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 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 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:
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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 supraphysiological.
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 levels.
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.
Estrogen
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.
Assay
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 measured.
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.)
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