Muscle gain slows down after 6-8 weeks on AAS, then hits a full plateau?

[T-600]

I was reading William Llewellyn’s “ANABOLICS” book recently, and there’s a part where he says:

Anabolic / Androgenic steroids tend to be most effective at a given dosage for approximately 6-8 weeks. After this point, the rate of new muscle gain will slow, and soon after will usually hit a full plateau.

If accurate, I’m surprised I haven’t seen more cycles where injectable / oral compounds are switched up every 6 weeks, with a consistent therapeutic foundation of Test throughout.

What is the truth behind this?

 

[brock8282]

Don’t we already kinda do that? Typically short esters and orals people will run for 6-8 weeks, long esters 12-16, those long esters take 4-8 weeks to build up so technically the dose is increasing for 4-8 weeks so once the dose hits a steady amount we run that dose about 8 weeks.

 

[Joliver]

In my opinion, that's wrong. For 6-8 weeks, you'll get increases in intramuscular glycogen and phosphocreatine retention--which is the noticable gains. But testosterone will always bind to the androgen receptor and call for gene transcription leading to tissue accumulation.

I believed the "limited time" efficacy myth for a while. I hit a bad plateau once....decided to run a gram of test for an entire year....met my family for Thanksgiving after that year and they nearly called the police on me I'd changed so much. I don't recommend that protocol...but test calls for protein synthesis via the AR--like death and taxes. I'll leave the others to argue about "down regulation" and the body's homeostatic efforts through other mechanisms.

 

[transcend2007]

If this were true the very concept of trt would seem to be invalid ... I've taken the same amount of test between 100 to 200mgs per week and had stable testosterone levels for 8 years ...

 

[Xxplosive]

I was reading William Llewellyn’s “ANABOLICS” book recently, and there’s a part where he says:



If accurate, I’m surprised I haven’t seen more cycles where injectable / oral compounds are switched up every 6 weeks, with a consistent therapeutic foundation of Test throughout.

What is the truth behind this?

Key in that quote: "...at a given dose".

Your body will become used to anything you do consistly at the same amounts. Remember the first time you drank 2 beers? Wonder why alcoholics drink un-Godly amounts of liquor?

 

[Adrenolin]

If this were true the very concept of trt would seem to be invalid ... I've taken the same amount of test between 100 to 200mgs per week and had stable testosterone levels for 8 years ...

Has literally nothing to do with stable blood concentrations of given hormones

In my opinion, that's wrong. For 6-8 weeks, you'll get increases in intramuscular glycogen and phosphocreatine retention--which is the noticable gains. But testosterone will always bind to the androgen receptor and call for gene transcription leading to tissue accumulation.

I believed the "limited time" efficacy myth for a while. I hit a bad plateau once....decided to run a gram of test for an entire year....met my family for Thanksgiving after that year and they nearly called the police on me I'd changed so much. I don't recommend that protocol...but test calls for protein synthesis via the AR--like death and taxes. I'll leave the others to argue about "down regulation" and the body's homeostatic efforts through other mechanisms.

Remember what Jin says about opinions. Lol I'd agree 6-8wks is a little on the lower side, more like 8-12 on short esters and 12-16 on longer esters at a given dosage. Myostatin increases while on gear slowly counteracting the effects of the anabolics the longer the cycle lasts also the AR becomes saturated and stressed to the point of down regulation ie your given number of receptors are bound... this is where a cycle starts losing its effectiveness if you don't increase your dosage. Though the more you increase the dosage, similar to xxplosive's analogy, the higher the chance of you developing a resistance to some extent to exogenous testosterone, meaning a given dose has less effect in the future.

Side note for newer users: since testosterone has a low binding affinity for the AR of only about 10% I tend to keep it lower to let other compounds freely bind the AR and exert their magic. Some good ol proviron or masteron helps free up some test by binding shbg allowing a lower dose of test to be effective without having it fight the main compounds in your cycle for the AR.

 

[Joliver]

Has literally nothing to do with stable blood concentrations of given hormones


Remember what Jin says about opinions. Lol I'd agree 6-8wks is a little on the lower side, more like 8-12 on short esters and 12-16 on longer esters at a given dosage. Myostatin increases while on gear slowly counteracting the effects of the anabolics the longer the cycle lasts also the AR becomes saturated and stressed to the point of down regulation ie your given number of receptors are bound... this is where a cycle starts losing its effectiveness if you don't increase your dosage. Though the more you increase the dosage, similar to xxplosive's analogy, the higher the chance of you developing a resistance to some extent to exogenous testosterone, meaning a given dose has less effect in the future.

