and
Aristotle Onassis [4]. In 1974, the International Olympic Committee banned
the use of testosterone and its derivatives. AASs were widely abused in a va-
riety of sports, including volleyball, cycling, swimming, soccer, and
bobsledding.
Testosterone was studied using different forms. Scientists quickly learned
it was ineffective, and even toxic (like 17 alpha-methyl testosterone), when
taken orally; instead, it was synthesized into tiny pellets that were inserted
subcutaneously. Longer-acting injectable forms of testosterone were synthe-
sized in the 1950s (ie, testosterone enanthate). Over the following decade,
the hormone was modified into derivatives that possessed more anabolic
qualities [5].
In the 1970s, oral testosterone undecanoate was synthesized; however, it
did not fare well in the oral form because of hepatic clearance and hepato-
toxicity. Transdermal scrotal patches were derived in the 1990s. These al-
lowed physiologic levels of testosterone to be acquired. Nonscrotal skin
patches were developed, and testosterone gels were marketed. Today, there
are short-acting buccal forms as well as the long-acting injectable testoster-
one undecanoate [5].
By the early 1990s, several pharmaceutical companies had stopped pro-
ducing AASs. It was about at this time that the black market sales of
AASs and counterfeit products increased secondary to the ease of Internet
shopping and availability. Authentic steroids, as well as placebos and un-
purified forms, were sold and abused. The US Congress placed anabolic
766 DOTSON & BROWN
steroids into the schedule III category of the Controlled Substance Act
(CSA) in the Anabolic Steroid Control Act of 1990. This act included testos-
terone and all related chemical or pharmacologic substances that promoted
muscle growth. Corticosteroids, progestins, and estrogens were not included
in this act. The Anabolic Steroid Act of 1994 was an amendment to the
CSA. It placed anabolic steroids as well as their precursors on the controlled
substance list. Possession of the drugs without a prescription was now a fed-
eral crime. Studies of the effects of supplemental testosterone on aging men
in the 1990s suggested an increase in word memory, special cognition, in-
creased libido, decreased bone resorption, and increased lean body mass
and strength [1]. McKinlay reported in the Journal of Urology that testoster-
one does not treat impotence [1]. In theory, prostatic tissue, including cancer
and benign prostatic hypertrophy, can be stimulated by testosterone, but no
compelling evidence has been reported that suggests an increased risk [8,9].
In summary, testosterone is produced in several areas within the human
body. In men, most of it is synthesized in the Leydig cells of testes and in the
adrenal glands; in women, testosterone is produced in the ovaries and adre-
nal glands, with a smaller fraction produced in other peripheral sites. Its
synthesis involves a cholesterol precursor and a series of enzymatic reac-
tions. Secretion is determined by a negative feedback mechanism that in-
volves the anterior pituitary gland. It is here that luteinizing hormone
(LH) and follicle-stimulating hormone are stored [4]. Elevated levels of tes-
tosterone affect the hypothalamus and pituitary. At high levels of testoster-
one, LH tends to be reduced (affecting sperm and endogenous testosterone
production). Studies by the World Health Organization examined the use of
anabolic steroids as a form of male birth control, but the results were not
promising [1].
The evolution of the history of testosterone therapies is as interesting as
the history of its development. Erectile dysfunction is one of the most re-
searched ailments treated with testosterone, although any positive effects
are questionable. In men with absent to low circulating levels of testoster-
one, treatment with testosterone increased libido, improved erectile func-
tion, and helped to maintain secondary sexual characteristics. In men with
normal or mild hypotestosteronemia, studies have not shown consistent re-
sponse to therapy. Those treated were reported to have increased sexual in-
terest, increased arousal, increased frequency of intercourse, and nocturnal
erections. In the early twentieth century, there was much interest in the hor-
monal influence of testosterone on sexuality and sexual preferences. It even
was prescribed to ‘‘treat’’ homosexuals because it was theorized that male
homosexuals had higher estrogen levels [4].
Testosterone has even played an important role in various ailments affect-
ing women, such as treatment for some metastatic breast cancers [4,8]. Ap-
proximately one third of breast cancers are hormone dependent and
respond to androgen therapies [1]. Other uses for testosterone are as postmen-
opausal hormone replacement therapy, for sexual dysfunction (by increasing
libido), and for increasing bone density [8]. Only a small percentage of doctors
in the United States prescribe testosterone creams to increase libido in women;
this practice seems to be more popular in England and Australia [1].
Testosterone has been used to treat a variety of wasting conditions from
HIV infection, posttrauma, including surgery and burns, and even after de-
tainment in concentration camps [1,8]. Some clinical case studies showed an
increase in appetite, lean muscle mass, and strength and an improved overall
sense of well-being. Before the use of erythropoietin and bone marrow trans-
plants, testosterone was used to help treat anemia (ie, chronic renal failure/
hemodialysis) [1]. Psychiatrists prescribed anabolic steroids from the 1930s
to the 1980s to treat psychoses, depression, and melancholia. Testosterone
has been used as an adjunct in people with growth hormone deficiency or
in boys with pubertal delay [1,8]. It even has been used in patients who
had prostate disease and cardiovascular disease [8].
Essentially, there are three types of testosterone: endogenous, synthetic,
and synthetic derivatives. AASs are discussed elsewhere in this issue.
AASs are available legally only by prescription from a doctor, and some-
times they are used by veterinarians; they are found most often on the black
market, typically smuggled into the United States from other countries
(most commonly from Europe, Mexico, or Thailand), manufactured in clan-
destine facilities, or even by way of illegal pharmacy transportation. The
black market forms are dangerous; the quality frequently is compromised
by chemical substitutions in production and dilution. Often, steroids are
purchased at gyms or by way of the Internet or mail order. Typically,
AASs have a higher anabolic to androgenic ratio.
Frequently, abusers take AASs by ‘‘stacking,’’ which means they take
two or more at a time, sometimes even mixed them with stimulants or anal-
gesics. Commonly, AASs are used cyclically, often ‘‘pyramiding.’’ Low
doses are increased gradually over a 6- to 12-week period and then de-
creased gradually over the second half of the cycle. This may be followed
by a drug-free training period. Those who participate in pyramiding believe
that it helps them to adjust to the high-dose AASs and allows the body to
adjust hormonally during the drug-free cycle. Despite a lack of scientific ev-
idence, users believe that they will see greater effects by ‘‘stacking’’ and ‘‘pyr-
amiding’’ the drugs [9].
It is estimated that more than 1 million Americans abuse AASs, including
many high school and college athletes [1,10]. A study survey conducted by
the National Institute on Drug Abuse in 2004 reported that approximately
1.5% (down from 3% in 1999) of high school seniors admitted to using
AASs [9]. It is difficult to estimate the true prevalence of abuse, perhaps be-
cause of the unwillingness of athletes to admit to using illegal drugs. AASs
are banned by most sports organizations, including the International Olym-
pic Committee.
Anabolic steroids possess a large side effect profile, including hepatotox-
icity (including jaundice, cancer, and cystic lesions called peliosis hepaticus),
768 DOTSON & BROWN
hypercoagubility, hypertension, left ventricular hypertrophy, acne, hyper-

cholesterolemia with increased low-density lipoprotein and decreased
high-density lipoprotein, as well as an increased risk for cerebrovascular
accident and acute myocardial infarction to name a few. Other risks include
those that are associated with sharing needles, such as hepatitis B and C,
HIV/AIDS, endocarditis, and local pain and abscess formations [9–12].
Steroid abuse among adolescents also can lead to precocious puberty and
premature closure of their growth plates, resulting in stunted adult height
secondary to premature epiphyseal closure. In men, side effects include dys-
uria, baldness, gynecomastia, testicular atrophy, decreased sperm produc-
tion, and even infertility. In women, side effects include masculinization,
decreased body fat and breast size, hair loss, and clitoral enlargement. Nu-
merous studies have linked aggression to high-dose steroid abuse, which in-
creases the likelihood of fighting, physical and sexual abuse, vandalism, and
burglary [9,10,13,14]. AAS withdrawal can lead to restlessness, insomnia,
decreased libido, headaches, arthralgias, myalgias, fatigue, decreased appe-
tite, depression, and even suicide [9–11].
The history of the development of AASs and their abuse for performance
enhancement stem from ancient endocrinology thousands of years ago and
spans to the present time of ongoing breakthrough research studies.
Acknowledgments
Special thanks to Dr. Peter Rogers for giving me this opportunity to write
one of the articles and to Dr. Robert Brown who worked diligently with me
as a coauthor and mentor.
Further readings
Center for Substance Abuse Research. Anabolic steroids. Available at: http://www.cesar.umd.
edu/cesar/drugs/steroids.asp. Accessed February 12, 2007.
Eaton D, Kann L, Kinchen S, et al. Youth risk behavior surveydUnited States 2005. MMWR
Surveillance Summaries. 2006;55(SS05):1–108.
Gomez JE. Performance-enhancing substances in adolescent athletes. Tex Med 2002;98:41–6.
Haupt HA, Revere GD. Anabolic steroids: a review of literature. Am J Sports Med 1984;12(6):
469–84.
Kuhn C. Anabolic steroids. Recent Prog Horm Res 2002;57:411–30.
National Institute of Drug Abuse. Drugs of abuse information. Available at: http://www.nida.
nih.gov/drugpages.html. Accessed February 12, 2007.
Parkinson A, Evans NA. Anabolic androgenic steroids: a survey of 500 users. Med Sci Sports
Exerc 2006;38(4):644–51.
References
[1] Hoberman JM, Yesalis CE. The history of synthetic testosterone. Sci Am 1995;272:76–81.
[2] Sheffield-Moore M, Urban RJ, Wolf SE, et al. Short-term oxandrolone administration stimu-
lates net muscle protein synthesis in young men. J Clin Endocrinol Metab 1999;84(8):2705–11.
[3] Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone
on muscle size and strength in normal men. N Engl J Med 1996;335(1):1–7.
[4] Freeman ER, Bloom DA, McGuire EJ. A brief history of testosterone. J Urol 2001;165(2):
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[5] Nieschlag E. The history of testosterone [abstract]. Endocrine 2005;10:S2.
[6] Henriksen JH. Ernest Henry Starling (1866–1927): the scientist and the man. J Med Biogr
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[7] David KG, Dingemanse E, Freud J, et al. On crystalline male hormone from testicles (testos-
terone). Hoppe Seylers Z Physiol Chem 1935;233:281.
[8] Margo K, Winn R. Testosterone treatments: why, when and how? Am Fam Physician 2006;
73(9):1591–8.
[9] Anabolic Steroid abuse. Available at: http://www.steroidabuse.gov/. Accessed February 12,
2007.
[10] Evans NA. Current concepts in anabolic-androgenic steroids. Am J Sports Med 2004;32:
534–42.
[11] United States Anti-Doping Agency. Available at: http://www.usantidoping.org/. Accessed
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[12] Dhal R, Stout CW, Link MS, et al. Cardiovascular toxicities of performance-enhancing sub-
stances in sports. Mayo Clin Proc 2005;80(10):1307–15.
[13] Choi PY, Parrott AC, Cowan D. High-dose anabolic steroids in strength athletes: effects
upon hostility and aggression. Hum Psychopharmacol 1990;5(4):349–56.
[14] Moss HB, Panzak GL, Tarter RE. Personality, mood and psychiatric symptoms among
anabolic steroid users. Am J Addict 1992;1(4):315–24.
Anabolic-Androgenic Steroids:
Use and Abuse in Pediatric Patients
Julie M. Kerr, MDa,b,*, Joseph A. Congeni, MDa,b
a
Northeastern Ohio Universities College of Medicine, 4209 State Route 44, PO Box 95,
Rootstown, OH 44272, USA
b
Division of Sports Medicine, Akron Children’s Hospital, Sports Medicine Center,
388 South Main Street, Suite 207, Akron, OH 44311, USA
The ‘‘win at all costs’’ mentality fuels athletes to seek performance-

enhancing substances, such as anabolic-androgenic steroids (AASs), to
gain an advantage over their opponents. Nonathletes espouse this same at-
titude to ‘‘win’’ the battle of attractiveness. They view AASs as the means to
achieving what they believe is a more desirable muscular physique. These
beliefs have filtered from professional, Olympic, and collegiate levels into
high schools, middle schools, and grade schools. An enhanced understand-
ing of AASs and the motivations behind their abuse will arm the pediatri-
cian with the ability to engage one’s patients in a balanced discussion of
the benefits and costly risks of AASs and successfully deter further use.
History
High levels of AAS abuse have been attributed to professional football
players, bodybuilders, weight lifters, and track and field throwers since
the 1960s. The exceptional athletic performance of the East German female
swimmers in the 1976 Montreal Olympics brought further public attention
to AAS athletic use. It was not until the 1980s, however, that the medical
community admitted that these substances were effective [1]. Since that
time, the pervasive use of AASs by professional athletes has garnered signif-
icant media attention, culminating most recently in the ongoing investiga-
tion of the use of illegal performance enhancing drugs by some of
baseball’s top players. Juiced, a book by Jose Canseco, details his steroid
use and the widespread use of anabolic steroids in Major League Baseball.
* Corresponding author. Division of Sports Medicine, Akron Children’s Hospital, Sports
Medicine Center, 388 South Main Street, Suite 207, Akron, OH 44311.
E-mail address: [email protected] (J.M. Kerr).
772 KERR & CONGENI
The fame achieved by such professional athletes may be what makes trying
AASs so enticing to adolescents.
Physiology
Several studies have contributed to an enlarging body of evidence regard-
ing the anabolic ‘‘tissue-building’’ effects of AASs on their primary target,
skeletal muscle. The actions of AASs on the musculoskeletal system have
been shown to influence lean body mass, muscle size and strength, protein
metabolism, bone metabolism, and collagen synthesis [2–8]. Over a period
of 10 to 20 weeks, a supraphysiologic dose of testosterone administered to
healthy young men can increase lean body mass, as well as muscle size
and strength with or without exercise [2,3,8]. These significant increases
are dose dependent and only occur with doses of 300 mg per week and
higher [3,8]. The most profound effects are noted when supraphysiologic
doses accompany a training program and are used in conjunction with
a diet adequate in protein and calories [2,9,10].
Testosterone-induced muscle hypertrophy and increases in muscle strength
are the result of increases in the cross-sectional area of muscle fibers and my-
onuclear number [8]. Research suggests that these anabolic effects are medi-
ated by testosterone-influenced increases in muscle protein synthesis,
creating a positive nitrogen balance [5,7,11]. Androgen receptors in skeletal
muscle regulate the transcription of the target genes that control the accumu-
lation of DNA needed for muscle growth. Complementary effects include
glucocorticoid antagonism, which minimizes the catabolic actions of cortico-
steroids released during the stress of athletic activity. Similarly, stimulation of
the growth hormone insulin-like growth factor-1 axis [12] and enhanced col-
lagen synthesis and bone mineral density [13] are additional anabolic effects.
AASs induce a state of euphoria and diminished fatigue that enables pro-
longation of training sessions by users. Recent data may explain how AASs
exert these psychoactive effects on the brain. Henderson and colleagues [14]
proposed that AAS-mediated acute and chronic changes in the gamma-
aminobutyric acid (GABA) receptor system cause many of the known behav-
ioral effects. For instance, the immediate effects of decreased anxiety and
enhanced sense of well-being that are experienced by AAS users likely arise
from enhancement of forebrain GABAergic circuits. In contrast, anxiety
and aggression are the result of a down-regulation of GABA receptor expres-
sion secondary to chronic AAS exposure. Further study may reveal that
expression of these behaviors is influenced by the age and gender of the
AAS user and the particular chemical composition of the AAS administered.
Clinical uses
The anabolic properties of AASs have proven beneficial for some thera-
peutic applications. They have been used in clinical practice since the 1940s
ANABOLIC-ANDROGENIC STEROIDS 773
for the treatment of trauma, burns, extensive surgery, radiation therapy, and
chronic debilitating illnesses [15–18]. Before the advent of bone marrow
transplantation and synthetic erythropoietin, AASs were used often in the
treatment of various types of anemias. AASs have shown promise in treating
short stature, as in Turner’s syndrome, or constitutional growth and puberty
delay. Since 1985, the clinical use of AASs has increased 400%, mostly due
to the management of AIDS-associated wasting syndrome. AASs may en-
hance the effects of the increased caloric intake and exercise regimen [19].
A pilot study in malnourished HIV-infected children as young as 4 years
old showed that oxandrolone treatment was well-tolerated and improved
nutritional status. After 3 months of treatment, the study subjects experi-
enced an accelerated rate of weight gain, increased body mass index, in-
creased muscle mass, and decreased fat stores as compared with
pretreatment values. The results were supported further by the improved
serum albumin levels noted during the course of treatment. Future studies
using a larger study population and longer- or higher-dose AAS administra-
tion would strengthen the current data [20]. In patients with severe burns,
AASs may play an important role in reversing the catabolic state. A small
prospective randomized study of patients who had burns showed that those
receiving oxandrolone in addition to a high-protein diet experienced a signif-
icantly greater increase in weight and physical therapy index than did
patients who were treated with diet alone [21]. AAS therapy seems to be
promising in the treatment of malnutrition and muscle wasting seen in
patients who have end-stage renal disease. In addition to the increase in
lean body mass, these patients also benefit from a stimulated erythropoiesis
resulting from the administration of AASs [22,23]. Such positive effects
warrant further study [19].
Legal issues
The nonmedical use of AASs has been banned by the International
Olympic Committee, the United States Olympic Committee, and the Na-
tional Collegiate Athletic Association. Such use also is denounced by the
American Medical Association, the American College Health Association,
the American Academy of Pediatrics, the American College of Sports Med-
icine, and the National Strength and Conditioning Association [24]. Steroids
are banned from use by all major sporting leagues, although each has its
own testing and penalization policies [25]. The US Federal Government
and most state governments have enacted laws regarding the distribution,
possession, or prescription of AASs. The Federal Food, Drug, and Cos-
metic Act was amended as part of the 1988 Anti-Drug Abuse act, such
that distribution of AASs or possession with intent to distribute without
a valid prescription became a felony. Such offenses are punishable by
a prison term of up to 5 years or fines totaling $250,000 [25]. In 1990, the
774 KERR & CONGENI
Anabolic Steroids Control Act was signed into law, thereby classifying
AASs as Schedule III drugs within the Controlled Substances Act. The
Drug Enforcement Agency now controls the manufacture, importation, ex-
portation, distribution, and dispensing of AASs [26].
Sources
Despite the above-mentioned barriers, AASs are still making their way
into the hands of adolescents and children. Most commonly, the sources
are bodybuilding gyms that obtain the drugs by way of a multimillion dollar
illicit black market: foreign mail order, Internet dealers, or Internet pharma-
cies [2]. Most concerning about such sources is that the purity and actual
content of the product received cannot be guaranteed.
Prevalence of adolescent anabolic-androgenic steroid use

