IMPAIRED PROCESSING OF PROOPIOMELANOCORTIN IN CORTICOTROPH MACROADENOMAS

The regulation and secretion of the ACTH precursors POMC and pro-ACTH were assessed directly using a a-site immunoradiometric assay in six p atients with pituitary macroadenomas (greater than or equal to 1.2 cm in diameter) and 27 patients with Gushing's disease due to a microaden oma. ACTH precursor levels were elevated in patients with macroadenoma s (150-3690 pmol/L; normal range, <5-40 pmol/L) and significantly high er than those in microadenoma patients (median, 29 pmol/L; range, 9-10 4 pmol/L; P < 0.001). Patients with macroadenomas also had increased A CTH precursor/ACTH ratios (15-181:1) compared with microadenoma patien ts (median, 5:1; range, 0.7-18.5:1; P < 0.001). ACTH precursors were u nresponsive to high dose dexamethasone in patients with macroadenomas, whereas ACTH and cortisol responses varied. After CRH administration, ACTH precursors mere unchanged, whereas cortisol increased significan tly, suggesting the release of biologically active ACTH. This study cl early demonstrates reduced processing of POMC to ACTH in large pituita ry tumors, a characteristic usually associated with tumors causing the ectopic ACTH syndrome, and provides evidence for differential regulat ion of ACTH precursors and ACTH by glucocorticoid and CRH. Variation i n the clinical symptoms of patients with corticotroph macroadenomas ma y be attributable to differences in biological potency between the ACT H precursors and ACTH.