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Smart Basics March 1996 IntelliScope

"Precursor Hormones That Feed The Tree of Life"

In April Smart Basics announced that we now carry DHEA (dehydroepiandrosterone) in 10, 25 and 50 mg. capsules. This is pharmaceutical-grade DHEA, assayed at 101% purity. The extra 1% is an artifact of the laboratory assay procedures. We prefer to be painfully truthful when we say our DHEA is 99.8% pure (the difference reflecting the slight amount of pregnenolone precursor used as the base). Smart Basics DHEA should not be confused with the Dioscorea (Wild Yam) extracts that have been on the market for some time now. While Wild Yam products have been marketed as potential precursors for the body's production of DHEA, we have yet to see a single study where DHEA-S levels have been elevated by one of these products.

We've also recently introduced PREGNENOLONE, a naturally occurring metabolite of cholesterol that acts as a precursor to DHEA and other steroid hormones. Animal research indicates that pregnenolone possesses memory enhancing activity approximately 100 times higher than that of other compounds with similar effects. Used in the 1940's for the treatment of arthritis, pregnenolone has a long history of use in humans without toxic side effects.

DHEA, or dehydroepiandrosterone, is produced by the adrenal glands, and is the most abundant, naturally-occurring hormone in the human body. DHEA is often referred to as the "Mother Hormone" because our body can convert it upon demand into a host of other necessary health-enhancing hormones such as estrogen, testosterone, progesterone, and corticosterone. DHEA blood levels reach their peak around age 20, then decline in a linear fashion, making it one of the most reliable markers for measuring biological aging. By age 80 DHEA blood levels have declined as much as 95%, signaling the onset of the aging process.

"DHEA is most abundant in the human bloodstream. Research has found it to have significant anti-aging effects. DHEA levels naturally drop as people age, and there is good reason to think that taking a DHEA supplement may extend your life and make you more youthful while you're alive. Additionally, DHEA may be an important player in cognitive enhancement."
- Dr. Ward Dean, M.D.

More than just a precursor for the synthesis of other hormones, scientists have also identified specific body cells designed to bind to DHEA. This receptor function indicates that DHEA plays a far more direct role in human health than was previously recognized. There have been over 2,500 published papers documenting DHEA's multiple benefits, but the most recent paper studied the quality of life enhancing effect of this natural hormone: "DHEA will improve the quality of life over a longer period and will postpone some of the unpleasant side effects of aging, such as fatigue and muscle weakness." The report also stated that those patients receiving DHEA supplements slept better, had more energy and were better equipped to handle stress compared to the placebo group not receiving the DHEA.

The potential benefits of DHEA have been known to the scientific community for over 20 years, but this is the first placebo controlled human study conducted that sought to assess the therapeutic benefits of DHEA replacement therapy. We'll have more on this and other studies next month.

" DHEA is currently being investigated as an anti-aging hormone. New evidence suggests this hormone is so beneficial that it may turn out to be the most important advance of the decade."
- Dr. Alan R. Gaby, M.D.

To offer a more balanced view of DHEA, especially in light of the many "miracle" effects commonly attributed to this supplement, Jim English recently had the opportunity to interview Steven Wm. Fowkes of CERI, (Cognitive Enhancement Research Institute). In addition to being the director of CERI, Mr Fowkes also edits the monthly newsletter, Smart Drug News. Steve has consistently been on the forefront of nutritional science and supplement development, and in the following interview addresses many questions regarding the use of supplemental DHEA and Pregnenolone, bringing a balanced view to the topic. We hope the following information will help to cut through the usual marketing hype to aid our clients in assessing not only the possible benefits, but the potential risks associated with these supplements.

Jim: Steve, thank you for taking the time to speak with us. To start out, what exactly is DHEA?

Steve: DHEA is a metabolite of cholesterol that acts as a precursor to the sex hormones estrogen and testosterone. DHEA is an important raw material from which the body manufactures hormones which are very important to normal physiological functions. DHEA levels normally decline markedly with age, so we're interested in knowing if supplemental DHEA may have health-enhancing or anti-aging properties.

