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


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Posted by Matty on December 29, 1996 at 22:51:21:

In Reply to: Re: Receptors actually UPREGULATE with the use of heavy androgens. READ!! posted by D on December 29, 1996 at 21:42:25:

: 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

I must agree!... I really appreciate the info... I've been meaning to say that for a while...

Matty



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