DHEA The Most Versatile Hormone

Restoring Youthful Levels of DHEA Provides an Astonishing Cornucopia of Benefits

Old age must be resisted and its deficiencies restored. - Cicero

In contemplating our own sexual self-image, we often forget that sexuality is a slightly fuzzy concept. Hormonally, none of us is either completely male or female, because we all have a bit of the opposite sex in our blood - literally. Men have a preponderance of the male hormone testosterone, with a little of the female hormone estrogen, and women have just the reverse. In this article, we will see how dramatically our sex hormones can affect our response to a certain nutritional supplement.

It is well known that males treated with female sex hormones become feminized not only in appearance but also in behavior, and females treated with male sex hormones become similarly masculinized. Men and women are thus different not only in their physical beings but also in their inner selves. How we view ourselves, how we think about things, and how we behave depend to a significant degree on our sex - or, to be more accurate, on our various sex hormones and the balance among them.

The differentiation begins early in life. No matter how hard some politically correct parents may try to rear their hapless children in a gender-neutral manner from day one, their little boys typically gravitate to toy trucks and guns as they grow older, and their little girls just as typically insist on playing with dolls and tea sets. Mother (Father?) Nature always has the last say-so.

WHERE DO SEX HORMONES COME FROM? 
In terms of biological activity, it's hard to imagine anything that more profoundly affects our sense of well-being and our very sense of identity than the sex hormones, of which there are five principal ones: testosterone, progesterone, estrone, estradiol, and estriol. (The last three are collectively referred to as estrogen. And did you notice that four of the five sex hormones predominate in women? Is that fair?) So it is natural to wonder where they come from, exactly. We know that they're manufactured primarily in our gonads (testicles and ovaries), but from what?

Surprisingly (or perhaps not, if you're a biochemist), the male and female sex hormones are not much different in molecular structure. They are amazingly similar, in fact, because all of them are steroids derived from the same precursor molecules. It all starts with cholesterol, the human body's most prevalent steroid, which is synthesized in the liver from smaller molecules. Through a long, complex series of reactions, cholesterol spawns a host of other steroids, many of which are hormones (cholesterol itself is not). Among the most important of these hormones is pregnenolone, which is a precursor to the one that this article is about: dehydroepiandrosterone, mercifully called DHEA for short.

DHEA: A BIT OF MYSTERY, A BIT OF PARADOX 
Our adrenal glands - those small, caplike organs sitting on top of our kidneys - manufacture most of the body's DHEA, along with about 150 other hormones. Actually, about 90% of the DHEA produced is quickly metabolized to DHEA sulfate (DHEAS), but the distinction between these two forms of the hormone is not usually important. (For more on this, see the sidebar "What the Body Does With DHEA.")

Strangely, although DHEA is by far the most abundant steroid hormone in our blood, we still know relatively little about its functions in the human body. We do know that it is a precursor to both testosterone and estrogen, yet DHEA itself is classified as an androgen (a male sex hormone). In the weird world of sex hormones, this kind of paradox is not unusual. Another hormone that is a precursor to both testosterone and estrogen is the female hormone progesterone (whose immediate parent in this complex web of biochemical pathways is pregnenolone).

The overall balance of sex hormones in our bodies is governed by many factors, the net result of which is our sexual identity, both physical and mental, along with many other aspects of our health and sense of well-being. As we age, the levels of many (but not all) of our hormones drop dramatically, and subtle shifts occur in the balance among them. Many researchers believe that some of the notable signs of aging, such as shrinking muscle mass and decreasing bone density, are related to this age-associated decline in hormone production.

DOES SUPPLEMENTING WITH HORMONES IMPROVE HEALTH AND LIFESPAN? 
This relationship suggests an obvious question: Can supplementation with hormones improve the health and perhaps even the lifespan of people who are otherwise healthy and free of incipient hormonal disorders (such as a low-thyroid condition that has not yet manifested any clinical symptoms)?

In one arena, hormone replacement therapy, the answer is definitely yes (see What Women Want to Know About Natural Progesterone – Nov. 2000). In addition, the use of pregnenolone - in both sexes - is of value for learning and memory, among other benefits (see Pregnenolone Review – Jun. 1999). And there is growing evidence that supplementation with DHEA can also greatly improve the quality of life for both men and women - although not always in the same ways or to the same extent, because of our different hormonal makeups.

