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by MESO-Rx
Disclaimer: Discussion of pharmaceutical agents below is presented for
information only. Nothing here is meant to take the place of advice
from a licensed health care practitioner. Consult a physician before
taking any medication.
June 1999
MESO-Rx:
Why did you start studying how steroids work?
Dharkam: Well, this was because of several factors such as
drug testing, increasing prices, reduced availability,.... Before
that we did not care about how it worked. More was always better. In
case of trouble we used more, period.
MESO-Rx:
I guess you had to find ways to get better results with lesser
drug amounts.
Dharkam: Exactly, this is the issue we faced at this time.
I started searching to understand how drugs like steroids worked in
order to elaborate new strategies to get the most out the least
amount. Strange as it may seem, natural bodybuilders can probably
benefit most from what I am going to say about steroid users. The
natural bodybuilders should keep in mind they produce testosterone,
too. They just have less than drug users. So it is even more
important for them to get the most out of this modest amount. Of
course, it won't do any harm to steroids users to better understand
what they are doing.
MESO-Rx:
Let's start with we beginning. What is going on in our muscles
after training?
Dharkam: This is not an easy question since we still
missing some crucial points. But as you can imagine there is a
positive side and a negative side. In other words, training will
induce an anabolic drive but will also have some negative catabolic
effects on the trained muscles. Another big problem is that the link
between the positive and the negative impacts of training is not
always very clear.
MESO-Rx:
What do you mean? Anabolism builds up muscles, catabolism
destroys it.
Dharkam: If only it were so simple! But some of the
catabolic effects of training will be essential to induce an
anabolic drive.
MESO-Rx:
In other words: no catabolism, no anabolism. We train to induce
some form of damages on our muscles. Then, to avoid future problems
when this kind of stress is re-imposed on the muscles, they grow
bigger and stronger. But are you sure we must induce damage to
induce hypertrophy?
Dharkam: The fastest way to get bigger muscles does
involved inducing damage. This assumes you can recover quickly and
completely. But there are some other ways to build up muscles
without having to induce too much muscle damage. The best strategy
being to combine the two techniques.
MESO-Rx:
When I think about it, isn't it stupid to induce damage and then
rebuild the muscle? It is like having to go bankrupt to get rich.
And bankrupt again to get richer...
Dharkam: I would not go so far. But to earn money you
first have to invest. So you spend money before getting a return on
that money spent. But investing into a project does not guarantee
that you will get a fair return. This is the same with training.
Causing damage is not a sure way of inducing hypertrophy. Just as
your investment must be wise and not excessive, you do not want too
much damage in order to produce what I call "positive catabolism."
It means when one wants to induce damage, it should be a damage
which will trigger anabolism.
MESO-Rx:
As in any investment, there will be some productive investment:
what you call positive catabolism and some invests will be a
complete waste given zero return. This is what you call negative
catabolism.
Dharkam: Right.
MESO-Rx:
So not every catabolism will trigger anabolism. Just like many
infectious diseases will induce muscle wasting but no anabolism at
all.
Dharkam: This is correct. This is the idea behind positive
and negative catabolism.
MESO-Rx:
OK, but I am not convinced that catabolism is essential for
muscle growth. For example, anabolic steroids are said to be both
anabolic and anti-catabolic at the same time. This indicates that
catabolism is not required for muscle growth.
Dharkam: Anabolic steroids are the perfect example of my
point. Do you have any evidence that they are anti-catabolic in
humans?
MESO-Rx:
This is the theory that is the most popular in the US. I guess
this is based on extrapolation from animal studies. And there has
been this assumption that steroids stop working on the muscle
steroid receptors after a few weeks, so one of the theories is that
steroids must be working on, or interfering with cortisol.
Dharkam: Well, get ready for a shock. I certainly do not
pretend to know everything about how steroids work, but one thing
that has been shown both in vitro and in vivo is that anabolic
steroids are catabolic for the muscles.
MESO-Rx:
Are we talking about the same drugs?
