Any Non-Responders Out There?

[Warrior21]

Yea Primo depot is injections.
There is a study I posted a little bit above that shows that cyp3a4 deals with all steroid hormones buddy.

I got nizoral here. Today I start grapefruit/nizoral/anavar and see how it goes.

[guest589745]

Im confused now lol.

[Warrior21]

wow the responses from those guys on the thread dosen't lok too promising. THEN AGAIN it could be that their CYP3A4 isn't very active as it is. Remember ours is most likely very active, therefore the grapefruit will have a more profound effect on us than the guys with already-slow drug metabolism. We have to look at this from every angle.

God I've gotten alot smarter in the past 48 hours, hehe.

[Warrior21]

Drugs That Inhibit CYP3A4

CYP3A4 is a minor metabolic pathway for the elimination of zaleplon because the sum of desethylzaleplon (formed via CYP3A4 in vitro) and its metabolites, 5-oxo-desethylzaleplon and 5-oxo-desethylzaleplon glucuronide, account for only 9% of the urinary recovery of a zaleplon dose. Coadministration of single, oral doses of zaleplon with erythromycin (10 mg and 800 mg, respectively), a strong, selective CYP3A4 inhibitor produced a 34% increase in zaleplon's maximal plasma concentrations and a 20% increase in the area under the plasma concentration-time curve. The magnitude of interaction with multiple doses of erythromycin is unknown. Other strong selective CYP3A4 inhibitors such as ketoconazole can also be expected to increase the exposure of zaleplon. A routine dosage adjustment of zaleplon is not considered necessary.

Ketoconazole=Nizoral just in cased you missed it.

[guest589745]

Everyone needs to read the whole damn thing lol, we didnt get into this until like page 3 really.

[Warrior21]

There's 10 people looking at the thread right now. But it seems more like we are PM'ing each other heh. Anyways lets look at what we have so far.

Grapefruit Juice=Natural, Potent Inhibitor of CYP3A4
Nizoral Shampoo=Ketaconazole, Potent Inhibitor of CYP3A4
CYP3A4=Most prominent enzyme in drug metabolism, over 20 different alleles of the gene for this enzyme have been studied. This gene is responsible for over 50% of human drug metabolism, including steroid hormones.
CYP2D6=Second most prominent enzyme in drug metabolism, makes up for about 30% of drugs. Also one to look at inhibitting.

Of course one thing to keep in mind. I'm young and healthy, therefore I don't need to worry about adverse reactions, as I don't take any medications. If you're taking medications you're going to have to watch for the buildup effect of them. I'd welcome the buildup of anabolics though.

[guest589745]

By lewdtenant:
(Couldnt find it because it was titled "graperuit")

http://forums.anabolicreview.com/showthread.php?t=36532

[guest589745]

There's 10 people looking at the thread right now. But it seems more like we are PM'ing each other heh. Anyways lets look at what we have so far.

Grapefruit Juice=Natural, Potent Inhibitor of CYP3A4
Nizoral Shampoo=Ketaconazole, Potent Inhibitor of CYP3A4
CYP3A4=Most prominent enzyme in drug metabolism, over 20 different alleles of the gene for this enzyme have been studied. This gene is responsible for over 50% of human drug metabolism, including steroid hormones.
CYP2D6=Second most prominent enzyme in drug metabolism, makes up for about 30% of drugs. Also one to look at inhibitting.
Claritin I believe, inhibits the CYP2D6

Of course one thing to keep in mind. I'm young and healthy, therefore I don't need to worry about adverse reactions, as I don't take any medications. If you're taking medications you're going to have to watch for the buildup effect of them. I'd welcome the buildup of anabolics though.

Yes but, I want to see more about how and if injectables are effected, Im still unsure due to conflicting findings.

[Warrior21]

By lewdtenant:
(Couldnt find it because it was titled "graperuit")

http://forums.anabolicreview.com/showthread.php?t=36532

LOL seems like he had a bit too much 'graperuit' with his lewd's when he titled that shit huh.

[Warrior21]

Yes but, I want to see more about how and if injectables are effected, Im still unsure due to conflicting findings.

Can you post up those conflicting findings? All my findings point towards the fact that AS, injects or orals, are metabolized by CYP3A4. And that there are up to 20 genetic makeups for CYP3A4, we most likely have an allele which was programmed to metabolize drugs much quicker than other alleles.

[Warrior21]

Going to throw frizby with with my baby cousin. Be back in a few.

Feel free to share your thoughts, or any studies on this.

[guest589745]

Can you post up those conflicting findings? All my findings point towards the fact that AS, injects or orals, are metabolized by CYP3A4. And that there are up to 20 genetic makeups for CYP3A4, we most likely have an allele which was programmed to metabolize drugs much quicker than other alleles.

