AAS tolerance

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    AAS tolerance


    So given that one needs increasing dosages of AAS to create the same effects as time passes, this must mean that the body is devloping tolerance to it.

    I do have a few questions regarding that

    1) how does this tolerance work? Is it the body's tolerance to the AAS itself, or simply because after a cycle, the body attins more muscle and hencem it is harder to gain more muscle WITH more mucle?

    2) if one stops AAS usage for an extended period of time (say a year), KEEPS the msucle, and then begins anotehr cycle, would teh second cycle be as good as teh first?

    3) if one stops AAS usage for an extended period of time (say a year), LOSES the msucle, and then begins anotehr cycle, would the second cycle be as good as the first?

    4) if one's body devlopes tolerance, then wouldnt people who are on long term TRT feel the effects of their TRT decline over time?

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    a lot of variables here.

    genetic limit is one. once u pass ur genetic limit u basically have to stay on AAS to stay that size. gains, even on AAS, are hard to produce once passed ones limit. this is when most incorporate HGH.

    many have done cycles of test only at moderate doses and still see great gains 10 cycles later at the same dose. this is mainly diet and goal dependent.

    as long as u take an adequate break after PCT to allow ur body to recover etc. then gains on ur next cycle should be just as good as ur first.
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    Whao ok hold on thats a lot of good stuff there.

    The thing is, I am on TRT for good now, but only at 200mg/week. Durnig my 'on cycle' I want to stack it with 150mg more TNE per week.

    When I go off cycle, and continue with the 200mg/wk TRT, would that be not giving my body a break or?

    What I propose to do is this: cycle of 8-12 weeks. Off (still on TRT) for 4-6 weeks, then on again. Repeat until I believe my genetic potential is reached (I have trained for 7 years already, but not much progress due to low testsoterone that required me to seek TRT). WHen I say genetic poetntial, I mean stagnant gains no matter how smart or hard I train.

    Does that sound 'ok'?
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    have u every heard of "blasting" and "cruising"? what u want to do is basically that. except that u will NEVER need to run a PCT, which personally i think is nice.

    what u have planned looks fine. what is TNE though?
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    Quote Originally Posted by nosnmiveins View Post
    over-saturation of receptors is the main culprit for slowed/stopped gains on cycle.
    What do you mean "over-saturation of receptors"? If all the receptors are bound to a ligand, that would produce an effect, not explain the lack of an effect.

    Do you mean that the main culprit is down-regulation of the androgen receptor? Because that's also not the case. Unlike clen and the adrenoreceptor, steroids actually up-reguate the androgen receptor.
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    Blasting and cruising. O I like the sound of that. Cruise is to give teh body a break while preserving gained mass right?

    Sweet.

    TNE = testosterone no ester (test base, test suspension).

    Yes receptor down regulation makes no sense also because if they are downregulated, then no matter how much yo increasse dosages, it shoudl not work, as theer are less recptors. Once a receptor is bound, it is bound, adding mroe will not make it bind 'more'.

    I think it could possibly be beucase when you run cycle after cycle, you are taxing your msuckes. I think maybe it is the musckles themelsves that need a break, AAS or no AAS. Ofcourse,m thats just an airy assumption..
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    i blast and cruise, it works but the constant pinning gets pretty annoying, and if i have to travel its a task to bring an amp or often much more with me. only had this problem one time, where i had to miss a pin for over a week due to a vacation which ended in me losing my sex drive at a very important time :P
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    i think you must consider that the first time you do a cycle, you probably was less strong, smaller; so when you begin at 180 lb you put 15 lb (for example) but when you stay at 200 is more difficoult to put another 15. the same without Roids, in the first years with a normal diet and normal training you get result, than you must train more or eat better to improve. because you're reaching the limit.

    the example you posted (like a man lose his muscle or not, in a couple of years, can't explain a lot, because even the other variable are changed, like receptor for example).

    for what I know, the androgen receptor don't downregulate for the presence of Androgens, but probably bigger muscle need more androgen (if 10kg of muscle need 100 ng/l testo to survive, probably 50 kg muscle need 500ng/l testo)
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    Quote Originally Posted by Conciliator View Post
    What do you mean "over-saturation of receptors"? If all the receptors are bound to a ligand, that would produce an effect, not explain the lack of an effect.

    Do you mean that the main culprit is down-regulation of the androgen receptor? Because that's also not the case. Unlike clen and the adrenoreceptor, steroids actually up-reguate the androgen receptor.

    good point, my mistake. dunno what i was thinking at the time, reps
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    "test susp (base) should be shot ED..."

    Does this also apply if I am stacking it with test E shot twice weekly?
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    Quote Originally Posted by rombusempire View Post
    "test susp (base) should be shot ED..."

    Does this also apply if I am stacking it with test E shot twice weekly?

    yes because test base has no ester attached to it, so it basically kicks in immediately. most people will pin twice a day, but im sure once is good
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    So if I ran phera at 45/60/60/45 right now, will I still be able to make gains on a later cycle with phera lets say at 15/30/30/45?
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    Quote Originally Posted by rombusempire View Post
    Blasting and cruising. O I like the sound of that. Cruise is to give teh body a break while preserving gained mass right?

    Sweet.

    TNE = testosterone no ester (test base, test suspension).

    Yes receptor down regulation makes no sense also because if they are downregulated, then no matter how much yo increasse dosages, it shoudl not work, as theer are less recptors. Once a receptor is bound, it is bound, adding mroe will not make it bind 'more'.

    I think it could possibly be beucase when you run cycle after cycle, you are taxing your msuckes. I think maybe it is the musckles themelsves that need a break, AAS or no AAS. Ofcourse,m thats just an airy assumption..
    Conciliator and I disagree on this one and I am sure he will rush in to debate me but here is the deal:

    A molecule of steroid binds to a receptor. Two receptors bind together to form a homodimer which then binds a "receptor" on DNA called a hormone response element. These response elements can either increase or decrease the expression of the genes that they regulate. So, for every nucleus (muscle cells are multinucleated) you have the genome of DNA and the "receptors" (HRE's) for the steroid-receptor complex. As you increase muscle size, you also increase the number of myonuclei and therefore, the body increases the number of androgen receptors to ensure that there is adequate stimulation per unit of DNA (so for example, you increase one unit of DNA and one unit of receptor but there is still a 1:1 ratio). This is the "upregulation" that a lot of papers mention. There is also another form of upregulation where the number of receptors per unit DNA is increased - this is true upregulation and occurs in the absence of androgen (for instance, castrated animals, women, and chemically castrated men). It is the bodies response to try to increase the likelihood of androgen receptor activation and The corollary also occurs, that is, the number of androgen receptors per unit DNA is decreased -- this occurs in response to androgenic stimulation. So, in the end, you could get an increase in the number of receptors but still have a net downregulation due to the ratio of androgen receptors to unit DNA actually being lower.
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    Quote Originally Posted by sethroberts View Post
    A molecule of steroid binds to a receptor. Two receptors bind together to form a homodimer which then binds a "receptor" on DNA called a hormone response element. These response elements can either increase or decrease the expression of the genes that they regulate. So, for every nucleus (muscle cells are multinucleated) you have the genome of DNA and the "receptors" (HRE's) for the steroid-receptor complex. As you increase muscle size, you also increase the number of myonuclei and therefore, the body increases the number of androgen receptors to ensure that there is adequate stimulation per unit of DNA (so for example, you increase one unit of DNA and one unit of receptor but there is still a 1:1 ratio). This is the "upregulation" that a lot of papers mention. There is also another form of upregulation where the number of receptors per unit DNA is increased - this is true upregulation and occurs in the absence of androgen (for instance, castrated animals, women, and chemically castrated men). It is the bodies response to try to increase the likelihood of androgen receptor activation and The corollary also occurs, that is, the number of androgen receptors per unit DNA is decreased -- this occurs in response to androgenic stimulation. So, in the end, you could get an increase in the number of receptors but still have a net downregulation due to the ratio of androgen receptors to unit DNA actually being lower.
    I think you raise some interesting issues, but get into semantics when you argue what "true" upregulation is. The total number of androgen receptors is increasing. With the addition of myonuclei, there might not be an increase of AR per unit DNA, but there would be an increase of AR per muscle fiber.

    I'd argue that what matters is the total number of androgen binding sites. Androgens increase the number of myonuclei in muscle fibers, which in turn increase the total number of androgen binding sites. This makes muscle more susceptible to androgens.

    Keep in mind that an increase in myonuclei is not the only mechanism of action for AR upregulation. There's research showing that androgens also increase the half life of the androgen receptor. So not only is there an increase in de novo receptor synthesis, but existing receptors are stabilized.
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    Quote Originally Posted by Conciliator View Post
    I think you raise some interesting issues, but get into semantics when you argue what "true" upregulation is. The total number of androgen receptors is increasing. With the addition of myonuclei, there might not be an increase of AR per unit DNA, but there would be an increase of AR per muscle fiber.

    I'd argue that what matters is the total number of androgen binding sites. Androgens increase the number of myonuclei in muscle fibers, which in turn increase the total number of androgen binding sites. This makes muscle more susceptible to androgens.

    Keep in mind that an increase in myonuclei is not the only mechanism of action for AR upregulation. There's research showing that androgens also increase the half life of the androgen receptor. So not only is there an increase in de novo receptor synthesis, but existing receptors are stabilized.
    In the end, what it comes down to for me is that androgen receptor antagonists and castration seem to result in greater sensitivity of the system (i.e. upregulation) while stimulation results in decreased sensitivity which is a basic tenant of receptor physiology as stated in several standard texts on the subject.
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    A molecule of steroid binds to a receptor. Two receptors bind together to form a homodimer which then binds a "receptor" on DNA called a hormone response element. These response elements can either increase or decrease the expression of the genes that they regulate. So, for every nucleus (muscle cells are multinucleated) you have the genome of DNA and the "receptors" (HRE's) for the steroid-receptor complex. As you increase muscle size, you also increase the number of myonuclei and therefore, the body increases the number of androgen receptors to ensure that there is adequate stimulation per unit of DNA (so for example, you increase one unit of DNA and one unit of receptor but there is still a 1:1 ratio). This is the "upregulation" that a lot of papers mention. There is also another form of upregulation where the number of receptors per unit DNA is increased - this is true upregulation and occurs in the absence of androgen (for instance, castrated animals, women, and chemically castrated men). It is the bodies response to try to increase the likelihood of androgen receptor activation and The corollary also occurs, that is, the number of androgen receptors per unit DNA is decreased -- this occurs in response to androgenic stimulation. So, in the end, you could get an increase in the number of receptors but still have a net downregulation due to the ratio of androgen receptors to unit DNA actually being lower.
    Reps.

    With the addition of myonuclei, there might not be an increase of AR per unit DNA, but there would be an increase of AR per muscle fiber.
    If new nuclei are made and fuse with existing cells while those cells are down regulating the androgen receptor, wouldn't you just be breaking even in terms of net androgen receptor availability?
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    Quote Originally Posted by LSU Gladiator View Post
    If new nuclei are made and fuse with existing cells while those cells are down regulating the androgen receptor, wouldn't you just be breaking even in terms of net androgen receptor availability?
    What do you mean that "those cells are down regulating the androgen receptor"? The half life of the receptor is increased and you're synthesizing new receptors. You're not "just breaking even". There's a net increase in androgen receptor binding sites. As several studies state, that leads to an increase in susceptibility to androgens.

    There are plenty of other possible explanations for the apparent functional loss seen with extended steroid use. Receptor down-regulation is simply not one of them.
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    Quote Originally Posted by Conciliator View Post
    What do you mean that "those cells are down regulating the androgen receptor"? The half life of the receptor is increased and you're synthesizing new receptors. You're not "just breaking even". There's a net increase in androgen receptor binding sites. As several studies state, that leads to an increase in susceptibility to androgens.

    There are plenty of other possible explanations for the apparent functional loss seen with extended steroid use. Receptor down-regulation is simply not one of them.
    In general what are you referring to here? Insulin sensitivity (I was thinking this was more diet related)?
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    Quote Originally Posted by sethroberts View Post
    In the end, what it comes down to for me is that androgen receptor antagonists and castration seem to result in greater sensitivity of the system (i.e. upregulation) while stimulation results in decreased sensitivity which is a basic tenant of receptor physiology as stated in several standard texts on the subject.
    Sounds like you're conflating functional downregulation with receptor downregulation. Just because there's decreased functionality does not entail that the androgen receptor has not upregulated (i.e. increased in density). The research clearly shows in vitro and in vivo that androgens upregulate the androgen receptor in humans.

    If you want to talk about the apparent reduction in general androgen effectiveness, there's definitely more to it than reduced androgen functionality. You need to address antecedant issues that affect androgen availability, such as metabolization by aromatase and 5-alpha-reductase, binding to SHBG, etc.
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    Quote Originally Posted by Royd The Noyd View Post
    In general what are you referring to here? Insulin sensitivity (I was thinking this was more diet related)?
    No, I was referring to homeostatic changes in androgen availability due to metbolization or binding. There's probably also posttranslational regulation.
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    Quote Originally Posted by rombusempire View Post
    So given that one needs increasing dosages of AAS to create the same effects as time passes, this must mean that the body is devloping tolerance to it.

    I do have a few questions regarding that

    1) how does this tolerance work? Is it the body's tolerance to the AAS itself, or simply because after a cycle, the body attins more muscle and hencem it is harder to gain more muscle WITH more mucle?

    2) if one stops AAS usage for an extended period of time (say a year), KEEPS the msucle, and then begins anotehr cycle, would teh second cycle be as good as teh first?

    3) if one stops AAS usage for an extended period of time (say a year), LOSES the msucle, and then begins anotehr cycle, would the second cycle be as good as the first?

