Androgen Receptor Regulation
by bill roberts
>Nothing in this article is intended to take the place of advice from a
licensed health professional. Consult a physician before taking any
One of the most common beliefs concerning anabolic/androgenic steroid (AAS)
usage is that the androgen receptor (AR) downregulates as a result of such
usage. This has been claimed repeatedly in many books and articles, and it is
claimed constantly on bulletin boards and the like. If I've heard it once,
I've heard it a thousand times. If it were just being stated as an abstruse
hypothesis, with no practical implications, with no decisions being based on
it, that might be of little importance.
Unfortunately, this claim is used to support all kinds of arguments and bad
advice concerning practical steroid usage. Thus, the error is no small one.
We will look at this matter fairly closely in this article. However, in brief
the conclusions may be summed up as follows:
' There is no scientific evidence whatsoever that AR downregulation occurs in
human muscle, or in any tissue, in response to above normal (supraphysiological)
levels of AAS.
' Where AR downregulation in response to AAS has been seen in cell culture,
these results do not apply because the downregulation is either not relative
to normal androgen levels but to zero androgen, or estrogen may have been the
causative factor, or assay methods inaccurate for this purpose were used, or
often a combination of these problems make the results inapplicable to the
issue of supraphysiological use of androgens by athletes.
' AR upregulation in response to supraphysiological levels of androgen in cell
culture has repeatedly been observed in experiments using accurate assay
methods and devoid of the above problems.
' AR downregulation in response to AAS does not agree with real world results
obtained by bodybuilders, whereas upregulation does agree with real world
results. (A neutral position, where levels in human muscle might be thought
not to change in response to high levels of androgen, is not disproven
' The "theoretical" arguments advanced by proponents of AR downregulation are
invariably without merit.
The belief that androgen receptors downregulate in response to androgen is one
of the most unfounded and absurd concepts in bodybuilding.
While this may seem perhaps an overly strong condemnation of that view, please
consider that the claims for downregulation seen in books such as Anabolic
Reference Guide (6th Issue), World Anabolic Review, Underground Steroid
Handbook, etc. are presented with absolutely no evidence whatsoever to support
them. The authors merely assert downregulation. They have done it so many
times that by now many people assume it is gospel. In this paper you will be
provided with evidence, and the evidence does not support their claim.
Overview of Regulation
Meaning of regulation
"Regulation" of a receptor refers to control over the number of receptors per
cell. "Sensitivity," in contrast, refers to the degree of activity each
receptor has. It is a possible in many cases for the receptors of a cell to be
sensitized or desensitized to a drug or hormone, independently of the number
of receptors. Similarly, it is possible for the receptors to upregulate or
downregulate, to increase or decrease in number, independently of any changes
If sensitivity remains the same, then upregulation will yield higher response
to the same amount of drug or hormone, and downregulation will result in less
So if we are discussing androgen receptor regulation, we are discussing how
many ARs are present per cell, and how this may change.
Changes in regulation must, of necessity, be between two different states, for
example, levels of hormone. In the case of bodybuilding, we are interested in
supraphysiological levels vs. normal levels (or perhaps, a higher
supraphysiological level vs. a lower supraphysiological level.) In most
research that is done, the comparison is often between normal levels and zero
levels, or the castrated state.
We may describe regulation with the two levels being in either order.
Upregulation as levels decrease from normal to zero is the same thing, but in
the reverse direction, as downregulation as levels increase from zero to
The term which would be used will depend on context, but does not change
meaning, so long as the direction of change in level of hormone is understood.
If upregulation occurs as levels decrease from normal to zero, as is probably
the case in some tissues, this would imply nothing about what may happen as
levels increase beyond normal. It does not prove that downregulation would
occur. It would be a serious error to take a study comparing normal levels and
zero levels and use that study to argue the effect of supraphysiological
levels. Unfortunately, such mistakes are commonly made by authors in
Forms of regulation
Broadly speaking, there are three things that control the number of receptors.
To understand them, let's quickly review the life-cycle of an individual AR.
