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If surgical cure is impossible, blockade of steroidogenesis is indicated and combination chemotherapy and/or radiation therapy may be administered. Ketoconazole is the most useful agent. It blocks adrenal steroidogenesis at several levels, the most important being the 20-22 desmolase step, which catalyzes the conversion of cholesterol to pregnenolone, thus avoiding accumulation of steroid biosynthesis intermediates that can cause or worsen hypertension and/or hirsutism (121). To control CD, doses of400-1200 mg/d po are usually required. One might start ketoconazole at 200 mg once a day, gradually increasing the dose over 2 to 3 wk, with frequent assessment of serum cortisol levels before and after administering the drug. Reversible side effects, including elevations of hepatic transaminases and gastrointestinal irritation, may occur and may be dose limiting. In this case, metyrapone can be added to achieve normocortisolemia (13,122). Other blocking agents that may be used alone or in combination with ketoconazole and/or metyrapone include aminoglutethimide and trilostane (122).

Metyrapone is a selective inhibitor of 11-^-hydroxylase. Monotherapy is limited by salt retention with development of hypertension and virilization (123). Aminoglutethimide inhibits the conversion from cholesterol to pregnenolone and thus leads to decline of all adrenal and gonadal steroids. Monotherapy is less efficacious for treating CD than combination therapy with other inhibitors of steroidogenesis. Side effects include nausea, sedation, and rash (122).

Mitotane, an adrenolytic agent, can produce short-term remission in approx 83% of patients with CD (107). Trilostane, an inhibitor of the 3-^-hydroxysteroid dehydrogenase, is less effective in treating CD than other agents.

If iv administration of inhibitors of steroidogenesis becomes necessary, etomidate can be given. This anesthetic agent is an imidazole derivative and inhibits 11-^-hydroxylase, thereby reducing cortisol levels (124).

Octreotide, cyproheptadine, bromocriptine, and valproic acid have all been used to inhibit ACTH secretion but are not effective (122).

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