Effective Medical Therapy for Cushing Disease Can Increase the Susceptibility to Relative Hypocortisolism

Abstract

Objective: Pasireotide is approved for treatment of adults with Cushing disease (CD) with persistent hypercortisolism for whom surgery has failed or is not an option. Effective medical therapy for CD may increase the susceptibility of relative hypocortisolism during acute stress because of a patient's inability to compensate by increasing endogenous adrenocorticotropic hormone (ACTH) and cortisol secretion. We describe a patient with CD on pasireotide therapy for 7 years in whom biochemical eucortisolemia was achieved but subsequently experienced several distinct episodes of relative hypocortisolism during periods of acute illness. Methods: A 67-year-old man with biochemical confirmation of CD exhibited clinical and biochemical features of persistent hypercortisolism after transsphenoidal surgery despite pituitary magnetic resonance imaging showing no residual or recurrent tumor. He was enrolled into a phase 3 study (NCT00434148) and was initated on twice-daily subcutaneous pasireotide. Results: Long-term pasireotide therapy normalized 24-hour urinary free cortisol, serum cortisol, and ACTH levels. The patient subsequently developed type 2 diabetes mellitus and was managed effectively with oral hypoglycemic agents and insulin therapy. During a routine clinic assessment 79 months after study enrollment, he reported symptoms suggestive of relative hypocortisolism during three distinct substantially acute stressful health events in the preceding 18 months. Conclusion: Successful achievement of eucortisolemia with long-term medical therapy may increase susceptibility to relative hypocortisolism and precipitate symptoms of adrenal insufficiency during periods of acute stress in patients with CD. We recommend that such patients should be counseled on glucocorticoid stress dosing to prevent such events that could lead to adrenal crisis. Abbreviations: ACTH adrenocorticotropic hormone CD Cushing disease FPG fasting plasma glucose GH growth hormone HbA1c hemoglobin A1c T2DM type 2 diabetes mellitus TSS transsphenoidal surgery UFC urinary free cortisol