Posted by E.A on December 29, 1996 at 14:48:03:
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
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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.
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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.
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> 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.
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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