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 prolac tin (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 po tent PRL-releasing factor. It thus remained unknown whether the effect s on pituitary VIP were due to E2 itself or to E2-induced hyperprolact inemia (HPRL). In order to test this hypothesis, various plasma PRL le vels were induced in rats either with ectopic pituitary grafts, PRL se creting tumours or E2 implants, and VIP mRNA expression in the anterio r pituitary was measured by in situ hybridization and Northern blot an alyses. Whereas decreases in VIP mRNA can be observed in pituitaries o f 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 inc rease in VIPmRNA observed following E2. The direct stimulation by E2 o f VIP mRNA expression was further demonstrated by the fact that statis tical analysis of the data indicated that both E2 and graft were actin g independently of each other, and that a new selective antiestrogen, RU 58668, almost totally blocked the effect of E2. Moreover, under sim ilar experimental conditions, pituitary PRL mRNA levels were reduced i n the graft group and a marked up-regulation was observed similarly in both E2 and in E2 rats bearing ectopic grafts. We observed furthermor e 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 associa ted with modifications in PRLmRNA size due to an increase in 3'polyA t ail lenghts. The present data demonstrate that E2 directly affects VIP mRNA and PRL mRNA expression in the pituitary and support the hypothe sis that VIP may play a role in the hypersecretion of PRL associated w ith the formation of E2-induced prolactinomas.