What is all the fuss about DHEA? If this is a substance that can retard aging, reduce obesity, fight cancer, enhance immunity and improve lupus, then why has it not come to light and been used more actively? Thus we explored the history of this compound focusing especially on how it may effect lupus, as we learned more about the answer to this question and what the future use of it may be.

DHEA dehydroepiandrosterone-is a hormone produced by the adrenal gland. It is a steroid hormone that is weakly androgenic and distinct from another major adrenal hormone, cortisol. In humans, it is most abundant during youth, up to about age 25, and then declines after that.

One of the first papers addressing the role of DHEA in health and disease was published by Bulbrook in 1961. While tracking 5,000 women in England, he found that 27 who developed breast cancer showed low urinary levels of DHEA prior to the appearance of the cancer. Years later, this observation led a Temple University researcher, Arthur Schwartz, to test DHEA in cell cultures exposed to carcinogenic chemicals. The DHEA had a protective effect on these cell cultures. He then gave DHEA to a strain of female mice who usually developed breast cancer by the age of 16 months. Here too, DHEA had a protective effect on the development of cancer. About the same time, in the early 1970s, Dr. T. Yen at Eli Lily. noticed that a strain of mice genetically bred to be obese did not become as obese when given DHEA.

How about the effect of DHEA on immunity? The effectiveness of a vaccine depends upon our body's ability to generate a vigorous antibody response when the vaccine is given, which can then recur if we encounter the infection for which the vaccine was given, thus helping our immune defense. The ability to mount such a response to vaccination declines as we age. Dr. Raymond Daynes, of the University of Iowa, found that aged mice could generate an immune response to a vaccine similar to that of a young mouse when given DHEA. Dr. Barbara Araneo, also at the University of Utah, found that severely burned mice healed more quickly when given DHEA.

Similar observations regarding various aspects of DHEA's influence on health of experimental animals abound. One estimate I read was that there were more than 4,000 articles on DHEA, many of them biochemical and/or related to use in animals. The picture that emerges is that the way DHEA works is quite varied, ranging from its effect on G6PD, an enzyme involved in the formation of fat, to its effects on cytokines and other immunomodulatory molecules, effects on growth hormones, etc. The list is quite lengthy. Thus, its ability to influence so many aspects of health and disease is not far fetched, given how many bio-chemical processes it, influences.

So fine, it helps genetically unique laboratory animals, how about humans? Well done studies on the effects of DHEA in humans are sparse. Fortunately, there is some preliminary investigation about its effects on lupus in humans, thanks to the efforts of a research team at Stanford. The rationale for trying an androgenic compound in the treatment of lupus is not new. It has been known that lupus predominantly affects women, that it can flare during pregnancy, and appears to correlate with the androgen/estrogen ratio. Also, it is known that female NZB mice (a genetic strain that develops lupus), which develop more severe disease earlier than male mice. may show less severe and later-developing disease when treated with androgens. When treated with OHEA, the NZB mice had less severe nephritis. These observations led the Stanford researches, Ron van Vollenhoven, Edgar Engleman. and James McGuire, to study DHEA in 10 women with mild to moderate lupus. Using 200 mg per day of DHEA powder* for three to six months, the following observations were made. Eight out of ten patients thought that their sense of well being, fatigue. and/or other subjective aspects of their disease improved enough to warrant taking it an additional three months. At six months, these improvements were maintained. Although the measured serum levels of DHEA. DHEA sulfate and testosterone increased with treatment, there was no correlation between the changes in the serum levels and indices of the activity of lupus. Importantly. 8 out of 10 patients taking steroids (prednisone) at the beginning of the study were able to reduce their prednisone dose from 15 mg to 10 mg per day at month three and 6 of these were able to reduce the dose to 5 mg per day at month six. Thus, DHEA seemed to have a steroid-sparing effect. Three patients also were observed to have improvement in the amount of protein in their urine. The medicine was tolerated well: four patients developed mild acne and two mild male hair growth pattern: no other major side effects were noted. Two possible explanations for the beneficial effect of the medication were considered:
1) favorable subtle alteration of the androgen/estrogen ratio; 2) possibly a boosting effect on a cytokine IL-2 and/or a diminishment of IL-4, 5 and 6. These hypotheses have not yet been studied. These investigators then conducted a double-blind placebo-control led study of 30 patients that confirmed the modest benefits of DHEA.2

