Steroidpedia
I wanted to get some feedback on some of you fellas thoughts..
Alot of people feel that androgen receptors down regulate .. I dont think it occurs..
Actually I feel that
AR receptors increase in the presence of more androgen's.. What shuts down growth is a build up of other reaction factors such as cortisol , glycogen and SHGB that your body put out to bring you back into hematosis...
thoughts ??
Merc.
Anabolic Member
I remember reading that it works the sam way as dopamine receptors. And it happens with nicotine and people who smoke know it well. Overtime you will have an increase in receptors, thus the % of receptors activated is smaller if the dosage remains the same, so people increase the amount of nicotine by smoking more to have the same response.
It is the same way with AR's. The increased number of receptors due to the presence of androgens makes the % of receptors activated drop reducing the response to that same dosage.
Was this clear?
Steroidpedia
check this out ..
Androgen Receptors Downregulate - Don't They? Part 1
By Bryan Haycock MS
Please send us your feedback on this article.
There is as much misinformation about steroids as there is good information had among bodybuilding enthusiasts. Go to any gym and you will hear some kid spouting off to his buddies about how steroids do this, or how they do that, or whatever. This soon starts somewhat of a pissing contest (excuse the expression) as to who knows more about steroids. It’s the same kind of titillating and infectious banter that adolescent boys get into about girls and sex. With steroid banter you hear all the popular terms like Deca, Test, GH, gyno, zits, raisins, "h-u-u-u-ge", roid, freak, monster, roid-rage, "I knew this guy once", etc., etc.. If by some rare chance they are smart and have been reading this or some other high quality bodybuilding site on the net, they may actually get a few details right. More often than not they know just enough to be dangerous. Fortunately steroids haven’t proven to be all that dangerous. Not only that, but most of these guys who are infatuated with steroids won’t ever use or even see them except in magazines.
This kind of ego driven gym talk doesn’t really bother me until they begin giving advice to other clueless people who actually have access to them. Spewing out steroid lingo gives other less experienced kids the impression that these kids actually know what they are talking about. That’s how all of the psuedo-science folklore about steroids perpetuates. This is also why most people who actually use steroids know little about them. This last fact should bother anyone who cares about bodybuilding and/or bodybuilders.
I started out with this article planning on giving some textbook style explanation as to why using steroids doesn’t down regulate androgen receptors (AR). Then after considering some of my critics views that I tend to write articles that hardly anyone can read, I decided to write an easy to read, yet informative explanation about what androgens actually do and how this precludes androgen receptor down regulation. I still have a few references but not so many that it looks like a review paper.
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
Last edited by Merc..; 10-05-2007 at 09:09 PM.
Steroidpedia
Androgen Receptors Downregulate - Don't They? Part 2
By Bryan Haycock MS
Please send us your feedback on this article.
In part 1 of this article we discussed the mistake of thinking about androgen receptors (testosterone receptors) in the same way we think of other receptors such as beta-receptors. Beta-receptors down regulate in response to beta-adrenergic stimulation whereas there is good evidence that androgen receptors increase in numbers in response to androgens. We also discussed the various affects of testosterone on muscle growth. Testosterone does far more than simply increase the rate of protein synthesis!
Now in part 2 we will finish our discussion of androgen receptor regulation as it pertains to the way muscle cells grow. The very mechanism of real muscle growth opens the door for increased androgen receptor number in response to testosterone treatment.
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.
References:
1. Kemppainen JA, Lane MV, Sar M, Wilson EM. Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activation. Specificity for steroids and antihormones. J Biol Chem 1992 Jan 15;267(2):968-74
2. Fryburg DA., Weltman A., Jahn LA., et al: Short-term modulation of the androgen milieu alters pulsatile, but not exercise- or growth hormone releasing hormone-stimulated GH secretion in healthy men: Impact of gonadal steroid and GH secretory changes on metabolic outcomes. J Clin Endocrinol. Metab. 82(11):3710-37-19, 1997
3. Thompson SH., Boxhorn LK., Kong W., and Allen RE. Trenbolone alters the responsiveness of skeletal muscle satellite cells to fibroblast growth factor and insulin-like growth factor-I. Endocrinology. 124:2110-2117, 1989
4. Rosenblatt JD, Yong D, Parry DJ., Satellite cell activity is required for hypertrophy of overloaded adult rat muscle. Muscle Nerve 17:608-613, 1994
5. Rosenblatt JD, Parry DJ., Gamma irradiation prevents compensatory hypertrophy of overloaded extensor digitorum longus muscle. J. Appl. Physiol. 73:2538-2543, 1992
6. Phelan JN, Gonyea WJ. Effect of radiation on satellite cell activity and protein expression in overloaded mammalian skeletal muscle. Anat. Rec. 247:179-188, 1997
7. Kadi F, Eriksson A, Holmner S, Thornell LE. Effects of anabolic steroids on the muscle cells of strength-trained athletes. Med Sci Sports Exerc 1999 Nov;31(11):1528-34
8. Antonio J, Wilson JD, George FW. Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles. J Appl Physiol. 1999 Dec;87(6):2016-9.
Senior Member
great post merc. Ive read things along these lines too, mostly saying that ar receptor downregulation is not the mode of maintaining homeostasis. What i have read is nowhere near as in depth a what you provided though. It'll will be good for a reread for sure
Steroidpedia
Originally Posted by millionairemurph
Let me know what you think after you read it..