The first reported adolescent use of AASs was in 1959 by a high school
football player [27]. Current estimates of high school steroid usage range
from 4% to 11% in boys and up to 3.3% in girls [28,29]. The landmark study
of prevalence that was performed by Buckley and colleagues [30] involved
a nationwide survey of more than 3000 boys. They found that 6.6% of
male high school seniors had tried steroids, with 67% initiating use by 16
years of age and 40% using multiple cycles. These results have been confirmed
in later studies of Indiana high school football players documenting a 6% use
rate [31] and a 2003 Centers for Disease Control and Prevention report finding
a 6.4% use of steroids by 12th-grade boys. The largest nationwide cohort of
nearly 50,000 students is being examined in the Monitoring the Future study
[32]. As of 2004, results of this ongoing study indicated a 1.3%, 2.3%, and
3.3% annual prevalence of male AAS users in the eighth, 10th, and 12th
grades, respectively. Girls in the 12th grade had a 1.7% use rate in this study,
whereas the Centers for Disease Control and Prevention reported a 3.3% life-
time prevalence in 12th-grade girls.
Prevalence studies have extended to middle school populations as well. A
1993 study of Modesto, California seventh-grade students was the first to
document the use of steroids in students aged 12 to 15 years [33]. The overall
rate of use reported was 3.8%, with more male students (4.7% versus 3.2%
in female students) admitting to using AASs. A later article published data
from a study of Massachusetts students between 9 and 13 years of age [34].
AAS use was reported by 2.7% of all middle school students surveyed, with
2.6% of boys and 2.8% of girls reporting use. As in other studies, the prev-
alence of AAS use increased with increasing age. Both of these regional
studies were consistent with data from Yesalis [35], who reviewed AAS prev-
alence rates among junior high school students in the United States (2% for
sixth graders and 2.3 to 3% for eighth graders).
AAS use by adolescents is not limited to the United States. Three Cana-
dian studies, two Swedish surveys, two South African investigations, one
British study, and one Australian investigation reported an overall preva-
lence range between 1% and 3%. Although slightly lower, these rates
approximate those reported in the United States, demonstrating that the
impact of AASs on athletic performance and physical appearance reaches
across cultures [36].
Risk factors for adolescent anabolic-androgenic steroid abuse

Many studies of adolescent AAS users and abusers have attempted to
create a profile of the typical user. The following discussion reviews some
of the data relating to demographics, school performance, athletic participa-
tion, and personality of AAS users.
Demographic factors
Generally, the relative risk of AAS use is at least two to three times
greater for male adolescents. The review of numerous studies shows
a wide variation in the age range of AAS users. Race and ethnicity of
AAS users is equally unclear. Some studies reported greater use among
minorities [30,33,37–40], whereas others revealed a higher rate among white
adolescents [41–46]. One regional study reported a significantly higher rate
in blacks [33]. Other studies reported no racial difference in adolescent
AAS use. Likewise, no clear-cut relationship exists regarding geographic
location, city size, or school size.
Academic factors
There may be some association between AAS use and poor academic
performance. In a large national study, DuRant and colleagues [47] stated
that students who reported below-average academic performance had a sig-
nificantly higher prevalence of AAS use than did average or above-average
students; however, two studies, reported no relationship between academic
achievement and AAS use [48,49]. Future studies regarding this question are
needed.
Athletic performance
Adolescents use AASs as a method to improve their athletic performance.
AAS users are significantly more likely than are nonusers to participate in
school-sponsored athletic programs [30,40,50–53]. Sports requiring muscu-
lar strength and power are those most closely associated with AAS use
among their participants. Such sports include football, wrestling, and track
and field [30,40,41,50,51,54–56]. Faigenbaum and colleagues [34] reported
776 KERR & CONGENI
greater AAS use in gymnastics and weight training in their study sample.
Strength undoubtedly is an asset to gymnasts, and, thus, correlates well
with the observed higher percentage; however, they were concerned with
the suggestion that some young gymnasts may use AASs to stunt their
growth because they believe that small stature confers an advantage in gym-
nastics. It is important to realize that approximately 30% to 40% of adoles-
cent AAS users do not participate in a school-sponsored sport. These users
likely participate in bodybuilding or weightlifting activities [30,40].
Personality and behavioral factors

A considerable percentage of adolescents turn to AAS use to help them
achieve an attractive physique. This is the second most popular reason for
using AASs. One study of bodybuilders suggests that the drive for a muscu-
lar physique sometimes reaches an unhealthy extreme and likens the use of
AAS to the ‘‘unhealthy extremes’’ that are characteristic of anorexic and
bulimic individuals. Just as eating disordered women see their bodies as
larger than they actually are, some men perceive themselves as smaller
than they actually are. Taylor [57] refers to this phenomenon as ‘‘bigamer-
exia’’ and suggests that this misperception may be a contributory factor in
AAS use. This misperception is likely evident in many ninth-grade boys,
whodin the early stages of pubertydare impatient with their muscular de-
velopment. Perceiving themselves smaller than their peers, these boys may
engage in AAS use as a shortcut to increasing muscle strength and size
[39]. Exposure to the media may intensify this body dysmorphia. Field
and colleagues [58] examined this possibility in a study of supplement use
among adolescents. They found that girls and boys who reported thinking
frequently about wanting more defined muscles and those who were trying
to emulate the look of same-gender figures in the media were more than
three times more likely to use agents to build muscle or improve appearance.
Adolescent AAS use has been associated with the use of other harmful
drugs, including cigarettes, smokeless tobacco, marijuana, alcohol, cocaine,
and injected drugs. These behaviors support a risk behavior framework hy-
pothesized by Jessor [59] in his Problem Behavior Theory. He proposed that
there are intraindividual similarities among adolescent problem behaviors
such that they cluster to form a ‘‘risk behavior syndrome.’’ Thus, AAS
use would be considered a part of this cluster rather than an isolated behav-
ior. Middleman and colleagues [60] applied this theory to a study of Massa-
chusetts high school AAS users. They noted that the frequency of AAS use
was associated with driving after drinking alcohol, carrying a gun, sexual
promiscuity, unprotected intercourse, injury in a fight requiring medical at-
tention, history of a sexually transmitted disease, not wearing a helmet on
a motorcycle, not wearing a passenger seatbelt, and a suicide attempt requir-
ing medical attention. Another concerning health-compromising behavior is
the sharing of needles and multidose vials by between 25% and 33% of
adolescent AAS users. This practice contributes to the risk for acquiring
infections, such as HIV, hepatitis B, and hepatitis C [61,62].
Dosage and patterns of use

Anabolic steroids may be taken orally or injected intramuscularly [63] and
are grouped into three main classes [14]. Testosterone esters, such as
testosterone propionate, are injected compounds and constitute class I. Class
II agents include the nortestosterone derivatives (eg, nandrolone decanoate
and nandrolone phenpropionate). Class I and II AASs exert effects at andro-
gen receptors as well as at estrogen receptors by way of aromatization to estra-
diol [17]. The third class of AASs are those alkylated at C-17 and are the orally
administered compounds oxymetholone, methandrostenolone, and stanozo-
lol. Alkylation of these compounds involves the addition of a methyl or ethyl
group to the carbon at position 17 of the steroid backbone. The alkylation
slows the hepatic metabolism of these agents [19]. These and other common
oral and injectable preparations are listed in Table 1.
A typical pattern of use consists of a combination of injectable and oral ste-
roids taken during 6- to 12-week cycles. Injectable forms tend to be favored by
users because they are less hepatotoxic than the oral forms [1]. Because oral
Table 1
More commonly abused anabolic steroids
How Recommended Abused
Generic name supplied dosage dosagea
Oxymetholone (O) 50 mg 1–5 mg/kg/d 50–100 mg/d
Oxandrolone (O) 2.5 mg 5–10 mg/d 15 mg/d
Nandrolone decanoate (I) 25 mg/mL, 5 mL 100–200 mg/wk 200–400 mg/wk
Methandrostenolone (O & I) 5 mg, 10 mg/mL d 15–30 mg/d,
50–100 mg/wk
Boldenone undecyclenate (I) 50 mg/mL d 5 mL/wk
Methenolone (O & I) 50 mg/ml; 50, d 50–100 mg/d,
100 mg/mL 200 mg/wk
Testosterone propionate, 250 mg/mL d 250 mg/wk
phenyl propionate,
isocaporate, decanoate (I)
Testosterone cypionate (I) 200 mg/mL 25–200 mg/wk 1–3 mL/wk
Testosterone enanthate (I) 200 mg/mL 25–200 mg/mL 1–3 mL/wk
Testosterone propionate (I) 100 mg/10 mL 50–150 mg/wk 200–400 mg/wk
Testosterone suspension (I) 100 mg/10 mL d 50 mg/d
Stanozolol (O & I) 2 mg, 50 mg/mL 6 mg/d, 16–30 mg/d,
3–5 mL/wk
Abbreviations: O, oral; I, injectable.
a
Abused dosages may vary greatly by gender, personal experience, availability of specific
steroids, performance and appearance goals, and the simultaneous use of several steroids.
Data from Bahrke MS, Yesalis CE, Brower KJ. Anabolic-androgenic steroid abuse and per-
formance-enhancing drugs among adolescents. Child Adolesc Psychiatr Clin N Am
1998;7(4):826.
778 KERR & CONGENI
preparations are cleared from the system more quickly, they are the preferred
form of steroids when drug testing is anticipated. The simultaneous use of mul-
tiple steroids is referred to as ‘‘stacking.’’ A pattern of increasing a dose
through a cycle is called ‘‘pyramiding.’’ Pyramiding can lead to doses 10 to
40 times greater than the dose recommended for medical indications. By stack-
ing and pyramiding doses, the user hopes to maximize steroid receptor bind-
ing, thereby reducing toxic side effects. These patterns have remained popular,
despite the lack of scientific evidence of a benefit [29]. Some users take other
drugs concurrently in an effort to minimize side effects. These ‘‘accessory’’
medications include clomiphene and human chorionic gonadotropin and
are administered to reverse the endogenous testosterone production. Addi-
tionally, tamoxifen and antiaromatase drugs can prevent or decrease gyneco-
mastia by limiting estrogenic effects and the metabolism of excess testosterone
derivatives to estradiol [63]. It is not uncommon for users to take other legal
performance-enhancing substances and dietary supplements, such as creatine,
glutamine, and protein, while using AASs [64].
Adverse effects
For years, scientists have attempted to dissociate the anabolic properties
from the androgenic characteristics of AASs, to no avail. Therefore, both
components exert adverse effects on various tissues and body systems.
Hepatic
Various studies have shown transient elevations in liver function tests in
conjunction with AAS use [10,65,66]. The C-17 alkylated oral preparations
are associated most often with liver toxicity [67]. Elevations in aspartate trans-
aminase, alanine transaminase, lactate dehydrogenase, and alkaline phospha-
tase have been reported [10]. Values measured can be two to three times the
normal range, peaking within 2 to 3 weeks of consumption. Usually, a return
to baseline is seen within several weeks of discontinuation [68]. Many AAS
users also abuse alcohol, thus compounding the hepatic adverse effects.
Anabolic-related cholestasis has been reported to occur in varying
frequency from a few cases to up to 17.3% in some studies [69,70]. The tran-
sient jaundice that results is secondary to biliary stasis rather than structural
hepatic injury. Structural lesions have been studied in case reports of the
blood-filled cysts of peliosis hepatis [71]. Internal hemorrhage or hepatic
failure can occur secondary to such lesions.
Hepatocellular adenomas have been associated with high-dose AAS, long
periods of administration of AAS, or in AAS users with a predisposing med-
ical condition [10,67]. It is particularly difficult to differentiate adenomas
from hepatocellular carcinoma by ultrasound. Prompt identification of these
lesions is critical because the potential for malignant transformation may
increase if a late diagnosis is made [72].
Cardiovascular
Altered lipid profiles in AAS users are reflected in increased low-density
lipoprotein and decreased high-density lipoprotein [66,71,73]. The oral C-17
alkylated steroids seem to exert the greatest effects on the lipid profile
[68,74,75]. Thrombus formation has been postulated by way of these ad-
verse lipid changes and is supported further by findings of AAS-induced in-
creased platelet aggregation, enhanced coagulation enzyme activity, and
coronary vasospasm [76].
Hypertension in AAS users has been reported and is likely the result of
blood volume increases and fluid retention [71,76]. This effect, as well as
the finding of increased septal thickness and left ventricular mass reported
in AAS users [77,78], can lead to significant detrimental cardiac remodeling.
Reproductive/endocrine
Exogenous steroid administration provides feedback inhibition of lutei-
nizing and follicle-stimulating hormones, which leads to testicular atrophy
and decreased spermatogenesis. This testicular impairment is reversed
upon cessation of AAS use. Excess steroids undergo peripheral aromatiza-
tion to estrogens, which results in feminizing changes of high voice pitch
and male gynecomastia [71]. In long-term AAS abuse, this gynecomastia
is irreversible, leaving surgical correction as the only solution [79]. In addi-
tion to the female side effects of decreased menstruation and breast tissue
atrophy, virilizing effects also occur and include deepened voice, clitorome-
galy, and hirsutism. Sometimes these effects are irreversible, even after dis-
continuation of AAS use [80].
Musculoskeletal
Experimental evidence exists that the use of AASs combined with intense
exercise can cause structural and biomechanical alterations of tendons re-
sulting in rupture. Structurally, the collagen fibril alignment is highly disor-
ganized. From a biomechanical perspective, when muscle strength is
increased with AAS use, the tendon becomes stiffer, absorbs less energy,
and is more likely to fail during physical activity [81].
Premature growth cessation due to physeal closure in younger users has
not been studied systematically. Such case reports of the resultant perma-
nent short stature have been described for several decades [82].
Dermatologic
Severe cases of acne, especially on the face and back of AAS users, are
common dermatologic findings. Premature baldness is noted as well. Dick-
inson and colleagues [83] reported multiple cases of serious muscular ab-
scesses resulting from the common practice of shared needles and shared
780 KERR & CONGENI
steroid vials among adolescent AAS users. A limited knowledge of sterile in-
jection technique, as well as limited access to sterile needles and syringes are
likely additional causative factors in these infections.
Psychiatric
AAS use has been associated with self-reported changes in mood and be-
havior. A study by Pope and Katz [84] identified psychiatric syndromes in
weightlifters using AASs. Twenty-three percent of AAS users experienced
major mood changes of mania, hypomania, or major depression. Also com-
mon in AAS users was aggressive behavior resulting in fights, domestic dis-
turbances, assaults, and arrests. Data from the National Household Survey
on Drug Abuse have demonstrated a strong association between AAS use
and self-acknowledged acts of violence against people and crimes against
property [85]. In general, the behavioral effects of AASs are variable,
short-lived on discontinuation, and seem to be related to the type and dos-
age of AAS.
The potential for physical dependence upon AASs does exist. In one study
of AAS users, 50% of them met the Diagnostic and Statistical Manual of Men-
tal Disorders, Fourth Edition criteria for dependence or abuse of steroids [86].
Physical symptoms of withdrawal are similar to those seen during alcohol and
opioid withdrawal, including diaphoresis, myalgias, nausea, and increases in
blood pressure and heart rate [87]. Withdrawal may also be characterized
by depressive symptoms [88]. Deeply entrenched body dissatisfaction and
body dysmorphic disorder may underlie a psychologic dependence. Clearly,
the addictive potential of AASs cannot be discounted [89].
Prevention efforts
The implementation of drug-testing policies has been considered as a pos-
sible preventive strategy. Data from the National Federation of State High
School Associations indicate, however, that only 13% of schools test ath-
letes and, of those schools, only 29% test for AASs. The reasons for the
low number of testing programs include financial constraints (w$120 per
test) and the fact that testing often can be circumvented by the user. Dose
titration with newer transdermal delivery systems of testosterone or discon-
tinuation of use before a scheduled test can maintain levels below a testing
threshold [90]. Testing only athletes also will miss a significant percentage of
nonathlete users.
Educational programs have been suggested as a more effective means of
deterring AAS use. Goldberg and colleagues [91] tested a team-based educa-
tional intervention designed to reduce Portland, Oregon high school football
players’ intent to use AASs. The Adolescents Training and Learning to
Avoid Steroids Program consisted of 50-minute class sessions that were de-
livered over a 7-week period by coaches and athlete team leaders. The
sessions combined drug education with attainment of personal skills to as-

