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Steroids working through different mechanisms
All right bro's, I thought I'd share one of my all time favorite reads which
explains some of the scientific reasoning behind combining different classes of
steroids,and mechanisms outside of the androgen receptor which certain steroids
activate...The following is from legendary guru,Bill Roberts-Enjoy!
Scientific Evidence for Multiple Modes of Action
The first thing to consider is whether or not a single mode of action is
sufficient to explain all results, as with the simplest case described for Drugs
A and B, or whether data is in conflict with such a model.
The equation given earlier allows one, given a measured Kd value, to calculate
what percentage of receptors is occupied for a given concentration of drug.
The Kd value for testosterone and the androgen receptor (AR) actually is not
known with great precision for humans, but is approximately .44 nmol/L.1 Free
testosterone levels in normal men average approximately .07 nmol/L.2,3,4
Contrary to previous statements made by me (although those statements had been
made in the scientific literature) this indicates that normal testosterone
levels are not sufficient to saturate the AR. The equation given shows that with
these values for free testosterone (Tf) and for Kd, one would expect only 14% of
ARs to be occupied at any time. Increasing Tf by ten times would improve this to
61% occupancy, which still is not saturated. Increasing twenty times would yield
further improvement to 76%. Perhaps this correlates well with the observation
that gains improve markedly relative to low dose as one increases amount of
testosterone used to 1 gram per week, but going to 2 grams per week offers only
a modest further increase.
These results surprise me and are definitely contrary to accepted wisdom. I can
only speculate at the moment that those who were trying to determine whether or
not receptors are saturated made the mistake of performing the calculation with
total testosterone levels instead of Tf. Doing so would lead to that conclusion
but is an incorrect method.
I had been going to argue as I had previously that the dose response curve,
which extends at least to the 1 gram per week level,5 indicates that there must
be more than one mechanism of action, since response increases even past the
point of saturation. However these calculations just performed indicate that the
dose response curve, through the range that has been studied, is in accord with
known values for Kd. This doesn't prove that there is only one mechanism, but
just that one mechanism is not disproven by the dose response curve.
Is there other evidence for multiple mechanisms?
Yes.
First, there are indisputably molecular targets that are not ARs within some
cells which bind androgen and give pharmacological response to androgen. These
targets may well have (and in some cases are shown to have) quite different
binding properties than the AR does. One AAS might be more potent than another
at the AR, but less potent at this other target.
Now these targets are not well known or characterized at all, but there is
compelling evidence for their existence. First, as discussed above, for any
given target (or receptor) drugs acting only at that receptor will behave the
same way and differ only in their potencies. Now if all AAS behaved the same way
and differed only in their potencies, and had the same ratios of potency
regardless of the activity being studied (whether in muscle or skin or nerves,
etc.) then this would be consistent with there being only one target or
receptor. However, if some AAS are effective in some activities but do nothing
in others, while other AAS do have these other activities, then this can't all
be occurring from the same receptor.
Most of the research in this area is rather far removed from bodybuilding, but
the principles still apply. Biochemistry is usually much broader than any one
specific cell being studied. (For example, most human biochemistry was actually
learned originally by study of E. coli and with later research found to be
identical in man.) Thus, while we may not care about ductal branching
morphogenesis in the developing rat prostate, the fact that a peculiar
biochemical mechanism of androgen response occurs here implies that such a
mechanism may well exist in things we are interested in, such as bodybuilding.
The possibility at least exists.
Speaking of ductal branching morphogenisis in the developing rat prostate,6 here
indeed different steroids behave differently. While to the AR testosterone is
less potent than DHT, here the reverse relationship was found. Furthermore,
methyltrienolone, which is a more potent agonist (activator) of the AR than is
DHT, was no more effective than DHT in inducing ductal branching and was less
effective than testosterone. This cannot be explained by assuming that
aromatization of testosterone to estradiol contributed to the process, because
5a -androstan-3a ,17b -diol (which cannot aromatize) was similarly potent. Thus,
there is some target or receptor in these tissues which has different
"preferences" (Kd values, and different rank order of potency) than the AR does.
Could this also be the case for muscle growth? Perhaps.
Another example is found in the virilization of the mammary gland of female
rats.7 The same results are seen here as in the above example of the rat
prostate. Testosterone (T) has more activity than DHT does, though at the AR
that would not be so.
Differences also are seen in the male accessory glands of the rabbit and rat.8
Testosterone propionate and DHT propionate were found to be equally potent in
supporting growth and secretory activity of these glands, but the
above-mentioned 5a -androstan-3a ,17b -diol was considerably more potent than
these in the prostate but completely ineffective in the epidydimis. Furthermore,
use of an antiandrogen (AR blocker) did not affect the function of the
epidydimis at all. Thus, the activity of testosterone and DHT in this tissue is
not via the AR. Are there muscle-building activities that are not via the AR? If
the mechanism exists in one tissue it probably does in others as well.
Here is an activity that is itself of more interest: regulation of lipolysis
(fat release) in adipocytes (fat cells).9 T, but not DHT, stimulated
catecholamine-induced lipolysis. The findings indicated that T but not DHT
induced upregulation of b -adrenergic receptors.
Use of an aromatase inhibitor did not change these results, so conversion to
estrogen was not responsible for the difference. If this activity were via the
AR, DHT would also have exhibited this effect. Clearly then, something is going
on that is not via the AR.
