CELL-PROLIFERATION AND DEATH IN THE IRRADIATED PITUITARY-GLAND AND ITS MODIFICATION BY GROWTH STIMULANTS

Purpose: This study was undertaken to show whether the rate of express ion of radiation injury in the rat pituitary gland could be accelerate d by the use of growth stimulants. Methods and Materials: Rat pituitar y glands were irradiated in situ with a range of single doses up to 20 Gy. The rats were then given subcutaneous slow-release implants conta ining 17 beta-estradiol (E-2) and sulpiride (S) to stimulate lactotrop h proliferation. Two sequential cycles were used, each consisting of s timulation (3 weeks) and withdrawal (2 weeks). Measurements were made of gland weight; BrdU-labeled, giant, and apoptotic cells; lactotrophs ; as well as pituitary prolactin content, in response to exogenous thy roid-releasing hormone (TRH). Results: The two cycles of stimulation/w ithdrawal resulted in marked changes in gland weight, BrdU-labeling in dex, and serum prolactin (PRL) levels in unirradiated rats. The propor tion of immunopositive growth-hormone-producing (GR) cells increased a fter irradiation. Radiation inhibited the hypertrophic response to E-2 + S and also inhibited increases in BrdU-labeling index and serum PRL levels. Also, giant lactotrophs were observed in the irradiated pitui taries. However, they were not seen in the unirradiated rats or in the irradiated rats treated with E-2 + S. TRH promoted PRL secretion in t he unirradiated rat. In contrast, TRH inhibited PRC secretion in the i rradiated rat and in all treatment groups receiving E-2 + S. Apoptosis was induced by irradiation and was substantially increased in lactotr ophs and in other cell types by withdrawal of the E-2 and S stimulus, although the highest observed incidence was only 7 per 10,000 cells. C onclusion: Both irradiation and E-2 + S treatment removed the hypothal amic control of PRL, secretion, which reveals this important inhibitor y action of TRH upon PRL secretion. This suggests that it is not suita ble as a dynamic test of pituitary PRL reserves in such abnormal situa tions, where there may also be damage to the hypothalamic-pituitary va sculature. The increasing proportion of GH cells after irradiation ind icates that lactotrophs respond more rapidly to irradiation. The stimu lation by E-2 + S somehow prevented the radiation damaged lactotrophs from becoming giant cells. Also, the ratio of apoptotic cells to BrdU- labeled cells was increased by the E-2 + S treatment, indicating that the E-2 + S did enhance radiation-induced cell death relative to cell renewal. However, overall, the E-2 + S stimulus protocol did not promo te a dramatic increase in cell death (apoptosis) nor a marked decrease in residual gland weight after irradiation. Hence, its use would prob ably not be beneficial in the treatment of slow-responding prolactinom as, if malignant lactotrophs respond similarly to the normal pituitary lactotrophs. However, the observation of induced apoptosis after horm one and drug withdrawal suggests that agents which promote tumor shrin kage may be effective by causing rapid apoptosis of tumor cells in viv o. (C) 1997 Elsevier Science Inc.