# Tren vs. test and receptors vs. dose



## lovinjane (Aug 2, 2013)

Ok so I've been reading everything I can find for the last few days regarding test and tren cycles, and androgen receptor competition. I'm currently on cycle, less than 2 weeks in, and was toying with the idea of dropping my test dose to 250, keeping my tren e at 400. 

The school of thought on this has to do primarily with the idea that eventually receptors will become flooded, and one may desire to have the much stronger tren filling these receptors, rather than making it compete with the test, and risking having excess testosterone left unbound increasing sides or converting, raising shbg or whatever else.

My biggest question and concern regarding this theory is that, even if the test is at 500 mg, that totals 900 mgs of anabolic between the tren and test, not a small number by any means, but in comparison to some regimens, it may be half or less. With that being said, are receptors truly maxed out at 900 mgs? Enough to forgo the extra test? I realize that everyone is different, but in addition to all I have been reading about dose ratios, I've also been reading about receptors... And is it not true that as you introduce more anabolics, accompanied by proper training and diet, the body makes more androgen receptors? Or maybe makes more available? 

I briefly dropped my test dose to 250, but quickly rethought my decision and raised it back to 500. I personally feel physically better with more test, so that's what I'm going to do. But after all the research I have been doing, it seems like there's a lot of speculation and bro science when it comes to these topics. 

I would love to hear some answers from people who really know the facts, as well as some good personal experiences to touch on the test vs. tren dose ratio or the androgen receptor availability issue.


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## The Prototype (Aug 2, 2013)

Interested to hear the replies on this subject.


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## Presser (Aug 2, 2013)

In for discussion.


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## OldSchoolLifter (Aug 2, 2013)

Give me a moment, I will write out for you how this works.


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## lovinjane (Aug 2, 2013)

Just ran across this article, It's rather lengthy but definitely worth the read!

_______this was written 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 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 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 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 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 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 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 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:

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.)

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 does exist

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 cells.

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 muscle-derived fibroblasts.

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 of androgen.

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 results.

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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## heavyiron (Aug 2, 2013)

The human body up regulates AR's when administering more testosterone. Your doses are likely no where near saturation.


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## Standard Donkey (Aug 2, 2013)

all aas competes for the AR.. that's why I like anadrol coupled with injects.. it's affinity for the AR is so low that it's not measurable. it's anabolism is non-ar mediated


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## Christsean (Aug 2, 2013)

Publication I found. 

Relative binding affinity of anabolic-androgenic steroids: comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormone-binding globulin.

Authors

Saartok T, Dahlberg E, Gustafsson JA.

Journal

Endocrinology. 1984 Jun;114(6):2100-6.

Affiliation

Abstract

It is unclear whether anabolic steroids act on skeletal muscle via the androgen receptor (AR) in this tissue, or whether there is a separate anabolic receptor. When several anabolic steroids were tested as competitors for the binding of [3H]methyltrienolone (MT; 17 beta-hydroxy-17 alpha-methyl-4,9,11-estratrien-3-one) to the AR in rat and rabbit skeletal muscle and rat prostate, respectively, MT itself was the most efficient competitor. 1 alpha-Methyl-5 alpha-dihydrotestosterone (1 alpha-methyl-DHT; mesterolone) bound most avidly to sex hormone-binding globulin (SHBG) [relative binding affinity (RBA) about 4 times that of DHT]. Some anabolic-androgenic steroids bound strongly to the AR in skeletal muscle and prostate [ RBAs relative to that of MT: MT greater than 19-nortestosterone ( NorT ; nandrolone) greater than methenolone (17 beta-hydroxy-1-methyl-5 alpha-androst-1-en-3-one) greater than testosterone (T) greater than 1 alpha-methyl-DHT]. In other cases, AR binding was weak (RBA values less than 0.05): stanozolol (17 alpha-methyl-5 alpha- androstano [3,2-c]pyrazol-17 beta-ol), methanedienone (17 beta-hydroxy-17 alpha-methyl-1,4-androstadien-3-one), and fluoxymesterolone (9 alpha-fluoro-11 beta-hydroxy-17 alpha-methyl-T). Other compounds had RBAs too low to be determined (e.g. oxymetholone (17 beta-hydroxy-2-hydroxymethylene-17 alpha-methyl-5 alpha-androstan-3-one) and ethylestrenol (17 alpha-ethyl-4- estren -17 beta-ol). The competition pattern was similar in muscle and prostate, except for a higher RBA of DHT in the prostate. The low RBA of DHT in muscle was probably due to the previously reported rapid reduction of its 3-keto function to metabolites, which did not bind to the AR [5 alpha-androstane-3 alpha, 17 beta-diol and its 3 beta-isomer (3 alpha- and 3 beta-adiol, respectively)]. Some anabolic-androgenic steroids (only a few synthetic) bound to SHBG (1 alpha-methyl-DHT much greater than DHT greater than T greater than 3 beta-adiol greater than 3 alpha-adiol = 17 alpha-methyl-T greater than methenolone greater than methanedienone greater than stanozolol). The ratio of the RBA in rat muscle to that in the prostate (an estimate of the myotrophic potency of the compounds) was close to unity, varying only between about 0.4 and 1.7 in most cases.(ABSTRACT TRUNCATED AT 400 WORDS)