sist athletes in resisting the social influences that fuel an athlete’s desire to
use AASs. Athletes in this intervention group gained a greater knowledge
of the consequences of AAS use, were more skeptical about the media’s pro-
motion of AASs, and had improved drug-refusal skills. These results are cer-
tainly encouraging and follow-up data are eagerly anticipated.
The pediatrician’s office can be a valuable educational setting as well. Us-
ing ‘‘scare tactics’’ as a prevention effort to dissuade adolescents from be-
coming AAS users has been proven to weaken physician credibility and
may even encourage use [92]. Rather, Metzl [93] offers the concept of
‘‘thoughtful discouragement’’ as the key to effective prevention. He recom-
mends that the clinician first recognize that a patient may be using AASs.
The sports preparticipation physical examination offers an ideal opportu-
nity to note any physical changes suggestive of AAS use and to ask whether
the patient is using a performance-enhancing substance. Education is the
next step and should be a balanced discussion focusing on the current re-
search, the physiologic effects, and the adverse events. A concerning trend
in 12th graders showed a steadily decreasing perceived risk for steroid use
yearly since 1993. Only 55% of seniors now consider steroid use as a great
risk [32]. Finally, healthy alternatives to AAS use must be presented. A su-
pervised strength-training program among children as young as 8 years of
age is a safe and effective means of increasing strength and improving ath-
letic performance [94]. By emphasizing repetitions rather than maximum
weight lifting, baseline strength can be increased by 30% to 40% [95].
Summary
Our society equates success with winning. The drive to win athletic com-
petitions or the obsession with achieving the perfect physique has made ad-
olescents and children increasingly vulnerable to the lure of AASs. The
increases in muscular size and strength that are characteristic of AASs occur
with attendant short-term adverse effects and the potential for long-term
health consequences. A mindset of invincibility that is typical of many ado-
lescents allows them to be willing to pay the price of these negative events
for the chance to gain a competitive edge.
Educational programs addressing the social, media, and peer influences
that perpetuate adolescent use of AASs have shown promise in decreasing
the intent to use. Such educational programs need to be directed toward
middle school classrooms to decrease the rate of first use in this age group.
Physician dissemination of accurate information to parents, coaches, and
school administrators is vital to the creation of intervention programs. By
demonstrating a knowledge base that earns adolescent respect, the pediatri-
cian will be able to effectively discourage AAS use and convince the patient
that there is no substitute for sound nutrition and a sensible strength-train-
ing program.
782 KERR & CONGENI
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Testosterone Precursors: Use and Abuse

in Pediatric Athletes
Troy M. Smurawa, MDa,b,*, Joseph A. Congeni, MDa,b
a
Northeastern Ohio Universities College of Medicine,
4209 State Route 44, PO Box 95, Rootstown, OH 44272, USA
b
Division of Sports Medicine, Children’s Hospital Medical Center of Akron,
One Perkins Square, Akron, OH 44308, USA
The popularity of dietary supplement use in the athletic population is

widely increasing in an attempt to enhance athletic performance. Marketing
and anecdotal evidence promote the use of these supplements as perfor-
mance enhancers without sufficient scientific research and data to substanti-
ate their performance-enhancing claims. Testosterone precursors, also called
prohormones, are precursors in the endogenous production of testosterone.
Androstenedione (Andro), dehydroepiandrosterone (DHEA), and androste-
nediol are the three testosterone precursors that are marketed heavily. The
efficacy and safety of these prohormones were not well established, but they
were believed to have the same androgenic effects on building muscle mass
and strength as anabolic-androgenic steroids (AASs). The theory is to in-
crease the body’s endogenous production of testosterone by increasing the
concentration of testosterone precursors exogenously. The short- and
long-term side effects also were not well known, but theoretically they
may cause the same adverse side effects as AASs.
In 1994, the Dietary Supplement Health and Education Act allowed for
the marketing and sale of ‘‘natural’’ dietary supplements without the US
Food and Drug Administration (FDA) regulation for guaranteeing the pu-
rity and safety of these substances. The passage of the Dietary Health and
Education Act of 1994 allowed for theses precursors to be sold over the
counter as ‘‘natural’’ dietary supplements without regulation.
In 1996, androstenedione and DHEA became available in the United States
market as over-the-counter nutritional supplements. Dosages as high as
* Corresponding author. Division of Sports Medicine, Children’s Hospital Medical

Center of Akron, One Perkins Square, Akron, OH 44308.
E-mail address: [email protected] (T.M. Smurawa).
788 SMURAWA & CONGENI
androstenedione,100 to 300 mg per day, and DHEA,150 mg per day, were rec-
ommended [1]. These prohormones became an attractive performance-
enhancing alternative to using illegal AASs, which were banned by most major
sports organizations. They were classified as natural substances and were not
regulated by the FDA. They became popular supplements among athletes,
and, thus, became readily available to the adolescent population.
The potential performance-enhancing benefits of testosterone precursors
were brought to the attention of the public and athletic community in 1998
when Major League Baseball player Mark McGwire set the home run re-
cord and openly admitted to using androstenedione [2]. Sales skyrocketed
by 500%, and many supplements containing prohormones became available
in the United States market. Questions and concerns of contamination with
other supplements arose but their purity was unknown because these supple-
ments were not regulated by the FDA. Also, their popularity was fueled by
the misperception that nutritional supplements are natural, and, therefore,
safe.
In 2004, after much controversy and debate, the US Department of
Health and Human Services (HHS) and the FDA announced a crackdown
on companies that manufacture, market, and distribute products containing
androstenedione [3]. They recognized the potential serious adverse health
risks that were similar to those associated with AASs. As part of their con-
cern about its safety, the FDA and HHS sent warning letters to 23 compa-
nies asking them to stop distributing dietary supplements that contained
androstenedione and warned them that enforcement actions would be taken
if they did not comply. As a result of this action, the Anabolic Steroid Con-
trol Act of 2004 was passed. This act added the steroid precursor androste-
nedione to the list of schedule III controlled substances in the United States
[4]. Schedule III substances have limited medicinal use, require a prescription
from a licensed physician, and allegedly can threaten public health without
government regulation. DHEA was not added to the controlled substance
list; industry lobbyists contended that it had proven effective as an antiaging
supplement and that its risks were minimal [4].
Use in pediatrics and adolescents

The extent of the use of testosterone precursors, such as androstenedione
and DHEA, in the pediatric and adolescent population is unknown. The
initial over-the-counter dietary supplement status and availability more
than likely led to a large increase in the number of adolescents using testos-
terone precursors. A 2002 survey of 475 high school students by Reeder and
colleagues [5] revealed that 4% of athletes and nonathletes admitted to using
steroid precursors in the past year. Surveys by the National Collegiate
Athletic Association (NCAA) revealed that 5.3% of athletes admitted to
using DHEA or androstenedione, 33.4% admitted to using nutritional
TESTOSTERONE PRECURSORS 789
supplements, and 1.2% admitted to using anabolic steroids [6]. With the
passage of the Anabolic Steroid Control Act of 2004, androstenedione be-
came illegal to purchase; the only available source is through the black mar-
ket or acquaintances. One would surmise that the use of testosterone
precursors among adolescents would be higher than the use of AASs. Stud-
ies have found the rate of anabolic steroid use among junior and senior high
students to be in the range of 3% to 7% [7–9]. This indicates that the trend
for the use of performance-enhancing substances is no longer restricted to
elite athletes but is pervasive in the pediatric and adolescent population.
The lure of scholarships, product endorsements, and million-dollar salaries
increases the pressure to get the competitive edge and the win-at-all-costs at-
titudes among young athletes.
Physiology
Testosterone precursors are involved in the endogenous production of
testosterone. DHEA is produced naturally in the adrenal glands and go-
nads. DHEA is converted to androstenedione or androstenediol in the ste-
roid synthesis pathway. Androstenedione and androstenediol are converted
to testosterone in the testes and any tissue cells that contain androgen or es-
trogen receptors [10,11]. Adipose, bone, muscle, breast, prostate, liver,
brain, and skin can be affected. The conversion of androstenedione and an-
drostenediol to testosterone is regulated by the enzymes 17b-hydroxysteroid
dehydrogenase and 3b-hydroxysteroid dehydrogenase, respectively.
The increased circulating levels of androstenedione and testosterone can
be aromatized to estrone and estradiol [11–13]. Gonadal production of tes-
tosterone and estrogen is regulated by a negative-feedback system. The pe-
ripheral conversion of androgens and estrogens depends upon the quantity
of circulating steroid precursors and not on any physiologic regulation
system (Fig. 1) [12,14].
These precursors bind poorly to androgen receptors and have few inher-
ent androgenic-anabolic properties. The theory is that by increasing the cir-
culating concentration of steroid precursors, the body’s endogenous
production of testosterone increases and promotes anabolic effects in pe-
ripheral tissues [15,16]. It has been found that low to moderate doses of
these precursors do not increase testosterone levels significantly; however, at
high doses, testosterone levels can be increased significantly. Therefore, the
increased testosterone levels may build muscle mass, increase strength, and
improve athletic performance [15].
Efficacy in performance enhancement

Athletes use testosterone precursors with the belief that they will boost
testosterone levels and, thereby, achieve the same anabolic effects of
Fig. 1. Steroid syntheses pathway.
AASs. They are promoted to enhance performance by reducing fat, build-

ing muscle mass, increasing strength, and improving sexual performance.
Studies of the efficacy of these testosterone precursors have not demon-
strated any significant improvements in enhancing performance. The ‘‘An-
dro Project’’ by Broeder and colleagues [17] in 2000 studied the effects of
healthy men, 35 to 65 years of age, taking androstenedione or androstene-
diol, 200 mg daily, in the setting of a 12-week high-intensity resistance-
training program. Total testosterone levels increased by 16% after 1 month,
but had returned to pretreatment levels by the end of the 12 weeks. The
study also found that estrone and estradiol levels remained elevated signif-
icantly (up to 97%). Neither androstenedione nor androstenediol signifi-
cantly improved lean body mass or increased muscle strength compared
with placebo. They also found that there was an adverse effect on high-den-
sity lipoprotein (HDL) cholesterol and an increase in the coronary heart
disease risk.
Brown and colleagues [18,19] studied the effects of daily oral supplemen-
tation with androstenedione, 300 mg, or DHEA, 150 mg, in healthy men 19
to 29 years of age with 8 weeks of resistance training. They found that serum
androstenedione levels were elevated, but no significant increases in testos-
terone levels occurred, and it did not significantly enhance the adaptations
to resistance training with changes in body composition or strength. They
also examined the effects of a single dose of DHEA, 50 mg, and found
a 150% increase in androstenedione levels within 60 minutes but no in-
creases in testosterone levels.
A 2002 review of studies by Ziegenfuss and colleagues [1] found that

most studies showed (1) acute oral ingestion of androstenedione or andros-
tenediol, at least 200 mg, modestly and transiently increased serum testos-
terone levels in men; (2) elevation of circulating estrogen levels; (3)
dosages of androstenedione or androstenediol, less than 300 mg/d for as
long as 12 weeks, had no effects on body composition, muscle mass, or per-
formance; and (4) significantly decreased serum HDL cholesterol levels and
increases in the cardiovascular disease risk. A summary of research from
1999, which was published by Powers [16] in 2002, showed a consensus in
that no significant increases in muscle mass or strength was found with a
single dose or daily ingestion. High dosages of androstenedione, 200 to
300 mg/d, significantly increased serum testosterone levels in young healthy
men by 34% and increased estradiol levels by 128%. The increases in testos-
terone levels were temporary, and daily doses up to 12 weeks showed signif-
icant increases in estradiol and estrone levels but did not show any
significant increases in baseline testosterone levels. Other studies also
showed no increase in muscle protein synthesis with supplementation with
DHEA or androstenedione [20–22] and no increase in muscle fiber cross-
sectional area with a combination of androstenedione ingestion and resis-
tance training compared with placebo [21,23,24]. Studies also showed that
androstenedione supplementation in men increased serum androstenedione
levels; a low daily dose (100 mg) did not increase serum testosterone levels
significantly, but a high daily dose (300 mg) increased serum testosterone
levels and serum estrogen levels [17,20,23,25]. Investigations on the efficacy
of DHEA, with dosages up to 150 mg/d, revealed no change in testosterone
levels nor significant changes in lean muscle mass or strength compared
with placebo [26–30].
Several reasons have been suggested for the lack of efficacy of androste-
nedione on improving muscle mass and strength. First, oral supplementa-
tion must undergo first-pass hepatic metabolism before it reaches the
circulation. Second, only 2% of an oral dose is converted to testosterone;
a large percentage is converted to testosterone glucuronide, which is biolog-
ically inactive. Third, the peripheral aromatization of testosterone to estra-
diol may limit the available level of testosterone to bind and activate
androgen receptors [1,17,20,23,25].
In summary, the testosterone precursors DHEA, androstenedione, and
androstenediol have little inherent androgen action. The ergogenic claims
regarding prohormone supplementation have not been supported by con-
trolled studies. Studies have demonstrated repeatedly that acute and long-
term administration of oral androstenedione, androstenediol, or DHEA
does not effectively increase serum testosterone levels and fails to produce
any significant changes in lean body mass, muscle strength, or performance
improvement compared with placebo. High doses of androstenedione
seem to increase serum levels of estrogens, primarily through peripheral
aromatization.
Safety and adverse effects

The adverse effects of oral supplementation with testosterone precursors
are not well known. The lack of long-term studies makes it difficult to iden-
tify the dangers and risks of using these nutritional supplements. Adverse
effects are most likely underreported because it is difficult to determine
the prevalence of prohormone use and the disparity in product labeling of
nutritional supplements. DHEA was reported to cause irreversible viriliza-
tion in women (hair loss, hirsutism, deepened voice) and gynecomastia in
men [31]. Androstenedione use was found to have an adverse effect on cor-
onary heart disease risk and to cause a significant reduction in serum HDL
cholesterol [20–22]. Long-term increased levels of unopposed circulating es-
trogens potentially could induce hormone-sensitive malignancies, such as
uterine, breast, and prostate cancer [32]. Theoretically, high doses of pro-
hormones could increase androgen levels and have the same adverse as
AAS use, such as liver dysfunction, glucose intolerance/diabetes, malignan-
cies, menstrual irregularities, infertility, testicular atrophy, impotence, male
pattern baldness, acne, or aggressive behavior.
Studies are especially lacking in the pediatric and adolescent populations.
Children and adolescents are vulnerable to the potential irreversible effects
of androstenedione conversion to sex hormones. These effects could result
in irreversible virilization in girls that is associated with hirsutism, severe
acne, deepening of the voice, enlargement of the clitoris, menstrual irregu-
larities, and even infertility. Excessive estrogens in boys can lead to femini-
zation with testicular atrophy, impotence, and gynecomastia. Boys and girls
potentially could experience precocious puberty, stunted growth, and pre-
mature closing of epiphyseal growth plates [23,28,29].
The public has the false perception that nutritional supplements are nat-
ural, and, therefore, safe. In fact, studies found that prohormone prepara-
tions often are contaminated with products that are not listed on the
label, including AASs [33,34]. An International Olympic Committee
(IOC)-funded study of 634 nonhormonal nutritional supplements found
that 14.8% of these supplements contained prohormones that were not
listed [35]. Baume and colleagues [36] analyzed the composition of 103 die-
tary supplements purchased on the Internet and found many contaminated
with AASs. One out of five supplements was contaminated with chemicals
not declared on the label, and creatine and mental enhancers were found
to contain prohormones not listed on the label. Athletes and consumers
need to be aware that the purity of nutritional supplements is not guaran-
teed; taking these supplements may result in a positive drug test and can
subject the users to the adverse effects that are associated with AASs. As
a result of increasing scientific evidence indicating real and significant health
risks with the use of androstenedione products, the FDA and HHS initiated
a campaign to educate consumers and cease the distribution, marketing, and
sale of dietary supplements that contain androstenedione [37].
Legal issues
Several questions are raised when discussing the legal issues of a perfor-
mance enhancing supplement. Is it safe? Does it work? Is it legal or fair?
Most performance-enhancing supplements are not illegal but are banned
by major sports-governing bodies. Testosterone precursors are banned by
most major sports, including the IOC, National Football League, NCAA,
Federation of International Football Association (FIFA), National Basket-
ball Association, and Major League Baseball. As a result of the Anabolic
Steroid Control Act of 2004, androstenedione is listed as a schedule III con-
trolled substance and is regulated by the FDA [4]. DHEA was not placed on
the controlled substance list. Theoretically, doping with androstenedione
and DHEA can increase testosterone levels in the body, which increases
levels of urinary testosterone secretion and can result in a positive urine
drug test [33]. Also, many performance-enhancing supplements are contam-
inated with AASs and can result in a positive drug test [33,34]. Studies have
demonstrated that the 7-Keto DHEA metabolites 7-hydroxylated-DHEA
compounds are present endogenously in small amounts; however, these me-
tabolites are abundant after the ingestion of exogenous 7-Keto DHEA
[34,38]. The metabolites of 1-androstenediol androstenalone and 1-andros-
tenedione are detectable for up to 120 hours after ingestion. Currently,
only qualitative analysis is available, and doping analysis will require quan-
titative analysis and determination of appropriate threshold values. Further
research and development of reliable drug tests will be needed to adequately
test for doping with these agents.
Current medical recommendations

