Adrenocorticotropic hormone-independent Cushing's syndrome

Endogenous Cushing's syndrome is adrenocorticotropic hormone (or corticotropin)-independent in 15-20% of cases. Primary Cushing's syndrome is most often secondary to adrenocortical adenomas or carcinomas, and more rarely to bilateral adrenal hyperplasias. Corticotropin-independent cortisol-producing hyperplasia is caused by micronodular diseases, including primary pigmented nodular adrenocortical disease and nonpigmented micronodular hyperplasia and adrenocorticotropic hormone-independent macronodular adrenal hyperplasia. Primary pigmented nodular adrenocortical disease can be found either alone or in the context of Carney complex, a multiple endocrine neoplasia syndrome.

In recent years, the pathophysiology of adrenocortical tumors and hyperplasias became better understood following the identification of genes responsible for syndromes associated with corticotropin-independent Cushing's syndrome and the demonstration of aberrant expression and function of various hormone receptors in adrenocortical adenomas and adrenocorticotropic hormone-independent macronodular adrenal hyperplasia. This article reviews findings on the molecular and genetic aspects of corticotropin-independent Cushing's syndrome including recent gene expression profiling studies of adrenocortical tumors and hyperplasias and animal models that provided clues on the pathogenesis of primary Cushing's syndrome.

A better understanding of molecular mechanisms involved in adrenocortical tumors and hyperplasias may lead to improved diagnostic and prognostic markers and treatment strategies to assist clinicians in the management of corticotropin-independent Cushing's syndrome.