|
by Bill Roberts
Bill Roberts received a bachelor degree in Microbiology and Cell
Science and completed the educational and research requirements
for a PhD in
Medicinal Chemistry. Bill entered the nutritional supplement
industry prior to completing his doctoral thesis but his education was invaluable so far as being able to
design/improve nutritional supplement compounds, since it was in
the field of designing drug molecules and secondarily some work
in transdermal delivery. It was not specifically "geared" toward
androgens other than expertise with pharmacological principles
having broad applications. This has allowed Bill to provide unique
insight into the field of anabolic pharmacology with knowledge
of points which he would not have known otherwise.
Publication Date:
July 2003 Nothing in this article is intended to take the place of advice from a licensed health professional. Consult a physician before taking any medication.
Athletic use of androgens Appropriate combinations of pharmaceutical anabolic/androgenic steroids (AAS, or androgens) that were developed for medical purposes have long proven effective for pro-athletic use. This is especially true in enhancing the development of muscle mass in response to resistance training, readily allowing achievement of a higher degree of muscle mass for any given individual than could be otherwise attained without the use of drugs. In bodybuilding applications, additional benefits include allowing much better retention of muscle mass under severe dieting conditions and enhancement of recovery ability, thus allowing more intensive training.
Disadvantages of pharmaceutical androgens While excellent effect can be achieved with pharmaceutical androgens, there are some possible disadvantages. These include conversion to estrogen; adverse metabolism by the 5alpha-reductase enzyme present in the scalp and skin; and either liver toxicity if orally bioavailable, or necessity of injection if not. Ideally, a highly effective combination of androgens would exist which presented none of these problems. Unfortunately, no such ideal combination of pharmaceutical AAS exists. At least two of these problems will typically be present in an effective cycle. The partial exception is cycles using only methenolone acetate (Primobolan Oral). However, even though a cycle using only this steroid avoids the aforementioned problems, it isn't highly effective. Another disadvantage that can exist with pharmaceutical anabolic steroids is their status in the United States and many other parts of the world as controlled substances.
Combinations of androgens An interesting phenomenon seen with androgens other than testosterone is that no one compound is by itself entirely satisfactory for most purposes, no matter the dose. I have never found an advanced user who believes that he achieves equal results with, for example, trenbolone acetate (TA) alone, or Dianabol alone, etc. as with certain combinations of steroids. While each synthetic androgen has an effect in improving anabolism, apparently it is not a complete effect, regardless of dose. Certain combinations of androgens lead to a greater total effect, while certain other combinations do not. To illustrate this, three different drug protocols may be tried: TA alone at 100 mg/day; Dianabol alone at 100 mg/day; and TA combined with Dianabol each at 50 mg/day. The differences are dramatic. The "stack" is highly effective, whereas both of the single-drug protocols are usually disappointing, even though the total dosage is the same in all cases. This indicates synergy, which most generally occurs when drugs work by different pathways or have differing limiting factors. In contrast, combining for example TA with Primobolan yields no greater total effect than is achievable by either androgen alone with sufficient dose. Only some drug combinations are synergistic; others are not. Where no greater total effect can be achieved by combination, this indicates lack of synergy.
Classification corresponding to synergistic effect: pharmaceutical androgens A method that has proven useful in predicting stacking behavior of androgens other than testosterone is to systematically group them as either "Class I" or "Class II." Pairs of androgens which combine with little or no synergy are assigned to the same class. Androgens combining very synergistically are assigned to different classes. The first assignment is arbitrary. Let us say that trenbolone is assigned to Class I. Then methenolone, nandrolone (Deca), boldenone (Equipoise), and oxandrolone are also assigned to this class, since none of them are strongly synergistic with trenbolone. In the cases of methenolone and oxandrolone a greater effect cannot be achieved by adding them than can be achieved with trenbolone alone at a sufficient dose; in the cases of nandrolone and somewhat moreso boldenone, there can be some improvement if doses added are quite high, but the synergy is not strong. It would appear that these compounds act mostly in the same manner as trenbolone, but may have weaker added activities that trenbolone would seem to lack entirely or almost entirely. In contrast, Dianabol combines very synergistically well with TA or other Class I compounds. It therefore is categorized as Class II. Other Class II pharmaceutical steroids include Anadrol® and Winstrol. It's interesting to note that while both are Class II steroids, some synergy is observed between Winstrol and Dianabol. It is not, however, nearly as strong as the synergy between either of them and any Class I compound. While differing in some common way from all Class I compounds, in some cases Class II compounds may have some differences among themselves: Winstrol may have an activity that Dianabol for example does not, or possesses to a lesser extent. It may be noted that where binding to the androgen receptor is known, those compounds that have good binding to the androgen receptor are invariably Class I, and those that do not (while having good anabolic effect regardless) are invariably Class II. If one prefers, Class I steroids may be defined as those binding well to the androgen receptor, while Class II steroids are those which do not, yet have good anabolic effect. Some discussion of the fact that androgens have more than one mechanism of action can be found in a previous article, Pharmacological Differences Among Anabolic/Androgenic Steroids. It is to be expected that where mechanisms of action may differ between drug compounds, combinations will yield synergy.
