Performance enhancing drugs

Question 1

What is erythropoietin (EPO)?

Answer 1

• Erythropoietin - a glycoprotein hormone
• Promotes red blood cell production
• Naturally made in kidneys
• In clinic to treat anemia due to

Chronic kidney disease,
Cancer chemotherapy,
HIV therapy

Question 2

Who is using anabolic steroids?

Answer 2

Sportspersons in sports such as cycling, american football, running

Associated with increased aggression, violence,
criminality etc

Question 3

What are anabolic steroids?

Answer 3

the most common doping agent is anabolic steroids

synthetic variants of testosterone; this is a vital hormone for tissue building:

The rational of anabolic steroids is to modify testosterone such that unwanted actions are removed
In normal physiology, testosterone is metabolised into DHT via 5α-reductase – this is a much more potent version of testosterone
Moreover, some testosterone converted to oestrogen via aromatase – steroid users will inject excess testosterone such that female hormone levels rise owing to gynea

Question 4

Desirable effects of anabolic steroids

Answer 4

Increased muscular mass
Increased muscular strength
Increased energy
Increased self-esteem

Question 5

Physical side effects of anabolic steroids

Answer 5

Gynaecomastia(man boobs)
Baldness
Striae – striations when muscle grows too fast
Testicular atrophy
Acne
Cardiovascular Diseases

Question 6

Common steroids on the market

Answer 6

Testosterone
Nandrolone
Methandrostenolone
Stanozolol

Question 7

Testosterone vs nandrolone- steroid metabolism

Answer 7

Testosterone binds to AR and exerts effect, whilst DHT gives 10x effect
Estrogen can also exert effects via ER

Nandrolone has CH3 group removed, making it a 5x less good substrate to aromatase such that the extent that is converted to estrogen is much lower
Moreover, is convered by 5a-reducase to Dinandrolone which is inactive on the AR

Question 8

How do testosterone and nandrolone exert their effects and also what are the side effects associated with?

Answer 8

In the muscles, there is very little 5α-reductase so the anabolic effects of muscle building are predominantly mediated by Testosterone and Nandrolone themselves
However, the androgenic effects associated with baldness, testicular atrophy (masculinsation et.c) are mainly exerted by ARs at the prostate where 5α-reductase levels are much high
Hence the ambition is to find a steroid with pure anabolic effect with as little androgenic side effects – not been done yet

Question 9

Modifications on D-ring of testosterone is done to..

Answer 9

make adjustments regarding administration

Testosterone by itself taken as a tablet will be immediately degraded

Therefore a long fatty acid can be added via ester binding which allows for injection into muscles as an oil form

If you want to take it orally, it is essential to protect –OH group because if this is oxidised the activity will be lost; addition of methyl group to do so (methylnone is the only exception)

Question 10

What happens at week 12 of administration which leads to injection of HCG for 3 weeks?

Answer 10

At week 12 of administration, HPG-axis shuts down due to the exerted negative feedback such that users become infertile (testicular atrophy)
Therefore at this point, they inject with HCG for 3 weeks to kickstart the HPG-axis again such that GnRH is released again allowing for endogenous testosterone production

Question 11

Why is an oestrogen receptor antagonist tamoxiphen (NOLVADEX) also used in addition to HCG injection after 12 weeks of administration?

Why might aromatase inhibitors also be used?

Answer 11

In addition to this, they will also use Estrogen Receptor antagonist Tamoxiphen (Nolvadex) to reduce the severity of side effects; can also use aromatase inhibitors which is available on the market to treat breast cancers

Question 12

Where is the androgen receptor (AR) found?

Answer 12

Androgen receptor is found in the brain; particularly dense expression in hypothalamus, hippocampus, VTA

Question 13

What are some CV complications?

Answer 13

The heart is just one big muscle therefore steroid use can lead to left ventricular hypertrophy
Same as having high BP over a long period of time
This can give rise to blood clots and MI

Question 14

How does an attachment of 17-alpha alkyl group and esterification of the OH on the testosterone molecule help?

Answer 14

DONE WHEN TESTOSTERONE IS ADMINISTERED ORALLY?

17 alpha alkyl group: confers oral activity

esterification confers depot activity (protects the OH group)- ENZYMES CANT OXIDISE THE HYDROXYL GROUP

Question 15

WHY IS CH (ethinyl) added to the OH group in estrogen

Answer 15

Protects it when administering orally

Question 16

We usually start with testosterone administration, what other common substances are used afterwards to regulate the effects of testosterone?

Answer 16

Anti-estrogens

Human chorionic gonadotropin (hCG) – to retain fertility

Stimulants – aids intense training e.g amphetamines

Sleeping agents (benzodiazepines) – need a good night sleep bc growth hormone is released at night

Analgesics – used to treat muscle pain
b2-agonists – increases oxygen supply

Diuretics – removes water from body to get shredded such that muscle looks more pronounced

Question 17

Anabolic steroids van also cause dependence- how?