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## kboy (Aug 2, 2013)

OldSchoolLifter said:


> Give me a moment, I will write out for you how this works.



I'll stay tune.......


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## theCaptn' (Aug 3, 2013)

Subbed


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## Christsean (Aug 3, 2013)

Can I bro it up for a minute.  Ok hear goes, blah blah blah receptor,  blah blah optimal does scientifically discovered in a double blind blah. But when I take tren and test,  I take my normal tren dose per week. Then I take the amount of test I need to keep energy, libido and well being in check. 

Maybe it's not optimal for muscle gains,  cost effectiveness,  etc. But I achieve my goals and feel great trying.

Going into my cycle I make tren my steroid of work  (goal winner). The test is my super ancillary with great benefits.  It allows me to manage the sides of my tren as stated above. 

That's my bro-cents


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## OldSchoolLifter (Aug 3, 2013)

Well there is alot of good write-ups in this thread,

Pretty much, Your body has a limited amount of androgenic receptors that can be utilized at any given time. When you run the traditional, High test, lower tren, Your body starts a war. The Test and the Tren start fighting over those receptors. The winner in most wars is the person with the highest numbers or in our case dose.

When your test dose is higher, it will constantly beat out tren for the majority of those receptors. The tren will bind to some, but you are still left not utilizing 100% of your tren, Leaving it to freely circulate waiting to fight and bind. In this case sides from tren occur, sweating, insomnia, aggression, increase in prolactin, and so on.

The sides can be reduced, and you can unlock the full power of tren, by using a maintenance dose of Test 300mg or so to keep primary male functions intact, while keeping tren at 500-600 double that of the test. Now that your tren is higher, it will start to win the androgenic battle, allowing more of the hormone to bind, and work for you rather than against you.

In my trials, and others who have ran it this way, have experience much less sides, much better gains, weather cutting, bulking or recomp. Easier to control prolactin and e2 levels, and overall much better experience while using tren. We can go into the science of this backwards and forwards, but at the end of the day its the real time trial an error by users like my self, and many others who will attest to the superiority, of running tren higher than test.

Think of it this way, Tren is 7 - 15 times stronger than test, What compound would you rather be utilizing more during your cycle for optimal results? TREN!  yes you will still get great results running it the norm, But when higher than test, libido will stay intact, ( if not higher in my experience ) and the gains are night and day. I literally would wake up every day looking different.


*Sample Cycle:

1-7 Test Prop 100mg/eod or 50mg/ed
1-7 Tren Ace 75-100mg/ed


Or

1-12 Test E 300mg/wk
1-12 Tren E 600mg/wk*


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## Standard Donkey (Aug 3, 2013)

OldSchoolLifter said:


> Well there is alot of good write-ups in this thread,
> 
> Pretty much, Your body has a limited amount of androgenic receptors that can be utilized at any given time. When you run the traditional, High test, lower tren, Your body starts a war. The Test and the Tren start fighting over those receptors. The winner in most wars is the person with the highest numbers or in our case dose.
> 
> ...



do people really believe this shit?


