Outline

• Introduction
• DHEA and Cancer
• The Anti-Obesity Factor
• DHEA and Glucose Metabolism
• DHEA and Appetite
• DHEA and Aging
• Enhancing Brain Function
• DHEA and Immune Function
• DHEA: The Buffering Steroid?
• Dosage
• Conclusion
• Regulatory Difficulties
• References
• Additional Information

I. Introduction
Dehydroepiandrosterone (pronounced dee-hi-dro-epp-ee-ann-dro-stehr-own), or DHEA as it is more often called, is a steroid hormone produced in the adrenal gland. It is the most abundant steroid in the bloodstream and is present at even higher levels in brain tissue. DHEA levels are known to drop precipitously with age, falling 90% from age 20 to age 90. DHEA is known to be a precursor to the numerous steroid sex hormones (including estrogen and testosterone) which serve well-known functions, but the specific biological role of DHEA itself is not so well understood. It is difficult for researchers to separate the effects of DHEA from those of the primary sex steroids into which it is metabolized. The apparent lack of any direct hormone action for DHEA has prompted the suggestion that it may serve the role of a “buffering hormone” which would alter the state-dependency of other steroid hormones. Although the specific mechanisms of action for DHEA are only partially understood, supplemental DHEA has been shown to have anti-aging, anti-obesity and anti-cancer influences. In addition, it is known to stabilize nerve-cell growth and is being tested in Alzheimer’s patients.
Our understanding of the specific mechanisms of DHEA in metabolism was advanced by the publication of The Biologic Role of Dehydroepiandrosterone (DHEA), edited by Mohammed Kalimi and William Regelson [1990]. This book presents 24 chapters from scientists around the world who are conducting DHEA research. The breadth of the work is impressive. As Drs. Regelson, Kalimi and Loria stated in their introductory remarks, “DHEA modulates diabetes, obesity, carcinogenesis, tumor growth, neurite outgrowth, virus and bacterial infection, stress, pregnancy, hypertension, collagen and skin integrity, fatigue, depression, memory and immune responses.”
The introductory chapter, by the editors and Dr. R. Loria, briefly reviews DHEA’s biochemistry, endocrinology, and potential clinical uses. The chapter contends that DHEA is perhaps the most significant endocrine biomarker known, and further postulates that all of the steroid’s effects may be explained by its action as a precursor hormone which provides “a host of steroid progeny with which to maintain the broad balance of host response related to species and individual survival.”

II. DHEA and Cancer
Early reports from England [Bulbrook, 1962, 1971] suggested that DHEA was abnormally low in women who developed breast cancer, even as much as nine years prior to the onset or diagnosis of the disease. Of the 5000 women followed in the study, 27 developed cancer. Most of the 27 had abnormally low levels of DHEA. If low DHEA levels contributed to breast cancer, might the opposite be true? Many years later, Dr. Arthur Schwartz of Temple University found that supplemental DHEA significantly protected cell cultures from the toxicity of carcinogens. Cell cultures usually respond to powerful carcinogens with mutations (changes in DNA), transformations (changes in cell appearance), and a high rate of cell death. But when Schwartz added DHEA along with the carcinogen, all three of these effects were significantly diminished.
Subsequent studies [Schwartz, 1979] identified powerful protective effects of supplemented DHEA for breast-cancer-prone mice. The results of the experiment were clear after eight months. The control animals were “developing cancer left and right” while the DHEA-augmented animals had no tumors. In two later studies with different strains of mice, Schwartz found 75% and 100% reductions in tumor incidence at eight months of age and 50% and 75% reductions at 15 months of age [Schwartz, 1981; 1984]. DHEA has demonstrated protective effects for cancers of the skin, lungs, bowel, breast and liver. According to Dr. Regelson, “Whenever it has been tested in a model of carcinogenesis and tumor induction, DHEA has preventative effects.” Although DHEA is now being tested in human cancer, it is still too early to know whether the successes achieved in animals will be realized in humans.

III. The Anti-Obesity Factor

At about the same time that Schwartz was investigating the anti-cancer properties of DHEA, Dr. Terrence T. Yen was studying the effect of DHEA on genetically obese mice. Although the DHEA-treated mice ate normally, they remained thin — and they lived longer than control mice. This “leanness” effect was also conspicuously noted by Dr. Schwartz. In another experiment, Dr. M. P. Cleary found that even middle-aged obese rats lost weight when fed DHEA-supplemented food. Diabetes, a typical complication of obesity, was also dramatically decreased.

