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- Review -
The physiological and pharmacological basis for the ergogenic
effects of androgens in elite sports
Karen Choong, Kishore M. Lakshman, Shalender Bhasin
Boston University School of Medicine, Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston,
MA 02118, USA
Abstract
Androgen doping in power sports is undeniably rampant worldwide. There is strong evidence that androgen
administration in men increases skeletal muscle mass, maximal voluntary strength and muscle power. However, we
do not have good experimental evidence to support the presumption that androgen administration improves physical
function or athletic performance. Androgens do not increase specific force or whole body endurance measures. The
anabolic effects of testosterone on the skeletal muscle are mediated through androgen receptor signaling.
Testosterone promotes myogenic differentiation of multipotent mesenchymal stem cells and inhibits their differentiation into the
adipogenic lineage. Testosterone binding to androgen receptor induces a conformational change in androgen receptor
protein, causing it to associate with beta-catenin and TCF-4 and activate downstream Wnt target genes thus
promoting myogenic differentiation. The adverse effects of androgens among athletes and recreational bodybuilders are
under reported and include acne, deleterious changes in the cardiovascular risk factors, including a marked decrease
in plasma high-density lipoproteins (HDL) cholesterol level, suppression of spermatogenesis resulting in infertility,
increase in liver enzymes, hepatic neoplasms, mood and behavioral disturbances, and long term suppression of the
endogenous hypothalamic-pituitary-gonadal axis. Androgens are often used in combination with other drugs which
may have serious adverse events of their own. In spite of effective methods for detecting androgen doping, the
policies for screening of athletes are highly variable in different countries and organizations and even existing policies
are not uniformly enforced. (Asian J Androl 2008 May; 10: 351_363)
Keywords: testosterone; dihydrotestosterone; muscle mass; mechanisms of androgen action; androgen doping; mesenchymal stem cells;
detection of androgen doping
Correspondence to: Prof. Shalender Bhasin, Boston University School of Medicine, Section of Endocrinology, Diabetes, and
Nutrition, Boston Medical Center, Boston, MA 02118, USA.
Tel: +1-617-414-2951 Fax: +1-617-638-8217
E-mail: Shalender.Bhasin@bmc.org
Received 2008-01-02 Accepted 2008-01-08
DOI: 10.1111/j.1745-7262.2008.00407.x
1 Introduction
George J. Mitchell, a former US Senator, in a
recent report on the use of illegal
performance-enhancing drugs in professional baseball, acknowledged
pervasive use of androgenic-anabolic steroids by Major
League Baseball players in the USA; the list of those
linked to steroid use included many well known names
in baseball. The keen observers of the professional sports
scene, who have been sounding the alarm over the
widespread use of ergogenic drugs worldwidenot just in
the USA, and in all professional sportsnot just
baseballfor the past two decade, were hardly surprised
by these revelations. The use of performance
enhancing agents in sports is not a new phenomenon;
documentation exists of the use of a variety of potions, plants,
animal extracts as far back as the original Olympiads in
ancient Greece. Long before the isolation and
synthesis of testosterone in the 1930s, Brown-Sequard and
later Zoth and Pregl had recognized that contents of the
testicular extracts could improve physical and mental
energy, and muscle strength [1_4]. Shortly after
successful synthesis of testosterone, Boje [5] suggested
that sex hormones might enhance physical performance.
The Germans are alleged to have administered anabolic
-androgenic steroids to soldiers going into combat
[6]. Although it has been alleged that some German athletes
were given testosterone in preparation for the 1936 Berlin
Olympics [6], the most cited account of systematic use
of androgens in elite sports is that of the Soviet weight
lifting team in the 1952 and 1956 Olympics. In 1954,
at the weight lifting championships in Vienna, Dr John
Ziegler, a physician associated with the US Weight Lifting
Team, learned about the use of androgens by the
Russian weight lifters [6, 7]. Zeigler returned to the United
States and experimented with testosterone on himself and
other weight lifters in the York Babel Club [7]. When
Ciba Pharmaceuticals introduced Dianabol
(methandrostenolone) in 1958, he began to experiment with this
new drug [6, 7]. The use of androgens that was
limited initially to strength-intensive sports, spread
gradually over the ensuing decades to other sports and to
recreational body building [6, 7]. The media lime light
surrounding the detection of androgen use by elite
athletes such as Ben Johnson, Lyle Alzado, Mark Maguire,
Barry Bonds, Floyd Landis, and Marion Jones has only
added to the allure of performance enhancing drugs.
