DHEA, Pregnenolone and Androstenedione
Preliminary Findings and Prospects
By Wesley James

This is not a definitive report on the effectiveness of any of the hormones named in the title. Such a report must await more directly targeted research. In the meantime, some of the misinformation currently being put forward by opportunistic supplement merchants can and should be dispelled. At the same time, some of the genuine potential of these substrates should be highlighted. The overall effort should prove useful in helping you determine whether you want to experiment with any of them. Since there are many other new products that have reached the market recently you may reasonably wonder why I have elected to examine only these three in one article. The answer is fairly obvious, each are related in that they are part of a pathway from Cholesterol to Testosterone. It should, therefore, be apparent why they have generated so much excitement among bodybuilders. They promise to provide a "natural," legal way to raise Testosterone levels. The real question, however great the promise, is, "Are any of them truly beneficial to bodybuilders?" This article will try to separate the hype from the real potential. While we won't be able to resolve all the questions about the efficacy of these hormones, we think we can resolve some and frame others. We'll also look at some the areas that remain unresolved to better define the nature of the outstanding questions.

The relationship between these three hormones and Testosterone is made fairly clear by the chart, below. The chart does not, however, illustrate the whole picture nor does it truly capture the relationship between the many elements. We have seen charts in other publications that purport to reflect the actual relationships; none of them actually do so, some don't come close. We endeavored to generate an accurate chart but failed miserably. The interplay between the various hormones and enzymes is so complex we could not reflect it in a single, comprehensible chart. This chart is, nevertheless, sufficient to convey a number of important ideas. If nothing else, it makes it clear that all three hormones are products of Cholesterol.
While the chain begins from Cholesterol, Pregnenolone is the first hormone of the group. It is also the least interesting product for bodybuilders. In spite of the marketing efforts to suggest otherwise, we can find no meaningful evidence that Pregnenolone has any anabolic, or even ergogenic, potential for bodybuilding. There is some evidence of a benefit to brain function, particularly memory. It is even possible it has some life extension applications. The only reasonable mechanism that could argue for an anabolic function, however, is that it provides additional building material for the manufacture of DHEA. This argument fails on at least two counts. Pregnenolone is as likely, if not more likely, to be converted to Progesterone as DHEA. Progesterone is directly estrogenic and thus likely counter productive to our goals. Even if one assumes that some portion of the Pregnenolone will become DHEA it would still be only potentially androgenic. The largest majority of DHEA is used for non-androgenic purposes. Moreover, and most obvious, efforts to raise DHEA levels can better be assured by use of supplemental DHEA, cutting out an extra and potentially detrimental stage.

DHEA, short for dehydroepiandrosterone, is the most abundant hormone in the human body. It is an essential component in a host of physiological functions. It plays a major role in the function of the immune system. It is an important factor in determining general levels of well- being and mood. Most important for our purposes, however, is that it is a building block for androgenic sex hormones. Although science has known about DHEA for almost 50 years, there were relatively few clinical studies until about ten years ago. The recent volume of research, however, has arguably made up for the previous short-fall. The research thus far is exciting in many ways. Perhaps the most scientifically interesting discovery is that DHEA may be the single most important chemical in the body for predicting disease states. As it happens, DHEA is measurably deficient in nearly every major category of disease, including obesity, diabetes, high blood pressure, cancer, immune deficiencies, coronary artery disease and autoimmune disorders. For this reason, whether or not it has meaningful ramifications for bodybuilder, we will continue to hear about DHEA for a long time to come. The fact that oral replacement of DHEA appears to be of benefit in all these maladies with no significant reported complications makes it all the more intriguing. On the other hand, there is now some indication that natural, non-exogenous, enhancement of DHEA levels may be feasible and more desirable and/or effective. We can, therefore, expect to hear about techniques for accomplishing this natural level elevation in the near future.
We will explore some of the other pathways that hold promise for bodybuilders in a later section. Before we do, we'll look at the chain of biological processes that has been most heavily touted in the muscle press, elevating Testosterone levels.
DHEA is manufactured from Cholesterol in the body. Interestingly, while DHEA levels decline with age Cholesterol levels tend to rise. This has lead to speculation that there is some enzymatic conversion process that degrades with age. As Pregnenolone levels also fall with age, it is likely that this degradation is related to the interaction of ACTH on the conversion of Cholesterol. Normally, Pregnenolone proceeds along metabolic pathways to become either Progesterone or DHEA. Progesterone proceeds to Cortisol and other glucocorticoids, Aldosterone and the mineral-corticoids via 21-Hydroxylase. This Hydroxylase enzyme is critical to the production of a wide range of corticosteroids. Individuals who are deficient in this enzyme experience significant, often devastating behavioral and physical sexual development problems. It is important, however, to know that excess levels of the enzyme are nearly equally problematic, though in very different ways. We have heard rumors that there is a black market in substances that inhibit this enzyme. They are being promoted as a natural way to cause your body to manufacture anabolic steroids. There is no truth to this assertion and use of such products, assuming they are not totally bogus, could cause heart failure due to potassium insufficiency. Stay clear!

