title: Cell proliferation and death in the irradiated pituitary gland and its modification by growth stimulants.
abstract: OBJECTIVE
  This study was undertaken to show whether the rate of expression of radiation injury in the rat pituitary gland could be accelerated by the use of growth stimulants.
  
  
  METHODS
  Rat pituitary glands were irradiated in situ with a range of single doses up to 20 Gy. The rats were then given subcutaneous slow-release implants containing 17beta-estradiol (E2) and sulpiride (S) to stimulate lactotroph proliferation. Two sequential cycles were used, each consisting of stimulation (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 thyroid-releasing hormone (TRH).
  
  
  RESULTS
  The two cycles of stimulation/withdrawal resulted in marked changes in gland weight, BrdU-labeling index, and serum prolactin (PRL) levels in unirradiated rats. The proportion of immunopositive growth-hormone-producing (GH) cells increased after irradiation. Radiation inhibited the hypertrophic response to E2 + S and also inhibited increases in BrdU-labeling index and serum PRL levels. Also, giant lactotrophs were observed in the irradiated pituitaries. However, they were not seen in the unirradiated rats or in the irradiated rats treated with E2 + S. TRH promoted PRL secretion in the unirradiated rat. In contrast, TRH inhibited PRL secretion in the irradiated rat and in all treatment groups receiving E2 + S. Apoptosis was induced by irradiation and was substantially increased in lactotrophs and in other cell types by withdrawal of the E2 and S stimulus, although the highest observed incidence was only 7 per 10,000 cells.
  
  
  CONCLUSIONS
  Both irradiation and E2 + S treatment removed the hypothalamic control of PRL secretion, which reveals this important inhibitory action of TRH upon PRL secretion. This suggests that it is not suitable as a dynamic test of pituitary PRL reserves in such abnormal situations, where there may also be damage to the hypothalamic-pituitary vasculature. The increasing proportion of GH cells after irradiation indicates that lactotrophs respond more rapidly to irradiation. The stimulation by E2 + 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 E2 + S treatment, indicating that the E2 + S did enhance radiation-induced cell death relative to cell renewal. However, overall, the E2 + S stimulus protocol did not promote a dramatic increase in cell death (apoptosis) nor a marked decrease in residual gland weight after irradiation. Hence, its use would probably not be beneficial in the treatment of slow-responding prolactinomas, if malignant lactotrophs respond similarly to the normal pituitary lactotrophs. However, the observation of induced apoptosis after hormone and drug withdrawal suggests that agents which promote tumor shrinkage may be effective by causing rapid apoptosis of tumor cells in vivo.
authors.affiliation: CRC Department of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester, UK.
authors.forename: Y P
authors.initials: YP
authors.lastname: Guo
authors.forename: J H
authors.initials: JH
authors.lastname: Hendry
authors.forename: I D
authors.initials: ID
authors.lastname: Morris
authors.forename: J R
authors.initials: JR
authors.lastname: Davis
authors.forename: C G
authors.initials: CG
authors.lastname: Beardwell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D002455:Cell Division / Q000187:drug effects* / Q000528:radiation effects*; D004958:Estradiol / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010902:Pituitary Gland / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D011388:Prolactin / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013469:Sulpiride / Q000494:pharmacology*
chemical_list: D006133:Growth Substances; D004958:Estradiol; D013469:Sulpiride; D011388:Prolactin