Approximately 85% of patients with pituitary ACTH-dependent Cushing syndrome, also called Cushing disease, have pituitary microadenomas. The origin, nature, and biochemical characteristics of these microadenomas are not clear.8,9 In most cases, the microadenomas are located in the periphery of the gland and can be identified by imaging techniques or transsphenoidal pituitary exploration. Occasionally, they are located deep in the central wedge of the pituitary and can be missed on imaging or at surgery.8 The suggestion has been made that excessive ACTH secretion may be caused by neurohypothalamic stimulation, which results in corticotrope hyperplasia.10,11 However, fewer than 17% of cases of Cushing disease are associated with ACTH hypersecretion by nonneoplastic corticotrope cells.12 Whether pituitary ACTH-dependent Cushing disease develops from a primary pituitary disorder or is the result of corticotrope stimulation by CRH has been unclear. In the case of a pituitary adenoma, the nonadenomatous corticotropes are usually suppressed, and removal of the adenoma is followed by ACTH and cortisol insufficiency. In the rare cases of corticotrope hyperplasia, the possibility exists that these corticotropes have been stimulated from a hypothalamic source. Clonal analysis of the pituitary tissue obtained from patients with Cushing disease shows that ACTH-secreting adenomas have a monoclonal pattern consistent with a monoclonal proliferation of a genetically altered cell. Thus, a spontaneous somatic mutation in pituitary corticotropes is the primary pathogenetic mechanism in this disorder. In contrast, the corticotrope hyperplasia seen in patients with CRH-secreting bronchial carcinoids is polyclonal.13 Direct measurement of CRH levels in patients with Cushing disease secondary to a pituitary adenoma has not been performed. In the few patients in whom CRH levels have been measured in the spinal fluid, low levels have been found, suggesting suppressed CRH secretion.