Continuing along the Progesterone pathway, we find it becomes a building block for Estriol (a form of Estrogen). As noted, it also become Cortisol through the intermediate of 17-Alpha Hydroxy Progesterone. As you probably know, Cortisol is the major adrenal stress hormone and plays an active role in the catabolic effect of exercise. One of the pathways for the affect of Anabolic Steroids is theorized to be the binding of Cortisol receptors by the exogenous steroids. This effectively foils the catabolic effect but at too high a price. As Cortisol plays an essential role in the replacement and regeneration of damaged joint and tendon tissue, blocking it encourages serious injury in the form of torn muscle attachments in steroid users.
Another hormone produced via the Progesterone pathway is Aldosterone which is the major adrenal hormone responsible for mineral balance. Along with other mineral corticoids, Aldosterone is critical to maintaining proper hydration, bone density and contractile strength in muscle. Some bodybuilders have experimented with manipulating these corticoids in an effort to reduce water retention before contest. Apart from the extreme difficulty with producing the intended effect, tampering with this class of substrates is potentially fatal.

As you can see in the chart, Progesterone also goes on to become Estrone and 17-Beta Estradiol. The dotted line indicates that there are a number of other stages along the way. There is also another pathway, not illustrated, which leads to its conversion to Testosterone. This is not, however, a major source of circulating levels. The volume and affect of the estrogens derived from Progesterone when compared to androgens strongly favors feminizing effects.

Returning to the top of the chain, the other product of Pregnenolone is DHEA. This is the ordinary pathway for the manufacture of DHEA in the body. Illustrated but not detailed in the chart are the actions of DHEA as a major regulator in the feedback loop for all other hormones in the body, including Thyroid and Pituitary hormones. It is this function that leads to many of the quality of life and longevity benefits that appear to accrue from DHEA. We will discuss some of them a little later. Also apparent from the chart is the path that leads from DHEA to Testosterone (and 17-Beta Estradiol, yet another form of Estrogen). The immediate precursor to Testosterone is 4-Androstene-3, 17-dione, commonly known as Androstenedione or Androstene. The regulating enzyme for the conversion of Androstene to Testosterone is a by-product of Luteinizing Hormone known as 17-Beta-hydroxysteroid dihydrogenase. As you can see from the chart, production of this enzyme is govern by a negative feedback loop involving secretions from the pituitary and hypothalamus glands. The control agent appears to be circulating Testosterone levels. This may prove very important as it may limit the amount of Testosterone that can be produced when one supplements Androstene levels. We'll look at this a bit more as we proceed.

