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 uro******* 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.
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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.
I hope that future careful observations of results obtained in bodybuilding will allow a more precise answer to this question in the future
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