7448 Endogenous ACTH But Not Intermittent Cosyntropin Prevents Dexamethasone-Induced Adrenal Suppression In Mice

Abstract Disclosure: L.S. Gaston: None. H.R. Friedman: None. J.A. Majzoub: None. Background: Iatrogenic adrenal insufficiency (IAI) can persist for up to a year after withdrawal of long-term glucocorticoids (GC) by unknown mechanisms. We developed a mouse model of IAI in which 8 weeks of dexamethasone (DEX) induced protracted adrenocortical dysfunction despite early ACTH recovery. We then asked if 1) adrenal secretory dysfunction after GC withdrawal exceeded the cellular defect, and 2) ongoing trophic ACTH signaling while on DEX (either exogenous cosyntropin [COS] or endogenous ACTH) prevented IAI. Methods: Adult, male, wild-type C56BL/6J (n=3-6) mice were treated for 8 weeks (long-term) or 4-days (short-term) with DEX ± daily, intraperitoneal COS. At 1-2-week intervals after DEX±COS withdrawal, basal and stimulated ACTH and CORT were measured (mean±SEM) followed by necroscopy for morphometric analysis of immunostained, equatorial adrenal sections. Experiments were repeated in mice with irrepressible, endogenous ACTH due to selective loss of the hypothalamic GC receptor (Sim1-Cre:GR fl/fl, or SGR) and their Cre-negative (WT) littermates. Results: Stimulated corticosterone (CORT) required 8 weeks to normalize after stopping long-term DEX. Notably, both basal (811±220 vs. 216±24 pg/mL) and stimulated (1708±85 vs. 876±44) ACTH increased above controls by 1-week post-withdrawal (p2x higher (10 and 11 mg/dL) than measured CORT (5 for both) at 1- and 2-weeks post-DEX. In subsequent experiments, short-term COS inhibited DEX-induced adrenocortical apoptosis (200±85 vs 1170±481 TUNEL+ cells/HPF, p