NAMA : juni suhada

NIM : 24089094

HARI / TANGGAL : selasa / 06 mei 2025

MATKUL : Farmakologi dan Doping

Tugas Minggu ke- 9

Ringkasan Bab 9. Agen Anabolik

Introduction
Anabolic agents are a classification of substances on the WADA
Prohibited List comprising of largely anabolic androgenic
steroids . Despite the fact that these substances were first
developed over 70 years ago, their efficacy is such that they
remain a popular choice of doping agent. Whilst research over
recent decades has confirmed the anecdotal evidence and
belief that many users held in terms of their efficacy, there
remains some conjecture regarding their purported side
effects. Clearly, research conducted to mirror their use by
athletes and recreational users alike is difficult as a
consequence of the extremely high, supra-physiological doses
administered in practice.

Whilst methods of detection for such substances have

developed throughout the years athletes have attempted to
circumvent such methods by turning to ‘designer steroids’. In
addition the use of endogenous AAS, such as testosterone,
androstenedione and dehydroepiandrosterone pose their own
specific problems with regards to detection as a consequence
of their natural occurrence in the body. As therapeutic agents
AAS use is limited but tends to centre on their anabolic
properties. In addition to AAS, under the classification of
anabolic agents on the Prohibited List there are β2-agonists,
including clenbuterol and zilpaterol, selective androgen
receptor modulators , and tibolone and zeranol .

Anabolic androgenic steroids

Whilst testosterone was first isolated in 1935 it was soon
realised that when administered orally or parentally
testosterone was broken down rapidly by the liver by first pass
metabolism. Since the effects of testosterone were believed to
be extensive both from an androgenic and anabolic perspective
there was great interest in its potential as a therapeutic agent.
However, as a non-therapeutic agent its use as an anabolic
agent was to be exploited in sport.

Testosterone
Testosterone is the primary male androgenic hormone,
responsible for the control of a wide range of processes, most
notably the development and maintenance of male
characteristics. Testosterone is produced largely in the testes
by the Leydig cells but also by the adrenal glands and via
conversion from weaker androgens such as androstenedione in
the periphery. After puberty, plasma testosterone levels are
approximately 250 to 1,045ng. As with males, testosterone has
an important role in the development and maintenance of lean
body mass in females.
Testosterone also affects the central nervous system and has a
significant role to play in human behaviour, particularly sexual
behaviour, namely libido. Whilst testosterone is considered the
primary androgen, it is by no means the only one, with a
number of androgens serving important roles in both the
development and maintenance of sex determining
characteristics. After testosterone, 5-dihydrotestosterone is
probably the most notable androgen and with a greater affinity
to the androgen receptor it has a direct role in the
development of secondary sex characteristics. Indeed
testosterone typically acts as a precursor to DHT in
reproductive tissue and the skin where the presence of 5-
reductase mediates its conversion, promoting prostate gland
and hair growth respectively.
In addition to the intracellular enzyme, 5-reductase in the skin
and reproductive tissue the presence of aromatase converts
testosterone into oestradiol in adipose tissue. In skeletal
muscle, however, 5-reductase is undetectable and therefore
testosterone exerts its effect directly via ARs. Testosterone
production is controlled by the hypothalamic-pituitary-gonadal
axis. Specifically, testosterone is produced in response to
luteinising hormone and folliclestimulating hormone secreted
by the pituitary gland.
Testosterone circulates in the bloodstream either freely or
bound to proteins such as sex hormone-binding globulin or
albumin. Testosterone bound to SHBG is essentially inactive
due to the high binding affinity of these molecules and the fact
that in this state testosterone is unable to penetrate the cell
walls of target cells. However, free testosterone and that which
is weakly bound to albumin is deemed to be bioavailable since
in its free form it may penetrate the cell wall and bind with the
AR. Clearly, such modifications aim to improve both the efficacy
of testosterone as an anabolic agent and its mode of
administration.
Whilst the anabolic potency, compared to testosterone, may
have been increased in some AAS, the disassociation from
androgenic effects has not been achieved and therefore as
performance and image enhancing drugs they all carry
potential androgenic side-effects. Testosterone has a 19-carbon
skeleton consisting of four fused rings, which may be commonly
modified at three positions to create synthetic AAS . Such
modifications include esterification of the 17-β-hydroxyl group
to form a group of AAS collectively known as testosterone
esters. Testosterone esters have enhanced lipid solubility and
when administered intramuscularly they are released slowly
into the circulation thus enabling prolonged activity and
reduced hepatotoxicity.
Structural modifications to other positions on the testosterone
skeleton will tend to increase anabolic potency. In addition to
testosterone, the naturally occurring 18-carbon AAS, 19-
nortestosterone is considered a doping agent and so too are its
modifications particularly its decanoate ester known as Deca-
durabolin . As a PIED nandrolone is attractive since it has less
androgenic effects in comparison to other AAS as it is not
converted to DHT and its 5-reductase metabolite, 19 nor-
dihydrotestosterone, has a low binding affinity to the AR .

Clinical uses of anabolic androgenic steroids

Despite the wide-ranging effects of AAS in terms of stimulating
not only muscle growth but also bone and red blood cell
production their current use in clinical settings is limited. Whilst
the traditional use of AAS was to promote muscle growth in
those with degenerative conditions their effectiveness has been
questioned. Remaining AAS are typically used in hormone
replacement therapy in males with hypogonadism. , research
involving AAS had significant shortcomings, which limited its
potential for making a significant impact on the field.
was able to clearly demonstrate that individuals who were not
deficient in testosterone could increase both muscle mass and
function following the administration of supraphysiological
doses of testosterone enanthate. Whilst exercise training was
shown to have an additive effect on muscle growth and
function, significant increases were still demonstrated in those
who did not perform exercise training. The potential anti-
catabolic effect relates to the fact that the release of cortisol in
response to heavy exercise has a catabolic effect as regards
skeletal muscle. Cortisol is released from the adrenal cortex in
response to stress to aid energy provision.
This is achieved by promoting gluconeogenesis in the liver and
the provision of gluconeogenic substrate in the form of protein
through the breakdown of skeletal muscle. Clearly, the ability
of AAS to limit the effects of cortisol might have a profound
effect on skeletal muscle growth and function. Clearly,
hypertrophy through genomic pathways is reliant on the
apparatus within myonuclei. Muscle fibres contain hundreds of
myonuclei however, there is thought to be a ceiling in terms of
the level of skeletal muscle hypertrophy, supported by a finite
number of myonuclei.
It is therefore suggested that by increasing myonuclei number,
AAS are able to enhance hypertrophy . Research recently has
provided evidence in support of the view held by many that the
performance enhancing effects of AAS last for much longer
than the period of administration. demonstrated, in an animal
model, that increased myonuclei numbers following the
administration of AAS are not lost during atrophy in response to
AAS abstinence and that following subsequent training there
was significant hypertrophy compared to a control group. This
research suggests that the increased myonuclei are an
important reserve that directly relate to hypertrophic potential,
which is much greater in those that have used AAS.
Further research is clearly needed to determine whether these
findings might be transferable to humans.If this is found to be
the case then it would be particularly significant from an anti-
doping perspective in terms of the consideration of appropriate
sanctions imposed on those caught misusing AAS . Whilst the
work by Bhasin and colleagues was able to show unequivocally
that AAS were effective as a PIED, the mechanisms by which
this result is achieved are complex. AAS, known to play an
important role in sexual behaviour in both male and females,
are also believed to be important in elevating mood and
reducing depression.

Liver effects
Whilst raised hepatic enzymes may signal toxicity they may fall
over time and hide the real extent of injury during prolonged
AAS exposure. The condition of peliosis hepatis is a vascular
condition, which is characterised by the development of blood
filled cysts throughout the liver and has been reported in
numerous cases involving AAS use .
Reproductive system effects
In females, suppressed secretion of gonadotrophins leads to
menstrual irregularities and increased circulating androgens
leads to clitoral hypertrophy following long-term AAS use.
Similarly, in females the menstrual cycle will recommence soon
after AAS use is discontinued. Cosmetic effects are most
pronounced in females as AAS result in an overall masculinising
effect, which may be irreversible following the discontinuation
of the drugs . Chronic use of AAS may produce male pattern
baldness, which has been reported in both males and females.
Acne is a common condition reported by many AAS users due
to androgenic stimulation of the sebaceous gland.
Consequently, users will often co-administer Tamoxifen, a
selective oestrogen receptor modulator , to combat such side
effects . During abstinence from AAS, users have been reported
to exhibit anxiety and depression , deemed to be attributed to
the low circulating levels of endogenous AAS as a consequence
of reduced production occurring in light of prior sustained
circulating exogenous AAS. Side effects that are prevalent
amongst AAS users that are not directly related to the doping
agent per se include those associated with inappropriate drug
administration.
Needle sharing and use of non-sterile equipment is a particular
issue amongst AAS users, which poses serious risks in terms of
infection and the acquisition of blood-borne diseases such as
hepatitis and HIV/AIDS . Possibly the greatest risk to AAS users
are the unknown health risks associated with the use of
products obtained from the illicit market. The illicit market
contains drugs that are no longer licenced, those that are
marketed as veterinary products, new drugs that have not been
fully tested and AAS that have not been authorised but
developed as part of pharmaceutical research projects . In
addition to a wide range of AAS that do not carry with them the
required safety checks and information that exists with licenced
products there are real concerns relating to the sterility and
authenticity of such products.
Use of anabolic androgenic steroids in sport
Whilst there is uncertainty as to who were the first to use AAS
in sports competition it is suggested that the 1950s heralded
the beginnings of their use in sport . In 1954 it is alleged that
Russian athletes under the influence of AAS won numerous
gold medals in the World Weightlifting Championships in
Vienna. Throughout the 1950s and 1960s AAS use escalated
and whilst the IOC introduced the first list of prohibited
substances in 1967 it was not until 1976 that AAS were added
to the list following the development of a reliable test for their
detection in urine in 1974. Following the reunification of
Germany in 1990 it was revealed that the German Democratic
Republic had run a systematic doping programme as part of
their state-run sports programme.
Particular emphasis was placed on females and their
performance where the effects of AAS are more pronounced.
The real impact of such a programme is, however, illustrated by
the incidence of serious doping-related side effects, many of
which are irreversible. The inquiry was to last one year and
included the admission of AAS use by 48 athletes and
recommendations that would help to improve doping control
globally through increased and improved drug testing and
stricter penalties for those who violate the rules . They are
designed specifically to circumvent routine anti-doping tests as
their existence as doping agents is unknown.
In the early part of this century several international athletes,
including sprinters Marion Jones, Dwain Chambers and Kellie
White, were convicted for the use of tetrahydrogestrinone , a
designer steroid. This case was part of what became known as
the BALCO affair whereby a newly developed AAS was
manufactured and distributed to numerous athletes from the
Bay Area Laboratory Cooperative in California, led by its
founder, Victor Conte . Other than use by elite athletes and in
competitive sport there is evidence of growing, widespread use
of AAS at a recreational level including among those engaged in
gym exercise and bodybuilding. Indeed much of the
information we know regarding efficacy and adverse health
effects is centred upon the anecdotal evidence obtained from
the gym community.
The illicit market consists of products that may come from
several sources. Products that are deemed to be legitimate may
be manufactured in countries where the purchase of such non-
prescription drugs is legal or where products have entered the
market as a result of theft. Alternatively, products may be
manufactured in clandestine laboratories outside of any
regulatory system . The trade in substandard and counterfeit
products is a particular problem.
Such products are a significant health concern since their
quality and thus safety cannot be guaranteed. In addition to the
sub-standard manufacturing of many products there is a real
issue concerning counterfeiting, that is deliberately mislabelling
products so there are no assurances that the alleged
ingredients are present and in the correct quantity. This issue
has been highlighted extensively in the research literature and
appears to be a particular issue with respect to nutritional
supplements .
Injectable oil-based preparations have a longer half-life but
produce a degree of pain at the injection site, have a slow
absorption rate into the blood stream, so that lower
concentrations pass through the liver, thereby reducing liver
toxicity. Injectable water-based steroids have a long half-life,
though normally less than oil-based preparations, produce less
discomfort at the site of injection and can be mixed with other
water-based steroids or other drugs . Topical gels or patches
result in low dose administration of un-modified testosterone
which has a short half-life requiring daily application. There are
a number of administration regimes in use, known as ‘cycling’,
‘pyramiding’ and ‘stacking’.
Experienced users will typically follow a combination of these
regimes concurrently. Each regime is reputed to offer a
particular advantage in terms of heightening the effect of a
particular drug or limiting the potential side effects
experienced. Cycling is the administration of a particular drug
over a period of time followed by a period of abstinence before
the administration is recommenced. Cycling patterns are
typically short or long .