Current evidence shows that the testosterone precursors DHEA, andros-
tenedione, and androstenediol do not offer any substantial performance-en-
hancing benefits. The potential adverse effects of these substances produce
a significant health risk, especially to the pediatric and adolescent popula-
tion. At higher doses, they were shown to minimally and temporarily elevate
testosterone levels and to increase estrogen levels. No significant health or
medical benefits exist, except for the possible antiaging properties of
DHEA. As a result of the increasing evidence of the potential harmful
health effects of these prohormones, the FDA has placed androstenedione
on the schedule III controlled substance list and has not approved andros-
tenedione or DHEA for any indication [4].
Summary
Dietary supplement use is increasing in the athletic population in an at-
tempt to enhance athletic performance and gain a competitive edge.
Marketing and anecdotal evidence promote the use of these supplements as

performance enhancers, often without sufficient scientific evidence to sub-
stantiate their performance-enhancing claims. Three testosterone precursors
that have come on the market after the passing of the Dietary Supplement
Health and Education Act of 1994 are androstenedione, DHEA, and
androstenediol.
These testosterone precursors have little inherent androgen action. The
ergogenic claims regarding prohormone supplementation have not been
supported by controlled studies. Studies have demonstrated repeatedly
that acute and long-term administration of oral androstenedione, androste-
nediol, or DHEA does not effectively increase serum testosterone levels and
fails to produce any significant changes in lean body mass, muscle strength,
or performance improvement compared with placebo. High doses of an-
drostenedione seem to increase serum levels of estrogens, primarily through
peripheral aromatization.
The extent of the use of testosterone precursors, such as androstenedione
and DHEA, in the pediatric and adolescent population is unknown. It seems
reasonable to believe that the use of testosterone precursors among
adolescents is higher than the use of AASs. The adverse effects of oral sup-
plementation with testosterone precursors are not well known. The lack of
long-term studies makes it difficult to identify the dangers and risks of using
these nutritional supplements. Consumers need to be aware that ‘‘natural’’
does not imply safety and the need to determine the efficacy, purity, safety,
and legality of these supplements before using them is imperative. Studies
are especially lacking in the pediatric and adolescent populations. Children
and adolescents may be vulnerable to the potential irreversible effects of
conversion to sex hormones.
Testosterone precursors are banned by most major sports, including the
IOC, National Football League, NCAA, FIFA, National Basketball Asso-
ciation, and Major League Baseball. As a result of the Anabolic Steroid
Control Act of 2004, androstenedione is listed as a schedule III controlled
substance and is regulated by the FDA. Quantitative drug testing for doping
needs to be well established to better monitor and control illicit use. No sci-
entific data exist to support the medical use of these supplements. Health
care professionals need to stay updated on current research and be well in-
formed to discuss supplement use with individual athletes.
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Sports Medicine:
Performance-Enhancing Drugs
Andrew J.M. Gregory, MD, FAAP, FACSMa,b,*,
Robert W. Fitch, MDa,b
a
Vanderbilt University Medical Center, MCE–South Tower, Suite 3200, Nashville,
TN 37232, USA
b
Vanderbilt University, MCE–South Tower, Suite 3200, Nashville, TN 37232, USA
Primary Care Sports Medicine has evolved as a field because of the need
for physicians who are able to take care of the whole athlete and not just
their orthopedic needs. This includes medical problems (eg, exercise-induced
asthma or concussion), mental disorders (eg, eating disorders or anxiety), as
well as an understanding of how medications affect training and exercise. To
protect the athlete, physicians who take care of athletes need to be able to
educate coaches, parents, and athletes about the benefits and risks of perfor-
mance-enhancing drugs from a scientific perspective.
First, physicians must educate themselves regarding performance-
enhancing drugs because this is not a subject taught in medical school or
residency; however, we also must be cautioned not to contribute to the prob-
lem because, historically, many physicians have been the ones providing
these drugs to the athletes (eg, steroids for Olympic programs in East
Germany or blood doping in the Tour de France). Regardless, if we are
employed by the team or acting voluntarily, the team physician must keep
the best interests of the athlete above everything else.
Performance-enhancing drugs, ergogenic aids, or sports supplements
have been a part of sports since sporting competition began and likely
always will be. Considered cheating by purists and necessary by some
athletes, we must accept the fact that they are used, understand why they
are used, and study how to prevent their use to institute change. This article
summarizes current scientific information regarding the use of performance-
* Corresponding author. Vanderbilt Sports Medicine Center, MCEdSouth Tower, Suite

3200, Nashville, TN 37232.
E-mail address: [email protected] (A.J.M. Gregory).
798 GREGORY & FITCH
enhancing drugs in young athletes so that physicians can take the informa-
tion and knowledgably educate others.
For this discussion, a drug refers to any substance that exerts an effect on
a body system, and a supplement refers to a substance that is taken to
augment the diet. Most vitamins and minerals are benign in nature and
are difficult to misuse; however, some supplements (stimulants, steroid
precursors) clearly are drugs and have the potential to cause significant mor-
bidity and death. The categorization of these more significant substances
with the more safe ones leads people to think that all supplements are
safe; therefore, they are taken without consideration of harmful effects.
There are many different drugs and supplements used by athletes to
enhance performance. Some of the more common classes are blood doping,
anabolic steroids, stimulants, growth hormones, amino acids, and proteins
[1]. Several of these productsdalthough initially believed to be ineffectived
have been shown to be good at increasing strength, decreasing fatigue, and
building muscle. Although some of these products are illegal, they are readily
available through prescription, supplements, local gyms, and the Internet
(mostly from Mexico).
Because dietary supplements are treated differently than drugs by the US
Government, supplement manufacturers do not have the same production
standards as drug manufacturers. Supplement dilution or contamination
is common as the same containers are used to process multiple different sup-
plements without cleaning out the residue from the first. US Pharmacopeia
and Consumer Labs perform purity testing and publish results on the differ-
ent products from supplement manufacturers.
The US Food and Drug Administration (FDA) is responsible under the
Federal Food, Drug, and Cosmetic (FD&C) Act for ensuring that manufac-
turers of foods, including dietary supplements, provide safe ingredients for
their products as well as accurate, complete labeling that is truthful and not
misleading [2]. Dietary supplements are treated as foods, as long as no drug
claims are made for them. When products are marketed for therapeutic use,
FDA regulates them through its Center for Drug Evaluation and Research.
The Nutrition Labeling and Education Act of 1990 (NLEA) [3], which
amended the FD&C Act, provides the FDA with specific authority to
require nutrition labeling of most foods and to require that all nutrient
content claims and health claims be consistent with agency regulations.
This drew the attention of supplement companies who were concerned
that the FDA would now have additional authority over dietary supple-
ments. They lobbied that the FDA would now be choosing for consumers
what they could and could not have.
The Dietary Supplement Health and Education Act (DSHEA) of 1994 [4],
which amended the NLEA, limits the FDA’s authority by imposing a more
relaxed standard for claims on supplements than for conventional foods. It
defines a dietary supplement as a product intended to supplement the diet
that contains one of the following ingredients: vitamin, mineral, herb or other
SPORTS MEDICINE: PERFORMANCE-ENHANCING DRUGS 799
botanical, amino acid or a concentrate, metabolite, constituent, extract, or

combination of any ingredient. The Act shifts the burden of proof of safety
from the manufacturer to the FDA. The Act also permits health claims if
they accurately represent the current state of scientific evidence concerning
the relationship between the supplement and a disease or other health-related
condition, a determination that is left to the manufacturer.
Since the DSHEA of 1994, the FDA has proven several ingredients to be
harmful and, therefore, required that they be removed from dietary supple-
ments. Ephedra (ephedrine alkaloids) was the first to be banned in 2004
because of concerns over its cardiovascular effects, including increased
blood pressure, irregular heart rhythms, and death. Also, in 2004, the
Anabolic Steroid Control Act [5,6] was passed in the US Congress. It
amends the Controlled Substances and Anabolic Steroids Control Acts to
clarify the definition of anabolic steroids and to provide for research and
education activities relating to steroids and steroid precursors. In addition
to adding steroid precursors to the controlled substances list, it increased
penalties for anabolic steroid offenses near sports facilities.
The most recent Act is the 2006 Dietary Supplement and Nonprescrip-
tion Drug Consumer Protection Act, which mandates manufacturers of
supplements and over-the-counter products to report serious adverse events
to the FDA within 2 weeks of the claim. Manufacturer contact information
is now required on the label, and all records of claims must be kept on file. It
is hoped that these recent changes will protect the athletes from potential
adverse events from products sold in supplements.
Although the Drug Enforcement Agency historically has concentrated on
street drugs, in 2002 they began prosecuting manufacturers, distributors,
and consumers of anabolic steroids. Victor Conte, who was the founder
of BALCO Labs in San Francisco and the manufacturer of THG (tetrahy-
dragestrinone), was arrested in 2004. Albert Saltiel-Cohen, a Mexico City
veterinarian and owner of three of the largest steroid-manufacturing compa-
nies in the world, was arrested in 2005 in San Diego. In 2007, the owners of
Signature Pharmacies in Orlando, Florida were arrested for fraudulently
prescribing steroids and human growth hormone over the Internet.
Given the fact that young athletes use supplements and steroids, it
behooves us to review what exactly they are using and why. There are few
studies on side effectsdespecially long-termdand none at all in children.
Most adolescent athletes do not make the most of their diet for performance
before considering supplements. Most public high schools do not have drug-
testing programs and are not likely to have them because of the cost. We are
not sure that testing is an effective deterrent to use, but we do know that
education works.
A 2003 survey showed that high school athletes frequently use supple-
ments, including sports drinks, vitamin and minerals, energy drinks, herbal
supplements, guarana, creatine, protein, and coenzyme Q10 [7]. They
reported that they use them because of perceived short-term health benefits,
800 GREGORY & FITCH
prevention of illness, improved immunity, parental supply, taste, energy

boost, better sports performance, and to rectify a poor diet.
In 15,000 adolescents from the 2006 National Longitudinal Study of
Adolescent Health, boys were more likely than were girls to use anabolic
steroids and legal supplements [8]. High school sports participation was
associated with an increased likelihood that adolescents would use legal
supplements in young adulthood. There was also a positive relationship
between the use of legal dietary supplements and anabolic steroid use.
In a 2006 study of high school athletes in Nebraska, one quarter reported
currently taking supplements [9]. Sports performance was the most reported
reason for use, and their coach was listed as their best source of information
on supplements. An anonymous survey of football and volleyball players
from 20 high schools in northwest Iowa in 2001 showed that 8% of the male
athletes and 2% of the female athletes were using supplements [10]. These
included creatine, androstenedione, beta-hydroxy beta-methylbutyrate,
amino acids, dehydroepiandrosterone, Phosphogen, Weight Gainer 1850,
Tribulus, Muscle Plus, multivitamins, calcium, Gamma-aminobutyric acid,
Shaklee Vita Lea, and Physique.
A survey of national track and field athletes competing at the 2004 World
Junior Championships reported that 62% of respondents used supplements
[11]. Of those, use among female athletes (75%) was higher than among
male athletes (55%). Seventeen different supplements were reported, with
an average of 2.5 products each (mostly multivitamins and minerals).
Persons with the most influence on practices included coaches (65%), sports
dieticians (30%), and doctors (25%).
In 1994, a questionnaire administered to all athletes at nine high schools
in one rural county in Minnesota showed that 38% used supplements,
equally by gender and grade in school [12]. Athletes with aspirations to
participate in college sports were more likely to consume supplements.
Healthy growth, treating illness, and sports performance were the most
important reasons reported for supplement use. Parents, doctors, and
coaches were reported as being the greatest influences on use. Most athletes
believed that supplement consumption improved athletic performance. In
1995, the Nutritional Supplement Use and Knowledge Scale found that
greater knowledge about supplements was associated with less use [13].
Protein supplements often are used by athletes with the hopes of adding
muscle or repairing muscle damage from workouts. They are sold as pow-
ders to be used in shakes and taken directly before or after a workout.
Most Americans consume the recommended daily allowance for protein
each day. Unless the athlete is vegetarian and does not get protein from
another source, supplementation is not indicated or necessary for building
muscle. Although protein supplementation seems to be safe, if taken at the
doses recommended, a significant protein load is placed on the kidneys. If
this occurs during a period of dehydration, such as in a particularly intense
workout in hot or humid conditions, the kidneys are at risk for acute failure.
Creatine probably is the protein supplement that is used most commonly

by athletes for increasing strength [14]. It was discovered in the 1920s and
made popular by Mark McGwire in Major League Baseball in the 1990s.
It is a protein that is stored in skeletal muscle that binds phosphate to serve
as an energy substrate for ATP. Creatine has demonstrated improved
performance in repeated bouts of high-intensity strength work and sprints.
There are no demonstrated effects in single-sprint activities, endurance exer-
cise, or competition. Therefore, it is useful for increasing training intensity
and volume to enhance physiologic adaptation.
One to 2 g of creatine per day are synthesized in the kidney, liver, and
pancreas from the essential amino acids arginine, glycine, and methionine.
An additional 1 to 2 g/d are obtained from a meat-containing diet. Once
the muscle stores are saturated, the remaining creatine is converted to creat-
inine and cleared by the kidneys. Creatine is sold in a powder or liquid form
in recommended dosages sometimes greater than 10 g/d. Taking dosages
greater than 2 g/d is unnecessary and potentially harmful to the kidneys. There
are two case reports of worsening renal failure in children who had underlying
kidney disease using creatine. Other reported side effects include weight gain
(water weight), nausea, and muscle cramping. Overall, creatine seems to be
safe in adults, but no study has been performed specifically in children.
In 2000, students aged 14 to 18 years were surveyed regarding creatine dur-
ing their preparticipation screen at a single institutional sports medicine center
in Minnesota [15]; 8.2% of athletes reported creatine use, and half were taking
creatine at the time of the survey. Most users believed creatine improved their
performance and did not know how much creatine they were taking or were
taking greater than the recommended dosage. They were more likely to
know other creatine users and to use other supplements. Most obtained infor-
mation from friends and purchased it from health food stores.
In 2001, athletes from 37 public high schools in Wisconsin took part in
a cross-sectional, multisite, anonymous, descriptive survey of creatine use
[16]; 16.7% of the athletes (25.3% boys, 3.9% girls) reported using creatine,
from 8% in the 9th grade to 25% in the 12th grade. The sport with the
lowest use was female cross country (1%), and football was the sport
with the highest use (30%). For football, use differed by grade: 10.4% of
grade 9 athletes and 50.5% of grade 12 athletes reported using creatine
[17]. School size was inversely proportional to use, with 41% of players at
small schools and 29% of players at large schools reporting use. Increased
strength was the most likely perceived benefit, whereas dehydration was
cited most often as a perceived risk. Users were encouraged to use most
often by their friends, whereas their parents discouraged its use.
In 2001, 1103 middle and high school athletes aged 10 to 18 years in
Westchester County, New York were surveyed before their preparticipation
screen [18]. Six percent of athletes admitted taking creatine in all grades
(6–12), but the highest use was found among the twelfth-grade students
(44%). Use was higher in boys (9%) than in girls (2%) and was more
802 GREGORY & FITCH
common in football, wrestling, hockey, gymnastics, and lacrosse. Users re-

ported enhanced performance and improved appearance as the most common
reasons for use. Safety was cited as the most common reason for not using.
Androgenic-anabolic steroids (AASs) are perhaps the best known and
most widely publicized of the performance-enhancing drugs. Shown to be
effective by the East German Olympic athletes in the 1950s, steroids are
known to permeate the sports of weight lifting, body building, professional
wrestling, and the Olympics. Anabolic steroids include derivatives and
precursors of the hormone testosterone. Testosterone exerts many effects
on the body, including increasing protein synthesis and euphoria and
decreasing catabolism. Initially, the medical community demonstrated that
steroids were not effective, but the tests were conducted using physiologic
dosing instead of what the athletes were using (10–100 times that).
There is no doubt now that steroids work; however, the potential side
effects are significant and must be taught to athletes. These include
decreased testosterone production, testicular atrophy, and gynecomastia
in boys and masculinization in girls. Cardiovascular effects are substantial,
with clotting, myocardial infarction, stroke, and death topping the list. If the
injectable form is used, aside from disease transmission risks, hepatitis, cho-
lestasis, and even, carcinoma can form in the liver. Psychologic effects are
common, including aggression, dependence, anxiety, depression, and psy-
chosis. In adolescents, early epiphyseal closure and increased suicidal idea-
tion and attempts have been described. Mood swings and irritability may be
clues to anabolic steroid use as well as drug abuse.
A 2000 systematic review showed that adolescent anabolic steroid users
were significantly more likely to be boys and to use other illicit drugs, alco-
hol, and tobacco. It also showed that student athletes were more likely than
were nonathletes to use steroids. Football players, wrestlers, weightlifters,
and bodybuilders had significantly higher prevalence rates.
In 2002, the Project EAT: Eating Among Teens study was performed on
4746 middle and high school students from St. Paul/Minneapolis public
schools. They completed surveys and anthropometric measurements regard-
ing eating patterns and weight concerns. Reported steroid use was 5.4% in
boys versus 2.9% in girls. In boys, AAS use was associated with poorer self-
esteem, depressed mood, attempted suicide, poorer knowledge and attitudes
about health, greater participation in sports that emphasize weight and
shape, greater parental concern about weight, disordered eating, and
substance use. Among girls, steroid use was less consistent in its associations
with other variables.
In 1999, varsity football players in Indiana were selected randomly from
27 high schools to complete a questionnaire. Out of 873 subjects, 6.3% were
current or former AAS users. The average age at time of first use was
14 years, but 15% began taking before the age of 10 years. Half of the
respondents indicated that they could obtain AASs if they so desired. Other
athletes, physicians, and coaches were listed as sources for AASs.
In 1998, a confidential self-report questionnaire was administered to male