There is a single gene in the DNA of each cell that codes for the AR. In the
transcription process, the DNA code is copied to mRNA. The rate (frequency) of
this process can be either increased (promoted) or decreased (repressed)
depending on what other proteins are bound to the DNA at the time. Increase or
decrease of this rate can be a form of regulation: the more AR mRNA is
produced, all else being equal, the more ARs there will be. However, all else
rarely is equal.
If efficiency is 100%, each mRNA will be used by a ribosome to produce an AR,
which is a protein molecule. The process of making protein from the mRNA code
is called translation. In practice efficiency will not be 100%. Changes in
efficiency of translation can also be a form of regulation.
The third contributing factor to regulation is the rate of loss of ARs. If the
cell produces x ARs per hour, and their half life is say 7.5 hours, then the
number of ARs will be higher than if ARs are produced at that same rate but
the half life is say only 3.3 hours. Thus, control of rate of turnover, or
change in half-life, can be another means of regulation.
The Arguments for Downregulation
Arguments from the popular literature
I am indebted to one of my former colleagues at Dirty Dieting for contributing
these first several arguments, which are from one of his published articles. I
could never have thought of them myself:
"Users of anabolics certainly have elevated levels of androgens, but they have
very few testosterone receptors in their muscles'The paradox for natural
bodybuilders is that they have plenty of receptors but not enough
Response: there are no studies in the literature demonstrating any such thing.
The above statement is an assertion only, and therefore cannot be accepted as
evidence that AAS use in athletes downregulates the AR.
"Users of anabolics, on the other hand, have more androgens than they need, so
their training should be oriented exclusively toward re- opening the
This statement deals with the issue of sensitivity, not of regulation, but
again the claim is unsupported. Users of anabolics find value in the increased
doses of androgen, and advanced users may well need all that they are using
simply to maintain their far-above-normal mass, let alone gain further mass.
The reference to "re-opening" the testosterone receptors is dubious at best,
since the receptors are not closed, nor is their any indication in any
scientific literature that such could possibly be the case, or that some given
style of training will remedy any such (nonexistent) condition.
"One group [natural trainers] needs more testosterone, the other needs more
receptors. Each group needs what the other has-which is the very reason that
the first cycle of anabolics has the most effect."
The statement that the first cycle has the most effect is true, in my opinion,
only by coincidence. More accurately, the cycle starting at the lowest
muscular bodyweight will have the most effect. This may be because the closer
you are to your untrained starting point, the easier it is to gain.
Let us look at the example of a person who achieved excellent development with
several years of natural training and then has gained yet more size with
several steroid cycles. He then quits training for a year and shrinks back
almost to his original untrained state.
If he resumes training and uses steroids, will his gains be less than in his
first cycle? Hardly. So what that it may be his fifth or tenth cycle, not the
first? There is no counter inside muscle cells counting off how many cycles
one has done. In examples that I know of, the gains in such a cycle have been
greater than in the first cycle. (No, that does not prove upregulation, but it
is strong evidence against the permanent-downregulation-after-first cycle
The greater the gains one has already made, the harder further gains are. This
is true under any conditions, regardless of whether AAS are involved or not.
Thus the "first cycle" argument proves nothing with regards to AR regulation.
In any case, regulation is a short term phenomenon, operating on the time
scale of hours and days. But if it were permanent or long-lasting as this
writer believes, then if steroid use were ceased for a long time, one ought to
shrink back to a smaller state than was previously achieved naturally, despite
continuing training. After all, one would have fewer receptors working, having
damaged them forever (supposedly) with the first cycle.
That is, of course, not the case. Which is not surprising, because the
"theory" is medically ridiculous.
"Various bodybuilding publications have recently featured articles stating
that as a bodybuilder's level of androgens increases, so does the level of
testosterone receptors in his muscles. In other words, testosterone is said to
be able to upregulate its receptors in the muscles. Needless to say, the more
testosterone receptors you have, the more anabolic testosterone will be. The
result of the above reasoning is that it gives license to a11 sorts of
Whether it "gives license to all sorts of excesses" or not has nothing to do
with whether it is true.
"First of all, if the theory were true, sedentary persons using androgens --
for contraception, for example -- would become huge. The extra testosterone
would increase the number of testosterone receptors. The anabolic effect of
testosterone would become increasingly stronger. In reality, untrained people
who use steroids have very limited muscle growth. hey rapidly become immune to
testosterone's anabolic effect. That doesn't sound like androgen receptor
upregulation, does it?"
