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Neurosurg Focus 23 (3):E10, 2007

Medical management of Cushing disease

BRADLEY A. GROSS, B.S.,1 STEFAN A. MINDEA, M.D.,1 ANTHONY J. PICK, M.D.,2 JAMES P. CHANDLER, M.D.,1 AND H. HUNT BATJER, M.D.1 1Departments of Neurological Surgery and Endocrinology, The Feinberg School of Medicine and McGaw Medical Center, Northwestern University, Chicago, Illinois

PAlthough transsphenoidal excision of the adrenocorticotropic hormone (ACTH)–producing is often the treatment of choice in patients with Cushing disease, medical management is itself a useful preoperative temporizing measure, an option for long-term management in nonsurgical candidates, and an option for patients in whom surgery and/or radiotherapy have failed. Three pathophysiologically based approaches exist in the research literature—neuro- modulation to limit ACTH levels, adrenal inhibition, and receptor antagonism. Unfortunately, the neuromodulatory approach involving agents such as bromocriptine, cyproheptadine, octreotide, and has yielded only suboptimal results. antagonism remains in its infancy but may overall be limited by side effects and a resultant increase in ACTH and levels. Adrenal enzyme inhibitors, however, offer sub- stantial future promise in the management of Cushing disease but are limited by the potential need to use them indef- initely and by dose-tolerance effects. Although etomidate is a potential intravenous alternative for acute cortisol level control, has shown in the long-term treatment of patients with the disease. and/or can be added to ketoconazole if additional control is needed. If success is still not achieved, the potent adrenolytic agent often used for adrenocortical carcinomas, , is another alternative. (DOI: 10.3171/FOC-07/09/E10)

KEY WORDS • aminoglutethimide • Cushing disease • etomidate • ketoconazole • metyrapone • mitotane

RANSSPHENOIDAL excision of tumors producing tempted—one involving neuromodulatory compounds ACTH is the optimum treatment for Cushing dis- aimed at limiting pituitary ACTH secretion, another T ease, with cure rates typically approaching 80%.19,28 involving glucocorticoid receptor antagonists such as At times, subtotal hypophysectomy (85–90%) is used in , and another involving adrenal enzyme patients without clearly identifiable adenomas. Nonsurgical inhibitors. approaches are advocated in patients with incompletely resected pituitary macroadenomas or carcinomas, patients with adenomas and multiple medical issues precluding Medical Management of Cushing Disease surgery, and patients with adenomas wishing to preserve Attempts with neuromodulatory compounds such as fertility. Whereas medical therapy has been used preopera- bromocriptine, cyproheptadine, octreotide, and valproate tively, it can also be employed alone or as an adjunct to have yielded only marginal results.4,12,18 Among these radiotherapy in such nonsurgical candidates and in those in agents, bromocriptine has had the highest documented whom surgical and/or radiation treatment has failed. Unfor- response rate—slightly less than 25%,16 potentially attrib- tunately, such an approach generally requires life-long use utable to the fact that some ACTH-secreting of the medications unless adjunctive radiotherapy has been express D2 receptors.22,23 Additionally, despite promising given. Three pharmacological approaches have been at- results in animals, rosiglitazone did not prove useful in the management of Cushing disease in humans.9 High-dose mifepristone, a well-known abortifacient (known as RU486) and competitive antagonist to gluco- corticoids, remains in its infancy in its utility in Cushing Abbreviation used in this paper: ACTH = adrenocorticotropic disease. Given this agent’s mechanism of action, efficacy hormone. must essentially be judged by clinical response rather than

