Testosterone. Trenbolone. Dianabol. Winstrol. Anadrol. Primobolan. How do anabolic steroids differ, and why do they have differing effects? How do they work? When and how much of what steroid should be used, and why?
It is one thing for writers to make statements about anabolic steroids, and to make recommendations. Some of what they say may be good, but some may be bad. It’s my goal to give you the understanding, when you read about steroids, to judge for yourself what is being said. When you understand how they work, then you can understand for yourself whether a given claim or idea is a good one or not.
In the next few articles, I will give you the background to have a good understanding of how these drugs work, so that you can develop informed plans for their use.
Mechanism of Action
First, let’s take the broadest view possible, but at the molecular level. Consider one molecule of an anabolic-androgenic steroid (AAS) in the bloodstream, bound to a molecule of testosterone binding globulin (TeBG). A receptor on the outside of the muscle cell will bring the TeBG/AAS into the cell. This process itself stimulates the metabolism of the cell by increasing cyclic AMP, but that is not the major effect of AAS use.
Alternatively, the AAS molecule may be free in the bloodstream, not bound to anything. If so, it can easily diffuse into the cell through the cell membrane, rather like water soaking through paper.
Next, inside the cell, the molecule of AAS binds to a molecule of androgen receptor (AR), which is inside the cell, not in the cell membrane. The androgen receptor is a very large molecule and is made of about a thousand amino acids. Thus, it is far larger than the molecule of AAS. The AR has a “hinge” region, and can be folded into either of two shapes. When it binds a molecule of AAS, the AR folds at the hinge, and is activated.
Think of the AR as being a machine that does nothing unless it is turned on. The AR either has an AAS bound to it, and is thereby switched on; or it does not, and is switched off. There is no intermediate condition that might cause an AAS to give a weak effect – there is no being “halfway folded” at the hinge. The only question is, How long does the AR stay activated before the AAS leaves? The answer, generally, is in the range of a couple of hours.
After the AAS leaves, the AR returns to its original state, and is ready to be used again.
Since the AR can only be either activated or not activated, it is just as much activated by say a bound molecule of methenolone (from Primobolan) as it is by a bound molecule from any other AAS.
This is not to say that differing AAS may give differing results for other reasons.
Once a molecule of AAS is bound to the AR, the receptor now travels to the nucleus of the cell, and forms a dimer (pair) with another activated AR. The dimer then binds to certain parts of the DNA, and certain genes then start producing more mRNA. This is a way for the body to selectively activate only certain genes. In this case, only those genes associated with androgens are activated, or have their activity increased.
mRNA is different for each gene, and carries the information the cell needs to make specific proteins. Myosin and actin, which are major components of muscle, are examples of proteins, and these are made, ultimately, as a result of mRNA production from the genes for those proteins.
At last: muscle protein, our goal. The molecule of AAS ultimately causes the muscle cell to make more of certain proteins, helping the user to get bigger. (There were steps needed to get from the mRNA to the protein, but we will skip them.)
Does each binding of AAS to an AR result in exactly one extra molecule of protein produced? No. Because even though the AR is fully activated by any AAS, that does not mean that it always succeeds in binding to DNA. And differing amounts of mRNA might be produced, because an AR remains active as long as an AAS remains bound to it. If many mRNA molecules are produced, then, generally, they will cause many corresponding protein molecules to be produced.
So the amount of extra growth per extra activated AR can vary.
The Androgen Receptor
Now, having a broad view of the process, let’s take a closer look at the AR itself.
The AR is a large protein molecule, produced from one and only one gene in DNA. There aren’t lots of different kinds of receptors, as some authors claim. There are not, for example, ARs specific for oral or injectable anabolics, nor for different esters of testosterone, nor for any different kinds of AAS.
The first important question to ask is, “How many ARs do you have? Is the number small or large? Can it be changed?” Since these are, in effect, little machines which are either on or off, and their effect is greater as more are activated, we want as many of them switched on as possible.
There are far fewer ARs than most people realize. Some authors who are opposed to AAS doses beyond 200 mg/week say that only this amount will be accepted by the receptors in muscle, and everything past that will “spill over” and go into receptors in the skin and elsewhere.
Research shows that muscle tissue has, roughly, 3 nanomoles of ARs per kg. Then your body probably has less than 300 nanomoles of ARs, grand total, let’s say.
A little math shows that all those receptors combined could bind only a small percentage of the molecules of AAS in one little 2.5 mg tab. So binding to ARs cannot appreciably reduce the concentration of AAS in the blood. Therefore, the ideas that ARs will bind most of whatever dose some author recommends, or that “spill-over” will occur beyond that, are entirely wrong. There just aren’t that many receptors.
Typical doses of AAS are high enough that a high percentage of the ARs are bound to AAS, whether the dose is say 400 mg/week or 1000 mg/week. If similar percentages of ARs are active – close to 100% in each case — then why do higher doses give more results? It’s a fact that they do, but there is not any large percentage of unoccupied receptors at the moderate dose. Thus, there is little room for improvement there. So at least part of the cause must be something other than simply occupying a higher percentage of receptors.