    4) if one's body devlopes tolerance, then wouldnt people who are on long term TRT feel the effects of their TRT decline over time?
    My experience has been, long periods in between cycles (6-12 months), and I respond very well. However, I have only done 4 cycles in the past 5 year, so in this sense I am somewhat unexperienced.
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    Quote Originally Posted by Gixxer82 View Post
    test susp (base) should be shot ED...
    I agree, that is a strange protocol for HRT. It seems like you would have some major peaks and valleys with that dosing. Depending on your weight, you should be on something like 100mg of test cyp/week. I know some guys who stop their TRT during the cycle, and build up a small cache Test from the TRT that they should have been using during that time, and cruise at a higher dose for a while to preserve gains.
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    Quote Originally Posted by Conciliator View Post
    Sounds like you're conflating functional downregulation with receptor downregulation. Just because there's decreased functionality does not entail that the androgen receptor has not upregulated (i.e. increased in density). The research clearly shows in vitro and in vivo that androgens upregulate the androgen receptor in humans.

    If you want to talk about the apparent reduction in general androgen effectiveness, there's definitely more to it than reduced androgen functionality. You need to address antecedant issues that affect androgen availability, such as metabolization by aromatase and 5-alpha-reductase, binding to SHBG, etc.
    All of those things do play a role along with a few others. The literature is not quite as one sided as you make it seem. There is one paper in particular that I know you like to reference as support for upregulation (Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment). I have torn it apart in the past and in reality it supports exactly what I am saying, that androgen activation of pluripotent satellite cells results in terminal differentiation to a muscle cell and incorpation into existing myofibers. With this comes an increase in receptor number in this cell - their evidence for this is even somewhat spurious(in one measure, they are looking at the percentage of myonuclei that stain positive for AR -- of course you are going to get a greater number of nuclear androgen receptor with androgen therapy since nuclear enrichment is a direct result of androgen receptor acrtivation). In fact they show no significant increase in androgen receptor quantity in muscle fiber cytoplasm which is where you would expect to see enrichment of new androgen receptors since that is were they are expressed in their pre-bound state.

    In their cellular assays they are using GAPDH as a single housekeeping gene. It is well know that you must use more than one housekeeping gene (usually people use three), particularly with nuclear hormones because they can activate many of these so-called housekeeping genes and change their expression. Even using this flawed method in a culture of almost pure staellite cells, they only saw a smal lincrease in AR quantity that was only significant at the 0.05 level and only with DHT, not testosterone.

    The sad part is, a lot of papers say upregulation when they are really speaking about nuclear enrichment. The way that you state that upregulation is accepted fact smacks of bro-lore. There is some contention surrounding this topic among some of the best minds in nuclear hormone physiology (even though the experts that write textbooks agree with downreguation) but the bros on the boards have it all figured out. Just because you have a calculator does not make you a mathematician.
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    Oh. nono

    The test base is not part of the HRT, only the 200mg/wk of test E is.

    The test base is soemthing I added in personally as I figured the HRT dosage is not enough for a true cycle.

    As for peaks and valleys, it is actually ok so far because I shoot test E twice a week (once per week indeed does suck towards then end of the week)

    The test base I use as a 'booster' b4 work outs.

    So no one here thinks that that is a good idea?

    Quote Originally Posted by LilPsychotic View Post
    I agree, that is a strange protocol for HRT. It seems like you would have some major peaks and valleys with that dosing. Depending on your weight, you should be on something like 100mg of test cyp/week. I know some guys who stop their TRT during the cycle, and build up a small cache Test from the TRT that they should have been using during that time, and cruise at a higher dose for a while to preserve gains.
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    Quote Originally Posted by sethroberts View Post
    The literature is not quite as one sided as you make it seem.
    ...
    The sad part is, a lot of papers say upregulation when they are really speaking about nuclear enrichment. The way that you state that upregulation is accepted fact smacks of bro-lore.
    Ok, so you disagree with the methods from one of the studies and say upregulation as an "accepted fact" smacks of brolore. Do you have any evidence to the contrary? What studies do you have that show that androgen administration "downregulates" the androgen receptor?

    Here's a compilation of references that I put together. You've probably already seen it. I could be wrong, but with so many papers saying the same thing, it doesn't sound like bro-lore to me:

    This 1992 study (the full text is free), entitled "Androgen Receptor Phosphorylation, Turnover, Nuclear Transport, and Transcriptional Activation" concluded:
    Androgen increased the amount of AR [androgen receptor] phosphorylation simply by slowing the rate of degradation of the AR protein. AR stabilization by androgen was observed previously in binding studies on tissue cytosols (34). Moreover, in a ductus deferens smooth muscle tumor cell line, endogenous AR stabilization increased about 2-fold with androgen, from t1/2 3.1 h without androgen to t1/2 6.6 h with R1881 (55). The mechanism of receptor stabilization by androgen is not known but the striking specificity for androgen suggests it may be closely linked with receptor functional activity. Although other groups have reported on steroidinduced phosphorylation of AR (25) and the glucocorticoid and progesterone receptors (21-24), no androgen-dependent enhancement of recombinant AR phosphorylation was detected in the present study. While the AR is clearly a phosphoprotein, the specific role of phosphorylation in receptor function is unclear. AR sites of phosphorylation are currently being mapped, and it is conceivable that androgen binding may increase phosphorylation of a single site not detectable in our assay system.
    This 1996 study (the full text is free), entitled "Testosterone Up-Regulates Androgen Receptors... of Porcine Myogenic Satellite Cells in Vitro" concluded:
    In summary, we demonstrate that cultured satellite cells and myotubes possess AR [androgen receptors], which are up-regulated in response to testosterone.
    This 1999 paper, entitled "Effects of anabolic steroids on the muscle cells of strength-trained athletes" stated:
    Enhanced satellite cells stimulation would provide more nuclei to the muscle fibers. Because androgen receptors are located in the myonucleus (23,38,47), the increased nuclear number would also give rise to an elevation of the number of androgen binding sites, thus making the muscle more susceptible to the anabolic compounds.
    This 1999 study (free text), entitled "Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles" spoke to bodybuilders saying:
    DHT administration to the castrated group upregulated AR levels in the bulbocavernosus and levator ani muscles.
    ...
    It is intriguing to speculate that the upregulation of AR levels via the administration of pharmacological amounts of androgens might convert some muscles that normally have a minor or no response to muscles with enhanced androgen responsiveness.

