Lecture 8: Pharmacological Ergogenic Aids

In this lecture we will:

1. Focus on pharmacological means prevalently used to enhanced exercise
performance

2. Explain the magnitude of effects on exercise performance and consequences

of specific drugs on health
v Pharmacological ergogenic aids: introduction
• Blurry distinction with nutritional supplementary aids

• Little demarcation exists between nutrient supplements (often at exposure levels greater than
in foods), and chemical agents (drugs) used to enhance training and gain a competitive edge

It is very difficult to distinguish whether the intake of a ‘natural’ nutrient obtained via
chemical processing reflects nutritional supplementation or a pharmacologic intervention
v Pharmacological ergogenic aids: in use since ancient times

• Ancient athletes of Greece reportedly used hallucinogenic mushrooms plant seeds and
ground dog testicles (testosterone) for ergogenic purposes, while Roman gladiators
ingested an ash drink, believing that bone strength would be increased

• Athletes of the Victorian era (19th century) routinely used alcohol, nitroglycerine,
heroin, cocaine, and the rat poison strychnine in the attempt to gain a competitive edge
v Prevalence of ‘pharmacological’ illegal use (doping) among current athletes
Abnormal blood profiles
indicative of blood doping

Assuming drug microdosing

Sottas et al. (2011). Clinical Chemistry

 ‘Everyone in cycling is doping’

Don Catlin
(anti-doping scientist)

‘Citius, altius, fortius – the Olympic motto – is supposed to be

reached solely by natural talent, proper training and diet.
How true is that today? Probably not true at all’

‘How can it be so bad with all the anti-doping activities and

Prof. Carsten Lundby
controls taking place?’ ‘is it really worth all the efforts and
expenses?’
Lundby et al. (2011). British J Pharm
v Pharmacological ergogenic aids: main categories
ALTER BODY WEIGHT AND
COMPOSITION
• Androgenic anabolic steroids
• ß2-agonists ENHANCE ENERGY
• Stimulants PRODUCTION
• ß-blockers
• Narcotic analgesics
• Peptide hormones and analogues IMPROVE
• Enhancers of oxygen transport (chemical and physical PRECISION
manipulation), and gene doping
• Glucocorticosteroids
FACILITATE
• Diuretics and other masking agents
RECOVERY
World Anti-Doping Agency (WADA)

MASK
DOPING
v Pharmacological ergogenic aids: anabolic steroids

• Anabolic steroids for medical use became prominent in the early 1950s to treat patients
deficient in natural androgens with muscle-wasting diseases (muscular dystrophies)

• Up to 4 million athletes in the USA currently use anabolic steroids, often combined with
other drugs

• Among all individuals using anabolic steroids, recent surveys indicate that nearly 80 %
are non-athletes who take these drugs for aesthetic purposes

Katch et al. (2008). Sports and Exercise Nutrition

Anabolic steroids function in a manner similar to the main male hormone testosterone. By binding
with special receptor sites on muscle and other tissues, testosterone contributes to male secondary
sex characteristics. These include sex differences in muscle mass and strength that develop at the
onset of puberty
v Pharmacological ergogenic aids: anabolic steroids
MODE OF USE BY (SOME) ATHLETES
• Supraphysiologic dosages of multiple steroid preparations in oral and injectable form
(combined because anabolic steroids may differ in physiologic action)—a practice called
“stacking”— are taken in a progressively increasing drug dosage (“pyramiding”), usually
during 4- to 18-week cycles. A drug-free period is included between cycles

• The drug quantities far exceed the recommended medical dose, often up to 200 times or
more the therapeutic amounts. The athlete then progressively reduces the dosage in
the months before competition to reduce risk of detection during drug testing

• The difference between dosages in research studies and the excess typically abused by
athletes has largely contributed to credibility gap between scientific findings (sometimes,
no effect of steroids) and what is “known” to be true in the athletic community