and female students, 9 to 13 years of age, from four public middle schools in
Massachusetts. The response rate was 82% (965/1175 eligible), and 2.7% of
all middle school students reported using steroids (boys and girls). More
steroid users than nonusers believed that steroids make muscles bigger
and stronger, improve athletic performance, make one look better, were
not bad for them, knew someone their own age who currently took steroids,
were asked by someone to take steroids, and reported that they would take
steroids in the future.
In 2006, 2924 Norwegian high school students (age 15–19 years) were
surveyed at 5-year intervals; 1.9% reported the use of AASs in 1994 and
0.8% reported their use in 1999. By multivariate logistic regression, future
AAS use was predicted by young age, male gender, previous AAS use,
power sports participation, and frequent alcohol use.
The 1997 Centers for Disease Control and Prevention Youth Risk Behav-
ior Surveillance was a nationally representative sample of more than 16,000
United States public and private high school students; 6.1% of students in
high school had taken illegal anabolic steroids. Binge drinking, cocaine
use, fighting, and sexual risk-taking were associated with higher odds of
lifetime steroid use. Neither athletic participation nor strength conditioning
predicted the odds of steroid use after controlling for problem behaviors.
Steroid-using athletes reported the same frequency of use as did steroid-
using nonathletes.
Stimulants may be the most widely and underrecognized supplement used
by high school athletes and yet are the least studied. Common stimulants
include caffeine (guarana [Paullinea cupana]), ephedrine (ephedra or ma
huang), pseudoephedrine, Neo-Synephrine, amphetamines, and metham-
phetamines. Stimulants can be found in coffee, colas, energy drinks, cough
and cold medications, muscle building or weight loss supplements, atten-
tion-deficit/hyperactivity disorder (ADHD) medication, and diet pills.
Most studies on stimulant use are with medication used to treat ADHD
and not on use with athletics. There are a few studies on their use for athletic
performance in adults, but no studies have been done in the young.
Stimulants act on the central nervous system (CNS) to increase arousal,
respiratory rate, heart rate, and blood pressure and, therefore, improve
performance. Side effects can include dizziness, insomnia, agitation and rest-
lessness, anxiety, confusion, paranoia, hallucinations, dyskinesias, gastroin-
testinal disturbances, heat intolerance, stroke, myocardial infarction,
arrhythmia, and death. Severe rebound of fatigue and depression occurs
after discontinuance. Contraindications for stimulant use include heart
disease, strokes, high blood pressure, thyroid disease, diabetes, or seizures.
Drug testing has drawn a lot of attention recently for use in high schools
because several states have mandated it (eg, New Jersey, Texas). There is
a long history of drug testing at the Olympic level, which is now centralized
through the World Anti-Doping Agency. Testing is now required in most
804 GREGORY & FITCH
professional sports, the National Collegiate Athletic Association (NCAA),

and most colleges and universities. Testing is difficult, expensive, and always
lags behind what athletes are currently using. Until it is known what substance
is being used, a test cannot be created to find it and sometimes one may never
be available (ie, autologous blood). There is no solid evidence that drug testing
prevents use, except when the athletes know that a test is imminent; however,
many states are considering steroid testing in public high schools.
In 2006, Aegis Labs in Nashville, Tennessee did drug tests for more than
60 high schools. From the approximately 30 private and 30 public high
school accounts, they tested more than 3000 samples. Fifty-six schools
tested for drugs only, 3 schools tested for steroids and drugs, and 7 schools
tested for steroids only. There are multiple testing profilesdnone of which is
all-inclusivedbut each costs less than $100.
Of the high school samples tested, 543 were positive (16.6% of the total)
for drugs of abuse. By far, the most positives were for CNS stimulants (116
amphetamine, 36 pseudoephedrine, 34 cocaine [benzoylecgonine, a metabo-
lite], 3 methylenedioxymethamphetamine [Ecstasy], 1 phentermine, 1 meth-
amphetamine), followed by CNS depressants ([opioids: 14 morphine,
13 hydrocodone, 6 oxycodone, 3 codeine], alcohol [17 ethyl alcohol], and
barbiturates [1 phenobarbital, 1 butalbital]), hallucinogens (marijuana
metabolite - 37 carboxy-tetrahydrocannabinol), and, finally, antianxiety
drugs (6 alprazolam) (Dr. David Black, personal communication, 2007).
We do drug testing at our institution as a means of monitoring for
athletes who may need help with substance abuse and preventing positive
tests at the NCAA level. The samples are collected by the certified athletic
trainer randomly and for cause. After a positive result we require weekly
counseling regarding drug and alcohol use as well as weekly testing until
deemed no longer necessary by the counselor. There are no penalties for
the first offense, a 1-year suspension for the second offense, and disqualifi-
cation from athletics for the third offense.
Although drug testing has not been proven to prevent drug abuse, educa-
tion of athletes by coaches, parents, and allied health professionals has
proven to be beneficial in prevention. In a 2002 study, 40 high school stu-
dents from a low-income community were separated into experimental
and control groups [19]. The experimental group was given five lessons on
various nutrition and sport supplement topics. Both groups were adminis-
tered a validated nutrition and sport supplement questionnaire consisting of
28 questions before and after. Postintervention scores improved 9 points in
the experimental group, from 6 to 15, but did not change in the control group.
A 2004 Swedish health promotion program intervention targeted all 16-
and 17-year-old boys and girls to create awareness of, and to discuss
attitudes toward, steroid hormones among these adolescents. Youth leaders
and health workers discussed these subjects with adolescents over a period
of 2 years. The intervention was well received by the adolescents, and the
misuse of AASs had a tendency to decrease after the program.
Two drug prevention programs were designed specifically for high school
athletes by Oregon Health & Science University. The ATLAS (Athletes Train-
ing and Learning to Avoid Steroids) drug prevention program is directed at
male athletes and the ATHENA (Athletes Targeting Healthy Exercise & Nu-
trition Alternatives) is for female athletes. ATLAS is a hands-on approach
with interactive activities. It uses coaches and peer leaders as facilitators in
a team setting. There are 10 45-minute interactive classroom sessions and
three exercise sessions regarding sports nutrition, exercise alternatives, the ef-
fects of substance abuse in sports, drug refusal role-playing, and the creation
of health promotion messages. The goal is to reduce risk factors that foster the
use of anabolic steroids and other drugs by using the athletic team to deter
drug use and promote healthy nutrition and exercise as alternatives.
The second program, ATHENA is a school-based, team-centered preven-
tion program for female athletes on sports, dance, and cheer teams. It
consists of eight 45-minute sessions integrated into their usual sport-training
activities. It is designed to reduce disordered eating and the use of diet pills
and other supplements, as well as promote healthy nutrition and exercise.
This program has not been proven to prevent eating disorders.
Further information regarding the ATLAS or ATHENA programs can be
obtained through the Oregon Health & Science University at 503/494-3727,
[email protected], or by visiting the Web site (www.atlasprogram.com).
The price of the 4- to 5-hour training program is charged per participant (min-
imum of 20 and maximum of 100) plus travel expenses and program materials.
The ATLAS program was tested in 31 high school football teams that
consisted of 3207 athletes in three successive annual cohorts (1994–1996)
[20]. Intentions to use and actual AAS use were significantly lower among
participants. Although actual AAS reduction was not significant at 1 year,
intentions to use AASs remained lower and students used less sport supple-
ments and had improved nutritional behaviors.
We know that many young athletes use drugs for sports enhancement and
that most are not aware of the potential risks of their use. Education of ath-
letes works for the prevention of supplement and steroid use. As physicians
who take care of young athletes, we need to be the ones to educate coaches
and parents, who, in turn, will educate their athletes. We also have opportu-
nities to discuss this with athletes during preparticipation screening or office
visits for other sports-related complaints. Testing likely will always be too ex-
pensive and impractical to be used effectively at the high school level. We also
need to work with the FDA to clarify dietary supplements from drugs so that
we can protect consumers against potential adverse events.
References
[1] Johnson RJ, et al. Current review of sports medicine. 2nd edition. Philadelphia: Current
Medicine Inc.; 1998.
[2] Farley Dixie. Dietary supplements: making sure hype doesn’t overwhelm science. FDA
Consumer Magazine 1993.
806 GREGORY & FITCH
[3] Guide to Nutrition Labeling and Education Act (NLEA) Requirements; August 1994.
[4] Dietary Supplement Health and Education Act of 1994; Public Law 103–417.
[5] Anabolic Steroids Control Act of 1990; Public Law 101–647.
[6] Anabolic Steroid Control Act of 2004–Amendment to the Controlled Substances Act; 108th
CONGRESS; 2d Session; S. 2195; March 2004.
[7] O’Dea JA. Consumption of nutritional supplements among adolescents: usage and per-
ceived benefits. Health Educ Res 2003;18(1):98–107.
[8] Dodge TL, Jaccard JJ. The effect of high school sports participation on the use of perfor-
mance-enhancing substances in young adulthood. J Adolesc Health 2006;39(3):367–73.
[9] Scofield DE, Unruh S. Dietary supplement use among adolescent athletes in central Ne-
braska and their sources of information. J Strength Cond Res 2006;20(2):452–5.
[10] Mason MA, Giza M, Clayton L, et al. Use of nutritional supplements by high school football
and volleyball players. Iowa Orthop J 2001;21:43–8.
[11] Nieper A. Nutritional supplement practices in UK junior national track and field athletes. Br
J Sports Med 2005;39(9):645–9.
[12] Sobal J, Marquart LF. Vitamin/mineral supplement use among high school athletes. Ado-
lescence 1994;29(116):835–43.
[13] Massad SJ, Shier NW, Koceja DM, et al. High school athletes and nutritional supplements:
a study of knowledge and use. Int J Sport Nutr 1995;5(3):232–45.
[14] Kraemer WJ, Volek JS. Creatine supplementation. Its role in human performance. Med Sci
Sports Exerc 1999;31(8):1147–56.
Clin Proc 2000;75(12):1257–63.
[16] McGuine TA, Sullivan JC, Bernhardt DA. Creatine supplementation in Wisconsin high
school athletes. WMJ 2002;101(2):25–30.
[17] McGuine TA, Sullivan JC, Bernhardt DT. Creatine supplementation in high school football
players. Clin J Sport Med 2001;11(4):247–53.
108(2):421–5.
[19] Little JC, Perry DR, Volpe SL. Effect of nutrition supplement education on knowledge
among high school students from a low-income community. J Community Health 2002;
27(6):433–50.
[20] Goldberg L, MacKinnon DP, Elliot DL, et al. The adolescents training and learning to avoid
steroids program: preventing drug use and promoting health behaviors. Arch Pediatr
Adolesc Med 2000;154(4):332–8.
Gene Doping: A Review

of Performance-Enhancing Genetics
Gary R. Gaffney, MDa,*, Robin Parisotto, BAb
a
Division of Children and Adolescent Psychiatry, Department of Psychiatry,
University of Iowa College of Medicine, 200 Hawkins Road, Iowa City, IA 52242, USA
b
International Centre for East African Running Science, Glasgow University,
Glasgow, Scotland
The World Anti-Doping Agency (WADA) [1] defines gene doping as ‘‘the
non-therapeutic use of genes, genetic elements and/or cells that have the
capacity to enhance athletic performance.’’ The WADA Code is the ethical
document developed by the quasi-governmental organization, in partner-
ship with the International Olympic Committee, to pioneer and coordinate
sports antidoping efforts around the world. Without a single known human
incident of gene doping, WADA bestowed the technique of gene doping
a dishonored place on the list of prohibited substances.
For an entire biomedical technique to be banned, before even acquiring
regulatory approval by any government or before acceptance by any branch
of organized medicine, seems to be unprecedented [2]. Why would a sports
regulatory administration express such preemptive concern about a putative
medical technique of the future? This article answers that question and
predicts the future of gene doping.
Drug doping uses therapeutic advances in exercise physiology and clinical
pharmacology to provide unfair advantages to athletes who covertly use
anabolic drugs, thus dramatically enhancing competitive performance.
Similar to drug doping, gene doping manipulates scientific advances origi-
nally developed for the treatment of disease. Rather than drug interventions,
the gene-doping athletes appropriate advances in gene therapies. Gene dop-
ing, in concept, uses scientific developments that manipulate DNA in the
most basic regulation of biologic processes, to dramatically improve aspects
of athletic performance, such as speed, power, or endurance [2–10].
Molecular biology, particularly the ‘‘discovery’’ of DNA by Watson and
Crick in 1953, revolutionized biology and medicine. The rate of genetic
E-mail address: [email protected] (G.R. Gaffney).
808 GAFFNEY & PARISOTTO
discovery in molecular biology rapidly accelerated throughout the last half

of the twentieth century and into the twenty-first century. The new millen-
nium was to be the dawning of practical, effective treatments for genetic
diseases, such as muscular dystrophy, X-linked hemophilia, and other
single-gene disorders [5]. Further, with molecular biology advances that in-
cluded insertions of new genes into organisms, cloning of organisms, and
use of human stem cells, more than single-gene diseases could be treated.
Any number of serious or fatal medical conditions might be altered with
the introduction of genes that would produce ‘‘in vivo pharmacies’’ deliver-
ing biochemicals, including proteins and hormones, to injured or impaired
tissue.
Gene therapy also could improve a general disadvantageous condition,
such as aging-related muscle atrophy, by introducing a transgene to produce
the depleted factors involved in muscle repair and regeneration [5]. Thera-
peutic genes could be targeted directly into cells, tissues, and organs limiting
effects to a localized site, thus reducing the systemic side effects produced by
a typical drug administration.
Implications of novel genetic interventions fascinated not only researchers,
physicians, and gene therapists, but also coaches, athletes, and trainers
looking for athletic performance enhancement of biologic parameters, such
as strength, power, and oxygen delivery, to create a critical edge in sporting
competition [5]. The creation of a superman or superwoman athlete could
be planned by well-placed genetic physiologic tweaks.
Background: from performance-enhancing drugs

to performance-enhancing genes
Drug cheats in sports long used steroid hormones, amphetamines, and
blood manipulations to achieve advantages in competition (performance-
enhancing drugs or PEDs [9]. Steroid hormones produced rapid gains in
muscle size, strength, and recovery. Amphetamines improved alertness and
concentration. Blood doping improved oxygen delivery to tissues allowing
more endurance in competition; however, each of these drugs/manipulations
showed significant side effects. Steroids produced atrophy of sex organs,
gynecomastia, emotional rages, and other serious side effects. Amphetamines
reduced appetite anddin large dosesdproduced paranoid or psychotic
symptoms. Blood doping resulted in a hematocrit so high that the erythrocy-
tosis caused thrombosis and embolism. These blood dyscrasias, combined
with erythropoietin (EPO)-related serious cardiac effects, seemed to be
particularly lethal [9].
As laboratory detection become more sophisticated in catching drug
cheats, the athletes turned to novel peptides, such as human growth hormone
(HGH), to gain an edge or to avoid detection by antidoping authorities.
Substances like HGH were expensive and dangerous, however; HGH was
GENE DOPING 809
harvested from cadavers, some of whom died from contagious spongiform

neurologic conditions. Other peptide hormones, including EPO, which
regulates red blood cell (RBC) production, remained unavailable as drugs.
The emerging biotechnology industry changed these limitations with the
implementation of recombination DNA production of peptide drugs and
hormones. Manipulating genes inserted into mammalian cells, the new in-
dustry produced recombinant (r) drugs, such as rHGH, rEPO, insulin-like
growth factor (r-IGF)-1, and r-insulin in great quantities. Essentially iden-
tical to human hormones, these advanced drugs produced a significant im-
pact on the medical treatment of anemia, growth deficiency, and diabetes,
for example; however, biotechnology advances did not go unnoticed by
the coaches and athletes who look for every advantage in competition [5].
Soon after introduction of a new recombinant peptide or hormone, the
sports doping community appropriated the drug if it offered an advantage
in competition. Unscrupulous physicians and trainers used rHGH and
rIGF-1 to increase strength and power among a wide variety of athletes, in-
cluding Major League Baseball and National Football League players.
rEPO proliferated among cycling competitors to increase oxygen delivery
to muscles during lengthy and demanding races like the Tour de France.
The detection of these new recombinant DNA–produced peptide
hormones in rogue athletes presented formidable challenges that continue
to be problematic for antidoping laboratories [9,10]. Although the use of
rHGH, rEPO, and insulin in sports like football, cycling, track, and baseball
is widespread, antidoping laboratories continuously must play catch-up in
developing detection procedures. Thus, the introduction of recombinant
drugs into the sports doping field might be considered the first step in genetic-
related doping.
With the advent of gene therapy, a more direct way to deliver proteins
and hormones to an athlete’s tissues and organs became reality. The sophis-
tication and the power of these biologic alterations piqued the ingenuity of
the drug-cheating coaches and athletes. A substance that can alter the basic
genetic expression of DNAdsuch that muscles grow larger, contract more
forcefully, and recover more quickly than non-doped musclesdand cannot
be detected by antidoping laboratories would be ideal to gain a competitive
advantage while not running afoul of the regulatory officials.
Genetic therapies
In the broad sense, genetic therapies include several categories of biotech-
niques [7,9,10]:
1. Use of recombinant DNA techniques to produce new peptides or drugs
(rEPO)
2. Pharmacogenetics, or the use of knowledge of the specific genome of an
athlete to tailor pharmacologic interventions
3. Somatic cell modification, which produces genetically modified cells (eg,

modified RBCs to increase blood-carrying capacity)
4. Germ-line modification, where the gametes or early embryos undergo
gene modification to express more athletically expedient traits
5. Genetic preselection, where a gene scan would inform parents about the
distribution of desired genes in a potential offspring
6. Genetic selection, where individuals are selected for particular traits
(widely practiced in animal husbandry)
This article’s main focus is on the modification of cells to express proteins
or other biochemicals to enhance athletic performance.
Defined as ‘‘the transfer of genetic material to human cells for the
treatment or prevention of a disease or disorder,’’ gene therapy uses genetic
materials, such as DNA, RNA, or genetically altered cells [3]. In the simplest
form, gene therapy introduces a ‘‘therapeutic gene’’ (transgene) into an
organism by way of a vector, often an inactive virus. Within the organism
itself, the new ‘‘transgene’’ synthesizes the defective/missing protein or
biologic substance to correct dysfunctional tissues and organs. Other gene
therapy strategies involve manipulation of genes, turning them on or off as
the desired physiologic response dictates.
Initial gene therapy trials included protocols to treat an X-linked immu-
nodeficiency disease and hemophilia variant [5]. A trial of human vascular
endothelial growth factor produced positive results in patients who had
angina [10]. More than 1000 gene therapy trials are ongoing in various states
of clinical study [2,6,7]. No gene therapy protocols have been approved for
medical practice by the US Food and Drug Administration, the regulatory
agency charged with overseeing the development and clinical use of the
medical procedure.
Genetic enhancement
Gene doping also could use the technique of genetic enhancement/
engineering. In practice in agricultural settings, genetic enhancement places
advantageous genes into organisms, not to cure disease, but to confer
advantages to the organism that would improve the organism’s survival or
the organism’s ‘‘product’’: hardiness, better insect resistance, or greater yield.
Genetic enhancement exploits the same techniques as gene therapy; however,
it can be applied outside of medicine [3].
Genetic performance enhancement: gene doping

