Researchers Ponder The Benefits Of DHEA On Many Fronts

Sidebar: DHEA - More Information Snake oil or magic bullet? Dehydroepiandrosterone (DHEA), a biochemical precursor to the sex hormones androgen and estrogen, has been touted in the last few years as the next cure-all for various ailments associated with aging. Human epidemiological and pilot clinical studies suggest that elevated levels of DHEA in the blood may be beneficial in preventing heart disease, improving immune function and well-being in the elderly, and combating depression. The hormone may also be helpful in treating systemic lupus erythematosus. Numerous animal studies have shown that DHEA may prevent obesity, diabetes, cancer, and heart disease, as well as enhance the immune system and expand life span. With passage in 1994 of the Dietary Supplement Health and Education Act, DHEA can now be sold as an over-the-counter nutritional supplement, so long as labels don't make any unsubstantiated health claims. But that isn't stopping a proliferation of advertisements from touting the benefits of DHEA as a dietary supplement. CONTENTIOUS SUBJECT: "There's much confusion in the field right now because of conflicting information and hype," says Arthur Schwartz. "There's much confusion in the field right now because of conflicting information and hype," observes Arthur Schwartz, a professor of microbiology at the Fels Institute for Cancer Research and Molecular Biology in the Temple University School of Medicine. Schwartz, a pioneer in the DHEA field, has been working on DHEA and cancer prevention for the last two decades. DHEA and research surrounding its biochemical activity and effects has captured the attention of scientists and the public for some time, notes neuroendocrinologist Caleb Finch, the Arco and William Kieschnick Chairman in the Neurobiology of Aging at the University of Southern California (USC). "It's one of the most dramatic hormonal changes during aging that's been described in humans." DHEA and DHEAS, the sulfated form, are made by the adrenal cortex, an endocrine organ near the kidney. The hormone is present in high levels in developing fetuses but is almost undetectable at birth. DHEA levels then rise, spiking at puberty, and reach their peak in the 20s and 30s. After that, DHEA concentrations decrease about 2 percent per year until death. This distinctive pattern has been identified only in primates and a few other non-primate species. "It's a fascinating question as to why the body's system was designed to have that endocrine factor decrease so strikingly during aging," comments Finch, who is an avid observer of the unfolding DHEA story. Finch and his colleagues study the role of estrogen in Alzheimer's and vascular disease. MOOD AND MEMORY: Researchers like Louann Brizendine have been eagerly pursuing the neurobiology of DHEA. Because DHEA is a public-domain compound-a molecule that is a natural body hormone and therefore can't be patented-not many companies are going to spend what it takes to research and market it, maintains Louann Brizendine, an associate professor of neuropsychiatry at the University of California, San Francisco. "The two main options are government or private funding. Because it's gotten into the health-food market, scientists at the National Institutes of Health think this is snake oil," and research in this area therefore hasn't been adequately funded, she notes. Some researchers view this as a problem. "Responsibility [for DHEA research] should exist with the NIH when you have drugs or hormones that are non-patentable and not going to go through the private sector," asserts William Regelson, a professor of medicine at the Medical College of Virginia. "The federal government has to be the one [to take the lead] to perform clinical trials to give it validity." RESEARCH RESPONSIBILITY: The federal government has to take the lead in clinical trials of DHEA, asserts William Regelson. The National Institute on Aging is one NIH institute that funds DHEA research. In late March, NIA's geriatrics section issued a request for proposals. "This invites research to answer a whole litany of questions, some of which can be done in humans, some of which in animals," explains Richard Sprott, the institute's associate director. "What NIA is trying to do is to foster good, peer-reviewed experiments to understand basic pathology of substances like DHEA. . . . That will be followed by appropriate clinical trials, but first we need some basic data." Many researchers agree that it's difficult to disentangle research on aging and the hype associated with DHEA as a fountain-of-youth dietary supplement. "Substances like DHEA-when being touted as anti-aging substances-rest on an underlying assumption: If you look at most of our hormone systems, they gradually decline over our life span," says Sprott. "That's correlated with the gradual decline of most of our organ systems and our functional abilities. So the next assumption is that one must cause the other, and further, if we could boost these hormones back to their youthful levels, that would be a good thing. Both of those assumptions are unproven." 