Jim: You're referring to the body's natural production of DHEA?

Steve: Yes. The enzymes that convert cholesterol into pregnenolone limit the amount of sterols and steroids the body produces. Furthermore, these enzymes decrease with age.

Jim: So, pregnenolone is actually a precursor to DHEA?

Steve: Exactly, and all other steroids. If you think of the steroid synthesis pathways as a tree, cholesterol is the root system, pregnenolone is the trunk of the tree, and DHEA is one of the main branches.

Jim: And the other sex steroids?

Steve: Estrogen and testosterone-and the corticosteroids-would be the crown of the tree, the leaves. Dihydrotestosterone is maybe one of the leaves that has turned yellow and is about ready to fall off the tree (laughs).

Jim: It needs to be pruned-that's a rather pastoral picture.

Steve: There's also aldosterone, which is used to regulate sodium and blood pressure in the body. Another main branch off the trunk would be progesterone, from which the corticosteroids are produced.

Jim: Isn't progesterone another precursor to the main sex hormones?

Steve: It can be, although typically it doesn't go that way. You can think of it as a place where the tree branches and then rejoins, but that rather stretches the tree analogy a bit.

Jim: Can you define some of the more common age-related health problems that can occur from a decline in the body's production of DHEA.

Steve: Well, we don't really know at this point in time what primary function DHEA has in the body. We know it has a precursor function, but there may be other direct effects that DHEA can have in and of itself. DHEA doesn't just sit there, inert, waiting to be converted into something else; it has an effect. Some of the effects that we know about are relatively indirect. For example, DHEA provides nutritional support for the body's repair mechanisms. In this case it has an anti-cortisol effect, so it moderates the potency of cortisol to minimize the damage that may be caused by stresses.

When you get injured or suffer stress, your body produces cortisol, and unrestrained cortisol levels can have a profound effect not only on our healing ability, but the immune system overall. If you get stressed-out, your body produces cortisol, and the degree to which we lose control of cortisol production can interfere with our immune system, the body's natural repair mechanism. In a sense, elevated cortisol levels cause accelerated aging and aggravate control of free radicals.

DHEA is also important for the modulation of estrogen. And because DHEA can produce estrogen and testosterone, there may be a downside for people who over-convert DHEA into estrogen or dihydrotestosterone. I think that's the real concern with high-dose DHEA. If you are merely taking a physiological replacement dose of DHEA in the range of 10-30 milligrams, then the DHEA may not go gushing down those other pathways. In other words, I don't think high DHEA levels are in themselves much of a risk, but the enzymes that can convert DHEA into other steroids could go into overdrive and cause problems. DHEA dosages in the hundreds of milligrams range could cause dramatic increases in dihydrotestosterone or estrogen levels, and that's why it's important to have medical supervision with high-dose DHEA.

Jim: Would someone taking DHEA in 25 milligram doses specifically need to test blood serum levels to measure their increase in DHEA levels?

Steve: I don't think it's absolutely necessary, but I think it's wise. Even at 25 milligrams, there could be significant increases in dihydrotestosterone or estrogen that could be aggravating factors in people with benign prostrate hypertrophy (BHP) or risks of cancer.

Jim: Particularly breast cancer which we know is estrogen respondent.

Steve: And estrogen in men should not be ignored; men get breast cancer, too. In my opinion, you don't have to measure DHEA or DHEA-S for safety reasons. DHEA itself is minimally toxic. Even an acute dose of 10-20 grams would probably would have minimal toxic effects on people. Natural DHEA levels vary dramatically between people, maybe even by a factor of 20 in people of the same age. If you compare teenagers and elderly adults, you're going to find them straddling a huge range. So DHEA itself is not a toxic agent that we need to be concerned about. We do assume that DHEA and DHEA-S levels indicate to some degree the appropriate amount, that as long as we do not push it way above normal, we are not going to have downstream effects. But that may not be true. We may, at fairly moderate levels of DHEA, convert too much of it into testosterone and other steroids. That conversion process could vary widely among people, and that's really what we should be looking at!

