posted January 12, 2000 08:32 PM            

The following represents some of the latest thoughts on cycle theory. It includes my own theories and the opinions of others from the Elite Fitness Discussion Board, Elite Fitness Select, and M.F.W. newsgroup.

Receptors actually UPREGULATE with the use of heavy androgens. ---the following is based on the work of Bill Roberts.

The following is it is in regard to the nature of A.S. receptors (AR). It gets a bit technical at times, and if you don't follow some of the "chem talk" at times, I apologize. But DO read it all as it will open a new way of thinking about this subject.

The journals are absolutely flooded with this new information, as a result of experiments done by researchers including those at the University of Florida. It's even being taught in the classroom in graduate research courses. (However, nothing much has made it to textbooks yet, which may be why you imagine that the subject is little-understood.) We know exactly which proteins and which genes are involved and how they are regulated in many cases. But this has nothing to do with androgen receptor responses whatsoever. My point was that it was wrong to apply knowledge about G protein associated receptors to the androgen receptor -- it works in an entirely different manner. Just because beta-adrenergic receptors, for example, downregulate in response to ligand does not show that the AR behaves in the same way -- it doesn't!

The point is that upregulation of androgen receptor transcription occurs at dosages of steroid well beyond that required for 100% saturation of the receptors, and the concept of receptor downregulation, misreferred to as "degradation" by Bill Philips and others, is wrong, and therefore pyramiding up is not sensible. (It also wouldn't be sensible if receptor number was downregulated as a result of greater receptor occupation -- if you had fewer receptors present later in the cycle, then extra drug wouldn't do any good at all -- you'd already have an excess. But that isn't the case anyway -- I just mention it to demonstrate that the pyramid-up advocates are not thinking. That would be OK perhaps if real-world results demonstrated that pyramiding-up works better than not -- but this isn't so. The greatest gains are seen from staying on the drug all the time, which refutes their argument, but agrees with the observation that AR's in muscle tissue upregulate in response to androgen, rather than "downgrade." So pyramiding-up is illogical. Good pharmacology research has been done re the androgen receptor, but no scientific research directly answers the pyramid vs. taper. vs. constant-does argument, which is why I don't cite such experiments to directly prove that pyramiding-up is inefficient.)

If you care about overall health and therefore wish to cycle rather than use drug continuously, get the AR's upregulated as soon, fast, and hard as possible. Then when you have them, they can do their work on less drug, or the same amount.

Also one should note that all commercially-available anabolic-androgenic steroids have such high affinity for the AR that differences in potency cannot be explained on that account. Yes, some difference is due to metabolism (conversion to reduced and/or aromatized versions of the drug.) But I suggest that the drugs were never assayed for potency in upregulating AR transcription, and since this occurs by a mechanism independent of the AR itself, there is no reason to think that the drugs should be equal in this regard. Very possibly the drugs which have been found to be much more effective are those which cause a greater increase in number of androgen receptors. Unproven, but a plausible hypothesis. (Sherlock Holmes would say that since all else has been eliminated as impossible, this must be the truth, but I wouldn't go quite so far.)

This would suggest that, if one is combining drugs, it would make more sense to use the anecdotally-more-potent drugs early in the cycle, until toxicity would become a problem, and then use high doses of low-toxicity (but less AR upregulating) drugs later in the cycle, once plenty of new AR's have been produced. And there is plenty of anecdotal evidence to show that this plan does work very well indeed. There is *no evidence whatsoever* that androgen receptors "downgrade" after 2-4 weeks. Bill Philips says so, but he's wrong.

This was *assumed* because many other types of receptors demonstrate this response. However, androgen receptors in muscle tissue in fact up-regulate in response to increased androgen!

This may be why gains usually aren't seen in the first couple of weeks. Initially, the relatively small number of AR's is completely saturated by endogenous hormone anyway. So additional androgen doesn't increase transcription. However, (in an unknown mechanism not mediated by the AR) additional androgen upregulates transcription of new AR's. As a result, later you have more AR's and therefore see more transcription of gene products promoted by the AR. This will probably also be seen with moderate doses of androgen, since the number of androgen receptors is far smaller than the number of molecules of hormone, and the binding constant is very high. (Yeah, B.P. thinks you have more receptors than hormone, etc., but again, that is nonsense. No, I'm not a B.P. basher -- I like him.)