Side note for newer users: since testosterone has a low binding affinity for the AR of only about 10% I tend to keep it lower to let other compounds freely bind the AR and exert their magic. Some good ol proviron or masteron helps free up some test by binding shbg allowing a lower dose of test to be effective without having it fight the main compounds in your cycle for the AR.

I'd like to see some sort of data on the claims of 10% binding and the myostatin increase.

From what I've seen, test is the standard by which all other hormones are measured regarding binding. It has a high affinity for the androgen receptor being as how it's the primary naturally occurring androgen in humans and animals....DHT being a secondary androgen through test reduction.

https://www.rcsb.org/structure/2q7i

And this is a study analyzing the decrease in myostatin after 22 weeks of exogenous testosterone administration.

https://pubmed.ncbi.nlm.nih.gov/30629183/

 

[liftsiron]

Here is a good article on the topic.

#1

liftsiron Administrator Join Date: Nov 2003 Location: Cimmeria Posts: 17,828

Androgen Receptors Downregulate - Don't they. 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. 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.

 

[liftsiron]

Here is a good article on the topic.

#1

Join Date: Nov 2003 Location: Cimmeria Posts: 17,828

Androgen Receptors Downregulate - Don't they. 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. 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.

 

[liftsiron]

Here is another.

Posted by Vision on wcbb. Let’s talk AR’s (Androgen receptors) and diminishing gains (studies included) Recently I’ve seen a few questions or concerns regarding AR (androgen receptors) site saturation.. Let me start off by stressing this, it’s a myth that has been regurgitated over the years,it simply does NOT exist. In fact AR’s do NOT down regulate,there’s no such thing as receptor down-regulation (pertaining to AAS usage) in fact with the presence of AAS/Androgens concerning a supraphysiological level they will up-regulate,increasing,and constantly expressing new AR sites THROUGH OUT THE BODY AND TISSUE!.. (However, there is 2-3 culprits that will hinder ones gains when ON cycle, fueling the myth of AR site saturation..”1-Progesterone 2-Mysostatin, 3- and at times E1/E2 estro” but we’ll get to that later) About the AR The AR gene principals are to provide instructions for creating proteins called “androgen receptors”.. As we all know, Andro’s are hormones and the first one that comes to mind is? That’s right, the king,Testosterone…AR’s allow the body to react/respond accordingly to these hormones allowing them to preform their direct action (sexual development,muscle growth and recovery,as well as other strong male sexual characteristics and growth and development)..Receptors are found present throughout the body/tissue..This is where they attach/bind to androgens resulting in AR complex binding to DNA in which regulates the activity of AR genes..DNA is the only thing that can turn the GENE off/on if necessary,NOT AAS! FYI- AR’s belong to a family of genes known as NR (nuclear hormone receptors), which are proteins that are found within cells that are responsible for sensing steroid hormones, and also play a pivotal role with homeostasis, which finds balance in the endocrine! Why do my gains seem to diminish after 10-14 weeks? This study below can explain why our gains tend to become stagnate,or slow down when using Test,deca/primo.. ( IMO this is the ideal time to add an oral such as Dbol,drol,Tbol,Winny,or Var, which predominantly work as a non AR mediated mechanism, unlike Testosterone,Deca,Primo..As these agents express differentiation of the satellite cells of the muscle,maturing muscle cells,thus this is independent of ARs) Mol Cell Endocrinol. 2009 Apr 10;302(1):26-32. doi: 10.1016/j.mce.2008.12.019. Epub 2009 Jan 21.Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration. Abstract Methodological problems, including binding of myostatin to plasma proteins and cross-reactivity of assay reagents with other proteins, have confounded myostatin measurements. Here we describe development of an accurate assay for measuring myostatin concentrations in humans. Monoclonal antibodies that bind to distinct regions of myostatin served as capture and detector antibodies in a sandwich ELISA that used acid treatment to dissociate myostatin from binding proteins. Serum from myostatin-deficient Belgian Blue cattle was used as matrix and recombinant human myostatin as standard. The quantitative range was 0.15-37.50 ng/mL. Intra- and inter-assay CVs in low, mid, and high range were 4.1%, 4.7%, and 7.2%, and 3.9%, 1.6%, and 5.2%, respectively. Myostatin protein was undetectable in sera of Belgian Blue cattle and myostatin knockout mice. Recovery in spiked sera approximated 100%. ActRIIB-Fc or anti-myostatin antibody MYO-029 had no effect on myostatin measurements when assayed at pH 2.5. Myostatin levels were higher in young than older men (mean+/-S.E.M. 8.0+/-0.3 ng/mL vs. 7.0+/-0.4 ng/mL, P=0.03). In men treated with graded doses of testosterone, myostatin levels were significantly higher on day 56 than baseline in both young and older men; changes in myostatin levels were significantly correlated with changes in total and free testosterone in young men. Myostatin levels were not significantly associated with lean body mass in either young or older men. CONCLUSION: Myostatin ELISA has the characteristics of a valid assay: nearly 100% recovery, excellent precision, accuracy, and sufficient sensitivity to enable measurement of myostatin concentrations in men and women. Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration. – PubMed – NCBI Progestin and AR’s Progesterone has powerful antiadrogenis effect in humans at sufficient levels,capable of decreasing circulating androgens,and estrogen concentraions to castrate levels on both sexes and significantly lowering the expression of the androgen receptor (AR), and the estrogen receptor – (which posses a pivotal in homeostasis/balance and growth).. Testosterone and up-regulation! Testosterone up-regulates androgen receptors and decreases differentiation of porcine myogenic satellite cells in vitro. Abstract Accumulation of DNA is essential for muscle growth, yet mechanisms of androgen-induced DNA accretion in skeletal muscle are unclear. The purpose of this study was to determine whether androgen receptors (AR) are present in cultured skeletal muscle satellite cells and myotubes and examine the effects of testosterone on satellite cell proliferation and differentiation. Immunoblot analysis using polyclonal AR antibodies (PG-21) revealed an immunoreactive AR protein of approximately 107 kDa in porcine satellite cells and myotubes. Immunocytochemical AR staining was confined to the nuclei of satellite cells, myotubes, and muscle-derived fibroblasts. Administration of 10(-7) M testosterone to satellite cells, myotubes, and muscle-derived fibroblasts increased immunoreactive AR. In satellite cells and myotubes, AR increased incrementally after 6, 12, and 24 h of exposure to testosterone. Testosterone (10(-10) – 10(-6) M), alone or in combination with insulin-like growth factor I, basic fibroblast growth factor, or platelet-derived growth factor-BB, had no effect (P > 0.01) on porcine satellite cell proliferation, and testosterone pretreatment for 24 h did not alter the subsequent responsiveness of cells to these growth factors. Satellite cell differentiation was depressed (20-30%) on days 2-4 of treatment with 10(-7) M testosterone. This effect was not reversible within 48 h after treatment withdrawal and replacement with control medium. These data indicate that satellite cells are direct targets for androgen action, and testosterone administration increases immunoreactive AR protein and reduces differentiation of porcine satellite cells in vitro. Testosterone up-regulates androgen receptors and decreases differentiation of porcine myogenic satellite cells in vitro. – PubMed – NCBI Androgen receptor in rat skeletal muscle: characterization and physiological variations. Abstract Androgen binding has been studied in the quadriceps femoris of recently castrated adult and intact immature male and female rats using a variety of techniques for separating and measuring hormone-receptor complexes. [3H]Testosterone, [3H]androstanolone (or 5 alpha-dihydrotestosterone). [3H]methyltrienolone (a potent synthetic androgen), and [3H]estradiol bind to the androgen receptor. Affinities are identical for the first two hormones (Kd = approximately 70 pM) and lower for estradiol (Kd = approximately 0.2 nM), as determined by Scatchard plots of binding data. Competition experiments indicate that in addition to the nonradioactive steroids corresponding to the above-cited tritiated compounds, progesterone, cyproterone acetate (an antiandrogen), and spironolactone compete for [3H]androgen binding by the receptor, but diethylstilbestrol, moxestrol (a potent synthetic steroidal estrogen), and cortisol do not. 3 alpha- and 3 beta-androstanediols slightly inhibit testosterone binding. Therefore, striated muscle androgen receptor specificity is identical to that of all androgen receptors of target tissues which have been previously studied. Binding is abolished by pronase and heat treatment, and displays an approximate 7S sedimentation coefficient in low salt ultracentrifugation gradient analysis. Preliminary observations suggest hormone-induced receptor translocation into the nucleus. No evidence has been found for an independent estrogen receptor. In the course of the binding experiments, extensive metabolism of androstanoloe and testosterone was observed in muscle cytosol at 0-4 C, during the 2-h incubation period used for most binding studies. Metabolite formation can jeopardize the binding data, specifically altering the significance of competition experiments with relatively high concentrations of steroids approaching the Km of metabolizing enzymes. Therefore, most quantitative studies were performed in enzyme-free, receptor-containing cytosol preparations. In adult male rats castrated for 2 days, the concentration of receptor in the cytosol was of the order of 1 fmol/mg protein and corresponded to 72 fmol/mg tissue DNA (that is, 100 and 20 times less than that in corresponding prostatic cytosol, respectively). In the adult female rat 2 days after castration, the concentration of receptor in