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Receptor Down Regulation
There is as much misinformation about steroids as there is good information had
among bodybuilding enthusiasts. Go to any gym and you will hear some kid
spouting off to his buddies about how steroids do this, or how they do that, or
whatever. This soon starts somewhat of a pissing contest (excuse the expression)
as to who knows more about steroids. It�s the same kind of titillating and
infectious banter that adolescent boys get into about girls and sex. With
steroid banter you hear all the popular terms like Deca, Test, HGH, gyno, zits,
raisins, "h-u-u-u-ge", roid, freak, monster, roid-rage, "I knew
this guy once", etc., etc.. If by some rare chance they are smart and have
been reading this or some other high quality bodybuilding site on the net, they
may actually get a few details right. More often than not they know just enough
to be dangerous. Fortunately steroids haven�t proven to be all that dangerous.
Not only that, but most of these guys who are infatuated with steroids won�t
ever use or even see them except in magazines.
This kind of ego driven gym talk doesn�t really bother me until they begin
giving advice to other clueless people who actually have access to them. Spewing
out steroid lingo gives other less experienced kids the impression that these
kids actually know what they are talking about. That�s how all of the psuedo-science
folklore about steroids perpetuates. This is also why most people who actually
use steroids know little about them. This last fact should bother anyone who
cares about bodybuilding and/or bodybuilders.
I started out with this article planning on giving some textbook style
explanation as to why using steroids doesn�t down regulate Androgen receptors
(AR). Then after considering some of my critics views that I tend to write
articles that hardly anyone can read, I decided to write an easy to read, yet
informative explanation about what Androgens actually do and how this precludes
Androgen receptor down regulation. I still have a few references but not so many
that it looks like a review paper.
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.
Testosterone: A multifaceted anabolic
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 HGH and IGF-1 levels. In a study by Fryburg the effects of testosterone
and stanozolol were compared for their effects on stimulating HGH release.2
Testosterone enanthate (only 3 mg per kg per week) increased HGH levels by 22%
and IGF-1 levels by 21% whereas oral stanozolol (0.1mg per kg per day) had no
effect whatsoever on HGH or IGF-1 levels. This study was only 2-3 weeks long, and
although stanozolol did not effect HGH 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 HGH 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.
In part 1 of this article we discussed the mistake of thinking about Androgen
receptors (testosterone receptors) in the same way we think of other receptors
such as beta-receptors. Beta-receptors down regulate in response to beta-adrenergic
stimulation whereas there is good evidence that Androgen receptors increase in
numbers in response to Androgens. We also discussed the various affects of
testosterone on muscle growth. Testosterone does far more than simply increase
the rate of protein synthesis!
Now in part 2 we will finish our discussion of Androgen receptor regulation as
it pertains to the way muscle cells grow. The very mechanism of real muscle
growth opens the door for increased Androgen receptor number in response to
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
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.
1. Kemppainen JA, Lane MV, Sar M, Wilson EM. Androgen receptor phosphorylation,
turnover, nuclear transport, and transcriptional activation. Specificity for
steroids and antihormones. J Biol Chem 1992 Jan 15;267(2):968-74
2. Fryburg DA., Weltman A., Jahn LA., et al: Short-term modulation of the
androgen milieu alters pulsatile, but not exercise- or growth hormone releasing
hormone-stimulated GH secretion in healthy men: Impact of gonadal steroid and GH
secretory changes on metabolic outcomes. J Clin Endocrinol. Metab.
3. Thompson SH., Boxhorn LK., Kong W., and Allen RE. Trenbolone alters the
responsiveness of skeletal muscle satellite cells to fibroblast growth factor
and insulin-like growth factor-I. Endocrinology. 124:2110-2117, 1989
4. Rosenblatt JD, Yong D, Parry DJ., Satellite cell activity is required for
hypertrophy of overloaded adult rat muscle. muscle Nerve 17:608-613, 1994
5. Rosenblatt JD, Parry DJ., Gamma irradiation prevents compensatory hypertrophy
of overloaded extensor digitorum longus muscle. J. Appl. Physiol. 73:2538-2543,
6. Phelan JN, Gonyea WJ. Effect of radiation on satellite cell activity and
protein expression in overloaded mammalian skeletal muscle. Anat. Rec.
7. Kadi F, Eriksson A, Holmner S, Thornell LE. Effects of anabolic steroids on
the muscle cells of strength-trained athletes. Med Sci Sports Exerc 1999
8. Antonio J, Wilson JD, George FW. Effects of castration and androgen treatment
on androgen-receptor levels in rat skeletal muscles. J Appl Physiol. 1999
Written By: Brian Haycock
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