'LITANY OF QUESTIONS': Richard Sprott notes that a recent NIA request for proposals seeks ideas for understanding basic DHEA biology. Raymond Daynes, a professor of pathology in the University of Utah School of Medicine, contends that he didn't "wander into the DHEA world because I wanted to figure out a way to immortality." He attributes his entry into the field to his studies on the effects of ultraviolet radiation on the immune system of mice. He started to experiment with improving the immune system in aging mice by feeding them low daily doses of DHEA. THROUGH THE BACK DOOR: Raymond Daynes attributes his entry into the DHEA field to his work in immunology, not aging. "The intensity of their immune response was every bit as good as a younger animal's," he recalls. "This piqued our interest even more. The one aspect that was most telling is that we observed that interleukin 6, an inflammatory cytokine, becomes dysregulated in old age in humans and mice." Daynes and colleagues describe this work in three seminal papers: R.A. Daynes et al., Journal of Immunology, 150:5219-30, 1993; S.E. Wiedmeier et al., J. Immunol., 152:3417-26, 1994; and N.F.L. Spencer et al., Annals of the New York Academy of Sciences, 774:200-16, 1995. What's more, the number of diseases related to aging and the dysregulation in the expression of a number of these inflammatory cytokines is "enormous," he says. Daynes's group is now concentrating on the role of DHEA in the function of the peroxisome, a cellular organelle that contains enzymes for the production and decomposition of a number of molecules. The transcription of these enzymes is controlled by a receptor system called peroxisome proliferator-activated receptors (PPAR). DHEA is an activator of one type of these receptors-PPARa. "The fact that DHEA is a peroxisome profilerator captivated me because activity in this organelle goes down with old age," he recalls. Daynes's team has recently demonstrated that NF-kB, a major transcriptional regulator of cytokines that are aberrantly expressed in many diseases associated with aging, exists in a continuously active state in the lymph organs of old mice. Treating the mice with antioxidants or agents like DHEA that activate PPARa corrected the abnormal NF-kB activity and eliminated the dysregulated expression of cytokines and other genes controlled by NF-kB. "I'm not saying DHEA is the only substance that is going to be helpful," remarks Daynes. He surmises that other substances might be able to change the regulation of NF-kB, such as omega-three fatty acids and vitamin E. MANY MODELS: Jeffrey Jacob notes that Aeson Therapeutics has performed preclinical trials in mouse models of colon, skin, breast, and prostate cancer. Another age-related area of DHEA research encompasses understanding its role in memory and mood in healthy people as well as those with ailments associated with depression and Alzheimer's disease (AD). Spurred by a growing number of studies since the early 1990s on the positive effect of DHEA on trial participants' mood and sense of well-being (for example, A.J. Morales et al., Journal of Clinical Endocrinology and Metabolism, 71:696-704, 1994), researchers like UC-San Francisco's Brizendine have been avidly pursuing the neurobiology of DHEA for the last couple of years. Brizendine and colleagues recently published the results of a pilot study on the possible role of DHEA in fighting depression (O.M. Wolkowitz et al., Biological Psychiatry, 41:311-8, 1997). For four weeks, six middle-aged to elderly patients with major depression and low plasma levels of DHEA were given enough of the hormone to raise blood levels to that of younger, healthy individuals. Improvements in ratings of mood and memory performance increased with plasma levels of DHEA and DHEAS. "This was a small pilot study with six participants, so we're cautious about interpreting results," she remarks. This preliminary investigation has led the scientists to pursue placebo-controlled studies to assess the action of DHEA on memory and mood. For example, in the area of AD, Brizendine is involved with a multicenter, five-year study, now in its third year. This trial, which is funded by Neurocrine Biosciences Inc., a biotech firm in San Diego, is investigating the hypothesis that DHEA might slow the collapse of mental functioning in AD patients. Brizendine is conducting another five-year study that will examine the effects of DHEA on memory and mood in healthy people. "At this point, we're still enrolling people," she says. In this placebo-controlled, double-blind study, Brizendine and colleagues will be looking at men and women aged 56 to 75, measuring their levels of DHEA and relating that to memory, energy level, and mood. Investigations in DHEA's role in cancer prevention really took off in the late 1970s when Temple's Schwartz reported that when mice prone to contracting breast cancer were given DHEA throughout their life span, the incidence of cancer in the rodents decreased significantly (A.G. Schwartz, Cancer Research, 39:1129-32, 1979). He is now working in collaboration with the National Cancer Institute and Aeson Therapeutics Inc., a Tucson, Ariz.-based biotech firm, on Phase I and upcoming Phase II trials on a fluorinated form of DHEA called fluasterone. This form doesn't show the same testosterone-producing effects as regular DHEA, which is considered a benefit for any potential therapeutic uses. FOR MORE INFORMATION: Endocrine Society 4350 East West Highway Suite 500 Bethesda, Md. 20814-4410 Tel: (301) 941-0200 Fax: (301) 941-0259 E-mail: endostaff@endo-society.org http://www.endo-society.org 8,000 members Executive director: Scott Hunt President: P. Michael Conn Relevant journal: Journal of Clinical Endocrinology and Metabolism National Institute on Aging fact sheet (includes section on DHEA): http://www.nih.gov/nia/ The following references provide reviews of basic and clinical research on DHEA: F.L. Bellino, R.A. Daynes, P.J. Hornsby, D.H. Lavrin, J.E. Nestler, eds., "Dehydroepiandrosterone (DHEA) and