Endocrine Abstracts

Background: Glucocorticoids are prescribed for >3 months to 1% of the UK population, principally to control inflammation. In 10–30% of patients, chronic glucocorticoid treatment suppresses HPA axis activity, causing atrophy of the adrenals and a failure to mount an adequate response during stress (potentially fatal) and following treatment withdrawal. Understanding the mechanisms resulting in HPA axis failure may allow us to predict those at risk, inform treatment strategies and reduce the potential risks of adrenal insufficiency. To explore these mechanisms, we have developed a mouse model of GC-induced HPA axis dysfunction.

Methods: 36 C57Bl6 12-week-old male mice were randomly assigned to receive Dexamethasone (DEX) (10 μg/day) or vehicle (CTL) via drinking water for four weeks. At 4 weeks (time 0) both groups received only water. Tissues were harvested at 0, 1 and 4 weeks following withdrawal of treatment. Serum 11-Deoxycorticosterone and Corticosterone were measured by LCMS/MS. Hypothalamus, pituitary and adrenal gene expression was assessed by qPCR.

Results: Dexamethasone treatment inhibited growth (weight at week 0, CTL:27.7±0.8 g DEX:23.0±0.9 g P<0.001) and resulted in adrenal atrophy at 4 weeks (CTL:5.8±0.5 DEX:4.6±0.1 mg). DEX treatment suppressed serum 11-Deoxycorticosterone (CTL:1.1±0.2 nM DEX:0.1±0.01 nM P<0.001) and Corticosterone (CTL: 58.6±21.5 nM 2.9±1.8 nM P<0.001) at week 0, which recovered by week 1. DEX treatment had no effect on Pomc, Nr3c1 or Crhr1 expression in whole pituitary, or on Avp or Crh expression in hypothalamus. In the adrenal, at time 0, Hsd3b2 and Cyp11a1 expression was reduced and Nr3c1 was increased; these returned to control level by 4 weeks.

Conclusion: Four weeks dexamethasone treatment in mice results in HPA axis dysfunction and adrenal atrophy which recovers 1 week following treatment withdrawal. Dysregulation occurs mainly at the level of the adrenal glands.