First, no one has claimed that weight training is not needed for the
steroid-using bodybuilder. This is a strawman argument. Resistance training is
demonstrated to upregulate the androgen receptor, for example, and also
stimulates growth by other means. Therefore it is not surprising that those
who do not train do not gain nearly as much muscle as those who do. The
argument that AAS use alone, without training, will not produce a championship
physique proves nothing with respect to how the androgen receptor is
regulated. It does not even suggest anything, to any person with judgment.
And the concept that upregulation could only exist as an uncontrollable
upwards spiral is entirely incorrect. Rather, for any given hormone level,
there will be a given AR level. There is no feedback mechanism, not even a
postulated one, where this would then lead to yet higher hormone level,
leading to yet higher AR level, etc. In fact there is negative feedback, since
upregulation of the AR in the hypothalamus and pituitary in response to higher
androgen would lead to greater inhibition of LH/FSH production, and therefore
some reduction in androgen production.
In the case of sedentary subjects, let us use the subjects in the NEJM study,
who received 600 mg/week testosterone, as our example. While I do not know if
these subjects did experience AR upregulation in their skeletal muscle tissue,
if their receptor numbers had let us say increased by some percentage, there
would come some point in increased muscle mass where catabolism again matched
anabolism, and further growth would not occur. No runaway spiral of muscle
growth would be expected either. Thus, my colleague is arguing against
Lastly, such persons do not, as he claimed, become immune to testosterone's
anabolic effect: they maintain the higher muscle mass so long as they are on
"After all, the heaviest steroid users are found among bodybuilders. In those
heaviest users there should be upregulation of androgen receptors. If that
were true, here's what would happen. The androgens would cause their receptors
to multiply and get increasingly more potent as time went on. If androgen
receptors were truly upregulated that way, steroid users would get their best
gains at the end of a cycle, not the beginning, and professional bodybuilders
would get far more out of their cycles than first-timers."
There is no reason to think that upregulation would become "increasingly more
potent as time went on." Control of regulation is fairly quick.
The concept that AR activity is measured by "gains" is simply ridiculous. The
function of the activated AR is not to produce gains per se, but to increase
protein synthesis. That will only result in gains if muscle catabolism is less
than the anabolism. As muscle mass becomes greater, so does catabolism. At
some point under any hormonal and training stimulus, equilibrium is reached,
and there are no further gains. With high dose AAS use, that point is at a far
higher muscle mass than if androgen levels are at only normal values. The
concept that the steroids are "not working" for the
bodybuilder who is maintaining 40 lb more muscular weight than he ever could
achieve naturally, and who might even still be gaining slowly (but not as fast
as in his first cycle) is, at best,an example of poor reasoning..
Moderate dose steroids, even though they are sufficient to saturate the AR,
don't take one as far as high dose steroids can. The difference cannot be
substantially increased percentage of occupied receptors, since almost all are
occupied in either case.
What does that leave as the possibilities? More receptors, or
Is there evidence that muscles are more responsive to the same level of
androgen after having been exposed to high dose androgen? That would be the
case, at least temporarily, if upregulation occurred. The answer is yes, there
is such evidence, anecdotally. If a brief cycle (2 weeks) of high dose AAS
with short-acting acetate ester is used, there can be substantially increased
androgenic activity, relative to baseline, in weeks 3 and 4 even though the
exogenously-supplied androgen is long out of the system. This is what would be
expected if upregulation occurred. It could not be the case if substantial
"The longer a course of treatment lasts, the more users are obliged to take
drugs to compensate for the loss of potency."
This is simply untrue. I know of no cases of steroid users who found that they
began losing muscle mass while remaining on the same dose. The illogic here is
confusing cessation or slowing of gains with cessation of effect. One instead
should look at,. What muscular weight set-point is the body experiencing with
this hormonal and exercise stimulus?
With higher dose AAS, that setpoint is higher. Once it is nearly achieved or
achiever, of course gains slow or stop. And besides this, even if the body has
not yet fully achieved the higher mass that may be possible with a given level
of AAS, it is harder for many reasons for the body to grow after it has
recently grown a fair deal. It needs time before being ready to again grow
some more. This is observed whether steroids are involved or not.