Use of classification system in planning androgen cycles Generally, cycles should include both a Class I and a Class II compound. Failure to adhere to this rule gives markedly inferior results; the sole exception is when testosterone is used at high dose, where combination may not be necessary. There is no anabolic advantage in combining more than one Class I compound. However, there may be practical or other reasons to combine more than one Class I compound. These may include limitations on availability; a desire to achieve a mixture of side effects; a desire to save a less-suppressing androgen for use in later parts of a cycle; a desire to avoid excessive injection volume if the most-desired androgen is available only in a low concentration, etc. Likewise, there is no anabolic advantage in combining more than one Class II compound, with the exception that adding Winstrol to other Class II compounds can be of some benefit. In a testosterone-based cycle, adding a Class I or Class II compound or both can provide the same anabolic effect as could be achieved with more testosterone, but can add less side effects, especially with Class I compounds. There are other considerations in cycle planning, of course, besides classification of androgens, but these would exceed the scope of this article.
Pharmaceutical androgens Whether a given androgen is defined as pharmaceutical or non-pharmaceutical in many cases will be a matter of arbitrary definition. Within this article I define a pharmaceutical androgen as a compound which: - is chemically and pharmacologically related to testosterone;
- has intrinsic anabolic/androgenic activity; and
- has been sold in the United States as a pharmaceutical drug, or is considered a controlled substance under the Controlled Substances Act, or is a synthetic compound not existing in nature.
Esters are considered equivalent to the parent steroid in these considerations, being converted with essentially 100% efficiency. The categorization of potent, naturally occurring androgens depends entirely on whether the compounds happen to have been sold as pharmaceutical drugs in the United States. For example, testosterone, nandrolone, and boldenone are effective, naturally occurring compounds which are classified as pharmaceutical androgens.
Non-pharmaceutical androgens A non-pharmaceutical androgen is a compound meeting the first two criteria, but not the third. The third criterion has nothing to do with the effectiveness of a compound. Some non-pharmaceutical androgens are quite potent and effective if sufficient blood levels are achieved. The first example compound is 4-androstenediol (4-AD). On injection, this androgen shows 95% the anabolic potency of testosterone in animal assays. Since conversion to testosterone is certainly far less than 95%, the anabolic effect of 4-AD cannot be attributed to conversion, but must be intrinsic. 4-AD generally does have problems with oral bioavailability, but not with effectiveness once in the system. 19-norandrostenediol is another example compound, except that, interestingly, it actually has been sold as an anabolic steroid (bolandiol) outside the United States. Within the US, however, it is not a pharmaceutical drug. For our third example, androst-1-ene (or its esters, etc.) is found on injection to have 2-4 times the anabolic activity of testosterone according to a number of assays. (The full name of this compound is 17beta-hydroxy-5alpha-androst-1-ene-3-one.) I have found all three of these non-pharmaceutical androgens to be of high value in enhancing development of muscle mass in response to resistance training, at least when method of administration is appropriate. By high value, I mean that when sufficient blood levels are achieved, the anabolic value is as great as is seen with individual pharmaceutical anabolic steroids. If these compounds were available as injectable pharmaceutical anabolic steroid preparations, they would be considered by physicians and athletes as being of equal stature to other pharmaceutical anabolic steroids. It is a matter only of chance, not effectiveness, that these non-pharmaceutical androgens were never sold as pharmaceuticals -- or in the case of 19-nor-4-androstenediol, that sale was in countries other than the United States.
Prohormones are not included among non-pharmaceutical androgens Incidentally, while both 4-AD and 19-norandrostenediol have been marketed as "prohormones," the term is not correctly applicable to them due to their intrinsic activity (a prohormone has no intrinsic activity). True prohormones such as androstenedione do not satisfy the definition for non-pharmaceutical androgens, and are not the type of compound discussed here. Unfortunately, a large number of fairly worthless or in some cases less than worthless prohormones have been brought to market, creating a general and mistaken impression that compounds legal for sale without prescription in the United States are never comparably effective to pharmaceutical androgens. The careful thinker will not make such blanket assumptions, however.
