Medical therapy in severe hypercortisolism.

Abstract

Severe hypercortisolism is characterized as a life-threatening endocrine condition in patients with Cushing syndrome, usually related to the concomitant onset of one or more comorbidities, requiring rapid normalization of cortisol concentrations and aggressive treatment of associated complications. It is mainly, but not exclusively, caused by ectopic ACTH syndrome, and the diagnosis of severity is more accurate when is based on simultaneous evaluation of the clinical course and manifestations of the disease, cortisol levels and systematic search of comorbidities. Once the severity and imminent risk to life are established, urgent therapeutic measures must be taken and etiological investigation postponed until the patient is stabilized. Adrenal steroidogenesis inhibitors (mainly etomidate, ketoconazole, and metyrapone), alone or in combined therapy, are commonly the first-line treatment for severe hypercortisolemia due to their rapid action, good efficacy and safety profile. The new drug osilodrostat is a future potential candidate to be included in the list. The glucocorticoid receptor antagonist mifepristone has also a rapid action, but its use has been limited due to difficulties to monitor its efficacy and safety. Other slow-acting cortisol-lowering drugs (mainly mitotane, cabergoline, and pasireotide) might be included in the therapeutic scheme to synergize and overcome a possible escape phenomenon frequently observed with the fast-acting drugs in the prolonged follow-up. When medical therapies fail, are unavailable or contra-indicated, bilateral adrenalectomy should be indicated as a life-saving measure. Adrenal arterial embolization is rarely encountered in routine clinical practice, being a last alternative in specialized centers when all other options fail or are contra-indicated.