Conclusion: pyramiding up is silly. Tapering down makes sense, but maintaining the same dose will certainly give at least equal results, though requiring more drug.

So, if you've got to maximize the gains from a certain amount of anabolic/androgenic steroid, it would seem to make more sense to take more initially (first 2-4 weeks) and then take somewhat less thereafter. But I know of no empirical evidence that results are better from doing that than they would be from taking the same dose every week.

Respected bio-chemist Patrick Arnold, takes a different view:

ENDOCRINOLOGY (1981) vol. 108, no. 4, p.1431 > > In adult intact rats the concentration of androgen receptors in muscle cytosol > from females was about 100 fmol/g tissue, the corresponding value for males > was 50 fmol/g. > > Short term castration increased the concentration of and ligand affinity for > the androgen receptor in male rats > > > conclusion: androgen receptor density and perhaps affinity is inversely > related to the level of circulating androgen in the skeletal muscle of rats. >

However, the main problem with this study is that castration of rats is notorious for producing false conclusions. A possible reason for this is that the cells (and indeed the entire system of the animal) undergo qualitative change (e.g., cessation of growth) from the sham-operated animals. (I didn't read the study you cite -- were there even sham-operated controls? If not, increased cortisol from the stress of the orchidectomy would confuse the results.) In other words, you simply do not see the true effects of reduction of testosterone in this type of study. Reducing testosterone by reducing LH/FSH would have been a far better approach.

Another reason why this study could be wrong is that even today concentrations such as 50-100 femtomoles (millionths of micromoles!) per gram is very hard to measure, and in 1981 in my opinion they were throwing darts to get at their numbers.

In any case, there haven't been any more recent studies (last 10 years) that I know of that support this study!

Some studies that at first glance might seem to support it neglect the fact that testosterone can be and is converted to estradiol, and estradiol does down-regulate transcription of the AR.

OK, what studies support what I say?

The most recent one that I know of is, "Testosterone up-regulates androgen receptors and decreases differentiation of porcine myogenic satellite cells in vitro," Endocrinology (1996 April) p1385-94

The classic study in which this was first proven was done by Syms et. al. By using isotopic-labeled amino acids, they demonstrated that de novo AR-synthesis increased in response to supplied androgen. See "Mechanism of Androgen Receptor Augmentation," J. Biol Chem (1985) v260 p455-61

Also see J. Steroid Biochem Mol Bio (1993) v45 p333-43, and v37 p553-558 (1990).

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Old concept: there are 2 main anabolic/androgenic hormones in the body (testosterone and DHT), so there ought to be 2 kinds of receptors.

Obviously (using the word sarcastically) one receptor will give us all the activities we desire, and the other one is responsible for all bad side effects.

This theory was the operative principle during the entire period during which testosterone analogs were developed as anabolic drugs, that is, the 1930s to the 1960s.=20

Of course, the theory is wrong.

Molecular biology proved that there is only one gene for the androgen receptor.

So, obviously (again, read that sarcastically) there is only one type of androgen receptor.

This theory utterly dominated all thinking in the field from the 1970s until the early 90s.

Of course, it, also, is wrong.

Actually, post-transcriptional modification of the gene product results in different populations of androgen receptors, with some degree of differential selectivity. I.e., some actually do bind DHT more so than others do.

It seems to me that the effect is rather subtle, and this data should not be misinterpreted to mean that you should stack 6 different steroids.

BP's concept that different testosterone esters will activate different receptors is false and demonstrates that he has never taken Organic Chemistry 1: these esters all become testosterone itself; they all become the same molecule. Furthermore, there is research showing that the drugs don't bind as esters -- the ester comes off first, and they bind the 17-beta-hydroxyl steroid.

Older theories also suggested that drugs converted into DHT. In the vast majority of cases, this is impossible.

