ANTAGONISM BY PROGESTERONE OF DIETHYLSTILBESTROL-INDUCED PITUITARY TUMORIGENESIS IN FISCHER-344 RATS - EFFECTS ON SEX STEROID-RECEPTORS ANDTYROSINE-HYDROXYLASE MESSENGER-RNA

It is known that chronic exposure of F-344 rats to diethylstilbestrol (DES) induces prolactin (PRL)-secreting pituitary tumors composed of p roliferating mammotropic cells. In the present work, we studied the ef fects of progesterone (P-4) on several parameters stimulated in the pi tuitary tumors (DES-T), such as nuclear estrogen receptors (NE(2)R), c ytosolic progestin receptors (CP(4)R) nd serum PRL. Additionally, we h ave measured in hypothalamus the mRNA levels for tyrosine hydroxylase (TH), the rate-limiting enzyme for synthesis of dopamine, the main PRL -inhibitory factor. We found that pellet implantation of P-4 during 1 month significantly reduced weight, ligand binding to NE(2)R and CP(4) R and serum PRL in the tumorous glands. Reductions in sex steroid rece ptor binding were due to changes in Bmax without changes in K-d, as ob served after Scatchard plot analysis. Receptor binding data, therefore , suggests a pituitary site of action of P-4. TH mRNA expression was s tudied in tuberoinfundibular dopaminergic (TIDA) neurons by in situ hy bridization techniques employing a S-35-labeled oligonucleotide probe. Mean number of grains/cell decreased significantly in DES-T, an effec t partly reversed by P-4 treatment. Frequency histograms were construc ted by plotting the number of cells versus the number of grains/cell a nd examined by chi(2) test and analysis of residuals. We found that DE S-T presented significantly more cells with less grains whereas in con trol glands, P-4-treated rats and DES-T receiving P-4, cells with a hi gher grain number prevailed. These results suggest that in addition to a direct pituitary effect, P-4 may also antagonize DES-induced tumori genesis acting on mRNA for TH and presumably on the activity of TIDA n eurons of the hypothalamus. The use of DES-T as a model for hyperprola ctinemia may allow further assessment of P-4 effects in pituitary aden omas in humans.