Prevention of adrenal suppression after chronic glucocorticoid therapy in mice

Glucocorticoid-induced adrenal insufficiency (GIAI) can persist for months after cessation of chronic corticosteroid therapy, predisposing patients to life-threatening adrenal crises. The mechanisms underlying this prolonged suppression are poorly understood but have been primarily attributed to delayed recovery of hypothalamic-pituitary function. We examined the timing of hypothalamic, pituitary, and adrenal (HPA) recovery after 8 weeks of dexamethasone (DEX) treatment in mice. During DEX exposure, HPA axis activity was fully suppressed. Surprisingly, within one week of withdrawal, Crh mRNA and plasma ACTH rebounded above control levels, yet corticosterone (CORT) remained low for an additional seven weeks. DEX-treated adrenals were atrophic and contained large clusters of lipid-associated macrophages. Even after accounting for these macrophages, CORT secretion was disproportionately low relative to the size of the adrenocortical cell mass despite supraphysiologic ACTH stimulation. With the adrenal being the primary site of post-withdrawal HPA axis suppression, we assessed whether trophic stimulation of the adrenal using either a pharmacologic or genetic approach prevented GIAI. Co-treatment with DEX and daily cosyntropin, an ACTH agonist, failed to prevent GIAI. However, mice with non-suppressible endogenous ACTH due to targeted deletion of Nr3c1 (encoding the glucocorticoid receptor) in hypothalamic neurons maintained normal adrenal function and histology despite long-term DEX. Translating this genetic approach to a pharmacological one by delivering sustained trophic support to the adrenal during the period of glucocorticoid exposure may prevent GIAI.