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Ergogenic Aids
In the context of sport, an elgogenic aid can be broadly dejined as a technique
or substance used for the purpose of enhancing performance. Ergogenic a i d
have been classzj?ed as nutritional, pharmacologic, physiologic, or psychologic
and range from use of accepted techniques such as carbohydrate loading to
illegal and unsafe approaches such as anabolic-androgenic steroid use. The
eflcacy of many of these techniques is controversial, whereas the deleterious
side effects are clear. nepurpose of this article is to review the epidemiology,
administration, eficacy, pharmacology, and side efects of commonly used
ergogenic: aids. Physical therapists should be able to recognize the signs of ergogenic aid abuse in inditliduals under their care, and they should be aware of
the side @cts of these aids. Moreover, the physical therapist can serve as a
resource-forthose individuals seeking information on the risks and benejits of
ergogenic aids. (Thein LA, Thein JM, Landy GL. Ergogenic aids. Phys n e r .
1995;75426- 439.J
Lori A Thein
Jill M Thein
Gregory L Landry
Key Words: Ergogenic aids, Pharmacology, Sports medicine, Sports physical therapy,
stmids.
Many athletes have turned to ergogenic aids in hopes of achieving an
edge on their opponents. The term
"ergogenic" means "tending to increase work" and, in the context of
sport, includes techniques used to
increase energy production and performance. Nutritional and psychologic
ergogenic aids continue to be used
regularly and safely. The use of carbohydrate loading, vitamins, electrolyte
solutions, ritual preparation procedures, visualization, and stress management techniques receives little
attention in the popular press, but
these can be considered ergogenic
aids. The ergogenic aids receiving the
greatest attention in the last several
decades are the pharmacologic and
physiologic aids. Anabolic-androgenic
steroids, blood doping, erythropoietin,
human growth hormone, clenbuterol,
and caffeine are some of the ergogenic
aids currently used by athletes attempting to achieve superior
performance.
Attempts to gain competitive advantages over competitors is not a new
phenomenon. The term "doping" has
roots in a South African dialect when
it referred to a liquor stimulant used in
Herbs and
religious ~eremonies.~
mushrooms were consumed by ancient Greek Olympic athletes in attempts to improve their perf~rrnance.~
LA Thein, PT, SCS, ATC, is Physical Therapist and Associate Lecturer, Department of Kinesiology,
Physical Therapy Program, University of Wisconsin Sports Medicine Center, 3313 University Ave,
Madison, Wl 53705 (USA). Address all correspondence to Ms Thein.
JM Thein, PT, ATC, is Physical Therapist, Outpatient Orthopedics, University of Wisconsin Hospital, 600 Highland Ave, Madison, WI 53792.
GL Landry, MD, is Assistant Professor, Department of Pediatrics, Head, Section of Sports Medicine,
and Head Medical Team Physician, University of Wisconsin Medical School, 600 Highland Ave,
Madison, W 53792.
Physical Therapy / Volume 75, Number 5 / May 1995
In the 19th century, the French concocted uin mariani, a drink mixture of
coca leaves and wine, which reportedly reduced fatigue and hunger senIn
sation during prolonged a~tivity.3,~
the late 1800s, marathon runners frequently drank alcohol during races.
Brandy, champagne, and another
then-popular "stimulant,"strychnine,
were used by American athletes.3
In the 20th century, the use of stimulants in the 1952 Olympic Winter
Games, followed by suspicion of anabolic steroid use by the soviet athletes
in 1954, focused attention on the use
of ergogenic aids.*The 1960s saw a
dramatic increase in drug abuse, with
amphetamines implicated in the
deaths of several cyclists.' The apparent widespread use of anabolic steroids at the 1964 Olympics was severe
enough to warrant drug testing at the
1968 Olympic Games.5 Improvements
in detection using mass spectrometry
and gas chromatography resulted in
the disqualification of 19 athletes from
the Pan-American Games in 1983, and
426 / 95
in the surrender of a silver medal by
Martti Vainio (1984 Olympic Games)
and a gold medal by Canadian Ben
Johnson (1988 Olympic game^).^,^^^
scriptions of anabolic steroids annually
in the United States.14Illicit use, however, results in a much larger and
untold number of annual usages.
Use of ergogenic aids by patients
being treated by physical therapists
might affect the patients' response to
treatment. Side effects of some ergogenic aids can affect heart rate, blood
pressure, or other physiologic measures. Individuals using injectable
drugs are at risk for disease transmission from shared needle~.~.9
Adolescents and their parents often look to
physical therapists providing sports
physical therapy services at local
schools for information on ergogenic
aids. The physical therapist can be a
valuable personal and community
resource for facts about ergogenic
aids.
Physical therapists may treat individuals who use anabolic steroids. Although some of these individuals may
be taking steroids legally for medical
purposes, it it more likely that patients
will be t a h g these drugs illicitly.
Knowledge of anabolic steroid side
effects can help the physical therapist
to recognize signs of abuse, and to
educate the patient about the longterm deleterious effects of anabolic
steroid use.
"Ergogenic aids" is a broad category of
topics (including physiologic, phannacologic, psychologic, and nutritional'),
and the choice of substances used as
ergogenic aids changes with improvements in technology and detection
procedures. The list of techniques and
substances used as ergogenic aids is
too extensive for a complete discussion within this article The purposes
of this article are to present several
commonly abused agents and techniques, to examine their potential risks
and benefits, and to discuss drug
testing procedures.
Phannacologic Ergogenic Aids
Anabolic-Androgenic Steroids
Anabolic steroids are synthetic derivatives of the male hormone testosterone. These androgens are prescription
drugs that have legitimate, therapeutic
uses. They are prescribed for children
and adolescents to treat delayed puberty, aplastic anemia, and hypogonadism.l0>" In the adult population,
steroids are used successfully to treat
certain types of anemias, hereditary
angioedema, some gynecologic conditions, protein anabolism, and male
hypogonadism. Additionally, they may
have a role in the treatment of osteop0rosis.~~J3
Medical indications account for fewer than 3 million pre-
Epidemiology. The use of anabolic
steroids for nonmedical purposes is
not a new phenomenon. The first
reported anabolic steroid use as an
ergogenic aid occurred in 1954, and
use became widespread in the athletic
community by 1964.l3Although anabolic steroid use by athletes has been
in existence for more than 40 years,
data from substance use surveys is
relatively new. The first reports in the
early 1970s revealed that 2.5% of Arizona high-school male athletes15 and
15% of Arizona State University athletes used anabolic steroids.16Data
have demonstrated that anabolic steroids are becoming increasingly popular among high-school athletes and
nonathlete~.l5.~7-~0
In a 1988 nationwide survey, Buckley et all7 found
that 6.6% of 3,403 male high-school
seniors were using anabolic steroids,
and 35.2% of these seniors were nonathletes. Of the steroid users, 38.3%
reported first using anabolic steroids at
age 15 years or younger, and another
one third of the population had started
by age 16 years. Steroid users reported
using cycles of steroids lasting 6 to 12
weeks, and 40% of the steroid users
had completed five or more cycles.
"Stacking," or using more than one
type of anabolic steroid concurrently,
was practiced by 44% of the respondents, and 38.1% of the steroid users
had used both oral and injectable
methods of adrnini~tration.~~
Similar
results were noted in an Arkansas
study, where 11.1% of the 853 male
1lth-grade students surveyed reported
past or present use of anabolic ste-
r o i d ~Of
. ~the
~ 1,881 Georgia highschool students surveyed in 1993,
6.5% of the boys were taking anabolic
steroids, with one fourth admitting to
sharing needles to administer the
drug.9 A recent sunrey of 3,047 highschool freshmen and seniors in Illinois
revealed that 3% of the males and
O.Y?of the females admitting use of
anabolic steroids.20 Of those individuals using steroids, 64% were athletes,
26% reported using a stacking technique, and 21% listed a teacher/coach
as the main source who got them
interested in using steroids. Twentyone percent of steroid users started
using steroids at age 15 years, 19??
started at age 14 years, and 7% started
before the age of 10 years.
