Re: Receptors actually UPREGULATE with the use of heavy androgens. READ!!

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: Wow, this information is incredible. I can see that EA is going to be a valuable asset to this board. I, for one, appreciate the info. Keep it coming !!!!!!!!!! D : : : The following is a thread between two people on the M.F.W newsgroup. It is in regard to the nature of A.S receptors. It gets a bit technical at times, and if you don't follow some of the "chem talk" at times, I apologize. But DO read it all as it will open a new way of thinking about this subject. : : -E.A : : ---------------------------------------------------------------------------- : : Simply because the matter is not well understood by you, perhaps, does not : : mean it is not well understood, as a result of experiments, by others. : : The journals are absolutely flooded with this new information, as a result : : of experiments done by researchers including those at the University of : : Florida. It's even being taught in the classroom in graduate research : : courses. (However, nothing much has made it to textbooks yet, which may : : be why you imagine that the subject is little-understood.) We know exactly : : which proteins and which genes are involved and how they are regulated in : : many cases. But this has nothing to do with androgen receptor responses : : whatsover. My point was that it was wrong to apply knowledge about G : : protein associated receptors to the androgen receptor -- it works in an an : : entirely different manner. Just because beta-adrenergic receptors, for : : example, downregulate in response to ligand does not show that the AR : : behaves in the same way -- it doesn't! : : : : The point of this thread is rapidly being lost. It was that upregulation : : of androgen receptor transcription occurs at dosages of steroid well : : beyond that required for 100% saturation of the receptors, and the concept : : of receptor downregulation, misreferred to as "degradation" by BP and : : others, is wrong, and therefore pyramiding up is not sensible. (It also : : wouldn't be sensible if receptor number was downregulated as a result of : : greater receptor occupation -- if you had fewer receptors present later in : : the cycle, then extra drug wouldn't do any good at all -- you'd already : : have an excess. But that isn't the case anyway -- I just mention it to : : demonstrate that the pyramid-up advocates are not thinking.That would be : : OK perhaps if real-world results demonstrated that pyramiding-up works : : better than not -- but this isn't so. The greatest gains are seen from : : from staying on the drug all the time, which refutes their argument, but : : agrees withthe observation that AR's in muscle tissue upregulate in : : response to androgen, rather than "downgrade." So pyramiding-up is : : illogical. Good pharmacology research has been done re the androgen : : receptor, but no scientific research directly answers the pyramid vs. : : taper. vs. constant-does argument, which is why I don't cite such : : experiments to directly prove that pyramiding-up is inefficient.) : : If you care about overall health and therefore wish to cycle rather than : : use drug continuously, get the AR's upregulated as soon, fast, and hard as : : possible. Then when you have them, they can do their work on less drug, or : : the same amount. (I am of course suggesting how to obtain maximum musclur : : hypertrophy and satellite cell differentiation *in laboratory rats*, not : : in readers of this posting. I would never suggest use of drugs not : : prescribed in a legal manner by an MD or by a retarded goat, whichever : : knows more about this subject.) : : Also one should note that all commercially-available anabolic-androgenic : : steroids have such high affinity for the AR that differences in potency : : cannot be explained on that account. Yes, some difference is due to : : metabolism (conversion to reduced and/or aromatized versions of the drug.) : : But I suggest that the drugs were never assayed for potency in : : upregulating AR transcription, and since this occurs by a mechanism : : independent of the AR itself, there is no reason to think that the drugs : : should be equal in this regard. Very possibly the drugs which have been : : found to be much more effective are those which cause a greater increase : : in number of androgen receptors. Unproven, but a plausible hypothesis. : : (Sherlock Holmes would say that since all else has been eliminated as : : impossible, this must be the truth, but I wouldn't go quite so far.) : : This would suggest that, if one is combining drugs, it would make more : : sense to use the anecdotally-more-potent drugs early in the cycle, until : : toxicity would become a problem, and then use high doses of low-toxicity : : (but less AR upregulating) drugs later in the cycle, once plenty of new : : AR's have been produced. And there is plenty of anecdotal evidence to show : : that this plan does work very well indeed. : : : : ------------------------------------------------------------------------------- : : There is *no evidence whatsoever* that androgen receptors "downgrade" : : after 2-4 weeks. Sure, B.P. says so, but he's