Dharkam: Yes, I am talking of stuff like nandrolone,
stanazolol, testosterone, oxymetholone,... If you read the human
studies you will see that those drugs increase creatine kinase
level. One more time, this has been proven both in test tube and in
real life. Other studies point out that anabolics increase the rate
of appearance of leucine which is a marker for proteolysis.
[Editor: For our readers -- creatine kinase is an
enzyme released from the skeletal muscles. It is used to measure
muscle damage.]
MESO-Rx:
So you mean steroids increase muscle damage as seen with elevated
levels of creatine kinase and muscle proteolysis. Is training
required to see this effect?
Dharkam: No, remember this is taking place even in test
tube when steroids are applied directly on muscle cells. However,
anabolics potentiate training-induced muscle damage.
MESO-Rx:
You mean that steroids plus training will induce more muscle
damage than the same training alone? This is very controversial. Is
an elevated creatine kinase level always correlative to trauma and
catabolism? Would there be another explanation for this? Like simply
longer, less traumatic training sessions? And from your rationale,
Accutane should be an anabolic, because it also increases creatine
kinase in the blood.
Dharkam: Steroids will make the muscle more vulnerable to
the damaging effects of training. This has a direct implication:
steroid users will not have to train as hard as a natural
bodybuilder to induce damage. Don't get me wrong -- I am not saying
that all the steroid users are not training hard. I am just saying
that they can get away with easy, light training and still give
their muscles the proper stimulation to induce growth.
As far as creatine kinase is concerned, it has to be understood
that it is a rough marker of muscle damage. With the right kind of
steroids, you can experience a huge CK increase. Smaller variations
have far less significance than big increases. Inducing muscle
damage is only one way of forcing muscle growth, not the only way.
Reducing muscle damage while the not altering the protein synthesis
rate will also increase muscle mass.
As far as all drugs that increase CK level being anabolic, this
is not true. CK is just a marker of catabolism. It does not say
whether it is a positive or a negative catabolism. By the way,
clenbuterol increases CK level at proper dosage. Another sign that
steroids or clen induce muscle damage is the more pronounced muscle
soreness sensation following a training session with the proper drug
choice (steroids that do not aromatize -- but this is another
story).
MESO-Rx:
Do you play with creatine kinase and leucine rate of appearance
to determine training volume and frequency?
Dharkam: First of all we use only creatine kinase (CK)
level to adjust training. Leucine rate of appearance is both too
complicated and way too expensive. On the other hand, creatine
kinase level is only a rough measure. It sure could be more
accurate. But it is useful at suggesting a trend. My goal in
bodybuilders is to shoot for a very high CK level.
MESO-Rx:
This is not for natural bodybuilders, is it?
Dharkam: No, of course not. This is for bodybuilders who
take injectable drugs to properly recover. I want a moderately high
level for steroid-free bodybuilders. Natural weight lifters should
be careful not to go overboard with their CK level. There might be a
role for anticatabolic supplements here. Of course, CK level
fluctuates a lot among individuals. For example, African American CK
level is far higher after training than for Caucasians. So CK level
should be measured before the training period and during the
training phase. I look at the increase rather than the absolute
value.
MESO-Rx:
If steroids induce catabolism how do they build bigger muscles?
Where do they act to produce their effects?
Dharkam: Steroids are both catabolic and anabolic at the
same time. There are just more anabolic than catabolic. Their
effects are mediated by the androgen receptors.
MESO-Rx:
Some studies show that taking androgen will greatly reduce the
number of androgen receptors located in the muscles. This is said to
be one of the major reasons why the average guy will not grow
significant amounts of muscles while on steroids.
Dharkam: This is correct, when too much androgen is
present in the blood, androgen receptor levels will decrease. But we
have many studies showing that training a muscle will renew those
receptors. This is why why there is a synergy between androgen and
training in bodybuilders while steroids only work to a limited
extent in untrained persons.
MESO-Rx:
So why has there been no reaction to this in the U.S.?
Dharkam: I do not know but they sure made it in my
country. If you look at a steroid user, it is so obvious. If only
the body part that he trains grows, it is simply that he renews or
re-opens the androgen receptors of this specific muscle by training.
