The Corticotropin-Releasing Factor Stimulation Test. An Aid in the Evaluation of Patients with Cushingʼs Syndrome

Corticotropin-releasing factor, a 41 -amino acid peptide, stimulates pituitary adrenocorticotropic hormone (ACTH) and β-endorphin secretion. Because of its selective stimulation of the corticotrope cells of the pituitary gland, and because of its relative safety, the factor offers a possible means of studying the conditions of aberrant ACTH secretion. The purpose of the present study was to characterize the hormonal responses to the releasing factor in a series of patients with Cushing's disease or the ectopic ACTH secretion syndrome (Cushing's syndrome of adrenal origin) and to explore its possible usefulness in the differential diagnosis of Cushing's disease. The authors studied 22 patients with Cushing's syndrome and 10 control subjects. Thirteen patients (ages, 19 to 62 years) had ACTH-secreting pituitary adenomas (Cushing's disease), and six patients (ages, 25 to 69 years) had nonpituitary ACTH-secreting tumors. A 5-year-old child had micronodular adrenal disease. Two patient's had Cushing's syndrome due to metastatic adrenal carcinoma. Patients in the group with untreated Cushing's disease and those in the group with untreated Cushing's syndrome due to ectopic secretion of ACTH had high evening basal plasma ACTH and cortisol concentrations. Corticotropin-releasing factor was given at a dose of 1 μg/kg of body weight at 8 PM as an intravenous bolus injection. All patients in the first group responded with elevations in plasma ACTH and cortisol. None of the patients with the ectopic ACTH syndrome responded to corticotropin-releasing factor. Three patients who were treated successfully by transsphenoidal adenomectomy had normal or nearly normal plasma ACTH and cortisol responses to corticotropin-releasing factor as early as 1 week after surgery. In these patients, glucocorticoid replacement had been discontinued at least 24 hours before testing. One of them, who had had more pituitary tissue removed than the others, had a slightly subnormal ACTH and cortisol response to the releasing factor. Unsuccessfully treated patients and those treated medically (with cyproheptadine or mitotane) or by bilateral adrenalectomy had plasma ACTH and cortisol patterns, after administration of the releasing factor, that were typical of untreated Cushing's disease. One patient, who had the ectopic ACTH syndrome and showed no response to corticotropin-releasing factor, was given metyrapone for 3 days and showed a response to the releasing factor when retested. No changes in plasma growth hormone, prolactin, lutein-izing hormone, plasma renin activity, insulin, or glucose were noted in either group of patients after administration of corticotropin-releasing factor. No endogenous corticotropin-releasing factor was detected by radioimmunoassay in plasma from any of the patients studied. The disappearance curves of exogenous corticotropin-releasing factor from plasma were similar in both groups of untreated patients (those with Cushing's disease and those with ectopic ACTH syndrome) and were within the normal range. Similarly, patients with Cushing's disease who were receiving medical therapy.