DHEA HAS A BROAD SPECTRUM OF BENEFITS 
Following are the principal benefits of DHEA supplementation, as described in detail in an excellent book on the subject by Dr. Ray Sahelian, DHEA: A Practical Guide.1

• Improved energy, mood, and memory. For most people who use DHEA - men and women with age-related low levels - there is no doubt that supplementation increases energy and improves mood, thus enhancing their overall sense of well-being, both physical and mental. Typical reactions include enhanced alertness, better sleep, and better ability to cope with stress. (There are even reports of increased REM sleep, the phase of sleep associated with dreaming.) These features alone make DHEA well worth considering as a nutritional supplement. Some people also report improvements in memory, although this feature has not been as well confirmed by clinical trials (it is well established in animal studies, however). 

DHEA's effects on mental functions are less surprising when we realize that it is not just a sex hormone but also a neurohormone that is manufactured in small amounts in the brain (by cells called astrocytes). Animal experiments suggest that, among the steroid hormones, DHEA and its parent, pregnenolone, play a special role in the human brain. And recent research has shown a marked antidepressant capability of DHEA, even in patients with major clinical depression who are resistant to conventional antidepressant medications (see DHEA A Better Antidepressant - Jul. 99).

• Enhanced libido. Many, but not all, users of DHEA - particularly women - notice an increase in libido. This may be due to a slight but significant increase in testosterone levels, which has a prosexual effect. The effect is dramatically evident in older women, who have been reported to experience not only increased desire but also increased sexual activity and satisfaction (see DHEA Can Help Keep Women in Love – Jun. 2000). These women also showed distinct improvements in bone density (which helps to counter osteoporosis) and various aspects of skin health.

• Strengthened immune function. As we age, we make ever fewer antibodies to pathogens, and our immune systems become weaker. We thus become more and more susceptible to infections, which are the fourth leading cause of death, after heart disease, cancer, and stroke. Animal studies show improvements in immune function caused by DHEA, and the results of more limited human studies are also promising. Under some circumstances, DHEA appears to stimulate the production of antibodies and also of natural killer cells; the latter seek and destroy not only viruses, but also abnormal cells that are prone to become cancerous.

• Resistance to autoimmune diseases. These are diseases in which, in a cruel irony, the body's immune system mistakes parts of the body as foreign invaders and attacks them. One such disease is systemic lupus erythematosus, or lupus for short. Lupus causes painful and swollen joints, skin rash, and mouth ulcers, among other symptoms. It afflicts about four times as many women as men and is not age-related. There is growing evidence that DHEA can alleviate the symptoms of this disease, especially in mild to moderate cases. (See also DHEA Combats the Autoimmune Disease Lupus in Life Enhancement, April 2000.)

There is also some evidence that DHEA may help with other autoimmune diseases, notably rheumatoid arthritis (but not osteoarthritis, which is not an autoimmune disease). This painful disease afflicts about 2% of the population and is most common in older women.

• Enhanced weight loss. There is evidence that DHEA helps promote weight loss in laboratory animals, and perhaps in humans as well, although the results are inconsistent, and it is unclear what the operative mechanism is. It may involve appetite suppression or thermogenesis (fat burning) or both. A curious observation is that, in men who lose weight without DHEA supplementation, the natural levels of this hormone tend to rise. This is not true of women, however - still more evidence of the different ways in which this remarkable hormone is metabolized by the two sexes.

• Resistance to heart disease. Countless studies on rodents have shown positive effects of DHEA. In humans, there is a correlation between heart disease and low levels of DHEA, especially in men, but if there is a causative effect (a correlation does not necessarily imply a causation), it is not yet clear whether low DHEA causes heart disease, or vice versa. If DHEA supplementation does prove to be valuable in helping to prevent heart disease, it appears that the primary beneficiaries will be men.

• Resistance to diabetes. Here too, rodent studies are very promising. There is some evidence in humans that DHEA increases insulin sensitivity, thus counteracting the age-related tendency toward insulin resistance, which can cause or exacerbate diabetes. Thus, it is believed that DHEA may prove to be beneficial against type 2 (adult-onset) diabetes, but probably not against type 1 (juvenile-onset) diabetes.