The National Collegiate Athletic Association (NCAA) has been collecting
data on the use of anabolic steroids in
collegiate athletes since 1985. Anabolic
steroid use among male football players dropped from 9.7% of the players
in 1989 to 5.0% of the players in
1993." Male basketball players
showed an increase in use from 1.6%
to 2.6941, and female basketball players
showed an increase in use from 0.8%
to 1.5%. For a list of the most commonly used anabolic steroids, see
Table 1.
Pharmacology and physiologic
effects. All anabolic steroids are derivatives of the male sex hormone testosterone. The synthetic agents have a
core steroid structure that gives them
both anabolic (tissue building) and
androgenic (masculinizing) e f f e ~ t s . ~ ~ ~ ~
Physiologically, the anabolic and androgenic effects are inseparable. When
the hormone binds with receptors in
various tissues, the same type of receptors produce anabolic and androgenic effects. In some sites throughout
the body, the hormone will bind and
produce anabolic effects, whereas at
other sites, it will bind and create
androgenic effects. The most appropriate name for these compounds is
"anabolic-androgenic steroids," but the
term is frequently shortened to "anabolic steroids." Attempts to enhance
the anabolic effects while diminishing
the androgenic effects have brought
about the creation of over 40 chemical
Physical Tht:rapy / Volume 75, Number 5 /May 1995
Table 1.
Commonly Used Anabolic ~ t e r o i d s " ' ~ ~ ~ ~
Generic Name
Brand Name
Derivative
--
Oral
Ethylestrenol
Maxibolin
Fluoxymesterone
Halotestin
Methandrostenolone
Dianabol
Methyltestosterone
Metadren, Oreton Methyl
Oxymetholone
Anadrol-50
Stanozolol
Winstrol
Injectable
19-Nortestosteroneester
Nandrolone
Deca-Durabolin
Nandrolone phenor~ouibate
Durabolin
19-Nortestosterone
Testosterone cypionate
Depo-testosterone
Testosterone ester
Testosterone propionate
Oreton
Testosterone ester
Testosterone enanthate
Delatestryl
Testosterone ester
modifications of the core ster0id.l
When taken orally or parenterally in
its origins[ state, testosterone is quickly
degraded by the liver, and blood levels necessary to achieve anabolic
effects are not sustained. Consequently, three modifications of the
testosterone molecule have been
made (designated as types A, B, and
C ) and demonstrate increased effect i v e n e s ~These
. ~ ~ are esterification of
the 17P-hydroxylgroup (type A),
alkylation of the 17a-position (type B),
and moddication of the ring structure
of the steroid (type C). Oral preparations are usually types B and C,
whereas parenteral compounds are
usually type A.25
Anabolic steroids work to increase
protein synthesis, lean body mass, and
nitrogen balance via several mechan i s m ~Many
. ~ ~ cells in the body, including skeletal muscle, possess receptors that bind testosterone or similar
hormones. A steroid-receptor complex
is formed. causing synthesis of enzymes, which in turn causes increased
protein synthesis in the cells. One of
the enzyme systems induced by this
process is the ribonucleic acid (RNA)polymerase system. Biochemically,
RNA polymerase promotes cellular
protein metabolism and synthesis,
causing the anabolic action leading to
increased muscle, lean body mass,
and ~trength.7JOJ~-~~
Anabolic steroids
may also enhance lean body mass via
an anticatabolic effect.27During episodes of stress, such as intense exercise, the body releases glucocorticoids,
which have a catabolic effect on body
tissue^.^ Anabolic steroids compete
with glucocorticoids for receptor sites
and inhibit protein degradationlo
Anabolic steroids also promote nitrogen retention by shifting the nitrogen
equilibrium to the positive side for
better utilization of ingested protein.
This is a temporary phenomenon due
to the body's homeostatic mechanisms. To obtain the full benefit of this
effect, athletes must maintain a diet
high in calories and protein while
taking anabolic steroids.ll Finally,
anabolic steroids may increase
strength and muscle mass through
their psychologic effect. Athletes taking
anabolic steroids frequently report
episodes of euphoria, increased aggressiveness, and decreased fatigue,
which may allow them to train at
a higher intensity for a longer
duration.lo
Administration. Anabolic steroids
may be taken orally or parenterally.
Orally ingested steroids are well absorbed from the stomach, excreted
fairly rapidly from the body due to
their short half-lives, more toxic than
injectable steroids to the liver, and
Physical 'Therapy / Volume 75, Number 5 /May 1995
highly potent. Injectable steroids are
characterized by delayed uptake from
the body, slower excretion, increased
detectability in dnig tests for longer
periods of time, less liver toxicity, and
less potency than oral steroids.ll Injectable preparations can be detected
for a month after discontinuation,
whereas oral doses are detectable up
to 14 days after discontinuation.
Athletes rely heavily on rumors or
anecdotal experiences to guide their
dosage of anabolic steroids. Athletes
frequently use the technique referred
to as "stacking," or the concomitant
use of two or more anabolic steroids
at high doses, although there is no
scientific basis of this t e c h q u e . The
combination may involve both injectable and oral forms. Athletes may
adhere to a pyramid-type of schedule,
starting with a low dosage, increasing
to peak usage (sometimes staclung
three to five drugs), and slowly tapering usage over 4 to 18 weeks. This
pyramid-type schedule is followed by
a drug-free period of several weeks to
months, which is referred to as "cycling."26During peaks of pyramid
schedules, athletes may be taking 10
to 100 times the normal therapeutic
dosage.1° Burkett et alZ8found the
lowest anabolic steroid dosage in the
24 athletes they surveyed to be 350%
of the usual therapeutic dosage. No
scientdic evidence exists suggesting
that stacking or a pyramid schedule is
necessary to achieve the anabolic
effects. The androgen receptors are
well saturated at much lower
dosages.10
Ergogenic efficacy. Studies on the
effects of anabolic steroids on muscular strength provide inconsistent results. Quantitative studies of the effects
of anabolic steroid use present many
metholologic dficulties. The side
effects of anabolic steroid use make
blind studies a challenge. Participants
are frequently able to guess correctly
when they are in the placebo or steroid portion of the study. Moreover,
the doses that can be ethically a h istered are well below those that athletes report using.
After reviewing and statistically analyzing 25 well-documented studles,
Haupt and Rovere7 concluded that
improvements in muscular strength
will result from anabolic steroid use if
the following criteria are met: (1) The
athlete must have been intensively
trained in weight lifting immediately
prior to the steroid regimen and must
continue with intense weight lifting
during the steroid regimen; (2) the
athlete must maintain a high-protein,
highcalorie diet; and (3) strength must
be assessed with a single-repetition,
maximal-weight technique using the
specific exercises with which the athlete trains, as opposed to single-joint,
isolation-testing techniques. These
criteria are partially supported by
Tingus and Carlsen," who found no
significant improvement in the growth,
contractile strength, or endurance of
hind-limb skeletal muscles of rats
receiving a continuous lnfusion of
stanozolol. The authors concluded that
anabolic steroids had no ergogenic
effect in the absence of high-intensity
exercise or muscle atrophy. Additionally, Crist et also found no improvement in isokinetic power measurements following administration of
anabolic steroids.