Admittedly, the exact prevalence of androgens use
by athletes is difficult to determine because the data
rely on self-reports and many users understandably do
not admit to the use of these drugs. But even surveys
based on self-report have found high rates of
androgens use among professional athletes and Olympians
[7, 8]. Yesalis estimated that approximately one million
Americans had used androgens sometime in their lives
[9]. Four to six percent of high school boys and one to
two percent of high school girls admit to using
androgens at least once [10_13]. The androgen use among
girls also has increased slightly during the past decade
although the overall use rates are substantially lower in
women than in men [7, 10].
The abuse of performance-enhancing drugs is not
limited to the USA; similar high prevalence rates of
androgen use have been reported in surveys conducted in
other countries [14, 15]. The most egregious example of
state-sponsored anabolic steroid doping was
uncovered in the former German Democratic Republic after the
fall of the communist government in 1990 [16];
classified documents revealed a secret state program
from 1966 to improve national athletic performance using
androgens with complicity of the sports medicine physicians.
A recent study of the use of anabolic steroids among
US college students found that the overall prevalence
of androgen use was 1% or less [17]. The number of
students reporting past-year use of androgens increased
among men from 1993 (0.36%) to 2001 (0.90%) [17] and has decreased slightly since then
[18]. The lifetime and past-year steroid use were associated with being
male, participation in intercollegiate athletics, and risky
behaviors, including cigarette smoking, illicit drug use,
drinking and driving, and alcohol use disorders [17].
One of the most alarming finding of this survey was
that approximately 70% of lifetime users of anabolic
steroids met criteria for an alcohol use disorder [17].
Thus, college athletes who abuse androgens are at
increased risk for other risky health behaviors.
2 Patterns of androgen abuse by athletes and
recreational body builders
Nandrolone, testosterone, stanozolol, methandienone,
and methenolol are the most frequently abused androgens
[19_21]. Intramuscular formulations of androgens are
used far more frequently than oral formulations [19].
Combinations of androgens are used more frequently
than single agents [19, 21]. Typically, athletes use two
or more androgens in progressively increasing doses over
a period of several weeks in a practice known as "stacking".
The doses of testosterone or other androgens used by
athletes are substantially larger than those prescribed
for the treatment of androgen deficiency. In one
survey [19], 50% of androgen users reported using at least
500 mg of testosterone weekly or an equivalent dose of
another androgen; in another survey [21], almost one
fourth of androgen users used 1 000 mg testosterone
weekly or an equivalent dose of other androgens.
Cycling of androgens refers to the intermittent use of
androgens in which weeks of androgen use are followed
by periods of drug holiday; this practice is based on the
unproven premise that cyclic prevents desensitization
to massive doses of androgen.
In addition to the use of androgens, athletes also
abuse other drugs to purportedly enhance muscle-building, muscle shaping, or athletic performance [19].
These accessory drugs include stimulants, such as amphetamine, clenbuterol, ephedrine, and thyroxine, other
anabolic agents such as growth hormone, IGF-1, and
insulin, and drugs perceived to reduce adverse effects
such as hCG, aromatase inhibitors or estrogen
antagonists [19]. The potential adverse effects of some
accessory drugs may be more serious than those of androgens.
3 Do androgens improve athletic performance?
Surprising as it might seem in light of the
widespread abuse of androgens, the evidence
demonstra-ting improvements in athletic performance after
androgen administration is sparse and weak. There is strong
evidence that androgens increase skeletal muscle mass,
maximal voluntary strength, and leg power [22_27];
even this assertion was debated rancorously for almost
five decades. Much of the controversy stemmed from
the well recognized difficulties in conducting
placebo-controlled, randomized, masked trials in athletes [27,
28]. It is not surprising that many of the earlier
androgen trials were neither randomized nor blinded. Some
studies included competitive athletes whose adherence
to rigid research protocols is always suspect [27,
28]. The protein and energy intake was not standardized; in
some studies, the participants continued to ingest
protein supplements ad lib. The exercise stimulus was not
standardized and, therefore, the effects of resistance
exercise could not be separated from those of
androgen administration.
