Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison's disease in a randomized, double blind trial

Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are adrenal precurso rs of steroid biosynthesis and centrally acting neurosteroids. Glucocortico id and mineralocorticoid deficiencies in Addison's disease require life-lon g hormone replacement, but the associated failure of DHEA synthesis is not corrected. We conducted a randomized, double blind study in which 39 patien ts with Addison's disease received either 50 mg oral DHEA daily for 12 week s, followed by a 1-week washout period, then 12 weeks of placebo, or vice v ersa. After DHEA treatment, levels of DHEAS and Delta (4)-androstenedione r ose from subnormal to within the adult physiological range. Total testoster one increased from subnormal to low normal with a fall in serum sex hormone -binding globulin in females, but with no change in either parameter in mal es. In both sexes, psychological assessment showed significant enhancement of self-esteem with a tendency for improved overall well-being. Mood and fa tigue also improved significantly, with benefit being evident in the evenin gs. No effects on cognitive or sexual function, body composition,lipids, or bone mineral density were observed. Our results indicate that DHEA replace ment corrects this steroid deficiency effectively and improves some aspects of psychological function. Beneficial effects in males, independent of cir culating testosterone levels, suggest that it may act directly on the centr al nervous system rather than by augmenting peripheral androgen biosynthesi s. These positive effects, in the absence of significant adverse events, su ggest a role for DHEA replacement therapy in the treatment of Addison's dis ease.