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  1. #1
    ulter's Avatar
    ulter is offline Associate Member
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    The AR doesn't downregulate!

    Ok I moved off the Ox thread. I will plagiarize this argument and any others I need to get it through to some people that the AR does not down regulate FROM USING AS.

    Taking issue with the idea of androgen receptor down-regulation.
    By Bryan Haycock MS.

    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 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.

    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. 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.

    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:

    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

    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

    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

    Rosenblatt JD, Yong D, Parry DJ., Satellite cell activity is required for hypertrophy of overloaded adult rat muscle. Muscle Nerve 17:608-613, 1994

    Rosenblatt JD, Parry DJ., Gamma irradiation prevents compensatory hypertrophy of overloaded extensor digitorum longus muscle. J. Appl. Physiol. 73:2538-2543, 1992

    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

    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

  2. #2
    iron4life79's Avatar
    iron4life79 is offline Retired Moderator
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    ulter
    good post, but i need clarification if you dont mind. this study is saying that receptors dont down regulate, but when muscle hypertrophy occurs new receptors are made? if so then this is indeed a breakthrough, and could change a lot of views on this subject. give me your .02 on this, instead of just the study language, ok?


    peace bb79

  3. #3
    ironfist's Avatar
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    Originally posted by barbells79
    ulter
    good post, but i need clarification if you dont mind. this study is saying that receptors dont down regulate, but when muscle hypertrophy occurs new receptors are made? if so then this is indeed a breakthrough, and could change a lot of views on this subject. give me your .02 on this, instead of just the study language, ok?
    peace bb79
    I think he's saying that it is not necessary to cycle off of roids to obtain continued growth...Right on, I'm never gettin off...



  4. #4
    Iron horse's Avatar
    Iron horse is offline Anabolic Member
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    maybe an advanced user has to take more because if u think about it, most novice and adanced users eating habits are the same, so they have to shoot more to see more results???

    OR as the bigger you get, the harder your body aims to bring it self to its set weight?? so they may also fight that.

    pluss 20 pounds on a 180 pound person is a lot, but not on someone thats 280, or atleast not as much. and they already have to just maintain there muscle as it is also.

    just a thought!

  5. #5
    dumblucky's Avatar
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  6. #6
    Cynical is offline Associate Member
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    i think the lessinging of results has more to do with natural potential then anything else, as many have stated. and the fact that AR down regulation dosnt exist kinda promotes this idea further

  7. #7
    ulter's Avatar
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    JJ it's like the man says. No one is arguing that you don't need to use more as you get bigger. The argument is that the reason for this is NOT receptor down-regulation. It is that as you push past your genetic limits it becomes harder to maintain that extra mass and you need more AS to do it. In other words.. It's not that your body is not getting enough because your receptors down-regulated it's that your body needs more to hold that unnatural mass.

  8. #8
    fantom604 is offline New Member
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    I wholeheartedly agree with you, Ulter... having said this, however, I am curious as to how long you all have been on... and do you guys bridge between cycles, or just go into new ones every once in a while?

  9. #9
    ulter's Avatar
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    I have been using AS since 1983 with a 3 year injury lay off. My current cycle started Jul 4 2000. I cycle for size and then cut right after that with a 3-4 week low dose bridge. Then after cutting I will stay low dose for 10-12 weeks and after I check the mirror I decide if I should do it again. I have to say that right now I am as big as I want to get except for my legs so I will probably do one more bulk just to kill my legs and get them where I want them to be and then coast the rest of my life low dose test/deca /eq.
    Bulk for 8 weeks

    test 800-1100mg
    deca 600mg
    eq 500mg
    tren 700mg
    dbol 30mg/day 4 weeks - this is just for fun

    Cut for 8 weeks

    Test 500mg
    deca 200mg
    eq 500mg
    Tren 700mg
    Masteron (I am still not sure this is real) 400mg
    Oxandrolone 50mg/day
    Winny 700mg

    clen , NYC, possibly T3, Proviron , gh 4.5iu/day, 1mg/day armidex

  10. #10
    The Iron Game Guest
    probably because its safer than running 1100mgs of deca at once, Ulter good to see you post and im glad you seem to have changed your view on proviron

  11. #11
    ulter's Avatar
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    Deca and eq together for a couple reasons. Eq removes water and deca put it back in your joints to keep them lubed. You don't want to eliminate the eq because of it's ability to add stamina. Eq will really shoot that RBC up and give you more wind. Deca of course is a good mass builder where eq is not. You only need to adjust your dosing to bulk or cut.
    I would guess that your question is because you've been told that you don't put these two together for whatever reason. The people who say that generally don't have a lot of experience using them together.

    IG I have come around to using Proviron with Tren at the request of my loved one.

  12. #12
    silverfox's Avatar
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    I read that study and well back. I think there is something to it.

    In terms of why do you do better after a long layoff, i think if you really where to look at it not the case, let say you have cycled a few times, take a long break and start again you put on 20lbs then go off, you drop 5lbs of water, 5lbs of LBM, so you net 10lbs not bad for cycle you go back on after right about of down time and you net 5lbs, but if you were to stay on for say 6 months, you would net more totals lbs in terms of LBM and reatian more, at least in my experice. No studies, just what i have found thought person exerince. YOu see each cycle you tend to net a bit less each time, why? Becasue your closed to your gentic limit, so if you stay on a long time yes gains come slower, why same reason your closer to gentic limit, you just get to that limit faster then you stay on, so gains become smaller and smaller.

  13. #13
    guest589745 is offline 2/3 Deca 1/3 Test
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    Old thread? Yes. But, I would like to continue this discussion. I still keep reading peoples opinions that the AR does downregulate and I can't come to a conclusive decision at to who is right and wrong.

    Is there any studies found that conflict with this above ?

  14. #14
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