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FIG. 1. Abbreviated summary of the site of action of adrenal enzyme inhibitors. Mitotane’s inhibition of 3␤-hydrox- ysteroid dehydrogenase (3␤) is omitted for clarity. DHEA = . serum levels of ACTH or cortisol; in fact, resultant elevat- ic agent mitotane, which additionally has inhibitory effects ed levels of ACTH may ultimately limit its utility given the on several adrenal . Figure 1 provides a summary inability to distinguish whether such an elevation is due to of the effects of these medications on adrenal syn- the medication alone or an enlarging adenoma, requiring thesis. Most often, therapy is initiated with ketoconazole. If frequent pituitary imaging. Furthermore, in addition to cortisol levels are not adequately controlled, metyrapone possible resultant skin hyperpigmentation due to excess and/or aminoglutethimide can be added to the medication ACTH, endogenous cortisol elevations may ultimately regimen as needed (Fig. 2). Such combinations of these overwhelm the receptor antagonism. The authors of one re- medications are quite common and allow usage of potential port used the drug as a last resort in an extremely ill patient synergistic effects among them while limiting side effects with an ACTH-secreting macroadenoma and profound that would occur if exceedingly high doses of one medica- metabolic disturbances, psychosis, and cardiomyopathy, tion were used. One drawback to adrenal enzyme inhibitors obtaining successful resolution of these symptoms (includ- is the need to increase doses with time because the relative ing significant reversal of heart failure).3 Notably, however, decrease in cortisol they cause can stimulate further ACTH was needed to manage resultant hypokal- secretion. Additionally, the side effects of these medica- emia, attributed to the unhindered activ- tions (Table 1) may ultimately limit their use. ity of excess cortisol. At any juncture, an alternative for patients becomes bi- Overall, the most well-studied and efficacious pharma- lateral laparoscopic .11 The authors of a re- cological therapies include the adrenal enzyme inhibitors cent publication showed that during a 3-month to 10-year ketoconazole, aminoglutethimide, metyrapone, and etomi- follow-up period, 79.4% of patients had undetectable se- date (intravenously administered) as well as the adrenolyt- rum cortisol levels whereas the procedure itself was asso-

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FIG. 2. Medical management of Cushing disease. TID = three times a day. ciated with a 0% morality rate and 10.3% morbidity rate.30 function should be closely monitored during keto- Such patients should, however, be monitored closely for conazole use considering the drug’s ability to cause idio- the development of Nelson syndrome. In the aforemen- syncratic reversible hepatic dysfunction and elevation of tioned study the investigators reported that 25.7% of pa- aminotransferase levels. These are likely to be dose-depen- tients had serum ACTH levels greater than 300 pg/ml, dent effects because the prevalence of overt hepatitis de- 8.6% had magnetic resonance imaging evidence of tumor creases in patients treated with lower doses of the drug for growth, and 11.1% had clinically significant hyperpigmen- onychomycosis (2.9% prevalence for a daily dosage of 200 tation. mg).1 Therapy should be promptly ceased in patients with hepatitis, but in patients with asymptomatic anicteric am- Ketoconazole Therapy inotransferase elevations, the decision is at the physician’s discretion, although the only investigators who have advo- Ketoconazole, the initial drug of choice, is administered cated continuing the drug were those using it at lower doses at initial doses of 200 mg (two to three times daily) with for onychomycosis.1 dose adjustments based on 24-hour free cortisol lev- In addition to hepatic side effects, , , els. Maintenance doses are often at 400 mg (two to three , and sedation may occur. Other noted side effects times daily). Its fast onset of action allows monitoring of of this medication include decreased libido and impotence, serum cortisol within as little as 1 day of use to observe its probably owing to its inhibitory effects on 17␣-hydroxy- efficacy and adjust its dosage. Although its strongest ef- lase and 17,20-lyase, vital enzymes for the synthesis of fects are on 17,20-lyase,32 it additionally blocks adrenal as shown in Fig. 1. Teratogenicity contraindi- steroid synthesis by preventing side chain cates use of this medication in pregnant women. Significant cleavage and 17␣-hydroxylase.8,14 Though controversial, medication interactions may occur due to ketoconazole’s it is generally accepted that it does not in fact block human potent inhibitory effects on the enzymes, 11␣-hydroxylase.14 particularly CYP3A4, CYP2C9, and CYP1A2. The The authors of a metaanalysis of eight trials involving a CYP3A4 substrates include most aside range of 400 to 1200 mg of ketoconazole daily in patients from ; many calcium channel blockers such as with Cushing disease revealed an average remission rate of and verapamil; 3-hydroxy-3-methyl-glutaryl- 70% (range 25–93%).7 Across these studies the most com- CoA reductase inhibitors, aside from pravastatin and flu- mon was , observed at an overall vastatin; and pimozide, generally contraindicating their rate of 12%.7 Notably, authors of the study with the most use. The CYP2C9 substrates include fluoxetine, glipizide, cases (34 patients) and longest follow-up period (up to 3 losartan, montelukast, , and . The years) reported 26 patients (76%) with normalized cortisol CYP1A2 substrates include mirtazapine, ropinirole, and levels when they used daily doses of ketoconazole ranging . Sildenafil, tadalafil, and vardenafil concen- from 400 to 800 mg.29 This percentage was further in- trations may also be increased. The CYP3A4 inducers such creased to 93% (26 of 28) when patients who initially dis- as aminoglutethimide, , and phenytoin may continued use of the medication were excluded. decrease ketoconazole levels, and as ketoconazole absorp-