Prevalence of anabolic androgenic steroid use

Most evidence in elite sport comes from data obtained from
WADA-accredited laboratories, which highlights on a yearly
basis the number of positive drug tests, according to the
specific anabolic agent . Whilst such data cannot provide an
accurate estimate of absolute numbers administering AAS, they
do reveal quite clearly that AAS remain an important choice for
those looking to enhance sports performance illegally. Recent
data suggests that AAS comprise half of all adverse analytical
findings and atypical findings reported by WADA-accredited
laboratories . In the United States prevalence rates would
appear to be higher, with 2.7 per cent of children attending
middle schools indicating that they had used AAS .
Use of AAS was reported in all regions, with a total of 7.7 per
cent of gym users admitting to taking AAS, of which 5 per cent
were current users . found that from a sample of 621 fitness
centre visitors 13.5 per cent reported the use of ‘anabolic
ergogenic substances’ , comprising 19.2 per cent males and 3.9
per cent females. Indeed, there is evidence of increased
prevalence of body dissatisfaction and low self-esteem amongst
males with respect to the level of musculature, which has been
termed muscle dysmorphia . The focus on enhanced
musculature is coupled with an increase in the use of image-
enhancing drugs such as AAS , particularly amongst gym users.
Unfortunately, as with elite sport, it is difficult to establish
reliable figures in terms of prevalence of AAS use. Data from
harm reduction programmes, such as needle exchange clinics,
offer some indication to the extent of use. In addition to
examining AAS use in gymnasia, Korkia also surveyed syringe
exchange clinics. Of the 88 clinics that responded 59 per cent
declared that AAS users had contact with the clinic.
Later, McVeigh and colleagues revealed an increase in
individuals attending syringe exchange clinics in the northwest
of England for AAS injecting equipment between the years 1991
and 2001. Such increases cannot necessarily be attributed to
increased AAS use but clearly illustrate the success of harm
reduction programmes in attracting different types of
recreational drug users.

Designer steroids
Tetrahydrogestrinone , otherwise known as ‘the clear’, was
supplied as a sublingual AAS preparation by BALCO, a US-based
company, to athletes for the purpose of enhancing
performance. Several high profile athletes tested positive for
THG and many others were implicated in the affair and
consequently received sanctions including suspension from
competition. In addition to track and field athletes, American
football players tested positive for THG and baseball players
were implicated in the affair. In addition several athletes were
convicted of perjury under state law, in the US.
Victor Conte and several coaches were convicted for their part
in the distribution of AAS to athletes and received sanctions
under state law, including imprisonment. Probably the first
designer steroid, however, was
dehydrochloromethyltestosterone , which was used by former-
GDR athletes as part of their state-run doping programme .
Their use by athletes therefore poses a significant, yet unknown
threat to health.

Prohormones
Increased circulating testosterone is then thought to impact
positively on skeletal muscle hypertrophy and function. Whilst
there is evidence to show that the ingestion of prohormones
can increase the circulating levels of DHEA and Andro, resultant
significant elevations in the circulating pool of testosterone has
only been demonstrated in females . This could be explained by
the fact that in females a significant proportion of circulating
testosterone is as a consequence of peripheral conversion of
weaker androgens, namely DHEA . However, in males,
circulating testosterone is almost entirely based upon its
production in the gonads .
Despite the positive outcomes, in terms of increased circulating
testosterone in females, there has been no indication that this
might manifest itself in gains in muscle size and strength .
revealed an adverse effect on blood lipid profiles and increased
levels of circulating oestrogens following the administration of
300mg. D-1 administration of Andro over an eight-week period.
Clearly, such widespread availability poses problems in terms of
both the intentional and unintentional use of AAS in elite
athletes and potential failed drug tests as a consequence.

Detection of anabolic androgenic steroids

Detection of exogenous AAS is generally based upon direct
quantification of a particular AAS and its metabolites in urine.
However, in the case of endogenous AAS it is reliant on the
investigation of various steroid profiles in order to establish
possible androgen misuse. The concentration of testosterone
and its stereoisomer, epitestosterone, is determined together
with additional endogenous androgens, including
androsterone, etiocholanolone, 5-androstane-3,17β-diol and
5β-androstane-3,17β-diol . In addition to reporting endogenous
AAS, ratios of several endogenous androgens are also
determined, including the ratio of testosterone to
epitestosterone , androsterone to testosterone , 5Adiol to
5βdiol and 5Adiol to epitestosterone.
An individual steroid profile is established as part of the
steroidal module of the Athlete Biological Passport . Alteration
of the endogenous androgens or ratios may constitute doping
and further confirmatory analysis maybe warranted . Micro-
dosing using topical application of testosterone via dermal
patches and gels is a particular concern to anti-doping
personnel not least because of the short half-life of the drug
and thus the potential to evade a positive drugs test.

Selective Androgen Receptor Modulators

Consequently their chemical characterisation and methods for
their detection have been developed . Indeed, recent anti-
doping testing figures confirm that SARMs have been detected
in doping control samples thus providing clear evidence of their
misuse in sport . Selective androgen receptor modulators may
offer a possible advantage over AAS both clinically and as PIED
due to their potential for tissue selectivity and in promoting
anabolic rather than androgenic effects. Several drugs classified
as β2-agonists are also included on the WADA Prohibited List as
anabolic agents, namely clenbuterol and zilpaterol .

The consumption of meat infected with prohibited growth

promoters and the impact on doping control
This is an obvious concern to athletes subject to doping control
tests. demonstrate that there is a real possibility that
consuming meat from cattle that have been given clenbuterol
may lead to a positive drugs test. In light of this, they suggest
the need to introduce a threshold for clenbuterol in an attempt
to limit the possibility of an inadvertent doping offence. An
alternative approach to limit inadvertent doping requiring
further research might be to differentiate between clenbuterol
from direct pharmaceutical origin and that from ingested food .
It is ironic that there is now concern regarding the possibility of
false positives from a doping perspective as a direct
consequence of improved analytical methods. The potential to
detect minute traces of prohibited substances brings in to
question the anti-doping movement’s guiding principle of strict
liability, particularly as the possibility of prohibited substances
entering the body unintentionally, in such small quantities, is
considered significant. During the 2011 FIFA U17 World Cup
clenbuterol was detected in over half of the doping control
samples. Whilst there have been cases of its presence in doping
control samples there is suggestion that this might be as a
consequence of food contamination with a mycotoxin,
zearalone .

Summary
Whilst the WADA classification of Anabolic Agents consist of
some new and emerging drugs of abuse, AAS remain the major
class of drugs misused by many who seek improvements in
terms of muscle size and strength. Potentially the most
disturbing issues in relation to the non-therapeutic use of
anabolic agents is the availability of ‘black market’ products
where there is no evidence of their legitimacy and thus their
safety.

Ringkasan Bab 10.

Peptida Hormon, Faktor Pertumbuhan, dan Zat
Introduction
The World Anti-Doping Agency prohibits the use of
a number of peptide hormones and related
substances , most of which occur naturally in the
body.
Table 10.

Erythropoietin-receptor agonists
Erythropoiesis-stimulating agents including
e.g.Darbepoetin ;Erythropoietins ;EPO-Fc;EPO-mimetic peptides
, e.g. CNTO 530 and peginesatide;GATA inhibitors, e.g. K-
11706;Methoxy polyethylene glycol-epoetin beta ;Transforming
Growth Factor-β inhibitors, e.g. sotatercept, luspatercept;
Non-erythropoietic EPO-receptor agonists, e.g.ARA-290;Asialo
EPO;Carbamylated EPO.
HIF activators, e.g. argon and xenon.
Chorionic gonadotrophin and luteinizing hormone and their
releasing factors, e.g.
buserelin, gonadorelin and leuprorelin, in males.
Corticotrophins and their releasing factors, e.g. corticorelin.
Growth hormone and its releasing factors including
• Growth hormone releasing hormone and its analogues, e.g.
CJC-1295, sermorelin and tesamorelin;
• Growth hormone secretagogues , e.g. ghrelin and ghrelin
mimetics, e.g. anamorelin and ipamorelin;
• GH-releasing peptides , e.g. alexamorelin, GHRP-6, hexarelin
and pralmorelin .
152 David R.
This class of substances includes hormones with significant
effects on the body, particularly in the early stages of bodily
development. The primary medical uses for these substances
include treatment of chronic kidney disease, acute anaemia,
short stature and aiding those born prematurely. Inappropriate
use of these potent agents by athletes carries severe potential
side effects and health risks.

Erythropoiesis-stimulating agents
Erythropoiesis-stimulating agents include the endogenous
peptide erythropoietin , which is commercially available as
recombinant-EPO and the synthetically produced darbepoetin
and methoxy polyethylene glycol-epoetin beta .Mode of action
of erythropoietin EPO increases oxygen supply to muscles,
thereby increasing an athlete’s endurance and performance .
EPO works synergistically with other growth factors to cause
maturation and proliferation of red blood cell precursors. The
net effect is an increase in the number of red blood cells that
are produced and in the rate at which they are released into
the circulation. Consequently, EPO increases the oxygen supply
for muscle tissue, allowing muscles to work longer before they
build up lactic acid .Recombinant erythropoietinThe gene
responsible for the synthesis of erythropoietin was cloned in
1985. Recombinant human erythropoietin was first patented by
Amgen in 1989. There are currently three generations of
rHuEPO in production, the prototype , novel erythropoiesis
stimulating protein and continuous erythropoietin receptor
activator . Second generation NESP differs from EPO in having
an additional 8-sialic acid residue. Third generation CERA differs
in having a long polymer chain incorporated into the molecule.
These genetically engineered modifications have increased the
elimination half-lives from 8.5 to 25.3 to 142 hours,
respectively. This has decreased the frequency of initial
intravenous dosing from three times weekly to once weekly to
once every two weeks, respectively.

Adverse effects of ESAs

EPO poses significant short- and long-term health problems to
the abuser. Adverse effects of recombinant human EPO include
injection site reactions, nausea, headache, dizziness, arthralgia,
allergic and anaphylactic reactions . Since ESAs stimulate
erythropoiesis, the resulting increase in red blood cells
increases the viscosity of the blood and therefore raises the risk
of microcirculation blockage , heart failure and strokes .EPO-
stimulated erythropoiesis vastly augments the demands of the
sportsperson for ferrous iron for the synthesis of haemoglobin.
To meet such demands, iron must be injected, leading to
potential iron overload. There is evidence from both France and
Italy that elite cyclists have exhibited ferritin levels indicative of
severe iron overload.

