Anterior pituitary trophic responses to dexamethasone withdrawal and repeated dexamethasone exposures

Glucocorticoid withdrawal, depending on the dose and duration of treatment, results in a transient but sometimes prolonged reduction in hypothalamo-pi tuitary-adrenal (HPA) axis secretory responsiveness. As the anatomic basis of HPA axis suppression remains uncertain, we have directly examined change s in trophic activity within the rat anterior pituitary gland following dex amethasone withdrawal and re-treatment. Treatment of adrenalectomised. male Wistar rats with dexamethasone results in a discrete, highly significant b urst of apoptosis in the anterior pituitary with concurrent suppression of mitosis. Despite a surge in mitotic activity immediately after dexamethason e withdrawal, calculated total anterior pituitary cell populations remain b elow that seen in untreated adrenalectomised controls. Repeated exposures t o dexamethasone show that the dexamethasone-sensitive cell population that is deleted by apoptosis is partially but not completely restored. As the am plitude of apoptotic bursts induced by second and third dexamethasone expos ures are similar but smaller than that induced by initial exposure, it appe ars that the very first exposure to dexamethasone deletes a subset of anter ior pituitary cells that are either not restored at all, or are only replac ed very slowly. The reduced proportion of corticotrophs contributing to the increase in mitotic index after dexamethasone withdrawal corroborates this . Although continued cell turnover within the pituitary predicts that the a bsolute cellular deficit would diminish with time, the effects seen may con tribute to the delayed recovery of pituitary axis function following cessat ion of glucocorticoid treatment.