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TABLE 1 Aminoglutethimide Therapy Side effects of adrenal enzyme inhibitors Aminoglutethimide, often used at a dose of 250 mg two Medication Side Effects to three times daily, prevents conversion of cholesterol to .25 In an original study of 33 patients with ketoconazole reversible hepatic dysfunction, nausea, sedation, Cushing disease receiving a 250-mg dosage of amino- decreased libido, impotence three times daily, the authors noted a clinical metyrapone hirsutism, , , nausea aminoglutethimide , nausea, , , blurred vision, and biochemical remission rate of 42%, the latter defined (rare: cholestasis, bone marrow as a 50% reduction in morning serum cortisol levels or a suppression) return to normal limits.17 Unclear, however, was the dura- mitotane , nausea, , confusion, tion of follow-up for these patients, and, in the authors’ , , vertigo extended discussion of a representative case of aminog- lutethimide therapy for Cushing disease, the patient ulti- mately required bilateral adrenalectomy for continued bio- tion depends on gastric acidity, -2 recepter block- chemical remission.17 Indeed, it is generally accepted that ers and proton-pump inhibitors should be avoided. aminoglutethimide is, overall, not efficacious as monother- Aside from side effects and medication interactions, an apy because its effect is generally not strong enough to nor- ultimate limitation of this medication used alone may be a malize urinary cortisol levels, likely owing to, in part, the resultant serum ACTH elevation that overwhelms the ability of resultant elevated ACTH to overwhelm its effect.7 drug’s inhibitory effects. Citing their own unpublished Thus, it is now most often used as an adjunct to cases, the authors of the aforementioned metaanalysis metyrapone, with one study showing efficacy up to 1 year found that mean serum ACTH levels rose by an average of when the drug was administered at 500 to 750 mg per day 35% in patients in remission whereas they rose by an aver- in conjunction with 2 g of metyrapone daily in four of six age of 80% in patients in whom there was no normalization patients;2 the other two patients discontinued the drug due of urinary cortisol levels.7 This limitation can be addressed to side effects. The primary side effect of this medication is by using additional adrenal enzyme inhibitors. a generalized, self-limited pruritic rash that is usually man- ageable with antihistamines without requiring drug cessa- Metyrapone Therapy tion. In addition, nausea and somnolence may occur, par- Metyrapone is often started at three daily doses of 250 ticularly at higher doses. Other neurological side effects mg, with titration up to a maximum of 6 g per day. It acts include dizziness and blurred vision. As the drug blocks as an inhibitor of 11␣-hydroxylase. Unfortunately, the re- hormone synthesis, hypothyroidism is a known, sultant relative decrease in cortisol may stimulate further albeit more rare, side effect.25 Cholestasis and bone marrow ACTH secretion, stimulating adrenal and miner- suppression are similarly rare side effects. In addition, alocorticoid production and leading to further hirsutism and aminoglutethimide is a strong inducer of several hypertension from these respective compounds. These side cytochrome P450 enzymes, including CYP1A2 and effects are less commonly observed in association with mi- CYP3A4, underscoring potential medication interactions, totane, another 11␣-hydroxylase inhibitor, presumably due including decreasing ketoconazole levels (see above for to its inhibitory effect on other enzymes involved in adren- other substrates of these enzymes). Because this medica- al androgen and mineralocorticoid synthesis. Other com- tion increases the of but not mon side effects of metyrapone include edema, nausea, and , the latter is often used if steroid replace- vomiting. ment is needed.25,26 Despite increased ACTH secretion, the inhibitory effect of metyrapone overcomes the increased drive to produce Mitotane Therapy cortisol and has shown efficacy over an extended period in case reports—one including a 13-year-old boy receiving Mitotane is often started at 250 to 500 mg nightly with a 2-g regimen of metyrapone for 4 years. All cushingoid slow escalation of the dose to 4 to 12g/day. Mitotane features disappeared and the patient grew 23 cm.5 In a larg- inhibits 11␣-hydroxylase, 18-hydroxylase, 3␣-hydroxy- er study including 53 patients with Cushing disease, the lase, hydroxysteroid dehydrogenase, and several choles- authors reported effective short-term mean serum cortisol terol side chain cleavage enzymes.10,18 At doses greater than level control (Յ 400 nmol/L) in 75% of patients with effec- 4 g per day, it has adrenolytic action because its metabolite tive long-term control in 83% of the 24 patients who were binds macromolecules in adrenal cortical cell mitochon- given metyrapone (mean 2250 mg/day, median 27 months) dria, leading to their destruction and cellular necrosis. This following pituitary irradiation.31 property underscores its primary use in patients with Of note, however, the criterion for “cortisol control” in . the latter study was a mean serum level less than 400 In a study of 46 patients with Cushing disease receiving nmol/L. When the more accepted, stringent criterion of anywhere from 4 to 12 g of mitotane per day, remission oc- Orth and Liddle21 is applied (280 nmol/L cutoff), only 19% curred in 8 months in 38 cases (83%).15 Unfortunately, of patients experienced an effective short-term response. however, in 60% of these patients relapse occurred after the Overall, Orth20 concluded that metyrapone is only useful as drug was discontinued, leaving only one third of patients adjunctive treatment for Cushing disease. Of note, mety- with long-term remission. In another study of 36 patients rapone is not available in pharmacies but can be provided undergoing adjunctive radiotherapy (4000 rad) the authors for compassionate use by contacting the manufacturer di- observed clinical and biological remission in 29 patients rectly. (81%) with 17 (47%) ceasing to undergo long-term mito-