In a recent meta-analysis, Elashoff et
alsl reviewed 30 studies evaluating the
effects of anabolic steroids on muscle
strength. Fourteen of these studies
were not included in the meta-analysis
for one or more of the following reasons: (1) There was no placebo group,
(2) there was a failure to randomize
subjects into groups, (3) strength measurements were not objective, or (4)
the percentage change in strength
could not be ascertained. Of the remaining studies, the statistical analysis
was unclear, not stated, or performed
incorrectly in 11 studies. Data analysis
in 9 studies with adequate available
information demonstrated a slightly
greater strength improvement in the
anabolic steroid-treated group of
trained individuals, with a mean dBerence of 5%. No evidence existed to
support enhanced muscle strength in
untrained individuals.
Weight gain is commonly associated
with anabolic steroid use and has
prompted study of body composition
changes. A review of the literature
indicates that athletes talung anabolic
steroids for 3 to 12 weeks gain an
average of 2.2 kg more weight than
their counterparts receiving a placebo.32833 Whether these gains reflect
muscle mass increases or fluid retention remains unclear. Although radiographic studies and body-density measurements indicate increases in muscle
size and lean body mass, the concurrent increase in total body potassium
and nitrogen are disproportionate to
the weight gain." Therefore, it is unclear whether weight gain is due to
increases in normal muscle, other lean
tissues, or intracellular fluid.26
Side effects. Although the potential
benefits associated with anabolic ster i d use remain questionable, the
immediate and long-term side effects
are well established. Anabolic steroids
have been linked to a myocardial
infarction in a 22-year-old world-class
weight 11fter3~and to a lefthemispheric cerebrovascular accident
(CVA) in a 34-year-old body builder.35
The death of National Football League
(NFL) star Lyle Alzado fmm a brain
tumor in 1992 raised concern about
the risk of cancer with chronic use of
steroids. Steve Courson, another retired NFL star, is speaking publically
about steroid abuse, which caused his
cardiomyopathy.ll More common
adverse effects involve the hepatic,
endocrine, musculoskeletal, cardiovascular, immune, reproductive, and
psychological systems.36.37
The extensive metabolism of the oral
forms of anabolic steroids leads to
sigmficant hepatotoxic effects. The
abnormalities in liver function caused
by anabolic steroids are usually reversible upon discontinuation of the
druge26Oral anabolic steroids may
cause cholestasis, jaundice, and, seldornly, a pathologic condition associated exclusively with oral anabolic
steroids, peliosis hepatis. Pelosis hepatis is the formation of blood-filled sacs
in the liver, which may rupture and
cause fatal hem0rrhage.~OJl.~6
Creagh
et a138 reported the fatal rupture of a
hepatic tumor in a 27-year-old body
builder who had been taking oral
anabolic steroids. Two cases of hepatocellular carcinoma have been reported in otherwise healthy athletes
who used anabolic steroids.39
Anabolic steroids have dramatic effects
on the reproductive system owing to
their androgenic effects. Significant
decreases in plasma testosterone have
been demonstrated in males taking
from 15 to 150 mg/d of anabolic ster0id.N-~2The exogenous androgen
creates testicular atrophy, which may
be irreversible (chemical castration).ll
Currently, it is thought that anabolic
steroids affect plasma hormone levels
via action at the pituitary and hypothalamus. Exogenous anabolic steroid
replaces testosterone in the negative
feedback system at the level of the
pituitary and hypothalamus, resulting
in a decreased production of gonadotropins. Reduction in serum concentrations of pituitary interstitial cellstimulating hormone (ICSH) and
follicle-stimulating hormone (FSH)
causes a decrease in testosterone production from the te~tes.lO~~6,~Z
Physical changes associated with anabolic steroids and the reproductive
system include prostate enlargement,
decreased sperm counts by W h or
more, testicular atrophy, impotence,
and gynecomastia.l1 Sperm counts
usually return to normal after discontinuing the drug, yet male infertility
has been reported up to 7 months
after cessation of steroid use.1° Gynecomastia is a well-known side effect
of anabolic steroids and is characterized by a subareolar, bunonlike unilateral or bilateral plaque of ti~sue.~3
Gynecomastia is caused by the estrogens estradiol and estrone, which are
produced when androgens are converted in extraglandular tissue. Estradiol levels in athletes who are stacking
steroids can be seven times the normal level of ovulating women.lO Attempts to use estrogen inhibitors, such
as human chorionic gonadotropin or
tarnoxifen, have proven to be unsuccessful. In extreme cases, the development of breast tissue is not totally
reversible, and mastectomy may be
required.43
Physical Therapy / Volume 75, Number 5 / May 1995
Evidence of increased musculotendinous injury has been noted in the
anabolic steroid user. Miles et aP4
discovered that tendons in exercised,
steroid-treated animals became less
elastic and more prone to injury. With
increased strength in the muscle and
decreased strength in the tendon, the
athlete is more likely to develop
strains or ruptures. In children, anabolic steroids cause premature closure
of the epiphyses, resulting in decreased adult height.11
Use of anabolic steroids has been
linked to alterations in lipid profiIes.l2J4,26,*5The most consistent side
effects of anabolic steroid use are a
significant rise in total serum cholesterol level and a decrease in highdensity lipoprotein (HDL). Reduced
HDL levels are such a consistent finding that it has been suggested that use
of HDL levels to detect steroid use
may be useful as a less expensive
screening test than urinalysis.1° Webb
et a145 studied 14 body builders during
training with and without the use of
anabolic steroids. Self-administration
of anabolic steroids by these athletes
reduced HDL concentrations by
greater than 50%.45Increases in lowdensity lipoproteins (LDL) and a tripling of the LDLIHDL ratio were also
observed after 2 months of steroid
use. This effect did not appear to be
permanent. The HDL concentrations
returned to near normal 7.3 months
after steroids were discontinued. During the time these athletes did not use
drugs, they had high HDL levels and
relatively low LDL levels. This observation was similar to that of Goldberg
et al," who reported that a group of
steroid-free athletes demonstrateed
favorable changes in lipid levels with
a weight training program. C0sti11~~
reported signdicantly lower HDL concentrations in athletes using anabolic
steroids when compared with untrained men and strength-trained men
who were not using these drugs. This
decline in HDL concentration with
anabolic steroid use was reversible
within 3 to 5 weeks after cessation of
steroid use. Although the underlying
mechanism of the decrease in HDL
levels with anabolic steroid use is
unclear, Costill et a147suggest that the
main effects of androgens on lipoproteins are the consequence of an inhibition of apoprotein A synthesis, the
main apoprotein in HDL-C. Although
studies have demonstrated a direct
relationship between low levels of
HDL and coronary artery disease, the
effect of long-term administration of
anabolic steroids on the development
of athlerosclerotic coronary artery
disease has not been determined.26.47
Psychologic side effects of anabolic
steroids include euphoria, aggressiveness, irritability, nervous tension,
changes in libido, mania, and psychosis. Up to 80% of steroid users are
aware of overly aggressive and violent
behavior during periods of high consumption of steroids.ll Studies suggest
that marked affective or psychotic
symptoms may sometimes occur in
individuals who are taking anabolic
steroids. In a study of 41 body builders, 9 (22%) exhibited full affective
syndrome in accordance with the
Diagnostic and Statistical Manual of
Mental Disorders (DSM-111-R) criteria,
and 5 (12%) reported psychotic symptoms with anabolic steroid use. Delusions, hallucinations, anorexia, hyperactivity, and grandiosity have been
correlated with anabolic steroid
~ s e . ~Pope
~ , ~and
9 Katz49describe case
reports of 3 men with no premorbid
psychiatric histories who cornrnited
violent crimes (including murder)
while taking anabolic steroids. Athletes
may also develop clinical depression
while withdrawing from steroids. This
can be a significant problem given the
on again-off again cycling pattern of
anabolic steroid use.