    Because athletes may self administer synthetic androgens for many months or years at even higher doses than used in this study (17), it is possible that upregulation of AR levels might be an important part in the anabolic effects of androgen abuse.
    In this 2004 study (free full text), the title says it all: "Androgen Receptor in Human Skeletal Muscle and Cultured Muscle Satellite Cells: Up-Regulation by Androgen Treatment". They concluded:
    In summary, although multiple cell types within the human skeletal muscle express AR protein, satellite cells, and myonuclei are the predominant sites of AR expression. ARs aggregate within the nucleoli of satellite cells and myonuclei. Testosterone and DHT up-regulate AR expression in vivo and in vitro.
    And finally, this 2005 paper (free full text), entitled "Androgen regulation of satellite cell function" couldn't have made it any more explicit:
    Increase in AR levels: Up-regulation of AR levels is one of the documented responses to androgens in target tissues or organs. Up-regulation of AR levels by androgen treatment in skeletal muscle has been observed in rat and human (Antonio et al. 1999, Kadi et al. 2000, Lee et al. 2003). The auto-regulation of AR levels by androgens may occur through stabilizing existing receptors or by increasing de novo receptor synthesis (Kadi et al. 2000). Up-regulation of AR levels by androgens could be one mechanism by which androgens have effects on muscle.

    The increase in AR levels with androgen treatment has been demonstrated in satellite cells in pig (Doumit et al. 1996). This study clearly demonstrated the presence and auto-regulation of AR in satellite cells and also myotubes. Immunoblot analysis revealed that AR expression in satellite cells and myotubes was up-regulated in response to testosterone. Moreover, immunocytochemical staining for AR was more intense in the nuclei of satellite cells and myotubes from androgen-treated cells. Because the AR is
    located in the myonucleus, the increased nuclear number could potentially give rise to an elevation in the number of androgen binding sites (Kadi et al. 1999). Taken together, these data suggest that androgens may have effects on satellite cells through up-regulation of AR levels in satellite cells, which could enhance the sensitivity of satellite cells to androgens.
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    Quote Originally Posted by Conciliator View Post
    Ok, so you disagree with the methods from one of the studies and say upregulation as an "accepted fact" smacks of brolore. Do you have any evidence to the contrary? What studies do you have that show that androgen administration "downregulates" the androgen receptor?

    Here's a compilation of references that I put together. You've probably already seen it. I could be wrong, but with so many papers saying the same thing, it doesn't sound like bro-lore to me:

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

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

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

    This 1999 study (free text), entitled "Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles" spoke to bodybuilders saying:

    In this 2004 study (free full text), the title says it all: "Androgen Receptor in Human Skeletal Muscle and Cultured Muscle Satellite Cells: Up-Regulation by Androgen Treatment". They concluded:

    And finally, this 2005 paper (free full text), entitled "Androgen regulation of satellite cell function" couldn't have made it any more explicit:
    It is clear to you because you do not have training as a pharmacologist and you do not know how to interpret the results of the studies in question. I have aleady stated that upregulation occurs in satellite cells due to the fact that they are differentiating from a pluripotent mesenchymal cell with limited androgen receptor binding sites to differentitated myocytes which require larger number of androgen recpetors to maintain the intracellular machinary associated with this cell type (i.e. the protein apparatus that elicits muscular contraction) This takes care of papers 2,3,5 and 6. I have also stated that nuclear enrichment is not upregulation, it is a consequence of androgen receptor activation whereby androgen receptors move from the cytoplasm to the nucleus -- the movement results in an increase in nuclear fraction of androgen receptor by virtue of this translocation takes care of papers 3,5,6. Increased phosphorylation of the androgen receptor is also a consequence of activation as is the stabilization (the author says as much: "suggests it may be closely linked with receptor functional activity") You would need to know that recombinant AR is inherently unstable because it does not have the associated proteins that help to keep it stable in the dormant state (this is where experience actually working with this field helps -- a lay person would not necessarily know this) This takes care of the paper 1. it has been established that castration results in upregulation of the androgen receptor followed by eventual downregulation. As for paper 4 see below:

    As far as my evidence for downregulation:

    Goodman and Gilman's The Pharmacological Basis of Therapeutics 10th edition ("the bible" to pharmacologists) pg 36 states "Continued stimulation of cells with agonists generally results in a state of desensitization (also referred to as refractoriness or down-regulation), such that the effect that follows continued or subsequent exposure to the same concentration is diminished.

    Androgen deprivation causes up-regulation of androgen receptor transcript in the rat prostate.

    Kumar VL, Majumder PK, Kumar V.

    Mol Cell Biochem. 1997 Jun;171(1-2):133-8.

    In this paper adrogen deprivation is shown to cause up-regulation of the androgen receptor. Granted, this is in the prostate but it is in line with the standard theory put forth by Goodman and Gilman. Agonists down-regulate and therefore antagonsits up-regulate.

    further support along these lines:

    The rat androgen receptor: primary structure, autoregulation of its messenger ribonucleic acid, and immunocytochemical localization of the receptor protein.
    Tan JA, Joseph DR, Quarmby VE, Lubahn DB, Sar M, French FS, Wilson EM.
    Mol Endocrinol. 1988 Dec;2(12):1276-85.

    This paper shows the same result in 6 different tissues. Upregulation with androgen deprivation, downregulation with agonist.

    Autologous down-regulation of androgen receptor messenger ribonucleic acid.
    Quarmby VE, Yarbrough WG, Lubahn DB, French FS, Wilson EM.
    Mol Endocrinol. 1990 Jan;4(1):22-8.


    Another paper supporting this pattern:

    Regulation of androgen receptor protein and mRNA concentrations by androgens in rat ventral prostate and seminal vesicles and in human hepatoma cells.
    Shan LX, Rodriguez MC, Jšnne OA.
    Mol Endocrinol. 1990 Nov;4(11):1636-46.

    An abstract showing downregulation to be the standrad model:

    Mol Cell Endocrinol. 1995 Dec 29;115(2):177-86. Links
    Androgen and glucocorticoid regulation of androgen receptor cDNA expression.Burnstein KL, Maiorino CA, Dai JL, Cameron DJ.
    Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, FL 33101, USA.

    Androgen receptor (AR) levels are regulated by androgens, other steroids and non-steroidal hormones via complex, tissue-specific processes. Since alterations in receptor levels may influence cellular sensitivity to androgens, understanding AR regulation is of fundamental and potentially therapeutic significance. In most target tissues and AR-containing cell lines, AR mRNA is down-regulated in response to androgens. We have reconstituted this androgen-mediated down-regulation of AR mRNA in COS 1 cells transfected with a human AR cDNA under the control of the cytomegalovirus (CMV) promoter. The sequences mediating receptor mRNA down-regulation are represented within the AR cDNA and not within the CMV promoter. Androgenic down-regulation of AR cDNA expression was time- and dose-dependent, resembling native AR mRNA down-regulation. In addition, androgenic regulation of the receptor cDNA was not dependent on protein synthesis suggesting that AR and/or another pre-existing protein(s) is involved in this process. In COS 1 cells co-transfected with androgen and glucocorticoid receptor cDNAs, dexamethasone mimicked the action of androgen in down-regulating AR mRNA. This response depended on glucocorticoid receptors. Androgen had little effect on steady-state levels of AR protein consistent with reports that androgen down-regulates AR mRNA but increases AR protein half-life (Kemppainen et al. (1992) J. Biol. Chem. 267, 968-974; Zhou et al. (1995) Mol. Endocrinol. 9, 208-218). However, glucocorticoids decreased AR protein levels in cells that co-expressed androgen and glucocorticoid receptors. These results indicate that sequences represented in the AR cDNA mediate AR mRNA down-regulation by both androgens and glucocorticoids. Inhibition of AR mRNA and protein by glucocorticoids suggests that these steroids may modulate androgen action in tissues, such as mammary gland and prostate, which express both androgen and glucocorticoid receptors.

