A 23-yr-old man who had been treated 8 yr previously with radiotherapy and o,p′-DDD for rapidly progressive Cushing's syndrome associated with a suprasellar mass, presented with clinical evidence of hypothyroidism and laboratory evidence of hypoadrenalism and hypothyroidism. Immunoassayable plasma ACTH and TSH levels were elevated, but there was adequate end organ responsiveness to exogenous ACTH and TSH. Plasma ACTH levels exhibited a normal circadian variation, and responded markedly to insulin induced hypoglycemia and to Pitressin® administration, with no associated change in plasma cortisol levels. Plasma TSH levels increased following TRH administration, with no change in serum T3 levels. In contrast to immunoassay results, bioassay demonstrated markedly diminished levels of plasma ACTH and absent TSH, indicating that the target organ deficiencies were secondary to lack of stimulation by biologically active hormone. Following trypsinization of the patient's plasma, levels of bioassayable ACTH were equivalent to those obtained by immunoassay, suggesting conversion of biologically inactive “big” ACTH to “little” ACTH.