AR CELL WALL REJUVENATION

[Newman]

Hi guys.

This is frustrating & embarrassing, but I'd rather have the info than save face, so I'm appealing to you all to see if any of you remember the thread I'm looking for or know the answer to the questions I'm asking.

Anyway, sometime within the last 2 weeks, I happened upon a thread where the bros were discussing the cellular mechanism for AAS reception & its impact on cycle dynamics.

One of the smarter dudes came on with good info on the structure of an AR & IIRC, the discussion started touching a little bit about how to help rejuvenate the limiting factor in AR reception & consequent cellular anabolism.

Now, I know I would look a lot less retarded if I just did some advanced Google searches on it & thereby hid my ignorance from everyone, but then that would only help my knowledge, but would do nothing to start a thread dedicated to discussing ways (if any exist) to expedite/optimise androgen/anabolic reception and metabolism.

If anyone reading this remembers that thread, please post a link. I tried to find it using the search feature, but couldn't seen to find it.

Alternatively, if anyone has knowledge on the inner workings of AAS reception & effected anabolism, then we could just start a discussion on it & go from there. Now, don't tell me nobody here knows about AAS reception & anabolism. I'm not the sharpest knife in the drawer, but I know better than to believe that...

Thanx in advance for any input you guys may have.

 

[Newman]

3rd bump.

Getting a little lonely here...

Seriously, nobody cares about increasing the efficiency, capacity, or metabolic "stamina" of the absorption of their AAS intake?

Sure, using proviron can bind SHBG to help free up AAS for anabolism, but the free AAS still need to get into the cell nucleus to do increase transcription.

I know that ARs are constantly being replaced by new ARs, but I could swear I read something on this board that kinda hinted at the possibility of aiding the musce cells in absorbing as much AAS as possible.

 

[whiteknucks]

i think you just have to add new cells to get new receptors. i dont believe the whole saturation of receptors thing personally. find a way to raise igf. then you get new receptors.

 

[Newman]

i think you just have to add new cells to get new receptors.

The receptors are constantly being used up & replaced. They are part of the cell wall & recieve the AAS, then break away from the wall (which closes again with some sorta proteins?), then the receptor becomes a transporter & carries the AAS into the cell nucleus for transcription. What interests me is finding out whether there are any supps that will aid the body in building new receptors faster, like calcium & vit D for bones.




i dont believe the whole saturation of receptors thing personally.

Neither do I. It has been disproved for a while now. What I'm talking about is enhancing the cells ability to replace the receptor nutritionally and/or pharmaceutically (hormonally?)




find a way to raise igf. then you get new receptors.

Really? That's it? IGF?

Got a link on that?

Thanx for your reply bro.

IGF noted, I wonder if there's a AR regeneration hormone?

Wouldn't that kick ass?

 

[Newman]

4th bump.

 

[hollywoood]

AR attenuation

Newman, your question is not a simple one; yes, AR receptor function attenuates, however it may not happen in the classical sense (i.e receptor inactivation/internalization such as with the beta adrenergic receptors). There is a pretty large body of evidence that AR attenuation may actually happen in the nucleus. Basically, upon activation the AR dimerizes and translocates to the nucleus, where it acts as a transcription factor, binding to the promoter of and activating AR-responsive genes. It turns out that there are a number of ancillary proteins in the nucleus, called transcriptional co-repressors (or co-activators) that provide a tighter level of control over gene activation (i.e transcription factor binding to target DNA is necessary but not sufficient for the activation of many genes) There is a school of thought out there that most androgen receptor "attenuation" happens at the transcriptional co-repressor level. If you buy into this (there is some compelling evidence out there), then AR attenuation in the "classic sense" may not actually happen, in which case cycle protocols based on the model of classic AR receptor attenuation may not be affective at all to the end of optimizing receptor function. I have not stayed current in this field, but at one time investigators were looking into antagonizing the SIRT1 histone deacetylase as a way to possibly inhibit this negative feedback on AR-mediated transcriptional activation.
*not to discredit anybody out there with ideas contrary to all this. We are really dealing with a "black box" here..the system is not well understood.

hope this helps. If you buy it, the transcriptional co-repressor model fits nicely with shorter cycles/shorter off times (or at least shorter off-times )

 

[Newman]

Newman, your question is not a simple one; yes, AR receptor function attenuates, however it may not happen in the classical sense (i.e receptor inactivation/internalization such as with the beta adrenergic receptors).