Detection of EPO
The first tests for EPO at the Olympic Games were introduced in
Sydney in 2000. To be deemed culpable, the athlete had to test
positive in both blood and urine tests . In 2003, WADA’s
Executive Committee accepted the results from an independent
report that urine testing alone could be used to detect the
presence of recombinant EPO. In 2009, WADA published a
Technical Document entitled «Harmonization of the method for
the identification of recombinant erythropoietins and
analogues » in which the methodology for detection was
specified as were the results for the major commercially
available epoetins . Demonstration of the presence of an
epoetin is based upon isoelectric focusing and
chemiluminescence .These techniques may be complemented
with a further technique known as SDS-PAGE .Note that the
technique can identify not only r-HuEPO, NESP and CERA but
also biosimilars .More recently, the use of Athlete Biological
Passports to detect EPO and other hormones, using an
«endocrine module» is described by Pitsiladis et al. ; Saugy et
al. andVernec . New methods for the direct detection of ESAs
are reviewed by Reichel .Figure 10.1 Results of the detection of
erythropoiesis stimulating agents obtained using isoelectric
focusing and chemiluminescence
Figure 10.
Abuse of EPO in sportThe first reports on the clinical use of EPO
were published in 1987. The drug company Amagen received a
licence for the production of r-HuEPO in 1989. In 1990, the IOC
added EPO to the list of banned substances. Around this time,
there were several newspaper articles which linked the deaths
of 18 Belgian and Dutch cyclists with rumours of EPO abuse in
the peloton . It is unlikely that the magnitude of the increase in
red blood cell production was accurately controlled at this time
and the haematocrit may have been raised to dangerously high
levels. Values of 60 per cent were rumoured. Indeed, one
cyclist, Marco Pantani, was found to have an Hct of 60.1 per
cent when admitted to hospital after an accident in a 1995
race . This concentration would cause significant increases in
both systolic blood pressure and blood viscosity. In the short-
term there would be an increased risk of thrombosis and
stroke. In the long-term, chronically elevated Hct and blood
viscosity could lead to left ventricular hypertrophy and,
ultimately, to left ventricular failure and death.There was much
conjecture about abuse of EPO in the 1990s. The former
professional cyclist Paul Kimmage referred in his book, Rough
Ride , to such suspicions within the peloton. He also referred to
the Donati dossier , which was an account of EPO abuse
involving elite Italian cyclists. Proof of the extent of abuse of
EPO did not exist until the 1998 Tour de France in what became
known as the «Festina affair». Subsequent detention of the
Festina team soigneur Willy Voet, prompted him to publish a
personal account of drug abuse within the peloton . He stated
that provision and administration of EPO were formalized
within the team and provided evidence of drugs, doses and
deductions from salaries according to drugs administered. It is
difficult to imagine that other teams could compete with
Festina without recourse to EPO, since there was evidence of
the ergogenic benefit derived from EPO .
The ergogenic effects of recombinant human EPO were
compared to those of transfusional polycythaemia by Ekblom
and Berglund who reported that r-HuEPO increased Hb
concentration equivalent to those evoked by re-infusion of
1350 ml of autologous blood. In a later study, time to
exhaustion was increased from 49374 s to 56782 s following
doses of r-HuEPO .There have been many examples of positive
tests for ESAs from athletes in a number of different sports
including cross-country skiers, biathletes, swimmers, rowers
and athletics including marathon runners, 5000m runners,
400m runners and 400m hurdlers. Confirmation that abuse of
EPO is not restricted to participants in endurance events was
demonstrated by USA sprinters Marion Jones and Kelli White
who tested positive for EPO.Given that there are well defined
methods for the detection of erythropoiesis stimulating agents,
why do athletes continue to abuse these drugs and risk
sanctions? A possible explanation is that the athletes believe
that they can avoid detection by means of diluting red cell
concentration using plasma volume expanders. A more subtle
strategy is to a microdosing regime which renders EPO
undetectable within a short period of administration, as
demonstrated in the Lance Armstrong case . Studies by
Ashenden et al. have demonstrated that a microdose regime
could be utilised to avoid detection of EPO use even when
monitored by Athlete Biological Passport software. An
approach such as this, whilst relatively simple to conduct within
a laboratory setting, requires a degree of sophistication and
support well beyond the compass of the athlete alone. In the
past, this has been thought to involve the coaching and medical
support staff.New techniques for the detection of the use of
recombinant human erythropoietin, using biomarkers, is being
developed .Cases of EPO abuse in sportSince the first reports of
EPO use in cycling, associated with the «Festina affair» , there
have been a number of high profile cases.

Hypoxia-inducible factor stabilizers

Erythropoietin production is regulated by oxygen availability
within the body. Oxygen availability is recognised by a gene
product called hypoxia-inducible factor , which is found in the
cells that make erythropoietin. Erythropoietin levels in the body
can therefore be elevated by HIFs which increase
erythropoietin gene expression and therefore increase red
blood cell levels . Pharmaceutical companies are developing
these «HIF-stabilizers» as potential medicinal agents for the
treatment of anaemias. Such potential performance enhancing
agents have become the target for athletes who cheat, indeed,
one such HIF-stabilizer, roxadustat was detected in four cases
arising from WADA laboratory statistics for 2015 .Experimental
research has also suggested that the elements argon and xenon
can activate HIF, although their effect is considered a minor
issue . However, a more recent study on the effects of xenon on
healthy volunteers showed significant increase in
erythropoietin levels . WADA has included these elements on
their Prohibited List . Other elements, including cobalt and
nickel are potential inducers of HIF and are the target for some
athletes seeking performance enhancement. A study by Thevis
et al. , in which analysis was made of 19 products obtained
online, showed widespread inclusion within these products of
prohibited substances such as EPO, HIF stabilizers and metals
such as cobalt and nickel.

Chorionic gonadotrophin
Chorionic gonadotrophin is produced by placental trophoblast
cells during pregnancy and also by a number of different types
of tumour cell. Its major physiological role is stimulation of the
corpus luteum in pregnant females, to maintain synthesis and
secretion of the hormone progesterone during pregnancy.
However, when injected into males, CG also stimulates the
Leydig cells of the testes to produce testosterone and
epitestosterone, and so it can mimic the natural stimulation of
testicular hormone produced by luteinizing hormone . This
increase in synthesis is rapid, a 50 per cent increase in plasma
testosterone concentration has been measured two hours after
intramuscular injection of 6,000 IU of CG . Injection of CG also
stimulates production of nandrolone metabolites and this may
indicate that it can stimulate production of endogenous
nandrolone itself . An excellent review of CG has been
published by Stenman et al.

Therapeutic use
CG is used to stimulate ovulation in conjunction with FSH in
infertile women. Occasionally, CG is used to stimulate testicular
hormone production when puberty is delayed.

CG abuse in sport
CG has been used because it stimulates the secretion from the
testes of both testosterone and epitestosterone. This led to the
banning of CG by the IOC in 1987. A standard doping regime for
CG has been described in which the abuser firstly injects
testosterone. Apart from any gains in strength or
competitiveness the testosterone causesinhibition of LH
secretion from the pituitary. When testosterone is withdrawn
before competition the athlete would be at a disadvantage with
lower than normal plasma testosterone levels. However,
administration of CG stimulates testicular testosterone
secretion. In a small, elegant experiment, Kicman et al.
reproduced this situation in three normal men and showed that
CG can stimulate the testosterone substitution claimed by
abusers and retain the testosterone/epitestosterone ratio
within WADA limits. In all three cases, the CG could be detected
in the urine by radioimmunoassay as long as plasma
testosterone levels were raised. Brower described three
separate regimes to restore endogenous testosterone secretion
to normal following its suppression due to administration of
testosterone or anabolic steroids. He has recorded descriptions
of CG 50 IU/Kg producing a doubling of endogenous
testosterone secretion within three to four days of
administration.A review by Handelsman concluded that whilst
CG produces marked increases in blood testosterone levels in
men, the effects are negligible in women and therefore
prohibition and testing for CG should be restricted to men.
Handelsman et al. showed a prominent dose-dependent and
sustained effect on blood and urine CG, LH and testosterone
levels after administration of recombinant CG.They further
concluded that testosterone:LH ratio measurements may be a
sensitive test to detect CG administration for at least one week
after injection.
Side effects of CG in sport The side effects of CG will be similar
to those for anabolic steroids. However, the incidence of
gynaecomastia may be greater as CG also stimulates oestradiol
production by the Leydig cells. The increase of oestradiol may
be linked to nandrolone metabolite production in the process
of aromatization .

10.5 Luteinizing hormone and its use in sportLuteinizing

hormone is produced by the gonadotroph cells of the anterior
pituitary in both males and females. In males LH stimulates
testicular sperm production and the synthesis and secretion of
testosterone, while in females it stimulates ovulation and the
production of progesterone. There are structural similarities
between LH and CG and a detailed comparison is made by
Kicman and Cowan . LH secretion is subject to negative
feedback control by testosterone, therefore as plasma
testosterone levels rise, so LH secretion is reduced. A recent
study on the effects of single doses of recombinant LH, up to
750 IU, had no influence on serum or urine LH or testosterone
LH abuse is limited by its scarcity and its high costs and because
its plasma half-life is 50 per cent less than CG . «Designer»
synthesis of LH, a dual chain peptide, is difficult owing to the
complexity of its structure. Problems associated with the
detection of LH are reviewed at length by Stenman et al. .It is
much more likely that LH releasing hormone, the substance
regulating LH release, will become a drug of abuse. It could be
used to stimulate endogenous LH release which will in turn
stimulate the testes to secrete testosterone in males
withdrawing from anabolic steroid abuse. Brower has described
several LH treatment regimes, which could be used to restore
testosterone secretion in males suffering anabolic steroid
withdrawal syndromes or in those who need to restore normal
testosterone before an event or tes

Corticotrophins
The peptide hormone Adrenocorticotrophic Hormone is
produced and secreted by the corticotroph cells of the anterior
pituitary. It is a polypeptide consisting of 39 amino acids, of
which only the 24 N-terminal amino acids are necessary for its
biological activity. ACTH stimulates the reticularis and
fasciculata cells of the adrenal cortex to synthesize and secrete
corticosteroids such as cortisol and corticosterone.
Administration of ACTHACTH itself is never used for treatment
or abuse, instead a synthetic derivative, the peptide
tetracosactrin consisting of the first 24 N-terminal amino acids
of ACTH, is administered by injection. Tetracosactrin
administration stimulates a rise in blood cortisol and
corticosterone concentration within two hours.Abuse of
ACTHACTH abuse is limited to short term boosting of plasma
cortisol and corticosterone in an attempt to reduce lethargy
and produce «positive» effects on mood during training and
competition. It is for this reason that it is banned by WADA
along with corticosteroids. ACTH and corticosteroids are
unsuitable for chronic use because they decrease muscle
protein synthesis, leading to skeletal muscle wasting.

