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Putting to bed the myth of AR downregulation
Androgen receptors down-regulate. Don't they?
One misunderstood principle of steroid physiology is the concept of androgen
receptors (AR), sometimes called "steroid receptors", and the effects of steroid
use on their regulation. It is commonly believed that taking androgens for
extended periods of time will lead to what is called AR "down regulation". The
premise for this argument is; when using steroids during an extended cycle, you
eventually stop growing even though the dose has not decreased. This belief has
persisted despite the fact that there is no scientific evidence to date that
shows that increased levels of androgens down regulates the androgen receptor in
muscle tissue.
The argument for AR down-regulation sounds pretty straightforward on the
surface. After all, we know that receptor down-regulation happens with other
messenger-mediated systems in the body such as adrenergic receptors. It has been
shown that when taking a beta agonist such as Clenbuterol, the number of
beta-receptors on target cells begins to decrease. (This is due to a decrease in
the half-life of receptor proteins without a decrease in the rate that the cell
is making new receptors.) This leads to a decrease in the potency of a given
dose. Subsequently, with fewer receptors you get a smaller, or diminished,
physiological response. This is a natural way for your body to maintain
equilibrium in the face of an unusually high level of beta-agonism.
In reality this example using Clenbuterol is not an appropriate one. Androgen
receptors and adrenergic receptors are quite different. Nevertheless, this is
the argument for androgen receptor down-regulation and the reasoning behind it.
The differences in the regulation of ARs and adrenergic receptors in part show
the error in the view that AR down-regulate when you take steroids. Where
adrenergic receptor half-life is decreased in most target cells with increased
catecholamines, AR receptors half-live's are actually increased in many tissues
in the presence of androgens.1
Let me present a different argument against AR down-regulation in muscle tissue.
I feel that once you consider all of the effects of testosterone on muscle cells
you come to realize that when you eventually stop growing (or grow more slowly)
it is not because there is a reduction in the number of androgen receptors.
Consider the question, "How do anabolic steroids produce muscle growth?" If you
were to ask the average bodybuilding enthusiast I think you would hear,
"steroids increase protein synthesis." This is true, however there is more to it
than simple increases in protein synthesis. In fact, the answer to the question
of how steroids work must include virtually every mechanism involved in skeletal
muscle hypertrophy. These mechanisms include:
??? Enhanced protein synthesis
??? Enhanced growth factor activity (e.g. GH, IGF-1, etc.)
??? Enhanced activation of myogenic stem cells (i.e. satellite cells)
??? Enhanced myonuclear number (to maintain nuclear to cytoplasmic ratio)
??? New myofiber formation
Starting with enhanced growth factor activity, we know that testosterone
increases GH and IGF-1 levels. In a study by Fryburg the effects of testosterone
and stanozolol were compared for their effects on stimulating GH release.2
Testosterone enanthate (only 3 mg per kg per week) increased GH levels by 22%
and IGF-1 levels by 21% whereas oral stanozolol (0.1mg per kg per day) had no
effect whatsoever on GH or IGF-1 levels. This study was only 2-3 weeks long, and
although stanozolol did not effect GH or IGF-1 levels, it had a similar effect
on urinary nitrogen levels.
What does this difference in the effects of testosterone and stanozolol mean? It
means that stanozolol may increase protein synthesis by binding to AR receptors
in existing myonuclei, however, because it does not increase growth factor
levels it is much less effective at activating satellite cells and therefore may
not increase satellite cell activity nor myonuclear number directly when
compared to testosterone esters. I will explain the importance of increasing
myonuclear number in a moment, first lets look at how increases in GH and IGF-1
subsequent to testosterone use effects satellite cells.
In part 2 we will discuss the role of satellite cells and myonuclei and how
testosterone (androgens) activates these systems to create muscle growth far
beyond what simple activation of the androgen receptor can produce.
Don't forget Satellite cells!
Satellite cells are myogenic stem cells, or pre-muscle cells, that serve to
assist regeneration of adult skeletal muscle. Following proliferation
(reproduction) and subsequent differentiation (to become a specific type of
cell), satellite cells will fuse with one another or with the adjacent damaged
muscle fiber, thereby increasing the number of myonuclei for fiber growth and
repair. Proliferation of satellite cells is necessary in order to meet the needs
of thousands of muscle cells all potentially requiring additional nuclei.