Anabolic steroid use is becoming
more popular among females, and the
adverse effects in women are not well
documented. Strauss et a150 studied 10
weight-trained women who consistently used anabolic steroids. The
women used stacking and cycling
techniques, taking up to nine times
the manufacturers' recommended
dosages. Perceived side effects included lower voice, enlarged clitoris,
increased libido, oligomenorrhea or
amenorrhea, increased aggressiveness,
acne, increased growth of body hair,
and decreased body fat. Side effects
Physical Therapy / Volume 75, Number 5 May 1995
such as enlarged clitoris and deepening of the voice are irreversible.26
Regulation. Federal and state effofls
have increased in attempts to control
the illegal sale and distribution of
anabolic steroids. Several states have
passed legislation making some ambolic steroid transactions illegal and
subject to felony charges.14Anabolicandrogenic steroids are banned by the
US Olympic Committee (USOC), the
International Olympic Committee
(IOC), the NCAA, and the NFL.
Human Growth Hormone
Human growth hormone (GH) is
identdied as a family of structurally
related proteins synthesized by anterior pituitary somatotropes, of which
the primary monomer is a 22,000-d,
191-amino acid polypeptide.jl Growth
hormone is used for replacement
therapy in children who are GH deficient. Additionally, GH is being studied for used in Turner's syndrome,
children with delayed growth, and
short children with intrauterine growth
retardation or similar disorders.5'
Pharmacology and physiologic
effects. The human pituitary contains
between 5 to 10 mg of GH, with daily
production of 0.4 to 1.0 mg in men
and with slightly higher rates in adolescents and women.'j Serum levels
vary throughout the day owing to its
intermittent, pulsatile release, but average 0.5 to 3.0 pg/L and are affected by
a number of factors. The half-life of
GH ranges from 17 to 45 minutes, and
proteolysis into a more bioavailable
two-chain form takes place in the
skeletal m~scle.~,5~153
The secretion of GH is controlled
through a feedback loop involving
GH-releasing hormone (GHRH) and
somatotropin-release-inhibitinghormone (SRIH). Growth hormone release can be affected by multiple factors, including sleep, exercise, stress,
hypoglycemia, alpha-adrenergic agonists, beta-adrenergic antagonists, GH
levels, and dopaminergic agonists
(Tab. 2).2.i2-55Growth hormone increases in response to hypoglycemia
and exercise, and the largest GH surge
Table 2.
whereas GH-mediated growth occurs
as a result of increases in the rate and
translation of existing RNA.52,54
Factors Affecting Growth Hormone Secretiona
Stimulative
Suppressiveb
Growth hormone has potent effects on
carbohydrate and lipid metabolism,
Functioning to decrease glucose and
protein metabolism by shifting oxidative metabolism toward the use of
fatty acids.53 Administration of GH
results in decreased peripheral fat
stores, increased hepatic lipid stores,
and increased plasma free fatty acids
(FFA).52-5+
Because of its lypolytic and
anabolic effects, GH has been abused
by body builders attempting to decrease fat and increase lean body
ma~s.5~
Physiologic
Sleep
Postprandial hyperglycemia
Exercise
Elevated free fatty acids
Stress (physical or psychological)
Postprandial hyperarninoacidemia
Postprandial hypoglycemia (relative)
Pharmacologic
Hypoglycemia:
Hormones:
Absolute: insulin or 2-deoxyglucose
Somatostatin
Relative: postglucagon
Sornatomedin C (IGF-1)
Hormones:
Growth hormone
Peptides (GRH, ACTH, a-MSH, vasopressin)
Progesterone
Estrogen
Neurotransmitters:
Neurotransmitters:
a-Adrenergic agonists (clonidine)
a-Adrenergic antagonists (phentolamine)
p-Adrenergic antagonists (propranolol)
P-Adrenergic agonists (isoproterenol)
Serotonin precursors (5-hydroxytryptaine)
Serotonergic antagonists (methysergide)
Dopaminergic agonists (L-dopa, apomorphine,
bromocritine)
Dopaminergic antagonists
(phenothiazines)
GABA agonists (muscirnol)
Cholinergic (muscarinic)antagonists
(pirenzepine)
Pathologic
Protein depletion and starvation
Obesity
Anorexia nervosa
Hypothyroidism and hyperthyroidism
Chronic renal failure
Acromegaly: dopaminergic agonists
Acromegaly:
TRH
GnRH
"GRH=growth-hormone-releasing hormone, ACTH=adrenocorticotropic hormone, MSH=
melanocyte-stimulating hormone, GABA=gamma-aminobutyric acid, TRH= thyrotropin-releasing
hormone, GnRH=gonadotropin-releasing hormone, IGF=insulinlike growth factor. (Reprinted
with permission from Frohman LA. Diseases of the anterior pituitary. In: Felig P, Baxter JD,
Broadus AE, Frohman LA, eds. Endocrinology and Metabolism. 2nd ed. New York, NY: McGrawHill Book Co; 1987:268.)
' ~ u ~ ~ r e s s ieffects
v e of some factors can be demonstrated only in the presence of a stimulus
occurs approximately 60 to 90 minutes
after the onset of sleep.53 Following
GH release, the pituitary becomes
unresponsive to further stimulation for
several hours, thus providing a negative feedback loop. This response is
true of both endogenous release and
exogenous administration of GH. The
result of exogenously adrninstered GH
is the down-regulation of endogenously released GH.'
The primary function of GH is to
promote growth via the generation of
somatomedins, spechcally insulinlike
growth factor (IGF-1). Growth hormone and IGF-1 promote anabolism,
facilitating muscle, bone, and cartilage
growth. Increased protein deposition
(anabolic effects) occurs owing to
facilitation of nearly all aspects of
amino acid uptake and protein synthesis by the cells, with concurrent reduction of protein catabolism.56 The GHmediated growth is dfierent from the
growth that occurs as a result of work.
New RNA must be synthesized for
exercise-induced muscle growth,
Administration. Therapeutic dosages
of GH for individuals with GH deficiency range from 0.06 mg/kg to 0.1
mg/kg three times weekly, depending
on the spechc medication2 Recombinant human growth hormone (rGH) is
currently used because of cases in
which Creutzfeldt-Jakob disease was
spread via use of the naturally occurring hormone.57 Two forms of rGH
are currently available, one containing
the entire natural sequence and a
second containing an additional methionyl amino acid re~idue.5~
Athletes
have reported taking up to 20 times
the therapeutic dosage in hopes of
gaining some of the effects of anabolic
steroids without being dete~ted.5~
Some athletes take propanolol, vasopressin, clonidine, and levodopa to
stimulate exogenous GH secretion.53
Because of the physiologic negative
feedback loop, however, it is likely
that the body would autoregulate the
GH levels to the proper physiological
amount. Injecting large quantities of
GH would increase the circulating
levels and concentrations of GH, leading to the anecdotal reports of increases in muscle bulk and ~trength.5~
Ergogenic efficacy. The observed
muscle size increase without simultaneous strength increase in individuals
with acromegaly prompted the study
of the effects of a concurrently administered GH and resistive exercise program. Yarasheski et a15"valuated the
effectiveness of exogenously administered GH on muscle growth in a
Physical The]rapy / Volume 75, Number 5 / May 1995
group of 16 untrained male subjects.
After 12 weeks of training in combination with 5-d/wk GH injections, the
treatment group demonstrated protein
balance when compared with a placebo group. Quadriceps femoris muscle protein synthesis rate, torso and
limb circumferences, and muscle
strength, however, were not increased.
The authors concluded that the increase in fiat-free mass (FFM) was due
to increases in lean tissue other than
skeletal muscle, but they d ~ d
not spectulate where these increases might
have occurred. Moreover, the authors
concluded that resistance training
supplemented by GH did not further
enhance muscle anabolism and
function.