Introduction

Growth hormone is one of the major hormones influencing

growth and development in humans. The period of human
growth extends from birth to the age of 20 years. A large
number of hormones influence this period producing many
complex interactions. Besides GH, testosterone, oestradiol,
cortisol, thyroxine and insulin have important roles at different
stages of growth and development. The exact role of GH is
difficult to evaluate, because of the many different
developmental and metabolic processes which GH can
influence. A review of GH and its abuse in sport has been
published by Holt and Sonksen . The regulation of muscle mass
by GH and growth factors has been reviewed by
Velloso .Release of growth hormone
The anterior pituitary, a small endocrine gland at the base of,
but not part of, the brain, contains somatotroph cells which
secrete growth hormone. Release of GH is under the control of
two hypothalamic hormones: somatostatin, which inhibits
secretion, and somatocrinin, which stimulates its secretion.
Oestradiol also stimulates GH secretion while testosterone has
very little effect. Various brain neurotransmitter systems
influence GH secretion. This is thought to occur via a controlling
influence on the hypothalamic production of somatostatin and
somatocrinin, but direct effects on the somatotroph cells
cannot be ruled out. The factors influencing GH secretion have
been reviewed in detail by Macintyre and Muller .Daily GH
secretion is episodic, the highest levels occurring 60-90 mins
after the onset of sleep. GH is metabolized in the liver; the
plasma half-life is only 12-45 minutesThe physiological
regulation of GH release is complex. Systemic factors
stimulating GHsecretion include hypoglycaemia, a rise in blood
amino acid concentration, stress and exercise, while conversely
GH secretion is inhibited by hyperglycaemia. Both endurance
exercise and resistance training have been shown to cause an
increase in GH secretion in female athletes .Growth hormone
actionThe most obvious action of GH is that it stimulates
somatic growth in pre-adolescents but it also has metabolic
effects. The importance of these metabolic actions in
homeostatic regulation of fuel usage and storage is unclear as is
the overall role of GH in the adult, this is discussed in detail by
Macintyre . Receptors for GH are present on the surface of
every cell in the body . GH stimulates the release, mainly from
the liver, of two hormonal polypeptides, somatomedin C or
insulin-like growth factor I and somatomedin A insulin-like
growth factor II and a full account of this is provided by Kicman
and Cowan . Growth hormone exerts its anabolic actions
through the generation of IGF-I , although Sonksen expressed
doubt as to whether many, if any, of the important metabolic
effects of GH are mediated via IGFs. IGFs are carried in the
plasma in two different forms: as ternary complexes and
simpler low molecular weight complexes .
Effects on muscleGH and IGF-1 have an effect on muscle growth
that appears similar to that of insulin in that it promotes amino
acid uptake and stimulates protein synthesis resulting, in
children, in an increase in the length and diameter of muscle
fibres, while only the latter growth occurs in adults. The action
of insulin is more likely to be an anti-catabolic effect on muscle
protein rather than a direct stimulatory effect on muscle
protein synthesis .Effects on boneGH stimulates the elongation
of bone in pre-adolescents both directly and via the IGFs. This is
achieved by a stimulation of cartilage proliferation in the
epiphyseal plates situated at each end of each long bone.
Cartilage cells possess receptors for GH and IGFs.Effects on
metabolismThe actions of GH on metabolism at both the
cellular and organ level are complex and appear to be biphasic.
In the first or acute phase, which seems to involve the action of
GH alone, amino acid uptake into muscle and liver is
stimulated, and there is increased glucose uptake into muscle
and adipose tissue together with reduced fat metabolism .
During the second, chronic phase, mediated by the IGFs, there
is increased lipolysis . Treatment with GH causes a rise in blood
free fatty acid levels or a rise in the blood glucose level and a
reduction in the triglyceride content of adipose tissue which
contributes to a decrease in adipose tissue mass and an
increase in fat-free weight .
Effects of exercise on growth hormone GH levels rise within 20
minutes of beginning exercise to 75-90 per cent VO2 max. The
intensity of the response depends on age, level of fitness and
body composition. The type of exercise undertaken also
produces varying GH responses. Intermittent intense exercise is
claimed to result in the highest GH levels .Growth hormone
disorders Inadequate secretion of GH is one of the causes of
the conditions known as dwarfism. This disorder is usually
recognized in childhood when the rate of growth is below the
90th percentile for that child’s age, race and sex. The treatment
is regular administration of synthetic GH until the end of
puberty. Treatment after adolescence is ineffective in
stimulating growth in stature because by this time the
epiphyseal plates in the long bones have fused, terminating any
further bone growth.Overproduction of GH as a result of a
tumour may occur in puberty and adolescence when it gives
rise to gigantism; the individual is well above average adult
height for their age, sex and race, and the limbs and internal
organs are also enlarged.In late adulthood, a tumour of the
anterior pituitary causing increased GH secretion results in the
condition known as acromegaly. The affected individual does
not grow any taller because the epiphyses have fused but their
internal organs enlarge , the fingers grow and the skin thickens.
Metabolic disorders occur which often precipitate Type II
diabetes mellitus.A deficiency in GH secretion in adulthood has
been recognized in elderly people, some of whom have
responded favourably to GH therapy . The investigations of this
syndrome while providing interesting data on the effects of GH
have not indicated a universal benefit for the elderly of GH
treatment.Administration and supply of Growth Hormone
GH is a peptide and must be injected. Therapeutically, GH
administration is usually recommended as either three single
injections, intramuscularly or subcutaneously or daily s.c.
injections in the evening.Human GH is produced synthetically.
In sport, many GH supplies are known to be illicitly obtained by
theft from pharmaceutical company production lines and from
retail pharmacies . The prevalence of GH use by athletes is
difficult to determine as much of the evidence arises through
anecdotal reports .
The abuse of growth hormone in sportThere appear to be four
major abuses of GH in sport: to increase muscle mass and
strength, to increase lean body mass, to improve the
«appearance of musculature», to increase final adult height.
However, scientific evidence to support these potential benefits
to athletes is sparse and contradictory.As early as 1988, Cowart
reviewed anecdotal reports by bodybuilders of increases in
strength following GH administration. Lombardo et al., describe
experiments where GH administration has caused significant
reductions in «fat weight», and increases in fat free weight
compared to placebo. When Yarasheski et al. examined
resistance training schedules before and during GH
administration in elderly men they found GH did not further
enhance muscle strength improvements induced by exercise
regimes. In younger adult men there is a similar picture. Sixteen
healthy men, aged 21–34 years, who had not previously trained
were given GH or placebo during 12 weeks of heavy resistance
training. At the end of the study, lean body mass and total body
water increased in the GH group compared to placebo, but
there was no difference in muscle strength or limb
circumference . Negative results have also been obtained with
male power athletes where no increases in biceps or
quadriceps maximal strength occurred in the GH group
compared to placebo . Ehrnborg et al. reviewed previous
research on GH use and concluded that the studies were «too
short and included too few subjects» to reach meaningful
conclusions.The potential performance enhancing effects of GH
may be attributed to other substances used in combination
with GH . In 2003, Rennie questioned whether the adverse
effect of GH outweighed the potential performance enhancing
effects and Liu et al. concluded, following a systematic review,
that scientific literature did not support claims of enhancement
of physical performance by GH.In 2010, Meinhardt et al.
demonstrated that GH administration in recreationally trained
athletes resulted in statistically significant improvements in
sprint capacity. Birzniece et al. reported that GH administration
has positive effects on aerobic exercise capacity and fat
metabolism and that a potential benefit for elite athletes could
be improved recovery from intensive exercise. On the other
hand, a review by Baumann concluded that scientific evidence
had failed to demonstrate an ergogenic effect with
supraphysiological doses of GH, although doses studied may
have been lower than those used by athletes.
The desire to produce tall offspring either for cosmetic reasons,
athletic potential or so they that they can qualify for a vocation
where there is a minimum height limit has prompted GH abuse
amongst children. An apparent drive for «bigness» and
«tallness» in sport and society by selective and drug-induced
means is discussed in a review by Norton and Olds and by Rogol
.In 2015, Momaya et al. concluded that the use of GH in sport
continues despite the lack of evidence-based medicine to
support its use in athletes and that many of the purported
benefits may apply only to those who are greatly hormone
deficient and not to athletes.Side-effects associated with
growth hormone abuse in sportBetween 40 and 80 per cent of
healthy adults who have received GH in controlled prospective
studies report side effects and most of the acute side effects
arise from fluid retention . The long-term risks of GH in athletes
are not well known since epidemiological data derived from
users in sport are not available .Major side-effects include
skeletal changes, enlargement of the fingers and toes, growth
of the orbit and lengthening of the jaw. The internal organs
enlarge and the cardiomegaly which is produced is often one of
the causes of death associated with GH abuse. Although the
skeletal muscles increase in size, there are often complaints of
muscle weakness. Adverse biochemical changes include
impaired glucose regulation , hyperlipidaemia and insulin
resistance. The changes described above contribute to the
prevalence of diabetes in GH abusers. Arthritis and impotence
often occur after chronic GH abuse .A consequence of the
increased protein synthesis during GH abuse is changes to the
skin. This includes thickening and coarsening – the so-called
«elephant epidermis» – which has been known to make the
skin almost impenetrable by standard gauge syringe needles .
Other skin effects include activation of naevocytes and an
increase in dermal viscosity .It is believed that many athletes
use doses of GH many times higher than those used
therapeutically and it is reasonable to expect that serious side
effects may develop . It is likely that the longer-term effect of
GH administration would also occur with IGF-I , as described in
clinical trials for mecasermin rinfabate, a drug consisting of
recombinant IGF-1 and IGF Binding Protein 3 .Who abuses
growth hormone and why?The reasons for GH abuse appear to
be based on some false premises that it is as effective as
anabolic steroids, with fewer side-effects and is less easily
detected.
Chapter 11
Beta-2 agonistsNeil Chester and David R.

Introduction
Maximum performance in aerobic events, at whatever level of
competition, is only achievable if respiratory function is
optimal. Competitors will always be concerned about
conditions that adversely affect the respiratory system be they
major disease, for example, asthma or minor ailment, such as
the common cold. Beta-2 agonists are a first line class of drugs
used to treat asthma. These drugs produce their therapeutic
effect through bronchodilation. Clearly, such an effect has the
potential to enhance athletic performance by improving oxygen
uptake. Therefore, Beta-2 agonists are included as a category
on the World Anti-Doping Agency Prohibited List, subject to a
complex set of regulations. Since beta-2 agonists are a
necessary component in the treatment regimes for asthmatic
patients, Therapeutic Use Exemption may be required for
asthmatic athletes in order to allow them to compete on equal
terms with fellow competitors.
Some beta-2 agonists, such as clenbuterol, possess anabolic
properties, although through a mechanism that is different
from that produced by anabolic steroids. Consequently, they
are included under the category of anabolic agents on the
WADA Prohibited List.
This chapter will review the condition of asthma and other
bronchoconstriction-related conditions and the use of beta-2
agonists in their treatment. The misuse of these drugs in sport
will be reviewed and the systems in place for controlling beta-2
agonists as performanceenhancing agents whilst permitting
therapeutic use, where appropriate.

What are beta-2 agonists?

In Chapter 1 of this book, we described how drugs interact
through specific targets within the body, known as receptors. In
the case of adrenoreceptors, through which the hormone
adrenaline produces its effects in the body, we reviewed the
five subclasses of these receptors.
This included the sub-class referred to as beta-2
receptors.Drugs that have been developed to interact
selectively on these receptors are known as beta-2 agonists.
Table 11.1 lists some of the more commonly prescribed beta-2
agonists.
The table categorises the drugs as short-acting and long-acting,
which has a significance regarding their clinical use in the
treatment of conditions such as asthma and chronic obstructive
pulmonary disease.
Table 11.

Pharmacology of beta-2 agonists

All selective beta-2 agonists are potent bronchodilators. They
differ in their time to onset and duration of action. Salbutamol
and terbutaline are short-acting and the most frequently used
beta-2 agonists in many countries. There are many
formulations of salbutamol and terbutaline including tablets,
slow-release tablets, elixirs, aerosols and dry powder inhalers,
solutions for injection and specialised inhalation from a
nebuliser. Inhalation is the route of choice because it is the
most rapidly effective and is associated with the fewest side-
effects. Tremor is the most common side effect after inhalation.
However, other side effects of beta-2 agonists are common .
This led Backer et al. to conclude that anti-asthmatic treatment
should not be used by non-asthmatic elite athletes. Side effects
after oral administration include: fine tremor , nervous tension
and headache. Tachycardia, peripheral vasodilation and
hypokalaemia may also occur after oral dosing.
The duration of action of salbutamol and terbutaline after
aerosol administration is approximately 4 hours. Formoterol
and salmeterol are the most frequently prescribed long-acting
beta-2 agonists with a duration of action of approximately 12
hours.

