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4-Androstenediol and Cyclodextrins
A Match Made In Bodybuilding Heaven?

By Dr. John M Berardi, Ph.D.
First published at www.virtualmuscle.com, 2001.

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4-Dione…
5-Dione…
Nor 4-Diol…
Nor 4-Dione…
4-Diol…
Frustrating isn't it?

If you are anything like I am, you're probably FED UP with all the conflicting opinions about which prohormones are actually effective, when to take them, and how to take them. For many people, perhaps going with a thoroughly-tested blend of prohormones is one answer. Another answer is to educate oneself as to what each one does in the body. And it is not just prohormones that are confusing, its most of the supplements on the market today. Should I take a loading dose or should I take my supplements with grape juice, coffee, hot or cool water, with little tingly bubbles or should I take them hanging upside down in a dark closet for maximum absorption.

Obviously I'm exaggerating the issue, but I'm not doing so simply to rant, I'm actually trying to make a point about how today's supplement industry has been running wild with theoretical ideas that are nothing more than spurious assumptions at best. Don't get me wrong, I am definitely in favor of scientific speculation, for it is this very type of exchange of ideas that leads to progress. I am NOT, however, in favor of the full throttle marketing of such assumptions and the parading around of subsequent products as being proven by real science. In keeping with my own personal philosophy of discussing theoretically sound products but only recommending those that are backed by actual scientific research, the following series of articles is an attempt to address the "andro extravaganza" that has been dominating the bodybuilding community.

Andro Science - Part 2: Absorption of Prohormones

Last month's interview with the esteemed Dr Tim Zeigenfuss provided a nice introduction to prohormones in general and to 4-androstenediol, the only prohormone that actually has sound scientific backing as far as testosterone elevation. The truth is, the Pinnacle Popper (a primarily 4-Adiol blend of prohormones) is the only prohormone product to date demonstrating potential to increase testosterone and lean body mass and physical performance in men (1). I am in full agreement that the -diols have some real potential and that the -diones are pretty much useless for raising testosterone (not to say they are without some role in bodybuilding). In addition, although I believe that nor-diols have some potential (from a theoretical and anecdotal standpoint) there is still no direct data at all that addresses their safety or effectiveness. Thus, as a research scientist (don't hold it against me), I can't recommend something that hasn't been researched. The bottom line is that products that contain largely 4-androstenediol seem to be the way to go if you are interested in increasing testosterone and garnering mild ergogenic effects.

Well, as expected, it is not as simple as choosing the "right" prohormone. The main hurdle that supplements, including prohormones, have to overcome is the problem of absorption into the body and stability in the body once absorbed. Each supplement has a unique set of "issues" with absorption and stability. The main point I want to make is that if effective amounts of a supplement can't get into the body, or if once in the body the supplement is broken down rapidly, it is just as useless as an ineffective supplement. Prohormones present an interesting problem with respect to both absorption and degradation.

The adult digestive tract, from the mouth to the small intestine where most nutrient absorption occurs, is lined with cells that "protect us" from large external substances. In order for these substances (some of which are very beneficial and some not so beneficial) to enter into the blood, the digestive tract must "have its way" with the substances and break them down. These broken-down parts can cross the protective cellular barriers. In most cases our "intestinal gatekeeper" is, of course, a good thing. If this protection didn't occur, foreign invaders would wreak more havoc on the body than Stone Cold on WWF RAW. In some cases, however, like when we are trying to get supplements like creatine or prohormones into the body, this isn't so great. In addition to this first (gut) barrier, substances then have to contend with the body's equivalent of airport security…the liver.

As substances are absorbed into the body they are shuttled to the liver where they are subject to something known as "first pass metabolism". The liver screens all passers-by and deactivates anything that it considers harmful. Unfortunately all of our supplements are subject to both modification during absorption and deactivation by first pass metabolism. Therefore supplements like creatine and prohormones are likely to be modified in the body and these modifications may actually inactivate them. In response to this, excessively large doses of supplements are taken in order to get just a small percentage of them into the blood where they can actually promote their effects. This is especially the case with prohormones. Depressing, isn't it? Well, don't despair, not all is lost. Read on.

As both pharmaceutical and supplement sciences advance, new methods of delivery have been discovered to allow the administration of drugs and supplements that would normally be inactivated by either the digestive tract or the liver. These novel delivery systems may just help make the supplements in our bodybuilding arsenal, whether they are prohormones or other performance enhancing supplements, more effective. Are you excited yet? You should be because the introduction of cyclodextrins to the supplement industry has changed the complexion of the prohormone debate.

Cyclodextrins are modified carbohydrates, strings of glucose molecules that, when bound together, form a donut shaped ring with a hollow interior cavity. The naming of the cyclodextrin molecule is based on the number and properties of the glucose molecules within the ring portion. Six, Seven, and Eight glucose units that form cyclodextrin molecules are referred to as Alpha, Beta, and Gamma respectively. The relevant and interesting properties of cyclodextrin molecules include the fact that they have two very different regions of activity. The outside portion of the cyclodextrin molecule is "hydrophilic" (it's attracted to and dissolves very well in watery environments) while the inside part of the cyclodextrin is "hydrophobic" (attracted to molecules that repel water).

