Remission in Cushing's Syndrome with o,p′-DDD1

Abstract

O,p''-DDD was administered orally in doses of 1-10 g daily to 2 subjects with Cushing''s syndrome (one with nontumorous adreno-cortical hyperfunction and one with metastatic adrenal carcinoma). The patients were treated for 199 and 125 days, respectively. Steroid studies were carried out before and at intervals during treatment with the drug. In the subject with nontumorous adrenocortical hyperfunction the studies were continued for 143 days after discontinuation of therapy. In both subjects the administration of o,p''-DDD resulted in a striking remission in the clinical and biochemical features of Cushing''s syndrome. There was a prompt reduction in the urinary excretion of 17-hydroxycorticoids (17-OH-CS) and in the early weeks of therapy this occurred in the absence of a commensurate decrease in the plasma levels of 17-OH-CS and in the cortisol secretion rate. The diminution in urinary 17-OH-CS correlated well with a decrease in the percentage of injected cortisol excreted as the glucuronide and in the urinary excretion of the tetrahydrocorticoids. The reduction in the tetrahydrocorticoids was associated with an almost quantitative increase in the "free" or unconjugated steroid fraction, which consisted of 6[beta]-hydroxycortisol and other highly polar Porter-Silber chromogens. More prolonged treatment with o,p''-DDD resulted in a marked fall in the cortisol secretion rate. This was due to a direct action of the drug on the adrenal cortex as manifested by an absence of response to the administration of corticotropin (ACTH). These data indicated that o,p''-DDD affected both the adrenal production and the extra-adrenal metabolism of cortisol. A clinical response was observed in both subjects before a significant decrease occurred in the adrenal secretory rate of cortisol. The mechanism of the response during the early treatment period is not clear, although it appears to be temporally related to the extra-adrenal effect of the drug. In the subject with nontumorous adrenocortical hyperfunction, prolonged administration of o,p''-DDD resulted in adrenocortical insufficiency, which has continued to persist for 5 months after cessation of treatment. Administration of ACTH to one of the subjects (nontumorous adrenocortical hyperfunction) produced a rise in the urinary excretion of "free" or unconjugated Porter-Silber chromogens without an associated increase in the cortisol secretion rate. This provided additional evidence in favor of the presence of an extra-adrenal effect of ACTH on cortisol metabolism.