Using basic principles of gene therapy (and genetic enhancement), gene
doping injects genes directly into the athlete’s body by one of two methods:
in vitro delivery and ex vitro delivery [5,10]. In gene therapy, the clinician
introduces a gene that covers for a deficient gene or modulates the activity
GENE DOPING 811
of an existent gene to correct a disease state. The goals of gene doping in-
clude the injection of novel genes or the modulation of existing genes too;
however, the gene doper introduces the gene products for the enhancement
of physiologic parameters expedient to the athlete’s competitive tasks, rather
than the treatment of a medical illness.
In vivo gene doping

The delivery of the new gene into the athlete can be through biologic,
physical, or chemical methods. Viruses can be modified to biologically insert
the artificial gene into cells in a specific organ or target tissue or into cells
throughout the competitor’s body. Virus lines modified to transfer genes
to mammalian cells include retroviruses, adenoviruses, and lentiviruses
[10,11]. Physical methods to deliver genes into cells use microsyringes, or
gene guns. Biochemical injection vehicles use plasmids or liposomes [10,11].
Ex vivo gene doping

The technique of exogenous gene doping involves gene transfer to cells in
culture first, then implantation of the tissue into the recipient. Once im-
planted into the athlete’s cells, the new genes express hormones or biochem-
icals that again enhance tasks of the athlete in competition [11].
Candidate genes for athletic gene doping

Any physiologic process involved in producing a motor action or assisting
in the implementation of a motor movement could be a candidate for gene
doping (Table 1; Fig. 1). The physiologic processes of pulmonary respiration,
cardiovascular circulation, oxygen delivery, striated muscle growth/effi-
ciency/repair, and even neuromuscular coordination could be altered to
give an athlete an edge over his or her competition. Although more esoteric,
neurophysiologic processes, such as mental alertness, motivation, and central
nervous system recovery, also might be amenable to gene doping. The list of
physiologic processes related to athletic competition is long and likely only
limited by current understanding of exercise physiology and exercise
psychology [10].
Even now, in the exploratory phase of gene therapy/gene doping, there
are obvious candidates for the aspiring gene cheat. These primary gene
candidates exist as targets of biomedical researchers looking for legitimate
disease treatments [10].
Hematopoietic/vascular systems
The classic example of a genetic alteration to enhance athletic performance
occurred naturally in 1964. A Finnish skier, Eero Mantyranta, dominated
Olympic Nordic skiing. Studies later demonstrated that Mantyranta benefited
812
Table 1
Candidate genes for sports doping
Gene/product System/organ targets Gene product properties Physiologic response
ACE Skeletal muscles Peptidyl dipeptidase ACE-D is involved in fast twitch muscles
ACE-I seems to correlate with endurance
ACTN3 Skeletal muscle Actin-binding proteins related to Involved in fast twitch muscles
dystrophin
Endorphins Central and peripheral nervous systems Widely active peptides Pain modulation
GAFFNEY & PARISOTTO

EPO Hematopoietic system Glycoprotein hormone Increases RBC mass and oxygen delivery
HGH Endocrine system 191–amino acid protein Increases muscle size, power, and recovery
HIF Hematologic and immune systems Multisubunit protein Regulates transcription at hypoxia
response elements
IGF-1 Endocrine/metabolic/skeletal muscle 70–amino acid protein Increases muscle size, power, and recovery
by increasing regulator cells
Myostatin Skeletal muscle 2-subunit protein Regulates skeletal muscle. Inhibition
increases muscle size, power, and
recovery.
PPAR-delta Skeletal muscle and adipose tissue Nuclear hormone receptor protein Promotes fat metabolism and increases
number of slow twitch fibers
VEGF Vascular endothelium Glycosylated disulfide-bonded Induces development of new blood vessels
homodimers
Abbreviations: ACE, angiotensin-converting enzyme; ACTN3, actinin binding protein 3; EPO, erythropoetin; HGH, human growth factor; HIF, hypoxia
inducible factor; IGF-I, insulin-like growth factor; PPAR-delta, peroxisome proliferators-activated receptor (delta); VEGF, vascular endothelial growth
factor.
GENE DOPING 813
Fig. 1. Gene doping: gene and system targets. ACE, angiotensin converting enzyme; ACTN,
actinin binding proteins; EPO, erythropoetin; HGH, human growth hormone; HIF, hypoxia
inducible factor; IGF-I, insulin-like growth factor; PPAR-delta, peroxisome proliferator-
activated receptor; VEGF, vascular endothelial growth factor.
from a natural mutation in the EPO gene that produced a greater number of
RBCs, with a concomitant increased oxygen-carrying capacity [3,5]. This
skier possessed what every blood doper in history tried to achieveda physio-
logic advantage in delivering more oxygen to various tissues, including
muscles.
rEPO (epoetin and darbopoetin) is a much-abused injected recombinant
protein that increases RBC production, leading to increased oxygen-carry-
ing capacity and oxygen delivery to tissues. The abuse of rEPO is epidemic
in cycling, leading to frequent controversy, tedious forensic investigations,
and serious side effects, including death [9].
Using gene doping, an additional EPO gene could be delivered to the
athlete by way of a viral vector. Once in the athlete, the gene would express
much more EPO than normally produced, even with training. The desired
result would be an increase in the oxygen-carrying capacity of the blood,
thus bestowing a clear competitive advantage in endurance sports.
Laboratory experiments have been successful in injecting the gene into

monkeys and mice. Although the procedures successfully raised hematocrit,
severe side effects, including a paradoxical anemia, resulted [12–15].
Hypoxia inducible factors

The hypoxia inducible factor (HIF) family of proteins modulates the
activity of genes in low-oxygen environments. Various HIFs increase
production of RBC, as well as increase cellular energy use. Enhancement
of these proteins clearly would benefit the aerobic athlete [16–18].
Vascular endothelial growth factor

Clinical studies are currently ongoing for vascular endothelial growth
factor (VEGF), a gene product that encourages development of new blood
vessels [3]. This genetic manipulation would be advantageous to patients
suffering from coronary artery disease. The gene-doping athlete would ben-
efit from a putative increase in vasculature and more delivery of oxygen and
nutrients to the peripheral tissues.
Skeletal muscle system

Actin-binding peptides
The proteins actin and myosin form the machinery of muscle contrac-
tion. The family of actin-binding proteins in humans includes a-actinin al-
leles ACTN2 and ACTN3. Alpha-actinins maintain the structure of the
myofibrillar array and regulate myofiber contraction. A defect of ACTN3
regulation occurs when the ACTN3 gene codes for a premature stop codon;
ACTN2 seems to compensate in these persons. Correlation studies found
evidence that the ACTN2 endows muscular endurance traits upon athletes.
Conversely, elite sprinters benefit from more copies of ACTN3. Depending
on the event of the competitor, gene doping with the appropriate ACTN
allele could enhance endurance capacity or sprint effectiveness [18].
Angiotensin-converting enzyme
Physicians are well aware of angiotensin-converting enzyme (ACE)
inhibitors used for the treatment of hypertension; however, the ACE gene,
like the ACTN gene, codes for proteins that seem to endow different exercise
capacities. Research suggests that the ACE-I allele endows advantages in
endurance, which would be useful for distance runners. The ACE-D allele
seems to be associated with elite sprinting performance [18–20]. Again,
a gene-doping athlete could inject the appropriate gene to influence better
performance in his or her event, be it a sport featuring short bursts of speed
and power or a sport in which endurance is the key to success.
GENE DOPING 815
Insulin-like growth factor

Several sophisticated studies, most notably at the University of Pennsylva-
nia [5,21], targeted IGF-1, a peptide, in conjunction with HGH, intimately in-
volved with muscle growth, repair, and power. These studies demonstrated
eloquent ways in which IGF-1 controlled mammalian muscle development
and demonstrated that targeted gene therapy could successfully produce
hypertrophied and powerful muscles in laboratory mice. The primary investi-
gator, Lee Sweeney, designed the procedure carefully so that the virus and
the gene were not expressed systemically; by avoiding systemic distribution
of the peptide, the researchers hoped to avoid the serious side effects of
IGF-1, including myocardial hypertrophy and carcinogenesis. Thus, for
therapeutic reasons, the researchers designed the gene therapy to be effective
locally, in injected muscles. That particular feature also would benefit a doping
athlete, because the transgene IGF-1 would not enter the systemic circulation
where it might be detected by laboratory testing. In this University of
Pennsylvania protocol, ‘‘fingerprints’’ of the gene therapy did occur; however,
the theoretic aim of the study itself would present problems for antidoping
agencies.
Myostatin
Myostatin, known to be a negative regulator of muscle development,
presents another candidate gene. This regulator protein seems to turn-off
muscle growth. Substances that block myostatin or genes that produce
ineffective myostatin proteins would allow superphysiologic muscle growth
in terms of number and thickness of cells (as seen in certain breeds of cattle
through a natural mutation) [22,23]. Not only do striated muscles hypertro-
phy without myostatin regulation, but less fat is gained on the body of the
animal. The manipulation of this regulatory protein has obvious advantages
for the athlete.
Peroxisome proliferator-activated receptor delta

The peroxisome proliferator-activated receptor delta (PPAR-delta) gene
seems to be a prime candidate for gene doping [24–26]. This gene codes
for an increase in mitochondrial biogenesis and promotes an adapted muscle
fiber transformation. The gene promotes an increase in type 1 muscle fibers
(slow twitch). Elite athletes show an increase in PPAR-delta gene levels.
A PPAR-delta gene was inserted into mice; it dramatically improved the
animal’s endurance capacity. It was concluded that ‘‘.these genetically
generated fibers confer resistance to obesity with improved metabolic pro-
files, even in the absence of exercise. These results demonstrate that complex
physiologic properties such as fatigue, endurance, and running capacity can
be molecularly analyzed and manipulated.’’
Central and peripheral nervous system

Endorphins
In injuries, as well as in competition, pain limits athletic achievement.
Athletes sustain countless painful injuries for which they consume an abun-
dance of anti-inflammatory drugs and pain-relieving medicines. Likewise,
the buildup of lactic acid during competition induces pain. Clearly, increas-
ing the pain thresholddand alleviating the discomfort of nagging injuriesd
would improve performance.
The introduction of genes producing analgesic endorphins and enkepha-
lins would increase the pain threshold in an athlete, for pain experienced in
competition as a result of lactic acid buildup and pain due to acute and
chronic injury. Clinical trials are testing the efficacy of genes encoding these
natural narcotic peptides for pain relief in humans [3].
Other potential candidate genes

Interleukin-15 may prove to be an anabolic protein amenable to gene
doping [27]. Interleukin-1RA gene injection trials reported good results;
this gene could be used therapeutically for osteoarthritis and to promote
joint superlubrication [28]. Mechano-growth factor may aid in the repair
of damaged skeletal muscle tissue [9].
Risks and complications of gene doping

Examining the history of clinical pharmacology reveals that side effects of
novel treatments can be unexpected and occasionally fatal. From thalidomide
to valdecoxib, newly introduced medications, even with exhaustive preclinical
trials, produce unanticipated untoward side effects. Consider the potential
side effects of introducing a foreign gene, by way of a viral vector, into an or-
ganism’s chromosomes. Gene therapy trials made headlines several times
with unexpected and fatal side effects. Then 18, Jesse Gelsinger died in 1999
as the victim of an immune response to the virus used in a well-publicized
gene therapy trial [4]. That death shocked the biomedical world and resulted
in regulation as well as multiple legal actions. Several patients who were
treated for an X-linked hemophilia with a gene therapy protocol developed
leukemia, an obviously unexpected side effect [4].
A gene therapy trial of EPO in macaque monkeys produced such
stimulation of RBC production that the monkeys’ blood thrombosed [13].
Moreover, many of the monkeys suffered anemia, the result of an immune
response to the gene therapy. The overactive immune response attacked
endogenous EPO as well as gene-stimulated EPO [14]. A similar experiment
using gene-therapy EPO revealed that the gene-induced EPO was slightly
different from natural monkey EPO [15]. Likewise, the use of transgene
GENE DOPING 817
EPO in human gene doping might induce erythrocytosis to a dangerous

level, with potentially lethal consequences.
Although not generally considered a risk from gene therapy, the virus
vector could infect other humans. Clinical trials monitor subjects for viral
shedding [3]. It would be unlikely that gene cheats would monitor their
secretions for viral contamination. Furthermore, rogue gene-doping labora-
tories (like their steroid-synthesizing counterparts) would not implement
proper preclinical trials. Thus, there may be a possibility of a modified
infectious virus passing from a gene cheat to other persons.
If the experience with anabolic steroids is any indicator, athletes generally
ignore common dosing recommendations. When a Maryland physician
introduced the anabolic steroid methandrostenolone (D-bol) to power lifters
in the 1960s, it was not long before the athletes increased the dose and the
duration of drug beyond medical recommendations. Contemporary ana-
bolic drug users stack multiple anabolic steroids mixed with other anabolic
drugs in megadoses that lead to serious side effects and even death. A prom-
inent and successful athlete like Barry Bonds, in a quest to become a more
powerful hitter, allegedly used multiple anabolic substances including ana-
bolic steroids, HGH, modafinil, insulin, clomiphene, and EPO [29]. Given
this phenomenon with drug doping, expect the use of multiple gene-doping
protocols by the athlete looking for every edge in competition. Genes for
strength, power, recovery, analgesia, oxygen delivery, concentration, injury,
and repair could be transferred to the same athlete. As with anabolic
steroids and other PEDs, there will be unpredictable side effects and fatal
interactions.
Laboratory detection of gene doping

Frequent battles occur between drug cheats, antidoping agencies, and the
lawyers representing all sides. The drug cheats eternally search for an
undetectable PED; thus, the antidoping laboratories play ‘‘catch-up’’
forensic detective in developing sensitive tests for any new PEDs. Elite sport
has entered the world of forensics, where winners and losers of competitive
events can be declared in the courtroom, not the playing field. Further, legal
proceedings take months. Because of forensic procedures, the 2006 Tour de
France will not declare a winner until months after the finish of the race. Are
regulatory agency antidoping laboratories developing methods to detect
possible gene-doping use, and will these methods stand up in court?
The WADA initiated research to prepare for the world of gene doping
[2,4]. Research scientists suggest several biologic/laboratory tests that could
operate to expose gene-doping cheats [2–4,9,10]. The usual parameters of
laboratory testsdsensitivity, specificity, validity, and reliabilitydwould
need documentation to allow such innovative tests to withstand the certain
legal scrutiny when elite athletes test positive for gene cheating.
Muscle biopsy
A biopsy of suspected muscle tissue could reveal viral vehicles or evidence
of altered genes; however, that possibility presents a invasive and low-yield
antidoping measure [2,4].
Blood monitoring
Proteins and hormones produced by doped genes could be exactly like
endogenous proteins. Thus, it may be extremely difficult to detect the differ-
ence between the endogenous gene product and the doped-gene product;
however, serial monitoring of blood parameters may reveal suspicious eleva-
tions of key biologic substances that indicate gene doping [2]. For instance,
the dramatic increase in hematocrit, in conjunction with several other hema-
tological parameters, could tip off a regulatory agency that an athlete used
a gene-doping technique to improve oxygen delivery to muscles.
Genetic activity tests

Interesting developments could use patterns of gene activity or gene
products to detect abnormal gene activity [2]. Detection of these patterns
uses cutting-edge microchip gene array technology or nanotechnology
breakthroughs. The monitoring or visualization of gene activity or gene
products through the expression of DNA and RNA by a sophisticated
microchip array could monitor thousands of genes, enabling the laboratory
to use a sophisticated detective tool for gene doping [9].
Protein fingerprints
In this process, similar to gene microarray testing, hundreds of biologic
proteins could produce a ‘‘protein fingerprint’’ or a ‘‘genetic map’’ of the
biochemistry of individual athletes [10]. Suspicious alterations of such an in-
dividualized fingerprint or map would alert sporting authorities to possible
gene doping.
Genetic barcodes
It may be possible to label the transgene products with a genetic ‘‘bar
code’’; however, this tactic would require the cooperation of a broad array
of professionals from the research scientists to the pharmaceutical houses to
the administrating physicians [4].
Regulation of gene doping

WADA is the preeminent doping regulatory agency in the world, con-
cerning itself with the ethical application of medical techniques, therapies,
GENE DOPING 819
and treatments in the realm of competitive sport. WADA develops the

‘‘code’’ and the ‘‘prohibited list’’ of banned substances for Olympic sport
athletes [1–3,6,8].
The ethical criteria for a drug or medical technique to be included on the
WADA prohibited list are ‘‘scientific evidence, proven pharmacological
effect or experience that substances or methods included have the potential
to enhance or enhances sport performance’’ [1–3,6,8]. Two arguments are
used for inclusion on the list: the substance or method may be harmful or
cause a health risk to the athlete and the use of doping violates the spirit
of sport, as defined by WADA criteria. Essentially, the substance or tech-
nique is outside ‘‘fair play,’’ which could be construed as ‘‘cheating.’’
The WADA tenets have been criticized as ambiguous [3]. Clearly, any
medical intervention can be a health risk; athletic competition itself is
a health risk. The key factor in determining the ethical use of a drug in
athletic competitions rests on the point of fair play. When is a drug not
given or taken for a therapeutic purpose, but for a purpose of obtaining
an unfair competitive advantage? That ethical battle continues every day
in many sporting venues. With the advent of gene therapy, the focus of
the debate will turn from drugs to transgene products; however, the key
element of therapeutic versus manipulative will remain unchanged.
Relevance of gene doping to the practicing pediatrician

