Treatment options for Cushing disease after unsuccessful transsphenoidal surgery

Abstract

USHING disease, which is induced by a functional ACTH-producing adenoma of the anterior pituitary gland, is the most common cause of ACTH-dependent Cushing syndrome. The treatment of Cushing disease remains challenging for neurosurgeons and endocrinologists. Transsphenoidal surgery is currently the treatment of choice in patients who harbor ACTH-secreting pituitary tumors associated with Cushing disease. This surgery provides the best option for rapid biochemical remission with excellent long-term results. Remission rates after transsphenoidal resection performed by experienced surgeons have ranged from approximately 70 to 90%. 3,9,15,17,26,37,38,42, 47,54 Long-term follow-up with biochemical testing is necessary to detect tumor recurrence because remission rates decline with longer follow-up periods. 14,16 Although many patients achieve complete remission, these tumors are difficult to cure surgically, and some patients may exhibit persistent or recurrent hypersecretion of ACTH and hypercortisolism resulting in increased morbidity and death related to their malignant endocrinopathy. Unfortunately, the results of endocrinological analyses after transsphenoidal surgery vary in the literature because different definitions of a biochemical cure are given in the various studies. If biochemical evidence of Cushing disease persists or recurs after an initial transsphenoidal surgery, the surgeon should be familiar with the treatment options available to offer the patient, including repeat transsphenoidal surgery, radiation therapy, medical therapy, and bilateral adrenalectomy. A multimodal approach using a combination of these treatments may be an appropriate strategy in some patients to achieve the best outcome. For optimal results, a multidisciplinary team approach should be coordinated at a specialized center. In this paper, we provide an overview of the management options available after unsuccessful transsphenoidal surgery and review the current outcome data for each option based on results reported in the literature. Repeat Transsphenoidal Surgery As indicated earlier, transsphenoidal surgical removal of ACTH-producing pituitary adenomas is currently recommended as the first-line treatment for Cushing disease. The reported rates of remission are variable because of the wide

Mifepristone for Management of Cushing's Syndrome

“…Other agents in this class include aminoglutethimide and etomidate (Table 2). 3,13,[16][17][18][19][20] Steroidogenesis inhibitors are considered adrenal-directed medical therapy because they control cortisol production by directly decreasing adrenal hormone production. Ketoconazole is the most commonly used steroidogenesis inhibitor because of its availability and relatively rapid onset of action.…”

“…It can also cause hypogonadism in men because of inhibition of testosterone synthesis. 16,[19][20][21] Metyrapone blocks the production of cortisol through inhibition of 11b-hydroxylase. This effectively reduces hypercortisolemia, but because metyrapone is specific for a single enzyme late in the steroid biosynthesis pathway, there is often a dramatic rise in steroids formed proximal to 11b-hydroxylase, particularly 11-deoxycortisol, a mineralocorticoid that causes the frequent adverse effects of hypokalemia, edema, and hypertension.…”

“…It is currently available in the United States directly from the manufacturer. 16,19,20,22 Mitotane is used most often for the management of adrenocortical carcinoma. It works through the inhibition of multiple enzymes 19 and, unlike other agents, is directly cytotoxic to adrenocortical cells.…”

“…Aminoglutethimide, which works by inhibiting the conversion of cholesterol to pregnenolone, is neither particularly effective as monotherapy nor readily available in the United States. 16,19 Etomidate, an intravenous agent used for anesthesia induction, inhibits cholesterol side chain cleavage and 11bhydroxylase. It has been used in emergent settings for the rapid control of hypercortisolemia but is not practical for routine use due to its sedative effects.…”

“…It has been used in emergent settings for the rapid control of hypercortisolemia but is not practical for routine use due to its sedative effects. 16,19,24 Drugs that suppress ACTH secretion have been investigated for use in the management of Cushing's disease. Among these are dopamine agonists and somatostatin analogs.…”