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Unauthenticated | Downloaded 10/03/21 01:07 AM UTC Medical management of Cushing disease tane therapy.27 Four patients had no response, two had par- effects. Etomidate is a potent intravenous alternative for tial responses, and the other patient died of an invasive acute cortisol control. pituitary malignancy. Patients were initially started at 4 g of mitotane per day and the dose was tapered to a final dose Acknowledgments of 500 mg twice weekly. We thank Dr. Walter A. Stoller and Jessica Kazmier for their The efficacy of mitotane is monitored by examining thoughtful contributions to this manuscript. morning serum cortisol levels. Once a decline is observed, or dexamethasone replacement therapy can be- References gin as needed. Although the longer half-life of dexameth- asone may make it seem to be a more attractive replace- 1. Chien RN, Yang LJ, Lin PY, Liaw YF: Hepatic injury during ment therapy, its metabolism is increased by mitotane (as is ketoconazole therapy in patients with onychomycosis: a con- the metabolism of ), requiring dose adjust- trolled cohort study. Hepatology 25:103–107, 1997 ments, whereas the metabolism of cortisol or prednisone 2. Child DF, Burke CW, Burley DM, Rees LH, Fraser TR: Drug has not been shown to be increased.24 Of note, patients who controlled of Cushing’s syndrome. Combined aminoglutethimide and metyrapone therapy. Acta Endocrinol (Copenh) 82: undergo medical mitotane adrenalectomy are at risk of 330–341, 1976 developing Nelson syndrome if they do not receive pitu- 3. Chu JW, Matthias DF, Belanoff J, Schatzberg A, Hoffman AR, itary radiotherapy. Feldman D: Successful long-term treatment of refractory Unfortunately, side effects of this medication may limit Cushing’s disease with high-dose mifepristone (RU 486). J Clin its use and have essentially set it as second or third line after Endocrinol Metab 86:3568–3573, 2001 ketoconazole. In the aforementioned studies, one group 4. Colao A, Pivonello R, Tripodi FS, Orio F, Ferone D, Cerbone G, documented hypercholesterolemia as a prevalent side ef- et al: Failure of long-term therapy with sodium valproate in fect15 whereas another, which also used pituitary irradia- Cushing’s disease. J Endocrinol Invest 20:387–392, 1997 tion, documented anorexia, nausea, diarrhea, decreased 5. Dickstein G, Lahav M, Shen-Orr Z, Edoute Y, Barzilai D: Primary 27 therapy for Cushing’s disease with metyrapone. JAMA 255: memory, and gynecomastia. Overall, the most commonly 1167–1169, 1986 documented drug-related side effects are nausea and hyper- 6. Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser cholesterolemia. At higher doses of the drug, neurological GM: Emergency and prolonged use of intravenous etomidate to side effects are common, including gait ataxia, vertigo, control hypercortisolemia in a patient with Cushing’s syndrome confusion, and difficulty with language expression.18 and peritonitis. J Clin Endocrinol Metab 83:3542–3544, 1998 Furthermore, the drug is contraindicated in pregnant 7. Engelhardt D, Weber MM: Therapy of Cushing’s syndrome with women owing to teratogenicity.13 steroid inhibitors. J Steroid Biochem Mol Biol 49: 261–267, 1994 8. Feldman D: Ketoconazole and other