    PMID: 8824893 [PubMed - indexed for MEDLINE]

    This is a case of established science going up against established myth. Unfortunately, upregulation flys in the face of standard receptor theory and logic.
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    Along these lines, it has been well-established that the anabolic response in skeletal muscles is correlated with androgen receptor quantity. So, when you say that androgens up-regulate the androgen receptor then you are saying that the muscle actually becomes more responsive to androgens which is in direct opposition to what we know to be true, that is that the responsiveness to androgens decreases with androgenic stimulation.
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    Quote Originally Posted by sethroberts View Post
    I have aleady stated that upregulation occurs in satellite cells due to the fact that they are differentiating from a pluripotent mesenchymal cell with limited androgen receptor binding sites to differentitated myocytes which require larger number of androgen recpetors to maintain the intracellular machinary associated with this cell type (i.e. the protein apparatus that elicits muscular contraction) This takes care of papers 2,3,5 and 6.

    ...

    As far as my evidence for downregulation:
    I don't see how you think that satellite cell differentiation "takes care of papers 2,3,5 and 6". It doesn't "take care" of anything. All you did was explain the mechanism of action, but that does nothing to undermine the fact that the AR is being up-regulated.

    I hope you realize that your "evidence" of down-regulation is incredibly weak. You present an argument of inductive syllogism: since "Continued stimulation of cells with agonists generally results in a state of desensitization," therefore, it's likely that continued stimulation of the AR with androgens results in AR down-regulation. However, the syllogism is crushed when you consider other relevant information, namely, the fact that numerous studies in human cells, both in vitro and in vivo, show AR upregulation. Just because receptors "generally" down-regulate in response to continued agonism does not mean that there are not exceptions. Androgens, nicotine, and the interleukins have been shown to up-regulate their own receptor. To ignore that and to point to a generalization is to present a very week inductive syllogism.

    Do you realize that every paper you posted was rat research looking at AR mRNA levels? The fact that androgen deprivation has been shown to up-regulate androgen receptor mRNA in rats is of little consequence. First of all, how about a study in humans, in vivo? Here, just 5 days of anavar administration "significantly increased mRNA concentrations of skeletal muscle AR". Second, you're being short-sighted by looking at AR mRNA while ignoring actual AR density (which is what we're arguing about). There can be down-regulation of AR mRNA while there's up-regulation of the receptor itself. And that's exactly what a nice 2008 review on androgens in humans explained:

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

    Do you have even one reference in humans showing that androgens down-regulate the AR itself? In contrast to the several, recent papers with explicit statements of receptor protein up-regulation in humans, you provided only a generalization on receptor function and a bunch of rat research looking at mRNA levels. This is not a case of "established science going up against established myth." It's a case of established science going against a weak inductive syllogism and a myopic look at mRNA animal research.
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    Quote Originally Posted by sethroberts View Post
    So, when you say that androgens up-regulate the androgen receptor then you are saying that the muscle actually becomes more responsive to androgens which is in direct opposition to what we know to be true, that is that the responsiveness to androgens decreases with androgenic stimulation.
    No. When I say that androgens up-regulate the androgen receptor, it in does not entails that there must be a net up-regulation in functionality. All else being equal, up-regulation would increase responsiveness to androgens. But as you well know, there are several other conceivable regulatory processes, including altered androgen availability, AR interaction with co-activators and co-repressors, posttranslational regulation, etc. Despite receptor protein up-regulation, these could exert an even greater negative effect on androgen function, resulting in a net reduction in functionality. I think you know this and are feigning ignorance.
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    good thread
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    Quote Originally Posted by Conciliator View Post
    No. When I say that androgens up-regulate the androgen receptor, it in does not entails that there must be a net up-regulation in functionality. All else being equal, up-regulation would increase responsiveness to androgens. But as you well know, there are several other conceivable regulatory processes, including altered androgen availability, AR interaction with co-activators and co-repressors, posttranslational regulation, etc. Despite receptor protein up-regulation, these could exert an even greater negative effect on androgen function, resulting in a net reduction in functionality. I think you know this and are feigning ignorance.
    Actually I wasn't. However, you raise an interesting point, if androgen receptor is upregulated is it in response to androgen or in response to a decreased sensitivity to androgens through another mechanism.

    Unfortunately, evidence to the contrary is not going to sway you so if you want to believe in androgen receptor upregulation then by all means you are entitled to your opinion. Just know that it is at odds with what true experts believe. That doesn't mean you are wrong because there is no absolute truth in science (also experts are wrong on occasion). New evidence comes to light every day and theories evolve over time.
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    Quote Originally Posted by sethroberts View Post
    Actually I wasn't. However, you raise an interesting point, if androgen receptor is upregulated is it in response to androgen or in response to a decreased sensitivity to androgens through another mechanism.
    We know at least part of the up-regulation is due to direct androgen action.
    Quote Originally Posted by sethroberts View Post
    Unfortunately, evidence to the contrary is not going to sway you
    Unfortunately, it's you who's ignoring an entire body of direct, relevant, and recent evidence that demonstrates up-regulation.

    Please answer the question from my last post: Do you have even one reference in humans showing that androgens down-regulate the AR itself?
    Quote Originally Posted by sethroberts View Post
    so if you want to believe in androgen receptor upregulation then by all means you are entitled to your opinion. Just know that it is at odds with what true experts believe.
    This is a completely baseless claim. What "true experts"? You haven't given a single reference that androgen administration in humans down-regulates the AR itself. Not a quote, not a link, not an inkling of evidence. So I'll ask again, WHAT TRUE EXPERTS? All the people involved in research on this topic (people I would call experts) repeatedly and uniformly say that the human AR up-regulates in response to androgen administration. I think someone is in denial.
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    You are ignoring that fact that animal evidence is used every day by the pharmaceutical industry to inestigate the actions of drugs. Lest you forget that almost all of the anabolic/androgenic ratios are determined using rats (the remainder in mice, dogs, and roosters). I presented evidence in several mammalian species and there is no evidence that androgen receptors behave any differently in humans. When I say you are at odds with the experts, I mean that ot is standard pharmacaological theory that receptors downregulate - crackpot theories are not often included in textbooks.

    I have exlained to you the problem with the papers that you have put forth. The problem is that you do not have the background in this type of work to comprehend what I am saying. Have you ever grown cell culture and tested compounds? Have you ever used immunogold staining? Have you had contact with experts in the field? Do you understand the difference between using recombinant androgen receptors, satellite cell culture, and non satellite cell culture (see the abstract I repasted below)? I would love to hear you explain the difference between these three.

