Pharmacology and toxicity of adrenal enzyme inhibitors and adrenolytic agents
- André Lacroix, MD
André Lacroix, MD
- Section Editor — Adrenal Disease
- Professor of Medicine
- University of Montreal, Quebec, Canada
These compounds have been used to study the enzymes involved in steroid synthesis, to evaluate the hypothalamic-pituitary axis (metyrapone), and to treat some patients with endogenous excess of cortisol, androgen, or mineralocorticoid secretion.
Indications for the use of these compounds include rapid control of severe hypercortisolism for any etiology of endogenous Cushing's syndrome, persistent hypercortisolism following pituitary surgery for Cushing's disease, while awaiting the control from radiotherapy for Cushing’s disease, and control of excess steroid production in adrenocortical carcinoma or ectopic corticotropin (ACTH) syndrome.
This topic provides an overview of the compounds that inhibit glucocorticoid biosynthesis or action. Their use in the treatment of Cushing's syndrome is reviewed in greater detail separately. (See "Medical therapy of hypercortisolism (Cushing's syndrome)".)
ADRENAL ENZYME INHIBITORS
Ketoconazole, metyrapone, etomidate, and mitotane block one or more of the enzymes in the cortisol and other steroid synthetic pathway. The subsequent decrease in cortisol secretion results in a compensatory rise in corticotropin (ACTH) release for most of these compounds. This tends to override the drug-induced cortisol blockade, but can also result in accumulation of precursor steroids. These drugs usually do not cause adrenal insufficiency in patients with normal hypothalamic-pituitary-adrenal function , but can do so in those with limited pituitary or adrenal reserve. (See "Medical therapy of hypercortisolism (Cushing's syndrome)", section on 'Oral drugs'.)
- LIDDLE GW, ISLAND D, LANCE EM, HARRIS AP. Alterations of adrenal steroid patterns in man resulting from treatment with a chemical inhibitor of 11 beta-hydroxylation. J Clin Endocrinol Metab 1958; 18:906.
- Pont A, Williams PL, Azhar S, et al. Ketoconazole blocks testosterone synthesis. Arch Intern Med 1982; 142:2137.
- DeFelice R, Johnson DG, Galgiani JN. Gynecomastia with ketoconazole. Antimicrob Agents Chemother 1981; 19:1073.
- Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987; 317:812.
- Loose DS, Kan PB, Hirst MA, et al. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest 1983; 71:1495.
- McCance DR, Hadden DR, Kennedy L, et al. Clinical experience with ketoconazole as a therapy for patients with Cushing's syndrome. Clin Endocrinol (Oxf) 1987; 27:593.
- Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing's disease: is it worth a try? J Clin Endocrinol Metab 2014; 99:1623.
- FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. US FDA Drug Safety Communication. Last updated October 21, 2013. Food and Drug Administration. (Available online at www.fda.gov/Drugs/DrugSafety/ucm362415.htm (accessed September 28, 2015)).
- Recommendation for maintenance of orphan designation at the time of marketing authorization: Ketoconazole HRA (ketoconazole) for the treatment of Cushing’s syndrome. European Medicines Agency/Committee for Orphan Medicinal Products orphan designation recommendation. Last updated January 30, 2015. European Medicines Agency. (Available online at www.ema.europa.eu/docs/en_GB/document_library/Orphan_review/2015/01/WC500181644.pdf (accessed September 28, 2015)).
- Riedl M, Maier C, Zettinig G, et al. Long term control of hypercortisolism with fluconazole: case report and in vitro studies. Eur J Endocrinol 2006; 154:519.
- van der Pas R, Hofland LJ, Hofland J, et al. Fluconazole inhibits human adrenocortical steroidogenesis in vitro. J Endocrinol 2012; 215:403.
- COPPAGE WS Jr, ISLAND D, SMITH M, LIDDLE GW. Inhibition of aldosterone secretion and modification of electrolyte excretion in man by a chemical inhibitor of 11 beta-hydroxylation. J Clin Invest 1959; 38:2101.
- Verhelst JA, Trainer PJ, Howlett TA, et al. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome. Clin Endocrinol (Oxf) 1991; 35:169.
- Schteingart DE. Drugs in the medical treatment of Cushing's syndrome. Expert Opin Emerg Drugs 2009; 14:661.
- Feelders RA, Hofland LJ, de Herder WW. Medical treatment of Cushing's syndrome: adrenal-blocking drugs and ketaconazole. Neuroendocrinology 2010; 92 Suppl 1:111.
- Daniel E, Aylwin S, Mustafa O, et al. Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients. J Clin Endocrinol Metab 2015; 100:4146.
- Aron DC, Schnall AM, Sheeler LR. Cushing's syndrome and pregnancy. Am J Obstet Gynecol 1990; 162:244.