Yeah, I know. It's waaaay over my head actually. I just wanted to start some discussion about it to see what the smarter dudes had to say & see what develops. Hopefully guys like Macro, IPrimate, DatBTrue etc will come on here & add something good.




There is a pretty large body of evidence that AR attenuation may actually happen in the nucleus. Basically, upon activation the AR dimerizes and translocates to the nucleus, where it acts as a transcription factor, binding to the promoter of and activating AR-responsive genes.

That's what read & there's actually a 3 letter acronym for the AR after it breaks away from the cell wall, but I can't remember the acronym.




It turns out that there are a number of ancillary proteins in the nucleus, called transcriptional co-repressors (or co-activators) that provide a tighter level of control over gene activation (i.e transcription factor binding to target DNA is necessary but not sufficient for the activation of many genes)

See, my question is whether or not there's any way to supplement all the proteins involved in this process or their constituent amino acids to aid in AR formation & nucleic co-activation? I don't know if the key protein mechanisms involved are any different than the usual ones used in BBing or if they're the same ones? Perhaps there are key enzymes that could be supplemented?




There is a school of thought out there that most androgen receptor "attenuation" happens at the transcriptional co-repressor level. If you buy into this (there is some compelling evidence out there), then AR attenuation in the "classic sense" may not actually happen, in which case cycle protocols based on the model of classic AR receptor attenuation may not be affective at all to the end of optimizing receptor function. I have not stayed current in this field, but at one time investigators were looking into antagonizing the SIRT1 histone deacetylase as a way to possibly inhibit this negative feedback on AR-mediated transcriptional activation.
*not to discredit anybody out there with ideas contrary to all this. We are really dealing with a "black box" here..the system is not well understood.

IIRC, our member, The Scientist believes that multiple short cycles are more efficient than longer ones because of either AR downregulation or the build up of catabolic substances. On the other hand, in Big Sa beginners thread, he advises to just stay on cycle permanently until the individual BBers goals are reached. Big A advised to supplement the injectibles with oralls in short oral cycles of maybe 2 or 3 months, while doing regular blood work to watch for health related warning signs. What's interesting is that some believe that longer cycles can push forward the bodies' own internal setpoint, leading to greater future growth potential.

I wish the stuff I typed was as detailed as yours, but I'm just not as erudite in biochemistry as you, but that's why opened this thread: to solicit expert input.




hope this helps. If you buy it, the transcriptional co-repressor model fits nicely with shorter cycles/shorter off times (or at least shorter off-times )

Most of it is waaaay over my head, but I'm trying to follow along. Mostly, I'm just hoping to learn more about the issues & maybe pick up some usefull advice. I know it's probably pretty unrealistic to hope to find applicable advice regarding something so complicated & unknown that even professional research scientists dissagree about it, but I'm an eternal optimist.

So, you mentioned shorter off times? That's interesting. Got any background info or technical references on that?

Thanx.

 

[hollywoood]

short off times

The notion of shorter off times, according to the transcriptional co-repressor model of AR receptor attenuation, makes sense because generally this type of signal attenuation hapenns on a much smaller time-scale than with classic receptor attenuation. According to this model, becuase the actual AR never stopped functioning, the cell will not need express new recptors and display them on the cell membrane. You can check pubmed for references (again, I am familiar with all this as a competitor but this is not my specifc field), but there are actually cellular contexts where AR receptor stimulation INCREASES AR expression (i.e the cell makes and displays more receptors in response to androgen stimulation). we also know that receptors which have attenuated by the classic mechanism (covalent modification of the active site, internalization/proteolysis, etc) take a painfully long time to recover baseline function. (most people employ off-times with clen as long as on-times for this reason, beta adrenergic receptors attenuate fast and regenerate slow.)