Classification corresponding to synergistic effect: non-pharmaceutical androgens 4-Androstenediol was quickly found to be of some limited value as an androgen when used orally at doses of 300 mg. I found it useful in the post-cycle situation where testosterone levels might still be low, certainly not giving results at all like being on an anabolic steroid cycle, but improving workouts and mood in the low-testosterone condition and being of limited benefit for natural trainers as well. The problem was low oral bioavailability. To achieve higher blood levels from a reasonable dosage, a novel drug-delivery technique (namely, applying a microscopically thin film over a very large area of the body to achieve enhanced flux over a long duration) was employed for the Androsol 4-AD product sold by Biotest, which incidentally is no longer in production. Blood analyses determined that 4-androstenediol levels increased to approximately 4000 ng/dL, and practical results found it to be an effective androgen for enhancing development of muscle mass in response to resistance training. Additionally, it was found that Androsol combined very synergistically with the model Class I compound trenbolone acetate. The combination gave much better results than could be obtained with TA alone regardless of dose. On the other hand, 4-AD did not combine synergistically with Dianabol, the model Class II compound. Adding Dianabol to maximum-dose Androsol gave little or no perceptible added benefit, nor did adding Androsol to 50 mg/day Dianabol. 4-Androstenediol is therefore categorized as Class II, as is 19-nor-4-androstenediol, for the same reasons. Androst-1-ene, on the other hand, has been found to be not synergistic with trenbolone acetate, but synergistic with Dianabol, 4-AD, and other Class II compounds. Accordingly, androst-1-ene is categorized as Class I. I therefore became interested in the idea of developing an oral formulation which efficiently delivered both 4-AD and androst-1-ene, differing from a synthetic pharmaceutical androgen product only in the matters of natural occurrence of the parent steroids and legal status -- not in efficacy. This product further was intended as a superior replacement for other androgen products in development at Biotest: first, cyclopent-1'-enyl ethers of testosterone and nandrolone; and second, certain other testosterone and nandrolone prodrugs, which need not be disclosed. This formulation also would have none of the disadvantages common to effective combinations of pharmaceutical anabolic steroids: no increases in estrogen, no adverse metabolism by 5alpha-reductase, no liver toxicity, and no necessity for injection.
Design considerations for an orally effective androgen Androgen steroids generally have very poor oral bioavailability due to extensive first-pass or early metabolism. The principle routes of elimination are via 17-oxidized A-ring-reduced metabolites including sulfated and glucuronidated forms. The pharmaceutical approach to this problem has generally been alkylation of the 17alpha position with either a 17alpha-methyl or occasionally a 17alpha-ethyl group. The presence of such a group prevents oxidation of the 17beta-hydroxy and therefore blocks the above routes of metabolism. An ester group while present also blocks such oxidation, as well as glucuronidation or sulfation of the 17 position, but no pharmaceutical androgen product has I think successfully used this method. Andriol, a capsule form of testosterone undecanoate, has little better oral bioavailability than testosterone itself and similar duration of action, instead of the greatly extended duration of action that would be expected for the intact ester; and methenolone acetate has little or no better oral bioavailability than methenolone itself would have. Its moderate bioavailabity, I think, may be attributed entirely to the 1-ene and 1-methyl functionalities in its structure rather than to the acetate ester. The reason for this is simple: esters of the above-described type (alkanoate esters) are generally cleaved prior to absorption for androgen steroids. They might as well not be present. In contrast, carbonate esters are known to have much greater enzymatic and chemical stability than alkanoate esters. My academic research in developing prodrugs of 5-fluorouracil, a drug used for treatment of skin cancer, involved both synthesis of carbonate prodrugs and access to stability data. Furthermore, I had previously employed a carbonate ester in Biotest's Methoxy-7 product to achieve enhanced oral bioavailability and duration of action compared to the methyl ether form previously used. While carbonate esters had never previously been employed to improve oral bioavailability of androgenic steroids, it was a type of chemistry which appeared suitable for the goal of achieving enhanced oral bioavailability of 4-AD and androst-1-ene. Another advantage of using these esters is that, as with other androgens administered as intact esters, duration of action would be at least one day, compared to a matter of hours for unesterified compounds. And in comparison with ethers, the carbonate esters could be expected to be superior in conversion efficiency. Results, both of those within the company testing the product and reports from customers, show the resulting product, MAG-10, to be a successful combination of non-pharmaceutical androgens. A rather typical result is 10 lb of retained muscle mass gain in two weeks of administration from experienced weight trainers who have not previously used anabolic steroids. With more prolonged use, 20 lb of retained muscle mass gain is common for such users.