It is interesting to note that both the Progesterone and DHEA pathways can lead to the production of Testosterone and the various estrogens. For this reason, in post-menopausal women, many symptoms can be treated by administering natural Progesterone. In the future, DHEA may prove to be an even more benign way of addressing such menopausal symptoms. It may be worth note that these two active pathways for the production of estrogens explain why throughout adulthood men actually produce more Estrogen (in various forms) than post- menopausal women. It also demonstrates the powerful androgenic effect of Testosterone.
Now that we've traced all the way through the pathways from Cholesterol to Testosterone, including all three of the hormones we are examining, we can proceed to explore their anabolic and ergogenic potential. I have already dismissed Pregnenolone but that still leaves us DHEA and Androstenedione. If it can be demonstrated that they can be used to elevate Testosterone levels then they may be very powerful products indeed.

I have seen a number of sources repeat the findings from an East German patent application which states that 50 Mg of oral Androstene raised Testosterone levels from 140-183% of normal. I've also seen reports, extracted from the same patent document, of increases to 211-237% of normal on a 100 Mg oral dose. There are a number of problems with these reports. Patent applications are not peer reviewed nor even validated. One can write anything in a patent filing without need of any additional documentation. To the best of my knowledge, though the patent was filed in the '70's, no documentation, scientific publication or peer review has ever appeared for this data. Of course, the test has never been duplicated by any other researcher either. None of this makes the reports false, merely unsubstantiated. Let us assume for the sake of examination that the report is accurate. There is still a major problem. Perhaps the biggest problem in documenting Testosterone levels is that for years researchers looked at the wrong number. Most measured total Testosterone in the bloodstream though that figure is quite deceptive, perhaps even meaningless. Most of the Testosterone in the body is tightly bound to a protein called Sex Hormone Binding Globulin (SHBG). This SHBG bound Testosterone is not readily available to body tissue and not anabolic. It must be in the unbound or "free" form, more correctly called bioavailable Testosterone. Only a very small amount of circulating Testosterone, about 4 percent, is bioavailable. To complicate matters further, as we age the amount of bound Testosterone increases, leaving less free for use. One theory holds that this decline is abnormal. The same theory suggests that increased production of Di-Hydro-Testosterone (DHT) and the prevalence of Benign Prostate Hyperplasia (BPH) are efforts the body makes to compensate for this abnormal reduction. This fails to recognize that as men age the number of special Leydig cells in the testes, which produce Testosterone, reduces. It also ignores that the secretion of Testosterone is regulated by the pituitary and hypothalamus glands. When Testosterone is needed the hypothalamus senses it triggering secretion of Luteinizing Hormone Releasing Hormone (LHRH). This, in turn, triggers the secretion of Luteinizing Hormone which, as mentioned earlier, elevates 17-Beta-hydroxysteroid dihydrogenase. The age related failure mechanism actually appears to lie in the fact that the testes become less sensitive to the secretion. The bottom line is that even if the German patent is completely accurate, none of the Testosterone may be bioavailable. Further, there may be serious backlash ramifications that are not addressed in the patent report. It is easy to hypothesize multiple mechanisms that could produce negative net results from Androstene supplementation. It is far to soon to dismiss the possibility that Androstene and/or DHEA and Androstene together will be effective. The rash of products, ads articles and hype are, nevertheless, quite premature for the predicate that they increase active Testosterone levels or anabolic effect through that pathway. By the way, it is beyond the scope of this article but we are quite aware of the assertion that Tribulus Terrestris, a source of Furostanol Saponins, (an herbal complex) raises 17-Beta hydroxysteroid hydrogenase levels. We have found no supporting research for the assertion and certainly none for the stack that employs it.

It may sound as though I'm ready to completely dismiss all three of these hormones but not just yet. In my investigations of DHEA, I became aware of a series of facts that lead me to suspect the reason DHEA has not been convincingly demonstrated to be anabolic is that its affect is not through the theorized pathway. I believe an alternate pathway explains its effect more readily. Following Occham's Razor, therefore, it is more probable an explanation. I postulate that DHEA raises Growth Hormone levels. I have not worked out every detail as I write this but for those who are interested I'm including a few facts that I think support the hypothesis. Some of this may be a bit complex so hang in.

