Anterior pituitary trophic responses to dexamethasone withdrawal and repeated dexamethasone exposures

Abstract

Glucocorticoid withdrawal, depending on the dose and duration of treatment, results in a transient but sometimes prolonged reduction in hypothalamo-pituitary-adrenal (HPA) axis secretory responsiveness. As the anatomic basis of HPA axis suppression remains uncertain, we have directly examined changes in trophic activity within the rat anterior pituitary gland following dexamethasone withdrawal and re-treatment. Treatment of adrenalectomised, male Wistar rats with dexamethasone results in a discrete, highly significant burst of apoptosis in the anterior pituitary with concurrent suppression of mitosis. Despite a surge in mitotic activity immediately after dexamethasone withdrawal, calculated total anterior pituitary cell populations remain below that seen in untreated adrenalectomised controls. Repeated exposures to dexamethasone show that the dexamethasone-sensitive cell population that is deleted by apoptosis is partially but not completely restored. As the amplitude of apoptotic bursts induced by second and third dexamethasone exposures are similar but smaller than that induced by initial exposure, it appears that the very first exposure to dexamethasone deletes a subset of anterior pituitary cells that are either not restored at all, or are only replaced 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 absolute cellular deficit would diminish with time, the effects seen may contribute to the delayed recovery of pituitary axis function following cessation of glucocorticoid treatment.

The parvocellular vasopressinergic system and responsiveness of the hypothalamic pituitary adrenal axis during chronic stress

“…These observations render unlikely that the increase in corticotrophs originates from the division of existing corticotrophs or already differentiated corticotroph precursors, but suggests that recruitment of corticotrophs during adrenalectomy occurs from undifferentiated cells. Other studies have also shown lack of co-localization of BrdU in corticotrophs following adrenalectomy (Gulyas et al, 1991;Nolan & Levy, 2001;Taniguchi et al, 1995). Nolan and Levy, (Nolan & Levy, 2006) also reported a minor incidence of mitogenesis in corticotrophs or gonadotrophs following 3-and 6-days adrenalectomy or gonadectomy in rats.…”

Enhanced anterior pituitary mitotic response to adrenalectomy after multiple glucocorticoid exposures

“…As unequivocal histological signs of apoptosis only appear when nuclear and cytoplasmic contents have been degraded, quantification of hormone transcripts or protein markers cannot be used to determine the prior phenotype of this population of cells. Subsequent withdrawal of dexamethasone elicits a further mitotic response, but this is not sufficient to restore the apoptotically sensitive cell population in adrenalectomized animals within the 2-week time frames of our previous studies (2).…”

“…the post-adrenalectomy mitotic surge remain uncertain (2,14,23,24). Dexamethasone induces a reproducible, temporally constrained burst of apoptotic activity in the anterior pituitary within 24 h of exposure (1, 2).…”

“…We have previously shown that when the recovery period after glucocorticoid withdrawal is # 2 weeks, the peak of anterior pituitary apoptotic activity induced by a second or third exposure to dexamethasone is significantly lower than that seen in adrenalectomized age-matched controls exposed to dexamethasone for the first time (2). This decline occurred irrespective of whether the first dose of dexamethasone is given to adrenalectomized or to intact animals.…”

“…In addition to rapid changes in hormone secretion, the anterior pituitary is able to mount mitotic and apoptotic responses to single and recurrent stimuli and their withdrawal (1,2). A degree of secretory, mitotic and apoptotic plasticity within the pituitary might enhance responses to recurrent stimuli.…”