The illogic of people who correlate rate of gains with AR level is amazing. I
suppose they would have it that the AR downregulates after the first 6 months
of natural training as well. After all, gains slow down then.
"Androgen upregulation would take place in every single muscle, not just in
the exercised muscles. Consequently, a user of anabolics who only trained his
arms should see his calves grow. That's not the case, however, even for the
professionals. I wish it were true, as they wouldn't look so silly with their
huge arms and puny calves. I don't have to keep demonstrating that the theory
is just plain stupid. It is refuted daily by the experiences of bodybuilders
who use anabolics, as well as by the research."
Again, no one claims that training is not also required for muscles. No one
ever said that AAS use alone is sufficient to induce muscular growth far past
the untrained state. This same logic used above could be used to argue that
steroids do nothing whatsoever. After all, if they worked, then you would not
need to train your calves, you could just train your arms.
The assertion that upregulation is refuted daily by the experiences of
bodybuilders, or by research, is just that: an assertion.
"The fact is, excessive androgen levels induce the rapid loss of muscle
The fact is, the author had to cite some utterly obscure journals in the
Polish language to support his claim. I rather doubt that were I able to read
Polish that I would find the actual article to support his claims.
"There is absolutely no increase. The muscle fights the excess and immunizes
itself against androgens, which is the reason steroids become less potent as
time goes by."
The statement that the body immunizes itself against androgens is medically
incorrect. The statement is severely enough in error that one must doubt the
competence of the author to discuss any medical or physiological matters, and
casts grave doubt on his judgment in such manners. Thus his statements cannot
be accepted by his authority: he has none. Nor are they supported by any
Let us then move on to more serious arguments to be found in the scientific
Scientific Evidence Apparently Favoring Downregulation
While there are no studies showing downregulation in human skeletal muscle
resulting from high-dose AAS use, there are some studies in cell culture, and
sometimes in vivo, which seem to indicate that downregulation can occur,
though not as a result of increase in androgen from normal to
This is seen both by measurement of AR mRNA, which is in an indicator of the
rate of AR production, and in measurement of receptor number.
All of these studies, however, are flawed from the perspective of the
bodybuilder wishing to know if downregulation of the AR has ever been observed
in any cell in response to increase of androgen from normal to supranormal
Range of measurement
First, the question is, downregulation relative to what? What is the control?
Unfortunately, the control for in vivo studies is castration, not the normal
state. The bodybuilder really doesn't care if normal testosterone levels may
result in fewer ARs for some cell types than would be seen with castration. We
would not want to get castrated just to have more ARs than in the intact
condition, if for no other reason than that the decrease in androgen level
would be more significant than any possible increase in AR number.
In vitro studies have generally been done with zero androgen as the control,
not normal androgen.
It cannot be projected that if AR number decreased as testosterone level was
increased from zero to normal, that therefore it would continue to decrease as
level was increased yet further. For example, the cause of this might be that
there is a promotion mechanism increasing AR mRNA production as testosterone
levels fall to zero. That would not mean that there would be any loss as
testosterone levels increase past normal. Or if it is a repression mechanism
that comes into play as testosterone levels rise past zero, that mechanism
might be fully saturated by the time levels reach normal, and no further
repression might occur as levels go past normal.
In fact, papers which report downregulation, even in their titles, often show
in the actual data that the range of downregulation was entirely between zero
and normal, or even zero and a subnormal level. Thus they give no evidence
whatsoever of downregulation occurring with supraphysiological levels of
androgen relative to normal levels.
Testosterone can aromatize to estrogen, which can itself lead to
downregulation of the AR. Thus, if a study used testosterone but did not
verify that the same results were seen with nonaromatizing androgen, or did
not verify that use of an aromatase inhibitor did not change results, there is
no way to know if any observed downregulation is due to androgen or not. It
might be due to estrogen.
Unfortunately, AR concentrations are very low in cells, and mRNA is not so
easily measured. It is possible for measurements to be misleading.