Katch et al. (2008). Sports and Exercise Nutrition

v Pharmacological ergogenic aids: anabolic steroids
43 healthy men randomized to 10 weeks of testosterone
(high dose, 600 mg per week) or placebo injections, with
or without strength training (3 days/wk, upper and lower
body exercises, 4 x 6 repetitions, 70-90 % RM)

testerone alone without resistance increase more when combined

training increase muscle mass with resistance training

Bhasin et al. (1996). NJEM

v Pharmacological ergogenic aids: anabolic steroids

NOT ONLY USED BY STRENGTH/POWER ATHLETES

Running
• In endurance athletes, natural
(72 % VO2max)
testosterone may be reduced after
prolonged exercise, and may be either
unaltered or reduced in resting
conditions

• Exogenous testosterone is used for

doping purposes in endurance
athletes to facilitate recovery.
Testosterone may also increase red
blood cell production and thereby
aerobic exercise capacity

MacConnie et al. (1986). NEJM

v Muscle mass gain in athletes: exogenous anabolic steroid hormones (slide 2 out of 2)
43 healthy men randomized to 10 weeks of testosterone
or placebo injections, with or without strength training
(3 days/wk, upper and lower body exercises, 4 x 6
repetitions, 70-90 % RM)

Bhasin et al. (1996). NEJM

v Muscle mass gain in athletes: genetic modification and muscle mass

Genetic mutation, disruption of myostatin leading to muscular hypertrophy and increased strength

• Studies assessing exogenous anabolic hormones or genetic modification demonstrates that

the absolute potential to develop muscular hypertrophy and strength is not reached
with training

• The absolute potential is intrinsically limited by genetic factors

Zou et al. (2015). Journal of Molecular Cell Biology
v Pharmacological ergogenic aids: anabolic steroids

POTENTIAL RISKS
• Large increase in estradiol concentration, the major female hormone, possibly leading to
gynecomastia (excessive development of the male mammary glands, sometimes
secreting milk) in men taking steroids

• Abnormal growth of internal organs leading to eventual (cardiovascular, kidney, liver)

dysfunction

• Increased risk of stroke and acute myocardial infarction due to increased blood
platelet aggregation and impaired myocardial blood supply
erectile dysfuntion
• Prolonged high dosages of steroids often impair normal gonadal endocrine function.
Gonadal function usually returns to normal after several months of steroid cessation

• …
v Pharmacological ergogenic aids: anabolic steroids

Exposure to anabolic steroids shortens life span of male rats

• Dramatic life-shortening effects of anabolic

steroids occurred in adult rats exposed to the
levels of steroids taken by physically active
humans

• One year after terminating the 6-month steroid

exposure, 52% of the mice given the high dosage
had died compared with 35% of the mice given
the low dosage and only 12% of the control
animals not given the anabolic steroids

• A 6-month exposure period represents about one-

fifth of a male mouse’s life expectancy, a
relative duration considerably longer than
exposures of most humans to steroid use
Bronson et al. (1997). MSSE
v Pharmacological ergogenic aids: anabolic steroids
Mortality in 545 male androgenic anabolic steroid (AAS) users and 5450 controls
matched by age and gender

3 times higher mortality

in anabolic steroid users

Horwitz et al. (2018). J Int Med

v Pharmacological ergogenic aids: anabolic steroids
Morbidity in 545 male androgenic anabolic steroid (AAS) users and 5450 controls

Horwitz et al. (2018). J Int Med

v Pharmacological ergogenic aids: ß2-agonists
• Clenbuterol, belonging to a group of chemical compounds (albuterol, clenbuterol,
salbutamol, salmeterol, terbutaline) classified as a ß2-adrenergic agonist, facilitates
responsiveness of adrenergic receptors to circulating epinephrine, norepinephrine, and
other adrenergic amines.

