ROLE OF THE PITUITARY IN TUMOR PROMOTION WITH ETHINYL ESTRADIOL IN RAT-LIVER

Synthetic estrogens act as tumor promoters in rat liver. Because estro gen treatment markedly increases the secretion of pituitary prolactin, also shown to be a tumor promoter in rat liver, the possibility of a pituitary influence in estrogen promotion was investigated in Wistar r ats. In diethylnitrosamine (DEN)-initiated hypophysectomized (hx) fema le rats, 24 weeks of ethinyl estradiol (EE) administration (500 mu g/k g/d, intraperitoneally) did not increase the number of hepatocyte nodu les and did not induce hepatocellular carcinoma (HCC) in a 2-year stud y. Very few placental forms of glutathione-S-transferase (GST-P)-posit ive foci were observed at the end of EE administration. Estrogen recep tor (ER) messenger RNA (mRNA) levels in hx females were 20% of the lev els in intact females. EE administration (range, 160-210 mu g/kg/d, su bcutaneous release pellets) to DEN-initiated intact males and females increased the number and size of hepatocyte foci. A significant increa se in HCC frequency was observed in EE-treated females compared with f emales receiving sham-release pellets, and the latency period for HCC induction was decreased by EE in both males and females. Inhibition of prolactin (PRL) secretion by bromocriptine (Brc) (ParlodelLAR, slow i ntramuscular release vehicles) during EE treatment decreased the numbe r of foci without affecting their size and markedly prolonged the late ncy period in both sexes. EE treatment also significantly increased th e expression of c-myc, and c-jun, enhanced the levels of growth hormon e receptor (GHr) mRNA in females and the levels of ER mRNA in males an d ''feminized'' the expression of the GH-regulated genes cytochrome P4 50 (CYP), 2C11, CYP 2C12, and GHr in male liver. Brc administration de creased the mRNA levels of the female-predominant CYP 2C12 in EE-treat ed males but otherwise had no effects. In conclusion, a decreased prom otive effect of EE was obtained by decreasing the PRL levels, indicati ng that estrogens exert at least part of their promotion effects indir ectly, by increasing the levels of pituitary PRL.