Differential effects of different AAS on human fat cells have also been seen.10
Oxandrolone was most effective in reducing subcutaneous abdominal fat and
visceral fat in obese middle-aged men while weight did not change, as a result
of muscle mass increase. Testosterone enanthate gave a small decrease in
subcutaneous fat but a slight increase in visceral fat. Nandrolone decanoate
also increased visceral fat while decreasing subcutaneous fat. If these
activities were via the AR, all three steroids should give the same effects,
differing only in potency or the dosage required.
There are some interesting studies on sexual receptivity of female rats.
Methyltestosterone, methandrostenolone (Dianabol), nandrolone decanoate, and
stanozolol all interfered with sexual receptivity (a different result than seen
in human bodybuilders) while testosterone propionate did not.11
In male rats,12,13,14 differential activities are also seen. In intact
(non-castrated) male rats, testosterone cypionate, nandrolone decanoate, and
methandrostenolone (Dianabol) were all able to support male sexual behavior,
while methyltestosterone, stanozolol (Winstrol), and oxymetholone eliminated
male sexual behavior. Again, these results are different than are seen in human
bodybuilders. Testosterone cypionate was able to maintain ejaculation in
castrated rats, while oxymetholone (Anadrol) was barely able to do so, and
stanozolol was unable to do so. This however might have to do with estrogenic
activity - use of an aromatase inhibitor was not tried.
Oxandrolone was found incapable of supporting reproductive development in the
young male rat.15 Weight of testes, prostate gland, and seminal vesicles were
all below controls, and Leydig cells were severely depleted. Again, it was not
ruled out that reduced estrogen levels of the oxandrolone-treated animals might
have been to blame, so this does not actually prove a non-AR-dependent mechanism
for reproductive development. It does indicate that androgens other than
testosterone combined with low estrogen levels can result in fertility problems
in the rat, and therefore long-term use of nonaromatizing steroids might affect
sperm count in the human as well.
Virilizing activities in female rat fetuses also showed a trend of potencies
different from trends of binding affinities to the AR.16 The specific test used
was measurement of the abridgment of urovaginal septum length: admittedly not so
directly relevant for female bodybuilders. The most active AAS was stanozolol,
which was more active than methyltestosterone despite having much poor binding
affinity to the AR than that steroid.17
In Syrian hamster embryo cells, trenbolone, a more potent agonist of the AR than
testosterone, was found unable to transform these cells while testosterone was
effective.26 This indicates that the mechanism cannot be simply via the AR.
The AR is not a membrane-associated receptor, but exists within the cell.
However, receptors for testosterone have been found in the cell membranes of T
cells. The activity of testosterone (increase of amounts of Ca++ within the
cell) occurs within seconds (and therefore cannot be via interaction with DNA
resulting in increased protein synthesis, since this is a slow process) and was
not affected by an AR blocker.18 This effect has also been seen in Sertoli
cells.19
Androgen binding receptors have also been found in cell microsomes - these
receptors cannot interact with DNA because of their location.20,21,22 Stanozolol
has been found to have activity in microsomes that testosterone does
not.23,24,25
Lastly, while only stanozolol was tested and therefore we cannot know if there
is differential activity between different steroids or not, stanozolol induced a
type of skeletal muscle injury that was thought perhaps to stimulate growth, and
to induce gene expression by an AR independent mechanism.27 At last, a specific
example related to muscle that shows that not all activity is via the AR alone.
We might also speculate that AR upregulation (which has been demonstrated to
occur under some conditions (see Androgen Receptor Regulation) is probably not
itself mediated by the AR. It would be an unstable mechanism to have the number
of ARs increase as a result of increasing numbers of activated ARs. More likely
there would be another mechanism.
We may also speculate that different AAS have different effects on nerves, and
these effects (being rapid) are not mediated by the AR. E.g., fluoxymesterone,
while it binds fairly poorly to the AR, is highly potent in stimulating
aggression, and this activity occurs quickly.
Conclusion
What to do with this information? Unfortunately we cannot yet identify how many
non-AR-mediated activities there may be. There are I think at least two:
activity in microsomes and activities in nerves. There may be more. For example,
differentiation of satellite cells of muscle into mature muscle cells might be a
non-AR mediated activity.
The practical application of this is that one should not use only a steroid
which is good at some things but not others. Examples of this would be Deca and
Primobolan (good agonists of the AR but this is not sufficient to make them
outstanding anabolics) and Anadrol and Dianabol, which are weaker agonists of
the AR yet effective anabolics. Combining drugs of one type with the other is
synergistic. It may also be that testosterone and trenbolone are synergistic -
trenbolone is much more potent at the AR but (as seen with the Syrian hamster
cells) testosterone has at least one activity that trenbolone does not. Winstrol
has metabolic properties that testosterone lacks.
Is there a reason to use both Dianabol and Anadrol together? Does one have one
non-AR mediated activity which the other lacks? I think not, although Anadrol
does seem to have progestogenic activity which Dianabol does not. In any case I
don't know anyone who likes to combine these drugs.
Right now I would say that all bases are covered with testosterone plus
trenbolone plus (Dianabol or Anadrol) plus Winstrol. I am not sure that there is
no overlap: perhaps the activities of testosterone are covered by the other
three.
by huckleberry finnaplex
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