    You do not understand that sometimes when authors say upregulation, they mean enrichment and nuclear enrichment is NOT upregulation, it is a natural consequence of nuclear hormone receptor activation. When lay people, such as yourself, read scientific literature without the proper background o interpret it, often a misinterpretation occurs. The sad fact is that in doing so, you perpetuate the bro-lore that permeates these boards.

    Mol Cell Endocrinol. 1995 Dec 29;115(2):177-86. Links
    Androgen and glucocorticoid regulation of androgen receptor cDNA expression.Burnstein KL, Maiorino CA, Dai JL, Cameron DJ.
    Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, FL 33101, USA.

    Androgen receptor (AR) levels are regulated by androgens, other steroids and non-steroidal hormones via complex, tissue-specific processes. Since alterations in receptor levels may influence cellular sensitivity to androgens, understanding AR regulation is of fundamental and potentially therapeutic significance. In most target tissues and AR-containing cell lines, AR mRNA is down-regulated in response to androgens. We have reconstituted this androgen-mediated down-regulation of AR mRNA in COS 1 cells transfected with a human AR cDNA under the control of the cytomegalovirus (CMV) promoter. The sequences mediating receptor mRNA down-regulation are represented within the AR cDNA and not within the CMV promoter. Androgenic down-regulation of AR cDNA expression was time- and dose-dependent, resembling native AR mRNA down-regulation. In addition, androgenic regulation of the receptor cDNA was not dependent on protein synthesis suggesting that AR and/or another pre-existing protein(s) is involved in this process. In COS 1 cells co-transfected with androgen and glucocorticoid receptor cDNAs, dexamethasone mimicked the action of androgen in down-regulating AR mRNA. This response depended on glucocorticoid receptors. Androgen had little effect on steady-state levels of AR protein consistent with reports that androgen down-regulates AR mRNA but increases AR protein half-life (Kemppainen et al. (1992) J. Biol. Chem. 267, 968-974; Zhou et al. (1995) Mol. Endocrinol. 9, 208-218). However, glucocorticoids decreased AR protein levels in cells that co-expressed androgen and glucocorticoid receptors. These results indicate that sequences represented in the AR cDNA mediate AR mRNA down-regulation by both androgens and glucocorticoids. Inhibition of AR mRNA and protein by glucocorticoids suggests that these steroids may modulate androgen action in tissues, such as mammary gland and prostate, which express both androgen and glucocorticoid receptors.

    PMID: 8824893 [PubMed - indexed for MEDLINE]
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    Quote Originally Posted by sethroberts View Post
    All of those things do play a role along with a few others. The literature is not quite as one sided as you make it seem. There is one paper in particular that I know you like to reference as support for upregulation (Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment). I have torn it apart in the past and in reality it supports exactly what I am saying, that androgen activation of pluripotent satellite cells results in terminal differentiation to a muscle cell and incorpation into existing myofibers. With this comes an increase in receptor number in this cell - their evidence for this is even somewhat spurious(in one measure, they are looking at the percentage of myonuclei that stain positive for AR -- of course you are going to get a greater number of nuclear androgen receptor with androgen therapy since nuclear enrichment is a direct result of androgen receptor acrtivation). In fact they show no significant increase in androgen receptor quantity in muscle fiber cytoplasm which is where you would expect to see enrichment of new androgen receptors since that is were they are expressed in their pre-bound state.

    In their cellular assays they are using GAPDH as a single housekeeping gene. It is well know that you must use more than one housekeeping gene (usually people use three), particularly with nuclear hormones because they can activate many of these so-called housekeeping genes and change their expression. Even using this flawed method in a culture of almost pure staellite cells, they only saw a smal lincrease in AR quantity that was only significant at the 0.05 level and only with DHT, not testosterone.

    The sad part is, a lot of papers say upregulation when they are really speaking about nuclear enrichment. The way that you state that upregulation is accepted fact smacks of bro-lore. There is some contention surrounding this topic among some of the best minds in nuclear hormone physiology (even though the experts that write textbooks agree with downreguation) but the bros on the boards have it all figured out. Just because you have a calculator does not make you a mathematician.
    I recognize (and stated as such) that there is competing evidence in the literature. I have reviewed that evidence and rejected it as insufficient to render null the standard hypothesis of desensitization through downregulation (for reasons that I have outlined for you in this thread). Did you address any of the evidence I put forth showing that the paper on which you rely most heavily has several major issues and in reality is not showing upregulation at all (I quoted above for you)? Maybe it's because you don't understand a single word I said. You can't just read titles of papers and make conclusions = it takes a little more than that.
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    Quote Originally Posted by sethroberts View Post
    You are ignoring that fact that animal evidence is used every day by the pharmaceutical industry to inestigate the actions of drugs. Lest you forget that almost all of the anabolic/androgenic ratios are determined using rats (the remainder in mice, dogs, and roosters). I presented evidence in several mammalian species and there is no evidence that androgen receptors behave any differently in humans.
    If animal research is so compelling maybe you should look at some done since the nineties instead of posting irrelevant in vitro/prostate/seminal vesicles crap.

    Quote Originally Posted by sethroberts View Post
    When I say you are at odds with the experts, I mean that ot is standard pharmacaological theory that receptors downregulate - crackpot theories are not often included in textbooks.
    Yes, if you are sufficiently ignorant of the human maturation process to not conceive of the obvious benefit of androgen receptors behaving in this way and you are unwilling to look at current data I suppose refering to 'standard pharmacological theory' would be your only real recourse. Biology is not always intuitive, sorry.

    Note that the studies below all deal with skeletal muscle; its not a coincidence.

    J Steroid Biochem Mol Biol. 2001 Nov;78(5):481-92.

    Properties of free and occupied androgen receptor in rat skeletal muscle cytosol: effect of testosterone.

    Osipova-Goldberg HI, Rogozkin VA, Feldkoren BI.
    St.-Petersburg Institute of Physical Culture, Dynamo Avenue 2, 197110, St.-Petersburg, Russia.

    Our aim was to investigate the effect of a single testosterone (T) injection on the androgen receptor (AR) in rat skeletal muscle (SM) cytosol. The properties of AR were studied in order to establish the protocol for differential determination of free and hormone-occupied AR in SM cytosols from non-hormone-deficient animals. Using the developed ligand-exchange protocol, we demonstrated that injection of T (1 mg/kg) caused alternating changes of the total AR binding. The binding minimum (23% of the control) was measured 1 h after the injection. It was followed by pronounced and lasting elevation of the AR binding. In the control cytosols, AR complexes constituted approximately 25% of the total receptor content. Changes of their relative content immediately after T administration were consistent with rapid nuclear translocation of the AR. Inhibition of protein synthesis by cycloheximide (CHI) injection demonstrated that delayed and lasting increase of the AR binding after T injection partially depended on the stimulated protein synthesis. Altogether, the obtained evidence supports the assumption that the AR mediates elevation of its own gene expression in SM upon administration of T.