Christ et aI6O studied the effects of GH
on body composition and endogenous
secretion of GH and IGF-I in adults.
Following 6 weeks of resistance exercise and a high-protein diet, those
subjects receiving GH demonstrated
significant increases in fat-free weight
and decreased percentage of body fat
compared with a placebo group.G0
Changes in the fat-free weight/fat
weight ratio were correlated with the
relative dosage
- of GH. Increases in the
mass of atrophied and normal muscles
have been found with the adrninistration of GH in rats. Neither improved
tension development nor enhanced
performance, however, were found
in the nonnal or hypertrophied
prohibited by the USOC, the IOC, and
the NCAA. The Federal Food, Drug,
and Cosmetic Act includes penalties
for illegal use or distribution of human
GH. Currently, the annual cost of rGH
($14,000-$20,000 for a 20-kg child) is
a prohibitive factor in abuse. No medical tests exist for the detection of human GH.
Clenbuterol
Clenbuterol is a beta2-adrenergic agonist that has proposed ergogenic properties resulting from central nervous
system (CNS) stimulation. It is a sympathomimetic drug that has a peripheral excitatory action on smooth muscle, a cardiac excitatory function, and
metabolic and endocrine actions.S2
These drugs are used primarily for
their ability to produce relaxation in
smooth muscle. The beta,-agonists are
widely used as bronchodilators for the
prevention and treatment of symptoms
of exercise-induced asthma and for
relaxation of the uterus in premature
labor (Tab. 3).
-
Table 3. Major Classijications of
Receptor Types and Action
~
-
-
~
Receptor
Action
a-1
Constriction of blood vessels
to skin, mucous membranes
muscle^.^^^^^
Side effects. Adverse effects of large
quantities of GH in adults include
acromegaly with associated myopathy,
peripheral neuropathy, glucose intolerance, increased plasma cholesterol
and triglyceride concentrations, coronary artev disease, and cardiomyopathy.2,27,52,54
In prepubescent athletes,
excessive quantities of GH result in
gigantism. The musculoskeletal and
cardiac effects associated with excessive GH use may be irreversible, even
after discontinuation of the hormone.
Moreover, needle sharing for intramuscular administration carries the risk of
disease transmission.
Phannacology and physiologic
effects. Clenbuterol is a potent
growth-promoting beta-agonist with
peripheral and central effe'ects.65These
effects include an increase in heart rate
and cardiac contractility, an increase in
the rate of glycogenolysis in the liver
and muscle, liberation of FFA, and
enhancement of pituitary hormone
release.65Sympathetic stimulation
results in peripheral excitation of
smooth muscle of the blood vessels
supplying the skin and mucous membranes and in ~nhibitionof smooth
muscle of the blood vessels supplying
the skeletal muscle, gastrointestinal
tract, uterus, bladder, and bronchial
tree. Central effects also occur from
sympathomirnetic drugs and include
respiratory stimulation, increased alertness, and decreased appetite.(*l
Pupillary dilatation
Relaxation of smooth muscle
in gut
a-2
Inhibits further release of
norepinephrine
P- 1
Increases heart rate and
contractility
P-2
Dilatation of blood vessels to
skeletal muscle
Relaxation of bronchial smooth
muscle
Relaxation of smooth muscle
to uterus
p-3e
Increasedmetabolic rate
The potential ergogenic properties of
clenbuterol stem from its array of
sympathomirnetic effects. Increased
lipolysis and decreased lipogenesis are
dramatic effects noted with chronic
beta-agonist treatment.63a65," This
process increases fat availability for
energy, theoretically increasing endurance. Increased glycogenolysis from
the liver may increase carbohydrate
availability, and increased skeletal
muscle blood flow may enhance the
peripheral delivery system.
Increasedthermogenic effect
Decreased appetite
Regulation. Human GH, synthetic
GH, and GH-releasing factors are all
The anabolic effects of clenbuterol are
purported to include the prevention of
muscle atrophy, an increase in lean
body mass, and a decrease in body
fat.63 Clenbuterol, therefore, has been
termed a "repartitioning agent," or an
agent that manipulates growth and
body composition, enhancing the
deposition of body protein and decreasing fat.64The beta2-agonistshave
been studied extensively in animals in
attempts to increase lean body mass
and decrease body fat in animals bred
for consumption. These substances are
also being evaluated for their role in
the treatment of obesity because of
their repartitioning effects and because
of the thermogenesis seen with betaagonist treatment.63a65
"Mects brown (fat) cells
Physical Therapy /Volume 75, Number 5 /May 1995
Protein anabolism is a consistent finding with clenbuterol administration.
This protein increase may be the result
of increased synthesis or decreased
catabolism, or both. The proposed
cellular mechanisms stem from the
control of protein metabolism via
increased calcium transport, increased
cyclic adenosine monophosphate
(CAMP) levels, and an activation of
protein kinase.65 Both indirect (insulin
release, increased peripheral blood
flow, pituitary hormones) and direct
(modulators of protein turnover, contractile activity) mechanisms may participate in the hypertrophy process65
Administration. Clenbuterol hydrochloride is used as a bronchodilator in
the management of asthma in usual
doses of 20 pg two or three times
daily by
It is available as
an oral preparation with a plasma
half-life of 34 hours and a slightly
longer tissue half-life. Changes in
muscle growth can be obsewed within
2 days of treatment, with the maximum growth within 8 days65 Attenuation takes place after approximately 14
days, likely due to beta-receptor saturation and subsequent receptor down
regulation. Rothwell et a169 demonstrated a 50% reduction in muscle
beta-receptor density after 18 days of
chronic clenbuterol treatment in rats.
Intermittent administration of betaagonists has been shown to attenuate
this effecL65 For this reason, athletes
often "cycle" clenbuterol, taking it on
and off in 2-day cycles. This cycle is
generally continued for 8 to 10 weeks,
followed by 10 to 12 weeks without
the drug." Currently, no research
supports this cycling schedule, although, as with many ergogenic aids,
anecdotal reports exist. Anecdotal
reports suggest that athletes often
combine clenbuterol with other hormones such as anabolic steroids or
GH to exponentially increase its effects, a practice that is supported by
animal research.6"
Ergogenic efficacy. Most studies of
ergogenic efficacy have been performed on animals, although studies
on humans with obesity are being
initiated. Anabolic effects have been
found, with 1@/o to 20% increases in
muscle weight noted after 1 to 2
weeks of clenbuterol administration in
rats.65,70Rothwell and Stock67 found
that a daily injection of clenbuterol (1
m g k g of body weight) produces a
12% weight gain and a 13% increase
in the body proteinfat ratio in rats.
Administration of beta,-agonists appears to promote fiber-specific (fasttwitch glycolytic) muscular hypertrophy, with increases in the crosssectional area reported to be 1@/0to
50% in a n i m a l ~ . ~Maltin
, ~ 5 et aF4
found hypertrophy in the fast-twitch
glycolytic fibers in animals treated
with a daily dose of clenbuterol, and a
combination of clenbuterol and GH
resulted in hypertrophy in fast-twitch
glycolytic, fast-twitch oxidative glycolytic, and slow oxidative fibers. Muscle
RNA was increased consistent with the
increase in muscle protein, and clenbuterol appeared to enhance protein
anabolic effects via a depression of
protein degradation rates, with little or
no change in protein synthesis. Although other researchers have found
similar anabolic changes, these effects
were the result of increases in protein
synthesis71 or increases in both synthesis and d e g r a d a t i ~ nInjection
.~~
of
clenbuterol (0.125 mg/kg of body
weight) in rats resulted in increases in
CAMP,blood lactate, muscle mass, and
protein synthesis as well as decreases
in muscle glycogen.67The increase in
muscle mass was attributed to the
protein synthesis increase, although
the authors noted that the results may
have been partly due to an altered
rate of muscle protein degradati0t-1.~~
Other beta,-agonists (albuterol, salbutamol, cimaterol) have been studied to
determine the potential ergogenic
effects of these drugs. Morton et a173
studied the acute effects of a 200-pg
dose of salbutamol inhalant on several
physiologic variables and performance
in high-level, nonasthrnatic athletes.
