By Dónal P. O’Mathúna, PhD
Systemic lupus erythematosus (SLE) is a chronic, inflammatory, autoimmune disease of connective tissue characterized by injury to many organs, especially the skin, joints, kidneys, nervous system, and mucous membranes. The American College of Rheumatology has developed, updated, and revised criteria for classifying SLE.1 Up to 10 times as many women as men are affected by the disease. Clinical manifestations of SLE are very diverse due to its widespread impact. Common symptoms include fever, joint pain, a characteristic butterfly rash, pleural effusion, and nephritis. Patients with SLE usually go through periods of remission and exacerbation, referred to as flares. SLE frequently leads to glomerulonephritis, cardiovascular diseases, pulmonary diseases, and gastrointestinal disturbances. Patients have high levels of various autoantibodies, especially those directed against cell nucleus molecules.
Treatment for the underlying disease is not available. Patients are typically instructed to avoid exposure to sunlight and ultraviolet radiation. Active disease and flares are treated with topical steroids, salicylates, systemic corticosteroids, and immunosuppressive agents. Given the adverse effects associated with these medications, agents with better side effect profiles are actively being sought. One that has generated much interest is the adrenal hormone, dehydroepiandrosterone (DHEA).
DHEA is a steroid hormone, closely related to testosterone and estrogen. DHEA is converted endogenously into its sulfate ester (DHEAS), the predominant form in which it circulates.2 DHEA and DHEAS are metabolically interconvertible and therefore their endogenous levels follow the same pattern.2 DHEA levels rise in humans, reaching a peak in their mid-20s, and then fall over the rest of their lives. This has led to unsubstantiated claims that DHEA supplementation could be the "elixir of youth."3 The precise role played by DHEA in normal metabolism is not known, except that it affects many body systems.4
Mechanism of Action
Use of DHEA to treat SLE has been explored because of the female preponderance of SLE, low circulating levels of DHEA and DHEAS in SLE, the immunomodulatory effects of DHEA, and the beneficial effects of DHEA when given to mice with SLE.4 In SLE, serum levels of adrenal androgens are lower than normal.4 Systemic inflammation leads to a shift in hormone secretion away from adrenal androgens to maintain cortisol levels. Glucocorticoids are administered to help maintain cortisol levels. Detailed studies with 72 patients revealed that those with SLE had severely reduced serum levels of DHEA and DHEAS, probably due to changes in the enzymes involved in adrenal steroidogenesis.5
An early study involved 10 patients with SLE given 200 mg/d DHEA.6 After 3-6 months of treatment, improvements were seen in patients’ symptom reports using the SLE Disease Activity Index (SLEDAI), physicians’ assessments, and need for corticosteroid use. In a double-blind, randomized controlled trial (RCT), 28 women with SLE received either DHEA (200 mg/d) or placebo. Patient SLEDAI scores, patients’ and physicians’ overall assessments, and corticosteroid use all improved significantly over the three months of the study (P = 0.022). Those taking placebo had more SLE flares (P = 0.053). Another open study found statistically significant improvements in these same outcomes, compared to baseline, when 50 patients took DHEA (50-200 mg/d) for six or 12 months.8
The aforementioned studies enrolled patients with mild-to-moderate SLE. Patients with severe SLE were enrolled in one study adding DHEA to conventional treatment with high-dose corticosteroids, with or without immunosuppressant agents.9 Responders were defined as those whose major SLE manifestation was stabilized after six months. The study authors randomized 21 patients to either placebo or 200 mg/d DHEA. No statistically significant differences were found between the two groups of subjects. However, the two study groups were found to have statistically significant differences at baseline in both the severity of SLE symptoms (P < 0.05) and types of other conditions. Those randomized to the DHEA group had greater disease activity and more instances of nephritis. These baseline differences may limit the generalizability of these results, and reflect a difficulty inherent to the study of diseases manifesting a variety of symptoms.10
The first relatively large RCT assigned 120 subjects to either DHEA (200 mg/d) or placebo.4 The subjects were all adult Chinese women with mild-to-moderate SLE who also were taking standard SLE medication (glucocorticoids and immunosuppressants). No significant differences were found in disease activity scores using two measures to compare baseline scores with those at the end of the six-month study. However, subjects taking DHEA had significantly fewer serious SLE disease flares and went longer before experiencing flares (P = 0.044). Patients’ global assessment scores were significantly improved (P = 0.005), but not physicians’ evaluations. DHEA was well-tolerated, although expected increases in serum testosterone levels and incidence of acne did occur.
