CONTEXT:Despite lifelong steroid hormone replacement, there is excess morbidity and mortality associated with autoimmune Addison's disease. In health, adrenocortical cells undergo continuous self-renewal from a population of subcapsular progenitor cells, under the influence of ACTH, suggesting a therapeutic possibility.OBJECTIVE:We aimed to determine if tetracosactide (synthetic ACTH1-24) could revive adrenal steroidogenic function in autoimmune Addison's disease.DESIGN, SETTING, PATIENTS:Thirteen patients (aged 16 to 65 yrs) with established autoimmune Addison's disease for more than 1 years, were recruited at the Newcastle University Clinical Research Facility.INTERVENTION:A 20-week study of regular subcutaneous tetracosactide (ACTH1-24)therapy.MAIN OUTCOME MEASURES:Serum and urine corticosteroids were measured during medication withdrawal at baseline and every five weeks during the study.RESULTS:Serum cortisol levels remained under 100nmol/L in 11 of 13 participants throughout the study. However, two women achieved peak serum cortisol concentrations >400nmol/L after 10 and 29 weeks of tetracosactide therapy, respectively, allowing withdrawal of corticosteroid replacement. Concurrently, urine glucocorticoid and mineralocorticoid metabolite excretion increased from subnormal to above the median of healthy controls. One of these responders remains well with improving peak serum cortisol (672nmol/L) 28 months after stopping all treatments. The other responder showed a gradual reduction in serum cortisol and aldosterone over time and steroid therapy was recommenced following a 28-week period without glucocorticoid replacement.CONCLUSION:This is the first study to demonstrate that established autoimmune Addison's disease is amenable to a regenerative medicine therapy approach.