In Biochemical and Biophysical Research Communications (1991) 177 488, Takeda,
Nakamoto, Chang et al. determined, "Our immunostaining [for amount of ARs] and
in situ hybridization data [for amount of AR mRNA] indicated that in rat and
mouse prostate, androgen-withdrawal decreased both androgen receptor content
and androgen receptor mRNA level, and that injection of androgen restored
normal levels, a process termed 'upregulation''.However, Northern blot data of
Quarmby et al. in rat prostate have shown a different result, downregulation:
the amount of androgen receptor mRNA increased by androgen withdrawal and
decreased below the control level after androgen stimulation. Our preliminary
Northern blot data (unpublished data) also showed the same tendency,
downregulation." [emphasis added]
The authors go on to explain in detail, somewhat beyond the scope of this
article, why Northern blot analysis can lead to false results. The in situ
hybridization method is indisputably a superior, more accurate method.
Many of the studies claiming downregulation depend on Northern blot data as
the sole "proof." This study, however, shows that such measurement might be
entirely wrong. In any case, regulation properly refers to control of the
number of receptors. Production of mRNA is one of the contributing factors,
but ultimately what must be measured to determine the matter is the number of
receptors. This has been done in some experiments.
Specific papers often cited to support downregulation of the AR
Endocrinology (1981) 104 4 1431. This paper compares the normal state of the
rat to the castrated state, and the muscle cytosol AR concentrations of the
female rat to the intact (sham-operated) male rat.
Objections to this study include the fact that the effect of
supraphysiological levels of androgen was not studied; that cytosolic
measurements of AR are unreliable since varying percentages of ARs may
concentrate in the nuclear region, and these are more indicative of activity;
and that castration of rats is notorious for producing false conclusions. The
cells, and indeed the entire system of the animal, undergo qualitative change
(e.g., cessation of growth) from the castration relative to the sham-operated
animals. Testosterone levels are not the only thing which change upon
castration. Another objection is that estrogen was not controlled and the
effects of estrogen were not determined or accounted for. Estrogen levels
certainly were not constant in this experiment.
Molecular Endocrinology (1990) 4 22. AR mRNA level, in vitro, was seen to
increase as androgen levels were reduced below normal. Supraphysiological
levels were not tested. Northern blot analysis was used. AR levels were not
Molecular and Cellular Endocrinology (1991) 76 79. In human prostate carcinoma
cells, in vitro, androgen resulted in downregulation of AR mRNA relative to
zero androgen levels. Levels of androgen receptor, however, increased,
relative to when androgen level was zero, by a factor of two. The researchers
noted, "At 49 hours, androgen receptor protein increased 30% as assayed by
immunoblots and 79% as assayed by ligand binding" [the later method is the
more reliable and indicative of biological effect.]
Molecular Endocrinology (1993) 7 924. In vitro, it was determined by Northern
blot analysis that mRNA levels decreased when supraphysiological levels of
androgen were compared to zero androgen in cancer cells. Levels of ARs were
measured, and there was no observed decrease despite the observed decrease in
mRNA level (as measured by Northern blot.)
Molecular and Cellular Endocrinology (1995) 115 177. COS 1 cells were
transfected with human AR DNA with the CMV promoter. The authors state that
the DNA sequence responsible for downregulation of the AR is encoded within
the AR DNA, not the promoter region. Dexamethasone [a glucocorticoid drug
similar to cortisol] was observed to result in downregulation of AR mRNA
relative to zero dexamethasone level. Androgen also had this effect, but did
not result in lower levels of androgen receptors. This was attributed to
increase in androgen receptor half life caused by androgen administration. The
observed androgen downregulation effect relative to zero androgen ended at a
concentration of 0.1 nanomolar of androgen (methyltrienolone) ' higher doses,
to 100 nanomolar, resulted in no further downregulation of AR mRNA production.
While this list is not complete, I am not omitting any studies that appear to
have any better evidence ' indeed, any evidence at all ' that
supraphysiological levels of androgen result in downregulation, relative to
normal androgen levels, of the AR The above is a reasonably complete picture
of the research evidence that might be used to support the bodybuilding theory
of AR downregulation. When analyzed closely, no scientific study provides
support for that theory.
