Adrenal insufficiency after incomplete resection of pituitary macrocorticotropinoma of Cushing's disease: role of high molecular weight ACTH.

A 15-year-old girl with Cushing's disease exhibited adrenal insufficiency following incomplete trans-sphenoidal resection of a large pituitary corticotropinoma, approximately 35 mm in diameter. Within two weeks following surgery, her plasma ACTH level decreased from 42 to 13 pmol/l, while, her plasma cortisol levels and urinary excretion of free cortisol decreased from 607 nmol/l and 1112 nmol/day to 94 nmol/l and 55 nmol/day, respectively. Immunoreactive ACTH was characterized in plasma using Sephadex G-75 column chromatography and measuring ACTH with immunoradiometric assay (IRMA) and radioimmunoassay (RIA) to determine additional peaks, other than the one demonstrated for 1-39 ACTH. In particular, when measured with RIA, a broad peak including the high molecular weight ACTH was detected as well as 1-39 ACTH. The bioactivity of the high molecular weight ACTH in patient plasma was lower than the reference range of 1-39 ACTH, which is determined by the ability of dispersed rat adrenocortical cells to secrete corticosterone. The large pituitary corticotropinoma found in this patient secreted not only 1-39 ACTH but also high molecular weight proopiomelanocortin (POMC)-derived peptides, which could be detected by measuring with IRMA and RIA for ACTH. Based on the results of biological activity and molecular ratios, no positive evidence could be found to support the hypothesis that the high molecular weight ACTH induced any postoperative adrenal insufficiency in this patient. However, based on this study, the possibility of adrenal insufficiency should be carefully monitored, even when post-operative remnant tumor tissue is clearly present in patients with Cushing's disease, accompanied by macrocorticotropinoma.