A larger RCT examined the hypothesis that DHEA could allow corticosteroid-dependent women (taking 10-30 mg/d prednisone) to reduce their dose without increasing SLE activity.11 The 191 subjects were randomized to receive either placebo, 100 mg/d DHEA, or 200 mg/d DHEA. Prednisone doses were reduced at monthly intervals by predetermined increments if patients’ SLEDAI scores were stable or improved. Successful responders were those who achieved a prednisone dose of £ 7.5 mg/d within seven months. The study was continued to nine months if the dose was still being successfully reduced but subjects had not yet reached or become stabilized at £ 7.5 mg/d. Among all subjects, the higher DHEA dose demonstrated a non-significant trend toward more responders than the lower dose or placebo (55%, 44%, 41%, respectively). Prior to unblinding, subjects were divided into those with active (SLEDAI score > 2) or inactive disease (SLEDAI score £ 2). Among those with active SLE, significantly greater numbers of responders were found among those taking 200 mg/d DHEA compared to 100 mg/d DHEA or placebo (51%, 38%, 29%, respectively; P = 0.031). Among subgroups, as the baseline SLEDAI score increased, the proportion of responders increased. The researchers concluded that in future DHEA trials only those with active SLE should be enrolled.
Patients taking DHEA have dose-related increases in serum DHEAS and testosterone levels. Use of DHEA, therefore, can lead to androgenic effects. In one study, 41% of corticosteroid-dependent patients receiving DHEA (100 or 200 mg/d) experienced an increased incidence of mild acne compared to 19% of those taking placebo (P < 0.05).11 Hirsutism and menstrual abnormalities also increased, but were not significantly different from those in the placebo group. Abdominal discomfort, including stomach cramping and pain, is commonly reported, but usually is transient and relieved by H2-receptor antagonists. No drug interactions have been reported with DHEA.
Epidemiological studies have noted a positive correlation between serum DHEA levels and incidence of breast cancer in postmenopausal, but not premenopausal, women.12 This correlation needs to be more fully researched, but is of particular concern for obese postmenopausal women.
DHEA is most commonly available as 50 mg capsules, with 200 mg usually taken in the morning. DHEA also is known by its United States Adopted Names Council designation, prasterone, and by its Genelabs formulation, GL701.11 Concern has been raised regarding the quality of DHEA products available on the U.S. market because of its regulatory status. The FDA categorized DHEA as an unapproved drug in 1985, making it available only by prescription. The 1994 Dietary Supplement Health and Education Act reclassified it as a dietary supplement, making it readily available over the counter. A 1998 study found commercial products containing 0-150% of the labeled amount, with nine of the 16 products failing to meet standard pharmaceutical specifications of 90-110% of labeled amount.13
SLE is a chronic, debilitating disease with many different manifestations. Current conventional treatment relies upon the use of medications associated with serious adverse effects. Although only a relatively small number of clinical trials have examined the effectiveness of DHEA in SLE, the results have been generally positive. Reduction in the severity of the illness itself and the ability to reduce the dose of concurrent medications have been documented. However, none of the studies have extended beyond one year, which is important given the cyclic nature of SLE and the likelihood that medications will be taken for many years. Long-term studies also are needed to resolve questions regarding adverse effects.
Adult women with SLE may find symptom relief from 200 mg/d DHEA and/or may be able to reduce doses of other medications. However, DHEA should be employed only under close medical supervision, especially if other medications are being scaled back. The ready availability of DHEA as a dietary supplement means that patients should be advised about where to obtain high-quality products. Recommendations for using DHEA in men with SLE cannot yet be given as studies have not been reported with male subjects.
Dr. O’Mathúna, Ph.D. teaches courses in bioethics and alternative medicine in Dublin, Ireland, and is Visiting Professor of Bioethics at the University of Ulster, Coleraine, Northern Ireland.
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