Reprinted with written permission from Alternative Medicine Review, Vol. 1, #2, 1996, pp. 60-69, Thorne Research, Inc. Dehydroepiandrosterone: Biological Effects and Clinical Significance Alan R. Gaby, M.D. Abstract Dehydroepiandrosterone (DHEA) is a steroid hormone secreted in greater quan- tity by the adrenal glands than any other adrenal steroid. For many years, scientists assumed that DHEA merely functioned as a reservoir upon which the body could draw to produce other hormones, such as estrogen and testosterone. However, the recent identification of DHEA receptors in the liver, kidney and testes of rats strongly suggests that DHEA may have specific physiologic actions of its own. Circulating levels of DHEA decline progressively with age; this age-related decline does not occur with any of the other adrenal steroids. Epidemiologic evidence indicates that higher DHEA levels are associated with increased longevity and prevention of heart disease and cancer, sug- gesting that some of the manifestations of aging may be caused by DHEA deficiency. Animal and laboratory data indicate that administration of DHEA may prevent obesity, diabetes, cancer (breast, colon and liver), and heart disease; enhance the functioning of the immune system; and prolong life. In humans, evidence exists that DHEA might be associated with autoimmune diseases such as lupus, rheumatoid arthritis and mul- tiple sclerosis; chronic fatigue syndrome; acquired immunodeficiency syndrome (AIDS); allergic disorders; osteoporosis; and Alzheimer’s disease. Although administration of DHEA appears to be safe, its long-term effects are unknown, and it is possible that adverse consequences will become evident with chronic use. It is therefore important that this hormone be used with care and that practitioners err on the side of caution when contemplating DHEA supplementation. (Alt Med Rev 1996;1(2):60-69.) Introduction Dehydroepiandrosterone (DHEA) (see Figure 1) is a steroid hormone secreted by the adrenal glands and to a lesser extent by the testes and ovaries. First identified in 1934, DHEA was subsequently shown to be produced in greater quantity than any other adrenal steroid. However, although circulating levels of DHEA and its ester DHEA-sulfate (DHEA-S) are 20 times higher than those of any other adrenal steroid, the function of DHEA in the body was, until recently, unknown. Since DHEA can be converted into other hormones, including estro- gen and testosterone, scientists assumed that DHEA is merely a “buffer hormone;” i.e., a reser- voir upon which the body can draw to produce the other hormones (see Figure 2). However, the recent identification of DHEA receptors in the liver, kidney and testes of rats strongly suggests that DHEA has specific physiologic actions of its own.1 Page 60 Alternative Medicine Review N Volume 1, Number 2 N 1996 Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Dehydroepiandrosterone FIGURE 1. Structure of DHEA. During the past O Second, numer- several years, there has CH 3 ous animal studies have been a great deal of in- shown that administra- terest in DHEA as a tion of DHEA prevents possible anti-aging hor- CH 3 H obesity, diabetes, can- mone and as a potential cer, and heart disease; treatment for a wide ar- enhances the function- ray of medical condi- H H ing of the immune sys- tions. This interest has HO tem; and prolongs been sparked by two life.2 Since most of different lines of evi- these studies were dence. First, circulating done in rodents, which levels of DHEA decline progressively with have little circulating DHEA, it is not clear age; the levels in 70-year-old individuals are whether the results have relevance to human only about 20% as high as those in young health. However, a growing body of human adults. This age-related decline does not oc- research, combined with the intriguing obser- cur with any of the other adrenal steroids. Fur- vations of innovative clinicians, suggests that thermore, epidemiologic evidence suggests DHEA may indeed have value in the treatment that higher DHEA levels are associated with of various medical conditions. If this hormone increased longevity and prevention of heart can be convincingly shown to retard the aging disease and cancer. It has therefore been sug- process and to fight certain diseases, then gested that some of the manifestations of ag- DHEA therapy will be recognized as a major ing may be caused by DHEA deficiency. breakthrough in clinical medicine. DHEA as an “Anti-aging” Cholesterol Cholesteryl Sulfate Hormone Preliminary results in mice suggest that DHEA might retard the Pregnenolone aging process. Animals treated with this hormone looked younger, had Dehydro- Dehydro- glossier coats, and less gray hair epiandrosterone 3 epiandrosterone sulfate than control animals. Testosterone Androstenedione In a recent study, 30 individu- als between the ages of 40 and 70 years received 50 mg/day of DHEA Estrone