• Resistance to osteoporosis. We saw above that elderly women taking DHEA experienced improved bone density. This is in keeping with the observation that postmenopausal women in general are more likely to have stronger bones if their DHEA levels are high for their age, and weaker bones if they are low. It is believed that the conversion of DHEA to estrogen by osteoblasts (cells that are involved in bone formation) is responsible for this effect, as estrogen is important in maintaining bone density after menopause. Paradoxically, however, androgens (notably testosterone) are also known to be "bone builders" in women, so it is possible that the androgenic effects of DHEA contribute to improved bone density as well.

• Resistance to cancer. Consider this one an open question. Laboratory studies on mice and rats have demonstrated that DHEA inhibits the development of experimental tumors of the liver, breast, lung, colon, skin, and lymphatic tissue, among others. This is encouraging, but because rodents are so different from humans with regard to natural DHEA levels (see the sidebar "Are Men Like Mice?"), it is a large leap from these results to what might be expected in humans. Much more research - on humans - is needed.

• Extended lifespan. Most studies of DHEA's effect on the lifespan of rodents have shown a positive life extension. Reliable data on humans are not available, mainly because humans live so much longer than rodents in the first place that controlled studies would take many years, even decades, to accomplish. Nonetheless, some veteran DHEA researchers are optimistic that this hormone may ultimately prove to confer longevity benefits on us as well as on our small furry friends.

NEW STUDY EXAMINES DHEA METABOLISM AND SAFETY
A distinguished team of French researchers has recently published a study in which the objective was to examine the metabolism of orally administered DHEA in healthy elderly humans, and particularly to determine whether the proposed dosages of 25 and 50 mg daily were physiological doses that did not lead to an excess of DHEA or any of its metabolites.2 The study was randomized, double-blind, and placebo-controlled (a crossover design, in which all the subjects acted as their own controls).*

The subjects were 12 men and 12 women (average age 68 ± 4 years) who had not had any health problems over the previous month, were not obese, and were not heavy smokers. Some were on hormone replacement therapy (which was withdrawn for at least one month prior to the tests) or were taking medications for hypertension, high cholesterol, or osteoarthritis. For the tests, they were given 25 or 50 mg of DHEA or placebo daily for two 8-day periods separated by a 2-week washout interval.

In describing this study, it is necessary to distinguish between DHEA and DHEAS. At baseline, the serum DHEAS levels were significantly higher (about 130%) in men than in women; this is typical. By contrast, there was no gender difference in the serum DHEA levels. After administration of DHEA, the serum levels of DHEAS rose rapidly in proportion to the dose. In men, both the 25-mg and 50-mg doses restored levels to the normal range for young adults. In women, the 50-mg dose induced peak levels of DHEAS, on day 8 of the test, just above those observed in young adults. The DHEA levels also showed significant increases in both sexes, to just above the normal values for young adults. At no time was there an accumulation of excess hormone of either form, in either sex. There was no mention of any side effects.

DHEA IS GENDER-SPECIFIC, AND SAFE 
Overall, the serum DHEA levels after DHEA administration at either dosage were higher in women than in men (but the serum DHEAS levels remained higher in men). Even allowing for the fact that the women were receiving more DHEA per unit of body weight, it appears that DHEA is metabolized differently in the two sexes (which comes as no surprise after all we've seen above). The results suggest that women might require smaller doses of DHEA in a long-term regimen than men would.

The authors' principal conclusion from this study was that a 50-mg dose of DHEA in healthy elderly men and women is a safe and potentially effective dose for further studies, and on this basis they selected 50 mg as the preferred dose for their larger study.3

DHEA'S ORIGIN AND DOSAGE 
The DHEA in high-quality supplement capsules is not obtained from human beings or primates, but from wild yams of the genus Dioscorea, found in abundance in the southern United States and Mexico. The yams contain a compound called diosgenin,which is converted to DHEA in the laboratory. Our bodies are unable to duplicate this chemical process, so certain products containing unprocessed extracts of yams and sold as "natural DHEA" or "DHEA precursor complexes" are worthless for their intended purpose. Caveat emptor.

Most DHEA formulations contain 25 or 50 mg of the hormone, a dose range that is considered to be safe and effective, especially in light of the new research cited in this article. Nevertheless, it is prudent to test one's levels, at the start of supplementation and as one proceeds. Some people may benefit just as much from smaller doses, and larger ones maybe required for some people. Testing can help this determination. For larger amounts, however, it is important to consult your healthcare professional before proceeding. Side effects are minor and uncommon, especially with low doses. The two reported most often are acne and unwanted facial hair in women. These can be eliminated by reducing the dosage or stopping altogether.