Adolescent athletes use anabolic drugs. Studies estimate that approxi-
mately 2% to 4% of adolescents have used some sort of anabolic drug [30]
by the time they graduate from high school. The entire story is not told,
however, because most survey studies focus on anabolic steroids. Many
teenage athletes possess sophisticated knowledge about anabolic drugs,
such that use of HGH, insulin, and even EPO could appear in this age group.
Sources of information about anabolic substances include the daily reports of
the athletes suspected or caught using PEDs, peers at the local gym, and, oc-
casionally, unethical coaches or trainers. Physicians must be alert for the use
of PEDs in the at-risk age group and alert for side effects, including endo-
crine, behavioral, hematologic, and cardiovascular complications, of PED
use [31].
If gene doping becomes reality among elite athletes, it is almost certain
that adolescent athletes will be exposed to the technique. Either through
their own volition or through peers, unscrupulous coaches, and overzealous
parents, adolescents will try to gain a competitive advantage for the glory of
athletic achievement and the scholarships that follow. Although the use of
anabolic drugs and techniques increases once the athlete engages in college
or professional sports, teenagers will use performance enhancing genetics
(PEGs) when such techniques arrive in the gym. Thus, if the technique
proves successful in elite athletes, gene doping will appear in the teenage
population; pediatricians should prepare themselves for new syndromes
and unusual side effects. A physician should understand the possible target
organs and putative doping genes.
Although most clinical research and clinical reports concern athletes look-
ing for a competitive advantage, nonathletes use anabolic substances for an
enhancement of physical appearance. Exhibiting muscle dysmorphia or the
Adonis Complex [32,33], these youth mimic the good looks and enhanced
bodies of actors and models. A thriving black market delivers anabolic drugs
to this group of adolescents for narcissistic purposes. If available, and if
successful, expect teenagers to use gene-doping techniques for cosmetic
purposes.
Perhaps the most sinister example of gene doping, in the broad sense,
would be germ cell modification and genetic preselection [34]. In germ cell
modification, a gamete or embryo would have DNA modified to enhance
the expression of athletic advantageous genes. This technique, as futuristic
as it sounds, would alter the entire genomic makeup of the developing human
to produce a superior athlete.
In genetic preselection, the genome would be scanned, allowing parents to
choose the most genetically athletically gifted offspring to survive. This
process is a sophisticated twenty-first century variant of the ancient Spartan
child-selection process. Although no reports exist of parents scanning the
genome of their prospective children, there are reports of a sporting
organization using a limited genome scan to select prospective athletes or to
genetically tailor training [35].
Summary
Examination of the history of sports competition reveals unethical
athletes who use medical advances, mostly pharmaceutics, to gain an edge
in competition. The elucidation of the genetic basis of biology leaves medical
science on the precipice of clinically useful gene therapy; however, it is
expected that unscrupulous athletes and their mentors will divert the new
techniques to gain an edge over competitors. Much remains to be deter-
mined in this area; however, a multitude of candidate genes exists [36].
The biologic techniques to introduce these genes into athletes are developing
rapidly; it seems to be only a matter of time before the genetically enhanced
performance athlete takes the field of competition. Sporting regulatory
agencies initiate and maintain programs to monitor and test for gene
doping. Physicians will be part of the professional net involved with these
futuristic gene-enhanced athletes.
Although gene doping sounds like a science fiction plot, the physician
should not underestimate the capacity of humans to find an edge in competi-
tiondlegal or illegal. As athletes, professionals, parents, and coaches, the
authors have experienced numerous examples of cheating in sports. From
the simple falsification of player records to the importation of foreign athletes
to the use of anabolic steroids and PEDs, athletes, coaches, boosters, parents,
GENE DOPING 821
and physicians will bend the rules of fair play. The greater the stakes, the
higher the rewards; the temptation to cheat becomes more alluring. If gene
therapy becomes reality in humansdand the technique is poised to become
clinically usefuldthose participants who hold no moral compunctions
against cheating fellow competitors will use the technique. Indeed, officials
expressed great concern that an unscrupulous coach was experimenting
with gene doping at the 2004 Turin Olympics [37]. At some point in time,
performance-enhancing genetics will be a reality; as professionals, be
forewarned and be prepared.
Acknowledgments
The authors acknowledge Elizabeth Gaffney, Kyle Gaffney, and Willem
Koert for their help in preparing the manuscript.
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Abuse of Growth Hormone Among

Young Athletes
Sergio R.R. Buzzini, MD, MPH
Departments of Pediatrics and Orthopaedics, Geisinger Medical Center,
100 North Academy Avenue, Danville, PA 17822, USA
Professional sports figures have received significant media attention asso-

ciated with allegations of abuse of growth hormone (GH) [1–11]. Many ath-
letes and bodybuilders believe that GH improves athletic performance and
appearance; however, scientific evidence suggests that, in healthy individ-
uals, GH supplementation does not offer any advantage. Although only
a few studies have investigated the abuse of GH among young athletes,
the use of ergogenic substances by famous athletes has long encouraged
young athletes and nonathletes to try them.
The existence of a growth-promoting factor from bovine anterior pitu-
itary was discovered in 1921 [12]; however, it was first used as a treatment
for dwarfism in 1932 [13]. Human GH (hGH) was isolated in 1944 [14].
The first purified preparation of hGH dates to 1956, and it was extracted
from human cadaver pituitaries [15]. The first clinical use of hGH was re-
ported in 1958 as a treatment for children who have GH deficiency (GHD)
to promote linear growth [16]. Cadaveric supplies remained the only
source of hGH for almost 3 decades. As a result, hGH was not widely
available, and world demand far exceeded supply. The clinical use of
hGH lasted until 1985, when its use was halted worldwide because of its
association with Creutzfeldt-Jakob disease [17]. Since 1985, all GH in clin-
ical use has been obtained by recombinant DNA technology through ge-
netic engineering and is named recombinant hGH (rhGH). The use of
this technology eliminated supply as the limiting factor [18,19]. Although
GH has a number of accepted medical uses in the United States, GH
also is widely used illegally as an antiaging agent and as a performance-en-
hancing substance in athletics. Published evidence does not indicate the use
of GH as an antiaging treatment for healthy older adults [20]. Athletes and
bodybuilders claim that GH has anabolic properties, increasing lean body
824 BUZZINI
mass and decreasing fat mass [21]. In 1989, the International Olympic
Committee made GH a banned substance as part of a new doping class
of ‘‘peptide hormones and analogues’’ [22], despite the lack of a legitimate
test for GH.
The performance-enhancing potential of GH use in sports was first advo-
cated in the Underground Steroid Handbook in 1983 [23]. Although it is be-
lieved that the use of GH is widespread in sports, evidence about its abuse is
largely anecdotal and circumstantial because of the technical laboratory dif-
ficulties in detecting its abuse. After Ben Johnson was stripped of his 100-m
gold medal from the Seoul Olympic Games in 1988, he admitted to having
taken a cocktail of drugs containing rhGH [9]. It is believed that GH has
become so popular with athletes that the 1996 Atlanta Olympics were
known informally as the ‘‘Growth Hormone Games’’ [8]. At the 1998
Tour de France, a large number of vials of rhGH were detected in the pos-
session of cycling teams [11]. A Chinese swimmer, Yuan Yuan was forced to
withdraw from the 1998 World Championship in Perth, Australia after 13
vials of rhGH were discovered in her suitcase at the Sydney airport [1].
At the 2000 Olympic Games in Sydney, a coach from Uzbekistan was
caught with a supply of rhGH [7], and a few months before the start of
the games, 1575 vials of rhGH were stolen selectively from a pharmacy in
Australia [3]. The sprinter Tim Montgomery (former 100-m world record
holder) admitted using rhGH in 2001 [5], and New York Yankees slugger
Jason Giambi admitted to injecting himself in 2003 with GH [6]. A physician
prescribed rhGH to several players on the Carolina Panthers football team
during the team’s 2003 championship season [10]. In 2006, investigators for
the US Government intercepted a package of rhGH sent to Arizona Dia-
mondbacks pitcher Jason Grimsley [4]. More recently, the actor Sylvester
Stallone was formally convicted of importing 48 vials of rhGH to Australia
[2]. The use of GH is not limited to professional sports figures; 3.5% of col-
lege student-athletes reported using GH in the past 12 months [24], and 5%
of male American high school students used or have used GH as an anabolic
agent [25].
Growth hormone physiology

The human genome carries two genes encoding for GH [26]. The normal
GH gene is transcribed and translated predominantly in the somatotrophs
of the anterior pituitary gland [27]. The variant gene is transcribed in the
placenta [28] and progressively replaces the pituitary GH in the circulation
of pregnant women [29,30]. In addition, synthesis of GH occurs at several
extrapituitary sites, including discrete neuronal populations within the central
nervous system, epithelial cells of the mammary gland, endothelial cells of
blood vessel fibroblasts, thymic epithelial cells, and cells of the immune
system, including macrophages, B cells, T cells, and natural killer cells [31,32].
ABUSE OF GROWTH HORMONE 825
In circulation, hGH is present in multiple molecular isoforms and frag-

ments differing in size, binding affinities, immunoreactivity, and bioactivity
[33–35]. The predominant form is made up of 191 amino acids, has a mo-
lecular weight of 22 kd, and accounts for about 50% of all GH molecules.
The 20-kd monomer, which is devoid of amino acids 32 to 46, has 176
amino acids and accounts for about 10% of GH molecules. Other types
of GH include modified GH (30%), acidic GH (7%), and variable amounts
of fragmented GH [36,37]. The rhGH molecule is identical to the 22-kd
isoform.
The secretion of pituitary GH is regulated by two hypothalamic peptides:
GH-releasing hormone (GHRH), which stimulates GH secretion, and so-
matotropin release inhibiting hormone (SRIH), formerly called somatostatin,
which inhibits GH secretion [38]. Ghrelin, another peptide synthesized mainly
in the gastrointestinal tract in response to the availability of nutrients, also
stimulates GH secretion [39]. It is believed that ghrelin acts as a GHRH
through hypothalamic mechanisms [40]. Negative feedback occurs at two
levels: GH itself and insulin-like growth factor (IGF)-I reduce GH release
by the somatotropes through enhancing SRIH tone and reducing GHRH re-
lease. The continuous secretion of placental GH into maternal circulation dur-
ing pregnancy is not affected by GHRH or SRIH [29,30].
The pituitary gland secretes GH in a pulsatile pattern that is modified by
gender and age [41–43]. In women, secretion of GH is higher, with lower
peaks and higher troughs [44,45]. Higher concentrations of GH are present
in neonates, and the highest levels are observed at puberty [46]. At puberty,
increasing levels of sex steroids alter the negative feedback effects and, there-
fore, increase levels of GH and IGF-I. Shortly after peak height velocity, se-
cretion of GH decreases by around 14% per decade [47]. Moreover, GH
also is reduced in obesity [48], carbohydrate-rich diets, and the intake of
b2 adrenergic agonists. Conversely, GH secretion is higher during slow
wave sleep, exercise, hypoglycemia, amino acid intake (leucine and argi-
nine), increased temperature, and stress [38]. Drugs, such as clonidine,
L-dopa, and g-hydroxybutyrate, increase its secretions, as do androgens
and estrogens. After secretion by the pituitary gland, nearly 50% of circulat-
ing GH binds to a GH-binding protein (GHBP) [49,50]. This protein, pro-
duced by cleavage of the GH receptor (GHR), represents its extracellular
component [51,52]. Circulating GHBP might reflect the amount of GHR ex-
pressed [53]. GHR is composed of preformed dimers that undergo conforma-
tional change when occupied by a GH ligand, promoting signaling [54]. In
fact, the stoichiometry of 1:2 (hormone/receptor ratio) occurs as a conse-
quence of two binding sites (GH sites 1 and 2) [55]. Depending on growth
hormone concentration and binding affinities of site 1 and 2, GH may exhibit
distinct effects ranging from full agonism to antagonism [56–58].
GHRs are present in all tissues in the body and stimulate many metabolic
processes. One of the best-known actions of GH is the generation of IGF-I
and its IGF-binding proteins (IGFBPs) [59] that prolong the half-life of
826 BUZZINI
IGF-I in circulation. Among the IGFBPs, IGFBP-3 seems to be unique in

having the capacity to bind a second ligand, ie, acid labile subunit; therefore,
a three-component etero-trimeric complex is present in the circulation [60].
In most tissues, IGF-I has local autocrine and paracrine actions, but the
liver is the main organ that secretes IGF-I (and IGFBPs) into circulation
[61]. The actions of IGF-I include stimulation of cell proliferation and apo-
ptosis inhibition [62]. In muscle, IGF-I affects protein synthesis by enhanc-
ing amino acid uptake and accelerating transcription and translation [63].
Although IGF-I levels usually reflect the integrated secretory activity of
GH, IGF-I levels are regulated by other factors as well [64]. In fact, subtly
elevated GH levels may not uniformly induce high IGF-I levels [65,66].
Therefore, circulating IGF-I should be considered more as a marker of
GH action on the liver rather than the ‘‘second messenger’’ of GH action.
In fact, the hypothesis of separate and distinct actions of GH and IGF-I
on protein turnover has been suggested [67]. Levels of IGF-I are highest
during late adolescence and decline throughout adulthood [68]; these levels
are determined by gender and genetic factors [69] and are elevated during
pregnancy. The production of IGF-I is suppressed in malnourished patients,
such as in anorexia nervosa, as well as in patients who have liver disease,
hypothyroidism, or poorly controlled type 1 diabetes.
Growth hormone pharmacodynamics

The serum half-life of free GH is about 20 minutes after secretion or in-
travenous injection [70,71] and is prolonged to several hours by binding to
GHBP. After subcutaneous or intramuscular administration, blood concen-
trations of GH reach a peak between 1 and 3 hours after injection and de-
crease to undetectable levels after 24 hours [72]. Healthy adults secrete
approximately 0.4 mg/d (18.6 nmol/d) and young adolescents secrete ap-
proximately 0.7 mg/d (32.5 nmol/d) of GH in circulation. In adults aged
30 to 50 years, endogenous GH production is approximately 0.2 mg/d in
women and 0.1 mg/d in men [73]. When GH is measured in healthy persons
with the use of standard assays, the level is usually undetectable (!0.2 mg/L
throughout most of the day), but there are approximately 10 intermittent
pulses of GH per 24 hours, most often at night, when the level can be as
high as 30 mg/L [74]. In patients who have acromegaly, the endogenous se-
cretion of GH often is increased more than 100-fold. The circulating GH is
cleared from the bloodstream through degradation, predominantly in the
liver and kidney [75]. Only minute quantities of GH appear in the urine.
There is considerable evidence that GH exerts metabolic effects in hu-
mans that continue after cessation of linear growth, including effects on
body composition [76], serum lipids, insulin status (insulin-like and insu-
lin-antagonistic effects) [77,78], bone turnover (increases bone mass, mineral
content, and the number of bone modeling units) [79,80], and physical per-
formance [81,82]. In addition, GH influences the homeostasis of water and
electrolytes and interacts with the immune system [83]. In adipose tissue,
GH leads to decreased glucose use and stimulation of lipolysis (hence insu-
lin-antagonistic or diabetogenic effects) [84]. In the heart, skeletal muscle,
and kidney, GH provokes glucose and amino acid uptake [85]. The anabolic
actions of GH mostly are mediated through IGF-I and include increases in
total body protein turnover and muscle synthesis. GH is at least as powerful
as testosterone in this effect and, because they both operate through distinct
pathways, their individual effects are additive and possibly synergistic. Hy-
posecretion of GH at an early age results in dwarfism, whereas GH hyper-
secretion occurring before or after puberty results in gigantism or
acromegaly, respectively [86,87].
Adults who have GHD have been reported to have an increased risk for
death from cardiovascular disease [88], reduced muscle mass and strength,
lower bone density, and higher serum lipids than do adults who do not have
GHD [81,82]. They also have been reported to have reduced energy, decreased
vitality, poorer psychosocial adaptation, increased feelings of isolation,
and other indices suggesting poor quality of life [81,82,89,90]. Although
longitudinal studies of GH therapy for adults who have GHD showed
improved clinical outcomes [91–93] and possibly lower mortality [94], there
is little evidence of clinical benefit of GH therapy in the healthy elderly [20].
Growth hormone and exercise

Exercise is a potent stimulus for GH release [95–100]. The exercise-
induced release of GH is influenced by many factors, including, but not lim-
ited to, the type, intensity, exercise duration, and training status of the par-
ticipants. Because different investigators have used different experimental
protocols and types of subjects, study result comparisons are difficult. Nev-
ertheless, an increase in plasma GH stimulated by exercise has been well
documented [95,96].
The exercise-induced release of GH is affected by gender. Women reach
the maximal GH concentration faster than do men [101,102]; however, the
relative increase in circulating GH is greater in men than in women, with the
latter demonstrating higher maximal serum GH concentration because of
greater resting levels in women [101,102].
In children, the release of GH in response to exercise increases with pu-
bertal development in boys and girls. The administration of estrogen to pre-
pubertal subjects increases the peak release of GH after exercise to pubertal
levels, which strongly suggests that sex steroids stimulate the release of GH
[103]. Coincidentally, the GH response to resistance exercise in women is
greater during the luteal phase than during the follicular phase of the men-
strual cycle [104].
The mechanisms responsible for the exercise-stimulated increase in GH
remain unresolved. One hypothesis is that the activation of anaerobic gly-
colysis and the formation of lactate increase the release of GH [105]. It
828 BUZZINI
also is believed that the release of GH primarily is mediated through central

cholinergic pathways [106] being augmented by pyridostigmine [107] and at-
tenuated by atropine [108]. Peripheral metabolic signals also influence the
GH response to exercise, with it being increased by fat intake and attenuated
by carbohydrate ingestion [109–112].
Although it might be expected that the observed exercise-associated in-
crease in GH would be paralleled by an increase in circulating IGF-I, study
results to date conflict [113]. Some research groups have observed incre-
ments [114–119], others have observed no variations [120–125], and a de-
crease in IGF-I with exercise has been reported [126,127]. This may be
due to differences in exercise type, intensity, duration and training status, in-
dividual nutritional and hormonal status variations, or technical differences
in assay protocols.
Therapeutic use of growth hormone