The authors found no Merences in
any measurements between treatment
and placebo conditions. In contrast,
Martineau et a174studied the chronic
effects of a 3-week, 16-mg/d administration of an oral form of sustainedrelease salbutarnol. The treatment
group demonstrated increases in
quadriceps femoris and hamstring
muscle group strength compared with
the control group. The single-dose and
chronic-treatment effects, therefore,
must be distinguished, and they may
help explain the differences in study
results. Length of treatment, dosage,
route, and timing of clenbuterol administration can affect results.
Side effects. Side effects of clenbuterol use are slmilar to those of any
beta,-agonist. Tremor, tachycardia,
anxiety, palpitations, headache, nausea, anorexia, and insomnia are common complaints. Additionally, potentially serious side effects include
cardiac muscle hypertrophy and dysrhythrnia, myocardial infarction, or
stroke.66
Regulation. All oral beta-agonists,
including clenbuterol, are banned by
the IOC, the USOC, and the NCAA.
Currently, oral clenbuterol is available
only for veterinary use in the United
States, whereas other oral betaagonists are widely used. Urine levels
of 0.5 ng/mL are detectable by gas
chromatography and mass spectrometry 2 to 4 days after the last dose.
Erythropoietin (EPO) is a glycoprotein
produced by the kidney that functions
to regulate red blood cell (RBC) production. This 36,000-d, 166-amino acid
glycoprotein has a half-life of 6 to 9
hours. Approximately 90% of EPO is
synthesized in the renal cortical cells,
whereas the remainder is synthesized
in extrarenal sites, primarily the live ~ - Recombinant
. ~ ~ , ~ ~ EPO (rEPO) was
first available in Europe in 1987 and
subsequently in the United States in
1989. Recombinant EPO is nearly
identical to natural EPO both biochemically and immunologically, although some minor differences exist.
Commercial production utilizes recombinant deoxyribonucleic acid (DNA)
technology to manufacture rEPO from
Chinese hamster ovary cells. Patients
with anemia from various conditions,
as well as patients anticipating blood
loss from upcoming surgery, can benefit from the use of rEP0.76,77
Pharmacology and physiologic
effects. Erythropoietin and rEPO are
used specifically by endurance athletes
Physical The:rapy / Volume 75, Number 5 / May 1995
to increase aerobic endurance, with
effects similar to that of blood doping.
Erythropoietin is a major factor in the
stimulation, proliferation, and maturation of the bone marrow stem cell,
which, in turn, increases the rate of
RBC pr0duction.~5Hypoxia, with a
subsequent decrease in renal blood
flow, or low levels of circulating hemoglobin stimulate the production
and secretion of EPO by these sites. In
normal bone marrow, stem cells differentiate into late burst erythroid colony
forming units (BFU-E), which replicate
and differentiate into early erythroid
colony forming unit cells (CFU-E) and
eventually into mature RBCs. This
process normally takes approximately
7 days, with no new RBCs appearing
for the first 2 days and with maximum
RBC production reached after 5 or
more days. Exogenous EPO is used in
patients wlth end-stage renal disease
and enhances RBC production by
expanding the BFU-E and stimulating
the CFU-E'~ (Figure).
@-@-@
Stem
vI
BFU-E
cell
@
cr
'.I\::
0
I
n
I
Administration. Administration of
rEPO in patients with end-stage renal
disease is recommended at a level of
150 U/kg three times per week with
adjustmen& as necessary to achieve a
response.7s The half-life of rEPO administered intravenously is approximately 5 to 11 hours, whereas the
half-life is 25 hours when administered
subcutaneously, depending on dosage. Absorption is slower with subcutaneous administration, with peak
concentrations occurring 10 to 15
hours after administration.7679
Ergogenic efficacy. The proposed
ergogenic benefits of EPO are derived
from the early release of marrow reticulocytes (young RBCs), stimulation
of megakarocytopoesis (platelet precursors), increased hemoglobin synthesis by KBC precursors, proliferation
of BFU-E, and proliferation and dfierentiation of CFU-E cells. The resultant
increase in RBCs will increase oxygen
carrying capacity, thereby increasing
oxygen availability to the tissues. Increased oxygen availability to the
tissues al1c)ws for increased adenosine
triphosphate (ATP) production and
improved aerobic performance. Patients receiving 600 U/kg of body
* 2s
Mature RBC
Figure. stimulation of red blood cell production by erytbropoeitin. BFU-E= burstforming unit-erytbmid, red cell precursor; CFU-E= colony-forming unit-erythroid, red
cell precursor; Epo= erytbropoietin; RBC= red blood cell. (Reprinted zcitb permission
from Wingard LB, Brody TM, LarnerJ, Scbujartr A. Human Pharmacology: MoleculartoClinical. St Louis, Mo: Mosby-Year Book lnc; 1991:860.)
weight intravenously twice weekly for
21 days demonstrated a 41% greater
RBC volume than did those receiving
a p l a c e b ~Ekblom
.~
and BerglundB1
administered rEPO to 15 well-trained
male subjects at a dosage of 50 U/kg
subcutaneously three times per week
for 6 weeks. Results demonstrated
increased hematocrit of lO?h, exercise
time to exhaustion by 17%, maximal
oxygen consumption by 8%, and
systolic blood pressure by 8%.
Physical Therapy / Volume 75, Number 5 / May 1995
Side effects. Adverse effects of EPO
or rEPO are due to the increase in
RBC production and are dosedependent. Hypertension and hyperviscosity (hematocrit over 55%) of the
blood are two potentially lifethreatening adverse effects. Athletes
are particularly susceptible to the
effects of hyperviscosity due to the
unpredictable clearance of rEPO from
the serum and the biological effects
that last for the life of the RBC (up to
434 / 103
120 days). Effects may be exacerbated
during prolonged endurance events
when dehydration increases the hyperviscosity. Symptoms of hyperviscosity include headache, dizziness,
vertigo, tinnitus, visual changes, angina, exercise-induced claudication,
encephalopathy, and s e i ~ u r e sThe
.~
athlete may also experience a thromboembolic hypoxic event because of
"sludging" of the blood. Several European cyclists mysteriously died (often
at rest or while sleeping) between
1987 and 1990, which coincides with
rEPO availability in Europe.82It has
been suggested that rEPO use in these
athletes produced a vascular sludging,
worsened by dehydration, eventually
causing coronary artery 0cclusion.~3
caffeine. Analgesics and cold preparations contain approximately 30 to 65
mg of caffeine.84The physical therapist
must be aware of the action and effects of caffeine because of its widespread use and its sympathetic and
diuretic side effects.
results in increased neurotransmitter
release and neuronal activation, regulation of hormone-induced glycogenolysis and lipolysis, and dose-specfic
CNS s t i m u l a t i ~ nCentral
. ~ ~ ~ ~nervous
system arousal is also facilitated directly by caffeine's inhibition of adenosine receptors in the brain. Adenosine
acts as a CNS depressant, hypnotic,
and anticonvulsant, and caffeine's
blocking of adenosine receptors increases neurotransmitter release and
lowers the threshold for neuronal
activati0n.~5In the athlete, the CNS
stimulation may increase mental alertness and reduce fatigue.
