Friedman, H. R. | bioRxiv Science

bioRxiv2025

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 measures of central axis activity. To identify the rate-limiting site of hypothalamic-pituitary-adrenal (HPA) axis recovery, we evaluated the timing of functional and histologic recovery at each node of the axis following 8 weeks of dexamethasone (DEX) treatment in adult, male 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-filled macrophages. Even after adjusting for macrophage content, CORT secretion was disproportionately low relative to the remaining adrenocortical cell mass despite supraphysiologic ACTH stimulation. The adrenal is thus the principal site of post-withdrawal GIAI, involving adrenocortical cell loss and a superimposed defect in steroidogenesis. We next tested whether preserving adrenal trophic signaling during glucocorticoid exposure could prevent GIAI. Adrenal function recovered more slowly in mice treated with DEX and daily cosyntropin (a synthetic ACTH analog) compared to those treated with DEX alone. In contrast, mice with non-suppressible endogenous ACTH due to targeted hypothalamic deletion of the glucocorticoid receptor maintained normal adrenal architecture and steroidogenic capacity despite prolonged DEX treatment. Pharmacologic treatments that mimic sustained trophic signaling to the adrenal during chronic glucocorticoid treatment may thus prevent GIAI.

physiology↗

bioRxiv2024

Absent, but not glucocorticoid-modulated, corticotropin-releasing hormone (Crh) regulates anxiety-like behaviors in mice

The hypothalamic-pituitary-adrenal (HPA) axis is a well characterized endocrine response system. Hypothalamic Crh in the paraventricular nucleus of the hypothalamus (PVH) initiates HPA axis signaling to cause the release of cortisol (or corticosterone in rodents) from the adrenal gland. PVH-specific deletion of Crh reduces anxiety-like behaviors in mice. Here we report that manipulation of PVH Crh expression in primary adrenal insufficiency or by dexamethasone (DEX) treatment do not alter mouse anxiety behaviors. In Experiment 1, we compared wildtype (WT) mice to those with primary adrenal insufficiency (MrapKO) or global deletion of Crh (CrhKO). We analyzed behaviors using open field (OF) and elevated plus maze (EPM), PVH Crh mRNA expression by spatial transcriptomics, and plasma ACTH and corticosterone after a 15-minute restraint test with ELISAs. EPM analysis showed CrhKO mice were less anxious than WT and MrapKO mice, and MrapKO mice had no distinguishing behavioral phenotype. In Experiment 2, we evaluated HPA axis habituation to chronically elevated Crh expression by comparing mice treated with 5-8 weeks of DEX with those similarly treated followed by DEX withdrawal for 1 week. All mice regardless of genotype and treatment showed no significant behavioral differences. Our findings suggest that reduced anxiety associated with low Crh expression requires extreme deficiency, perhaps outside of those PVH Crh neurons negatively regulated by glucocorticoids. If these findings extend to humans, they suggest that increases in Crh expression with primary adrenal insufficiency, or decreases with exogenous glucocorticoid therapy, may not alter anxiety behaviors via modulation of Crh expression.

neuroscience↗