Recovery of the rat hypothalamic-pituitary-adrenal axis after discontinuation of prolonged treatment with the synthetic glucocorticoid agonist dexamethasone

To evaluate the recovery of the hypothalamicpituitary- adrenal (HPA) axis after discontinuation of prolonged exposure to glucocorticoids, we employed adult male Sprague- Dawley rats which were implanted sc with osmotic minipumps filled with saline (vehicle) or dexamethasone (DEX), 100 μg/ day, for 7 days. At the end of the glucocorticoid treatment period, the minipumps were removed and both saline- and DEX-treated rats were randomly assigned to five different groups tested at 1, 3, 7, 14, and 21 days after removal of the minipumps. Each group was divided into two subgroups receiving either arecoline (ARE), or ovine CRH (oCRH) stimulation tests. ARE was chosen because it has been shown to selectively stimulate the hypothalamic CRH neuron, whereas oCRH was selected as a probe of the pituitary component of the HPA axis. ARE (0.2 mg/kg) and oCRH (10 μg/kg) were injected iv to catheterized, freely moving rats and serial blood samples for plasma ACTH and corticosterone determinations were drawn from the catheter before, and 5, 15, 30, and 60 min after the injection. The day after the tests were performed, the rats were killed by decapitation, and body, adrenal and thymus weights, as well as hypothalamic CRH and pituitary ACTH content were determined. On the day of the stimulation tests, basal plasma levels of ACTH and corticosterone were not different between saline- and DEX-treated rats at any time-point after discontinuation of treatment. The ACTH response to ARE, on the other hand, was suppressed one day after, but became normal 3 days after discontinuation of DEX treatment. ACTH response to oCRH normalized later, after 7 days. Interestingly, corticosterone responses to both ARE and oCRH normalized 7 days after discontinuation of glucocorticoid administration. Body, adrenal and thymus weights were significantly reduced by DEX treatment. They recovered slowly and only after 22 days there was no difference between DEX- and saline-treated rats in body and adrenal weight. In contrast, thymus weight was still low on day 8, began to increase after 15 days, and by day 22 did not reach the values recorded in salinetreated rats. Hypothalamic immunoreactive CRH content was not different between DEX- and saline-treated rats, whereas the content of ACTH in the pituitary gland was lower in the DEXtreated rats the second day after discontinuation of GC treatment, normalized after 4 days and increased significantly after 8 days. These results suggest that in the rat, prolonged treatment with DEX reduces the ability of each component of the HPA axis to respond to an appropriate stimulus. This reduction is transient. Normalization of the hypothalamus occurs by the third day and of the pituitary gland and the adrenal cortex by the seventh day. This sequence of events is distinctly different from that which has been proposed in human beings.