MESO-Rx:
Does this re-opening only take place in steroid users or does
training also increase the number of androgen receptors in natural
bodybuilders? And saying "re-opening" do you mean that more
receptors are being made, or the life of steroid receptor is
extended? Or both?
Dharkam: This is a good question. When I say "re-open"
this is not strictly correct. A bodybuilder who has never taken
steroids does not suffer much androgen receptor downregulation.
Training will simply increase the number of ready-to-work androgen
receptors. He will have far more receptors than the average
untrained Joe. This is why the first cycle of anabolics is very
often the best. Plenty of receptors. As the cycle continues, the
number of androgen receptors will go down. But with proper training
targeted at re-opening the androgen receptors, we can prevent the
stagnation we see in numerous western bodybuilders after several
drug cycles. Where do the receptors come from? I assume their
expression is increased. I do not know if their half life is
extended.
MESO-Rx:
How should we train to re-open those receptors? Does this
strategy work the same in natural bodybuilders and steroid users? I
seem to recall that the study on upregulating steroid receptors was
done on endurance athletes, who are notorious for having low
testosterone.
Dharkam: Natural bodybuilders will not react the same way
as steroid users. Remember, natural bodybuilders want more androgen
to get the most of their endogenous testosterone, but their training
capacity is limited as they do not want to overtrain which reduces
androgen production. On the other hand, steroid users have enough
androgen hormones, what they need is more receptors. So goals and
limitations are radically different. Their training strategies
should reflect those different goals. Too much training in natural
bodybuilders will reduce their testosterone level to almost zero.
With zero testosterone, you can have all the receptors you want you
will not grow, period. On the other hand, steroid users need to
avoid undertraining. They do not really care what happens to their
androgen level, it is artificially high. But they want enough
training and the right kind to increase their androgen receptor
level, which is reduced by high exogenous androgens.
MESO-Rx:
Let's see if I understand you: Natural bodybuilders want to use
training to both increase their testosterone level and up-regulate
androgen receptors. But the only goal of steroid users is to
increase androgen receptor levels no matter what the cost, because
they can artificially control their androgen level. How would you
explain Dorian Yates? He does very little training, but he has grown
quite large. Are you saying that if he increased his training load,
he'd get bigger?
Dharkam: Correct -- different goals, different training
strategies. As far as Yates is concerned, if you look at his video,
you will realize that he does far more sets that what most magazines
claim. Since muscle contraction is one of the main up-regulators of
androgen receptors, the harder your muscle contracts, the more
androgen receptors you'll get. A Yates training season is likely to
induce more intense contractions than most bodybuilders will ever
experience.
Another common question for Yates or any other bodybuilder is,
wouldn't they be bigger faster by training another way. It takes 5
to 10 years to make a good pro. That's far too long. It should not
take more than 6 to 12 months. It only shows us we are doing things
the wrong way.
To make things more complicated, intense muscle contractions are
not the only up-regulators of androgen receptors. Training volume is
another important aspect. Many people will not grow by following
Yates' training style. They need frequent, moderate intensity
training. Many Blacks in Europe only respond to this kind of
stimulation. By the way one can only respond to this kind of
training with steroids. They lose mass when they train less often
with more weight. It means there are different ways to up-regulate
androgen receptors. You just have to figure out which one is the
most efficient for you.
MESO-Rx:
So far, so good. Can you tell us how training can induce an
androgen receptor up-regulation?
Dharkam: Androgen receptors are not the only receptors
affected by weight training. Levels of muscle GH-receptors,
IGF-receptors, cortisol-receptors,... are all altered by exercise.
As far as the mechanism of actions are concerned, it is still too
early to tell. We know that the degree of tension applied on a
muscle, the training frequencies, ... are important factors. Also,
positive reps do not produce the same kind of effects than eccentric
reps on androgen receptor level. Furthermore, not all the different
muscle groups respond with the same up regulation of androgen
receptors. This is why some muscles respond better to training than
others.
MESO-Rx:
What you are saying is that you can modulate the level of muscle
androgen receptors by using different training strategies.