Growth hormone (GH) is a powerful Insulin antagonist. This is one of the mechanisms through which it causes fat burning. Insulin halts fat burning. Fasting increases both GH secretion and DHEA. GH is stimulated by Norepinephrine and Serotonin. Low catecholamines and low levels of serotonin are seen in patients with depression, along with low DHEA. Obesity decreases GH (and DHEA). Niacin is essential for the production of Serotonin which, as noted, raises GH levels. Stay with me! L-tryptophan and L-dopa both improve the sensitivities of the brain in Dexamethasone Suppression Tests. Dexamethasone is a cortisone analog. Thus, the tryptophan/serotonin and dopamine/epinephrine systems are intimately related to DHEA metabolism. Norepinephrine stimulates the secretion of gonadatropins but it is inhibited by dopamine (which is a precursor of epinephrine) along one of the secretory pathways. High levels of gonadatropins (boosters for the testes and ovaries) suggest higher DHEA levels but is that the case? High levels of both serotonin and melatonin inhibit reproductive function. The Hypothalamus is extremely sensitive to negative feedback, such as increased levels of cortisol with decreased levels of DHEA, but this sensitivity decreases in older individuals. Coincidentally, free Testosterone also decreases with age, largely as a result of increased binding to SHBG and lower levels of DHEA. High blood glucose levels inhibit GH while low blood glucose levels stimulate it. In theory this is good for DHEA but high blood levels of fatty acids decrease GH thus inhibiting DHEA. When blood glucose levels become low, fat is mobilized, raising fatty acid levels. You see the loop. By the way, high carbohydrate diets prevent the increase in GH which normally occurs when one ingests Arginine. Arginine is, therefore, complimentary with DHEA if DHEA works through the GH mechanism.

Let's put some of these facts together. Obesity is perhaps the most controversial illness for which DHEA supplementation may be indicated. The evidence of benefit is, nevertheless, compelling, at least under some conditions. While there is no doubt that DHEA serves to enhance fat metabolism (the GH pathway explains this nicely) and to assist in weight reduction in overweight patients, to date the research is less definite for normal individuals. Since obese individuals have notably lowered GH levels DHEA may be able to raise those levels in spite of the obesity. In a research study, overweight dogs on a high fiber diet lost 31 percent of their body weight, whereas those placed on a high fiber diet and DHEA lost 65.7 percent of their excess body weight. Even without the high fiber diet, 68 percent of the dogs experienced weight loss of four percent per month with just DHEA supplementation. What is less often noted about this often cited test is that the dogs in the test were castrated. Thus the Testosterone pathway could not be the explanation for the weight loss. I another test, this one of obese men, there was a 31 percent decrease in body fat in men treated with DHEA (exactly the same as in dogs). Interestingly, there was no change in body weight in the men-- suggesting the addition of some muscle--; a 31 percent decrease is quite significant. In rats, DHEA supplementation leads to a voluntary reduction in food intake. Apparently, DHEA curbs hunger. This is consistent, as we've seen, with the elevated Serotonin and Epinephrine levels that accompany elevated DHEA levels. Incidently, it is well known that Estrogen can be produced in fat tissue and in obese men there is a decrease in both Testosterone and DHEA levels and an increase in Estrogen. Certainly in patients who are significantly obese DHEA supplementation might be considered, along with the usual diet and exercise protocol, to offset these elevated Estrogen levels. The latest research on DHEA in obesity reveals that weight loss leads to Insulin reduction and 125 percent increase in DHEA in men. This seems to suggest that the body likes to lose weight through the DHEA pathway, but that may be wishful thinking.

It is somewhat superfluous to examine the anabolic effect of elevated GH levels. They are well documented. I will only point out that muscle growth is muscle growth. Frankly, I'm not too particular whether it comes from elevated Testosterone levels or elevated GH levels. If you feel the same way, you may want to try DHEA. Unless you are obese, it is unlikely you will lose much weight from its use but you just might gain some muscle. You may also want to try using it with and without Arginine to see if you find a difference. So the next question becomes, "How much DHEA should be used?