Since prohormones are hydrophobic and tend to repel water, they fit nicely into the inner part of the donut and remain there, tucked away, safe from the water of the body. The outer part of the cyclodextrin, however, is free to move through and dissolve in the watery parts of the body. This is important because these properties allow prohormones to use the cyclodextrin to chaperone them to the cell membranes and interact with the membrane very quickly. This actually can occur in the sublingual space in the mouth, avoiding the fate of regular old oral prohormones, which tend to be inactivated "lower down" in the small intestine and/or liver.

Essentially, the cyclodextrin complexed prohormones can quickly sneak into the body before the body "has its way" with them. To put this into perspective, let's examine how cyclodextrin delivery has changed prohormone delivery: Consumers' only option two years ago was to swallow large (or multiple), prohormone capsules totaling 150 to 250 mg and allow them to be degraded by either the hostile environment of the stomach or the liver. Now athletes can simply let cyclodextrin-complexed prohormones dissolve in the watery saliva of the sublingual space. In this latter situation as little as 15-25 mg of prohormone - or about one-tenth of the dose - is needed to produce double the effect. Essentially the process of cyclodextrin complexation of prohormones allows virtually all of the prohormone to be absorbed without much degradation. Sounds pretty exciting, doesn't it?

Before you run out to buy the first cyclodextrin-complexed prohormone you can find, I want you to realize that not all cyclodextrins are created equal. The two predominant forms of cyclodextrin used in prohormone complexes are the Beta and Hydroxypropyl Beta (HPB) cyclodextrins. Let's talk safety and effectiveness. HPB cyclodextrins have been shown to have a better safety profile and to be more water-soluble and than Beta cyclodextrins and therefore seem to be the best choice for use in prohormone complexes (2,3,4,5). In terms of safety, when administered in small oral doses neither cyclodextrin appears to be associated with any toxicity, so the relative safety profiles need not be a concern for the doses used in prohormone complexes (2,4). Since there has never been a study comparing the efficacy of HPB and Beta cyclodextrin complexed prohormones head to head, no one is really sure if HPB cyclodextrin's increased solubility actually leads to increases in prohormone absorption. All else being equal, in choosing a supplement that might increase my testosterone, appearance, and performance, I would probably choose the supplement more likely to produce the desired result.

Unfortunately all else is not equal as HPB cyclodextrin is a bit more expensive than Beta cyclodextrin. Since the Beta cyclodextrin is the most cost-effective compound, some companies have used Beta cyclodextrin instead of HPB cyclodextrin to complex their prohormones in an attempt to lower the costs of their product. As I said, although there has never been a head to head study comparing the two in terms of absorption, HPB seems as if it might be a more efficacious choice (based on existing, albeit indirect data). In this case though, it is every man for himself in choosing between cost and relative efficacy. As usual, I'm still waiting for the research showdown between HPB and Beta cyclodextrins before I truly say one is better than the other.

At this point, I would like to review by stating that in terms of the available research, it appears that the combination of 4-Androstenediol and HPB cyclodextrin is a match made in bodybuilding heaven. Depending on one's goals, other prohormones may also be revealed as equally attractive partners for cyclodextrin. As with all knowledge, only time will give us the definitive answers. Currently I am aware of a few projects being conducted to investigate the effects of HPB cyclodextrin complexed 4-Androstenediol. Hopefully the results will soon be available for scrutiny and will add to our current knowledge of prohormones and bodybuilding.

As a quick afterthought, although the focus of this article has been prohormones, cyclodextrins are beginning to prove themselves in the nutritional supplementation industry and a variety of interesting applications for cyclodextrins are being explored. The pharmaceutical industry has been experimenting with manipulating a drug's release time into the blood by combining a cyclodextrin molecule that will quickly release its drug component with delayed-release molecules that will bind their drug components for longer (3). In this case, a drug combination can have an immediate release and a delayed release component. This will allow for a short period of drug delivery in order to raise blood levels rapidly and a delayed period in which to "save" some of the drug for later and to release it when necessary. With this "quick/slow combination method", the anatomical area that a drug is released into can also be manipulated. By using a fast absorbing cyclodextrin complex, part of the drug can be absorbed in the oral cavity, while the delayed release component may wait until in the small intestine or another area to release its active drug. Progressive dietary supplement companies are already using compounds like inulin as a method for extending nutrient delivery/availability. Perhaps we'll see cyclodextrin/inulin products in the future? Keep your eyes open for applications of such delivery technology.

References

1. TN Ziegenfuss and DJ Kerrigan. Safety And Efficacy Of Prohormone Administration In Men. JEPonline Vol 2 No4 1999
2. T Loftsson, ME Brewster. Pharmaceutical applications of cyclodextrins 1. Drug solubilization and stabilization. Journal of Pharmaceutical Science 1996 Oct; 85(10): 1017-25
3. RA Rajewski, VJ Stella. Pharmaceutical applications of cyclodextrins 2. In vivo drug delivery. Journal of Pharmaceutical Science 1996 Nov; 85(11): 1142-69
4. T Irie, K Uekama. Pharmaceutical applications of cyclodextrins 3. Toxicological and safety evaluation. Journal of Pharmaceutical Science 1997 Feb; 86(2): 147-62
5. J Pitha, EJ Anaissie, K Uekama. Gamma-Cyclodextrin:testosterone complex suitable for sublingual administration. Journal of Pharmaceutical Science 1987 Oct; 76(10): 788-90