Clinical uses of beta-2 agonists

Asthma and its treatmentDefinitionAsthma is a chronic

inflammatory disorder of the airways. In susceptible individuals,
this inflammation causes recurrent episodes of coughing,
wheezing, chest tightness and difficulty in breathing.
Inflammation makes the airways sensitive to stimuli such as
allergens, chemical irritants, tobacco smoke, cold air or
exercise. When exposed to these stimuli, the airways may
become swollen, constricted, filled with mucus and hyper-
responsive to stimuli. The resulting airflow limitation is
reversible in most patients, either spontaneously or with
treatment. An individualised approach to asthma therapy
including regular use of inhaled corticosteroids can ensure that
over the long term, symptoms can be reduced in both severity
and frequency .Pathophysiology
An asthma attack always consists of an early phase and
frequently contains a late phase. The early phase, consisting of
bronchoconstriction, occurs within minutes of exposure to the
trigger factor, reaches a maximum in 15 to 20 minutes and
normally resolves within an hour. The late phase, characterised
by inflammation of the airways, occurs 2 to 4 hours after
exposure to the trigger factor and reaches a maximum after 6
to 8 hours. Appreciation of the change of emphasis from
bronchoconstriction to inflammation as the cause of airway
obstruction has underpinned the change in approach to the
management of asthma.Trigger factorsThere are numerous
factors which can trigger an asthma attack. The most common
are allergens, which can be either inhaled or ingested . Viral,
but not bacterial, infection of the upper respiratory tract can
trigger asthma. Indeed, the initial presenting feature of asthma
may be a persistent wheeze after a self-limiting, upper
respiratory tract, viral infection. Occupational pollution can also
cause asthma. Asthma attacks can be precipitated by emotional
factors. This should not be misinterpreted as an indication that
asthma is psychosomatic. Rather it is a reflection of
neuroendocrine changes which, as yet, are poorly understood.
Certain drugs may precipitate an asthma attack such as beta-
blockers and nonsteroidal anti-inflammatory drugs , particularly
aspirin. Beta-blockers cause bronchoconstriction by blocking
the bronchodilating beta-2 receptors on airway smooth muscle
and should not be administered to asthmatics. The mechanism
by which NSAIDs evoke bronchospasm is hypothetical but may
involve a shift in balance between bronchodilating and
bronchoconstricting metabolites of arachidonic acid.
Approximately 10 per cent of asthmatics are aspirin-sensitive
and will bronchoconstrict if given the drug. For this reason,
aspirin and other NSAIDs should be used with caution in
asthmatics. An asthmatic may be sensitive to a variety of trigger
factors or to just one.Management of asthmaNon-drug
treatment of asthma involves avoidance of known trigger
factors. Drug treatment of asthma is primarily directed at
arresting and reversing the inflammatory process with the
emphasis shifting from the excessive and inappropriate use of
beta-2 agonist bronchodilator therapy towards the earlier use
of anti-inflammatory drugs. Beta-2 agonists merely relieve the
symptoms of asthma without addressing the underlying
inflammation. Guidelines for treatment of chronic asthma have
been prepared in several countries. They constitute a
systematic approach to the treatment of increasing severity of
symptoms.Essentially, the first step involves the occasional use
of short-acting inhaled beta-2 agonists to relieve the symptoms
of bronchoconstriction. Thereafter, depending on the severity
of symptoms, more regular use of short-acting beta-2 agonists
is recommended, with the addition of inhaled corticosteroids. If
the symptoms are more severe, long-acting beta-2 agonists or
other bronchodilators are used with inhaled corticosteroids.
Corticosteroids are subject to WADA regulations, as described
in Chapter 20 of this book.
It must be remembered that the treatment of asthma can also
be stepped down if the severity of the symptoms declines.
Exercise-induced asthma and exercise-induced
bronchoconstriction Exercise-induced asthma can be defined as
a lower airway obstruction and symptoms of cough, wheezing
or dyspnoea induced by exercise in patients with underlying
asthma . The same presentation of symptoms in individuals
without asthma can be defined as exercise-induced
bronchoconstriction . EIB probably includes an interplay
between environmental training factors, such as allergens,
temperature, humidity and air pollutants and an athlete’s
personal risk factors such as genetic and
neuroimmunoendocrine determinants .
In 2014, a systematic review by Price et al. investigated the
impact of EIB on athletic performance. The authors concluded
that, whilst it was reasonable to suspect that EIB does impact
on athletic performance, there was insufficient evidence to
provide a definitive answer.
Diagnosis of asthma and EIBA major issue with respect to
ensuring the effective healthcare of individuals with respiratory
conditions such as asthma relates to accurate diagnosis. There
is, however, no standardised diagnosis of asthma as a
consequence of the fact that no consistent definition of the
symptoms exists . As well as a clinical history, individuals who
present themselves with asthma symptoms to their clinician
will typically undertake a simple peak flow assessment.
Unfortunately a normal peak flow recorded whilst an individual
is asymptomatic does not preclude them from a positive
diagnosis of asthma. There are, however, a number of tests
that include the assessment of lung function pre and post a
bronchoprovocation challenge. A marked reduction in lung
function from baseline is required in order for an individual to
test positive to a specific bronchoprovocation challenge and
thus form the basis of a diagnosis of asthma or EIB.
Broncoprovocation challenges may include the administration
of Histamine, Mannitol, Metacholine and saline or a bout of
exercise. Whilst an exercise challenge is the most ecologically
valid test it is difficult to control factors such as ventilation and
environmental conditions. The Eucapnic Voluntary Hyponea
challenge has been established to mimic exercise in a
controlled manner and involves an individual attaining a minute
ventilation equivalent to 85 per cent of their predicted maximal
voluntary ventilation rate for six minutes during which dry,
CO2-rich air «

Chapter 12
Hormone and metabolic modulatorsNeil
Chester

Introduction
According to the WADA Prohibited List both S1 and S2 classes
of doping agents are comprised of by and large naturally
occurring hormones and their synthetic derivatives. The S4
class entitled, ‘Hormone and Metabolic Modulators’ contains
several groups of synthetic compounds, or otherwise, which act
by modulating various endogenous hormonal pathways and
local muscle-specific transduction pathways. The aim of such
modulators is in most cases to enhance exercise performance,
however in the case of aromatase inhibitors, selective
oestrogen receptor modulators or other anti-oestrogenic
substances, it may be to counteract the unwanted side effects
of anabolic androgenic steroid administration.
Hormone and metabolic modulators and the WADA Prohibited
ListThe class of doping agents categorised as Hormone and
Metabolic Modulators are prohibited at all times, both within
competition and out-of-competition.
Table 12.1 Class S4 of the 2017 WADA List of prohibited
substances and methods S4.
Hormone and metabolic modulators1. Aromatase inhibitors
including but not limited to: 4-androstene-3,6,17 trione ;
aminoglutethimide; anastrozole; androsta-1,4,6-triene-3,17-
dione ; androsta-3,5-diene-7,17-dione ; exemestane;
formestane; letrozole; testolactone2. Selective estrogen
receptor modulators including, but not limited to: raloxifene;
tamoxifen; toremifene
Other anti-estrogenic substances including, but not limited to:
clomiphene; cyclofenil; fulvestrant4. Agents modifying
myostatin function including, but not limited, to: myostatin
inhibitors5. Metabolic modulators:
Activators of the AMP-activated protein kinase , e.g. AICAR; and
Peroxisome Proliferator Activated Receptor agonists, e.g. GW
1516;

Trimetazidine

2008. Prior to this many of these substances were classed as

Agents with Anti-oestrogenic Activity. These substances were
combined as a class in 2012 and included metabolic
modulators, namely peroxisome proliferator activated receptor
agonists and activators of AMP-activated protein kinase , which
were formerly classified under the prohibited method of gene
doping since their introduction to the Prohibited List in 2009.
Insulin was added as a metabolic modulator in 2013 after
formerly being included as Peptide Hormones, Growth Factors
and Related Substances. The most notable recent additions to
this classification of prohibited substances were Trimetazidine
in 2015, having previously been classified within the Stimulants
category in 2014 and Meldonium added in 2016.
As regards to the positive drug tests attributed to the use of
substances within this class, the most common is that of the
SERM, tamoxifen, which accounted for almost 40 per cent of
the total number of adverse analytical findings reported by
WADA-accredited laboratories in 2015. There was however,
significant representation, in terms of AAFs, from anti-
oestrogenic substances and aromastase inhibitors . Although
not represented in the latest WADAaccredited laboratory
testing figures there has been a spate of positive cases for
meldonium since its introduction to the Prohibited List in 2016 .

Aromatase inhibitors
Androgens are readily converted to oestrogens by the enzyme
aromatase. Aromatase inhibitors are therefore a class of drugs
that limit this conversion by binding to aromatase and
rendering it inactive. As a doping agent, they are only of
potential benefit to males and are typically used in an attempt
to elevate testosterone levels and to combat some of the
unwanted side-effects attributed to the use of anabolic
androgenic steroids .

Clinical use of aromatase inhibitors

Aromatase inhibitors have been used in the treatment of breast
tumours, particularly in post-menopausal women. Since
oestrogens have been implicated in the development and
progression of such tumours, the objective of treatment is to
deprive the tumour of oestrogens. This can be accomplished by
inhibiting aromatase, the enzyme that catalyses the final step in
the biosynthesis of oestrogen . Post-menopausal women tend
to have tumours that are positive for oestrogen receptors and
are therefore more responsive to treatment involving hormone
antagonism.

Aromatase inhibitors include both steroidal and non-steroidal

mechanism-based inhibitors. The steroidal agents are mostly
analogs of androstenedione and include testolactone,
formestane, exemestane and atamestane, whilst the non-
steroidal analogues include fadrozole, letrozole, anastrozole,
vorozole and finrazole .

Use of aromatase inhibitors in sport

Natural androgens, such as testosterone and androstenedione,
are the precursors of the principal oestrogen, estradiol, and this
conversion is achieved by the enzyme aromatase. Clearly, the
inhibition of aromatase will lead to elevated levels of the
endogenous androgens, testosterone and androstenedione,
thereby increasing potential anabolic effects. The most potent
natural androgen, dihydrotestosterone, cannot be aromatised
and therefore cannot be converted to an oestrogen .
Aromatase inhibitors may also be used by AAS users in an
attempt to treat the development of breast tissue , a common
side effect associated with androgen use in men, although the
clinical efficacy for this is debatable .
Selective Oestrogen Receptor ModulatorsSelective Oestrogen
Receptor Modulators are particularly attractive anti-oestrogen
drugs since they target specific tissues without affecting other
organs. Tamoxifen is by far the most common SERM, misused
by elite athletes subject to doping control measures and gym
users alike.Clinical use of Selective Oestrogen Receptor
ModulatorsThe first drugs to be used clinically as blockers of
oestrogen receptors were non-steroidal drugs such as
clomiphene and tamoxifen. Newer anti-oestrogens such as
raloxifene, toremifene, droloxifene and lasoxifene have been
developed. These drugs also possess partial agonist activity and
therefore became collectively described by the term selective
oestrogen receptor modulators. Most SERMs act as an
oestrogen receptor antagonist in breast tissue whilst acting as
an oestrogen receptor agonist in bone, resulting in increases in
bone mineral density. As such, they are widely used in the
management of breast cancer and osteoporosis in
postmenopausal women . There are however safety concerns
with the use of SERMs, for example, long-term use of tamoxifen
has been associated with an increased risk of endometrial
cancer . The partial agonist effect of tamoxifen has also been
associated with the development of ‘tamoxifen resistence’,
where the drug ceases to inhibit tumour growth and appears to
promote it .
Use of Selective Oestrogen Receptor Modulators in sportAs
anti-oestrogens, SERMs have the potential to elevate
testosterone levels through competitive binding of oestrogen
hypothalamic and pituitary receptors, thus blocking the
negative feedback loop and stimulating follicle-stimulating
hormone and luteinising hormone release . Nevertheless, this is
only evident in males since in females circulating testosterone
is derived largely from the adrenal cortex and peripheral
conversion of circulating androgens and is not controlled by
homeostatic feedback .
Despite the potential effects on testosterone, use of SERMs as
performance and imageenhancing drugs has tended to centre
on the treatment of adverse side effects attributed to AAS use.
Indeed, tamoxifen is widely used in the treatment of
gynecomastia and was attributed to widespread use in a survey
of recreational gym users in South Wales . Indeed, 22 per cent
of respondents who reported AAS use also reported using
tamoxifen. In a survey conducted by Bates and McVeigh it was
reported that a high proportion performance- and image-
enhancing drug users in the UK were also administering
tamoxifen.
Other anti-oestrogenic substancesAs already mentioned anti-
oestrogens are drugs that act as oestrogen receptor
antagonists to block the action of oestrogen. Whilst SERMs are
selective in terms of their target tissue, traditional anti-
oestrogens are non-selective and include clomiphene, cyclofenil
and fulvestrant.
Clinical use of anti-oestrogenic substancesThis sub-class of
drugs is also used primarily for the treatment of breast cancer
in postmenopausal women. Fulverstrant is an oestrogen
receptor antagonist that competitively binds to the receptors
with an affinity similar to that of oestradiol but higher than that
of tamoxifen . The binding of fulvestrant to the oestrogen
receptor sets off a series of changes to down regulate receptor
function. Unlike tamoxifen, fulvestrant has no partial oestrogen
receptor agonist activity and therefore has fewer side effects.
Clomiphene is an approved drug in the treatment of ovulatory
dysfunction in females.