The problem with pulling a specific study and taking it as gospel is that studies often conflict; this is dependent on the model being used, the research group, and other intangibles. Science evolves slowly and we simply don't understand the system enough at this point to manipulate it in the specific ways that you seek.
You mentioned other members on the board seem to have different methods..truth is, everybody is right...if their methods are effective for them. People can argue till blue in the face about what the right method may be, but with lack of a complete understanding of the system, this would amount to philosophy, not science. (throw a rock in a pond.... what happens? Perturb a cell at homeostasis (or the entire organism) and you have an analagous situation)

Anyways, hope this helps bro. My research keeps me from posting much, but I have endlessly pondered this question myself and I have a pretty extensive background in science/research so I thought I would give you my .02- for what it is worth.

 

[iprimate]

Newman, your question is not a simple one; )

Yes this isn't as simple as I initially thought and the research doesn't really help with most of the research on AR regulation focussed on prostate cells rather than skeletal muscle cells.

Receptor theory in pharmacology suggests that chronic exposure to an agonist (or ligand) produces receptor downregulation[7]. This is seen with many drugs so it is reasonable to assume this is the case with the AR and its agonists and natural ligand until contrary evidence appears.

There is some evidence for AR upregulation in skeletal muscle in response to agonist/ligand exposure[1][2][3][4]. However, these studies do not test the effects of chronic, high dose exposure.

There are studies that confirm that testosterone has a linear dose-response relationship in doses up to 600mg/week for increases in muscle mass[5]. Anecdote suggests that we see the standard hyperbolic dose-response curve if we continue dosing beyond 600mg/week. Given that this dose-response relationship is explained using (occupancy) receptor theory[6] we are led full-circle back to the idea that AAS do conform to the generally accepted idea that chronic and/or high exposure of a receptor to its ligand or an agonist results in receptor downregulation.

I think Newman's question is "Can we do anything to assist AR upregulation or to assist replacement of translocated AR?" I don't think there is any substance you can take to help this, not at this time anyway.

 

[angel]

You might get more play on the Peptide forum. Worth a try.

ANGEL

 

[Newman]

I found some interesting reading on another forum, but I wasn't sure if it was okay to link to it or not, so I copied it for you guys 2 read:




Putting to bed the myth of AR downregulation

Androgen receptors down-regulate. Don't they?
One misunderstood principle of steroid physiology is the concept of androgen receptors (AR), sometimes called "steroid receptors", and the effects of steroid use on their regulation. It is commonly believed that taking androgens for extended periods of time will lead to what is called AR "down regulation". The premise for this argument is; when using steroids during an extended cycle, you eventually stop growing even though the dose has not decreased. This belief has persisted despite the fact that there is no scientific evidence to date that shows that increased levels of androgens down regulates the androgen receptor in muscle tissue.

The argument for AR down-regulation sounds pretty straightforward on the surface. After all, we know that receptor down-regulation happens with other messenger-mediated systems in the body such as adrenergic receptors. It has been shown that when taking a beta agonist such as Clenbuterol, the number of beta-receptors on target cells begins to decrease. (This is due to a decrease in the half-life of receptor proteins without a decrease in the rate that the cell is making new receptors.) This leads to a decrease in the potency of a given dose. Subsequently, with fewer receptors you get a smaller, or diminished, physiological response. This is a natural way for your body to maintain equilibrium in the face of an unusually high level of beta-agonism.

In reality this example using Clenbuterol is not an appropriate one. Androgen receptors and adrenergic receptors are quite different. Nevertheless, this is the argument for androgen receptor down-regulation and the reasoning behind it. The differences in the regulation of ARs and adrenergic receptors in part show the error in the view that AR down-regulate when you take steroids. Where adrenergic receptor half-life is decreased in most target cells with increased catecholamines, AR receptors half-live's are actually increased in many tissues in the presence of androgens.1

Let me present a different argument against AR down-regulation in muscle tissue. I feel that once you consider all of the effects of testosterone on muscle cells you come to realize that when you eventually stop growing (or grow more slowly) it is not because there is a reduction in the number of androgen receptors.