Caffeine
Pharmacology and physiologic
effects. Caffeine (1,3,7-trimethylxanthine) is one of three xanthine
derivatives producing similar physiological responses.84-%,8'The other two
derivatives, theobromine and theophylline, are found in cocoa and tea,
respectively. Of the three xanthine
derivatives, caffeine produces the most
CNS activity and theobromine produces the least CNS activity.% After
consumption, caffeine is completely
absorbed from the gastrointestinal tract
and reaches peak blood levels in
approximately 30 to 60 minutes. Caffeine enters the brain quickly after
absorption, thus producing the rapid
alertness noted after c o n s u m p t i ~ n . ~ ~
The highest concentrations following
absorption are found in tissues with
the highest water content, primarily
the skeletal mu~cle.~5
The state of
hydration, therefore, can affect caffeine
distribution. The half-life of caffeine
ranges from 2 to 12 hours in asymptomatic adults, with an average halflife of 4 to 6 hours. Children do not
eliminate caffeine as readily as adults,
and the effects may last up to 3 to 4
days in this p0pulation.~6
Caffeine is the most widely consumed
stimulant known today. Approximately
80% of the adult population in the
United States consumes coffee or tea
daily.H%offee is responsible for 90%
of the caffeine consumption in the
United States, totaling approximately
210 mg per person per day.85 Caffeine
is also found in chocolate, soft drinks,
weight-loss and cold preparations, and
analgesics. Currently, the National
Center for Drugs and Biologics lists
caffeine as an ingredient in more than
1,000 over-the-counter pharmaceuticals.% Consequently, caffeine consumers include children as well as adults.
Depending on preparation, a cup of
coffee contains approximately 100 to
120 mg of caffeine, whereas a 12-02
soft drink contains 30 to 60 mg of
Ergogenic efficacy. Studies examinCaffeine is proposed to exert its effects
ing the glycogen sparing effect of
by (1) antagonism of adenosine recepcaffeine have provided mixed results.
tors:* (2) inhibition of enzyme activity
Dserences in the quantity and timing
such as phosphodiesterase,75 (3) alterof caffeine administration, variations in
exercise protocols and subject nutriing the release or uptake of calcium
from the sarcoplasmic r e t i c u l ~ m , ~ 5 > ~ ~tional status, and inconsistency in the
caffeine "naivet~"of the subjects have
(4) altering the calcium permeability of
the sarcolemma, or (5) facilitating
likely produced this disparity. Tolerneuromuscular impulse transmi~sion.~~ ance to many of the effects of caffeine
Caffeine acts as a CNS stimulant, indevelops within a few days, and the
creasing arousal, reducing fatigue,
results of caffeine ingestion on perfordecreasing motor reaction time, and
mance are highly dependent on an
individual's normal quantity and
changing normal electroencephalogram recordings. Excessive caffeine
schedule of caffeine c o n ~ u m p t i o n . ~
usage can produce irritability, restlessHabitual caffeine consumption can
ness, diarrhea, insomnia, and anxiety.
attenuate heart rate and blood presInhibition of phosphodiesterase results
sure, and catecholaminergic responses
in elevated levels of CAMP, an importo acute caffeine administration can
tant regulator of cellular functions.
occur within a few days.91 Fisher et
Maintenance of elevated CAMP levels
aP2 found that habitual caffeine users
Regulation. Blood doping of any
kind, including use of EPO, is banned
by the NCAA, the IOC, and the
USOC.83 Unfortunately, detection of
naturally occurring substances is difficult. Recombinant EPO is slightly
different from EPO, and advances in
technology may detect these ditferences. Assessment of the RBC age
may be beneficial, as athletes abusing
EPO should demonstrate a younger
RBC population. Although the estimated yearly cost of legitimately obtained EPO of $5,000 to $6,000 may
impede its use by some athletes, no
definitive deterrents exist.83
In addition to decreasing the perception of fatigue, athletes use caffeine as
an ergogenic aid because of its proposed ability to increase circulating
levels of FFA and to "spare" glycogen
by altering substrate utilization. Caffeine ingestion produces an increase
in the plasma concentration of FFA
and catecholamines and increases
l i p o l y ~ i sIncreased
.~~
lipolysis has been
attributed to either increased intracellular CAMP,which accelerates hydrolysis of stored triglycerides, or to direct
xanthine inhibition of phosphodiesterase.8' The caffeine-facilitated increases
in blood EFA levels are suggested
to produce shifts in substrate utilization, increasing FFA oxidation and
slowing glycolysis, thereby "sparing"
glyc0gen.~99%
Physical Th~erapy/ Volume 75, Number 5 /May 1995
developed a tolerance to the effects of
caffeine, which was negated after a
4-day withdrawal period.
Costill et a189 found that elevated
plasma FFA levels in seven cyclists
who ingested 330 mg of caffeine resulted in a 40% decrease in the rate of
muscle glycogen depletion, whereas
several other researchers have failed to
find an increase in FFA oxidation
associated with increased blood FFA
levels,'l-!'5
suggesting no change in
substrate utilization.%Additionally,
have found
several researchers93~95~97,~
increased blood lactate levels following caffeine ingestion and exercise.
Ravussin et a199 observed a higher rate
of fat oxidation and decreased carbohydrate oxidation rates with increased
plasma FFA levels only during the first
30 minutes of a 150-minute exercise
session. Moreover, higher FFA levels
did not alter substrate utilization after
glucose feedings during exercise.
Flinn et allo0studied the effects of a
10-mg/kg-' caffeine dose given 3
hours prior to an incremental cycle
ergometer test in nine male caffeinenaive subjects. Subjects worked
longer, performed more work, and
exhibited higher FFA levels in the
caffeine trial than during control or
placebo trials. The authors concluded
that caffeine was ergogenic when
taken 3 to 4 hours prior to exercise in
fasting subjects with diets normally
low in caffeine. The effect of time of
caffeine ingestion was evaluated in six
trained, caffeine-naive men who consumed 10 mg/kg-' of caffeine immediately before a treadmill run to exhaustion.lol The athletes ran farther
during the caffeine trial, and they had
increased blood lactate and blood
glucose responses at the end of exercise during the caffeine trial.
In contrast, Tarnopolsky et algl concluded that a 6-mg/kg-' caffeine dose
administered 60 minutes prior to exercise in six habitual (200 mg/dP1) caffeine consumers had no potential
ergogenic effect. Caffeine administration incrt~asedplasma FFA levels prior
to and during exercise, but did not
change oxygen consumption, heart
rate, respiratory exchange ratio (RER),
Physical Therapy / Volume 75, Number
rate of perceived exertion (RPE), or
neuromuscular function (maximal
voluntary strength, peak twitch torque,
and motor unit activation). Plasma
levels of glucose, epinephrine, and
norepinephrine were also unchanged.
Although blood levels of FFA were
increased in the caffeine trial, an associated increase in FFA oxidation was
not observed.
A similar paradox was found in a
study of five competitive cyclists who
ingested a variety of potentially ergogenic substances in a crossover,
single-blind protocol.% Caffeine given
60 minutes prior to exercise resulted
in a reduction in muscle glycogen
utilization when compared with the
control trial. No difference, however,
was noted in the RER between the
caffeine and control trials, suggesting
similar substrate utilization. These
findings are similar to the results of a
study of caffeine intake on performance in nine male marathoners,
where an increase in plasma FFA was
noted, with no change in RER." Titlow et a1102also found no ergogenic
benefit from ingesting 200 mg of caffeine prior to a treadmill test in five
male subjects. The authors found no
difference in performance or substrate
utilization. Information on the caffeine
habits of subjects in these studies was
not provided, and tolerance to the
effects of caffeine may explain the
results. Additionally, it has been suggested that RER may not accurately
reflect substrate utilization after caffeine ingesti0n.9~
Side effects. Side effects of caffeine
may include trembling and tremors,
insomnia, nervousness, irritability, and
anxiety. Caffeine also has a diuretic
effect, which may result in fluid imbalance and inconvenience for the
athlete.