Dharkam: Yes, this is why it is so important for
bodybuilders (natural or not) to understand how the way they train
will affect androgen receptor level. For example, if some techniques
up-regulate androgen receptor level, others will down-regulate it.
It is not necessarily bad as long as you are aware of which strategy
is doing what. You just take more days off when your muscles are
"poorer" in androgen receptors. On the other hand, it is a waste not
to train more frequently when the androgen level and the receptor
level are both high.
MESO-Rx:
But more precisely by what mechanism does muscle tension
influence muscle androgen level? And is this validated by research,
or it's your speculation?
Dharkam: Let me first state again that training affects
androgen receptors of the trained muscle ONLY. The most likely
mechanism of actions is that training induces the local release of
different growth factors. For example, Platelet Derived Growth
Factor (PDGF) could be at least partially responsible for the
up-regulation. Of course we all try to find substances that can
duplicate this upregulating effect.
MESO-Rx:
You mean like Prostaglandin F2?
Dharkam: Ah, the cat's out of the bag.
MESO-Rx:
Do anabolic steroids block cortisol receptors? Or do they reduce
the number of cortisol receptors? Do they do anything on cortisol
receptors? They must be doing something, because too many
weightlifters complain about joint pains after cycle.
Dharkam: First, let's review the theories of anabolic
steroid effects on cortisol receptors. The first theory claims
androgens bind cortisol receptors without activating those
receptors. In short, anabolics would block cortisol receptors. Our
researchers were unable to see such a thing in test tube. I know
some old studies showed it. Most including very recent ones are
unable to reproduce those results. Of course, that is in test tube
It could be different in real life. But if androgen did block
cortisol receptors in bodybuilders, we would see a sudden increase
in cortisol level. According to all the blood tests I have see this
is not the case. Within a few days, the body would produce more
cortisol receptors. I think it is not a secret for anyone to say
that the studies of Rosen and Mayer (the first scientists to have
shown a possible cross reaction between androgen and cortisol
receptors) were flawed.
MESO-Rx:
Can you expand on that point.
Dharkam: Oh yes. Simply said they postulated that there
were no androgen receptors on muscles. That was in the 70's. We now
know this is not true. The receptors they thought to be cortisol
receptors could have been in fact androgen receptors. But to be
fair, there are several Russian studies showing a possible cross
reaction. I just do not buy it.
MESO-Rx:
So you're saying that this theory is unlikely to happen in real
life?
Dharkam: If it did the body would compensate in doing two
things: in a matter of a few hours cortisol level would skyrocket.
In a few days the body would create new cortisol receptors on the
muscles. Even if the theory was correct, it would not explain the
muscle gains seen with anabolics as the body would overcome any
blocking effect at the cortisol receptors.
MESO-Rx:
What about the second theory?
Dharkam: It claims that steroids will reduce the number of
cortisol receptors on the muscles. It seems to be able to do that
without touching the cortisol receptors according to some studies
but not all. Again it might be possible, but I do not think it
happens in real life. Whenever the brain would detect this reduction
in receptor level, it would increase the cortisol release. The blood
concentration of cortisol would increase in parallel with the down
regulation. So, no anabolic effect would be seen as the decrease in
cortisol receptors would be canceled out by more cortisol.
MESO-Rx:
But this has been shown to take place in animal muscles with
trenbolone!
Dharkam: This is true and not only with trenbolone but
also with other androgens such as testosterone, nandrolone,... But
let's talk about the most documented anabolic: trenbolone. From the
animal studies where cortisol receptor downregulation was seen, we
learn that trenbolone is not truly anabolic. In fact, trenbolone
reduces protein synthesis rate: it is a mild androgen blocker. Let
me state that again, in animals, trenbolone is an androgen receptor
blocker. On the other hand trenbolone reduces muscle catabolism even
more. That is how it produces its muscle building effects.
MESO-Rx:
If I understand you, trenbolone reduces both muscle synthesis and
degradation rates at the same time. But it reduces degradation rate
far more than synthesis. So, the balance of the two is positive and
muscle mass can be increased.