• A review of the available studies of animals (no human studies) indicates that when fed
to sedentary, growing livestock in dosages higher than those prescribed for bronchial
asthma, clenbuterol increases skeletal muscle mass and decreases fat mass

• Clenbuterol has particular appeal to female athletes because it does not produce the
androgenic side effects of anabolic steroids
growing beard, hair…
v Pharmacological ergogenic aids: ß2-agonists

• Clenbuterol as well as other ß2-agonists (e.g., salbutamol) are commonly prescribed as

inhaled bronchodilators for treating obstructive pulmonary disorders

Percentage of athletes approved for B2-agonist use and the percentage of medals won by these athletes

asthma inhaler can enhance exercise performance

2000 to 2006 Olympic Games Sheel et al. (2012). Exp Physiol

v Pharmacological ergogenic aids: ß2-agonists
v Pharmacological ergogenic aids: ß-blockers
• ß-blockers are competitive antagonists that block the receptor sites for catecholamines
adrenergic beta receptors of the sympathetic nervous system, which mediates the fight-or-
flight response

• ß-blockers seem to be effective performance enhancers when the performance in question

induces anxiety in a public setting
prohibited during competition
v Pharmacological ergogenic aids: ß-blockers
v Pharmacological ergogenic aids: narcotic analgesics

• Narcotic analgesics (e.g., morphine, codeine, tramadol, fentanyl) are used in sports to
treat pain and inflammation associated with injury

• Growing evidence: some athletes might be taking these substances in an attempt to

enhance performance via reducing the feeling of muscular fatigue

• Increased number of falls in road cycling elite competitions have been suggested to be
related to the use of narcotic analgesics

• The use of narcotic analgesics may not be necessarily ergogenic but can be harmful if
used to allow the participation in competition of an athlete with a severe injury

Holgado et al. (2017). Exp Physiol

v Pharmacological ergogenic aids: peptide hormones

Growth hormone (GH)

• Essential for growth (anabolism)

• Regulates metabolism

• Circadian rhythm

• Mainly stimulated by:

• Sleep

• Exercise
v Pharmacological ergogenic aids: peptide hormones

Growth hormone (GH) administration and lean mass (systematic review and meta-analysis)

Liu et al. (2008). Ann Int Med

v Pharmacological ergogenic aids: peptide hormones

Insulin

• Peptide hormone produced by beta cells of the

pancreatic islets

• Considered to be the main anabolic hormone of

the body

• It regulates the metabolism of carbohydrates,

fats and protein by promoting the absorption of
glucose from the blood into liver, fat and skeletal
muscle cells
v Pharmacological ergogenic aids: peptide hormones

Insulin

• Insulin is being used in a haphazard way to increase muscle bulk in body builders,
weight lifters and power lifters.

• Insulin also helps endurance athletes to facilitate recovery

• High insulin doses are usually injected along with oral consumption of carbohydrates to
preserve blood glucose levels

There is no established antidoping test to differentiate between natural and synthetic insulin
v Pharmacological ergogenic aids: enhancers of oxygen transport

TWO MAJOR MEANS TO INCREASE OXYGEN TRANSPORT

• Blood reinfusion

• Erythropoietin administration
v Pharmacological ergogenic aids: enhancers of oxygen transport
1970s
‘Reinfusing blood in order to improve sporting performance only
gained prominence in the 1970s. The outcomes of innumerable
races were decided by one simple question: who’d reinfused the
most blood?’

‘While ‘power’ athletes popped pill after pill throughout the 1970s
and ‘80s, anabolic steroids offered only minor benefits to their
endurance counterparts — cyclists, long-distance runners and
swimmers. What these elite sportsmen and women needed was
stamina, not strength. What they needed was more blood.’

Parisotto et al. (2010). The inside dope on drugs in sport

v Pharmacological ergogenic aids: enhancers of oxygen transport

Lasse Viren (long-distance runner, Finland)

• 5,000 and 10,000 m Olympic champion

• His doctor recognized multiple blood transfusions

• Outstanding performances only at great events

v Pharmacological ergogenic aids: enhancers of oxygen transport
1984 Olympic Games, Los Angeles

• 7 members of the USA team blood doped (blood reinfusion)

• 9 medals, 4 of them gold

• USA team was never before nor after in the podium

v Pharmacological ergogenic aids: enhancers of oxygen transport

Frank Beckenbauer (soccer player, Germany)

• Captain of the Germany team winner of 1974 World Cup

• ‘I have a particular method to stay on top of my game:

re-injecting my own blood’