IV. DHEA and Glucose Metabolism

Investigators have shown that DHEA inhibits glucose-6-phosphate dehydrogenase (G6PDH), an enzyme that breaks down glucose. There are two glucose-metabolizing pathways in the body: the catabolic, energy-yielding pathway, and the anabolic, biosynthetic pathway. G6PDH happens to be the first enzyme in the biosynthetic pathway, the one which results in the synthesis of fatty acids and ribose (the sugar used in making deoxyribonucleic acid, or DNA). In simple language, G6PDH turns glucose into fat.DHEA’s inhibition of G6PDH may redirect glucose from anabolic fat-production into catabolic energy metabolism, thus creating a leaner metabolism. This function of DHEA is well reviewed by Dr. Schwartz and colleagues in their chapter on “The Biological Significance of Dehydroepiandrosterone” in The Biologic Role of Dehydroepiandrosterone. They assert that DHEA-mediated reductions in ribose-5-phosphate activity may be centrally responsible for the anti-tumor promoting, anti-tumor initiating, and possibly the anti-atherogenic properties of DHEA. They also note that DHEA:
1. produces hepatomegaly (liver enlargement),
2. stimulates liver catalase activity (a protective antioxidant enzyme), and
3. causes proliferation of peroxisomes (cellular organelles which specialize in oxidative processing and the decomposition of hydrogen peroxide).
The absence of such influences with synthetic analogs of DHEA (e.g., 16-alpha-fluoro-5-androsten-17-one) prompts Schwartz and colleagues to recommend that such analogs be considered for clinical applications in humans. Toxicity factors remain to be assessed.

V. DHEA and Appetite

In other experiments, DHEA supplementation has resulted in increased, decreased and unchanged food consumption. Dr. Schwartz found that it is the level of dietary fat which influences food consumption. DHEA-treated rats on a high-fat diet ate less food than control rats, while those on a low-fat diet ate more.Since DHEA inhibits G6PDH activity and suppresses the body’s ability to synthesize fat from carbohydrate, dietary sources of fat become more important. This can affect changes in appetite. But despite possible increases in food intake, DHEA-treated animals consistently weighed less than control animals. In other words, increases in appetite, when indulged, did not negate the anti-obesity property of DHEA.

VI. DHEA and Aging

The body’s production of DHEA drops from about 30 mg per day at age 20 to less than 6 mg per day at age 80. According to Dr. Regelson of the Medical College of Virginia, DHEA is “one of the best biochemical bio-markers for chronologic age.” In some people, DHEA levels decline 95% during their lifetime — the largest decline of an important biochemical yet documented.
In animal studies, DHEA extends rodent lifespans up to 50%. The animals not only lived longer, they appeared younger. The graying, coarse-haired controls could easily be distinguished from the sleek, black-haired, DHEA-treated animals.
DHEA levels are directly related to mortality (the probability of dying) in humans. In a 12-year study of over 240 men aged 50 to 79 years, researchers found that DHEA levels were inversely correlated with mortality, both from heart disease and from all other causes. This finding suggests that DHEA level measurements can become a standard diagnostic predictor of disease, mortality and lifespan. Furthermore, if animal results hold true, supplemental DHEA may prevent disease, reduce mortality, and extend lifespan in humans.

VII. Enhancing Brain Function

DHEA may also be intimately involved in protecting brain neurons from senility-associated degenerative conditions, such as Alzheimer’s Disease. Not only do neuronal degenerative conditions occur most frequently when DHEA levels are lowest, but brain tissue contains many times more DHEA than is found in the bloodstream. One of the scientists at the forefront of this field of research is Dr. Eugene Roberts, who determined that very low concentrations of DHEA were found to “increase the number of neurons, their ability to establish contacts, and their differentiation” in cell cultures. He also found that DHEA enhanced long-term memory in mice undergoing avoidance training. It may play a similar role in human brain function.Drs. Roberts and Fitten report initial research on “serum steroid levels in two older men with Alzheimer’s Disease before, during and after oral administration of DHEA” in the book The Biologic Role of Dehydroepiandrosterone. Roberts’ and Fitten’s data are the best we’ve seen regarding acute and chronic changes in numerous hormone levels following various oral doses of DHEA. Because of the short peak duration of DHEA, they recommend that future studies or therapeutic trials use time-release capsules or transdermal patches to provide more uniform delivery of DHEA.
Levels of pregnenolone and 17-alpha-pregnenolone, the direct precursors to DHEA, were too low to be measured in the two patients discussed, but Roberts and Fitten present data from three other Alzheimer’s patients. Their data indicate that in all three patients, “control values for pregnenolone and 17-alpha-pregnenolone not only were below the mean averages for the population controls, they were lower than the lowest values.” In other words, the highest of the Alzheimer’s patients was lower than the lowest of the population controls. When administered 400 mg of DHEA, all three patients experienced decreased levels of 17-alpha-pregnenolone. Pregnenolone levels increased in two patients and fell in the third. In the two patients experiencing increased pregnenolone and decreased 17-alpha-pregnenolone in response to DHEA, levels of 17-alpha-pregnenolone rebounded strongly at 24 hours. Roberts and Fitten suggest that “a prolonged inhibition of 17-alpha hydroxylation occurred as a result of continued DHEA intake.”