Use of anti-oestrogenic substances in sport

Synthetic anabolic steroids are used by athletes, primarily for
their anabolic effects. However, most have some androgenic
effects that inhibit the release of gonadotropin-releasing
hormone from the hypothalamus and follicle-stimulating
hormone and leutinising hormone from the anterior pituitary
gland. With prolonged use, the resulting hypogonadotropic
state results in testicular atrophy. This decreases serum
testosterone levels, causing impotence and decreased libido.
Clomiphene has been reported to be used to treat these
conditions by an anti-oestrogen effect on the hypothalamus
resulting in increased gonadotropin-releasing hormone release
and oestrogen-like effects on the pituitary increasing the
sensitivity to gonadotropin-releasing hormone . The relatively
high numbers of samples testing positive for clomiphene at
WADA-accredited laboratories suggest widespread use by
athletes .
In women, it has been argued that there is no convincing
evidence that oestrogen blockers cause any consistent,
biologically significant increase in blood testosterone
concentrations . Furthermore, Handelsman suggests that
oestrogen blockade poses no unusual medical risks to female
athletes and there is therefore no basis on which to ban
oestrogen blockade in female athletes.
Agents modifying myostatin functionAs introduced in Chapter
10, the myostatin signalling pathway is important in the
regulation of skeletal muscle growth. As its name suggests,
myostatin is involved in the inhibition of muscle growth,
opposing the mTOR pathway. In a healthy individual there is
abalance between both pathways to ensure that normal muscle
growth is maintained. As a local signalling molecule, myostatin
initiates protein breakdown through its binding with a
membrane-bound receptor on skeletal muscle. As
demonstrated in animals such as thoroughbred horses,
myostatin deficiency manifests itself in muscle hypertrophy and
heightened physical performance . Therefore the myostatin
gene is the focus of much attention with regards to gene
therapy and doping, however the focus in this chapter relates
to agents with the potential to inhibit myostatin function.
Clinical uses of agents modifying myostatin functionMyostatin
is a member of the transforming growth factor-β group of
proteins that regulates muscle growth during embryogenesis .
Myostatin contributes both to muscle development during
growth and regulation of muscle growth in adulthood and
protects against uncontrolled cellular proliferation.
Myostatin is upregulated in disease states and during
prolonged bed rest where muscle wasting is symptomatic . It is
also present in relatively high levels, in the muscle of aging
individuals . It therefore follows that inhibition of myostatin
would have a huge potential in promoting health.
The clinical applications for the development of myostatin-
based medicines include muscular dystrophy, cachexia ,
myopathies resulting from inflammation and sarcopenia, the
loss of muscle associated with increasing age . However, drugs
that manipulate myostatin signalling are also being considered
as lifestyle drugs in anti-aging therapies and for their potential
to enhance physical performance in athletes . Therapies for
inhibiting myostatin function are under clinical investigation
however as yet there are no reliable treatments available .
Follistatin appears to be an attractive therapeutic agent for the
future that works by blocking the activation of the myostatin
pathway .
Use of agents modifying myostatin in sportIn humans,
resistance or endurance training has been shown to suppress
myostatin expression . This allows muscle to grow in size. It is
not surprising, therefore, that suppression of myostatin
function is deemed to be a potential method for increasing the
growth response to training or even to stimulate muscle growth
independently of training. It is for this reason that WADA
introduced agents modifying myostatin function to the
Prohibited List in January 2008 despite there being no
therapeutic agents at present. Nevertheless, the sale of
potential counterfeit myostatin inhibitor has been identified via
the internet .

Metabolic modulators
As the name suggests this class of substances are concerned
with controlling metabolic processes and pathways. Until
recently the metabolic modulators comprised of two distinct
groups, namely insulins and peroxisome proliferator activated
receptor delta agonists and activators of AMP-activated protein
kinase . In 2015, Trimetazidine was included as a metabolic
modulator, followed by Meldonium in 2016. Although
pharmacologically different, both of these drugs are used
therapeutically for their anti-ischemic effects.
Clinical use of metabolic modulatorsInsulin is a commonly used
therapy in the millions of individuals worldwide who suffer
from diabetes mellitus. Insulin therapy can take several forms
and is typically based upon the type of diabetes that an
individual suffers from. Type I diabetes, often termed
insulindependent diabetes, requires regular daily insulin
injections to combat the body’s inability to produce insulin.
Type II diabetes may vary in the therapeutic approach to reflect
the condition of the patient. In mild cases alternative strategies
to drug therapy might be considered, such as lifestyle changes
including exercise and weight loss. However, drug therapy
including insulin is usually prescribed. Insulin is administered
subcutaneously via injection or an infusion pump.
Whilst insulin was exclusively derived from animals it now
tends to be human insulin produced by recombinant DNA
technology. Analogues of insulin are also manufactured in
order to modify the action of insulin in terms of its onset and
duration of action. Insulin may also be categorised according to
its onset and duration of action.

3 Long-acting .Regular human insulin has a time for onset of

action of 30 to 60 minutes with a duration of action of between
five and eight hours. An ultra-long acting treatment is a new
generation insulin with a time for onset of action of 30 to 90
minutes and a duration of action of greater than 42 hours .
Both PPAR and activators of AMPK are relatively new drugs
whose capabilities as therapeutic agents are currently being
developed. PPAR agonists are a class of drugs that have the
potential to treat both cardiovascular and metabolic diseases.
By and large these drugs show great promise, although they are
not without their problems. Indeed, clinical trials of the PPAR
agonist, GW501516, which was developed by GlaxoSmithKline,
were stopped due to concerns over potential carcinogenic
effects . Nevertheless, this has not prevented its availability and
illicit use as a performance and image-enhancing drug
undergone clinical trials for the treatment of ischemia-
reperfusion injury during heart surgery . It has also been
considered as a possible treatment for a wide range of diseases
including diabetes mellitus and cancer .
Both meldonium and trimetazidine are recent additions to the
WADA Prohibited List and both are anti-ischemic drugs
designed as a cardioprotective drug in the treatment of
problems associated with cardiovascular disease such as angina
. Trimetazidine works by reducing oxygen demand by shifting
energy provision from lipid to carbohydrate metabolism .
Meldonium inhibits L-carnitine biosynthesis, thus supressing
lipid metabolism and enhancing glycolysis and, as such, also
reduces the oxygen demand of energy provision .
Use of metabolic modulators in sportAlthough insulins are
essential in the pharmacotherapy of diabetes mellitus, they are
thought to have huge potential as performance-enhancing
agents. Indeed, Sonksen the inhibition of protein breakdown by
insulin would limit the catabolic effects associated with heavy
training and further enhance the effectiveness of resistance
training in increasing muscle bulk. Insulin would therefore
appear to work in synergy with other anabolic agents such as
anabolic androgenic steroids , growth hormone and insulin-like
growth factor-1 .
The use of insulin as anabolic agents was reported by Dawson
and Harrison amongst patents at a needle exchange and
support clinic in the UK. Also, it has been reported by Rich et al.
that 25 per cent of AAS users were using insulin concurrently. A
recent investigation reported that of 41 non-diabetic insulin
users 95 per cent also administered AAS . Since bodybuilders
are a group particularly prone to using insulin in order to
increase muscle mass there are particular risks associated with
competitive bodybuilders who may be using insulin with
concurrent fasting prior to a competition. Clearly this practice
poses a particular risk in terms of hypoglycaemia. Indeed, there
are reports whereby individuals have suffered from
hypoglycaemic coma .
Insulin was added to the list of prohibited substances by the
IOC after concerns regarding its possible misuse at the Nagano
Olympics in 1998 . Clearly athletes with diabetes may use
insulin with a valid therapeutic use exemption. From a drug
testing perspective it is difficult to differentiate between the
endogenous hormone and that which might be administered
exogenously. In addition the pulsatile nature of insulin release
coupled with its short half-life makes doping control extremely
challenging.
PPAR agonists are important regulators of substrate utilisation
and are involved in the regulation of muscle fibre type . Whilst
research involving an animal model, examining the effect of a
PPAR agonist, namely GW501516, resulted in a shift from
carbohydrate to fat utilisation in skeletal muscle, no
improvement in endurance performance was found in
sedentary mice. Nevertheless, endurance performance was
improved when exercise training was combined with
GW501516 . The same research study also demonstrated the
effectiveness of the AMPK-agonist, AICAR on enhanced
endurance running in mice .
AMPK is often described as the master metabolic regulator due
to its effect on lipid and glucose metabolism. It is activated in
response to changes in energy levels that occur during stress .
Drugs that target AMPK have been termed exercise mimetics
due to their ability to activate numerous signalling pathways
and regulate the expression of particular genes in a similar way
to exercise. It is for this reason that such drugs have become
attractive to individuals looking to enhance sports
performance.
From a drug testing perspective the first case of GW501516 use
was in cycling and coincided with the development of a test for
its detection by Thevis et al. . The cyclist in question was the
Russian Valery Kaykov, who won European Track Championship
team pursuit gold in 2012. AICAR is a naturally occurring AMPK
agonist which is readily detected in urine and therefore
quantitative analysis and the implementation of a suitable
threshold is likely to determine its misuse .
In a study by Jarek et al. the use of trimetazidine was
monitored in Polish athletes over a wide spectrum of sports
prior to its inclusion on the Prohibited List. Widespread use was
determined by the WADA-accredited laboratory in Warsaw
between 2008 and 2013 supporting its prohibition in 2015.
Meldonium was placed on the WADA Monitoring Program in
2015 and analysis of athletes’ samples from the 2015 European
Games in Baku showed a high prevalence of use. In
communicating these findings from Baku, Stuart et al.
highlighted that 8.7 per cent of samples tested positive for
meldonium and a significant number did not declare the use of
the drug on their doping control form. The study further
highlights concern over the widespread prescription of the drug
in healthy athletes.
The following year meldonium was added to the Prohibited List.
A series of positive tests followed, including the former world
number one and multiple grand slam tennis champion, Maria
Sharapova. Sharapova immediately pleaded ignorance and
stated that she was not familiar with the name meldonium,
rather a brand name, Mildronate and that she had been using
the drug for ten years for therapeutic reasons. Nevertheless,
she had concealed the use of the medication to her support
staff and had not declared the use of the medicine on the
doping control form when tested . Subsequently a two-year
period of ineligibility was imposed by the International Tennis
Federation, which was subsequently reduced to 15 months
following an appeal to the Court of Arbitration for Sport. This
case was particularly interesting since it suggested that the
athlete was not aware of the substance being added to the
Prohibited List, nor were her support staff. As a Ukraineborn
athlete currently residing in the United States this drug was a
registered prescription drug in East European nations including
the Ukraine but not in the USA.
The considerable number of positive tests for meldonium
during the early part of 2016 led to questions over the
pharmacokinetics of the drug. The suggestion that meldonium
might be retained in erythrocytes and other tissues causing
release of the drug over an extended period of time has been
considered as a plausible explanation for the elevated number
of positive tests .
Both trimetazidine and meldonium are promoted as
performance enhancers in sport, particularly endurance sport,
through reduced oxygen cost of exercise. However, there is
limited evidence to support their efficacy in healthy athletes .
Further research is needed to clarify the reputed benefits of
such drugs.