Testosterone: A multifaceted anabolic
Consider the question, "How do anabolic steroids produce muscle growth?" If you were to ask the average bodybuilding enthusiast I think you would hear, "steroids increase protein synthesis." This is true, however there is more to it than simple increases in protein synthesis. In fact, the answer to the question of how steroids work must include virtually every mechanism involved in skeletal muscle hypertrophy. These mechanisms include:

· Enhanced protein synthesis

· Enhanced growth factor activity (e.g. GH, IGF-1, etc.)

· Enhanced activation of myogenic stem cells (i.e. satellite cells)

· Enhanced myonuclear number (to maintain nuclear to cytoplasmic ratio)

· New myofiber formation

Starting with enhanced growth factor activity, we know that testosterone increases GH and IGF-1 levels. In a study by Fryburg the effects of testosterone and stanozolol were compared for their effects on stimulating GH release.2 Testosterone enanthate (only 3 mg per kg per week) increased GH levels by 22% and IGF-1 levels by 21% whereas oral stanozolol (0.1mg per kg per day) had no effect whatsoever on GH or IGF-1 levels. This study was only 2-3 weeks long, and although stanozolol did not effect GH or IGF-1 levels, it had a similar effect on urinary nitrogen levels.

What does this difference in the effects of testosterone and stanozolol mean? It means that stanozolol may increase protein synthesis by binding to AR receptors in existing myonuclei, however, because it does not increase growth factor levels it is much less effective at activating satellite cells and therefore may not increase satellite cell activity nor myonuclear number directly when compared to testosterone esters. I will explain the importance of increasing myonuclear number in a moment, first lets look at how increases in GH and IGF-1 subsequent to testosterone use effects satellite cells.

In part 2 we will discuss the role of satellite cells and myonuclei and how testosterone (androgens) activates these systems to create muscle growth far beyond what simple activation of the androgen receptor can produce.

Don't forget Satellite cells!

Satellite cells are myogenic stem cells, or pre-muscle cells, that serve to assist regeneration of adult skeletal muscle. Following proliferation (reproduction) and subsequent differentiation (to become a specific type of cell), satellite cells will fuse with one another or with the adjacent damaged muscle fiber, thereby increasing the number of myonuclei for fiber growth and repair. Proliferation of satellite cells is necessary in order to meet the needs of thousands of muscle cells all potentially requiring additional nuclei. Differentiation is necessary in order for the new nucleus to behave as a nucleus of muscle origin. The number of myonuclei directly determines the capacity of a muscle cell to manufacture proteins, including androgen receptors.

In order to better understand what is physically happening between satellite cells and muscle cells, try to picture 2 oil droplets floating on water. The two droplets represent a muscle cell and a satellite cell. Because the lipid bilayer of cells are hydrophobic just like common oil droplets, when brought into proximity to one another in an aqueous environment, they will come into contact for a moment and then fuse together to form one larger oil droplet. Now whatever was dissolved within one droplet (i.e. nuclei) will then mix with the contents of the other droplet. This is a simplified model of how satellite cells donate nuclei, and thus protein-synthesizing capacity, to existing muscle cells.

Enhanced activation of satellite cells by testosterone requires IGF-1. Those androgens that aromatize are effective at not only increasing IGF-1 levels but also the sensitivity of satellite cells to growth factors.3 This action has no direct effect on protein synthesis, but it does lead to a greater capacity for protein synthesis by increasing fusion of satellite cells to existing fibers. This increases the number of myonuclei and therefore the capacity of the cell to produce proteins. That is why large bodybuilders will benefit significantly more from high levels of androgens compared to a relatively new user.

Testosterone would be much less effective if it were not able to increase myonucleation. There is finite limit placed on the cytoplasmic/nuclear ratio, or the size of a muscle cell in relation to the number of nuclei it contains.4 Whenever a muscle grows in response to training there is a coordinated increase in the number of myonuclei and the increase in fiber cross sectional area (CSA). When satellite cells are prohibited from donating viable nuclei, overloaded muscle will not grow.5,6 Clearly, satellite cell activity is a required step, or prerequisite, in compensatory muscle hypertrophy, for without it, a muscle simply cannot significantly increase total protein content or CSA.

