Rapid hypothalamic-pituitary recovery after chronic glucocorticoid therapy enables strategies that prevent adrenal suppression

Glucocorticoid-induced adrenal insufficiency (GIAI) can persist for months after discontinuation of chronic corticosteroid therapy, placing patients at risk for life-threatening adrenal crises. This prolonged suppression has been attributed primarily to delayed restoration of hypothalamic-pituitary signaling based on indirect, clinical measures of central axis activity. To identify the rate-limiting site of hypothalamic-pituitary-adrenal (HPA) axis recovery, we systematically evaluated the timing of functional and histologic recovery at each node of the axis following 8 weeks of dexamethasone (DEX) treatment in mice. DEX administration fully suppressed HPA axis activity. Unexpectedly, within one week of DEX withdrawal, hypothalamic Crh mRNA and plasma ACTH rebounded above control levels, whereas corticosterone (CORT) remained suppressed for an additional seven weeks. DEX-treated adrenals were markedly atrophic and contained large clusters of lipid-associated macrophages. Even after adjusting for macrophage content, CORT secretion was disproportionately low relative to the remaining adrenocortical cell mass despite supraphysiologic ACTH stimulation. These findings identify the adrenal gland, rather than the hypothalamus or pituitary, as the principal site of persistent dysfunction following glucocorticoid withdrawal. We next tested whether preserving adrenal trophic signaling during glucocorticoid exposure could prevent GIAI. Co-treatment with DEX and daily cosyntropin (a synthetic ACTH analog) failed to preserve adrenal function. In contrast, mice with non-suppressible endogenous ACTH due to targeted deletion of Nr3c1 (encoding the glucocorticoid receptor) in hypothalamic neurons maintained normal adrenal architecture and steroidogenic capacity despite prolonged DEX treatment. Pharmacologic treatments that mimic sustained, physiologic trophic signaling to the adrenal during chronic glucocorticoid treatment may thus prevent GIAI.