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.
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LA Nolan, CK Thomas, and A Levy
We have previously identified a series of age-dependent, temporally constrained and closely interdependent mitotic and apoptotic events in the male rat anterior pituitary that occur in response to timed single and repeated hypothalamo-pituitary-adrenal axis stimuli. One of the most dramatic of these is the short burst of apoptosis that occurs 24-48 h after exposure to dexamethasone. If bilateral adrenalectomy precedes exposure to dexamethasone by 1-2 weeks, mitotic activity is transiently increased and the subsequent apoptotic response to dexamethasone greatly enhanced. This study was designed to determine whether adrenalectomy-induced augmentation of the apoptotically sensitive pituitary cell population is mediated via glucocorticoid withdrawal at the level of the pituitary, or whether increased exposure to hypothalamo-hypophyseal trophic hormones of paraventricular origin is responsible. We used stereotaxic surgery to isolate both paraventricular nuclei without disturbing either median eminence input from the arcuate and supraoptic nuclei, or the hypothalamo-hypophyseal-portal blood flow that carries a significant proportion of the pituitary systemic supply. When bilateral adrenalectomy and paraventricular nucleus disconnection were combined, the adrenalectomy-induced increase in anterior pituitary pro-opiomelanocortin (POMC) transcript prevalence was abolished, confirming the loss of paraventricular corticotrophin-releasing hormone (CRH) input. However, the amplitude and pattern of the adrenalectomy-induced anterior pituitary mitotic response and enhancement of the apoptotic response to dexamethasone 1 week later remained completely intact. These data demonstrate that anterior pituitary trophic responses following bilateral adrenalectomy are more likely to be mediated through direct glucocorticoid withdrawal at the level of the pituitary rather than via changes in hypothalamo-hypophyseal releasing factor exposure. This finding highlights the presence of distinct control systems for pituitary hormone gene expression and pituitary mitotic and apoptotic responses.
LA Nolan, CK Thomas, and A Levy
The anterior pituitary is active mitotically and apoptotically under basal conditions and in response to a variety of physiological and pathophysiological stimuli. Hypothyroidism in man is associated with a modest but very occasionally dramatic increase in overall pituitary size. The mechanisms underlying this reversible phenomenon remain obscure. In the present study we have examined young adult rat anterior pituitary following surgical thyroidectomy and subsequent thyroid hormone treatment and withdrawal using an extremely accurate system for quantifying directly identified mitotic and apoptotic events. Despite the expected increase in the number and/or proportion of immunohistochemically identifiable thyrotrophs three weeks after thyroidectomy, mitotic and apoptotic activity remained unchanged, as did pituitary wet weight, in comparison with sham-operated and intact controls. In contrast, mitotic but not apoptotic activity was enhanced by treatment of thyroidectomized animals with thyroid hormones (triiodothyronine (T3) and thyroxine (T4) 1.8 microg and 3.6 microg/100 g body weight per day respectively), and once again declined to levels seen in intact animals within 72 h of subsequent thyroid hormone withdrawal. Thyroid hormone-induced enhancement of mitotic activity was also seen in intact rats treated with similar doses of thyroid hormones for 7 days and in thyroidectomized rats treated for a similar period with very low dose thyroid hormone replacement at a level that had no effect on raised hypothalamic TRH- or pituitary TSHbeta-transcript prevalence (0.018 microg T3 plus 0.036 microg T4/100 g body weight per day). Thus changes in mitotic and apoptotic activity are unlikely to be the principle mechanism for the apparent increase in thyrotrophs up to 4 weeks after thyroidectomy. In contrast, the data indicate that thyroid hormones have a permissive effect on anterior pituitary mitotic activity in thyroidectomized male rats. Thyroid hormone-induced enhancement of mitotic activity in intact rats further suggests that in euthyroid rats, ambient thyroid hormone levels are a limiting factor for anterior pituitary mitotic activity. In summary, this time course study of young, male rats has shown for the first time that thyroidectomy, thyroid hormone replacement and subsequent withdrawal has no significant effect on anterior pituitary apoptotic activity. Secondly, it has shown that the anterior pituitary mitotic response to thyroidectomy is blocked by complete thyroid hormone deprivation, but can be restored by very low level thyroid hormone replacement, and thirdly that in intact animals thyroid hormone levels significantly limit anterior pituitary mitotic activity.