Aligning treatment to physiology: when to use chronotherapy, block and replace, or titration to treat hypercortisolism.

Medical treatment of Cushing syndrome (CS) with steroidogenesis inhibitors or ACTH-directed agents is typically given using a titration strategy to achieve "normal" exposure to cortisol, as determined by a 24-hour urine free cortisol (UFC) measurement. This approach generally achieves similar serum cortisol levels across the day and fails to provide a normal diurnal pattern of cortisol. Chronotherapy addresses this problem through weighted afternoon/evening dosing of cortisol-lowering drugs. Additionally, because of day-to-day variability of cortisol production, patients may be undertreated on days of higher cortisol production and overtreated on days of lower cortisol production. A "block and replace" strategy is an alternative approach in which consistent biochemical glucocorticoid deficiency is the goal, with added glucocorticoid replacement to provide physiologic diurnal exposure to cortisol. Recently, the term mild autonomous cortisol secretion (MACS) has been used to describe patients without clinical features of CS who fail to suppress cortisol after 1 mg dexamethasone. MACS includes individuals with an adrenal mass(es) who may have hypertension, type 2 diabetes mellitus, and/or osteoporosis. The role of medical vs surgical treatment of MACS is currently debated. We here review the advantages and disadvantages of each approach to medical treatment of CS and MACS, concluding that "block and replace" deserves wider consideration, especially in patients who have severe disease, and to avoid adrenal insufficiency in those with highly variable UFC, or are taking agents that may cause adrenal insufficiency. Conversely, in those with mild disease, chronotherapy normalizes nighttime cortisol exposure while reducing drug burden.