Anabolic Research Update Aug 2002

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A relatively new theory has been gaining quite a bit of attention in the bodybuilding community. It involves the classification of anabolic/androgenic steroids according to the primary method in which they promote muscle growth. As the theory goes, there are two specific, or dichotomous, groups of steroids. The first, referred to as Class I steroids, promote muscle growth by interacting with the cellular androgen receptor. This mode of action for steroids, of course, is well documented and understood. The second group, the Class II steroids, are weak activators of the androgen receptor, and accordingly are said to promote muscle growth primarily through other, less understood, mechanisms.
As the theory progresses, an advantage would really only be found with stacking a Class I with a Class II steroid, as each type promotes anabolism via non-competing mechanisms. Stacking two steroids of the same Class, however, would not be recommended, as the two would serve only to compete against one another. The Class System essentially represents a simplified reference for the steroid-using bodybuilder, for how and why certain drugs should, or should not, be stacked together. As we will see in this article, however, this theory grossly oversimplifies and misunderstands the actions of the various anabolic steroids, and cannot be supported with solid science.
Origins of the System
The Class System began to surface a couple of years ago, when it was first noted in bodybuilding media that many potent muscle-building steroids, such as Dianabol, Anadrol and Winstrol, were demonstrated to bind the cellular androgen receptor very weakly, compared to a steroid such as testosterone. Searching for an explanation as to why these potent steroids work so well, yet bind the androgen receptor so weakly, the assumption that “something else” must be at work was born.
The logic behind this is summed up well in an article by Bill Roberts, the man really credited with originating the Class System theory. He explains, when discussing Dianabol, “Contrary to what many would expect, this compound is actually only a weak agonist of the androgen receptor (AR), with poor binding. It follows, then, that its value must mostly come from non-AR-mediated effects. It is therefore a Class II steroid.” I will not fault Bill for coming to this conclusion, as it is a good attempt at explaining something that did not seem immediately logical at the time. If we look a little deeper, however, we can find a much more solid explanation for this peculiar trait of the supposed Class II steroids.
Other Factors in Potency
There are several other factors that affect steroid activity than just its affinity for the androgen receptor, and it would be a mistake to pass judgment on the potency and mode of action of any compound without first taking them into account. Three things here are extremely important to look at. The first is the half-life of the steroid. Even if a steroid is somewhat weak in attaching to its corresponding receptor, if it stays active in the body for a much longer time than other compounds, it could actually be more potent. This is one of the reasons clenbuterol is such a potent medication; each dose stays active in the body for days instead of hours .
We also need to consider steroid binding to constraining serum proteins such as TeBG (testosterone-estradiol-binding globulin, also call SHBG or sex-hormone-binding globulin) and albumin. When bound to these proteins, a steroid hormone cannot activate the androgen receptor, and is essentially inactive. In many regards, the less binding the better if we want a potent androgen. Thirdly, we need to see what the steroid converts to in the body. Obviously the receptor binding affinity of all active metabolites is relevant to understanding steroid potency, especially if some are actually more potent than the originally administered steroids themselves.
Looking at these things, the Class System quickly falls apart. Not one of the three factors discussed above appears to have been taken into account by its proponents. And the fact that all of the supposed Class II steroids are 17-alpha methylated compounds says a lot, as they share a trait that comes to explain, clearly, why these steroids display high potency yet poor androgen receptor binding. For starters, methylated steroids were designed so that they can resist a major path of metabolic breakdown in the liver, allowing them to be orally active. As a consequence of this resistance they have very extended half-lives compared to their non-methylated analogs. Testosterone, for example, has a half-life of only a few minutes in the body, while methyltestosterone has a half-life of roughly 2.7 hours. This difference has a significant impact on overall drug potency.

 

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Studies also show that 17-alpha methylation lowers a steroid’s affinity for serum binding proteins. Looking into this we see that Dianabol, Anadrol and Winstrol all bind TeBG with an affinity far lower than that of a non-methylated steroid-like testosterone or nandrolone. This same trait is attributed in studies to the higher biological potency of methyltestosterone over testosterone as well. A common factor again surfaces that contributes to the high potency of these steroids. Further, we note that our Class II androgen, Anadrol, is metabolized to 17-alpha-methyldihydrotestosterone (mestanolone). MethylDHT for short, this is a very potent steroid, and its presence absolutely must be taken into account when looking at the potency of Anadrol.

Methylestradiol
Looking at the aromatization of methyltestosterone, we see an irrefutable example of just how methylation can increase the potency of a steroid, despite decreasing its receptor binding. We start by noting that there is little argument among bodybuilders today that methyltest is much more estrogenic than testosterone milligram for milligram. In fact, it’s known as one of the worst offenders in this regard, and most bodybuilders don’t go near it for this reason. In my first book, Anabolics 2000, I mistakenly attributed this to a greater rate of aromatization (estrogen conversion). Why else would it be so bad? It must be that more estrogen is produced with methyltestosterone, naturally. I was, however, making very much the same mistake as the proponents of the Class System. I was making assumptions without looking at the whole picture. Upon further investigation, my theory of course crumbled, as I found that methytestosterone is aromatized at only 44 percent the rate of testosterone. It is a much less active estrogen producer, which at first glance didn’t make sense. How can this be possible if it is so much more estrogenic? I needed an explanation, and wasn’t resting until I had one.

