hhajdo
Community Veteran
by Bill Roberts
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 Anabolic Androgenic Steroids (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 Anabolic Androgenic Steroids (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 however.)
• 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 in sensitivity.
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 response.
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 normal.
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 bodybuilding.
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 testosterone."
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 Anabolic Androgenic Steroids (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 testosterone receptors."
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 "theory.")
The greater the gains one has already made, the harder further gains are. This is true under any conditions, regardless of whether Anabolic Androgenic Steroids (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 excesses."
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 Anabolic Androgenic Steroids (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 non-issues.
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 the drug.
"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 Anabolic Androgenic Steroids (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 non-receptor-mediated activity.
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 Anabolic Androgenic Steroids (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 downregulation occurred.
"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 Anabolic Androgenic Steroids (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 testosterone receptors."
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 facts.
Let us then move on to more serious arguments to be found in the scientific literature:
--------------------------------------------------------------------------------
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 Anabolic Androgenic Steroids (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 Anabolic Androgenic Steroids (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 however.)
• 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 in sensitivity.
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 response.
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 normal.
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 bodybuilding.
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 testosterone."
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 Anabolic Androgenic Steroids (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 testosterone receptors."
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 "theory.")
The greater the gains one has already made, the harder further gains are. This is true under any conditions, regardless of whether Anabolic Androgenic Steroids (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 excesses."
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 Anabolic Androgenic Steroids (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 non-issues.
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 the drug.
"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 Anabolic Androgenic Steroids (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 non-receptor-mediated activity.
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 Anabolic Androgenic Steroids (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 downregulation occurred.
"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 Anabolic Androgenic Steroids (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 testosterone receptors."
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 facts.
Let us then move on to more serious arguments to be found in the scientific literature:
--------------------------------------------------------------------------------