The US Food and Drug Administration (FDA) has approved the use of
GH in children for the treatment of growth failure secondary to GHD,
chronic renal failure, Turner syndrome, Prader-Willi syndrome, persistent
growth failure following intrauterine growth retardation, and idiopathic
short stature. In adults, FDA-approved use is indicated in GHD and
AIDS wasting syndrome. Nonconventional uses of GH therapy in children
include achondroplasia and hypochondroplasia, dysmorphic syndromes,
cystic fibrosis, juvenile chronic arthritis, short bowel disease, congenital
adrenal hyperplasia, and burns [128].
The use of GH in adults who have GHD is based on evidence that GH
can reverse some of the abnormalities common in this population. These ab-
normalities include changes in body composition (increased total body fat,
decreased lean body mass) [129–132], worsening of lipoprotein profile, and
impaired ventilatory function [81,82,130–134]. In addition, studies have
demonstrated an increase in hemoglobin concentration [135,136] and im-
provements in wound healing and ligamentous strength [132], bone mineral
density, strength [137–141], cardiac function [142,143], and quality of life in
adult patients who have GHD and are treated with GH [144].
Dosing and cost

In children who have GHD, GH is prescribed in doses that are consid-
ered physiologic, so that they may achieve a height within the range of their
genetic potential [144]. The mean duration of therapy for this indication is 4
to 7 years [145]. Although long-term data about GH therapy for adults is
not available, it is suggested to be life-long [146].
Dosing plans have evolved from weight-based to individualized dose-
titration strategies, with final maintenance doses being lower in the latter
scenario [147,148].
Although suggested dosages vary, all sources recommend a low starting

dose with a gradual increase to a maintenance dose [144]. The maintenance
dose typically is higher in women than in men [149,150] and is higher still in
women receiving oral estrogen replacement [151]. GH secretion normally
decreases with age, and older patients have an increased susceptibility to
GH-related side effects [41]. Therefore, GH dosing should be lower in older
patients. By the same token, higher doses may be appropriate in some tran-
sition and young adult patients [152]. Available from several pharmaceutical
companies, current preparations of rhGH have a biopotency of 3 IU/mg, us-
ing the World Health Organization reference preparation 88/624. In prepu-
bertal children, GH is used routinely in the range of 25 to 50 mg/kg/d
[153,154]. Doses as high as 100 mg/kg/d have been used in pubertal children
who have GHD [155]. In adults, it is recommended that therapy start with
a low dose of around 0.15 to 0.30 mg/d (0.45–0.90 IU/d). Additionally, al-
though the maintenance dose may vary considerably from person to person,
it seldom exceeds 1.0 mg/d (3 IU/d) [156,157]. In accordance with the clinical
practice of treating GH-deficient children, it is recommended that GH be
administered through daily subcutaneous self-injections in the evening [48].
During GH treatment, patients should be monitored at 1- to 2-month in-
tervals during dose titration and semiannually thereafter. Such monitoring
should include a clinical evaluation, an assessment of side effects, and mea-
surement of IGF-I levels. The lipid profile and a fasting glucose should be
assessed annually. Assessment of quality of life also is used for monitoring
the response to therapy [152,158]. In children, the response to therapy is
monitored by following growth curves carefully and by monitoring radio-
graphic bone age. Peak bone mass generally has not been achieved at the
time that final height is attained. Therefore, monitoring bone mineral den-
sity before discontinuation of GH therapy should be considered.
GH is expensive, and the estimated annual cost depends on dose, fre-
quency, and the proprietary preparation used [159,160]. The annual esti-
mated cost of GH treatment for a 30-kg child is approximately $20,000 [161].
Growth hormone as a doping agent

Despite the lack of evidence supporting significant positive effects of GH
as an ergogenic aid, there are underground reports of the abuse of GH by
athletes and bodybuilders for its anabolic properties. Such abuse rests on
the belief that GH augments performance in endurance and power sports,
is hard to detect [36], and is without major side effects [162,163]. In addition,
it is believed that GH strengthens tendons and ligaments, prevents stress
fractures, and speeds the healing process [23]. Among bodybuilders striving
to achieve the ‘‘ripped look,’’ GH misuse is believed to decrease the subcu-
taneous fat through a repartitioning effect and to promote hypertrophy of
their muscle fibers [162,164]. Although it is unknown how popular GH is
among female athletes, its appeal stems from the lower risk for androgenic
830 BUZZINI
side effects than are seen with anabolic steroids. Moreover, its use for endur-
ance sports, in combination with erythropoietin as a method for enhancing
oxygen transport, is gaining popularity; however, the few controlled studies
involving supraphysiologic doses of GH to athletes have failed to show sig-
nificant positive effects [162,165–171].
The applicability of these studies to a potential ergogenic effect in elite
competitive sports may be limited. Athletes are highly trained to know their
performance and to evaluate small changes in response to changes in train-
ing. At elite competitive levels, the differences in performance required to
win can be measured in fractions of a percent, whereas clinical trials are de-
signed to evaluate large changes because of their small sample sizes [162].
The durations of the studies were short to assess any improvements, espe-
cially given that athletes likely would take GH for prolonged periods in cy-
cles lasting for 6 to 12 weeks or longer [59]. Moreover, the doses of GH used
in studies, although supraphysiologic, were low. Underground reports men-
tion that athletes take much larger doses of up to 25 IU/d [36], with a cost
from $3000 to $5000 per month [172]. In addition, no study has evaluated
the use of a combination of GH and anabolic steroids in power sports or
GH and erythropoietin in endurance sports, which are theorized to be syn-
ergistic in their action [173].
Adverse effects of growth hormone

The short- and long-term risks of GH use in athletic training are not well
known because epidemiologic data are lacking. There is evidence that acute
administration of rhGH results in exaggerated increases in plasma lactate
and glycerol as well as serum fatty acids in endurance-trained athletes.
The increase in plasma lactate has been hypothesized to explain the decrease
in exercise performance observed in these athletes [174]; however, a bigger
danger probably is the exaggerated high fatty acidemia resulting from the
additive effects of the acute rhGH administration and exercise on lipolysis,
which could promote cardiac arrhythmias [164]. Moreover, the chronic
abuse of supraphysiologic doses of GH in athletics is likely to be associated
with significant side effects, as illustrated by studies of acromegalic patients
[175–180]. Table 1 describes the potential side effects associated with GH
supplementation in athletes. The adverse effects of GH therapy occur in
fewer than 3% of treated children compared to approximately 10% of
adults using therapeutic doses that are much lower than what athletes might
use without supervision.
Detection of growth hormone doping

Until the 2004 Olympic Games in Athens, rhGH doping was considered
undetectable. The difficulty of providing court evidence of the illegal use of
GH derives mainly from its biochemical properties. The amino acid sequence
Table 1
Potential side effects of growth hormone misuse in athletes
Cardiovascular Hypertension, cardiomyopathy, congestive heart
failure, arrhythmia
Pulmonary Respiratory failure, sleep apnea, narcolepsy, sleep
disturbances
Musculoskeletal Osteoarthritis, carpal tunnel syndrome, slipped
capital femoral epiphysis, worsening of existing
scoliosis, osteoporosis, arthralgias, muscle
weakness, myopathy, avascular necrosis of the
femoral head, gigantism
Endocrine and metabolic Diabetes mellitus, insulin resistance, glucose
intolerance, dyslipidemia, peripheral edema,
hypothyroidism, menstrual irregularity, erectile
dysfunction, multiple endocrine neoplasia type 1
(for those who have a genetic mutation)
Neurologic Idiopathic intracranial hypertension (pseudotumor
cerebri), visual field defects, cranial nerve palsy,
headache
Malignancy Increased risk of leukemia, solid tumors (breast,
colon, prostate, and endometrial cancer), and
increased risk of second neoplasms
Infection HIV/AIDS, hepatitis B and C (nonsterile or
contaminated syringes), Creutzfeldt-Jakob disease
(GH extracted from human pituitary glands
obtained on the ‘‘black market’’)
Cosmetic Prognathism and jaw malocclusion, coarsened facial
appearance, increased skull circumference,
dentition problems, acral overgrowth, frontal bone
bossing, gynecomastia
Visceromegaly Tongue, thyroid gland, salivary glands, liver, spleen,
kidney, prostate
Skin and gastrointestinal Hyperhydrosis, oily texture, skin tags, colon polyps
Injection injuries Direct and indirect trauma to nerves and soft tissue,
abscess
Other Counterfeit products (unable to advise on the
relative safety of each product), compromised
quality of life, increased mortality
Data from Refs. [116,164,174–192].
of the recombinant molecule is identical to the major 22-kd isoform secreted

by the pituitary gland. In addition, the high intraindividual and interindivid-
ual variability in secretion makes it difficult to detect doping.
To overcome these problems, two independent approaches have been de-
vised based on the use of blood samples to develop a valid test. The first has
been the development of double immunologic tests: one preferentially rec-
ognizes 22-kd GH, and the other recognizes all other isoforms secreted
by the pituitary gland [193]. Thus, the administration of GH increases the
relative abundance of the 22-kd GH major isoform over all other circulating
forms. When the ratio between the two proportions is calculated, it differs
832 BUZZINI
from that seen when only pituitary-derived GH is present [36,193]. This test
was used for the first time during the 2004 Olympics in Athens, with no
samples declared positive [21]. The lack of positive findings may result
from this test’s short window of detection, believed to be approximately
24 hours after injection. After this time, no rhGH will be detected in the cir-
culation, and levels of the two GH forms will return to normal [194]. Hence,
this method is best suited for ‘‘out of competition’’ testing, when an unan-
nounced blood sample might be taken within 24 hours of the last rhGH in-
jection [59].
The second approach relies on the analysis of more stable serum variables
implied in the biologic cascade produced by GH secretion or doping appli-
cation. These include combining measurements of IGF-I, IGFBP-3, and the
acid-labile subunit as markers of acute GH ‘‘doping’’ [195] and using
markers of collagen and bone turnover [196], such as N-terminal peptide
of type III procollagen, collagen I C-terminal telopeptide, osteocalcin, and
collagen I C-terminal propeptide [197,198]. These markers are similar to
those that have been reported to be elevated in acromegaly [199,200]. These
tests have the advantage of using stable variables with a much longer half-
life than hGH, so that the ‘‘window of opportunity’’ (days or months) varies
in relation to the extent and duration of abuse. Thus, this antidoping ap-
proach would be best suited for postcompetition samples [85]. Although
promising, this approach requires the construction of a reference range of
markers in plasma of elite athletes from different ethnicities and sport disci-
plines [201], a dataset that is unavailable [162].
Urine samples are used most frequently for doping analyses. Because GH
has a short half-life in the circulation [202], the analysis of urine samples
could provide a longer opportunity of time for a ‘‘diagnostic window.’’
The problem is that the average urine concentration of GH is between
100 and 1000 times less than in blood, and the complex molecular changes
resulting from the renal excretion process are not understood well enough to
provide a meaningful evaluation [203,204].
Although attention currently is focused on the ergogenic properties of
GH, there is evidence that other components of the hypothalamic-pitui-
tary-IGF-I axis also are being abused. IGF-I, in particular, is associated
with several specific side effects, in addition to those common to GH. These
include severe lipodystrophy (if injected repeatedly at the same site); enlarge-
ment of the spleen, kidney, and lymphoid tissue; and severe hypoglycemia
[204].
Another potential way GH circulatory levels are increased while circum-
venting standard detection methods is by using GH secretagogues (GHSs).
GHSs are synthetic molecules that stimulate and amplify pulsatile pituitary
GH release by way of a separate pathway distinct from GHRH/SRIH.
Various GHSs can be used intravenously, subcutaneously, intranasally, or
orally. Examples of GHSs include GHRP-1, hexarelin, MK-0677,
SM-130686, and EP-01572 [205].
Studies suggest that youth are not likely to volunteer information about
drug or supplement use to health professionals [206]. Consequently, it is
important to screen routinely for performance-enhancing substances during
office visits and preparticipation physicals. When young people do admit
use of these substances, they should be queried regarding the reasons, dos-
ing, and frequency of use. Additionally, information regarding the sub-
stance’s source and cost should be obtained. This is important because
illegally obtained substances have the additional risk of being counterfeit
products with unsafe components. Some athletes may be purchasing the
cheaper, black market GH extracted from human pituitary glands. Pro-
duced in this way, GH is associated with the potential transmission of dis-
eases. To gain the confidence of the young person, the health provider
should be able to openly discuss the perceived performance effects as
well as the adverse effects, including what is and is not known about a given
substance. The provider should explain that lack of information does not
imply safety. It should also be acknowledged that benefits occur for those
who are deficient in GH, but are much less certain for normal individuals,
even at high doses, which increase the risk of side effects. Healthy ways to
improve sports performance and appearance should be discussed with
youth.
Approaches to combat the use of drugs by young athletes generally have
involved changes in rules and testing and preventative educational initiatives
[207]. Some schools use drug testing of high school athletes [208]; however,
the GH testing is complex and is unlikely to be implemented in high schools
in the near future. A more promising approach to combating youth drug use
in sports may be educational programs that are designed to teach students
about the facts and the myths of these substances. Examples of such inter-
ventions include the Adolescent Training and Learning to Avoid Steroids
Program for boys [209,210] and Athletes Targeting Healthy Exercise and
Nutrition Alternatives Program for girls [211]. It is important that educa-
tional programs include information on the dangers of these drugs from
a medical perspective as well as the value of making good decisions and
playing by the rules.
Summary
The underground abuse of GH among young athletes presents a challenge
to medical professionals. Health care professionals providing knowledge-
able guidance regarding healthy ways to improve performance and appear-
ance, as well as accurate information regarding the substances’ perceived
benefits, risks, and unknown qualities, is invaluable to the young athlete.
Further research focused on the profile and motivation of young people
who use GH is essential to understanding and better intervening with those
who use these substances.
834 BUZZINI
Acknowledgments
The author gratefully acknowledges critical assistance from Teresa N. D.
Buzzini, PsyD, and pediatric endocrinologist John J. Jaramillo, MD.
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Pediatr Clin N Am 54 (2007) xv–xvi

Peter D. Rogers, MD, MPH, FAAP Brian H. Hardin, MD

The use of performance enhancing drugs (PEDs) has become a bur-

Peter D. Rogers, MD, MPH, FAAP

Participation in athletic activities can beneﬁt adolescents in numerous

* Adolescent Medicine, Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205.

information is derived from adult studies. More extensive descriptions of the

approximately 3% of high school seniors have used anabolic-androgenic

Identifying the at-risk adolescent

improved physique may try using exogenous substances as a means of

Interviewing the adolescent

important the adolescent feels it is to participate in and excel at his or her

interviewing an adolescent about performance-enhancing substance use, in-

The physical examination

Box 1. Questioning the adolescent patient about the use

excessive quantities of creatine. Keep in mind that these laboratory values

anabolic-androgenic steroids, clearly have been shown to increase muscle

Undoubtedly, athletes always have striven, and will continue to strive, to

adolescents to use performance-enhancing substances with disregard to po-

Overview of performance-enhancing substances

minimal requirements or regulation, and they are readily available at local

Prevalence of use of performance-enhancing substances

CASTILLO & COMSTOCK

PREVALENCE OF USE OF PERFORMANCE-ENHANCING SUBSTANCES

respondents (25.3% boys, 3.9% girls). Grade-speciﬁc rates included 8.4% of

Other performance-enhancing substances

General performance-enhancing substance use

Knowledge, attitudes, and beliefs about the use

Although adolescents seem to have diﬃculty understanding, or at least ac-

Consequences of Use of Anabolic

Whether providing anticipatory guidance to the young adolescent

* Corresponding author. Central Ohio Poison Center at Children’s Hospital, 700

administered in clinical studies do not approximate the supraphysiologic

schedules as control subjects, AAS users had a signiﬁcantly decreased max-

Neurologic and psychiatric consequences

sleep) correlated with cerebrospinal ﬂuid 5-hydroxyindole acetic acid levels

not taking AASs [79,80]. Of particular concern in this age group is

common, but often is asymptomatic or associated with subclinical elevation of

Erythropoietin and Other

Why do athletes use performance-enhancing substances (PESs)? It is not

The role of oxygen transport in athletic performance

Recombinant human erythropoietin

rHuEPO use in elite professional cyclists was organized, widespread, and

Ergogenic eﬀectiveness of recombinant human erythropoietin

Detection of recombinant human erythropoietin

The test relied on mathematical models applied to the measurements of in-

Other blood-boosting methods

[9]. Autologous or heterologous blood transfusions were used most preva-

Novel erythropoiesis-stimulating protein (darbepoietin)

Artiﬁcial oxygen carriers

Hemoglobin oxygen carriers

The World Anti-Doping Program

E-mail address: [email protected]

Box 1. Definition of doping as defined in the Code

organization. The Abbreviated TUE applies only to corticosteroids admin-

organizations (NADO), sports federations, and athletes with the common

The World Anti-Doping Program

The International Standards

Therapeutic Use Exemptions

Box 2. Prohibited list of pharmaceuticals, substances,