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## moodyman1 (Aug 3, 2013)

Standard Donkey said:


> do people really believe this shit?



Who are u to argue with bro-science??


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## OldSchoolLifter (Aug 3, 2013)

You don't need to believe it, I didn't. Almost all research with aas is bro science, unless it has a functional use our government and its scientists deem worthy of. A few years ago I came across a guy who ran the above, and he has his theory. It worked well for him. After looking into the nature of this type of cycling, I tried it, followed by many others. The difference really was night and day.


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## ctr10 (Aug 3, 2013)

The Donkey knows his Tren, trust me


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## theCaptn' (Aug 3, 2013)

Standard Donkey said:


> do people really believe this shit?



I noticed the difference with low test high tren. I now run test 100-200mg

I know you run tren- only - you've got alternate views and experience. What's your rational SD?


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## lovinjane (Aug 3, 2013)

Wow, a lot of great discussion, thanks. I really started this thread because I believed that the concept saying both my test and tren ( or any two anabolics ) couldn't be fully utilized by my body is completely untrue. However, I previously had no concrete knowledge to support my belief... And although I still don't fully understand the chemistry and biology behind the bioavailability of my drugs, I firmly believe I can expect maximum benefit from both my high test and high tren doses. (As long as my diet, training, and ancillary hormone support coincide with my goals) 

For example: if you lower your test because you're "cutting" and want to look harder, wouldn't controlling your estrogen with AI enable that same goal while also benefiting from the higher test levels? (Assuming you don't buy into the receptor competition garbage at normal doses)

I'd like to hear SD's experience.


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## slownsteady (Aug 3, 2013)

Every time I use tren I say to myself hey no big deal. Then I find myself weeks later talking to myself outloud about unbelievable crazy shit. I soon catch myself and laugh and say that I'm a stupid and crazy dude. Lol Plus everybody can see your on aas if you take enough tren and test. I think people just look at me with disgust and think I am stupid for what I'm doing. I will say I love being the muscle freak 99.99999% of the time no matter where I go. Sorry to mess around in your thread just having fun and others can relate a little I think.


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## lovinjane (Aug 3, 2013)

slownsteady said:


> Every time I use tren I say to myself hey no big deal. Then I find myself weeks later talking to myself outloud about unbelievable crazy shit. I soon catch myself and laugh and say that I'm a stupid and crazy dude. Lol Plus everybody can see your on aas if you take enough tren and test. I think people just look at me with disgust and think I am stupid for what I'm doing. I will say I love being the muscle freak 99.99999% of the time no matter where I go. Sorry to mess around in your thread just having fun and others can relate a little I think.



Haha there's no doubt tren can make you feel a little crazy. I just love that feeling when that extra weight you've never done goes up in one beautiful exhale! Glad you're having fun bro, I am too. Two weeks in today, beast mode on!


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## s2h (Aug 3, 2013)

high tren..low test..and sandwhich a dht derived drug like masteron in the middle...works real well..


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## OldSchoolLifter (Aug 3, 2013)

s2h said:


> high tren..low test..and sandwhich a dht derived drug like masteron in the middle...works real well..




Yes High Tren, Low Test, Mast or Proviron and your in for a great ride.


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## Christsean (Aug 4, 2013)

Christsean said:


> Publication I found.
> 
> Relative binding affinity of anabolic-androgenic steroids: comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormone-binding globulin.
> 
> ...



The present data indicate that 1) the existence of a putative anabolic receptor distinct from the AR must be questioned, 2) many anabolic steroids interact with the AR (generally with lower RBA than NorT or T), 3) some steroids with anabolic-androgenic activity in vivo do not bind to the AR, and must have an indirect mechanism of action (e.g.*via biotransformation to active compounds, by influencing the metabolism of other steroids, or by displacing them from SHBG). (Endocrinology*114:*2100, 1984)Received*June 24, 1983.


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## lovinjane (Aug 4, 2013)

s2h said:


> high tren..low test..and sandwhich a dht derived drug like masteron in the middle...works real well..