Using the tree analogy, we shouldn't be looking at the diameter of the DHEA branch, we should be looking at the growth of the crown of the tree. Although it is a more difficult process to measure all of the steroids, I think that it is clinically warranted when high-dose DHEA is indicated.

We shouldn't be prejudiced by sex stereotypes. Women make testosterone and men make estrogen. So it's important to look at all the hormones to know what's going on. For women, a little extra testosterone increases their libido and their enjoyment of life, and that's often a good thing. But if women take 50 or 200 mgs, too much testosterone can make them uncomfortable libido-wise or can produce masculine characteristics, like a deepening voice or facial hair growth. So women should definitely be careful of those issues. There are significant biological consequences of taking DHEA, and just because some of them are beneficial does not mean it should be used like candy.

Jim: Most people I've spoken with want to increase their energy levels to those closer to those they experienced as adolescents. Are there any specific guidelines people should follow?

Steve: One factor is how far back you want to push it. The radical approach is to push DHEA back to age twenty. My advice is to push it back ten to twenty years younger-so if you're 50, you might want to shoot for a 30-year-old DHEA level-because there may be downstream problems. In other words, the way in which the body converts DHEA into testosterone, dihydrotestosterone and estrogen may change with age, so it may be the case that as we get older we have more of a tendency to produce dihydro-testosterone and estrogen and less of a tendency to produce testosterone.

Jim: And that could exacerbate the kinds of problems we were talking about earlier.

Steve: Like BPH in men, and endometriosis and breast cancer in women. We don't have enough experience with DHEA to say absolutely that there is no risk in humans.

Jim: What would you recommend as a dosage for a normal, healthy individual starting out taking DHEA?

Steve: One 25 mg capsule first thing in the morning (or right before bed) is the standard recommendation. For those getting medical supervision, they may want to do it at both times. There may be some usefulness in exploring 5-15 mg dosages.

Jim: Is there any problem with taking DHEA with food?

Steve: It's best to take it on an empty stomach. The liver gets rid of 50% to 90% of DHEA, and I think that taking it with food tends can increase the percentage of loss. I think it's best taken on an empty stomach first thing in the morning or right before bed.

Jim: Personally I find DHEA to be pleasantly stimulating so I would likely avoid taking it right before bedtime.

Steve: Not everybody has that reaction. That's one difficulty with DHEA; you can't really tell people what they should expect. Some people don't notice anything at all - I'm like that. A fair number of people notice some hard-to-define feelings of improved well being.

Jim: Now lets talk a bit about pregnenolone, which you mentioned earlier as the direct precursor to DHEA.

Steve: Pregnenolone probably has more pronounced cognitive effects. Pregnenolone and progesterone are produced in fairly large quantities in the central nervous system, which is unusual given that it could be transported from the liver or adrenal glands. The brain must have a special need for pregnenolone. Amounts are fairly large when we're young and our brains are rapidly growing. Also, this may account for Dr. Eugene Roberts observations that even minute quantities of pregnenolone as small as a few hundred molecules have a very potent effect on the ability of mice to learn and navigate mazes1. That's an exceedingly small amount of material.

Jim: Would this increase memory in a person taking other cognition enhancing products such as piracetam or hydergine?

Steve: There's research that suggests that's the case with piracetam, (2-4) and I suspect it would be the same with the other cognitive enhancing products. I suspect that this is one of the reasons that Alzheimer's studies using piracetam have not been fruitful. Alzheimer's is known to be characterized by exceedingly low sterol and steroid levels. Therefore, you would expect that this would undercut the piracetam mechanism. Also, we might expect the combination of piracetam and pregnenolone would be worth trying.

Jim: When dealing with pregnenolone, would you also recommend that one get tested by a doctor to establish a baseline to measure one's progress?