wrong. : : This was *assumed* because many other types of receptors demonstrate this : : response. However, androgen receptors in muscle tissue in fact up-regulate : : in response to increased androgen! : : This may be why gains usually aren't seen in the first couple of weeks. : : Initially, the relatively small number of AR's is completely saturated by : : endogenous hormone anyway. So additional androgen doesn't increase : : transcription. However, (in an unknown mechanism not mediated by the AR) : : additional androgen upregulates transcription of new AR's. As a result, : : later you have more AR's and therefore see more transcription of gene : : products promoted by the AR. This will probably also be seen with moderate : : doses of androgen, since the number of androgen receptors is far smaller : : than the number of molecules of hormone, and the binding constant is very : : high. (Yeah, B.P. thinks you have more receptors than hormone, etc., but : : again, that is nonsense. No, I'm not a B.P. basher -- I like him.) : : Conclusion: pyramiding up is silly. Tapering down makes sense, but : : maintaining the same dose will certainly give at least equal results, : : though requiring more drug. : : If you've got to maximize the gains from a certain amount of : : anabolic/androgenic steroid, it would seem to make more sense to take : : more initially (first 2-4 weeks) and then take somewhat less thereafter. : : But I know of no empirical evidence that results are better from doing : : that than they would be from taking the same dose every week. : : --------------------------------------------------------------------------- : : > ENDOCRINOLOGY (1981) vol. 108, no. 4, p.1431 : : > : : > In adult intact rats the concentration of androgen receptors in muscle cytosol : : > from females was about 100 fmol/g tissue, the corresponding value for males : : > was 50 fmol/g. : : > : : > Short term castration increased the concentration of and ligand affinity for : : > the androgen receptor in male rats : : > : : > : : > conclusion: androgen receptor density and perhaps affinity is inversely : : > related to the level of circulating androgen in the skeletal muscle of rats. : : > This is in direct contradiction of your claim. : : > : : > : : > PA : : : : Patrick, your conclusion certainly follows from the research you cite. I : : certainly prefer this posting to the one in which you declared what I had : : to say to be horseshit. :) : : The main problem with this study is that castration of rats is notorious : : for producing false conclusions. A possible reason for this is that the : : cells (and indeed the entire system of the animal) undergo qualitative : : change (e.g., cessation of growth) from the sham-operated animals. (I : : didn't read the study you cite -- were there even sham-operated controls? : : If not, increased cortisol from the stress of the orchidectomy would : : confuse the results.) In other words, you simply do not see the true : : effects of reduction of testosterone in this type of study. Reducing : : testosterone by reducing LH/FSH would have been a far better approach. : : Another reason why this study could be wrong is that even today : : concentrations such as 50-100 femtomoles (millionths of micromoles!) per : : gram is very hard to measure, and in 1981 in my opinion they were throwing : : darts to get at their numbers. : : In any case, there haven't been any more recent studies (last 10 years) : : that I know of that support this study! : : Some studies that at first glance might seem to support it neglect the : : fact that testosterone can be and is converted to estradiol, and estradiol : : does down-regulate transcription of the AR. : : OK, what studies support what I say? : : The most recent one that I know of is, "Testosterone up-regulates androgen : : receptors and decreases differentiation of porcine myogenic satellite : : cells in vitro," Endocrinology (1996 April) p1385-94 : : The classic study in which this was first proven was done by Syms et. al. : : By using isotopic-labeled amino acids, they demonstrated that de novo : : AR-synthesis increased in response to supplied androgen. See "Mechanism of : : Androgen Receptor Augmentation," J. Biol Chem (1985) v260 p455-61 : : Also see J. Steroid Biochem Mol Bio (1993) v45 p333-43, and v37 p553-558 : : (1990). : : I also read and enjoyed your other response. I did not know that you are a : : chemist. I myself am working on my PhD in Medicinal Chemistry (With this : : semester, I will have completed all my coursework but one course on : : metabolism, but still have to research and write the thesis to get the : : degree.) You are quite right that chemistry concepts certainly apply. : : You asked me to explain some of the concepts I mentioned, and I am glad to : : do so. : : Binding constant, or as it's called Kassociation, is the same as Keq. : : Thus, : : [bound ligand-receptor] : : Ka = ---------------------------- : : [free ligand] [free receptor] : : We treat receptor binding equivalently to Michaelis-Menten kinetic We : : assume binding to be reversible and specific, with only one ligand binding : : to receptor (no cooperativity -- this is valid for AR.) Only equilibrium : : conditions