Classic and recent etiologies of Cushing's syndrome: diagnosis and therapy

Abstract

Endogenous Cushing's syndrome can result from excess adrenocorticotropic hormone (ACTH; corticotropin) production by a pituitary adenoma (Cushing's disease) or by ectopic tumors secreting ACTH or corticotro- pin-releasing hormone (CRH). ACTH-independent Cushing's syndrome is caused by adrenocortical tumors or hyperplasias. Initial diagnosis is performed using 24-hour urinary free cortisol, low-dose dexamethasone tests, salivary cortisol, or night-time plasma cortisol values. A dexamethasone CRH test can discriminate between Cushing's syndrome and pseudo-Cushing's syndrome. If ACTH is elevated, combinations of high-dose dexamethasone tests, CRH/desmopressin tests, and pituitary magnetic resonance imaging can indicate a pituitary source. Discrimination from an ectopic ACTH tumor often requires inferior petrosal sinus sampling to confirm the ACTH source. If ACTH is low, adrenal computed tomography scan will identify the adrenal lesion(s) implicated. Some cortisol-producing adrenal tumors or, more frequently, bilateral macronodular hyperplasias, are under the control of aberrant membrane hormone receptors, or altered activity of eutopic receptors. The initial therapy of choice for patients with Cushing's disease is the selective transsphenoidal removal of the corticotroph adenoma; this induces remission in approximately 80% of patients, but long-term relapse occurs in up to 30% of these cases. The choice of second-line therapy remains controversial. Repeat surgery can be successful when residual tumor is detectable on magnetic resonance imaging, but carries a high risk of hypopituitarism. Bilateral adrenalectomy may be a better choice in patients without visible residual tumors, particularly in women desiring fertility. Radiotherapy combined with ketoconazole or radiosurgery was recently found effective, but longer-term evaluation of hypopituitarism and brain function is required. Current studies do not support the systematic use of prophylactic radiotherapy after bilateral adrenalectomy to decrease the risk of Nelson's syndrome; however, as soon as the residual tumor progresses, surgery and radiotherapy should be initiated. Various drugs which inhibit steroid synthesis (ketoconazole, metyrapone, aminoglutethimide, mitotane) are often effective for rapidly controlling hypercortisolism either in preparation for surgery, after unsuccessful removal of the etiologic tumor, or while awaiting the full effect of radiotherapy or more definitive therapy. Surgery is usually the treatment of choice for removal of cortisol-secreting adrenal tumors or ectopic ACTH/CRH-secreting tumors. The identification of aberrant adrenal receptors has recently allowed normalization of cortisol secretion by specific ligand receptor antagonists in limited cases of Cushing's syndrome secondary to bilateral macronodular adrenal hyperplasia. The long-term follow-up of patients treated for Cushing's syndrome should include the adequate replacement of glucocorticoids and other hormones, treatment of osteoporosis, and detection of long-term relapse of Cushing's syndrome.