Based on the apparent beneficial effect of DHEA in these studies with lupus patients, the Stanford team is now leading the effort to study the effects of the conmpound in mild and severe lupus, to determine optimal dose, and to further compare the drug with placebo. Our clinic [Minor and James Medical] will be involved in these studies, beginning this summer. The upside of an individual participating in such a study will be the ability to potentially have pharmaceutical-grade DHEA, to be carefully observed, and to contribute to our understanding of lupus treatment. The downside will be the possibility of being on placebo. Other medications for the treatment of lupus will be permitted to be continued.

So why has testosterone not been effectively used to treat lupus, since it is an even stronger androgenic steroid? In one study, nortestosterone (similar to testosterone) did not lead to improvement of lupus in female patients and led
to worsening in males. Could nortestosterone's inhibition of pituitary follicle-stimulating hormone luteinizing hormone be responsible or other factors? DHEA would not cause this feedback inhibition.

If DHEA has such interesting and potentially beneficial effects, with so few side effects, why hasn't there been more study in humans to prove its benefit compared to placebo? One major practical point is cost to do these studies. To do the quality and quantity of study required by the FDA Food and Drug Ad-ministration, in order for a drug to be approved for a particular therapeutic indication, requires mega bucks to run all the kinds of efficacy and safety studies required. In order to mount this effort. a company needs some assurance of return on its research money with a drug that not only will be successful, but can be patented. Yet here we have a compound that has been around a long time. made by various manufacturers, and is thus not patentable. In addition, its benefits may in most people be subtle not "blockbuster" dramatic in its benefits. Thus, it is primarily through the efforts of an investigative team like the one at Stanford, along with a well-intentioned company. that can bring this type of compound to more general clinical use. As it is studied more. especially in the harsher light of placebo-control trials, wherein we know that even placebo can lead to improvement in up to 30% of patients, we may discover it is only slightly helpful in the majority of patients or its benefit may not be sustained. However, if side effects are few, some symptom reduction allows reduction of prednisone or other toxic medication use, and it's not too costly, then it may be a worthwhile addition to our therapeutic armamentarium.

Can DHEA be obtained now? Yes. DHEA has been available in various forms for some time. In weak strength and mixed with other substances, it has been available in health food stores and pharmacies. It can be prescribed in the form of sublingual drops or capsules, both locally and by mail order. The comparable strength and purity of these forms may not be known. The pharmacists that I know who are familiar with this compound are cautious and concerned about patient welfare, so I am not too concerned that there is negligent pharmaceutical practice going on.

Who may benefit from DHEA? As you can see, we are still in the process of learning about that, so the answer is not fully in. More will be known as we interpret the results of multi-center placebo-controlled studies. There are several ways of measuring DHEA in the body, both by means of blood tests as
well as measurement of saliva. Whether a "low" level will predict response to the drug is still unknown.

How about the usefulness of DHEA for similar or potentially associated diseases such as Sjögren's, undifferentiated autoimmune syndrome and fibromyalgia? This appears to be open territory for study. So while the effects of DHEA on aging, cancer, immunity, AIDS, etc. are being studied by other researchers, we rheumatologists should extend the inquiry within the realm of rheumatic diseases.

In conclusion, I feel it is fair to say that there is some encouraging preliminary information about the potential usefulness of DHEA as an adjunct, along with other medicines, to treat the symptoms of lupus. How useful? For what symptoms? For how long? How safe? The full answer to these questions awaits the results of placebo-control trials that are either now or soon to be under way. Stay tuned. In the meantime, if you have questions, you may either ask your rheumatologist or direct your questions to me in my office or through the Lupus Society.
*DHEA powder for this study was obtained from Sigma in St. Louis. DHEA being used for current studies is being made by Diosynth/Genelabs. *