However, a growing body of data over the past
decade has established that androgens increase muscle mass
[25, 26] and that the androgen-induced gains in skeletal
muscle mass and muscle strength are correlated with the
administered dose and the circulating concentrations
(Figure 1) [23, 24, 29, 30]. Thus, administration of
replacement doses of testosterone to healthy, hypogonadal
men [31_35] and of supraphysiologic doses to eugonadal
men [22, 23] increases lean body mass, muscle size and
strength (Figure 2). Systematic reviews of randomized
clinical trials have confirmed that testosterone therapy
is associated with greater gains in lean body mass and
grip strength than placebo in older men with low or
low normal testosterone levels [25]. Similarly,
testosterone therapy in HIV-infected men with weight loss
and in men with chronic obstructive lung disease
promotes greater gains in lean body mass and muscle
strength than placebo. There is considerable
inter-subject variability in the anabolic response to androgen
administration. A large part of the variance in anabolic
response can be explained by the circulating androgen
concentrations; however, polymorphisms in the polyglutamine and polyglycine tract length in androgen
receptor protein, testosterone metabolism, and other
unknown genetic factors may contribute to this
variance [30].
The effects of testosterone on muscle performance
are domain specific; testosterone administration improves
muscle strength and power, but does not affect specific force or muscle fatigability.
The gains in maximal voluntary strength during testosterone administration are
highly correlated with increments in muscle mass;
testosterone does not improve the contractile property of
the skeletal muscle. In contrast, resistance exercise
training increases muscle mass as well as specific force.
Androgens have not been shown to improve measures of whole body endurance, such as
VO2max and lactate threshold.
Based on their demonstrable effects on maximal voluntary muscle strength, androgens would be
expected to improve performance in events such as power
lifting in which performance is dependent upon muscle
strength. Therefore, not surprisingly, high rates of
androgen use have been reported among power lifters.
Body builders use androgens to increase skeletal muscle
mass and decrease fat mass, which provides greater
definition to the muscles. However, the use of
androgens by athletes participating in endurance events such
as long distance running and bicycling is not easily
comprehensible because androgens have not been shown to
improve endurance measures [36, 37]. It is possible
that the androgen-induced increments in hemoglobin may
improve the oxygen carrying capacity of blood [38].
The speculation that androgens might allow the athletes to train harder by improving the regenerative
response of the skeletal muscle to injury has not been
tested rigorously. Others have suggested that
androgens might increase "motivation" and
"aggression", which may be advantageous in competitive sports.
The widespread use of androgens by baseball
players and sprint runners also is not easily explained by the
available data on the effects of androgens. The ability
to hit a home run against a ball traveling at speeds
approaching 100 mph requires extraordinary degree of
hand-eye coordinationthe ability to locate the ball in a
specific coordinate of space and to place the bat in that
precise coordinate with considerable strength and power. There is some evidence that androgens decrease
reaction time by improving neuromuscular transmission [39, 40].
Improved reaction time in conjunction with increased strength and power could potentially
explain the perceived improvements in athletic
performance by baseball players, although the evidence to
support these hypotheses is lacking.
The use of androgens by legendary sprinters like
Ben Johnson is even more difficult to explain. Among
sprint runners, androgen-induced gains in body weight
might potentially increase the amount of work done in
carrying that body weight against gravity and resistance
across the race track. Thus weight gain might be viewed
as potentially deleterious to performance. The improved
reaction time, the psychological edge gained because
of the motivational effects of androgens, and the ability
to train harder, have been cited as possible explanations
without verifiable evidence.
