Management of Cushing's disease: An update

Most cases of hypercortisolemia seen in the adult population are caused by microadenomas of the anterior pituitary gland. Cushing's disease is the life-shortening illness caused by hypercortisolism secondary to an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. More than any other secretory tumor of the pituitary gland, the basophilic ACTH-producing adenoma responsible for Cushing's disease continues to provide the clinician with diagnostic and therapeutic challenges. Recent advances in surgical strategy, endocrinologic assessment, and adjuvant therapies have improved the surgeon's ability to treat this medically devastating disease. The distinction between primary (adrenal) and secondary [pituitary ACTH or ectopic ACTH and/or corticotropin-releasing hormone (CRH) excess] hypercortisolemia is based upon the absence or presence of a measurable ACTH level. Establishing the presence of Cushing's syndrome with elevated serum cortisols and 24-hour urinary-free cortisols is mandatory before proceeding with further testing. Bilateral simultaneous sampling of blood from the inferior petrosal sinuses for ACTH measurement provides additional information that may be important for the diagnosis or management of some patients with ACTH-dependent Cushing's (i.e., either pituitary or ectopic ACTH overproduction). In our algorithm, petrosal sinus blood collection and sampling for ACTH after CRH stimulation are performed in all patients with Cushing's syndrome and normal or questionable magnetic resonance imaging (MRI). If the initial or dynamic MRI confirms an abnormality suggestive of an adenoma, and the endocrine data are secure, we do not do petrosal sampling. In our experience, even with modern MRI, including rapid sequence studies, 45% of patients with Cushing's disease have normal MRI studies. The treatment of choice for Cushing's disease is transsphenoidal exploration of the pituitary gland, with selective adenomectomy, although results thus far have been less than perfect. For those with very large or invasive tumors, we perform surgery for diagnosis and debulking, followed by conventional radiation therapy, stereotactic radiotherapy or radiosurgery, medications, and, occasionally, adrenalectomy. Outcomes do not correlate with the presence of a lesion on preoperative imaging or histology-documented tumor. "Cure" in the setting of Cushing's disease is defined as remission of clinical symptoms secondary to hypercortisolemia, biochemical confirmation of normal cortisol diurnal secretion levels, and resumption of normal hypothalamic-pituitary-adrenal function. Recurrence rates have been reported from 3.7 to 9.3%.