The authors (Lindsey S. Gaston, Brenna C. Jorgensen, Hannah R. Friedman, Marc S. Sherman, Joseph A. Majzoub) of this preprint identified that the adrenal is the bottleneck for corticosterone recovery in a mouse model after long-term exposure to dexamethasone putting the focus on the adrenal for therapy. Access the preprint here.
Key Highlights
1. Rapid central recovery, but prolonged adrenal failure after withdrawal from long-term dexamethsone (8 weeks)
- Hypothalamic and pituitary function rebound within one week of steroid withdrawal, with CRH expression and ACTH secretion returning to, or exceeding, baseline levels.
- Adrenal glucocorticoid output (corticosterone) remains suppressed for up to eight weeks
2. The adrenal and not the brain is the bottleneck in recovery
- Adrenal steroid output remains disproportionately low relative to recovered adrenocortical mass for at least two weeks after steroid withdrawal
- Adrenal mass rebound quickly after withdrawal, but steroidogenic capacity lags behind
3. Structural and cellular remodeling of the adrenal gland
Chronic glucocorticoid exposure induces:
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Marked adrenocortical atrophy
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Accumulation of large, lipid-laden adrenal macrophage clusters at the corticomedullary junction, that persists beyond 8 weeks after withdrawal
4. Continuous endogenous ACTH signaling is protective; intermittent ACTH is not
- Pharmacologic ACTH (daily cosyntropin injections) during dexamethasone exposure fails to prevent adrenal suppression
- Mice genetically engineered to maintain non-suppressible, CRH-driven endogenous ACTH signaling retain normal adrenal morphology and function throughout chronic glucocorticoid exposure
Implications
This study challenges a decades-old clinical paradigm that attributes prolonged adrenal insufficiency primarily to delayed hypothalamic or pituitary recovery. Instead, it positions the adrenal gland as the principal site of persistent dysfunction after glucocorticoid withdrawal.
Because the adrenal is anatomically and pharmacologically accessible, these findings open the door to preventive strategies focused on sustaining adrenal trophic signaling during glucocorticoid therapy.
Limitations and Open Questions
1. Preclinical model
While the murine HPA axis is highly conserved, direct translation to humans is not guaranteed, particularly with respect to recovery timelines and dosing equivalency.
2. Sex-specific effects not addressed
Only male mice were studied. However, adrenal biology and HPA axis dynamics are sexually dimorphic, warranting future investigation in females.
3. Mechanism of impaired steroidogenesis remains unresolved
The molecular basis of reduced steroid output and the role of adrenal macrophages remains to be defined.
4. Genetic model is not directly therapeutic
While hypothalamic GR deletion elegantly proves principle, it is not a clinically deployable strategy. Translating “sustained trophic signaling” into safe, controllable therapies remains a major challenge.
Bottom Line
This preprint provides compelling evidence that glucocorticoid-induced adrenal insufficiency is fundamentally an adrenal problem, not a failure of hypothalamic-pituitary recovery. By shifting the focus downstream, it reframes both our understanding of glucocorticoid-iduced adrenal insuffciency and the strategy space for preventing it.