imidazole derivatives as in- Etomidate Therapy hibitors of steroidogenesis. Endocr Rev 7:409–420, 1986 9. Giraldi FP, Scaroni C, Arvat E, Martin M, Giordano R, Albiger N, Etomidate, a commonly used short-acting intravenous et al: Effect of protracted treatment with rosiglitazone, a anesthestic, is an exceedingly potent inhibitor of 11␣-hy- PPARgamma , in patients with Cushing’s disease. Clin droxylase as well as an inhibitor of 17␣-hydroxylase at a Endocrinol (Oxf) 64:219–224, 2006 strength comparable to ketoconazole.32 It essentially serves 10. Hart MM, Straw JA: Studies on the site of action of o, p'-DDD in as an intravenous alternative to the aforementioned med- the dog adrenal cortex. 1. Inhibition of ACTH-mediated pregnen- ications; however, given its sedative effects and availabili- olone synthesis. 17:559–574, 1971 ty in intravenous form alone, it is mainly used for acute 11. Hawn MT, Cook D, Deveney C, Sheppard BC: Quality of life control of hypercortisolemia. Most investigators to date after laparoscopic bilateral adrenalectomy for Cushing’s disease. have analyzed its use in hospitalized patients with neo- Surgery 132:1064–1069, 2002 plasms secreting ACTH. In one study in which the authors 12. Koppeschaar HP, Croughs RJ, Thijssen JH, Schwarz F: Response to neurotransmitter modulating drugs in patients with Cushing’s used it at a nonsedating dose of 0.3 mg/kg/hour, it normal- disease. Clin Endocrinol (Oxf) 25:661–667, 1986 ized serum cortisol levels within 12 hours in six patients 13. Leiba S, Weinstein R, Shindel B, Lapidot M, Stern E, Levavi H, 6 with Cushing disease. et al: The protracted effect of o, p'-DDD in Cushing’s disease and its impact on adrenal morphogenesis of young human embryo. Ann Endocrinol (Paris) 50:49–53, 1989 Conclusions 14. Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D: Keto- conazole blocks adrenal steroidogenesis by inhibiting Although medical management of Cushing disease is cytochrome P450-dependent enzymes. J Clin Invest 71: generally not considered a first-line option, it has exhibited 1495–1499, 1983 adequate success as a preoperative, radiosurgical adjunct, 15. Luton JP, Mahoudeau JA, Bouchard P, Thieblot P, Haute- or even as a stand-alone measure. Attempts to control couverture M, Simon D, et al: Treatment of Cushing’s disease by ACTH levels with neuromodulators have demonstrated O, p'DDD. Survey of 62 cases. N Engl J Med 300:459–464, 1979 only limited success, but the use of adrenal enzyme in- 16. Miller JW, Crapo L: The medical treatment of Cushing’s syn- hibitors has shown some promise to date. Given its tolera- drome. Endocr Rev 14:443–458, 1993 bility and average efficacy of 70% (range 25–93%) in tri- 17. Misbin RI, Canary J, Willard D: Aminoglutethimide in the treat- 7 ment of Cushing’s syndrome. J Clin Pharmacol 16:645–651, als, ketoconazole is often the initial pharmacological agent 1976 utilized. Subsequently, one may add metyrapone and/or 18. Nieman LK: Medical therapy of Cushing’s disease. Pituitary 5: aminoglutethimide for further control of cortisol levels. 77–82, 2002 The adrenolytic agent mitotane is another alternative that is 19. Orth DN: Cushing’s syndrome. N Engl J Med 332:791–803, often used as a second or third choice owing to its side 1995