4 Mechanisms of anabolic effects of androgens
Testosterone-induced increase in skeletal muscle
mass is associated with dose-dependent increase in
cross-sectional area of both type I and type II muscle
fibers [41]. Testosterone administration does not
affect the absolute number or the relative proportion of
type I and type II muscle fibers [41]. Testosterone
administration increases the numbers of myonuclei and
satellite cells [42], muscle progenitor cells that reside in
a unique niche adjacent to the muscle fiber. Androgen
receptors are expressed in the satellite cells and other
stem-like cells in the interstitium of the skeletal muscle
fibers and in some myonuclei of the myofibers
[43]. A growing body of evidence supports the hypothesis
that androgens promote the differentiation of
mesenchymal multipotent stem cells into the myogenic lineage
and inhibit their differentiation into the adipogenic lineage
[44_46]. Thus, in cultures of mesenchymal multipotent
C3H10T1/2 cells, androgens upregulate markers of myogenic differentiation, such as MyoD and myosin
heavy chain II and downregulate markers of adipogenic
differentiation, such as PPAR-gamma and C/EBP-alpha
[46]. These effects of testosterone and DHT on myogenesis are mediated through the classical
androgen receptor-mediated signaling and are blocked by
bicalutamide, an androgen receptor antagonist [46].
Upon binding to its cognate ligand, androgen receptor undergoes conformational change and
associates with its co-activator beta-catenin [45].
The androgen receptor-beta catenin complex moves into the
nucleus, forms a complex with LEF/TCF-4, and activates a number of Wnt target genes, including follistatin
[45]. The signal from androgen receptor is
cross-communicated to the TGF-beta pathway through
beta-catenin and TCF-4. Beta-catenin and follistatin play an
essential role in mediating the effects of testosterone
on myogenic differentiation [45].
Testosterone also has been reported to promote
satellite cell entry into the cell cycle [47_51].
Additionally, testosterone and DHT inhibit the differentiation of
preadipocytes into adipocytes [45]. Androgens also
stimulate fractional muscle protein synthesis and to
increase the efficiency of reutilization of amino acids by
the skeletal muscle [32, 52_54]. The effects of
testosterone on muscle protein degradation need further
investigation.
5 Potential adverse effects of androgen use
Because of the variability in the dose, frequency,
duration, and the type of drugs used, systematic
investigations of the adverse effects of androgens in athletes
and recreational body builders have been difficult to
conduct. These analyses are further complicated by
the concurrent use of accessory drugs. The low
frequency of serious adverse effects reported with
androgen use is surprising; it is likely that the adverse effects
are under-reported. Furthermore, the accuracy of
self-reported drug use is difficult to verify.
Adverse events associated with androgen use include deleterious changes in the cardiovascular risk
factors, including a marked decrease in plasma
high-density lipoproteins (HDL) cholesterol level [55] and
changes in clotting factors [56], suppression of
spermatogenesis resulting in infertility, increase in liver
enzymes, hepatic neoplasms, and mood and behavioral
disturbances [57_63]. Elevations of liver enzymes,
hepatic neoplasms, and peliosis hepatic and even hepatic
rupture have been reported with the use of oral,
17-alpha alkylated androgens [57, 58, 64], but not with
parenterally administered testosterone or its esters
[65]. Acne and premature hair loss can occur with androgen
use. Women using large dose of androgens are at risk
for menstrual irregularities, infertility, and virilizing side
effects, including hirsutism, deepening of voice, changes
in body habitus, and clitoral enlargement; some of these
virilizing adverse effects may be irreversible.
A number of deaths due to unexpected coronary and cerebrovasuclar thrombotic events among
androgen users have been reported [66_68], but these
reports are largely anecdotal and do not establish a cause
and effect relationship. In a stunning report that has
received surprisingly little attention, Finnish world class
power lifters suspected of AAS intake during their sports
career experienced five times higher mortality than
age-matched controls [69]. The findings of this small study
need further confirmation. The changes in plasma
lipids vary depending on the dose, the route of administration
(oral or parenteral), and whether the androgen is aromatizable or not.
Thus, orally administered, 17-alpha-alylated, nonaromatizable androgens produce
greater reductions in plasma HDL cholesterol levels than
parenterally administered testosterone.
Orally-administered, 17-alpha alkylated androgens also have been
associated with insulin resistance and glucose
intolerance [70]. Androgen use has been associated with
increases in hematocrit, homocysteine levels, blood
pressure and peripheral arterial resistance, and left ventricular
hypertrophy and diastolic dysfunction [71_81]. However, it is not clear whether myocardial
hypertrophy reported in power lifters is the result of resistance
exercise or androgen use. In a cross-sectional
investigation [82], power athletes who had used androgens
showed subclinical impairment of both systolic and
diastolic myocardial function that was correlated with the
dosage and duration of androgen use. Also, one
controlled trial in healthy volunteers [83] and other
uncontrolled, open-label studies in weight lifters, have
not found significant changes in left ventricular mass
or function with androgen use [84]. The long term
effects of androgen abuse on the risk of prostate and
cardiovascular disease are unknown.