Merc.
Associate Member
Good read.
Veritas, Aequitas ~
interesting, so for example, when taking clen, what would it be that causes the effects to wear off other than receptor downregulation? What about the benadryl and keitofen (sp) theory on upgrading receptors, does this not validate the receptor theory?
Steroidpedia
Clen decreases beta receptors but steroids increase Androgen receptors..
Merc.
Veritas, Aequitas ~
gotcha, i wasnt thinking straight on that one. beta downregulation, duhhh
Cycle King/AR-Hall of Famer/RETIRED
last time i had blood work done my SHGB cortisol and glycogen was all fine. But yet i still was not gaining an more. this was after being on for 9 month.
Steroidpedia
Do you think Diet and training played a factor as to why you weren't gaining ?
Merc.
Junior Member
I think that with steroids you can get receptor saturation, or DNA saturation as long as the chaperone proteins are unregulated indefinitely. Remember that most drugs work on cellular receptors outside the cell, these are the ones that get down regulated as the body compensates for the change whereas steroids actually enter the cell where they bind to chaperone proteins and are then attaching to your DNA to increase transcription of mRNA.... If you can saturate the DNA then you will no longer increase the transcription of mRNA which leads to protein synthesis.... bla bla you know the rest... I guess that you could start causing hyperplasia of muscle cells and then by increasing the cell number you increase the amount of DNA available for binding and therefore increase the receptor sites..
This is all just a guess though because I don't know it the chaperone proteins that are required by the steroid to bind to the DNA are up-regulated indefinitely or not..... And I'm not sure of the amount of steroid taken is anywhere near the amount needed to saturate the DNA receptors or not.. Fun to think about though....
Banned- Scammer!
No one really knows to be honest.
Have you read the thread where Pinn, Bajan and a few others discuss this. Its about 8 pages long?
Steroidpedia
?????
Associate Member
Here is a thread of great debate on the topic:
http://forums.steroid.com/showthread.php?t=209272
Steroidpedia
Originally posted by Nandi
You can read some of my speculations, based on published research, why gains seem to slow after a while here, in the article archives. There are many other posssible explanations as well, including Big Cat's. Another reason why bodybuilders just don't get infinitely large after years of AAS use is that there may be a limit to the ability of satellite cells to keep proliferating and contributing to muscle hypertrophy. The number of divisions a cell can undergo is finite (except for immortalized, cancerous cells) due to the fact that normal cells lack telomerase. Telomeres are sections of DNA that shorten each time a cell divides. Eventually the telomeres are "used up" and the cell can no longer divide. Telomerase replaces the telomeres allowing for continued cell division. Since anabolic steroids promote satellite cell proliferation, they may lead to the premature exhaustion of the ability of satellite cells to proliferate and contribute to hypertrophy. This is speculation; the real answer to your question is yet to be determined.
http://www.cuttingedgemuscle.com/For...ticle.php?id=8
Q: Often times you hear people talking about taking a break from taking steroids so their receptors can clean out otherwise their gains will come to a halt. Is there any truth to this?
A: Receptors are continually being degraded and remanufactured in cells, so they never really clog up and require cleaning. I think this is a sort of fanciful way of talking about receptor upregulation/downregulation, which is a complex topic. “Do gains slow because receptors downregulate (decrease in number and/or sensitivity) during a cycle?” is probably a more accurate way of posing the question. There are conflicting data in this regard. Short-term in vitro and in vivo studies generally show that androgens upregulate the androgen receptor (AR) in skeletal muscle. For example, in humans given 15 mg of oxandrolone daily for 5 days, the skeletal muscle AR density nearly doubled (13). When exposed to testosterone in vitro, skeletal muscle AR expression increased significantly (14).
In longer-term studies the picture is somewhat different. One study looked at AR expression in androgen treated sedentary rats vs nontreated exercised rats over 8 weeks. The androgen treated rats showed a decrease in the number of receptors, whereas the exercise trained rats showed an increase. (15) Unfortunately, the authors failed to address the question of interest to bodybuilders, and that would be the combined effects of exercise and androgen use on skeletal muscle AR regulation.
In long term studies in humans we get yet a different picture. In work conducted by Sheffield-Moore et. al., (16) older men were supplemented with testosterone so as to bring their testosterone levels into the mid to high physiological range. Androgen receptor expression had more than doubled after one month of treatment, yet by 6 months had returned to baseline. If this downregulation occurs when supraphysiological doses of testosterone are used, it could very well explain why gains tend to slow during a long cycle.
So, unfortunately the data are equivocal. The definitive experiment of combining supraphysiological AAS with resistance training and looking at AR regulation does not appear to have been carried out yet. Would exercise combined with AAS maintain increased AR expression, or would the addition of exercise serve to offset the AAS induced AR downregulation observed in the study by Bricout et al? Do the extremely high doses of AAS used by bodybuilders lead to more or less downregulation ( or even upregulation ) compared to what was seen by Sheffield-Moore et al? These are just a couple of questions that require further research, and could lead to answers on why exercise combined with AAS use is so much more productive than simply using steroids alone when it comes to building muscle mass.
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