the cytosol was 0.34 fmol/mg protein. Treatment with testosterone pellets (20 mg for 15 days) increased androgen receptor concentration significantly. In spite of the relatively low concentration of androgen-binding sites, the typical binding specificity of the androgen receptor and the regulatory effects of androgens on their own receptor support the possibility that some effect(s) of androgens upon skeletal muscles may be initiated directly at the cellular level through this receptor, a concept which is also in agreement with recently demonstrated in vitro effects of androgens on cultured myoblasts. Androgen receptor in rat skeletal muscle: characterization and physiological variations. – PubMed – NCBI Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Abstract Steroid receptors are hormone-activated transcription factors, the expression and activities of which are also highly dependent upon posttranslational modifications including phosphorylation. The remarkable number of phosphorylation sites in these receptors and the wide variety of kinases participating in their phosphorylation facilitate integration between cell-signaling pathways and steroid receptor action. Sites have been identified in all of the functional domains although the sites are predominantly in the amino-terminal portions of the receptors. Regulation of function is receptor specific, site specific, and often dependent upon activation of a specific cell-signaling pathway. This complexity explains, in part, the early difficulties in identifying roles for phosphorylation in receptor function. With increased availability of phosphorylation site-specific antibodies and better means to measure receptor activities, numerous roles for site-specific phosphorylation have been identified including sensitivity of response to hormone, DNA binding, expression, stability, subcellular localization, and protein-protein interactions that determine the level of regulation of specific target genes. This review summarizes current knowledge regarding receptor phosphorylation and regulation of function. As functional assays become more sophisticated, it is likely that additional roles for phosphorylation in receptor function will be identified. Pharmacological doses of testosterone upregulated androgen receptor and 3-Beta-hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase and impaired leydig cells steroidogenesis in adult rats. Abstract Anabolic androgenic steroids (AAS) are testosterone derivatives originally designed to enhance muscular mass and used for the treatment of many clinical conditions as well as in contraception. Despite popular interest and abuse, we still lack a broad understanding of effects of AAS on synthesis of steroid hormones on the molecular level. This study was designed to systematically analyze the effects of pharmacological/high doses of testosterone on steroidogenic machinery in Leydig cells. Two different experimental approaches were used: (1) In vivo experiment on groups of adult male rats treated with testosterone for 1 day, 2 weeks, and 2 months; (2) Direct in vitro testosterone treatment of Leydig cells isolated from intact rats. Result showed that prolonged in vivo treatment with testosterone decreased the expression of Scarb1 (scavenger receptor class B type 1), Tspo (translocator protein), Star (steroidogenic acute regulatory protein), Cyp11a1 (cholesterol side-chain cleavage enzyme), and Cyp17a1 (17α-hydroxylase/17, 20 lyase) in Leydig cells. Oppositely, the expression of Hsd3b (3-beta-hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase), Ar (androgen receptor), and Pde4a/b (cyclic adenosine monophosphate-dependent phosphodiesterases) was increased. Androgenization for 2 weeks inhibited Cyp19 (aromatase) transcription, whereas 2-month exposure caused the opposite effect. Direct in vitro testosterone treatment also decreased the expression of Cyp11a1, Cyp17a1, and Cyp19a1, whereas Hsd3b was upregulated. The results of expression analysis were supported by declined steroidogenic capacity and activity of Leydig cells, although conversion of pregnenolone to progesterone was stimulated. The upregulation of AR and 3βHSD in testosterone-impaired Leydig cells steroidogenesis could be the possible mechanism that maintain and prevent loss of steroidogenic function. Androgen Receptor in Human Skeletal Muscle and Cultured Muscle Satellite Cells: Up-Regulation by Androgen Treatment Abstract Androgens stimulate myogenesis, but we do not know what cell types within human skeletal muscle express the androgen receptor (AR) protein and are the target of androgen action. Because testosterone promotes the commitment of pluripotent, mesenchymal cells into myogenic lineage, we hypothesized that AR would be expressed in mesenchymal precursor cells in the skeletal muscle. AR expression was evaluated by immunohistochemical staining, confocal immunofluorescence, and immunoelectron microscopy in sections of vastus lateralis from healthy men before and after treatment with a supraphysiological dose of testosterone enanthate. Satellite cell cultures from human skeletal muscle were also tested for AR expression. AR protein was expressed predominantly in satellite cells, identified by their location