VIII. DHEA and Immune Function

DHEA is known to enhance general immune response. Oral and subcutaneous DHEA has been observed to protect rodents against the lethality of RNA and DNA viruses, and lethal bacterial infections. Drs. Loria, Regelson and Padgett report in The Biologic Role of Dehydroepiandrosterone (DHEA) that a single subcutaneous dose of DHEA is considerably more effective in protecting against infection than oral dosing. Intraperitoneal [within the abdominal cavity] injections were completely ineffective.Dr. Loria and colleagues noted that subcutaneous dosing did not result in the typical weight loss observed with oral DHEA. DHEA has been reported to counteract the thymic involution [shrinking of the thymus gland] and immuno-suppression caused by corticosteroids. But the special role of skin tissues in the immune facilitating properties of DHEA suggests a different mechanism is involved. Cutaneous immune cells, such as Langerhans cells and keratinocytes, are believed to play a role in “immune surveillance” and “antigen presentation.” These cells may be a site of DHEA’s action. Subcutaneous injection of DHEA results in the “formation of a local deposit leading to a relatively prolonged exposure to the lymphoid system.” DHEA skin patches might provide a similar exposure.
The delay in protective effect of subcutaneous DHEA has prompted Loria and colleagues to postulate that a DHEA metabolite is involved in cutaneous immune enhancement. In their 1993 paper, Drs. Loria and Padgett advance androstenediol [5-androsten-3-beta-17-beta-diol] as the active metabolite, the production of which is predominantly localized in the skin and brain. They found that androstenediol was significantly more effective than DHEA (10,000 times more with coxsackievirus B4!).
Neither DHEA nor androstenediol have any direct (in vitro) antiviral activity. The amount of viral load in heart, spleen, pancreas, liver and blood tissues was unaffected by either DHEA or androstenediol administration. The effect of these steroids appears to be strictly mediated through stimulation of lymphocytes, lymphoid organs, and immune-modulating cytokines [immune hormones].

IX. DHEA: The Buffering Steroid?

DHEA may be unique among hormones for its lack of specificity for hormone receptor sites. Just as vitamin E has never been shown to have a specific metabolic role (it is only proven essential as a general antioxidant), DHEA may serve an equally general purpose. “DHEA is the first example of a buffer action for hormones that I know of,” states Dr. Regelson. “It is a broad-acting hormone that only demonstrates itself under a specific set of circumstances. In that way, it is comparable to a buffer against sudden changes in acidity or alkalinity. That is why when you get older, you’re much more vulnerable to the effects of stress. As DHEA declines with age, you are losing the buffer against stress-related hormones. It is the buffer action that [helps prevent] us from aging.” The decrease of DHEA with age may result in gradual decline of a system for suppressing enzyme systems responsible for creating the building blocks of new cells, such as lipids, nucleic acids (RNA and DNA), and sex steroids. The resulting rise in enzymatic activity in advanced age may be responsible for the proliferative events (e.g., cancer) and degenerative disease that become more frequent in advanced age. In this respect, DHEA might be best considered to be an anti-hormone, which may “de-excite” steroid-sensitive receptors that would otherwise lead to enhanced metabolic activity.X. Dosage

Exact dosages of DHEA for humans have not been clearly determined. Daily dosages vary from 5 to 10 mg to as much as 2000 mg, with 5, 10, 25 and 250 mg being the range for typical tablet and capsule sizes. DHEA is usually split into 2-4 daily doses, especially at the higher dosage levels. We recommend that dosage be adjusted to bring blood DHEA and DHEA-S measurements towards young-adult levels. These blood tests can be ordered by your physician. A base-line test is required before you start taking DHEA.XI. Conclusion
Because of its generally universal function in human metabolism, DHEA is being associated with numerous human maladies. For example, DHEA has been found to have a highly statistically significant correlation with vertebral bone density in postmenopausal women, suggesting that DHEA (and other weak androgens) may help protect against osteoporosis. This, and its low toxicity, may tend to give DHEA the same panacea stigma that the antioxidants vitamin E and C suffer.
For additional information on DHEA,