Dr. V.M. Dilman of the Center for Bio-Gerontology considers the physiologic and biochemical parameters of a healthy 20 to 25-year-old to be those that we should consider "normal." Anything that decreases from this 25-year-old level is, by his lights, maladaptation and leads to the problems of aging, including cancer and atherosclerosis. Dilman goes so far as to recommends 5 to 6 mg of Melatonin at bedtime for every individual as well as caloric restriction and physical exercise. This puts him outside the mainstream. His guideline, however, is probably correct. Proceeding from that assumption, as a starting point we want to bring DHEA levels to 750-1250 ng/dl in men and 550-980 ng/dl in women (the GH pathway works for you ladies also). What I've just told you is of very little use to you, however, if you don't know your DHEA levels. I know of only one way to determine your level, blood test. I wish I could tell you this was an easy test to get. There are, however, a number of problems with obtaining accurate information. You may not find your doctor unwilling to order the test. Most physicians are unaware of the potential benefits of DHEA and so are uncooperative. You may be more successful consulting a doctor listed in the Alternative Medicine Yellow Pages (available through many health food stores). Assuming you can find a cooperative physician, your problems may not be over. Dr. C. Norman Shealy M.D., Ph.D, an eminent DHEA researcher, reports that he has had difficulty obtaining accurate lab results. The test is simple yet Shealy asserts that only one lab has given him consistently reliable results. That lab, Corning Nicholas Institute (33608 Ortega Highway, San Juan Capistrano, CA 92676, (800) 553-5445), will work with physicians through the mail but prior arrangement must be made.

No matter what I say, I know that many of you will take DHEA without benefit of blood tests to monitor actual levels. Now that DHEA (though not DHEA-S) is available through health food stores, and some pharmacies, there is little to stop you. I will, therefore, warn that while there are no reported significant complications from DHEA supplementation some side effects have been observed. Mild acne and, rarely, some facial hair growth in older women has been reported. This may not be directly attributable to DHEA (older women frequently develop some facial hair). Women with a family history of breast cancer or even benign cysts should not experiment with DHEA without the assistance of a knowledgeable physician. Men with any prostate problem, including BPH, should also use DHEA only under medical supervision. Apart from these caveats, the most important contraindication is patients with diagnosed cancer (although it may be helpful with some cancers). Women with endometriosis or fibroids are also ill advised to use DHEA. With these warnings out of the way, I can offer some recommendations.

Dosages as high as 4000 Mg. per day have been used with some symptomatic cessation (numbness and spasticity) in cases of Multiple Sclerosis. This is, however, the highest dosage for which a significant body of clinical experience exists. Certainly, anything approaching that level, apart from the expense, would be foolhardy. Our best recommendation would be to begin with a morning dose of 25 Mg. for up to two weeks. You can then increase to 25 Mg. twice day, then three times a day. Four doses a day would be the limit. It has been asserted that all dosages should be taken at one time, in the morning, to more closely approximate the body's pattern. I have found no supportive evidence for this assertion. If you have detected no benefit from supplementation by the time you've worked your way up to a total of 100 Mg. daily intake, you may never find a benefit. I can not in good conscience advise that anyone exceed 250 Mg. per day divided into four doses. Regardless of the level of supplementation, you should know that stopping supplementation abruptly can produce a rebound effect which may include lethargy, depression and/or diminished libido. More meaningful to bodybuilders it may result in some loss of muscle tissue and/or deposition of fat. This result is easily avoided by withdrawing from supplementation over a two to four week period (dependant on the previous level of supplementation).

In closing this article, I am going to allow myself to express a hunch. I don't usually express opinion without a scientific basis but I'm making an exception so I want to make it clear. This opinion is just that, a hunch. I don't expect that individuals under forty years of age will see much in the way of benefit from DHEA supplementation. Men in particular-- I'm not so sure about women-- above forty will feel a benefit in mood and sense of well being. Those who are already in regular training are unlikely to observe a significant increase in growth, and almost certainly no weight loss, but it will benefit them in subtle ways. This will include improved recuperation and better sustained long term growth. These are significant enough benefits to persuade me that supplementation is justified. To quote Dennis Miller, "But that's just my opinion, I could be wrong."
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