Regulation. Caffeine was considered
a doping agent by the IOC until 1972,
when caffeine was removed from the
list of banned substances. This ruling
was reconsidered, however, and in
1984 caffeine was again added to the
list of doping agents. The illegal dosage is 12 mg/L of urine, and this dosage is equivalent to between 500 and
600 mg of caffeine in a 1- to 2-hour
period.86 Caffeine is also banned by
the NCAA at a urine level of 15 mg/L.
Drug Testing
Mandatory drug testing at international
athletic events has been in existence at
the Olympic Games since 1968. Comprehensive testing was not available
until 1972, and testing for anabolic
steroids was first initiated in 1976.2,103
The USOC and the NCAA have developed drug testing and drug education
programs in attempts to ensure safe,
fair competition. Mandatory drug testing programs were initiated in 1985
(USOC) and 1986 (NCAA) to eliminate
the use of performance-enhancing and
recreational drugs. Testing protocols,
as well as analytical procedures for the
most commonly used screening and
confirmation tests, will be discussed.
Currently, the USOC drug testing program applies to the US Olympic Festival, the Pan-American Games, the
World University Games, and the
Olympic Trials and Games. The USOC
athletes are subject to testing at any
time throughout the year, including
the off season. Athletes may be tested
while out of competition for the presence of anabolic-androgenic steroids,
diuretics, and masking agents.lo4
Short-notice testing requires only 48
hours' advance notice via phone,
personal contact, or return-receipt
correspondence. Division I-A and I-AA
football players and Division I men's
and women's track athletes can be
tested throughout the academic year
for anabolic steroids and related masking agents. All other athletes are tested
at championship events and bowl
games. Under NCAA and USOC protocols, athletes may be chosen for testing in a variety of ways. For example,
first-, second-, and third-place finishers
in addition to a random sample from
the remaining field may be chosen for
testing.lo4Moreover, national governing bodies or NCAA schools may
request or conduct their own drug
testing programs.lo4
Although blood samples are currently
under consideration for some drugs,
such as EPO, urine is still the pre-
ferred specimen for three reasons: (1)
Most misused drugs are present in
higher concentrations in the urine than
in blood, (2) larger specimens are
obtained in an easier fashion, and (3)
urine sampling is a noninvasive process.lo4After selection for drug testing
at an event, the athlete has 60 minutes
in which to report, and a courier stays
with the athlete during this time. After
urine samples are collected under
supervision at the drug testing station
(at least 80 mL for KCAA athletes and
at least 100 mL for USOC athletes), the
urine is divided into two separate
bottles. The urine in one bottle will
undergo testing, and the other bottle is
saved for use in the event of appeal.
Drug analysis involves two phases:
screening and confirmation. Screening
allows for rapid testing of many samples and is designed to eliminate all
negative samples from further testing.
If a screening test is positive, illicit
drug use is presumed only, and the
sample undergoes confirmation.
Screening tests are sensitive, but confirmatory tests are specific for drug
detection. A positive sample is confirmed by a second test performed on
urine taken from the same test bottle.
Testing procedures most commonly
used in screening include thin-layer
chromatography (TLC), irnmunoassay
(IA), gas chromatography (GC), and
high-performance liquid chromatography (HPLC). Gas chromatography/
mass spectrometry (GC/MS) is most
often used for confirmation, as it provides the most specific and definitive
identification possible.104
Thin-Layer Chmmatography
Thin-layer chromatography testing is
based on the differences in the migration rate of various substances through
a porous supporting medium.2 The
degree of migration and the color are
characteristic of certain drugs. Thinlayer chromatography can demonstrate the presence of a drug, but this
procedure cannot speclfy the quantity
of drug present.lo4This technique is
both time consuming and nonspecific,
and provides only a positive or negative response. Thin-layer chromatography is capable of detecting only a
limited number of substances 12 to 24
hours after ingestion, resulting in a
high number of false-negative results.
lmmunoassay
Imrnunoassays use antigen-antibody
interactions to detect illegal substances. Antibodies that bind selectively to certain drugs or drug metabolites are chosen, and the sensitivity
and the specdicity of this test are only
as good as the antibody chosen2 The
binding is proportional to the amount
of drug in the urine and can be detected through enzymes, radioisotopes, or fluorescent compounds. With
this technique, very small amounts of
drug can be detected in a very small
amount of urine, although this test
may not differentiate between specific
drugs within a class of drugs. Immunoassay has yielded false-positive
results with some decongestants and
nonsteroidal anti-inflammatory drugs.2
Radioimmunoassay (RIA) and fluorescence polarization immunoassay
(FPIA) are specific IA techniques currently being used. Radioimmunoassay
can detect some 17a-methyl, 17aethyl, and 1Pnortestosterone steroids
despite its low ~pecificity.~O5
Immunoassay is both more sensitive and more
specdic than TLC.
Gas Chromatography
Gas chromatography uses a separation
technique to divide the urine extracts
into the component parts. An inert gas
carries the urine through chromatographic columns, and the samples are
separated by their boiling temperature
and by their affinity for the column.
Compounds are identdied by separation time, called retention time.The
retention time is unique and reproducible for each drug in a given chromatographic c01urnn.~High-performance
liquid chromatography is similar to
GC, except a liquid carries the sample through the chromotographic
columns and the columns are not
placed in a heated compartment.
High-performance liquid chromatography is both sensitive and specdic, and
it is simpler and faster than GC. Gas
chromatography and HPLC are reliable
methods for screening, and they allow
for simultaneous determination of a
wide variety of different compounds.
High-performance liquid chromatography is used to screen for urinary caffeine levels and has been used to
confirm the positive results obtained
from other screening te~hniques.~
Some steroids can be analyzed with
this technique, whereas HPLC and GC
lack appropriate sensitivity to detect
beta-adrenergic blo~kers.~O5J~~
Gas ChmmatographyIMass
Spectrometry
The most precise procedure for detection of banned substances is a combination of GC and MS.1°3J05 Gas chromatography/mass spectrometry is a
two-step process, where GC separates
the sample into its constituent parts,
while MS provides the exact molecular
identdication of the compounds. Compounds are separated by GC and are
then introduced, one at a time, into a
mass spectrometer. As the sample
constituents enter the MS, they are
bombarded by electrons, which cause
the compound to break up into molecular fragments. The fragmentation
pattern is reproducible and characteristic, and is considered the "molecularfingerprint" of a specdic compound.
Gas chromatography/mass spectrometry is considered to be the most definitive method for confirming the presence of a drug in the urine and is
approximately 100 to 1,000 times more
sensitive than TLC.* Selective ion monitoring has been used to improve the
GC/MS results.1°5 This procedure is
the most costly, averaging approximately $200 per sample to test.2
Summary
A variety of ergogenic aids are used
by athletes attempting to gain an edge
on a competitor. These aids fall into
categories of nutritional, pharamcologic, physiologic, and psychologic.
Some of these techniques have been
shown to be efficacious when used in
specific situations, whereas the benefit
of others remains controversial. This
controversy may be due to the ethical
inability to test these substances in the
same manner in which they are used.
Moreover, blind testing is unable to be
Physical Thera.py / Volume 75, Number 5 / May 1995
~erformedin some situations (anasteroids) because of the psychoactive effects. Knowledge of these
agents
- and techniques is important to
the physical therapist because patients
may be using them recreationally or to
performance and because
the possibility of disease transmission.
the .
physical
thera~istmay
,
play a
in educating the
or the public regarding ergogenic aids.
Individuals may seek information
after media pubabout ergogenic
licity involving athletes and drugs.
bolic
oreo over.
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Physical Therapy / Volume 7 5, Number 5 / May 1995