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.