The anecdotal reports of "roid
rage" among androgen users have received much attention in lay press.
However, in placebo-controlled trials, testosterone
administration has not been associated with a statistically
significant increase in anger scores or measures of
aggressive behaviors [63, 85_90]. It is possible that the
self-reporting questionnaires lacked the sensitivity to
detect small but significant changes in aggression.
In controlled trials, a small number of subjects have
demonstrated marked increases in aggression measures with
the use of supraphysiologic doses of testosterone, while
a majority of participants show little or no change,
leading to speculation that high doses of androgens might
provoke rage reactions in a subset of individuals with
pre-existing psychopathology. Kouri et al. [88] reported
that administration of supraphysiologic doses (600 mg
weekly) of testosterone enanthate to healthy, young men
was associated with a significant increase in
aggressive responses to provocation than placebo
administration. Testosterone doses that approximated the replacement
doses or were slightly above the replacement dose did
not produce significant changes in aggressive response
in this experimental setting [88].
A wide range of psychiatric side effects, including
increased aggression and hostility, and mood
disturbances (e.g. depression, hypomania, and psychosis)
have been reported among androgen users [91]. Dependence and withdrawal effects (such as depression)
occur in a small number of steroid users.
Dissatisfaction with the body and low self-esteem is common among
androgen users and may predispose these individuals to
the abuse of muscle building drugs [91]. Both increased
and decreased sexual desire and function have been
reported [61].
Breast tenderness and breast enlargement
("bitch tits" in street parlance) are frequently associated with
the use of aromatizable androgens. It is not
uncommon for athletes to use an aromatase inhibitor or an
estrogen antagonist in combination with androgens to
prevent breast enlargement.
The long-term suppression of the
hypothalamic-pituitary-testicular axis with its attendant risk of
dependence and continued use of androgens is a serious
complication of androgen use that has not been widely
appreciated. Androgen administration suppresses
endogenous testosterone and sperm production by
suppressing the hypothalamic-pituitary-testicular axis [92,
93]. Men using androgens may experience subfertility
or infertility [94]. The recovery of the
hypothalamic-pituitary axis after discontinuation of the exogenous
androgen, may take weeks to months, depending on the dose and duration of prior androgen use
[95_98]. During the period immediately after discontinuation of
androgen use when circulating testosterone levels are
low, the users experience symptoms of androgen deficiency, including loss of sexual desire and function,
lack of energy, depressed mood, and hot flushes.
Some patients may find these withdrawal symptoms difficult
to tolerate and may revert back to using androgens,
thus perpetuating the vicious cycle of abuse, withdrawal
symptoms, and dependence [96_98]. Others may resort to off-label use of aromatase inhibitors or hCG
obtained illicitly based on the presumption that these
agents accelerate the recovery of the
hypothalamic-pituitary-testicular axis, although there is no evidence to
support this premise and it is possible that the use of
hCG may delay the ultimate recovery of the hypothalamic-pituitary-gonadal axis.
Self administration of intramuscular injections
increases the risk of infection, muscle abscess, and even
sepsis [20]. Transmission of HIV infection has been
reported among anabolic steroid users presumably because
of needle sharing or the use of improperly
sterilized needles and syringes.
Excessive muscle hypertrophy without commensurate adaptations in the associated tendons and
connective tissues may predispose athletes using
androgens to the risk of tendon injury and rupture and
unusual stress on joints [99].
A vast majority of androgen users also abuse
additional drugs [19]. Some of these additional drugs of
abuse, such as cocaine, amphetamine, and ephedra may
be associated with potentially serious complications.
