Adrenocorticotropic Hormone-Independent Adrenal Hyperplasia

Abstract

Cushing's syndrome with bilateral adrenal hyperplasia usually is caused by chronic adrenocorticotropic hormone (ACTH) stimulation of the adrenal cortex. Until recently, the existence of ACTH-independent bilateral adrenal hyperplasia has not been firmly established. Evidence that such disorders do exist has accumulated, and in some instances, the mechanism is understood. Bilateral adrenalectomy is most often the appropriate therapy. Activation of the adrenocortical adenylate cyclase system by ACTH-independent mechanisms will cause ACTH-independent Cushing's syndrome with bilateral adrenal hyperplasia. Increased cAMP activates downstream signaling and subsequently cell division and Cortisol production. In food-dependent Cushing's syndrome there is functional evidence for ectopic gastric-inhibitory peptide receptor expression in the adrenal cortex. Food ingestion stimulates gastric-inhibitory peptide release and activates the adrenal adenylate cyclase system. ACTH-independent Cushing's syndrome with bilateral hyperplasia may be the initial presentation of the McCune-Albright syndrome. A R201C or R201H substitution in the alpha subunit of Gs constitutively activates adenylate cyclase. In other variants of ACTH-independent adrenal hyperplasia, the mechanisms are less defined. Primary pigmented nodular adrenocortical disease may occur sporadically or in a familial form, and activating adrenal antibodies have been postulated in its etiology. ACTH-independent bilateral macronodular adrenal hyperplasia is characterized by marked adrenal gland enlargement with multiple large nodules. Its etiology is unknown.