ACTH PRECURSORS CHARACTERIZE THE ECTOPIC ACTH SYNDROME

OBJECTIVE ACTH is secreted by the pituitary following processing of la rger molecular weight precursors, proopiomelanocortin and pro-ACTH. Ec topic ACTH syndrome refers to the secretion of ACTH by non-pituitary t umours, but the predominant circulating form of proopiomelanocortin-re lated peptides remains unclear. PATIENTS Fifteen patients with ectopic ACTH syndrome were compared to 20 patients with pituitary-dependent C ushing's syndrome, 22 patients with small cell lung carcinoma but no e vidence of Cushing's syndrome, and 25 controls. DESIGN AND MEASUREMENT S Measurement of plasma ACTH and ACTH precursors using specific monocl onal-based immunoradiometric assays at 0900 h and, in five patients wi th ectopic ACTH syndrome, at 15-minute intervals for 6-24 hours. RESUL TS ACTH precursors were grossly elevated in patients with ectopic ACTH syndrome (median 2194, range 139-18000 pmol/l) compared to patients w ith Cushing's disease (median 33, 8-73 pmol/l, P<0.001), patients with small cell lung carcinomas (38, 8-117 pmol/l, P<0.001) and controls ( 26, 10-39 pmol/l, P<0.001). ACTH levels were also elevated in ectopic ACTH syndrome (0900 h median 34, 11-152 pmol/l) compared to patients w ith Cushing's disease (0900 h median 8, 3-19 pmol/l), but not to the s ame degree as ACTH precursors. In contrast with Cushing's disease, ACT H was secreted in a non-pulsatile fashion. ACTH precursors but not ACT H itself correlated wtih plasma cortisol in patients with ectopic ACTH syndrome (r=0.65, P<0.05). Chromatographic analysis of plasma from a patient with ectopic ACTH syndrome confirmed ACTH precursors and not A CTH to be the predominant circulating form. With the cross-reactivity of proopiomelanocortin and pro-ACTH in the ACTH IRMA of <1 and <10% re spectively, ACTH precursors could represent all the ACTH immunoreactiv ity in patients with ectopic ACTH syndrome. CONCLUSIONS Ectopic 'ACTH' is characterized by aberrant processing of proopiomelanocortin and sh ould be more accurately referred to as 'ectopic ACTH precursor syndrom e'.