Summary
Hormone and metabolic modulators are a diverse group of
substances with a diverse range of therapeutic uses. As
performance and image-enhancing drugs they have the
potential to boost skeletal muscle growth and function by
increasing the availability of testosterone or limiting protein
breakdown and increase endurance capacity via PPAR- and
AMPKagonists. In addition, by modulating oestrogen and its
receptors the side effects attributed to androgen use may be
tackled. New additions to this category of prohibited
substances include the anti-ischemi drugs trimetazidine and
meldonium. Although evidence supporting widespread use led
to their inclusion on the Prohibited List there is limited
evidence to support their use as performance enhancers.
In many respects this group of substances represents a group of
emerging performanceand image-enhancing drugs that in many
cases remain under development and therefore may prove
attractive to athletes in the future. A high profile case involving
the drug meldonium highlights the need for athletes and their
entourage to be vigilant with regards to the annual updates of
the Prohibited List and Monitoring Program.
Ringkasan 1 Video YouTube
Pada Olimpiade Soul 1988, Sprinter Kanada Ben Johnson
memenangkan medali emas untuk lari cepat 100 meter.
Kemudian logam ini dilucuti karena ia menggunakan doping.
Mengonsumsi stanazolol yang merupakan steroid sintetis. Maju
cepat ke 28 tahun kemudian, obat terlarang tersebut sekarang
menjadi zat yang paling sering terdeteksi di antara atlet,
setidaknya dalam hal zat anabolik. Seperti steroid anabolik
lainnya, cazol membantu meningkatkan pertumbuhan otot
yang dapat meningkatkan kekuatan dan daya tahan sehingga
memberikan atlet kesempatan yang tidak adil untuk
menggunakan stanazolol.
Keuntungannya adalah zat ini berada dalam kelompok zat yang
sama dengan hormon testosteron pria, tetapi tidak seperti
testosteron, zat ini tidak terjadi secara alami. Jadi, inilah fungsi
stanazolol. Zat ini mengikat protein yang disebut reseptor
androgen. Ketika reseptor ini diaktifkan, mereka memicu reaksi
berantai yang pada akhirnya mengarah pada pembentukan
otot. Namun, zat ini juga membantu menunda kerusakan otot.
Obat ini pertama kali muncul pada tahun 1962. Obat ini
digunakan untuk mengobati kelainan darah seperti anemia
aplastik, suatu kondisi yang terjadi ketika tubuh tidak
memproduksi cukup sel darah. Pemikirannya adalah bahwa
stanazol La akan membantu menciptakan lebih banyak jenis sel
ini tetapi pada tahun 2010 obat sintetis tersebut ditarik dari
pasar AS pemerintah tidak menganggapnya cukup efisien untuk
digunakan pada manusia meskipun kadang-kadang masih
digunakan pada hewan dalam beberapa tahun terakhir
beberapa atlet elit termasuk pitcher Major League Baseball dan
atlet angkat besi Olimpiade telah dinyatakan positif
menggunakannya Selain merusak kredibilitas mereka
penyalahgunaan stola dapat menjadi bumerang bagi kesehatan
perubahan suasana hati peningkatan agresi jerawat kerusakan
hati dan atrofi testis adalah beberapa efek samping obat
tersebut.
Ringkasan 2 Video YouTube
Steroid telah menyebabkan skandal global. Steroid dilarang di sebagian
besar kompetisi atletik. Namun, apakah steroid benar-benar buruk bagi
Anda? Istilah "steroid" mengacu pada kategori molekul yang luas yang
memiliki struktur molekul yang sama, tetapi memiliki banyak fungsi
yang berbeda. Ketika orang berbicara tentang steroid dalam konteks
olahraga, mereka mengacu pada subkelompok steroid yang
menyerupai testosteron.

Meskipun atlet elit dan binaragawan mulai menggunakan steroid ini

pada tahun 1950-an, saat ini, sebagian besar pengguna steroid
sebenarnya bukan atlet kompetitif, tetapi orang-orang yang mencari
penampilan tertentu. Steroid ini memiliki dua efek utama: androgenik,
atau maskulinisasi, dan anabolik, atau pemacu pertumbuhan. Efek ini
meniru testosteron yang terjadi secara alami, yang mendorong
perkembangan dan pemeliharaan karakteristik seks sekunder pria dan
pertumbuhan umum pada setiap orang. Itu berarti testosteron dan
steroid sintetis yang didasarkan padanya mendorong pertumbuhan
rambut tubuh dan wajah, pembesaran pita suara dan pendalaman
suara, peningkatan massa dan kekuatan otot, serta peningkatan
perawakan dan massa tulang.

Pengguna steroid rekreasional mengejar efek anabolik dan pemacu

pertumbuhan. Untuk menumbuhkan otot, steroid pertama-tama
meningkatkan sintesis protein—protein merupakan bahan pembangun
penting dari semua sel, jaringan, dan organ, termasuk otot. Steroid juga
memblokir kortisol, molekul pemberi sinyal yang mendorong
pemecahan zat termasuk protein. Terakhir, steroid dapat mendorong
perkembangan otot, bukan lemak, dan meningkatkan metabolisme
kita, sehingga lemak menyusut.

Sifat-sifat ini membuat steroid berharga untuk mengobati banyak

penyakit dan cedera. Steroid dapat membantu orang dengan penyakit
yang melemahkan, seperti AIDS dan kanker tertentu, mempertahankan
massa otot, dan membantu korban luka bakar memulihkan jaringan
otot yang hilang. Jadi, jika steroid digunakan sebagai obat, steroid pasti
aman untuk digunakan sebagai rekreasi, bukan? Nah, tidak
sesederhana itu. Untuk menciptakan pertumbuhan otot yang
diinginkan, pengguna steroid rekreasi biasanya harus mengonsumsi
dosis yang jauh lebih tinggi daripada yang diresepkan untuk kondisi
medis tertentu. Penggunaan steroid dosis tinggi dalam jangka panjang
dapat menimbulkan efek yang tidak diinginkan dan sangat berbahaya—
beberapa di antaranya bergantung pada faktor-faktor seperti usia, jenis
kelamin, dan kondisi kesehatan yang mendasarinya. Kami tidak yakin
apa saja faktor risikonya, tetapi kami tahu penggunaan steroid rekreasi
sangat berisiko bagi remaja. Selama masa pubertas, penggunaan
steroid dapat menyebabkan tulang menjadi matang sebelum selesai
tumbuh, yang menyebabkan cacat pertumbuhan.

Remaja juga paling berisiko mengalami efek psikiatrik berbahaya dari

penggunaan steroid. Yang paling umum dari efek ini adalah
peningkatan impulsivitas dan peningkatan agresi, yang dikenal sebagai
"roid rage." Hingga 60% pengguna mengalami efek ini. Namun, ada juga
efek samping psikiatrik yang lebih jarang terjadi dan lebih merusak
seperti mania dan bahkan psikosis. Penggunaan steroid dapat merusak
organ termasuk hati dan ginjal, dan menyebabkan masalah
kardiovaskular seperti tekanan darah tinggi.Meskipun sebagian atau
semua efek tersebut dapat dipulihkan, penggunaan steroid juga dapat
menyebabkan kanker hati, terutama pada pria. Meskipun pengguna
rekreasional mengonsumsi steroid untuk mendapatkan efek
anaboliknya, mereka juga mengalami efek androgenik—sering kali tidak
diinginkan. Itu dapat berarti bertambahnya bulu tubuh, pembesaran
klitoris, dan suara yang semakin dalam secara permanen pada wanita.

Pada saat yang sama, steroid yang mirip testosteron secara berlebihan
dapat menyebabkan feminisasi pada pria, karena tubuh mengubah
kelebihan tersebut menjadi estrogen. Hal ini dapat menyebabkan
perkembangan payudara dan penyusutan testis. Efek ini tidak jarang
terjadi—sekitar sepertiga pengguna steroid pria mengalaminya sampai
tingkat tertentu. Penggunaan steroid yang berlebihan juga dapat
mengurangi kesuburan pada pria dan wanita—dengan mengurangi
sperma dalam air mani atau dengan menyebabkan periode menstruasi
yang terlambat dan kondisi seperti sindrom ovarium polikistik. Semua
efek ini dapat dipulihkan jika penggunaan steroid dihentikan—tetapi
mungkin juga tidak. Steroid tertentu, durasi penggunaan, dan faktor-
faktor lain dapat berperan dalam pemulihan. Terakhir, ada banyak bukti
bahwa pengguna rentan terhadap ketergantungan steroid. Mereka
dapat mengembangkan toleransi dan membutuhkan dosis yang
semakin besar dari waktu ke waktu. Hal ini meningkatkan risiko efek
berbahaya, yang semuanya semakin umum terjadi pada dosis yang
lebih tinggi yang dikonsumsi dalam jangka waktu yang lebih lama.

Namun, masih sedikit informasi pasti tentang seberapa umum dan

seberapa reversibel hampir semua bahaya tersebut pada berbagai
tingkat penggunaan. Kami tidak cukup tahu, baik tentang faktor risiko
maupun tingkat paparan, untuk secara pasti mengatakan bahwa
penggunaan steroid rekreasional akan bebas bahaya.masih sedikit
informasi pasti tentang seberapa umum dan seberapa reversibel
hampir semua bahaya tersebut pada berbagai tingkat penggunaan. Kita
belum cukup tahu, baik tentang faktor risiko maupun tingkat paparan,
untuk secara pasti mengatakan bahwa penggunaan steroid rekreasional
tidak akan menimbulkan bahaya.masih sedikit informasi pasti tentang
seberapa umum dan seberapa reversibel hampir semua bahaya
tersebut pada berbagai tingkat penggunaan. Kita belum cukup tahu,
baik tentang faktor risiko maupun tingkat paparan, untuk secara pasti
mengatakan bahwa penggunaan steroid rekreasional tidak akan
menimbulkan bahaya.

Ringkasan 3 video YouTube

video ini tidak bias dan hanya berisi fakta tentang apa yang mereka
lakukan pada tubuh Anda baik secara positif maupun negatif Jadi apa
itu Clenbuterol? Nah Clenbuterol atau disingkat Clen juga dikenal
sebagai sepupu efedrin ingat teman-teman Clen bukanlah steroid Ini
adalah antagonis agonis Beta-2 selektif dan bronkodilator dan tujuan
penggunaannya adalah untuk mengobati gangguan pernapasan seperti
asma Clen hadir dalam bentuk pil semprot atau cair dan ilegal untuk
dibeli di AS tanpa resep.

Di dunia binaraga, obat ini terutama digunakan untuk menghilangkan

lemak yang tidak diinginkan dan menjadi sangat berotot dan
sebenarnya clen digunakan di antara [selebriti] yang ingin menurunkan
[berat badan] dengan cepat juga misalnya Britney Spears dan Lindsay
Lohan adalah selebriti yang secara terbuka mengakui mengonsumsi
obat tersebut untuk yang mana yang bekerja, pil semprot terbaik, atau
cairan Ada banyak pembicaraan tentang bentuk clen mana yang lebih
baik tetapi tidak ada konsensus beberapa orang menyukai kenyamanan
pil sementara yang lain lebih suka cairan karena penyerapannya yang
cepat dan karena betapa mudahnya mengukur dosis sekarang di sinilah
hal itu menjadi nyata 99% dari waktu ketika seseorang memberi tahu
Anda bahwa mereka melakukan bulking kotor Yaitu ketika Anda
mendapatkan banyak lemak dalam waktu singkat Ketika tiba saatnya
bagi mereka untuk menghilangkan semua lemak yang tidak perlu
dengan cepat Clen biasanya adalah obat pilihan inilah mengapa banyak
dari Anda menggaruk-garuk kepala bertanya-tanya mengapa atlet alami
favorit Anda bisa menjadi sangat berotot begitu cepat ketika Anda
hampir tidak bisa memperlihatkan perut Anda setelah empat minggu
makan makanan yang bersih dan Hanya untuk memberi Anda orang ini
visual yang bagus. Berikut contoh sebelum dan sesudah hanya satu
siklus clen Tapi apa yang sebenarnya dilakukan clen dengan baik alasan
mengapa clem bekerja sangat baik untuk mendapatkan otot yang
kencang adalah karena ia merangsang Reseptor beta 2 Anda yang
secara aktif membalikkan penyumbatan saluran napas dan
meningkatkan pernapasan Anda Tapi stimulasi reseptor Anda yang
sama ini juga dapat digunakan untuk [meningkatkan] laju metabolisme
Anda.

