Piroli G, Torres A, Grillo C, Lux-Lantos V, Aoki A, De Nicola A F
Instituto de Biología y Medicina Experimental, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
J Steroid Biochem Mol Biol. 1998 Jan;64(1-2):59-67. doi: 10.1016/s0960-0760(97)00139-8.
Chronic exposure of F344 rats to diethylstilbestrol (DES) induces pituitary tumors (DES-T) composed of proliferating lactotrophs. Presently, we studied the effect of progestins on parameters related to tumor growth and function, due to previous evidences of progesterone antagonism of pituitary tumorigenesis acting at pituitary and hypothalamic levels [Piroli, G., Grillo, C., Ferrini, M., Lux-Lantos, V. and De Nicola, A. F., Antagonism by progesterone of diethylstilbestrol-induced pituitary tumorigenesis in Fischer 344 rats: Effects on sex steroid receptors and tyrosine hydroxylase mRNA, Neuroendocrinology, 1996, 63, 530-539]. In search of a quantitatively more important effect, animals bearing DES-T were treated with synthetic progestins. Competition assays using DES-T as source of progestin receptors indicated that levonorgestrel (LNG), gestodene and R5020 showed higher affinities (IC50 1-2 nM) than progesterone, norethisterone and medroxyprogesterone (IC50 10-25 nM). Treatment with LNG reduced DES-T weight by 45%, and serum PRL by one half. Small (monomeric) and big (polymeric) PRL increased 5- and 2.5-fold, respectively, in DES-T in comparison with pituitaries of ovariectomized (OVX) rats. However, LNG produced no changes indicating that synthesis and storage of PRL was conserved in rats receiving both hormonal treatments. DES induced a 15-fold increase in cell proliferation, measured as bromodeoxyuridine incorporation into cell nuclei, in comparison to OVX rats, while LNG treatment of DES-T bearing rats reduced this index by 72%. Electron microscopic images showed that LNG markedly reduced hypertrophy and hyperplasia of lactotropes, increasing the proportions of degenerating cells and cells of high electronic density with alterations of cytoplasmic organelles. However, histopathological signs of apoptosis were absent. Therefore, reduced cell proliferation and non-apoptotic cell death are part of the mechanisms employed by progestins to antagonize tumorigenesis at the pituitary level. The results may open a new therapeutic strategy for treatment of PRL secreting adenoma in humans.
将F344大鼠长期暴露于己烯雌酚（DES）会诱发由增殖的催乳素细胞组成的垂体肿瘤（DES-T）。目前，鉴于先前有证据表明孕酮在垂体和下丘脑水平对垂体肿瘤发生具有拮抗作用[皮罗利，G.，格里洛，C.，费里尼，M.，卢克斯 - 兰托斯，V.和德尼古拉，A.F.，孕酮对Fischer 344大鼠己烯雌酚诱导的垂体肿瘤发生的拮抗作用：对性类固醇受体和酪氨酸羟化酶mRNA的影响，《神经内分泌学》，1996年，63卷，530 - 539页]，我们研究了孕激素对与肿瘤生长和功能相关参数的影响。为了寻找更具量化意义的效果，对患有DES-T的动物用合成孕激素进行治疗。以DES-T作为孕激素受体来源的竞争试验表明，左炔诺孕酮（LNG）、孕二烯酮和R5020的亲和力（IC50为1 - 2 nM）高于孕酮、炔诺酮和甲羟孕酮（IC50为10 - 25 nM）。用LNG治疗可使DES-T重量减少45%，血清催乳素（PRL）降低一半。与去卵巢（OVX）大鼠的垂体相比，DES-T中的小（单体）PRL和大（聚合物）PRL分别增加了5倍和2.5倍。然而，LNG并未产生表明在接受两种激素治疗的大鼠中PRL的合成和储存保持不变的变化。与OVX大鼠相比，以溴脱氧尿苷掺入细胞核来衡量，DES使细胞增殖增加了15倍，而对患有DES-T的大鼠用LNG治疗可使该指标降低72%。电子显微镜图像显示，LNG显著减少了催乳素细胞的肥大和增生，增加了退化细胞和具有细胞质细胞器改变的高电子密度细胞的比例。然而，不存在凋亡的组织病理学迹象。因此，细胞增殖减少和非凋亡性细胞死亡是孕激素在垂体水平拮抗肿瘤发生所采用机制的一部分。这些结果可能为治疗人类分泌PRL的腺瘤开辟一种新的治疗策略。