    J Appl Physiol. 2002 Jul;93(1):242-50.

    Steroid receptor concentration in aged rat hindlimb muscle: effect of anabolic steroid administration.Carson JA, Lee WJ, McClung J, Hand GA.
    Integrative Muscle Biology Laboratory, Exercise Science Department, University of South Carolina, Columbia 29208, USA.

    Skeletal muscle is a target of anabolic steroid action; however, anabolic steroid's affect on aged skeletal muscle is not well understood. The effect of 4 wk of nandrolone decanoate (ND) administration on hindlimb muscles of 5- and 25-mo-old Fischer 344/Brown Norway rats was examined. ND (6 mg/kg body wt) was injected every 7th day for 4 wk. Controls received an oil injection. ND significantly reduced 25-mo-old rat perirenal fat pad mass by 30%. Soleus (Sol) and plantaris (Plan) muscle-to-body weight ratios were reduced in 25-mo-old rats. ND did not affect Sol or Plan muscle-to-body weight ratios at either age. Sol DNA concentration was reduced by 25% in 25-mo-old rats, and ND increased it to 12% greater than 5-mo-old rats. ND did not affect Plan DNA content. Sol androgen receptor (AR) protein in 25-mo-old rats was reduced to 35% of 5-mo-old values. ND increased AR protein by 900% in 25-mo-old rat Sol. Plan AR concentration was not affected by aging but was induced by ND in both age groups. Aging or ND treatment did not affect glucocorticoid receptor levels in either muscle. These data demonstrate that fast- and slow-twitch rat hindlimb muscles differ in their response to aging and ND therapy.

    J Appl Physiol. 2003 Mar;94(3):1153-61.

    Overload-induced androgen receptor expression in the aged rat hindlimb receiving nandrolone decanoate.Lee WJ, McClung J, Hand GA, Carson JA.
    Integrative Muscle Biology Laboratory, Exercise Science Department, University of South Carolina, Columbia, South Carolina 29208, USA.

    This study's purpose was to examine whether functional overload with nandrolone decanoate (ND) administration increased muscle mass and steroid receptor concentration in aged rat soleus (Sol) and plantaris (Plan) muscle. ND (6 mg/kg body wt) was administered once a week for 4 wk, whereas control rats received sesame seed oil injections. Functional overload of the hindlimb Sol and Plan was induced by synergistic gastrocnemius muscle ablation at the beginning of the fourth week. Adult (5 mo of age) and aged rats (25 mo of age) were randomly assigned to four groups: control, overload, control-ND, and overload-ND. Seven days of functional overload increased adult Sol muscle mass 27%, whereas the aged Sol muscle mass did not change. The aged overloaded Sol muscle receiving ND significantly increased muscle weight by 35% and total muscle protein by 24%. Aged Plan muscle did not increase muscle weight with overload or ND treatment. Androgen receptor protein was induced by ND treatment and functional Ov, and combining the two treatments induced Sol androgen receptor protein concentration above either alone. Sol glucocorticoid receptor protein concentration increased in overload groups of both ages. ND administration can increase aged Sol muscle mass and protein content after 7 days of functional overload, and the cooperative induction of androgen receptor may be important for this response.
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    Quote Originally Posted by zaosha View Post
    If animal research is so compelling maybe you should look at some done since the nineties instead of posting irrelevant in vitro/prostate/seminal vesicles crap.



    Yes, if you are sufficiently ignorant of the human maturation process to not conceive of the obvious benefit of androgen receptors behaving in this way and you are unwilling to look at current data I suppose refering to 'standard pharmacological theory' would be your only real recourse. Biology is not always intuitive, sorry.

    Note that the studies below all deal with skeletal muscle; its not a coincidence.

    J Steroid Biochem Mol Biol. 2001 Nov;78(5):481-92.

    Properties of free and occupied androgen receptor in rat skeletal muscle cytosol: effect of testosterone.

    Osipova-Goldberg HI, Rogozkin VA, Feldkoren BI.
    St.-Petersburg Institute of Physical Culture, Dynamo Avenue 2, 197110, St.-Petersburg, Russia.

    Our aim was to investigate the effect of a single testosterone (T) injection on the androgen receptor (AR) in rat skeletal muscle (SM) cytosol. The properties of AR were studied in order to establish the protocol for differential determination of free and hormone-occupied AR in SM cytosols from non-hormone-deficient animals. Using the developed ligand-exchange protocol, we demonstrated that injection of T (1 mg/kg) caused alternating changes of the total AR binding. The binding minimum (23% of the control) was measured 1 h after the injection. It was followed by pronounced and lasting elevation of the AR binding. In the control cytosols, AR complexes constituted approximately 25% of the total receptor content. Changes of their relative content immediately after T administration were consistent with rapid nuclear translocation of the AR. Inhibition of protein synthesis by cycloheximide (CHI) injection demonstrated that delayed and lasting increase of the AR binding after T injection partially depended on the stimulated protein synthesis. Altogether, the obtained evidence supports the assumption that the AR mediates elevation of its own gene expression in SM upon administration of T.

    J Appl Physiol. 2002 Jul;93(1):242-50.

    Steroid receptor concentration in aged rat hindlimb muscle: effect of anabolic steroid administration.Carson JA, Lee WJ, McClung J, Hand GA.
    Integrative Muscle Biology Laboratory, Exercise Science Department, University of South Carolina, Columbia 29208, USA.

    Skeletal muscle is a target of anabolic steroid action; however, anabolic steroid's affect on aged skeletal muscle is not well understood. The effect of 4 wk of nandrolone decanoate (ND) administration on hindlimb muscles of 5- and 25-mo-old Fischer 344/Brown Norway rats was examined. ND (6 mg/kg body wt) was injected every 7th day for 4 wk. Controls received an oil injection. ND significantly reduced 25-mo-old rat perirenal fat pad mass by 30%. Soleus (Sol) and plantaris (Plan) muscle-to-body weight ratios were reduced in 25-mo-old rats. ND did not affect Sol or Plan muscle-to-body weight ratios at either age. Sol DNA concentration was reduced by 25% in 25-mo-old rats, and ND increased it to 12% greater than 5-mo-old rats. ND did not affect Plan DNA content. Sol androgen receptor (AR) protein in 25-mo-old rats was reduced to 35% of 5-mo-old values. ND increased AR protein by 900% in 25-mo-old rat Sol. Plan AR concentration was not affected by aging but was induced by ND in both age groups. Aging or ND treatment did not affect glucocorticoid receptor levels in either muscle. These data demonstrate that fast- and slow-twitch rat hindlimb muscles differ in their response to aging and ND therapy.

    J Appl Physiol. 2003 Mar;94(3):1153-61.

    Overload-induced androgen receptor expression in the aged rat hindlimb receiving nandrolone decanoate.Lee WJ, McClung J, Hand GA, Carson JA.
    Integrative Muscle Biology Laboratory, Exercise Science Department, University of South Carolina, Columbia, South Carolina 29208, USA.