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20. Orth DN: Metyrapone is useful only as adjunctive therapy in 28. Shimon I, Ram Z, Cohen ZR, Hadani M: Transsphenoidal surgery Cushing’s disease. Ann Intern Med 89:128–130, 1978 for Cushing’s disease: endocrinological follow-up monitoring of 21. Orth DN, Liddle GW: Results of treatment in 108 patients with 82 patients. Neurosurgery 51:57–62, 2002 Cushing’s syndrome. N Engl J Med 285:243–247, 1971 29. Sonino N, Boscaro M, Paoletta A, Mantero F, Zilotto D: Keto- 22. Pivonello R, Ferone D, de Herder WW, Kros JM, De Caro ML, conazole treatment in Cushing’s syndrome: experience in 34 pa- Arvigo M, et al: Dopamine receptor expression and function in tients. Clin Endocrinol (Oxf) 35:347–352, 1991 corticotroph pituitary tumors. J Clin Endocrinol Metab 30. Thompson SK, Hayman AV, Ludlam WH, Deveney CW, Loriaux 89:2452–2462, 2004 DL, Sheppard BC: Improved quality of life after bilateral laparo- 23. Pivonello R, Matrone C, Filippella M, Cavallo LM, Di Somma C, scopic adrenalectomy for Cushing’s disease: a 10-year experi- Cappabianca P, et al: Dopamine receptor expression and function ence. Ann Surg 245:790–794, 2007 in clinically nonfunctioning pituitary tumors: comparison with the effectiveness of cabergoline treatment. J Clin Endocrinol Metab 31. Verhelst JA, Trainer PJ, Howlett TA, Perry L, Rees LH, Grossman 89:1674–1683, 2004 AB, et al: Short and long-term responses to metyrapone in the 24. Robinson BG, Hales IB, Henniker AJ, Ho K, Luttrell BM, Smee medical management of 91 patients with Cushing’s syndrome. IR, et al: The effect of o, p'-DDD on replacement Clin Endocrinol (Oxf) 35:169–178, 1991 therapy requirements. Clin Endocrinol (Oxf) 27:437–444, 1987 32. Weber MM, Lang J, Abedinpour F, Zeilberger K, Adelmann B, 25. Santen RJ, Misbin RI: Aminoglutethimide: review of pharmacol- Engelhardt D: Different inhibitory effect of etomidate and keto- ogy and clinical use. Pharmacotherapy 1:95–120, 1981 conazole on the human adrenal steroid biosynthesis. Clin Investig 26. Santen RJ, Wells SA, Runic S, Gupta C, Kendall J, Rudy EB, et 71:933–938, 1993 al: Adrenal suppression with aminoglutethimide. I. Differential effects of aminoglutethimide on glucocorticoid metabolism as a rationale for use of hydrocortisone. J Clin Endocrinol Metab 45:469–479, 1977 Manuscript received June 6, 2007. 27. Schteingart DE, Tsao HS, Taylor CI, McKenzie A, Victoria R, Accepted July 26, 2007. Therrien BA: Sustained remission of Cushing’s disease with Address correspondence to: Bradley Gross, B.S., 244 East Pear- mitotane and pituitary irradiation. Ann Intern Med 92:613–619, son Street, No. 310, Chicago, Illinois 60611. email: b-gross@md. 1980 northwestern.edu.

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