6 Detection of illicit androgen use
Thirty four laboratories around the world have been
accredited by the International Olympic Committee to
perform doping tests. Traditional radioimmunoassay
techniques were used initially to detect androgens in
the urine specimens. However, since 1981, the accredited laboratories have used either gas
chromatography-mass spectrometry (GC-MS) or in some
instances liquid chromatography mass spectrometry
(LC-MS) to detect androgen or their metabolites that show
poor gas chromatographic properties or are temperature labile [100]. Also, during the past ten years, the
introduction of the high resolution mass spectrometry
(HRMS) and tandem mass spectrometry (MS/MS) has further improved the sensitivity of androgen steroid
detection techniques. Derivatization of samples is
often used to improve the sensitivity of the gas
chromatography [101]. Thus, silylation reaction converts the
polar groups such as hydroxyl and keto groups to less
polar trimethylsilyl ethers and improves the signal to
noise ratio [101].
For detection of testosterone abuse, the analysis
of testosterone to epitestosterone ratio in conjunction
with isotope ratio combustion mass spectrometry is
used [102_109]. Urinary testosterone to epitestosterone
ratio typically is less than 6 and is constant in any
individual. There are genetic differences in
testosterone to epitestosterone ratio. Administration of exogenous
testosterone increases the urinary excretion of
testosterone glucoronide and increases the testosterone to
epitestosterone ratio. Testosterone to epitestosterone
ratio greater than 4 is viewed suspiciously. Ratios greater
than 4 need evaluation of previous urine samples or
additional urine samples obtained after a time
interval. If the high ratio is due to genetic variation, then all
samples obtained from the subject would show the high
ratio. A high testosterone to epitestosterone ratio that is
higher than that observed in previous samples is viewed
as a positive test.
If the results of the testosterone to epitestosterone
ratio test are abnormal and suggest exogenous
testosterone use, then additional confirmation by using gas
chromatography combustion isotope ratio mass
spectrometry is required [101, 104]. This method is based on
the measurement of 13C/12C isotope ratio in testosterone.
In nature, 1.1% of carbon exists as 13C. Synthetic androgens are synthesized from plant sterols
diosgenin and stigmasterol that have less 13C than their
endogenous homologs. Therefore, synthetic testosterone, in a manner similar to other synthetic
organic compounds, has lower 13C to 12C ratio than a
reference gas standard. During the course of the GC
combustion isotope ratio mass spectrometry, the steroids
are separated by gas chromatography and oxidized to
carbon dioxide in a combustion chamber. The ratio of
13CO2 (m/e 45) and 12CO2 (m/e 44) is monitored in an
isotope ratio mass spectrometer, and the δ value is
calculated (δ value refers to the decrease in 13C relative to
the reference gas with a standardized 13C to 12C ratio)
[110]. A negative δ value along with a high
testosterone to epitestosterone ratio suggests exogenous
testosterone administration.
The procedures for the collection and
transportation of samples for doping tests follow strict rules that
have been established by the individual sports
organizations [101]. Typically, each urine sample, collected
under direct visual oversight of an accredited supervisor,
is divided in to two parts (A and B samples) and
transported to the testing laboratory using strict
"chain of custody" procedures. If A sample is deemed positive,
then B sample is analyzed in the presence of the athlete
or an authorized representative of the athlete. If B
sample is also positive, then doping with an androgen is
confirmed, and the sports organization can impose
punitive sanctions [101].
Some controversy has erupted recently over the
large number of positive tests for nandrolone. Small
quantities of nandrolone, 17beta-hydroxy-19-nor-4-androsten-3-one, and its metabolite 19-norandrosterone,
are excreted in the urine naturally in men. The
International Olympic Committee has established a threshold
level of 2 ng/mL for 19-norandrosterone. Levels higher
than this threshold have been reported in some
individuals eating a high meat diet in conjunction with
intense resistance exercise [111] and in individuals
ingesting dietary supplements such as
delta4-androstenedione [112].
7 The abuse of androgen precursors and designer
androgens
7.1 δ-4-androstenedione
δ-4-Androstenedione is a precursor of testosterone
that is converted by the enzyme 17beta hydroxy-steroid dehydrogenase to testosterone.
Androstenedione witnessed a brief period of rapid growth in sales
following Mark McGuire's admission of its use during an
extraordinary season replete with 68 home runs.