• Claimed generalized blood transfusions in Germany in 1970s

v Pharmacological ergogenic aids: enhancers of oxygen transport

Blood reinfusion (doping)

v Pharmacological ergogenic aids: enhancers of oxygen transport

Effects of blood reinfusion on performance and aerobic capacity (VO2max)

- 800 ml of blood

+23 % Maximal running time

+9 % VO2max

Ekblom et al. (1972). J App Physiol

v Pharmacological ergogenic aids: enhancers of oxygen transport

Synthetic erythropoietin (EPO), 1987

• Better and longer life for millions of patients with anemia, cancer and kidney disease

• Same doping effects as blood transfusion

• Undetectable until year 2000

v Pharmacological ergogenic aids: enhancers of oxygen transport

1990s: the golden EPO decade

• Hematocrit > 50 %, estimated VO2max ≈ 100 ml/kg/min

• ‘Superhuman’ performances in professional cycling

• Impossible to win without EPO

Prof. Beng Saltin
 The EPO Myth
• EPO ‘killed’ 18 Dutch and Belgian cyclists in the late 1980s and early 1990s

• EPO abuse caused blood clotting, hyperviscosity and hypertension, which

provoked fatal heart attack, stroke or embolism
The Invention of a ‘Drug of Mass Destruction’: deconstructing the EPO Myth
https://doi.org/10.1080/17460263.2011.555208

• Thoroughly examination of existing evidence (anecdotal and scientific)

concerning the claim that EPO ‘killed’ cyclists

• Almost absolutely lack of empirical evidence

• Existing truly experimental and epidemiological research downplays or

even rules out the existence of a causal link between EPO intake and
sudden death in healthy adults.

• The story about the ‘EPO deaths’ is to be seen as anti-doping propaganda

Lopez et al. (2011). Sport in History

v Pharmacological ergogenic aids: enhancers of oxygen transport

2000s: back to blood transfusion

• EPO test available

• Back to blood transfusion

• EPO still used but ‘micro-dosing’

• < 10 % of ‘normal’ dose is enough to keep high Hbmass

• Undetectable after 24-48 hr

v Pharmacological ergogenic aids: enhancers of oxygen transport
The effects of microdose EPO in endurance athletes

• 10 days high EPO dose (260 IU/kg) → High Hbmass ([Hb]=17 g/dL)

• 20 days of EPO microdose (< 26 IU/kg) → Preserve Hbmass ([Hb]=17 g/dL)

Threshold for a positive sample

Ashenden et al. (2006). Haematologica

2009: Athlete Biological Passport

Sottas et al. (2011). Clinical Chemistry

 3 months EPO microdosing

+10 % Hbmass
Equivalent to
2 blood bags

No individual values were flagged as abnormal by the Athlete Biological Passport

Ashenden et al. (2011). Eur J Appl Physiol

v Pharmacological ergogenic aids: enhancers of oxygen transport
Increased aerobic capacity (VO2max) for at least 3 weeks after EPO

Lundby et al. (2011). British J Pharm

Further limitations of the Athlete Biological Passport

• Virtually impossible to detect abnormalities with blood

transfusion and withdrawal performed in the same day

• Manipulation of hematological values to fit in the Passport

• Biological variability → False positives

v Pharmacological ergogenic aids: glucocorticosteroids

Cortisol: the main human glucocorticoid

• Crucial for fuel mobilization in the course of and recovery from prolonged/intense exercise
• Facilitates prolonged and intense training as well as weight loss

• May induce massive increases in red blood cell volume

↑ Growth, differentiation and

release of erythroid progenitor cells

via Notch 1-2 receptors

↑ Cortisol

Montero et al. (2018). Compr Physiol

v Pharmacological ergogenic aids: glucocorticosteroids

Potency of a drug: the amount of drug required to induce a given effect

Longui et al. (2007). J Pediatr

https://www.uci.org
v Pharmacological ergogenic aids: diuretics
• Diuretics are often abused by athletes to:
• Excrete water for rapid weight loss
• Dilute urine and mask the presence of other banned substances

Positive findings of diuretics by all World Anti-Doping Agency (WADA) laboratories (2004-2009)

Cadwallader et al. (2010). Br J Pharmacol

 Many thanks for your attention

I am available if you have any question or comment