outside sarcolemma and inside basal lamina, and by CD34 and C-met staining. Many myonuclei in muscle fibers also demonstrated AR immunostaining. Additionally, CD34+ stem cells in the interstitium, fibroblasts, and mast cells expressed AR immunoreactivity. AR expression was also observed in vascular endothelial and smooth muscle cells. Immunoelectron microscopy revealed aggregation of immunogold particles in nucleoli of satellite cells and myonuclei; testosterone treatment increased nucleolar AR density. In enriched cultures of human satellite cells, more than 95% of cells stained for CD34 and C-met, confirming their identity as satellite cells, and expressed AR protein. AR mRNA and protein expression in satellite cell cultures was confirmed by RT-PCR, reverse transcription and real-time PCR, sequencing of RT-PCR product, and Western blot analysis. Incubation of satellite cell cultures with supraphysiological testosterone and dihydrotestosterone concentrations (100 nm testosterone and 30 nm dihydrotestosterone) modestly increased AR protein levels. We conclude that AR is expressed in several cell types in human skeletal muscle, including satellite cells, fibroblasts, CD34+ precursor cells, vascular endothelial, smooth muscle cells, and mast cells. Satellite cells are the predominant site of AR expression. These observations support the hypothesis that androgens increase muscle mass in part by acting on several cell types to regulate the differentiation of mesenchymal precursor cells in the skeletal muscle. Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration. Lakshman KM, Bhasin S, Corcoran C, Collins-Racie LA, Tchistiakova L, Forlow SB, St Ledger K, Burczynski ME, Dorner AJ, Lavallie ER. Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Medical Center, 670 Albany Street, Boston, MA 02118, United States. Methodological problems, including binding of myostatin to plasma proteins and cross-reactivity of assay reagents with other proteins, have confounded myostatin measurements. Here we describe development of an accurate assay for measuring myostatin concentrations in humans. Monoclonal antibodies that bind to distinct regions of myostatin served as capture and detector antibodies in a sandwich ELISA that used acid treatment to dissociate myostatin from binding proteins. Serum from myostatin-deficient Belgian Blue cattle was used as matrix and recombinant human myostatin as standard. The quantitative range was 0.15-37.50 ng/mL. Intra- and inter-assay CVs in low, mid, and high range were 4.1%, 4.7%, and 7.2%, and 3.9%, 1.6%, and 5.2%, respectively. Myostatin protein was undetectable in sera of Belgian Blue cattle and myostatin knockout mice. Recovery in spiked sera approximated 100%. ActRIIB-Fc or anti-myostatin antibody MYO-029 had no effect on myostatin measurements when assayed at pH 2.5. Myostatin levels were higher in young than older men (mean+/-S.E.M. 8.0+/-0.3 ng/mL vs. 7.0+/-0.4 ng/mL, P=0.03). In men treated with graded doses of testosterone, myostatin levels were significantly higher on day 56 than baseline in both young and older men; changes in myostatin levels were significantly correlated with changes in total and free testosterone in young men. Myostatin levels were not significantly associated with lean body mass in either young or older men. CONCLUSION: Myostatin ELISA has the characteristics of a valid assay: nearly 100% recovery, excellent precision, accuracy, and sufficient sensitivity to enable measurement of myostatin concentrations in men and women. PMID: 19356623 [PubMed – in process] —————————————————————————————————————————————————— ——————————————————————————————————– The final analysis, the conclusion! Now that we’ve read the studies and what science has demonstrated and well articulated in the installations, I feel its fair to say that AR down regulation does not exist in the presence of Androgen’s,and furthermore to speculate that AR’s as a perennial position for the androgen ligand.. Truth (supported by medical journals world wide) AR’s up-regulate,increasing,and constantly expressing new AR sites THROUGH OUT THE BODY AND TISSUE! (articles in medicine/science suggest the following) When unattached to an androgen they have a half life of approximately three hours and are ultimately replaced with new ones. However, in the presence of an androgen (i.e. when they’re attached), they become more sensitive, their half life is doubled and the amount of new receptors being formed also increases substantially. It’s also important to remember that AR-mediated effects are not the whole story when it comes to anabolic steroid activity in the body. There are still a host of other effects that have little to nothing at all to do with AR, known as non-AR dependent effects, which include central nervous system stimulation and a host of other anabolic and potentially anabolic activities. But that still leaves us with the question of why our gains seem to slow down after a few cycles, and why we need to keep upping the dose. In truth, the answer probably has more to do with the body attempting to return to homeostasis through other mechanisms than it has with the androgen receptor. I hope this brings some clarification to the subject! Vision _________