The answer, I later found, lies in the fact that methyltestosterone converts to a completely different estrogen than does testosterone. Because its added 17alpha-methyl group cannot be removed metabolically, it aromatizes to 17-alpha-methylestradiol (17ME) instead of regular estradiol. 17ME is clearly a much more potent estrogen in comparison, which obviously explains the more problematic nature of methyltestosterone regarding estrogenic side effects. The truly enlightening thing, however, comes in understanding exactly why 17ME is such a potent estrogen. It’s not because it binds the estrogen receptor more avidly than estradiol. In fact, it was shown to be weaker in studies. It is more potent for some of the very same reason that our Class II androgens are. Methylation had, again, dramatically increased the half-life of the steroid hormone, and presumably its affinity for serum binding proteins, creating a much more active hormone despite weakening its ability to bind the estrogen receptor. The relationship to our Class II steroids is obvious.

In Conclusion
I’m not disputing that there are non-androgen-receptor mediated activities inherent in many, or possibly all, anabolic/androgenic steroids. More research needs to be done, but clearly there are other mechanisms involved in muscle growth, such as those that may be mediated through glucorticosteroid displacement, estrogen conversion, or the level or activity of other hormones and proteins. I do, however, dispute the broad classification system discussed here. When held up to the light, the whole theory falls apart. We can clearly see, and explain away, the logic that went into its inception. Early proponents had mistaken poor binding and obviously high potency to indicate that certain steroids worked primarily through different pathways. Steroid half-life, serum binding protein affinity, and the potency of active metabolites all failed to be taken into account. When these factors are examined, we no longer see any true Class II steroids. We are left only with a collection of misunderstood oral steroids, and a theory that doesn’t hold water.

References
Steroid Profiles: Dianabol. Mesorx.com
Pharmacokinetics of plasma and urine clenbuterol in man, rat, and rabbit. Yamamoto I, Iwata K, Nakashima. J Pharmacobiodyn 1985 May;8(5):385-91
Metabolism of Anabolic Androgenic steroids. V. Rogozkin. 1991 CRC press.
Sublingual and Oral Administration of Methyltestosterone. A comparison of Drug Bioavailability. Alkalay et al. J Clin Pharm April 1973 p 142-51
Relative binding affinity of anabolic-androgenic steroids: Comparison of the binding to the androgen receptor in skeletal muscle and in prostate, as well as to Sex Hormone-Binding Globulin. Endocrinology 114 (1984) 2100-06
Binding of 17a-methyltestosterone In Vitro to Human Sex Hormone Binding Globulin and Rat Ventral Prostate Androgen Receptors. Wiita, Artis et al. Ther Drug Monit 17 (4) 1995 p 377-80
Estrogen Formations by the Human Placenta: Studies on the Mechanism of Steroid Aromatization by Mammalian Tissue. K. J. Ryan. Acta Endocrinol 35 (suppl. 51) 1960 p 697-8
Estrogen Receptor Binding Radiopharmaceuticals: II. Tissue Distribution of 17a-Methylestradiol in Normal and Tumor-Bearing Rats. Feenstra, Vaalburg et al. J Nuclear Med 24 (6) 1983 p 522-28

Black Market Update
By William Llewellyn
There is a new counterfeit testosterone cypionate on the market of which bodybuilders should be aware. This latest one is a copy of Upjohn’s Depo-Testosterone. The fake vial is actually a very good attempt at duplicating the unique appearance of this American testosterone product, so take note. You can see in the picture that both the real and fake Depo-Testosterone vials have a similar small neck and stopper. These vials and tops are somewhat unusual for counterfeit and underground steroids, and no doubt were specifically sought after by the illicit manufacturers. Furthermore, the real vial bears a very non-distinct screen-printed expiration date, making the duplicate that much harder to discern. The fake, however, stands out for two very important reasons. First, the vial is much shorter than the one used to make our real product. No doubt these exact vials were harder to get than the tops. Secondly, the label is in classic “bogus product” style, peeling right off the vial. Real U.S. drug products adhere to strict FDA manufacturing requirements, which do not allow for labels that are easily removed or replaced.
Growth hormone is an extremely expensive drug, and consequently a big target for counterfeit manufacturers. Fakes of the popular U.S. growth hormone product Serostim, for example, are currently a big problem on the black market. At $600-$700 a box, it’s no wonder there are so many illegitimate kits around these days. Over the years, many other brands fell, and will continue to fall, victim to counterfeiters, as well. GH is an item simply too profitable for them to ignore. With the high costs involved, some bodybuilders are opting to avoid the common products altogether. Fearing they might not be able to spot fakes, they are instead holding out for the more obscure GH products they hope haven’t been copied yet. This particular box of Norditropin is a good example of such an item. It is manufactured in the Eastern European country of Slovenia, and contains 10 milligrams (approximately 30 IU) of synthetic human growth hormone. It is not a common find on the black market at this time, and no fakes are known to exist. Likewise, on the rare occasion it is located, the buyer can be confident he’s getting a legitimate product. It may even provide a more economical alternative to many other products, as pharmaceuticals in general tend to be much cheaper in this area of the world.