- Buescher MA, McClamrock HD, Adashi EY. Cushing syndrome in pregnancy. Obstet Gynecol 1992; 79:130.
- Bertagna X, Pivonello R, Fleseriu M, et al. LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab 2014; 99:1375.
- Forman SA. Clinical and molecular pharmacology of etomidate. Anesthesiology 2011; 114:695.
- Wagner RL, White PF, Kan PB, et al. Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N Engl J Med 1984; 310:1415.
- Fry DE, Griffiths H. The inhibition by etomidate of the 11 beta-hydroxylation of cortisol. Clin Endocrinol (Oxf) 1984; 20:625.
- de Jong FH, Mallios C, Jansen C, et al. Etomidate suppresses adrenocortical function by inhibition of 11 beta-hydroxylation. J Clin Endocrinol Metab 1984; 59:1143.
- Wagner RL, White PF. Etomidate inhibits adrenocortical function in surgical patients. Anesthesiology 1984; 61:647.
- Fraser R, Watt I, Gray CE, et al. The effect of etomidate on adrenocortical function in dogs before and during hemorrhagic shock. Endocrinology 1984; 115:2266.
- Fellows IW, Bastow MD, Byrne AJ, Allison SP. Adrenocortical suppression in multiply injured patients: a complication of etomidate treatment. Br Med J (Clin Res Ed) 1983; 287:1835.
- Schulte HM, Benker G, Reinwein D, et al. Infusion of low dose etomidate: correction of hypercortisolemia in patients with Cushing's syndrome and dose-response relationship in normal subjects. J Clin Endocrinol Metab 1990; 70:1426.
- NELSON AA, WOODARD G. Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2,2-bis(parachlorophenyl)-1,1-dichloroethane (DDD or TDE). Arch Pathol (Chic) 1949; 48:387.
- CUETO C, BROWN JH, RICHARDSON AP Jr. Biological studies on an adrenocorticolytic agent and the isolation of the active components. Endocrinology 1958; 62:334.
- Kamenický P, Droumaguet C, Salenave S, et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metab 2011; 96:2796.
- BLEDSOE T, ISLAND DP, NEY RL, LIDDLE GW. AN EFFECT OF O,P'-DDD ON THE EXTRA-ADRENAL METABOLISM OF CORTISOL IN MAN. J Clin Endocrinol Metab 1964; 24:1303.
- Chortis V, Taylor AE, Schneider P, et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5α-reductase, explaining the need for personalized glucocorticoid and androgen replacement. J Clin Endocrinol Metab 2013; 98:161.
- Yeung SC, Chiu AC, Vassilopoulou-Sellin R, Gagel RF. The endocrine effects of nonhormonal antineoplastic therapy. Endocr Rev 1998; 19:144.
- Robinson BG, Hales IB, Henniker AJ, et al. The effect of o,p'-DDD on adrenal steroid replacement therapy requirements. Clin Endocrinol (Oxf) 1987; 27:437.
- van Seters AP, Moolenaar AJ. Mitotane increases the blood levels of hormone-binding proteins. Acta Endocrinol (Copenh) 1991; 124:526.
- Takamatsu J, Kitazawa A, Nakata K, et al. Does mitotane reduce endogenous ACTH secretion? N Engl J Med 1981; 305:957.
- Zatelli MC, Gentilin E, Daffara F, et al. Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model. Endocrinology 2010; 151:2453.
- Leiba S, Weinstein R, Shindel B, 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) 1989; 50:49.
- Hogan TF, Citrin DL, Johnson BM, et al. o,p'-DDD (mitotane) therapy of adrenal cortical carcinoma: observations on drug dosage, toxicity, and steroid replacement. Cancer 1978; 42:2177.
- Gaillard RC, Poffet D, Riondel AM, Saurat JH. RU 486 inhibits peripheral effects of glucocorticoids in humans. J Clin Endocrinol Metab 1985; 61:1009.
- Bertagna X, Basin C, Picard F, et al. Peripheral antiglucocorticoid action of RU 486 in man. Clin Endocrinol (Oxf) 1988; 28:537.
- Bertagna X, Bertagna C, Laudat MH, et al. Pituitary-adrenal response to the antiglucocorticoid action of RU 486 in Cushing's syndrome. J Clin Endocrinol Metab 1986; 63:639.
- Fleseriu M, Biller BM, Findling JW, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab 2012; 97:2039.
- Castinetti F, Fassnacht M, Johanssen S, et al. Merits and pitfalls of mifepristone in Cushing's syndrome. Eur J Endocrinol 2009; 160:1003.
- Bilgin YM, van der Wiel HE, Fischer HR, De Herder WW. Treatment of severe psychosis due to ectopic Cushing's syndrome. J Endocrinol Invest 2007; 30:776.