A STUDY OF THE MECHANISM OF THE STEROID WITHDRAWAL SYNDROME. EVIDENCE FOR INTEGRITY OF THE HYPOTHALAMICPITUITARY-ADRENAL SYSTEM*

Abstract

Cushing''s syndrome developed in 10 male patients with pulmonary tuberculosis who were receiving predni-sone, 30 mg. daily, and zinc-corticotropin (ACTH), 40 units every other day, for about six months in addition to antituberculosis chemotherapy. The responsiveness of the adrenal cortex to intravenous ACTH was tested before, during and after the period of prednisone-ACTH therapy. Although the baseline level of plasma cortisol before initiation of therapy was higher than that of normal controls, a smaller rise occurred in response to ACTH, resulting in similar final levels. During treatment both the baseline plasma cortisol level and the response to ACTH were reduced compared to normal controls. Despite very gradual tapering of the dosages of prednisone and ACTH after five to six months of therapy, striking symptoms developed, reminiscent of those occurring in Addison''s disease or after bilateral adrenalectomy for Cushing''s syndrome; these symptoms responded to reinstitution of prednisone therapy. However, both the baseline plasma cortisol level and the response to ACTH were normal, even while the patients were experiencing withdrawal symptoms. By utilizing insulin-induced hypoglycemia, the integrity of the hypothalamic-pituitary-adrenal system was evaluated in both the steroid-ACTH withdrawal patients and in controls who also had pulmonary tuberculosis. Surprisingly, the steroid-ACTH withdrawal patients experienced fewer hypoglycemic symptoms, following the administration of 0.15 unit of insulin per Kg. intravenously than did the controls, associated with a significantly smaller decline in blood sugar concentration. Furthermore, they exhibited normal hypoglycemia responsiveness and a normal rise in plasma cortisol concentration in response to the hypoglycemia. These data indicate that, under the conditions studied, the hypothalamic-pituitary-adrenal system was intact following withdrawal of steroid-ACTH therapy despite the development of withdrawal symptoms. The etiology and pathogenesis of the withdrawal symptoms in these patients remain to be elucidated.