XII. Regulatory Difficulties

In Europe, DHEA is available as a drug in 5 and 10 mg doses. It is used primarily for the treatment of menopause. In the United States, DHEA must first be approved as a drug by the FDA before it can be marketed for medical purposes. Unfortunately, this is an adversarial process (the drug companies advocating for the drug and the FDA demanding proof of efficacy and safety) which takes up to 100 million dollars and a decade to accomplish. Without a patent to restrict competition, prices cannot be raised high enough to recover the investment in the approval process. DHEA is an unpatentable substance.XIII. References

1. Barrett-Connor E, Khaw KT and Yen SS. A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. New England Journal of Medicine 315(24): 1519-24, 11 December 1986.
2. Bulbrook RD, Hayward JL and Spicer CC. Abnormal excretion of urinary steroids by women with early breast cancer. Lancet 2: 1238-40, 1962.
3. Bulbrook RD, Hayward JL and Spicer CC. Relation between urinary androgen and corticoid excretion and subsequent breast cancer. Lancet 2: 395-98, 1971.
4. Chen TT, et al. Prevention of obesity in Avy/a mice by dehydroepiandrosterone. Lipids 12: 409-13, 1977.
5. Cleary MP and Fisk JF. Anti-obesity effect of two different levels of dehydroepiandrosterone in lean and obese middle-aged female Zucker rats. International Journal of Obesity 10(3): 193-204, 1986.
6. Coleman DL, Leiter EH and Applezweig N. Therapeutic effects of dehydroepiandrosterone metabolites in diabetes mutant mice (C57BL/KsJ-db/db). Endocrinology 115: 239-43, 1984.
7. Coleman DL, Leiter EH and Schweizer RW. Therapeutic effects of dehydroepiandrosterone (DHEA) in diabetic mice. Diabetes 31: 830-33, 1982.
8. Coleman DL, Schweizer RW and Leiter EH. Effect of genetic background on the therapeutic effects of dehydroepiandrosterone (DHEA) in diabetes-obesity mutants and in aged normal mice. Diabetes 33: 26-32, 1984.
9. de Peretti E and Forest MG. Pattern of plasma dehydroepiandrosterone sulfate levels in humans from birth to adulthood: Evidence for testicular production. J Clin Endocrinol Metab 47: 572-77, 1978.
10. Kahn, Carol. Beyond the Double Helix: DNA and the Quest for Longevity, Times Books, 1985, page 143. A thorough and highly readable “inside” account of DHEA research.
11. Loria RM, Regelson W and Padgett DA. Immune response facilitation and resistance to virus and bacterial infections with dehydroepiandrosterone (DHEA). In: The Biologic Role of Dehydroepiandrosterone (DHEA), Mohammed Kalimi and William Regelson [Eds], page 107-130, Walter de Gruyter, New York, 1990. ISBN 3-11-012243-X.
12. Loria RM and Padgett DA. Androstenediol regulates systemic resistance against lethal Infections in mice. Annals of NY Academy of Sciences 685: 293-95, 1993.
13. Nyce JW, Magee PN, Hard GC and Schwartz AG. Inhibition of 1,2-dimethylhydrazine-induced colon tumorigenesis in Balb/c mice by dehydroepiandrosterone. Carcinogenesis 5: 57-62, 1984.
14. Orentreich N, Brind JL, Rizer RL and Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 59: 551-55, 1984.
15. Pashko LL and Schwartz AG. Effect of food restriction, dehydroepiandrosterone, or obesity on the binding of 3H-7,12-dimethylbenz(alpha)anthracene to mouse skin DNA. J Gerontology 38: 8-12, 1983.
16. Schwartz AG. Inhibition of spontaneous breast cancer formation in female C3H(Avy/a) mice by long-term treatment with dehydroepiandrosterone. Cancer Research 39: 1129-32, 1979.
17. Schwartz AG, Hard GC, Pashko LL, Abou-Gharbia M and Swern D. Dehydroepiandrosterone: An antiobesity and anti-carcinogenic agent. Nutrition and Cancer 3: 46-53, 1981.
18. Schwartz AG, Nyce JW and Tannen RH. Inhibition of tumorigenesis and autoimmune development in mice by dehydroepiandrosterone. Mod Aging Res 6: 177-84, 1984.
19. Schwartz AG, Fairman DK and Pashko LL. The Biological Significance of Dehydroepiandrosterone. In: The Biologic Role of Dehydroepiandrosterone (DHEA), Mohammed Kalimi and William Regelson [Eds], Walter de Gruyter, New York, 1990.
20. Yen TT, Allan JA, Pearson DV, Acton JM and Greenberg MM. Prevention of obesity in Avy/a mice by dehydroepiandrosterone. Lipids 12: 409-13, 1977. by Ward Dean, M.D., and Steven Wm. Fowkes