Is DHEA Effective in Treating the Symptoms of Sjögren's Syndrome?

April 22, 2009

Question

What are the results to date of trials using DHEA in the treatment of Sjögren's syndrome?

Response from Robert I. Fox, MD, PhD
Professor and Member, Scripps Memorial Hospital and Research Foundation; Rheumatologist, Scripps Memorial Hospital, La Jolla, California

Pillemer and colleagues[1] reported a pilot double-blind trial of dehydroepiandrosterone (DHEA) 200 mg/day vs placebo for treatment of SjÖgren's syndrome (SS). They concluded that DHEA treatment showed no evidence of efficacy in treating SS.

Further, they suggested that patients with SS should avoid using unregulated DHEA supplements, since the long-term adverse consequences of exposure to this hormone are unknown. The above DHEA trial is listed as "completed" on ClinicalTrials.gov, and no further studies of its use in SS are listed as planned or in progress.

DHEA is a multifunctional steroid that has been implicated in a broad range of biological effects in humans and other mammals. Together with its sulfate ester (DHEA-S), DHEA is the most abundant steroid in humans. DHEA is produced by the adrenal glands but is also synthesized de novo in the brain. This hormone acts on the androgen receptor, both directly and through its metabolites, which include androstenediol and androstenedione. These metabolites can undergo further conversion to produce the androgen testosterone and the estrogens estrone and estradiol.

In the Pillemer study,[1] randomization of SS patients resulted in 14 DHEA and 14 placebo group subjects. Outcome measures at baseline (placebo vs DHEA group) were:

  • Schirmer I tests were 4.5 ± 4.5 vs 5.4 ± 6.1 mm/5 minutes;

  • Van Bijsterveld scores were 5.3 ± 2.1 vs 5.5 ± 2.2; and

  • Unstimulated saliva flow was 0.03 ± 0.05 vs 0.04 ± 0.10 mL/minute.

No significant differences were noted between the DHEA and placebo groups for dry eye symptoms, objective measures of ocular dryness, or stimulated salivary flow. Four DHEA patients and 1 placebo group patient dropped out because of adverse effects. The adverse effects seen in the trial were generally mild, consisting of mostly minor acne in the DHEA group.

One positive finding in the study[1] was a statistically significant improvement in visual analog scale (VAS) for dry mouth symptoms in the DHEA group compared with the placebo group. However, the improvement in the DHEA group represented only 9 mm on a 100-mm scale (ie, 9% improvement), which, by the definition used in the study, is not clinically meaningful. The placebo group showed a 10% worsening in mouth dryness. The study had defined at least 20% improvement in VAS score as clinically meaningful, in keeping with that used for symptoms in rheumatoid arthritis clinical trials.

In 1988, a small, randomized, double-blind trial of another mild steroid androgen, nandrolone, showed some evidence of subjective, but not objective, improvement in primary SS.[2] Thus, an isolated effect of DHEA on symptoms of dry mouth cannot be ruled out.

Evidence suggests that DHEA sulfate levels may be decreased in patients with SS.[3,4] Serum DHEA and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from the adrenals[5] in patients with systemic lupus erythematosus (SLE).

Recent studies on the androgen-dependent saliva protein (crisp-3) suggest that DHEA or similar compounds may play an important role in oral symptoms by affecting aquaporin or other water channels.[6]

Also of importance, there is a poor correlation between oral symptoms and objective measurements of "water flow" in SS patients,[7] and this may be due to alterations in the mucin content of saliva that provides more lubrication (and subjective benefit). DHEA is known to upregulate mucin production in other organs.[8]

DHEA levels are frequently decreased in patients with SLE[9] and SS.[10] A recent study suggested a beneficial effect of DHEA on quality of life in SLE.[11] However, when these data were presented to the US Food and Drug Administration for approval of DHEA, approval was denied. Many patients will continue to purchase DHEA (or equivalents), which are available over the counter as nutritional supplements, and there may be significant variation in the actual content of these preparations.[12]

In conclusion, although the published data do not support an objective role for increased tear flow or saliva flow, the patient's improved VAS score in oral symptoms should not be readily dismissed. DHEA may need to be used in conjunction with other agents rather than as a single agent. At the present time, the evidence suggests that although further studies are warranted, DHEA cannot yet be recommended for treatment of SS.

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