More myonuclei mean more receptors

So it is not only true that testosterone increases protein synthesis by activating genetic expression, it also increases the capacity of the muscle to grow in the future by leading to the accumulation of myonuclei which are required for protein synthesis. There is good reason to believe that testosterone in high enough doses may even encourage new fiber formation. To quote the authors of a recent study on the effects of steroids on muscle cells:

"Intake of anabolic steroids and strength-training induce an increase in muscle size by both hypertrophy and the formation of new muscle fibers. We propose that activation of satellite cells is a key process and is enhanced by the steroid use."7

Simply stated, supraphysiological levels of testosterone give rise to increased numbers of myonuclei and thereby an increase in the number of total androgen receptors per muscle fiber. Keep in mind that I am referring to testosterone and testosterone esters. Not the neutered designer androgens that people take to avoid side effects.

Another group of researchers are quoted as saying:

"it is intriguing to speculate that the upregulation of AR levels via the administration of pharmacological amounts of androgens might convert some muscles that normally have a minor or no response to muscles with enhanced androgen responsiveness"(8)

This is not an argument to rapidly increase the dosages you use. It takes time for these changes to occur and the benefits of higher testosterone levels will not be immediately realized. It does shed some light however on the proportional differences between natural and androgen assisted bodybuilders physiques.

Maintenance of the kind of muscle mass seen in top-level bodybuilders today requires a given level of androgens in the body. That level will vary from individual to individual depending on their genetics. Nevertheless, if the androgen level drops, or if they were to "cycle off" the absolute level of lean mass will also drop. Likewise, as the level of androgens goes up, so will the level of lean mass that individual will be able to maintain. All of this happens without any evidence of AR down regulation. More accurately it demonstrates a relationship between the amount of androgens in the blood stream and the amount of lean mass that you can maintain. This does not mean that all you need is massive doses to get huge. Recruitment of satellite cells and increased myonucleation requires consistent "effective" training, massive amounts of food, and most importantly, time. Start out with reasonable doses. Then, as you get bigger you can adjust your doses upwards.


***I frequently see stuff reposted onto different internet locations, but I'm unsure of the etiquette involved. If I'm breaking any rules by reposting this info here, please delete this post.*** Newman

 

[bigraf]

good find newman, thanks

 

[iprimate]

I found some interesting reading on another forum, but I wasn't sure if it was okay to link to it or not, so I copied it for you guys 2 read:

Newman, as per your invite in the PM I read the article and here are my thoughts.

The first problem that I noticed with the article is that the author doesn't define what he is arguing against. If the aim was to demonstrate that AR downregulation never occurs in the context of sustained supraphysiological doses of AAS then it doesn't achieve that aim. I am unsure exactly what he is arguing against, some of the points he is contending against seem like "straw men".

From my reading of the article it can be reduced to this simple claim:

More myonuclei mean more receptors

The rest of the article seems like a scatter gun approach intended to support the above claim.

AR are expressed principally in satellite cells. Myonuclei express AR significantly less so that satellite cells[1]. However, yes, myonuclear proliferation will mean AR proliferation. But is this a sufficient basis upon which to describe a central pillar of pharmacological theory as "myth"? No, I don't think so.

The article author appears to have no idea of the timescales over which these physiological and biochemical processes take place. Ligand-AR complexes translocate to the nucleus in minutes (i.e. <1 hour)[2]. Satellite cell and myonuclear proliferation on the other hand occurs over a period of 48 hours following exercise induced microtrauma[3]. In other words, the AR proliferation that occurs as a result of satellite cell and myonuclear proliferation doesn't occur fast enough to prevent the AR downregulation that would result from AR destruction outstripping AR synthesis in the first 24-hours that follow IM depot injection (when AAS levels are highest[4]). More AR will come but they will come in days whereas AR-ligand complexes translocate to the nucleus in as little as 15 minutes.

AR receptors half-live's are actually increased in many tissues in the presence of androgens.