Scientific evidence indicating that a biochemical mechanism for upregulation
Even in the above evidence which apparently (at first sight) might seem in
favor of downregulation, it was sometimes seen that actual levels of the AR
increased, even going from zero to normal (rather than normal to
supraphysiological.) This is upregulation of the receptor, since as we recall,
regulation is the control of the number of receptors, and this control may be
achieved by change in the half life of the receptors. Increased half life of
the receptor, all else being equal, or perhaps with change in half-life
overcoming other factors, can yield higher receptor numbers. Kemppainen et al.
(J Biol Chem 267 968) demonstrated that androgen increases the half life of
the AR, which is an upregulating effect.
Endocrinology (1990) 126 1165. In fibroblasts cultured from human genital skin
which contained very low amounts of 5-alpha reductase, 2 nanomolar
tritium-labeled testosterone [which is sufficient to saturate ARs] produced a
34% increase in androgen receptors as measured by specific AR binding, the
best assay method known, and 20 nanomolar tritium-labeled testosterone
produced an increase of 64% in number of ARs.
Note: 20 nanomolar free testosterone is approximately 400 times physiological
level (normal level in humans is approximately 0.05 nanomolar).
J Steroid Biochemistry and Molecular Biology (1990) 37 553. In cultured
adipocytes, methyltrienolone and testosterone demonstrated marked upregulation
of AR content upon administration of androgen. 10 nanomolar methyltrienolone
increased AR content (as measured by binding to radiolabeled androgen) by more
than five times, relative to zero androgen.
J Steroid Biochemistry and Molecular Biology (1993) 45 333. In cultured smooth
muscle cells from the penis of the rat, mRNA production was found to be
upregulated by high dose testosterone (100 nanomolar) or DHT. When 5-alpha
reducatase was inhibited by finasteride, thus blocking metabolism to DHT, AR
mRNA production was downregulated in response to testosterone. Blockage of the
aromatization pathway to estrogen by fadrozole eliminated this downregulation
effect. Estradiol itself was found to downregulate AR mRNA production in these
Endocrinol Japan (1992) 39 235. One nanomolar DHT was demonstrated to increase
AR protein by over 100% within 24 hours, relative to zero androgen level. The
half life of the AR was demonstrated to increase from 3.3 h to 7.5 h as a
result of the androgen administration.
Endocrinology (1996) 137 1385. 100 nanomolar testosterone was found to
increase AR levels in vitro in muscle satellite cells, myotubes, and
Conclusions from Scientific Research
As androgen levels decrease from normal to zero, production of AR mRNA may
increase in some tissues. However, the number of ARs does not necessarily
increase, because the half life of the ARs decreases with lower concentrations
As androgen levels increase from normal to supraphysiological, numbers of ARs
in some tissues have been shown to increase. Such an increase is upregulation.
The increase may be due primarily or entirely to increase in half-life of the
AR resulting from higher androgen level.
There is no scientific evidence to support the popular view that AAS use might
be expected to result in downregulation of the AR relative to receptor levels
associated with normal androgen levels.
Conclusions from Bodybuilding Observations
I find it rather unreasonable to think that the most likely thing is that
athletes who have been on high dose AAS for years, and are far more massive
than what they could be naturally, and who are maintaining that mass or even
slowly gaining more, could possibly have less androgen receptor activity than
natural athletes or low-dose steroid users.
It might, hypothetically, be possible that their AR activity is the same, and
the extra size due to steroids is due entirely to non-AR mediated activities
of the androgens. However there is no evidence for that and it seems unlikely.
I believe the most logical possibility is that these athletes are experiencing
higher activity from their androgen receptors than natural athletes, or low
dose steroid users, are experiencing. Since the majority of androgen receptors
are occupied at quite moderate levels of AAS, the explanation cannot be simply
that a higher percentage of receptors is occupied, with the receptor number
being the same. That would not allow much improvement. In contrast,
upregulation would allow substantial improvement, such as is apparently the
case (unless non-AR mediated activities are largely or entirely responsible
for improved anabolism, which would be an entirely unsupported hypothesis.)
Upregulation in human muscle tissue, in vivo, is not directly proven but seems
to fit the evidence and to provide a plausible explanation for observed
I leave the matter, however, to the reader. Weigh the evidence, and decide if
downregulation, as popularly advocated, is supported by science, or by what is
experienced in bodybuilders
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