are dealt with. : : In saturation analysis, the number of receptors is held constant (eg, same : : tissue homogenate) and concentration of ligand-receptor is determined as a : : function of increasing radioligand concentration. From this you can : : derive the number of receptors and the association constant (actually you : : do the dissociation constant, because at Kd 50% of available receptors are : : occupied: a point which can be measured fairly precisely.) This is done by : : plotting bound/free as a function of bound ligand in the Scatchard : : plot. : : You have to correct for non-specific binding to other proteins, but this : : is easily done. : : So this is the basic starting point on where experimental results come : : from in this field. : : As you mentioned in the research you cited, the concentration of the AR is : : in the femtomolar range. Yet Ka is very high, response follows occupancy : : theory not rate theory, and biological response over time does not : : increase according to a rectangular hyperbolic curve at drug doses in : : excess of Kd, but approximately a linear response. : : Why does all this fit everything I said before and refute the receptor : : "downgrade" theory, and show that pyramiding is illogical? Patrick, you : : yourself may see it just from this data, put together with other things : : you already know. For others, I hope to write the information in an : : article for Dan's newsletter. Typing stuff in off the top of my head : : results in poor organization and inclusion of unnecessary detail. I think : : this information is too complex for off-hand posts such as this, and a : : carefully-written article would make this information much more : : understandable to the average person. It really isn't hard to see why all : : this must be so. And it has the great virtue of making sense and agreeing : : with real-world observations, which the opposing theory does not. : : -------------------------------------------------------------------------- : : Old concept: there are 2 main anabolic/androgenic hormones in the body : : (testosterone and DHT), so there ought to be 2 kinds of receptors. : : Obviously (using the word sarcastically) one receptor will give us all the : : activities we desire, and the other one is responsible for all bad side : : effects. : : This theory was the operative principle during the entire period during : : which testosterone analogs were developed as as anabolic drugs, that is, : : the 1930s to the 1960s.=20 : : Of course, the theory is wrong. : : Molecular biology proved that there is only one gene for the androgen : : receptor. : : So, obviously (again, read that sarcastically) there is only one type of : : androgen receptor. : : This theory utterly dominated all thinking in the field from the 1970s : : until the early 90s. : : Of course, it, also, is wrong. : : Actually, post-transcriptional modification of the gene product results in : : different populations of androgen receptors, with some degree of : : differential selectivity. I.e., some actually do bind DHT more so than : : others do. : : It seems to me that the effect is rather subtle, and this data should not : : be misinterpreted to mean that you should stack 6 different steroids. : : BP's concept that different testosterone esters will activate different : : receptors is utterly stupid and demonstrates that he has never taken : : Organic Chemistry 1: these esters all become testosterone itself; they all : : become the same molecule. Furthermore, there is research showing that the : : drugs don't bind as esters -- the ester comes off first, and they bind the : : 17-beta-hydroxyl steroid. So, BP is wrong. How could that happen... it : : threatens to shatters entire belief systems of the MM2k faithful! What : : next? Will the Pope blunder? (no offense intended to Catholics.)=20 : : The Plug also likes to talk about drugs "converting into DHT." In the vast : : majority of cases, this is utterly impossible. : : What can happen is that they can be reduced (a double bond converted to a : : single bond) and this will generally change the activity. E.g., nandrolone : : (Deca) will become less potent; therefore it is not likely to cause acne : : or prostate enlargement. : : BP is also in error (no, not again!) in ascribing evil to DHT itself. He : : thinks DHT is the source of all evil (hey, he's advanced all the way to : : 1930s thinking... give the man credit.) The last issue of MM2k (yes, I'm : : ashamed, I did give Phillips some money: I like to read his rag) had a : : statement that you wouldn't want to take DHT as an anabolic unless you : : wanted a prostate the size of a grapefruit, or something. : : If Phillips knew anything, he would know that DHT, supplied as a drug, has : : in fact been demonstrated to REDUCE the size of the prostates of elderly : : men with BHP, as well as to improve blood lipid profiles and improve : : cardfiovascular parameters in elderly men. It ain't the evil substance he : : thinks. And a little thought will make it clear why this is so. : : ---the above was stolen from Bill Roberts and was originally posted to the Misc.Fitness.weights newsgroup-- : : : : -E.A

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