Yes this is true too. The presence of ligand has been found to extend AR half-life from 1 hour to 6 hours[5] and this appears to at least be part of the mechanism of the observed AR upregulation in the presence of ligand[6]. Nevertheless this isn't sufficient to demonstrate that AR downregulation does not occur. Even if the half-lfe of existing AR is extended the binding capacity of these AR remains limited i.e. once the AR-ligand complex is created and the complex translocated the AR has to be recreated. This limit will eventually produce a net reduction in AR when the rate of binding exceeds the rate of resynthesis, which would occur from sustained supraphyisological doses of AAS. The author appears to implicitly concede this:

This is not an argument to rapidly increase the dosages you use. It takes time for these changes to occur and the benefits of higher testosterone levels will not be immediately realized. It does shed some light however on the proportional differences between natural and androgen assisted bodybuilders physiques.

(emphasis mine)

A major deficicency of the article is that it fails to account for observed phenomena. The author wishes to displace the idea of AR downregulation ( which has much explanatory power) yet he doesn't tell us how he would account for the hyperbolic dose-reponse curve that most AAS users experience. Why don't we see a linear dose-response relationship beyond 1g/day of testosterone ester? Why does blast 'n' cruise appear to work?

Another article on this topic (perhaps by the same author) fills the vacuum left by throwing out receptor theory with cortisol. The implication being that if cortisol were controlled a sustained linear dose-response relationship could be realised. Cortisol can be controlled and it has been controlled but I don't know of anyone reporting continued dose-proportionate gains.

In case it isn't clear I am contending that AR downregulation does occur in the short-term (<48 hours) and that AR upregulation occurs in the medium and long-terms (>48 hours). Receptor theory is a pillar of pharmacology and until compelling evidence is produced AAS shouldn't be excluded from the principles of receptor theory as a special case.

 

[Newman]

Yes this is true too. The presence of ligand has been found to extend AR half-life from 1 hour to 6 hours[5] and this appears to at least be part of the mechanism of the observed AR upregulation in the presence of ligand[6]. Nevertheless this isn't sufficient to demonstrate that AR downregulation does not occur. Even if the half-lfe of existing AR is extended the binding capacity of these AR remains limited i.e. once the AR-ligand complex is created and the complex translocated the AR has to be recreated. This limit will eventually produce a net reduction in AR when the rate of binding exceeds the rate of resynthesis, which would occur from sustained supraphyisological doses of AAS. The author appears to implicitly concede this:

A major deficicency of the article is that it fails to account for observed phenomena. The author wishes to displace the idea of AR downregulation ( which has much explanatory power) yet he doesn't tell us how he would account for the hyperbolic dose-reponse curve that most AAS users experience. Why don't we see a linear dose-response relationship beyond 1g/day of testosterone ester? Why does blast 'n' cruise appear to work?

In case it isn't clear I am contending that AR downregulation does occur in the short-term (<48 hours) and that AR upregulation occurs in the medium and long-terms (>48 hours). Receptor theory is a pillar of pharmacology and until compelling evidence is produced AAS shouldn't be excluded from the principles of receptor theory as a special case.

As you can see, I chopped some out of your post. I hope you don't mind.

I'm glad you responded. I don't know enough yet to accurrately argue the merrits/weaknesses of the article I posted, so it's nice to get properly erudite input.

If you don't mind, I've got a question for you:

How do you feel about Dan Duchaines' theory on post AR mediated AAS metabolism?

Here's a link from the articles section to our thread on that:

http://www.professionalmuscle.com/forums/showthread.php?t=13609

I can't remember whether you posted your opinion on that thread already, LOL. I guess linking to it again won't hurt.

I'm a long way from ever being able to mega dose the way the giant pro class boys do, but it's an interesting theory anyway.

 

[iprimate]

How do you feel about Dan Duchaines' theory on post AR mediated AAS metabolism?

It's probably true and accounts for observed phenomena without arbitrarily rejecting foundational concepts in pharmacology, something that the article you posted fails to do.

It is tempting to try to substantiate Duchaine's theory with reference to the low binding affinity some (effective) AAS have to the AR but this doesn't appear to be a productive approach. A recent paper concludes that AAS with a low binding affinity to AR in vitro -- stanozolol and methanedienone-- are able in vivo to activate the AR.

I have no idea what the non-AR mediated pathway is -- and I doubt anyone else does -- but it is a plausible theory nevertheless.

 

[Newman]

I have no idea what the non-AR mediated pathway is -- and I doubt anyone else does -- but it is a plausible theory nevertheless.