When you say high tren, low test, and you are running your test at 250 or 300, would a tren dose of 400 mg give you the results you're talking about simply because the tren is higher? or would you need to bump it to 600 or so?


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## OldSchoolLifter (Aug 4, 2013)

lovinjane said:


> When you say high tren, low test, and you are running your test at 250 or 300, would a tren dose of 400 mg give you the results you're talking about simply because the tren is higher? or would you need to bump it to 600 or so?




In my personal experience, I keep Test at 300, Tren will be at least 500 weekly and upwards from there. I know for most this sounds like bro science.. Frankly some of it is still left to the unknown, but too many people have now run it this way since My self, and others really started to preach this method, and I still havent heard from one that does not believe this is the superior route.


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## hoyle21 (Aug 4, 2013)

The best results I've ever had with gear was test at TRT levels off 200mgs a week with Tren and Mast at 700mgs a week.


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## Christsean (Aug 4, 2013)

s2h said:


> high tren..low test..and sandwhich a dht derived drug like masteron in the middle...works real well..



Yes sir!! I love my Dht to be Var. To me it is a three way punch. Test, Nor-test and Dht. This combo definitely elicits the "are you on steroids" question.


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## Standard Donkey (Aug 4, 2013)

theCaptn' said:


> I noticed the difference with low test high tren. I now run test 100-200mg
> 
> I know you run tren- only - you've got alternate views and experience. What's your rational SD?



well of course steroids upregulate the AR, and cause AR proliferation IIRC.. but this actually makes steroids less effective though it increases the amount of aas that can be utilized. more receptors have to be filled to reach maximum anabolism.. so you have to increase your dose to make the SAME amount of gains as you were before... which is gay  im actually gunna go on a cruise dose again here.. been blasting for way too long and I don't respond to gear as well as I used to.. so id argue that it's not the "competition for receptors" that is the problem.. it's the multiplication of our receptors that reduces the effectiveness of our gear that's the problem..


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## lovinjane (Aug 4, 2013)

hoyle21 said:


> The best results I've ever had with gear was test at TRT levels off 200mgs a week with Tren and Mast at 700mgs a week.



How did you feel during this cycle? Any rough side effects or pronounced fatigue? How was your appetite? 

I may eat my previous words stating I would rather keep the high test, because frankly how will I know unless I try. I am hesitant however, because on a previous cycle I was using tren a, and test e, and the test turned out to be bunk while the tren was very good. And during the time I had very little to no test I just plain felt like shit. Mainly exhausted to the point that my training was nearly worthless, and once a blood test revealed my issue, and good test was put in place, I immediately felt much better. And eventually had a successful cycle. 

I'm just trying to learn here. Keep it coming guys!


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## hoyle21 (Aug 4, 2013)

lovinjane said:


> How did you feel during this cycle? Any rough side effects or pronounced fatigue? How was your appetite?



I felt good during the cycle.  My energy was fine, intensity was through the roof. I had the occasional night sweats and poor sleep but it wasn't anything I couldn't deal with.   Appetitive however was bad.   It was a struggle to eat, but I was cutting so it played in my favor.


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## OldSchoolLifter (Aug 4, 2013)

lovinjane said:


> How did you feel during this cycle? Any rough side effects or pronounced fatigue? How was your appetite?
> 
> I may eat my previous words stating I would rather keep the high test, because frankly how will I know unless I try. I am hesitant however, because on a previous cycle I was using tren a, and test e, and the test turned out to be bunk while the tren was very good. And during the time I had very little to no test I just plain felt like shit. Mainly exhausted to the point that my training was nearly worthless, and once a blood test revealed my issue, and good test was put in place, I immediately felt much better. And eventually had a successful cycle.
> 
> I'm just trying to learn here. Keep it coming guys!



We can all speculate, But you wont know until you do try it. Maybe its not for you? Maybe you will prefer it? When I run test/tren the normal way, My sleep is terrible, I'm a sweaty mess, and being I am very sensitive to 19nor compounds, for some reason prolactin was difficult for me to control. I'm not sure why, but ever since I lowered my test. and ran my tren higher, I'm able to keep prolactin in check, sides are much more manageable, and I can actually enjoy the results tren brings again.