Under the Dietary Supplement Health and Education Act
passed by the US Congress, for many years, androstenedione was sold over the counter as a dietary
supplement [113_114]. Unlike other androgens, whose sales
were regulated within the dictates of Anabolic Steroid
Control Act, androstenedione's sales had not been
subject to regulatory oversight of Food and Drug
Administration and Drug Enforcement Agency. However, the
US Congress recently added androstenedione to the list
of banned anabolic steroids and it is no longer sold over
the counter.
Administration of 100 mg androstenedione orally
daily is associated with little or no change in
circulating testosterone concentrations, while administration
of 300-mg dose produces only modest increments in testosterone area-under-the-curve. However, Jasuja
et al. [115] demonstrated that 500-mg
androstenedione administered thrice daily for 12-weeks to hypogonadal
men increased serum testosterone and free
testosterone concentrations into the eugonadal range, and
increased fat-free mass and muscle strength. Similarly,
in women, administration of 100-mg androstenedione
significantly increased serum testosterone
concentrations above the physiologic range for women [116].
In female hyenas and several other mammalian species,
circulating concentrations of androstenedione are higher than those in male members of these species
and are associated with virilization of external
genitalia and increased aggression [117]. Jasuja
et al. [115] demonstrated that androstenedione binds androgen
receptor albeit with a substantially lower binding
affinity than testosterone, and that it promotes myogenic
differentiation in a mesenchymal, multipotent cell line.
Thus, androstenedione meets all the criteria for an
anabolic steroid: it has structural resemblance to
testosterone, it binds androgen receptor, and it promotes
myogenic differentiation in vitro and when administered in
sufficiently high doses, it increases muscle mass [115]. Based on these data, the US Congress recently
classified androstenedione as an anabolic steroid and
banned its over the counter sales.
Androstenedione administration produces substantial increments in serum estradiol and estrone
concentrations [116, 118_121]. Most of the orally
administered androstenedione is inactivated during its
presystemic metabolism as indicated by a marked increase in its urinary metabolites, including testosterone
glucuronide with only a small increase in serum
testosterone [122].
The over the counter preparations of
androstenedione have not been subject to the rigorous quality
control required of the FDA-approved pharmaceuticals
[123, 124]. Substantial variability has been observed in
androstenedione content of different preparations and
among different batches from the same manufacturer
[112, 125]. Some batches of over the counter
androstenedione have been found to contain one or more banned
androgens such as nandrolone; thus, ingestion of
androstenedione may result in the doping tests becoming
positive [112].
7.2 Potential adverse effects of androstenedione
The long-term side effects of androstenedione use
are unknown. Short term administration of androstenedione is associated with a significant increase in
estradiol levels. The long-term consequences of the
marked increase in estrogen levels in men taking
androstenedione are unknown. In men, the increases in
serum estrogen concentrations may potentially affect
semen quality, increase inflammatory markers, cause
gynecomastia, and induce epigenetic and cytogenetic
effects on sperm.
The supplementation of androstenedione decreases
HDL levels and increases low-density lipoprotein
(LDL)/HDL ratio. Other adverse effects of androstenedione
stem from the potential increase in testosterone levels.
These may include adverse effects on plasma lipids,
erythrocytosis, acne, sleep apnea, and increased risk
of detecting prostate events.
Given the lack of efficacy data and total absence of
long term safety data, the use of androstenedione is not
clinically recommended for any indication, including the
treatment of androgen deficiency in men or women.
7.3 Dehydroepiandrosterone (DHEA)
DHEA is a weak androgen by itself, but it is
converted in peripheral tissues to testosterone and estradiol.
In addition to being a weak androgen and an androgen
precursor, DHEA has been shown to function as a neurosteroid
[126].
DHEA binds androgen receptor with a binding affinity that is substantially lower than that of
dihydro-testosterone (DHT). A separate G-protein coupled
membrane receptor for DHEA has been proposed [127];
however, the existence of such a DHEA-specific membrane receptor has not been
confirmed. DHEA also has been shown to modulate the activities of
N-methyl-D-aspartate (NMDA) and γ-amino-butyric acid (GABA)
receptors [128].
The literature on DHEA is difficult to
interpret. DHEA studies in rodents have limited applicability to
humans, because rodents have very little endogenous
circulating DHEA. Many DHEA studies reporting beneficial neurotropic and anti-cancer effects, and immune
enhancement were conducted in rodents.