Assuming that Duchaines' pathway actually does exist, I hope that one day some bright scientist discovers a substance that unlocks that pathway so that mega doses of AAS would no longer be required to bypass/negate downregulation.

 

[Conciliator]

Receptor theory in pharmacology suggests that chronic exposure to an agonist (or ligand) produces receptor downregulation[7]. This is seen with many drugs so it is reasonable to assume this is the case with the AR and its agonists and natural ligand until contrary evidence appears.

Although it's seen with many drugs and is a general rule, it's not always the case. Nicotine, the interleukins, and androgens have been shown to up-regulate their own receptor. In the case of androgens, this has been shown in humans after chronic exposure to supraphysiological doses of testosterone. However, although there's apparently receptor up-regulation (e.g. an increase in androgen receptor density), that's not to say that there's not some kind of "functional downregulation" (e.g. at the posttranslational level).

Here are several references I've complied:

This 2004 study (free full text), gave 600mg of testosterone enanthate to healthy males for 20 weeks. The study was titled "Androgen Receptor in Human Skeletal Muscle and Cultured Muscle Satellite Cells: Up-Regulation by Androgen Treatment". They concluded:

In summary, although multiple cell types within the human skeletal muscle express AR protein, satellite cells, and myonuclei are the predominant sites of AR expression. ARs aggregate within the nucleoli of satellite cells and myonuclei. Testosterone and DHT up-regulate AR expression in vivo and in vitro.

This 1992 study (the full text is free), entitled "Androgen Receptor Phosphorylation, Turnover, Nuclear Transport, and Transcriptional Activation" concluded:

Androgen increased the amount of AR [androgen receptor] phosphorylation simply by slowing the rate of degradation of the AR protein. AR stabilization by androgen was observed previously in binding studies on tissue cytosols (34). Moreover, in a ductus deferens smooth muscle tumor cell line, endogenous AR stabilization increased about 2-fold with androgen, from t1/2 3.1 h without androgen to t1/2 6.6 h with R1881 (55). The mechanism of receptor stabilization by androgen is not known but the striking specificity for androgen suggests it may be closely linked with receptor functional activity. Although other groups have reported on steroidinduced phosphorylation of AR (25) and the glucocorticoid and progesterone receptors (21-24), no androgen-dependent enhancement of recombinant AR phosphorylation was detected in the present study. While the AR is clearly a phosphoprotein, the specific role of phosphorylation in receptor function is unclear. AR sites of phosphorylation are currently being mapped, and it is conceivable that androgen binding may increase phosphorylation of a single site not detectable in our assay system.

This 1996 study (the full text is free), entitled "Testosterone Up-Regulates Androgen Receptors... of Porcine Myogenic Satellite Cells in Vitro" concluded:

In summary, we demonstrate that cultured satellite cells and myotubes possess AR [androgen receptors], which are up-regulated in response to testosterone.

This 1999 paper, entitled "Effects of anabolic steroids on the muscle cells of strength-trained athletes" stated:

Enhanced satellite cells stimulation would provide more nuclei to the muscle fibers. Because androgen receptors are located in the myonucleus (23,38,47), the increased nuclear number would also give rise to an elevation of the number of androgen binding sites, thus making the muscle more susceptible to the anabolic compounds.

**broken link removed** (free text), entitled "Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles" spoke to bodybuilders saying:

DHT administration to the castrated group upregulated AR levels in the bulbocavernosus and levator ani muscles.
...
It is intriguing to speculate that the upregulation of AR levels via the administration of pharmacological amounts of androgens might convert some muscles that normally have a minor or no response to muscles with enhanced androgen responsiveness.

Because athletes may self administer synthetic androgens for many months or years at even higher doses than used in this study (17), it is possible that upregulation of AR levels might be an important part in the anabolic effects of androgen abuse.

**broken link removed** (free full text), entitled "Androgen regulation of satellite cell function" couldn't have made it any more explicit:

Increase in AR levels: Up-regulation of AR levels is one of the documented responses to androgens in target tissues or organs. Up-regulation of AR levels by androgen treatment in skeletal muscle has been observed in rat and human (Antonio et al. 1999, Kadi et al. 2000, Lee et al. 2003). The auto-regulation of AR levels by androgens may occur through stabilizing existing receptors or by increasing de novo receptor synthesis (Kadi et al. 2000). Up-regulation of AR levels by androgens could be one mechanism by which androgens have effects on muscle.