 

[brock8282]

I'd like to see some sort of data on the claims of 10% binding and the myostatin increase.

From what I've seen, test is the standard by which all other hormones are measured regarding binding. It has a high affinity for the androgen receptor being as how it's the primary naturally occurring androgen in humans and animals....DHT being a secondary androgen through test reduction.

https://www.rcsb.org/structure/2q7i

And this is a study analyzing the decrease in myostatin after 22 weeks of exogenous testosterone administration.

https://pubmed.ncbi.nlm.nih.gov/30629183/

And just to add to your points,
The worry about binding affinity of certain hormones is just mental masturbation and doesn’t have much use in practice. people act like we have such a limited amount of androgen receptors to bind to, most people who use gear somewhat responsibly aren’t filling up all of their androgen receptors. People will feel pretty shitty and side effects ridden long before that happens. Plus the longer we stay on gear the more androgen receptors are created to bind to.

 

[liftsiron]

Here is one last article by the late Nandi12 (super smart guy)

Below are explanations in regard to AR's up-regulation, down regulation, half lifes, etc.) by Nandi12 admin at CEM. IMO Nandi12 is likely the most brillant researcher and writer (see articles by Karl Hoffman) on these boards.

Although reported half-lives and production rates of the androgen receptor (AR) vary somewhat according to the cells examined, the values reported in the abstract below are fairly typical. In the absence of androgen the AR has a half-life of about 3 hours. This means that after 3 hours 50% of the androgen receptors initially present have been degraded and replaced with new androgen receptors. In the presence of ligand, the half life of the AR is extended to over 6 hours and the production rate of new AR was almost doubled.

Androgen receptors do not fill up. They are constantly being produced, enzymatically degraded, and replaced with new receptors.

J Biol Chem. 1985 Jan 10;260(1):455-61.

Mechanism of androgen-receptor augmentation. Analysis of receptor synthesis and degradation by the density-shift technique.

Syms AJ, Norris JS, Panko WB, Smith RG.

The ductus deferens smooth muscle tumor cell line (DDT1MF-2) contains receptors for, and is stimulated by, androgens. Cells cultured in the absence of androgens maintain a basal level of androgen receptors. Following incubation with various concentrations of the synthetic androgen methyltrienolone (R1881) for 1-6 h, the concentration of these receptors increased from 6.0 to 12.2 fmol/micrograms of DNA, while the equilibrium dissociation constant (Kd) of 0.5 nM for this steroid remained unchanged. The steroid-induced increase in androgen receptor levels was specific for androgens and dependent upon protein synthesis. The mechanism of receptor augmentation was examined by utilization of isotopically dense amino acids to determine rates of receptor appearance and degradation in the presence or absence of [3H]R1881. In the absence of androgens, the half-life of the androgen receptor was 3.1 h, with a rate constant (kD) of 0.22/h. In the presence of 1 nM [3H]R1881, however, the half-life was 6.6 h, with kD = 0.11/h. The rate constant for receptor synthesis (ks) in the absence or presence of [3H]R1881 was calculated to be 1.35 and 2.23 fmol/micrograms of DNA/h, respectively. Thus, androgen-induced androgen-receptor augmentation is explained by an increase both in receptor half-life and in rates of receptor synthesis.

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.

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.

 

[snake]

I'm with Jol on this. Like Brock said, with long esters like the ones I run, the party is just getting started at 5 weeks. No way am I bailing out at 8 weeks!

I always felt that what is important is the exposure time your gear has to your training. Even at a lower dose, you will get more out if a cycle if you get more training in and there's a limit to the amount of training you can do.

I have no data on this other then my personal experience but if what you're saying is true, One 8 week cycle every 6 months should yield a better result in the end than one 16 week cycle a year. I just don't see that happening in the final product.