The human trials of DHEA have been characterized
by heterogeneity of doses, formulations, and study
populations. DHEA studies have been conducted in
patients with adrenal insufficiency [129_133], older men
and women [134_139], peri- and post-menopausal women
[140, 141], and in patients with autoimmune disease
[142_144]. These trials used doses as high as 1500 mg daily and as low as 25 mg daily. Most human
trials used 50 mg DHEA daily for three to six months,
included small samples, and were of relatively short
durations.
A Cochrane review of DHEA trials concluded that
there was insufficient evidence of beneficial effect of
DHEA on cognition in older men and women [138,
139]. One randomized trial has reported greater improvements
in bone mineral density in older men and women receiving 50 mg DHEA daily than with placebo
[145].
DHEA trials in women with adrenal insufficiency
have yielded inconsistent results. Arlt et
al. [129] used a double-blind, placebo-controlled, crossover study
design in women with primary or secondary adrenal
insufficiency who received either placebo or 50 mg DHEA
daily for 16 weeks each. DHEA administration was associated with improvements in scores for depression
and anxiety, sexual function, and circulating osteocalcin
levels, but no significant changes in body composition
[122]. Other trials of DHEA supplementation in women
with adrenal insufficiency failed to confirm the
beneficial effects of DHEA on mood, well being or sexual
function that were observed in the Arlt study
[130_132]. DHEA has not been shown to consistently improve body
composition, physical function, or insulin
sensitivity. The effects of DHEA administration on cardiovascular
event rates or cancer incidence rates are unknown.
In a placebo-controlled trial that used
pharmacological doses of DHEA (200 mg daily), modest
improvements in lupus outcomes and a greater reduction in
disease flares and disease activity were reported in
patients receiving DHEA than in those receiving placebo
[142_144]. The effects of DHEA on bone mineral
density in patients with SLE have been inconsistent.
Thus, the efficacy of DHEA has not been
demonstrated in any disease state and DHEA use cannot be
recommended for any clinical indication at present.
7.4 Other androgen precursors and designer steroids
Precursors of testosterone (4-androstenediol and
5-androstenediol in addition to 4-androstenedione and
DHEA discussed above), dihydrotestosterone
(5-alpha-androstane-3beta-17 beta-diol, 5-alpha-androstane-3
alpha, 17 beta diol, 5-alpha-androstane-3, 17 dione,
5-alpha-androst-1-ene-3, 17 dione, 17
beta-hydroxy-5-alpha-androst-1-en-3-one, 5-alpha-androst, 1-ene, 17
beta-diol) or nortestosterone (4-norandrostenedione,
4-norandrostenediol, and 5-norandrostenediol) [101] that
are weakly androgenic by themselves, but that are
converted in the body to potent androgens, have become
available on the internet. Even a precursor
(androsta-1,4-diene-3, 17-dione) of boldenone
(17-beta-hydrox-yandrosta-1, 4-dien-3-one) has been introduced [101].
The androgens abused by athletes had been
synthesized initially for medicinal or veterinary indications.
However, recent years have witnessed the appearance
of designer steroids, such as tetrahydrogestrinone
(THG) [146, 147] and madol [148] that were
developed solely for abuse [149]. The detection of these novel
androgens has proven challenging to the testing
laboratories because detection methods have not been
standardized for these new designer androgens. These
designer compounds have not undergone any formal
toxicological or safety testing in animals or humans;
consequently, their growing use by athletes poses
significant health concerns. The government agencies have
found themselves stymied in their efforts to regulate
this underground marketplace of designer steroids
because there are no published data with the use of these
novel designer steroids, and generating new data of their
androgenic and anabolic efficacy that would withstand
scientific and legal scrutiny is a time consuming and
laborious task.
8 Conclusion
The abuse of androgens by athletes and recreational
body builders is wide spread and worldwide. Androgens increase skeletal muscle mass through their
effects on mesenchymal stem cell differentiation through
an androgen receptor-mediated mechanism. In spite of
significant improvement in detection methods, the
problem of doping in sports is unlikely to disappear anytime
soon because of societal values and economic incentives that emphasize winning at all costs and because
of the lack of will on the part of governments
throughout the world to enforce stricter screening and penalties.
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