ESTRADIOL INDUCES VASOACTIVE-INTESTINAL-PEPTIDE AND PROLACTIN GENE-EXPRESSION IN THE RAT ANTERIOR-PITUITARY INDEPENDENTLY OF PLASMA PROLACTIN LEVELS

It is well established that estrogens are potent stimulators of prolactin (PRL) secretion. It has also been demonstrated that estradiol (E2) can increase the expression and the anterior pituitary levels of the vasoactive intestinal peptide (VIP), a peptide which also acts as a potent PRL-releasing factor. It thus remained unknown whether the effects on pituitary VIP were due to E2 itself or to E2-induced hyperprolactinemia (HPRL). In order to test this hypothesis, various plasma PRL levels were induced in rats either with ectopic pituitary grafts, PRL secreting tumours or E2 implants, and VIP mRNA expression in the anterior pituitary was measured by in situ hybridization and Northern blot analyses. Whereas decreases in VIP mRNA can be observed in pituitaries of rats with pure HPRL, a 6-fold increase in VIP mRNA can be seen in E2-treated rats, E2 increased both 1.0 and 1.7 Kb VIP mRNA species. The presence of the graft in E2-treated rats significantly reduced the increase in VIPmRNA observed following E2. The direct stimulation by E2 of VIP mRNA expression was further demonstrated by the fact that statistical analysis of the data indicated that both E2 and graft were acting independently of each other, and that a new selective antiestrogen, RU 58668, almost totally blocked the effect of E2. Moreover, under similar experimental conditions, pituitary PRL mRNA levels were reduced in the graft group and a marked up-regulation was observed similarly in both E2 and in E2 rats bearing ectopic grafts. We observed furthermore that not only revels of the mature 1.0 Kb PRL mRNA but also the 1.7 and 3.8 KbPRL precursor RNAs were increased, Such changes were associated with modifications in PRLmRNA size due to an increase in 3'polyA tail lenghts. The present data demonstrate that E2 directly affects VIP mRNA and PRL mRNA expression in the pituitary and support the hypothesis that VIP may play a role in the hypersecretion of PRL associated with the formation of E2-induced prolactinomas.