Enhanced anterior pituitary mitotic response to adrenalectomy after multiple glucocorticoid exposures

Abstract

Objectives: Glucocorticoid withdrawal in man is associated with transient but sometimes prolonged impairment of hypothalamo -pituitary -adrenal axis secretory responsiveness. This has led to continued concern in the clinical arena. The acute anterior pituitary response to glucocorticoids in the rat includes apoptosis-mediated deletion of a cell population. Whilst continued cell turnover following glucocorticoid withdrawal and the potential for differentiation of uncommitted precursor cells and transdifferentiation of other secretory cell types predicts that, given sufficient time, complete anterior pituitary trophic recovery is likely, this hypothesis has not previously been tested. Design and methods: We have quantified pituitary mitotic and apoptotic rate, as well as corticotroph number and pro-opiomelanocortin transcript prevalence, together with hypothalamic corticotrophin-releasing hormone and vasopressin transcript prevalence 5 weeks after three short dexamethasone treatments each separated by a week. Bilateral adrenalectomy was then carried out as a maximal secretory and trophic stimulus, and the response to a fourth dexamethasone treatment assessed 1 week later. Results: Anterior pituitary mitotic index was significantly higher in rats previously exposed to dexamethasone compared with age-matched controls exposed to dexamethasone for the first time. No differences were found in the subsequent apoptotic response to a fourth dexamethasone treatment or in the levels of paraventricular corticotrophin-releasing hormone or vasopressin transcripts or pituitary pro-opiomelanocortin transcripts. Conclusions: These data indicate that full recovery of pituitary mitotic activity takes longer than the recovery of secretory parameters, and suggest that, for several weeks after glucocorticoid exposure, the ability of the pituitary to meet fresh demands placed on it may be suboptimal.

Lack of Annexin 1 Results in an Increase in Corticotroph Number in Male but not Female Mice

“…The clustering of corticotrophs in the male ANXA1 null pituitary strongly suggests that cell proliferation was the cause of the approximately four‐fold increase in corticotrophs. Corticotroph turnover is dependent on the mitogenic actions of corticotropin‐releasing hormone (CRH) (32–34) and the antiproliferative and pro‐apoptotic actions of glucocorticoids (35). The striking increase in corticotrophs in male ANXA1 null mice initially suggested that in males, but not females, a lack of ANXA1‐mediated glucocorticoid feedback at the hypothalamus (36) had increased CRH secretion causing proliferation of corticotrophs.…”

Physiological Studies of Stress Responses in the Hypothalamus of Vasopressin‐Enhanced Green Fluorescent Protein Transgenic Rat

“…Dexamethasone (0.3 ml; approximately 50 µg/100 g) was administered subcutaneously between 16.00 h and 19.00 h for the first 3 consecutive days after ADX. The treated rats also received dexamethasone in their drinking water [0.75 µg/ml dexamethasone in 0.9% (w/v) saline available ad libitum ] after ADX until they were sacrificed; modified from (19). Five days after surgery, the same procedures as experiment 1 were used to sacrifice all animals and prepare hypothalamic sections.…”