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## hoyle21 (Aug 4, 2013)

OldSchoolLifter said:


> We can all speculate, But you wont know until you do try it. Maybe its not for you? Maybe you will prefer it? When I run test/tren the normal way, My sleep is terrible, I'm a sweaty mess, and being I am very sensitive to 19nor compounds, for some reason prolactin was difficult for me to control. I'm not sure why, but ever since I lowered my test. and ran my tren higher, I'm able to keep prolactin in check, sides are much more manageable, and I can actually enjoy the results tren brings again.



I was in the same boat.   My first run with tren I took 100mgs Test, Tren, Masteron ED and sides were nuts.   I woke up freezing and sweat soaked every night.

Another change I made was buying pharmacy grade Cabaser from AY instead of research.

I would recommend finding and buying HG ancillaries over research.   To me it might be more important than the quality of the gear.


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## lovinjane (Aug 4, 2013)

hoyle21 said:


> I would recommend finding and buying HG ancillaries over research.   To me it might be more important than the quality of the gear.



^^^^ this. 

Right now I've got Adex and prami, both research. 

The prami is seriously killing me. Yesterday marked two weeks on cycle, and I'm at .6 mg prami. It keeps me up all night and makes me sick. I thought this would go away gradually. I can't even get to the dose I need. If I could get it in a reasonable amount of time, it would be time to switch to pharm caber. Although I think the prami really does a better job with prolactin. Just not worth the misery.


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## lovinjane (Aug 4, 2013)

Standard Donkey said:


> well of course steroids upregulate the AR, and cause AR proliferation IIRC.. but this actually makes steroids less effective though it increases the amount of aas that can be utilized. more receptors have to be filled to reach maximum anabolism.. so you have to increase your dose to make the SAME amount of gains as you were before... which is gay  im actually gunna go on a cruise dose again here.. been blasting for way too long and I don't respond to gear as well as I used to.. so id argue that it's not the "competition for receptors" that is the problem.. it's the multiplication of our receptors that reduces the effectiveness of our gear that's the problem..



^^ this cleared things up for me. Thanks SD


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## heavyiron (Aug 4, 2013)

lovinjane said:


> ^^^^ this.
> 
> Right now I've got Adex and prami, both research.
> 
> The prami is seriously killing me. Yesterday marked two weeks on cycle, and I'm at .6 mg prami. It keeps me up all night and makes me sick. I thought this would go away gradually. I can't even get to the dose I need. If I could get it in a reasonable amount of time, it would be time to switch to pharm caber. Although I think the prami really does a better job with prolactin. Just not worth the misery.


Your Prami dose is fine brother. I would check your Prolactin before upping the dose.


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## lovinjane (Aug 4, 2013)

heavyiron said:


> Your Prami dose is fine brother. I would check your Prolactin before upping the dose.



What's the normal effective dose you would use? I'm very estrogen sensitive and consequently I'm also cautious regarding prolactin.. But I'd like to use as little as humanly possible at this point.


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## heavyiron (Aug 4, 2013)

Your Prolactin may be completely normal but without labs there's no way to know.

0.5 mg Prami daily is usually plenty.


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## vassille (Aug 4, 2013)

Standard Donkey said:


> well of course steroids upregulate the AR, and cause AR proliferation IIRC.. but this actually makes steroids less effective though it increases the amount of aas that can be utilized. more receptors have to be filled to reach maximum anabolism.. so you have to increase your dose to make the SAME amount of gains as you were before... which is gay  im actually gunna go on a cruise dose again here.. been blasting for way too long and I don't respond to gear as well as I used to.. so id argue that it's not the "competition for receptors" that is the problem.. it's the multiplication of our receptors that reduces the effectiveness of our gear that's the problem..



I run into the same issue. Taking some time off from gear too. I dont feel like running 1gr of test to make gains as I did with 500mg a week. But you sir are correct in your assenment.


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## lovinjane (Aug 5, 2013)

heavyiron said:


> Your Prolactin may be completely normal but without labs there's no way to know.
> 
> 0.5 mg Prami daily is usually plenty.



Thanks heavy, it's awesome to have so many knowledgable people here participating and answering questions, even when they may have been answered before.


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