Differentiation is necessary in order for the new nucleus to behave as a nucleus
of muscle origin. The number of myonuclei directly determines the capacity of a
muscle cell to manufacture proteins, including androgen receptors.
In order to better understand what is physically happening between satellite
cells and muscle cells, try to picture 2 oil droplets floating on water. The two
droplets represent a muscle cell and a satellite cell. Because the lipid bilayer
of cells are hydrophobic just like common oil droplets, when brought into
proximity to one another in an aqueous environment, they will come into contact
for a moment and then fuse together to form one larger oil droplet. Now whatever
was dissolved within one droplet (i.e. nuclei) will then mix with the contents
of the other droplet. This is a simplified model of how satellite cells donate
nuclei, and thus protein-synthesizing capacity, to existing muscle cells.
Enhanced activation of satellite cells by testosterone requires IGF-1. Those
androgens that aromatize are effective at not only increasing IGF-1 levels but
also the sensitivity of satellite cells to growth factors.3 This action has no
direct effect on protein synthesis, but it does lead to a greater capacity for
protein synthesis by increasing fusion of satellite cells to existing fibers.
This increases the number of myonuclei and therefore the capacity of the cell to
produce proteins. That is why large bodybuilders will benefit significantly more
from high levels of androgens compared to a relatively new user.
Testosterone would be much less effective if it were not able to increase
myonucleation. There is finite limit placed on the cytoplasmic/nuclear ratio, or
the size of a muscle cell in relation to the number of nuclei it contains.4
Whenever a muscle grows in response to training there is a coordinated increase
in the number of myonuclei and the increase in fiber cross sectional area (CSA).
When satellite cells are prohibited from donating viable nuclei, overloaded
muscle will not grow.5,6 Clearly, satellite cell activity is a required step, or
prerequisite, in compensatory muscle hypertrophy, for without it, a muscle
simply cannot significantly increase total protein content or CSA.
More myonuclei mean more receptors
So it is not only true that testosterone increases protein synthesis by
activating genetic expression, it also increases the capacity of the muscle to
grow in the future by leading to the accumulation of myonuclei which are
required for protein synthesis. There is good reason to believe that
testosterone in high enough doses may even encourage new fiber formation. To
quote the authors of a recent study on the effects of steroids on muscle cells:
"Intake of anabolic steroids and strength-training induce an increase in muscle
size by both hypertrophy and the formation of new muscle fibers. We propose that
activation of satellite cells is a key process and is enhanced by the steroid
use."7
Simply stated, supraphysiological levels of testosterone give rise to increased
numbers of myonuclei and thereby an increase in the number of total androgen
receptors per muscle fiber. Keep in mind that I am referring to testosterone and
testosterone esters. Not the neutered designer androgens that people take to
avoid side effects.
Another group of researchers are quoted as saying:
"it is intriguing to speculate that the upregulation of AR levels via the
administration of pharmacological amounts of androgens might convert some
muscles that normally have a minor or no response to muscles with enhanced
androgen responsiveness"(8)
This is not an argument to rapidly increase the dosages you use. It takes time
for these changes to occur and the benefits of higher testosterone levels will
not be immediately realized. It does shed some light however on the proportional
differences between natural and androgen assisted bodybuilders physiques.
Maintenance of the kind of muscle mass seen in top-level bodybuilders today
requires a given level of androgens in the body. That level will vary from
individual to individual depending on their genetics. Nevertheless, if the
androgen level drops, or if they were to "cycle off" the absolute level of lean
mass will also drop. Likewise, as the level of androgens goes up, so will the
level of lean mass that individual will be able to maintain. All of this happens
without any evidence of AR down regulation. More accurately it demonstrates a
relationship between the amount of androgens in the blood stream and the amount
of lean mass that you can maintain. This does not mean that all you need is
massive doses to get huge. Recruitment of satellite cells and increased
myonucleation requires consistent "effective" training, massive amounts of food,
and most importantly, time. Start out with reasonable doses. Then, as you get
bigger you can adjust your doses upwards.
Written by WCP
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