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Mechanisms of hypothalamic-pituitary-adrenal axis suppression and recovery after long-term glucocorticoids

Award Number: K08DK142004
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Mechanisms of hypothalamic-pituitary-adrenal axis suppression and recovery after long-term glucocorticoids - Project Summary/Abstract Chronic glucocorticoids can suppress the hypothalamic-pituitary-adrenal (HPA) axis for up to a year after steroids are withdrawn, rendering patients vulnerable to life-threatening adrenal crises. In humans, this has been largely attributed to prolonged hypothalamic-pituitary suppression after glucocorticoid withdrawal. In a novel preclinical model of glucocorticoid-induced adrenal insufficiency (GIAI), we demonstrated that mice have delayed recovery of corticosterone (CORT) secretion after chronic dexamethasone (DEX) treatment despite early restoration of hypothalamic-pituitary function. Previously undescribed, giant macrophages infiltrated DEX- exposed adrenals, but CORT secretion was disproportionately low relative to the size of the adrenal cortex even after excluding these macrophages for up to 2 weeks after DEX withdrawal. Having established the adrenal as the major site of post-withdrawal GIAI, we then tested whether trophic support to the gland during the period of DEX exposure prevented GIAI. CORT secretion recovered more slowly in mice treated with dexamethasone and daily, intraperitoneal cosyntropin vs. DEX alone. However, maintenance of endogenous ACTH signaling during the period of DEX exposure using transgenic mice preserved adrenal mass and function on long-term steroids. Aim 1 of this grant tests two potential mechanisms of ACTH hypo- responsiveness after cessation of chronic glucocorticoids. First, we hypothesize that actively replicating zona fasciculata (zF) cells downregulate steroidogenic pathway genes as a trade-off between proliferative vs. biosynthetic function (Aim 1a). This will be assayed in a spatially informed, single-cell manner using fluorescent in situ hybridization for steroidogenic pathway genes multiplexed with immunofluorescence for proliferative markers. Aim 1b tests the hypothesis that activated, Trem2-positive adrenal macrophages contribute to post- withdrawal GIAI via paracrine suppression of StAR, the rate limiting enzyme in CORT biosynthesis, in zF cells. CORT secretion and StAR expression will be measured one week after discontinuing chronic DEX in mice following 1) global macrophage depletion with a CSF1R-blocking antibody, and 2) macrophage-specific Trem2 deletion vs. controls. In Aim 2b, we aim to develop a pharmacologic strategy that phenocopies our prior genetic model and prevents GIAI by providing constant, potentially CRH-driven, ACTH stimulation to the adrenal during the period of glucocorticoid exposure. Mice will be treated with long-term DEX and either constant a) CRH, b) cosyntropin, or c) vehicle via osmotic minipump. HPA axis function and histology will be assessed at the time of and 1 week after treatment completion. Pharmacokinetic studies will quantify systemic ACTH exposure on treatment. In Aim 3, we investigate whether early hypothalamic-pituitary recovery occurs in children withdrawn from chronic glucocorticoids, as observed in mice. Early, post-withdrawal ACTH levels will be compared to controls, and median time to axis recovery will be calculated. These studies may collectively inform the development of therapies that prevent or expedite recovery from GIAI.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $168,543 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/17/2026	NEW	$168,543
														Subtotal = $168,543

Grand Total All Awards = $168,543

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Mechanisms of hypothalamic-pituitary-adrenal axis suppression and recovery after long-term glucocorticoids

Award Number: K08DK142004

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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