And why did I pick those doses, rather than comparing normal levels with say 400 mg/week?
The fact that the ARs must form dimers to be active has an interesting consequence. The mathematics are such that if two ARs must join together to form an activated dimer, and both must bind a molecule of AAS, then the square must be taken of the percentage. This means that if say 71% of receptors are binding steroid, only 50% of the dimers will be activated. Thus, at low levels, there is more room for improvement than one would think. But if say 95% are occupied, then even after squaring that, there would still only be 10% room for improvement.
But actual improvement – increase in effect – seems to be much more than 10%. Anabolism increases even as the dose becomes more than sufficient to ensure virtually complete binding. Why?
One popular explanation is that high doses of AAS block cortisol receptors and are thus anti-catabolic. But if this were an adequate explanation, then one could use anti-cortisol drugs together with low doses of AAS and get the same results as with high doses of AAS. This isn’t the case. In fact, if cortisol is suppressed, this simply results in painful joint problems. And if the cortisol-blocking theory were true, we also would expect that persons with abnormally low cortisol ought to be quite muscular. That isn’t the case either.
Three other possibilities come to mind:
Possible Explanations for the Effect of High Dose Anabolic- Androgenic Steroids
1. High doses of Anabolic Steroids could upregulate Androgen Receptor production
Although activity cannot be greatly increased by increasing occupancy of existing receptors, it might potentially be greatly increased by increasing the number of receptors. This is mentioned here as a possible explanation for the effects of high dose AAS, not as an established observed fact in muscle tissue of bodybuilders. I am not aware of any such studies.
Upregulation is observed from supraphysiological doses of nonaromatizing AAS in other tissues, and is observed in humans in response to resistance exercise.
2. High doses of Anabolic Steroids could stimulate growth independently of the Androgen Receptor
In muscle tissue, androgen has been observed to activate the immediate-early gene zif268 in a process not involving the AR. This activity is almost certainly related to muscle growth, and it requires high doses.
Testosterone is observed to increase the efficiency of mRNA translation of cellular proteins, and this may be mediated by a mechanism independent of the AR.
Nerve tissue has been observed to respond almost instantly to androgen. This cannot be a result of the AR mediated process I have described here, because that process takes much more time.
Generally speaking, the hypothesis that a drug acts by only one mode of action can be tested by examining the dose/response curve. If an effect is dependent only upon the activity of a receptor, then the log response should follow a sigmoidal function (an S shaped curve). The graph would be nearly flat both at low and high doses, and approximately linear at moderate doses.
At moderate doses the linear function is indeed seen.
The problem is, for the range of approximately 100 to 1000 mg/week, the graph remains linear regardless of dose! By the way, this does not mean that twice the dose gives twice the effect. Rather, about four times the dose is required to give twice the effect.
This response is not consistent with a simple receptor-only model; such a model is not supported by the dose/response curve. But this type of response is to be expected if there are other variables besides receptor binding. This can be explained if one or more of the mechanisms is saturated at lower levels of drug, and one or more other mechanisms do not become saturated until much higher levels of drug are used.
3. High doses of Anabolic Steroids might improve the efficiency of action of Androgen Receptors
Not only the number of ARs is important, but also their efficiency of operation. The entire process, as was partially described above, involves many proteins, some of which may be limiting. Increases in the amounts of these proteins might increase activity dramatically. For example, ARA70 is a protein which can improve the activity of the AR by ten times.
I am not aware of any study determining how ARA70 may be regulated by high doses of AAS. I cite this as an example of the type of pharmacology that may be going on, and also, incidentally, as a potential target. If you happen to see where some other drug has been seen to increase ARA70, that might be very interesting!
Other proteins which can affect efficiency include RAF, which enhances the binding of the AR to DNA by about 25-fold; GRIP1, and cJun. None of these, unfortunately, could themselves be taken as drugs.
But you can see that there are many ways by which AR activity could change besides any “upregulation” or “downregulation” of receptors. Authors who make such claims as the be-all and end-all of their steroid theories essentially do not know what they are talking about. Without specific evidence – without actual measurement of AR levels – it is always unjustified to claim that “androgen receptor downregulation must have occurred,” especially on the basis of anecdotal evidence. Actual measurements are always lacking from such claims.
Nor is it justified to assume that increasing the occupancy of ARs is the only way to increase the effect of androgens, as we have seen. It is justified, on the basis of real world results, to say that high dose AAS are more effective than low dose AAS, and certainly more effective than natural levels of AAS. This is true even if use is sustained over time. That however is not consistent with any claims of downregulation of androgen receptors in response to high doses of AAS.
It also is justified both from bodybuilding experience and from scientific evidence that low AAS doses, such as 100 or 200 mg/week, will generally not give much results for male athletes.
Next, we will consider regulation of the androgen receptor more closely. There have been many opposing claims concerning this. Which claims are valid? How should these theories affect an athlete’s planning?