Pharmacological management of severe Cushing's syndrome: the role of etomidate

Abstract

Cushing's syndrome (CS) is an endocrine disease characterized by excessive adrenocortical steroid production. One of the mainstay pharmacological treatments for CS are steroidogenesis enzyme inhibitors, including the antifungal agent ketoconazole along with metyrapone, mitotane, and aminoglutethimide. Recently, osilodrostat was added to this drug class and approved by the US Food and Drug Administration (FDA) for the treatment of Cushing's Disease. Steroidogenesis enzyme inhibitors inhibit various enzymes along the cortisol biosynthetic pathway and may be used preoperatively to lower cortisol levels and reduce surgical risk associated with tumor resection or postoperatively when surgery and/or radiation therapies are not curative. Because their selectivities for steroidogenic enzymes vary, they may even be administered in combination to achieve relatively rapid control of severe hypercortisolemia. Unfortunately, all currently available inhibitors are accompanied by serious adverse side effects that limit dosing and often result in treatment failures. Although more commonly known as a general anesthetic induction agent, etomidate is another member of the steroidogenesis enzyme inhibitor drug class. It suppresses cortisol production primarily by inhibiting 11β-hydroxylase and is the only inhibitor that may be given parenterally. However, the sedative-hypnotic actions of etomidate limit its use as an acute management option for CS. Thus, some have recommended that it be used only in intensive care settings. In this review, we discuss the initial development of etomidate as an anesthetic agent, its subsequent development as a treatment for CS, and the recent advances in dosing and drug development that dissociate sedative-hypnotic and adrenostatic drug actions to facilitate CS treatment in non-critical care settings.

Keywords: Cushing’s syndrome; corticosterone; cortisol; etomidate.

Figure 1.

Schematic of the hypothalamic-pituitary-adrenal axis with the cortisol and corticosterone biosynthetic pathways emphasized. Etomidate (and many etomidate-based analogs) potently inhibits the action of 11β-hydroxylase, thereby preventing steroidogenesis of cortisol. Etomidate also inhibits cholesterol side-chain cleavage enzyme, but this occurs at higher concentrations than those required to inhibit 11β-hydroxylase. The green arrows symbolize stimulating effects, while red arrows symbolize negative feedback.