or a placebo, each for 3 months, in double-blind crossover fashion. During DHEA treatment, a remark- Estradiol-17b Estriol able increase in physical and psy- chological well-being was reported FIGURE 2. Biosynthetic Pathways of DHEA and its Metabolites. by 67% of the men and 84% of the Alternative Medicine Review N Volume 1, Number 2 N 1996 Page 61 Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission women. There was no change in libido and no lines can be developed regarding DHEA side effects were seen.4 therapy and cancer. The observation that some postmenopausal women with breast cancer In my experience, elderly patients who have elevated DHEA levels, and the fact that suffer from weakness, muscle wasting, tremu- DHEA is converted in part to estrogen and tes- lousness, fatigue, depression, declining tosterone should be cause for concern. It is memory, and other signs of aging frequently not known whether the possible anti-cancer have serum DHEA-S levels near or below the effects of DHEA might be stronger than the lower limit of normal. Treatment with DHEA prostate cancer-promoting effects of additional (usually 5-10 mg/day for women and 10-20 testosterone or the breast cancer-promoting ef- mg/day for men) often results in improved fects of additional estrogen. Until those ques- mood, energy, memory, appetite, and skin tions can be answered, DHEA therapy should color, sometimes after as little as two weeks. be approached with caution in patients who are With continued treatment, the benefits may be- at risk for developing hormone-dependent can- come even more pronounced and muscle wast- cers. ing may be partially reversed. Effects on Immune Function Cancer Prevention DHEA exerts a number of different Administration of DHEA inhibited effects on the immune system. Some of these tumor formation in a strain of mice that effects appear to result from the anti-gluco- develops spontaneous breast cancer.5 DHEA corticoid actions of DHEA. For example, in also has been shown to prevent chemically- mice DHEA antagonized the suppressive ef- induced colon6 and liver7 cancers, as well as fects of dexamethasone on lymphocyte pro- skin papillomas in mice.8 liferation12 and prevented glucocorticoid-in- duced thymic involution.13 Administration of Premenopausal women with breast DHEA also has been shown to preserve im- cancer had significantly lower plasma levels mune competence in burned mice,14 an effect of DHEA than age-matched controls without that extends beyond its anti-glucocorticoid breast cancer, whereas postmenopausal action.15 Administration of DHEA also pro- women with breast cancer had significantly tected against acute lethal infections with higher DHEA levels than age-matched con- coxsackie virus B4 and herpes simplex type 2 trols.9 In another study, women with DHEA encephalitis in mice. DHEA appeared to act levels in the highest tertile were 60% less likely by preventing the suppression of immune to develop breast cancer than were women in competence caused by the viral infections.16 the lowest tertile.10 In a prospective case-con- trol study, serum DHEA and DHEA-S levels DHEA has also been shown to influ- were significantly lower in individuals who ence immune function in humans. In a double- subsequently developed bladder cancer than blind study, administration of 50 mg/day of in those who did not.11 DHEA to postmenopausal women (mean age, 56.1 years) produced a two-fold increase in These findings suggest that DHEA has natural killer cell activity and a 6% decrease anti-cancer activity and that low DHEA lev- in the proportion of helper T cells.17 While els might be a risk factor for cancer. However, the increase in natural killer cell activity might additional research must be done before guide- be expected to enhance immune surveillance Page 62 Alternative Medicine Review N Volume 1, Number 2 N 1996 Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Dehydroepiandrosterone against cancer and viral infections, the decline Administration of relatively large in helper T cells could have adverse conse- doses of DHEA has also been reported to in- quences. On the other hand, since DHEA is crease stamina and improve the sense of well- known to mediate T cell responses,18 the de- being in patients with multiple sclerosis.21 cline in helper T cells merely could be a re- flection of enhanced T cell function. Although During the past five years a number of the implications of these changes in immune practitioners have been prescribing DHEA for function are not entirely clear, it should be patients with autoimmune disease. Pre-treat- noted that 50 mg/day of DHEA has been ment plasma levels of DHEA or DHEA-S are shown to produce supraphysiologic serum lev- usually below normal in patients receiving els in postmenopausal women.19 Lower doses prednisone or related drugs, because these may therefore be more appropriate and might medications cause adrenal suppression.