Steve: Yes, because your dealing with the same pathways. Pregnenolone is amazingly safe. I think Dr. Ray Peat recounted an episode where he took a heaping tablespoon of pregnenolone - and nothing happened. So I would worry only about the downstream effects.

The advantage that pregnenolone has is that your not "nesting" in only one side of the tree. Pregnenolone is not committed to any specific steroid pathway. As long as your body doesn't have some kind of screwy imbalance in terms of the way that steroids are metabolized, you're feeding everything with pregnenolone. Unless I know otherwise, I would trust the wisdom of the body to balance it out.

Jim: So basically the body can determine the best use of pregnenolone as it disseminates it throughout the body.

Steve: And you can measure it by measuring before-and-after DHEA levels. When you are taking pregnenolone, DHEA is a downstream hormone.

It's important to realize that sex steroids are hundreds of times more potent biologically - in terms of dose - than pregnenolone or DHEA. That's why I think we need to pay more attention to what's going on with these end hormones.

Jim: Should someone who is in their 40's, 50's or 60's feel at high risk from taking a 10 mg capsule of pregnenolone or 25 mg of DHEA? What I'm trying to determine is how necessary is it to go out and get the blood studies, especially if you have a doctor who doesn't really know what you're asking for.

Steve: I think the risks are minimal when you're dealing with replacement dosages, i.e., less than the amount your body would produce if it were healthy. When the DHEA and pregnenolone levels are within the normal range of what the body would be producing at one's general state of age, that's a fundamentally benign state of affairs. When you start dealing with dramatic increases in DHEA and/or pregnenolone, then the issue changes dramatically.

Jim: I know of people that are taking 600 mgs of DHEA a day; that strikes me as exceedingly high.

Steve: It is. I know people who take from 500 to 2,500 milligrams a day, but they are typically HIV positive with abnormally low DHEA levels who are dealing with serious immune system dysfunction. It is not clear to what degree this benefits or harms them. I believe that estrogen is very counter-productive in HIV positive people and that it has an immunosuppressant effect. It has, at the same time, cognitive enhancing effects because of it's neurotoxicity, so it stimulates neurons and makes people more awake and more alert, but in doing so causes damage like that of cysteine or MSG would do in excess.

Jim: In other words, you're getting a temporary benefit but your accelerating the damage at a much higher rate.

Steve: At least causing stress, even if no overt damage is done. I don't know the mechanism of that excitotoxicity, but I believe it is direct. I've looked into aspartame excitotoxicity and how it relates to pyroglutamate and piracetam, but I haven't researched estrogen yet.

Jim: Lets take a little side step here because you raise the interesting issue of aspartame. We have one or two products which contain very small amounts of aspartame. Some of our customers are very concerned. They won't take aspartame in any amount.

Steve: It's a choice. As long as people are informed of the potential risks, that's fine. My experience is that aspartame sensitivity varies dramatically from person to person. There are people who can take it with minimal immediate consequences. Others take it and have immediate overt symptoms, like headaches, blood pressure changes, ringing in the ears, vision problems or seizures. They just have to stay away from it, period.

1. Floor, J.F., Morley, J. E.,and Robers, E,. Memory-Enhancing Effects In Male Mice Of Pregnenolone And Steroids Metabolically Derived From It. Proc. Natl. Acad. Sci. USA 89: 1567-71, March 1992.
2. Burov YV et al. Castrated rats: Influence of amiridine, tacrine and piracetam on passive avoidance response and brain biochemical parameters. Biological Amines 9(4): 327-35, 1993.
3. Mondadori C, Bhatnagar A, Borkowski J and Hausler A. Involvement of a steroidal component in the mechanism of action of piracetam-like nootropics. Brain Research 506(1): 101-8, 1 January 1990.
4. Mondadori C and Hausler A. Aldosterone receptors are involved in the mediation of the memory-enhancing effects of piracetam. Brain Research 524(2): 203-7, 6 August 1993.

ARTICLE: DHEA - Smart Drug Update

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