Namun clen tidak secara aktif membakar lemak dengan menyerang sel-
sel lemak. Secara sederhana, clen mengarahkan tubuh Anda untuk
membakar lemak melalui otot yang benar-benar merangsang
metabolisme Anda dengan meningkatkan suhu tubuh Anda yang
membantu Anda membakar lebih banyak kalori dari waktu ke waktu
dan seperti banyak obat lain, orang biasanya menumpuk Clen dengan
obat lain untuk meningkatkan hasilnya. Tambahan umum untuk siklus
bersih adalah hormon tiroid buatan manusia yang membantu Anda
membakar lemak [bahkan] lebih cepat, dan saya tidak akan
membahasnya sekarang. Tetapi saya akan membuat video tentangnya
di masa mendatang. Sekarang istilah yang sering saya gunakan adalah
perolehan ramping dan untuk memperoleh perolehan ramping sebagai
atlet alami, Anda harus menjaga surplus kalori kecil sekitar 250 hingga
500 kalori di atas TDEE atau Total pengeluaran energi harian total Anda.
Dan tetap memasukkan hal-hal seperti melakukan kardio beberapa kali
seminggu. Jadi, ketika Anda melihat orang mengklaim bahwa mereka
sedang dalam bentuk ramping atau perolehan ramping, tetapi sangat
jelas bahwa asupan kalori mereka meledakkan jendela kecil 250 hingga
500 kalori. Seharusnya sudah jelas. Itu karena mereka menggunakan
narkoba. Dan saya perlu mengatakan ini karena saya tidak ingin kalian
berpikir bahwa mendapatkan tubuh ramping berarti makan apa pun
yang kalian inginkan dan hanya melakukan kardio nanti

Ini tidak sesederhana itu Anda [harus] sangat berhati-hati dengan

asupan protein karbohidrat dan lemak Anda untuk menumbuhkan otot
dengan sedikit mungkin penambahan lemak juga perlu diingat bahwa
jika Anda seorang pengangkat berpengalaman selama empat tahun
Secara alami Anda hanya akan bisa mendapatkan sekitar empat hingga
lima pon otot maksimal setahun Dan Anda dapat mempelajari lebih
lanjut [tentang] apa yang diharapkan dalam hal pertumbuhan otot
dalam empat tahun pertama angkat beban di video saya Bulking Anda
melakukannya dengan salah, dan saya akan meletakkan [tautan] itu di
bagian info di bawah ini juga Tetapi tren baru di antara atlet fisik adalah
menggunakan obat ini saat Bulking untuk menjaga penambahan berat
badan mereka di sisi yang paling bersih sambil memberi makan otot
mereka sebanyak mungkin dengan makanan dan steroid Ini karena
manfaat lain dari Clen. Bahasa Indonesia: Apakah itu benar-benar dapat
membantu retensi otot dan mencegah Katabolisme otot saat cutting
Ingat teman-teman, cobaan tersulit yang harus diatasi oleh lifter alami
saat cutting atau mendapatkan otot yang lebih ramping adalah tidak
menjadi Katabolik dan menjaga tampilan penuh pada otot Anda untuk
menurunkan berat badan, Anda harus membuat tubuh Anda defisit
kalori Jadi pemborosan otot selalu menjadi risiko bahkan jika Anda
hanya memotong 250 hingga 500 kalori sehari dari TDEE Anda. Jadi
benar-benar duduk sejenak dan pikirkan tentang perjuangan yang
dialami lifter alami untuk menambah berat badan atau memotong saat
menambah berat badan, Anda harus mendapatkan sedikit lemak. Anda
berada dalam surplus Kalori Ini sains teman-teman dan untuk
memotong Anda harus berada dalam defisit yang akan mengakibatkan
hilangnya beberapa otot bersama dengan hilangnya lemak Jadi tidak
heran mengapa clenbuterol begitu populer di kalangan pesaing fisik, ia
tidak hanya membantu Anda memotong lemak yang tidak diinginkan
Tetapi juga memudahkan untuk menjaga massa otot Anda selama fase
leaning out.
Jadi apa efek sampingnya? Bahasa Indonesia: Jauh sebelum Anda mulai
berfantasi tentang bagaimana Anda bisa [memperoleh] obat
penghancur lemak ajaib ini Anda mungkin baru saja mempelajarinya,
sekarang saatnya untuk membicarakannya sekarang Sama seperti
ketika kita berbicara meskipun [Anda] mungkin tidak mengalami semua
efek samping yang datang dengan obat ini Mereka semua masih
[sangat] efek samping yang umum termasuk kram otot peningkatan
tekanan darah peningkatan detak jantung, Insomnia Mulut kering
muntah gemetar terutama pada tangan pria gugup kesulitan bernapas
berkeringat Tremor Vertigo kecemasan sakit kepala dan bahkan jantung
berdebar-debar kebanyakan orang biasanya mengonsumsi magnesium
dan kalium untuk membantu kram otot yang bisa brutal dan saya tahu
itu banyak Risiko teman-teman, tetapi sekarang saya ingin Anda
mengingat semua yang baru saja saya sebutkan dan berpikir tentang
seberapa keras latihan ketegangan dan berapa banyak yang dibutuhkan
Secara mental untuk [berlatih] keras dan berat dan pertanyaan saya
kepada [Anda] adalah Bagaimana Anda akan berlatih sebaik mungkin
dengan sakit kepala yang mengamuk gemetar di seluruh tubuh Muntah
mulut kering dan efek samping lain yang tercantum sekarang apa yang
akan saya lakukan untuk kalian dan menunjukkan kepada Anda
beberapa contoh yang saya temukan di posting forum [dari] orang
sungguhan yang berbicara tentang pengalaman mereka menggunakan
Clenbuterol dan efek samping yang mereka alami karena saya merasa
lebih mudah bagi kalian untuk melihatnya daripada hanya
mendapatkan Saya memberi kalian semua fakta dan membuatnya jelas
dan mudah dipahami Saya merasa posting seperti ini membuatnya
sedikit lebih nyata dan lebih mudah untuk memahami apa yang bisa
terjadi pada Anda.
Jadi postingan pertama ini dari T-nation dari seorang pria bernama
Sunder. Dia berkata Anda akan menjadi vibrator manusia yang dapat
menghancurkan batu hanya dengan memukulkannya dengan palu
godam dengan genggaman Anda. Jangan makan sup. Jangan makan
dengan peralatan makan apa pun di sekitar orang lain. Jangan juga
bersiaplah untuk menjawab beberapa pertanyaan. Jika pekerjaan Anda
[memerlukan] ketangkasan manual seperti menggambar atau operasi,
bersenang-senanglah. Jelaslah para pria di sini. Dia bersenang-senang
dengan postingannya. Namun, Anda jadi tahu bahwa Shake adalah efek
samping yang sangat umum. Berikut adalah beberapa postingan forum
lainnya. Pria ini berkata. Berhati-hatilah dalam dosis, bahkan di utas ini.
Kami memiliki toleransi yang sangat berbeda. Saya mengonsumsi batch
clen yang sama sebagai teman. Dan dia berjuang untuk menulis apa
pun pada 80 mikrogram sehari karena Shakes sedangkan saya menguap
di sebelahnya pada seratus empat puluh mikrogram sehari. Memang
saya sangat toleran terhadap Stim tetapi saya yakinkan Anda untuk
mengonsumsi kalium dan taurin bersamaan dengannya karena clen
menyebabkan peningkatan ekskresi keduanya juga. Saya percaya
beberapa masalah panas dengan clen disebabkan oleh kadar tur rendah
di jantung dan ini postingan lainnya. Ya, saya pikir saya mungkin hanya
menjadi pelit dan malas.

Saya punya yang bersih dan saya ingin menggunakannya dan saya
punya lemak untuk dihilangkan Tapi saya juga punya teman seusia saya
yang meninggal karena beberapa masalah jantung kemungkinan besar
genetik dan bukan karena clen Tapi saya sedikit lebih waspada daripada
sebelumnya seperti yang kalian lihat di awal beberapa efek sampingnya
termasuk jantung berdebar-debar dan kematian mendadak, jadi Kami
tidak tahu pasti tapi mungkin itulah yang terjadi pada temannya
sekarang. Dia agak khawatir dan postingan berikutnya Inilah yang
dikatakan orang ini Clen, saya tidak suka menggunakannya sebelumnya
tetapi sisi-sisinya [oh], astaga. Goyang goyang goyang Anda tidak dapat
melakukan hal lain untuk bekerja makan menjadi masalah besar
[karena] Anda tidak dapat meletakkan garpu di mulut Anda Anda tidak
dapat minum kopi di tempat kerja tanpa orang-orang bertanya apakah
Anda baik-baik saja? Bung? Tidak, tidak, saya sedang mengalami
serangan Parkinson. Saya baik-baik saja. Gunakan efedrin, efek
sampingnya lebih sedikit dan pembakar lemak yang hebat. Selain itu,
harganya murah. Clen bekerja pada satu penerima. [efedrin] bekerja
pada beberapa penerima, sama seperti kafein, jadi Anda akan merasa
lebih berenergi, lebih bertenaga untuk berlatih tanpa gemetar
selamanya. Clen adalah pembakar lemak yang hebat, tetapi Anda akan
merasa buruk hampir setiap saat. Ini satu lagi posting forum untuk
Anda. [Saya] tidak percaya tidak ada yang menyebutkannya. Clen
menguras taurin tubuh Anda. Minum empat gram Taurin sehari untuk
membantu mengatasi kram. Sayangnya, itu mungkin tidak
menghilangkannya sepenuhnya.

Saya ingat berbaring di lantai sambil menangis dan menjerit karena

kram yang bervariasi dari kedua paha depan hingga kedua paha
belakang sekarang itu adalah situasi yang cukup [kacau] karena
menghentikan kram paha depan memicu kram paha belakang, kawan
Itu menyebalkan, haha Lucu juga mengatakan haha di akhir Sekarang
Anda dapat mengetahui dari postingan tersebut bahwa efek
sampingnya nyata dan Clen memiliki waktu paruh sekitar 48 hingga 72
jam Jadi sebagian besar efek samping akan hilang begitu Clen keluar
dari tubuh Anda Tetapi ada juga efek samping jangka panjang
sebenarnya ada penelitian pada hewan yang menunjukkan hipertrofi
jantung atau pembesaran jantung juga telah [ditunjukkan] bahwa Clen
menyebabkan infiltrasi Kolagen ke dalam Struktur jantung mengubah
struktur ototnya yang dapat menyebabkan kematian mendadak Selain
itu, penggunaan Clenbuterol dapat memperburuk kondisi jantung atau
tekanan darah yang sudah ada sebelumnya Masalah, jadi jika ini adalah
Anda, Anda harus benar-benar menjauh dari obat ini jangan anggap
enteng ini teman-teman detak jantung istirahat lebih tinggi tekanan
darah tinggi semangat Palpitasi semua hal ini dapat menyebabkan
kematian [sebagaimana] dosis yang dikonsumsi orang dapat bervariasi
berdasarkan jenis kelamin, pengalaman, dan tujuan. Namun, titik awal
yang umum untuk permulaan adalah 20 mikrogram sehari dan
disarankan untuk meningkatkannya secara perlahan hingga empat
puluh hingga enam puluh mikrogram sehari pada akhir dua minggu.
Kemudian, tingkatkan dosis secara bertahap setelah dua minggu.

beberapa orang seperti yang baru saja Anda dengar di salah satu
posting forum bahkan akhirnya mengonsumsi hingga seratus empat
puluh mikrogram per Hari tetapi ingatlah bahwa semakin banyak
[Anda] mengonsumsi semakin parah efek sampingnya dan itu akan
selalu menjadi [Faktor] penentu di sini, dan bagaimana obat ini akan
memengaruhi Anda sekarang alasan mengapa orang suka bersepeda
clen adalah karena pada akhirnya reseptor yang mengikatnya [menjadi]
jenuh atau penuh dan hasilnya berkurang Faktor lain yang perlu
dipertimbangkan adalah uang satu pil dua puluh mikrogram dapat
berharga antara 50 sen hingga $1 Jadi itu akan bertambah seiring waktu
terutama jika Anda mempertimbangkan obat atau suplemen tambahan
yang akan Anda konsumsi di samping Hal lain yang ingin saya sebutkan
adalah jika Anda kelebihan berat badan secara signifikan Anda bahkan
tidak boleh berpikir untuk mengonsumsi Clen Terutama mengingat efek
samping yang mungkin sudah menjadi masalah bagi seseorang dengan
lemak tubuh berlebih Clen akan cocok untuk seseorang yang sudah
dalam kondisi cukup baik yang mencari Edge ekstra Jadi, apakah
manfaatnya lebih besar daripada risikonya? Yah, itu adalah sesuatu
yang perlu Anda putuskan sendiri [dan] bagi saya pribadi jawabannya
adalah tidak. Terakhir, saya ingin menyebutkan bahwa ada suplemen di
pasaran dengan nama yang sangat mirip dengan Clenbuterol seperti
Clenbutrx yang bukan clenbuterol, ini hanyalah suplemen yang
seringkali tidak lebih dari pembakar lemak efedrin. Dan mereka sengaja
diberi nama agar terdengar seperti Clen untuk mengelabui Anda agar
membelinya.