Asynchronous development of bilateral nodular adrenal hyperplasia in gastric inhibitory polypeptide-dependent Cushing's syndrome

Gastric inhibitory polypeptide (GIP)-dependent Gushing's syndrome has been reported to occur either in unilateral adrenal adenoma or in bilateral macr onodular adrenal hyperplasia. A 33-yr-old woman with Gushing's syndrome was found to have two 2.5- to 3-cm nodules in the right adrenal on computed to mography scan; the left adrenal appeared normal except for the presence of a small 0.8 x 0.6-cm nodule. Uptake of iodocholesterol was limited to the r ight adrenal. Plasma morning cortisol was 279 nmol/L fasting and 991 nmol/L postprandially, and ACTH remained suppressed. Plasma cortisol increased af ter oral glucose (202%) or a lipid-rich meal (183%), but not after a protei n-rich meal (95%) or iv glucose (93%); the response to oral glucose was blu nted by pretreatment with 100 mu g octreotide, sc. Plasma cortisol and GIP levels were positively correlated (r = 0.95; P = 0.0001); cortisol was stim ulated by the administration of human GIP iv (225%), but not by GLP-1, insu lin, TRH, GnRH, glucagon, arginine vasopressin, upright posture, or cisapri de orally. A right adrenalectomy was performed; GIP receptor messenger ribo nucleic acid was overexpressed in both adrenal nodules and in the adjacent cortex. Histopathology revealed diffuse macronodular adrenal hyperplasia wi thout internodular atrophy. Three months after surgery, fasting plasma ACTH and cortisol were suppressed, but cortisol increased 3.6-fold after oral g lucose, whereas ACTH remained suppressed; this was inhibited by octreotide pretreatment, suggesting that cortisol secretion by the left adrenal is als o GIP dependent. We conclude that GIP-dependent nodular hyperplasia can pro gress in an asynchronous manner and that GIPR overexpression is an early ev ent in this syndrome.