Context: Dehydroepiandrosterone (DHEA) and DHEAS are the major circulating adrenal steroids and substrates for peripheral sex hormone biosynthesis. In Addison's disease, glucocorticoid and mineralocorticoid deficiencies require lifelong replacement, but the associated near-total failure of DHEA synthesis is not typically corrected.

Objective and Design: In a double-blind trial, we randomised 106 (44 males, 62 females) subjects with Addison's disease to receive either 50mg daily of micronised DHEA or placebo orally for 12 months, to evaluate its longer-term effects on bone mineral density (BMD), body composition and cognitive function, together with well being and fatigue.

Results: Circulating DHEAS and androstenedione rose significantly in both sexes, with testosterone increasing to low normal levels only in females. DHEA reversed ongoing loss of BMD at the femoral neck (p<0.05) but not at other sites; DHEA enhanced total body (p=0.02) and truncal (p=0.017) lean mass significantly with no change in fat mass. At baseline, subscales of psychological well-being in questionnaires (SF-36, GHQ-30), were significantly worse in Addison's patients versus control populations (p<0.001), and one subscale of SF-36 improved significantly (p=0.004) following DHEA treatment. There was no significant benefit of DHEA treatment on fatigue, cognitive or sexual function. Supraphysiological DHEAS levels were achieved in some older females who experienced mild androgenic side effects.

Conclusion: Although further long-term studies of DHEA therapy, with dosage adjustment, are desirable, our results support some beneficial effects of prolonged DHEA treatment in Addison's disease.