Aging," Annals of the New York Academy of Sciences, Vol. 774, 1995. M. Kalimi, W. Regelson, eds., The Biologic Role of Dehydroepiandrosterone (DHEA). New York, Walter De Gruyter, 1990. W. Regelson, C. Coleman, The Super-Hormone Promise. New York, Simon and Schuster, 1996. A.A. Skolnick, "Scientific verdict still out on DHEA," JAMA-Journal of the American Medical Association, 276:1365-7, 1996. Jeffrey Jacob, chairman of Aeson Therapeutics, says that his company and Schwartz have performed preclinical trials in mouse models of colon, skin, breast, and prostate cancer over the last year and a half. "We also have animal data for lupus, multiple sclerosis, and Type II diabetes that show that our compound is very effective. We went into the clinic in late January." The first two safety studies in the cancer clinical trials are just finishing up, notes Jacob. These are performed in healthy people to look for safety and tolerance in humans, toxicity in blood levels, and androgen markers, because fluasterone isn't converted into testosterone and other sex hormones. Phase II trials in breast cancer prevention with the National Cancer Institute are planned for this summer, he reports. Fluasterone, which isn't a public-domain compound like natural forms of the hormone, is more attractive to private firms. "It's a proprietary form of DHEA," Jacobs explains. "We have numerous patent applications on fluasterone throughout the world. We expect the patents in the United States to be issued sometime this year." VERDICT STILL OUT: "Research is still a long way away from convincing me of DHEA's benefit as a daily supplement," remarks Stephen Hursting. Stephen Hursting, an assistant professor of epidemiology and carcinogenesis at the M.D. Anderson Cancer Center in Houston who also works on DHEA's role in cancer prevention, finds the fluasterone research some of the most promising so far in the field of DHEA and cancer. Within the past year, Hursting and colleagues have published three studies on DHEA and mouse lymphomas. In 1995, Hursting conducted a panel study (S. Hursting et al., Cancer Research, 55:3949-53, 1995) and found that DHEA "was by far and away the most effective. It particularly shut down the lymphoma development in p53 knockout mice." This year, Hursting and colleagues also found that the fluorinated form of DHEA delays tumor development (S. Perkins, S. Hursting et al., Carcinogenesis, 18:101-6, 1997, in press) "In my view, it is the more promising agent," he comments. "It doesn't have the androgenic or estrogenic activity, and that's very appealing." REDUCING DEPENDENCE: One lupus Phase III trial asks whether a patient’s use of prednisone might be pared down, reports Kenneth Schwartz. In another study that is due to be published soon, Hursting and Ellen Richie, an immunologist also at M.D. Anderson, are delving into the mechanism of DHEA in retarding tumor growth (T. Wang et al., Cancer Letter, in press). This paper will show the apoptotic effect of DHEA on tumors. "My [jury] is still out as far as DHEA as a chemopreventative is concerned because of its apoptotic and androgenic capabilities," says Hursting. "Research is still a long way away from convincing me of its benefit as a daily supplement." Many lines of evidence have suggested a role for sex steroids in the pathogenesis of systemic lupus erythematosus-such as flare-ups of the disease during pregnancy. Mouse studies in the mid-1980s also demonstrated that DHEA improved chronic kidney inflammation in mice with a lupus-like disease. This work prompted Ronald Van Vollenhoven, a rheumatologist at Stanford University School of Medicine, to study the role of DHEA in treating women with lupus. In 1994, Van Vollenhoven and colleagues first published results from a small-scale, open-label (no placebo control) trial with DHEA and women suffering from mild to moderate lupus (R.F. Van Vollenhoven et al., Arthritis and Rheumatism, 37:1305-10, 1994). The findings of that study pointed to a possible benefit and led to a second trial. In this double-blind, placebo-controlled study, participants receiving DHEA reported less disease activity and decreased their prednisone dosage (R.F. Van Vollenhoven et al., Arthritis and Rheumatism, 38:1826-31, 1995). Lupus flares-a suite of symptoms including fatigue, rashes, and depression-occurred more frequently in the placebo group. Now Van Vollenhoven is one of the principal investigators in two ongoing DHEA-lupus Phase III trials with Genelabs Technologies Inc., a biotech firm in Redwood City, Calif. "The first trial asks whether DHEA can reduce a patient's dependence on prednisone," notes Genelabs' senior medical director, Kenneth Schwartz. "We expect to announce the findings from the first study sometime before the end of the second quarter. The second trial will determine whether DHEA can improve clinical outcome or disease symptoms in lupus patients. About 75 percent of the patients have been enrolled for this study, with a target of about 300. We'll be tracking each patient for one year." USC's Finch believes that DHEA research will continue to be a long and interesting story. "I think where it goes from here is completely unpredictable," he says. "It's too soon to tell. Most human studies are still under way, and preliminary data are only now being worked up. It's not the fountain of youth, but it's an interesting, intriguing set of observations that collectively make one take it quite seriously, although I'm not about to bet the farm on it."

Researchers Ponder The Benefits Of DHEA On Many Fronts

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