The increase in AR levels with androgen treatment has been demonstrated in satellite cells in pig (Doumit et al. 1996). This study clearly demonstrated the presence and auto-regulation of AR in satellite cells and also myotubes. Immunoblot analysis revealed that AR expression in satellite cells and myotubes was up-regulated in response to testosterone. Moreover, immunocytochemical staining for AR was more intense in the nuclei of satellite cells and myotubes from androgen-treated cells. Because the AR is
located in the myonucleus, the increased nuclear number could potentially give rise to an elevation in the number of androgen binding sites (Kadi et al. 1999). Taken together, these data suggest that androgens may have effects on satellite cells through up-regulation of AR levels in satellite cells, which could enhance the sensitivity of satellite cells to androgens.

Also, when examing the research, keep in mind that there can be down-regulation of AR mRNA while there's up-regulation of the receptor protein itself. That's what a nice 2008 review on androgens in humans explained:

AR expression itself is regulated at both the mRNA and protein levels by androgens (Lee and Chang 2002). Androgens predominantly decrease AR mRNA at the transcriptional level (Trapman et al 1990; Krongrad et al 1991) however, they simultaneously increase AR stability and translational efficiency thereby even in the presence of decreased AR mRNA levels, androgens increase AR protein levels in most cell types (Yeap et al 1999).

Hope that helps,
Conciliator

 

[iprimate]

Although it's seen with many drugs and is a general rule, it's not always the case. Nicotine, the interleukins, and androgens have been shown to up-regulate their own receptor. In the case of androgens, this has been shown in humans after chronic exposure to supraphysiological doses of testosterone. However, although there's apparently receptor up-regulation (e.g. an increase in androgen receptor density), that's not to say that there's not some kind of "functional downregulation" (e.g. at the posttranslational level).

Thanks for the response.

The largest supraphysiological dose of testosterone administered to humans in a study is 600mg/week and that was in one of the studies you cited. That same study found increase AR expression in skeletal muscle after 20 weeks (IIRC). That is fine but 600mg/week is small by today's dosing standards and I'm interested to know what happens beyond 1g/week. Anecdotal evidence tells us that we start seeing the expected hyperbolic dose-response curve for amounts in the range 1-4g/week then beyond 4g/week we see a different dose-response curve which Duchaine described as being the result of some post-AR mediated pathway.

I conjecture that AR downregulation occurs for amounts 1-4g/week.

Hopefully I haven't argued right passed your point. I will try and read Lee & Chang (2002) tommorow.

 

[Newman]

I feel like a mental midget interjecting this question in between you two very knowledgeable dudes, but it's a question you might be interested in:

How do you guys feel about Chavo's SARMS-4 ?

I think it's a very interesting product, probably best used for PCT to preserve gains while natty test levels are still low & climbing back to normal.

Some have complained about vision issues after using Chavos' SARMS-4, but AFAIK, there weren't any such problems noted in the published formal research results, so it's probably just a minor chemistry issue that will eventually be cleaned up in the lab. Residues or something...

 

[Conciliator]

I feel like a mental midget interjecting this question in between you two very knowledgeable dudes, but it's a question you might be interested in:

How do you guys feel about Chavo's SARMS-4 ?

I think it's a very interesting product, probably best used for PCT to preserve gains while natty test levels are still low & climbing back to normal.

Personally, I'm excited we're to the point where SARMs are being made available. I agree that PCT would be an excellent time for them, granted they're antagonistic at the HPTA.

Some have complained about vision issues after using Chavos' SARMS-4, but AFAIK, there weren't any such problems noted in the published formal research results, so it's probably just a minor chemistry issue that will eventually be cleaned up in the lab. Residues or something...

It might be contaminants. Or it could be because what Chavo is selling is not actually S-4. Or it could be from the relatively massive doses that are being taken. It appears that Chavo is incompetent to identify the clinical trials on which he claims to base his dosing recommendation of 1-3 mg/kg.