Comparison of MAG-10 with pharmaceutical anabolic steroids I can draw on personal experience to compare results of
MAG-10 users who have never used anabolic steroids with users of pharmaceutical anabolic steroids, since I have extensive experience in the field. However, such conclusions can rather fairly be called only my own opinion, and as the designer of the product, one might fairly consider me to be biased, though I try to avoid allowing bias to affect my judgment in these things. Personally, I think results are excellent, but more information would certainly be of value. While one university study is underway, it is not a comparison with use of pharmaceutical anabolic steroids. Scientifically, it is currently impossible to perform a study on the effectiveness of synthetic anabolic steroids in athletic use, nor are there useful studies already done, so no means exists to do a direct comparison with MAG-10. We must instead rely on practical observation. Some difficulties arise. First, most experienced anabolic steroid users have an immediate, reflexive response to the idea that any product not banned by the Controlled Substances Act could possibly be equal to pharmaceutical androgens. They find the idea absurd on its face. This is due not really to any specific technical or medical reason, but to a prejudice acquired by the failure of prohormone products (not directly comparable, however) to meet claims. It is often difficult to move on to an unbiased evaluation with a person having such a response. He may not be interested in trying. Second, most experienced anabolic steroid users will see no need to try MAG-10 unless they have problems with their black-market supplier. They may also have a misperception that MAG-10 is more expensive for any given degree of effectiveness than pharmaceutical androgens are. While this is true for many cut-rate Mexican or veterinary steroids, many legitimate pharmaceutical products, for example Sustanon, are as expensive or more expensive than MAG-10 for achieving any given effect. But I digress. The point is, if MAG-10 is not used due to a perception of cost, then a comparison cannot be made. Third, while there are many who have done one or two steroid cycles and now have also used MAG-10, unfortunately they do not have the experience to make a good comparison. When comparing one drug protocol with another, one must have the ability to predict what would have happened had the known drug protocol been used. This can be known either because essentially the same circumstances are being duplicated, including starting lean-body mass, or because the user has such extensive experience that the effects of whatever may be different may be accurately estimated. A novice user has neither the same starting conditions (generally) nor the experience to estimate corrections for differences. As an example of a typical error, let us say that someone who had gone nearly as far as he could go with natural training adds 20 lb of retained LBM with his first steroid cycle. He still has the added muscle when beginning his second cycle, which is done with the same steroids at the same dosages. As an amusing twist, however, the user thinks the drug protocol is different (perhaps the brand names are different and he thinks they are completely different drugs.) Will he gain another 20 lb of retained LBM? Should the same drugs give the same increase in muscle mass? No. The drugs may be the same but the starting point is different, and if this individual adds 10 lb LBM he will be doing very well. This is not a lesser result: in fact, the endpoint achieved is higher. It might even require a more effective steroid stack to achieve this gain, rather than merely an equal one. However, all too many novice users will say, "The second cycle was very inferior, it only gave me 10 pounds." They simply are not able yet to accurately compare one drug protocol to another. This is true also when the second steroid combination is MAG-10. What might be an equal or even greater performance, when a more muscular starting point is taken into account, may be called an inferior performance by the novice user. Therefore, inexperienced steroid users generally do not provide useful comparisons of MAG-10 to pharmaceutical anabolic steroids. So the problem is that experienced users tend not to make the comparison (though fortunately there have been some, especially in-house and associates) and inexperienced users are usually not equipped to make very accurate or valid comparisons.
Answering the question On MESO-Rx, there are a good number of experienced steroid users who can say accurately what they "would have" gained had they used any of various pharmaceutical androgen combinations, or testosterone alone, instead of MAG-10 at the time of using MAG-10. They can thereby provide information on direct comparisons. One reason for being able to make this judgment is that they have in fact done a number of cycles starting from the same approximate degree of muscle mass under similar training and dietary conditions. There is then no guesswork involved. Another situation making a valid judgment possible is that experienced users may happen to be at a level of muscular bodyweight where a given amount of androgen is known to be required simply to maintain. Therefore, maintenance over a long enough period of time proves comparable effectiveness of the new androgen to the previously used androgen, losses prove lesser effectiveness, and gains prove greater effectiveness. These sorts of experienced anabolic steroid users, of which I hope to find some on MESO-Rx, are in an ideal position to evaluate MAG-10's degree of effectiveness relative to pharmaceutical anabolic steroids. |