Question 18

Can anabolic steroids cause dependence?

Answer 18

Drug dependence – DSM 5

Effects on the brain reward system
– Endorphins, dopamine, GABA etc.

Depression

Link between anabolic steroids and opiate
addiction.

Question 19

What happens to people who try to stop using anabolic steroids

Answer 19

Can get depression (DSM 5)

Withdrawal:
- characteristic withdrawal syndrome- characterised for AAS by 2 or more of the following features: depressed mood, hypersomnia or insomnia, prominent fatigue, decreased appetite and loss of libido

• AAS are used to relieve or avoid withdrawal symptoms

Question 20

AAS are used to relieve or avoid withdrawal symptoms

HOW?

Answer 20

Anabolic steroids increase the levels of endorphins in the drug reward system
Endorphine level in VTA increases with higher doses of anaboloic steroids which will correspond with dopamine release to nucleus accumbens (not a clear euphoria like cocaine for example, its more the expectation factor of having a good training sesh rather than actual effect of CNS)
After 2 weeks of use, D1 receptor expression in Nucleus accumbens decreases due to internalisation – this is a homeostatic mechanism

Question 21

STUDY: effect of AAS on alcohol intake was investigated in rodent modes:

Answer 21

The rats choose alcohol over water
Steroid users usually avoid alcohol bc they have difficult regulating their intake
This is likely due to the fact that steroids trigger reward system

Question 22

How is AAS associated with increased aggression?

A study in which rats were provoked by pushing a rod to their noses found that AAS rats will attack the rod whilst control rats just walk away

Answer 22

The amygdala, hypothalamus and periaquiductal grey matter are important in mediating aggression

The variations in transmitter systems all correspond to increased aggression

Question 23

How does AAS increase competitiveness?

Answer 23

A study in which rats were put in different cages found that the control and ASS rats drink same amount of water However when placed into same cage with only one bottle, the ASS rats totally dominate and drink the majority – note that AAS rats that don’t train are actually 20% smaller than the control!

Question 24

AAS and anxiety

Answer 24

Anxiety is decreased

When a loud bell is rang, control rats spend more time running away and then hiding compared to AAS

Question 25

How do high doses of AAS impair cognition?

Answer 25

There are reports indicating that steroids induce impairments in cognitive function in AAS abusers Experimental animal studies using water maze (MWM) demonstrated that AAS may produce negative effects on cognition
Male rats exhibited impaired Performance in the Morris water maze (MWM) following exposure to the AAS nandrolone decanoate.

AAS causes reduction in the number of neurons in hippocampus, parietal cortex and prefrontal cortex regions and increases oxidative damage

Question 26

HALLBERG RESEARCH:

If a decline in cognitive impairment is observed after drug use, how can this damage be repaired?

Answer 26

There are a lot of nerve cells within the hippocampus
Primary cell cultures can be carried out such that nerve cells are isolated from mice and grown

Long-term use of opiates may lead to negative effects on learning and memory
Higher doses of morphine lead to nerve cell death – a toxic effect

GROWTH HORMONE has been used as a doping agent; may have a role in reversing this damage
GH replacement therapy produces improved short term as well as long term memory (Deijen et al., 1998)
GH affects cognitive functions in rats (Schneider-Rivas et al., 1995)
GH improves cognitive capabilities in hypophysisectomized rats (removal of pituitary) (LeGrevés et al., 2000, 2006, 2011) - NMDA subunits are up-regulated

Question 27

Cell culture found that co-treating nerve cells with morphine AND growth hormone….

Answer 27

indeed protects the cell

Now working with gene therapy to stimulate endogenous GH production in specific regions of the hippocampus in order to improve cognitive function
Take home message is that Growth hormone (GH) may reverse brain damages

Question 28

Angiotensin IV - IRAP-inhibitors: use?

Answer 28

Improve cognitive function?

Angiotensin IV does not bind to AT-1 or AT-2 receptors and IS NOT involved in mediating blood pressure
Instead, binds to IRAP enzyme where it acts as an inhibitor
In terms of hippocampal nerve cells…
Increased synaptic contacts allow for greater communication between neurons and this in turn facilitates learning and memory
The density of dendritic spines (connections) correlates extremely well with both the capacity to learn as well as a marker for acquired knowledge (O’Malley et al., 2000)

Question 29

What is Angiotension IV?

Answer 29

peptide – a peptide drug as an oral pill will never work as would be broken down immediately, and will only half a short-half life even if injected
Important part of the molecules were conserved to synthesize new molecules – these are peptidemimetics of Angiotensin IV
When added to nerve cell cultures, the number of dendritic spines increases which corresponds to enhanced learning and memory
Tested in rodent models; treated mice perform much better in mazes compared to controls but does not affect movement speed or other behaviours, they just find their way around bette