MECHANISMS IN PROGESTIN ANTAGONISM OF PITUITARY TUMORIGENESIS

Chronic exposure of F344 rats to diethylstilbestrol (DES) induces pitu itary tumors (DES-T) composed of proliferating lactotroghs. Presently, we studied the effect of progestins on parameters related to tumor gr owth and function, due to previous evidences of progesterone antagonis m of pituitary tumorigenesis acting at pituitary and hypothalamic leve ls [Piroli, G., Grille, C., Ferrini, M., Lux-Lantos, V. and De Nicola, A. F., Antagonism by progesterone of diethylstilbestrol-induced pitui tary tumorigenesis in Fischer 344 rats: Effects on sex steroid recepto rs and tyrosine hydroxylase mRNA, Neuroendocrinology, 1996, 63, 530-53 9]. In search of a quantitatively more important effect, animals beari ng DES-T were treated with synthetic progestins. Competition assays us ing DES-T as source of progestin receptors indicated that levonorgestr el (LNG), gestodene and R5020 showed higher affinities (IC50 1-2 nM) t han progesterone, norethisterone and medroxyprogesterone (IC50 10-25 n M). Treatment with LNG reduced DES-T weight by 45%, and serum PRL by o ne half. Small (monomeric) and big (polymeric) PRL increased 5- and 2. 5-fold, respectively, in DES-T in comparison with pituitaries of ovari ectomized (OVX) rats. However, LNG produced no changes indicating that synthesis and storage of PRL was conserved in rats receiving both hor monal treatments. DES induced a 15-fold increase in cell proliferation , measured as bromodeoxyuridine incorporation into cell nuclei, in com parison to OVX rats, while LNG treatment of DES-T bearing rats reduced this index by 72%. Electron microscopic images showed that LNG marked ly reduced hypertrophy and hyperplasia of lactotropes, increasing the proportions of degenerating cells and cells of high electronic density with alterations of cytoplasmic organelles. However, histopathologica l signs of apoptosis were absent. Therefore, reduced cell proliferatio n and non-apoptotic cell death are part of the mechanisms employed by progestins to antagonize tumorigenesis at the pituitary level. The res ults may open a new therapeutic strategy for treatment of PRL secretin g adenoma in humans. (C) 1998 Elsevier Science Ltd. All rights reserve d.