RESISTING OLD AGE WITH DHEA 
Those for whom supplementing with DHEA is appropriate may expect to realize some combination of benefits in the areas of energy, mood, and memory; libido; immune function; weight loss; resistance to diseases, including autoimmune diseases, heart disease, diabetes, osteoporosis, and perhaps even cancer. Last but not least, DHEA may confer a life-extension benefit: the ultimate bonus.

References

  1. Sahelian R. DHEA: A Practical Guide. Avery Publishing Group, Garden City Park, NY, 1996.
  2. Legrain S, Massien C, Lahlou N, Roger M, Debuire B, Diquet B, ChatellierG, Azizi M, Faucounau V, Porchet H, Forette F, Baulieu ÉÉ. Dehydroepiandrosterone replacement administration: pharmacokinetic and pharmacodynamic studies in healthy elderly subjects. J Clin Endocrinol Metab2000;85(9):3208-17.
  3. Baulieu ÉÉ, Thomas G, Legrain S, Lahlou N, Roger M,Debuire B, Faucounau V, Girard L, Hervy MP, Latour F, Leaud MC, Mokrane A, Pitti-Ferrandi H, Trivalle C, de Lacharrière O, Nouveau S, Rakoto-Arison B, Souberbielle JC, Raison J, Le Bouc Y, Raynaud A, Girerd X, Forette F. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue. Proc Natl Acad Sci 2000 Apr 11;97(8):4279-84.

* Actually, this study was designed as a necessary prelude to a much larger one that we reported on in detail in DHEA Can Help Keep Women in Love – Jun. 2000

WHAT THE BODY DOES WITH DHEA 
When a drug or nutrient is administered, it is important to know what level of that substance will show up in the blood or tissues. For starters, will it be a physiological dose or a pharmacological dose? The implications are often very different.

Anything we swallow must run the formidable chemical gauntlet of our digestive system - hydrochloric acid, bile, and a potent brew of digestive enzymes - just to make it to the intestinal wall that it must penetrate in order to be absorbed by the bloodstream. How well it fares in this complex physiological journey depends on many factors, including what foods we took it with and our age and state of health.

Most of the molecules that make it through the intestinal wall enter the portal vein, which conducts blood from the digestive organs, spleen, pancreas, and gall bladder to the liver. The liver thus gets "first crack" at our nutrients and decides, so to speak, whether or not it likes them in the form received. In the case of DHEA, it doesn't much like that form, so it attaches a sulfate group to about 90% of the molecules, making DHEA sulfate, or DHEAS (it also converts some of the DHEA to testosterone and estrogen). Thus, when one speaks of DHEA in the system, it is to be understood that it exists mainly in the form of DHEAS.

Whatever chemical processing the liver may impose on our nutrients, they wind up in our blood again, to be delivered, as needed, to the various organs and tissues of our body. This is where it is often vital to know just how much of whatever we intended to put in our bloodstream is actually there as such, because only then can we know for sure whether the dose is physiological or pharmacological.

ARE MEN LIKE MICE?

Although we're not overly fond of admitting it, rodents are much more like us, in terms of basic biochemistry and physiology (and behavior as well) than not. They have, to a high degree, the same genes, the same biochemical makeup, and the same metabolic processes that we do. This allows researchers - usually - to make reasonably confident predictions, from the pharmacological effects observed in them, about the probablepharmacological effects in us.

But not always. Aside from a few fairly obvious differences between rodents and us, it turns out that they have almost no DHEA (nor do any other animals except primates). They do have plenty of sex hormones, lord knows, but they get them via different biochemical pathways than we do. Therefore, studying the effects of DHEA in rodents is problematic, because what would be a physiological dose in us is a very large pharmacological dose (even on a weight-adjusted basis) in them. This makes it difficult to extrapolate their results to ourselves with much confidence.

Yet the fact is that most of our knowledge of DHEA's benefits comes from experiments on laboratory mice and rats, because testing them is so much easier, quicker, and more economical than testing humans. It is important to note two things, however: (1) the experience of both medical researchers and practicing physicians is that DHEA is effective in humans for a variety of conditions, and (2) there are human studies demonstrating the safety of DHEA, notably a new one discussed in this article.