Dharkam: Right. Now, let's apply that to humans. If true
we would have a mild anti-androgen effect with a strong
anti-catabolic effect. Think about it, this drug would be perfect
for women. No androgenic effect, just bigger muscles.
MESO-Rx:
Ok, I see your point. It does not take a genius to see this is
not the case in humans. Trenbolone being a strong androgenic steroid
so it rules out any possibility of being an androgen receptor
blocker.
Dharkam: True. Trenbolone would not cause any acne in that
case. In fact if we apply the animal results to humans, trenbolone
could cure acne. Isn't that funny? And if we cannot apply this
effect of trenbolone, who would extrapolate its effect on cortisol
receptors to humans? We have to get use to the idea that sometimes
animal findings just do not apply to humans.
MESO-Rx:
What is the third theory?
Dharkam: The last theory states that androgens can alter
cortisol effects by acting at the post receptor level on something
called HRE: hormone response element.
MESO-Rx:
Let's stop right here, this looks complicated. Cortisol binds its
receptor normally. It sends a message. Then what?
Dharkam: Then the androgen prevents the message from
arriving properly. This is like a letter you try to send. The first
cortisol theory states that you cannot put it in the mail box as the
opening is blocked. The second theory states that you cannot post
your letter as you cannot find a mail box. But the last theory
states that you can find a mail box, and you can put your letter
into it. But the letter is stolen along the way before it reaches
its destination. This would mean a post (after) mail box defect. In
scientific terms, we call it a post receptor defect. Let's not go
any further. This is the most documented theory. But again the body
would compensate with more cortisol and more receptors.
MESO-Rx:
Didn't you tell me that a recent study performed on HIV+ humans
does not seem to support those theories?
Dharkam: They were unable to see any cross reaction
between androgen and cortisol receptors even at the HRE level. Of
course, it is hard to extrapolate from that study as it was not
performed in healthy trained people. But this still provides some
indications anyway.
MESO-Rx:
OK. But what if we combine all the theories into one. It would
mean a cortisol receptor blockage (theory one) plus a reduction in
cortisol receptor level (second theory) plus the post receptor
defect (third theory)?
Dharkam: This is possible but again there would be a huge
boost in cortisol secretion. This is not what I have seen in steroid
user blood tests. Here is a last detail to convince you. Cortisol
receptors are found all over the different muscles. If anabolics
acted to reduce cortisol catabolic effect, it would do it all over
the body. This is not what I have seen in my athletes. Someone who
never trains calves does not get bigger calves with steroids. A
muscle grows only if specifically stimulated.
MESO-Rx:
I see where you are going. Every single muscle would grow, not
just the trained muscles.
Dharkam: Exactly. A bodybuilder who only works his arms
would see his legs and calves grow too. The cortisol muscle wasting
effect takes place 24 hour a day, 365 day a year. It takes place in
all the muscles. A reduced cortisol wasting effect will make every
muscle grow.
MESO-Rx:
You are ruling out any effect of anabolics on cortisol?
Dharkam: I did not say that. Androgens do influence
cortisol but not at the receptor level. Some anabolics tend to
increase cortisol level. Most attenuate training-induced rises in
cortisol level.
MESO-Rx:
Which anabolics control the cortisol increases that result from
training?
Dharkam: I cannot tell you that. Not that it is a well
kept secret but it depends on the users. The same anabolic will
increase cortisol in some while it will keep it at a moderate level
in others. This is why we rely on blood tests so much. In fact, this
is one parameter we use to determine which steroid or which
combination of steroids suit the user best.
MESO-Rx:
So I guess I will not ask you about dosages or stacking?
Dharkam: They must be tailored to meet the specific user
needs.
MESO-Rx:
If some steroids reduce cortisol level we should expect growth
all over, not just the trained body parts.
Dharkam: Well, I did not exactly use the word reduce.
Training tends to increase the cortisol level. The more one trains
the higher the cortisol level should be. This is not always true as
we can find exceptions but it is generally true in most people.
Taking the right steroids will blunt or prevent this effect of
training. Steroids do not reduce the cortisol level, they reduce
stress-induced rise in cortisol. This is different. It is more
correct to say that it keeps the cortisol effect neutral when
compared to the average natural bodybuilders. Again, natural
bodybuilders should keep that in mind whenever they look at a pro
bodybuilder's training routine.
