BIOCHEMICAL PARAMETERS IN THE ANTERIOR-PITUITARY DURING THE COURSE OF TUMORIGENESIS INDUCED BY DIETHYLSTILBESTROL TREATMENT

Treatment of F-344 rats with diethylstilbestrol (DES) for 1-2 months induces a prolactin (PRL)-secreting pituitary adenoma. After 8 weeks of DES treatment, we have shown that the ratio of regulatory subunits of the cAMP-dependent protein kinase (RI/RII) increased in the tumors. Presently we report the variations in RI/RII ratio, pituitary weight, DNA content, serum PRL, nuclear estrogen receptor (E(2)R) and of ornithine decarboxylase (ODC) activity from the time of DES pellet implantation until 8 weeks. Pituitary weight, DNA content and serum PRL rose significantly at 4 weeks with a maximum at 6-8 weeks, and significantly correlated with each other. E(2)R and ODC activity increased from week 1 onwards, with a maximum at 2 weeks and decreased at 8 weeks. Both variables showed a positive correlation but neither E(2)R nor ODC activity correlated with pituitary weight, DNA or serum PRL. Values for RI remained stable with time, but RII decreased progressively. The RI/RII ratio was maintained around unity between 1-4 weeks, increasing to 1.6-2 thereafter. This ratio positively correlated with pituitary weight and DNA. It is suggested that during tumor induction by estrogen in a sensitive strain of rats, growth signals with different time-courses become activated. Increases in pituitary weight and DNA content, indicators of mammotroph hypertrophy and hyperplasia, were preceeded by early rises in E(2)R and ODC activity. Increases in the RI/RII ratio accompanied the adenomatous change, suggesting their role in cell transformation after 6 weeks of estrogen exposure.