I did already in that other post, and you showed me one that says otherwise. Not really a definative answer to go off of ya know what Im sayin?

[AnabolicBoy1981]

try looking up how or if allergy meds such as claritin inhibit CYP3A4. I found this:

Metabolism: In vitro studies with human liver microsomes indicate that loratadine (Claritin) is metabolized to descarboethoxyloratadine predominantly by cytochrome P450 3A4 (CYP3A4) and, to a lesser extent, by cytochrome P450 2D6 (CYP2D6). In the presence of a CYP3A4 inhibitor ketoconazole, loratadine is metabolized to descarboethoxyloratadine predominantly by CYP2D6. Concurrent administration of loratadine with either ketoconazole, erythromycin (both CYP3A4 inhibitors), or cimetidine (CYP2D6 and CYP3A4 inhibitor) to healthy volunteers was associated with substantially increased plasma concentrations of loratadine (see Drug Interactions section).

Well, this here may explain why warrior's brother started seeing results after he started taking antihistamines. You see the loratadine is broken down by the CYP3A4 right? So if that is true,in your brothers case(and hopefully yours) it may be that the CYP3A4 is being "occupied" by the loratadine antihistamine, therefore leaving less to gobble up his AS. So if you took a harmless antihistamine, some Grapefruit juice, and washed with the nizoral, you could be hitting this from like 3 angles. The nizoral and the Grapefruit juice would inhibit the CYP3A4, and then whatever CYA3A4 is left would be "occupied" by your anthistamine. Therefore leaving the majority of your AS untouched...............theoretically. Sound good? However, the combo may be TOO MUCH, and for safety we have to assume we should start out with one, and proceed cautiosly from there. This is gonna be important if using bromo or caber with yer cycle since those drugs can possibly be dangerous if blood concetrations too high. However it occured to me writing this that the addition of such ancillaries may also increase the levels of blood steroid since they too are drugs and MIGHT be "occupying" at least some CYPA3A4, even if it wasnt on the list in that other post....yet.
It would make sense that the body has a limited amount of CYPA3A4, therfore if you took small safe doses of a few drugs that require CYPA3A4, along with your AS, then you could leave your AS level high enough to reap results. This worries me when i think of how many drugs my dad is on for, BP, cholesterol, kidneystones etc., and if they are affecting and increasing each others bllood levels, due to the bodies limited ability to have enough CYPA3A4 to break down all of them. Hmm.

Anyway, good research. Great thread. My hats of too ya guys. Alota work in TWO DAYS, wow. But i DEFINETLY think your onto something. Im disapointed some of the heavier hitters arent responding to this. This is important.

Theoretically, someone without your problem could get away with lower dasages of stuff, making cycles somewhat safer.

[guest589745]

Im disapointed some of the heavier hitters arent responding to this. This is important.

I agree, saw a few people that didnt post and had me dissapointed somewhat.

In the even that caber would be an issue, you could simply lower the dose I presume?

And thank you for your input!

[guest589745]

Apparently at the gene level, we may have a polymorphism in the AR protein that reduces test and DHT binding efficiency. Other tighter binding steroids (Such as tren ) have a salutory effect despite a lack of response to exogenous test. More likely, one or more factors is downregulating AR expression.

[Warrior21]

AnabolicBoy I fkin love you! Thanks for your support. I'm glad you recognize me and Skull, Hippo too have been busting our asses for this.

What's up Skull anything new?

I'm going to follow Anabolic Boys recommendation and start inhibiting my CYP3A4 with Nizoral 1x daily/8 oz. Grapefruit juice with each Var dosage 2x daily/ antihistamine

Anabolic do you know the chemical in my brother's allergy injections? I searched for allergy shots but did not find anything.

I too am disappointed the 'more informed' guys haven't helped. But you know what? Were doing damn good without em!

CHeck this link for a product which is supposed to have the effects we are looking for (blocking CYP3A4);
http://forum.bodybuilding.com/showth...ht=p450+cyp3a4

PS. Reps to you AnabolicBoy, thanks for the help. Any further input is hugely appreciated. If I fall into some money or new cleints soon anyone who helps me respond from gear will receive 4g Oxandrolone from me.

[Warrior21]

Apparently at the gene level, we may have a polymorphism in the AR protein that reduces test and DHT binding efficiency. Other tighter binding steroids (Such as tren) have a salutory effect despite a lack of response to exogenous test. More likely, one or more factors is downregulating AR expression.

I didn't gain anything off of Fina bro. I think we have something here. To get to the bottom of that...do you respond well to DBol ? Dbol is pretty much Non-AR dependant. If you see awesome gains from Dbol then you are onto something with that as well.

Then again I don't think we have problems with out AR receptors, I think we'd be feminine if we had trouble responding to our own test, don't you think?

[guest589745]

Long read but interesting.