MESO-Rx:
I see. Certain steroids -- which may be different from person to
person -- allow users to avoid the major obstacles caused by too
much cortisol.
Dharkam: It avoids cortisol negative effects before they
can take place so there is no need to fix it.
MESO-Rx:
But as cortisol causes wasting, anabolics are anti-catabolic not
catabolic?
Dharkam: Again there are several kinds of catabolism. It
seems that anabolics reenforce the "positive catabolism" while
reducing the "negative catabolism." So it is not correct to say it
is an anti-catabolic drug. Also the cortisol wasting effects are due
in large part to its anti-anabolic effects (it reduces the anabolic
drive). Restoring this anabolic drive has to do with anabolic rather
than anti-catabolic properties of androgen.
MESO-Rx:
If the proper steroids prevent cortisol rises and if they do not
act at the receptor level, how do you explain the pain killing
effect experienced during a cycle?
Dharkam: During is the right word. Once steroids are
stopped, the effect is gone. If this effect was mediated at the
cortisol receptor level, this would not take place at the end of a
cycle. Remember we said steroids moderated cortisol level. Once the
cycle is stopped, the cortisol level will start to rise as the
preventive effects of anabolics slowly disappear. Sometime there is
an overshoot in cortisol production.
MESO-Rx:
What you mean is if anything, cortisol level is higher at the end
of the cycle than during...
Dharkam: So if the pain killing effect of anabolics was
due to androgen acting on cortisol receptors, the pain would not
come back at the end of a cycle.
MESO-Rx:
I see. But how do you explain the anti-inflammatory effect
produced by anabolics?
Dharkam: I did not use the term anti-inflammatory. I use
the term pain killer. Can you give me the name of a natural pain
killer?
MESO-Rx:
Opioids.
Dharkam: Very good. Opioids are pain killers. Their effect
is mimicked by drugs such as morphine.
MESO-Rx:
Do you mean that steroids act on opioid receptors just like
morphine?
Dharkam: Not exactly like morphine but this is basically
what I have suggested. Do you know how morphine influences cortisol
level?
MESO-Rx:
It tends to keep cortisol secretion low especially in case of
stress.
Dharkam: Exactly. I will not go much further into this
theory. But by acting on some opioid receptors, anabolics effect
both cortisol concentration and pain.
MESO-Rx:
Morphine also reduces testosterone secretion. Wouldn't androgens
down-regulate their own secretion?
Dharkam: Correct again. This is one of the numerous
negative feedbacks of androgens on their own secretion.
MESO-Rx:
Is this the only way that anabolics reduce pain sensation?
Dharkam: No, there is research showing that anabolics act
on the nervous system where they reduce the perception of pain. So
we are far away from cortisol. And you can understand why the pain
comes back upon steroid withdrawal.
Here are some take-home points:
- Proper weight training increases androgen receptor
level on the trained muscles.
- This explains the synergy seen between anabolics and
training in bodybuilders.
- Natural bodybuilders and drug users should be aware of the
different effects of the different training techniques and
frequencies on androgen receptor level.
- The primary goal of a natural bodybuilder is to increase
testosterone level with intense, short training sessions.
Upregulating androgen receptor level will potentiate
testosterone anabolic effects.
- The primary goal of a steroid user is to re-open androgen
receptors at any cost!
Overall, natural bodybuilders should not train like drug users.
And the training of drug users should be radically different from
that of natural bodybuilders. In other words, drug free athletes
need to avoid training advice from champions and listen to natural
bodybuilders even though they are not as big as professional
bodybuilders.
References:
- Stein TP. 1999 Jan.
Endocrine relationships during human spaceflight. Am J
Physiol. 276:E155-62.
- Fagan JM, Goldberg AL. 1986 Apr.
Inhibitors of protein and RNA synthesis cause a rapid block in
prostaglandin production at the prostaglandin synthase step.
Proc Natl Acad Sci U S A. 83(8):2771-5.
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