What can happen is that they can be reduced (a double bond converted to a single bond) and this will generally change the activity. E.g., nandrolone (Deca) will become less potent; therefore it is not likely to cause acne or prostate enlargement.

BP is also in error (no, not again!) in ascribing evil to DHT itself. He thinks DHT is the source of all evil (hey, he's advanced all the way to 1930s thinking... give the man credit.) The last issue of MM2K (yes, I'm ashamed, I did give Phillips some money: I like to read his rag) had a statement that you wouldn't want to take DHT as an anabolic unless you wanted a prostate the size of a grapefruit, or something.

If Phillips knew anything, he would know that DHT, supplied as a drug, has in fact been demonstrated to REDUCE the size of the prostates of elderly men with BHP, as well as to improve blood lipid profiles and improve cardiovascular parameters in elderly men. It is not the evil substance he thinks. And a little thought will make it clear why this is so.

Practical application of this new information on AR upregulation would indicate that optimal muscle hypertrophy would come from cycles such as the following:

The Modified Ski Jump or Inverted Pyramid:

The modified ski jump is the ideal way to use steroids because it : minimizes side effects. The body's feedback mechanism isn't instantaneous. It takes the body 10 to 14 days to start to react to steroids. So, it makes sense to use as much as you can during the first 10 days and then taper down from there over the next month or so.

The ideal stack would be to use 200mg of testosterone propionate (because it is short acting) every day for the first 10 days and then taper down from there. Sustanon would be the ideal taper steroid.

The purpose of tapering down is to allow your body to start producing its own testosterone again. If you just cut off the steroid, then there will be a time lag where your body will have no test. You'll go into a catabolic state and lose all that you gained. So a cycle with a taper or ski jump would be two weeks of 500, then a week of 400, then 300, then 200, then 100.

With the common occurrence of counterfeits on the black market, and with the concern over side effects and toxicity as well as the fact that people may react differently from anabolic steroids, some athletes add a �on-ramp� to this �ski-jump� cycle to make sure that there will be no averse reactions to the initial dose of the drugs. In the above scenario, the initial week would be in the 200 range.

2x2x2

Like the inverted pyramid cycle with the heaviest dose first, then taper for the rest of the cycle, the 2x2x2 cycle requires that you use 2000mg/week for two weeks then take two weeks off, then repeat. I know of a few people who have tried this and have had awesome results.

The 2x2x2 is based on theory of rapid receptor down-regulation. The theory states that receptor attenuate after only two weeks. In order to capitalize on this brief period of time, it is necessary to blast your receptors while they are still fully functional. Dan Duchaine, Bruce Kneller, and Will Brink have discussed this several months back. The 2x2x2 protocol is a simple yet powerfully effective cycle style and the side-effects are remarkably low. It basically consists of short bursts of high doses. 2 weeks of 2000mg and then 2 weeks off, hence the name 2x2x2. Start with androgens (Testoviron or Sust) and alternate with more refined anabolics (Primo or even Deca) the next time. Use this in a cyclic pattern until your desired weight is reached, then take a full 6 weeks off. It is speculated that smaller milligram doses may work (1000mg/week), but results are usually not as impressive.

Cyclone

Another cycle theory based on receptor down-regulation is called the Cyclone. It's basically a better variation of the 2x2x2...if you will, it's a 2x2x3. Instead of two weeks off you take three. A sample:

Weeks 1-2 2000mg of Anadrol and Sustanon
Week 3 Off
Week 4 5000 IU APL (HCG) and 1 Clomid/day for 7 days
Week 5 Off
Weeks 6-7 2000mg of Deca and Primo Repeat...

Using this style, then 1500mg will work but no lower. The rational behind switching from androgens to anabolics is simple. They work on different receptor sites therefore this pattern gives more receptor up-regulation time between mini-cycles. The Cyclone can be used continuously for up to 1 year before a complete time off is required.

APL is another name for HCG 2000mg is the total of the two steroids combined Weeks listed off simply means no drugs at all (except GH/insulin/IGF-1 if you can afford it)

Side effects are comparable to a regular pyramid cycle, but the difference lies in the gains.

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Yours in sport,

George

George Spellwin
Research Director