    This study's purpose was to examine whether functional overload with nandrolone decanoate (ND) administration increased muscle mass and steroid receptor concentration in aged rat soleus (Sol) and plantaris (Plan) muscle. ND (6 mg/kg body wt) was administered once a week for 4 wk, whereas control rats received sesame seed oil injections. Functional overload of the hindlimb Sol and Plan was induced by synergistic gastrocnemius muscle ablation at the beginning of the fourth week. Adult (5 mo of age) and aged rats (25 mo of age) were randomly assigned to four groups: control, overload, control-ND, and overload-ND. Seven days of functional overload increased adult Sol muscle mass 27%, whereas the aged Sol muscle mass did not change. The aged overloaded Sol muscle receiving ND significantly increased muscle weight by 35% and total muscle protein by 24%. Aged Plan muscle did not increase muscle weight with overload or ND treatment. Androgen receptor protein was induced by ND treatment and functional Ov, and combining the two treatments induced Sol androgen receptor protein concentration above either alone. Sol glucocorticoid receptor protein concentration increased in overload groups of both ages. ND administration can increase aged Sol muscle mass and protein content after 7 days of functional overload, and the cooperative induction of androgen receptor may be important for this response.
    Did you bother to read the full-text of the articles that you pasted or just the abstracts. Let me give you a few quotes from the full text of the first article you sited (Osipova-Goldberg et al.):

    "T injection, in a dose of 1 mg/kg, caused alternating
    changes of the total AR content beginning with its
    rapid and pronounced decrease."

    "We concluded that disappearance of the occupied receptor from cytosol, 1 h after the injection, most probably, was a manifestation of the receptor nuclear translocation."

    Should I conclude from these statements that the receptor is downregulating? They are from your paper after all. In reality what they are trying to demonstrate in this paper is the activation and translocation of the receptor from the cytoplasm to the nucleus -- all very short term stuff after a single dose -- in fact they show a very short term increase in receptor quantity in the hours after receptor depletion. Does this mean that prolonged administration of an androgen results in upregulation - no. Of course you show your ignorance in presenting this paper as some kind of support for your position - -either you didn;t read it or didn;t understand it.

    Your second paper is a joke-- they are measuring AR protein content through western blotting (without determining the functionality of that protein) not to mention that nandrolone did not have a positive effect on body weight - in fact they saw a significant weight loss in aged rats when you woud expect to see a gain. Not to mention that nandrolone is not really an acceptable standard for the action of androgens since it has significant off-target effects that differ from natural androgens. So you accept this as proof of upregulation -- is it also proof that nandrolone doesn't have an anabolic effect? Or is it just a lousy paper?

    Your final paper is again in aged animals and again uses nandrolone decanoate but at least they show a significant anabolic effect. Again they utilize western blotting as a quantitative technique but they do not show a significant incease in AR protein content with steroid treatment alone compared to control. They only show a significant difference in overload plus nandrolone treated but it is well known that overload ITSELF increases androgen receptor content. Also, they do not provide any evidence of functionality of any increased protein nor was there any standardization of receptor quantity to unit DNA.

    You can cherry pick the literature and misinterpret papers all you want. The fact is, desensitization through downregulation is the accepted model and it would take some serious data to unseat it as the standard.
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    What happened, you couldn't answer my critique of thatpaper so you changed your ID? You can keep on trying but I've done these types of studies, I know the pitfalls and I know the body of literature on the subject -- I doubt you have any one of these three.
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    Quote Originally Posted by sethroberts View Post
    You are ignoring that fact that animal evidence is used every day by the pharmaceutical industry to inestigate the actions of drugs. Lest you forget that almost all of the anabolic/androgenic ratios are determined using rats (the remainder in mice, dogs, and roosters). I presented evidence in several mammalian species and there is no evidence that androgen receptors behave any differently in humans. When I say you are at odds with the experts, I mean that ot is standard pharmacaological theory that receptors downregulate - crackpot theories are not often included in textbooks.

    I have exlained to you the problem with the papers that you have put forth. The problem is that you do not have the background in this type of work to comprehend what I am saying. Have you ever grown cell culture and tested compounds? Have you ever used immunogold staining? Have you had contact with experts in the field? Do you understand the difference between using recombinant androgen receptors, satellite cell culture, and non satellite cell culture (see the abstract I repasted below)? I would love to hear you explain the difference between these three.

    You do not understand that sometimes when authors say upregulation, they mean enrichment and nuclear enrichment is NOT upregulation, it is a natural consequence of nuclear hormone receptor activation. When lay people, such as yourself, read scientific literature without the proper background o interpret it, often a misinterpretation occurs. The sad fact is that in doing so, you perpetuate the bro-lore that permeates these boards.
    There you go, try to talk up the animal data, lol. And keep ignoring that 1) there is much better, recent, direct human data, 2) the animal data you posted is indirect, not on the AR itself, but AR mRNA, and 3) more relevant animal data in skeletal muscle contradicts you. I'm sure pharmaceutical companies would take animal mRNA data in the prostate/seminal vesicle over human, skeletal muscle, AR data when what they want to know about is the latter. Contrary to what you said, there is evidence that androgen receptors behave differently in humans. I just recently posted a study showing an increase in AR mRNA after a few days in response to anavar. Then there are the numerous studies showing an increase in the AR itself. You presented NO EVIDENCE about the AR itself, not "in several mammalian species", not in any species.

    It blows me away that you completely ignore all of the human data and the explanation for how a reduction in AR mRNA is still completely consistent with AR up-regulation (the indented quote in this post). It also blows me away that you claim that AR up-regulation is "at odds with what true experts believe" when you are referring to people who are not specifically experts on the androgen receptor at all. In fact, the quote from Goodman and Gilman says nothing about receptors, but appears to be talking about functional down-regulation ("a state of desensitization"). And even if they were talking about receptors, do you know what the word "generally" means? They say that "Continued stimulation of cells with agonists generally results in a state of desensitization"... not always, generally. That means there are exceptions. Your reasoning is abysmal here. You're the one ignoring study after study after study showing AR up-regulation in humans. The ad hominem is completely unwarranted, as is your self-promotion. To top things off, you end your post by quoting a study on AR mRNA again, completely ignoring the AR itself, and the human data. Unbelievable.

    So to be clear, Seth does not have a shred of evidence that androgens down-regulate the AR in humans. Nor does he have any counter evidence against the claim the androgens up-regulate the AR itself. Very lame.
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    Quote Originally Posted by sethroberts View Post
    The fact is, desensitization through downregulation is the accepted model and it would take some serious data to unseat it as the standard.
    Identifying something as an exception to the rule does not unseat it as a standard. It is not a hard and fast rule. There are things that are known to up-regulate their own receptor, including androgens, nicotine, and the interleukins. That doesn't mean that there can't still be a net reduction in functionality through other mechanisms. It's just ridiculous to try to rebut an entire body of evidence with merely a rule about what's generally the case.
  

  
 

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