Androgen Receptor Regulation

--------------------------------------------------------------------------------

Publication Date: August 1998 by bill roberts

Nothing in this article is intended to take the place of advice from a licensed health professional. Consult a physician before taking any medication.

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.


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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.


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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..

[guest589745]

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:


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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.)

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.


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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.


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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.

[guest589745]

I was reading on some other boards and found this article, I am also discussing something similar and will post the results of any useful findings.

[Warrior21]

Correct me if I'm wrong. It seems that this article argues against AR downregulation. I don't beleive in AR down-regulation myself.

[guest589745]

Correct me if I'm wrong. It seems that this article argues against AR downregulation. I don't beleive in AR down-regulation myself.

Yes, I thought this may have something to do with my problem pertaining to injectables but after reading this I agree with you.

[Warrior21]

Dude, the problem lies in CYP3A4. We got this bro.

Like I said I'm doing the Nizoral/Grapefruit Juice/Antihistamine/Var stack. Lotta stuff hehe, anyways i'll let you know how it goes. Why not do a stack like mine? I'm thinking if I take 150mg Var for a couple days it will get the levels in my blood high very quickly, therefore I can see results. Can't blame me for wanting to see results quick eh, I been on almost 5 weeks now and nothing.

[guest589745]

Dude, the problem lies in CYP3A4. We got this bro.

Like I said I'm doing the Nizoral/Grapefruit Juice/Antihistamine/Var stack. Lotta stuff hehe, anyways i'll let you know how it goes. Why not do a stack like mine? I'm thinking if I take 150mg Var for a couple days it will get the levels in my blood high very quickly, therefore I can see results. Can't blame me for wanting to see results quick eh, I been on almost 5 weeks now and nothing.

yea keep us posted, I am going to be researching nizoral more thoroughly. I will have to put a little mroe thoguht into my next cycle.......

[guest589745]

For anyone Chiming in now, to help save you time of reading the now 4 pages of this thread.......

Our basic purpose of this thread now I think is to find out as much as possible about increasing the bioavailability of steroids or how and if inhibition of CYP(s) (CYP3A4) or (CYP2D6) (cytochrome P450 ) will possibly increase the effect of steroids both injectable and/or oral. Or how/why someone may not respond well to steroids considering training/diet is well enough to support growth and what to do about it. Thats basically it.

[ironaddict69]

I just wanna let you BOTH know that i am amazed by both of your responses, posts and research. Great Job. I think i might have an issue with this as well, becuase im in week 6 of test cyp and dont feel a damn thing. im getting grapefruit juice today. but i got blood tests and they say my test is like 1400, so does that mean that i CANT have a problem with this DMMS stuff?

[guest589745]

I just wanna let you BOTH know that i am amazed by both of your responses, posts and research. Great Job. I think i might have an issue with this as well, becuase im in week 6 of test cyp and dont feel a damn thing. im getting grapefruit juice today. but i got blood tests and they say my test is like 1400, so does that mean that i CANT have a problem with this DMMS stuff?

Not sure man, sorry.


And thanks.

[ironaddict69]

oh and quick responses too, my kinda guy!

[taiboxa]

theres another thread where pinnacle and a few others go into depth on this subject as well i kant remember where it is at but someday i may dig it up

[taiboxa]

grapefruit never did anything for me

[guest589745]

FYI I meant intramuscularly in my posts, not intravenously. oops.

[guest589745]

theres another thread where pinnacle and a few others go into depth on this subject as well i kant remember where it is at but someday i may dig it up

FIND IIIIT!!!

[Warrior21]

Thanks for the props addict. We are going to get to the bottom of this! Addict your test levels seem kind of low for being on cycle. I think you may be in the same boat, but just not as bad as us. For someone injecting test into their body, 1400ng/dl is not that high.
Tai plz find it. I'm not going to just say, "I can't respond to steroids , oh well". No, I won't roll over and die like that.

[taiboxa]

FIND IIIIT!!!

YOU! lol its not in a private forum

[guest589745]

damn you tai lol.

[guest589745]

just run a search on pinnacles threads he started, TONS of interesting stuff.

[Warrior21]

Can you post links to these 'interesting articles'? You know me, research research.

Just got back. Gotta say I took my var capsule and didn't see that extremely dark pee 5 min later. My pee has been darker throughout the day. But not really dark at once, and then clear throughout the day. It would seem I'm metabolizing it a bit slower. I'm excited about the next few days, I might just start to feel something!

[Warrior21]

Off to shower, will be back in 15 min. Anyone who wanted to post something or contact me... don't go I'll be back. Like I said I will never rest well until I figure this out. I've wasted so much gear. 3 grams of Oxandrolone down the drain just this month. The sooner I figure this out, the more precious gear I can save!

[guest589745]

Just click on pinnacles profile and search through his threads.

[Warrior21]

K Ill be checking some