Role of estrogens as promoters of hepatic neoplasia.
Role of estrogens as promoters of hepatic neoplasia.
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雌激素作为肝肿瘤促进剂的作用。
DOI：
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发表时间：
1982
期刊：
影响因子：
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通讯作者：
A. Medline
中科院分区：
文献类型：
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作者：
Wanless Ir;A. Medline
人类服用雌激素与良性和可能恶性的肝细胞肿瘤的发展有关。这项研究旨在探讨这种关联的机制。我们提供了一个大鼠模型，证明己烯雌酚(DES)和乙炔雌二醇促进了以前用二乙基亚硝胺(DEN)诱发的大鼠肝肿瘤的发展。80只雄性和12只雌性Fischer-344大鼠被单次腹腔注射其中一种DEN(200 mg。每公斤。体重)或生理盐水。从注射后4周开始，大鼠每周两次服用雌激素或玉米油，持续时间长达50周。治疗在牺牲时或牺牲前11至29周停止。雌激素治疗包括高剂量DES(5 mg。每剂量)，低剂量DES(0.5 mg.每剂量)和乙炔雌二醇(0.2毫克。每剂)。同时给予DEN和高剂量DES的雄性和雌性大鼠在DES 20周后出现明显的肝脏增生性结节(平均每个肝脏9.1个)。如果将DES治疗的开始推迟到开始治疗后28周，也会出现结节。单独给予DEN或单独给予DES的大鼠在20周后没有出现结节。在给予DEN+DES、单独给予DES和单独给予DEN的大鼠中，也出现了微小的增生灶。单独给予DES的大鼠的病灶在停止雌激素治疗后基本上是可逆的。在雌激素治疗期间，病灶和结节的有丝分裂活性显著，但在停止治疗后显着下降。乙炔雌二醇也有类似的促进作用。小剂量DES对肿瘤形成无明显促进作用。这些数据表明，雌激素可能通过增加肝细胞有丝分裂活性，从而促进先前启动的细胞进化为肿瘤克隆，从而促进肝脏肿瘤的发生。与人类疾病进行比较应该谨慎，特别是因为注射的雌激素剂量大约是人类通常避孕剂量的200倍。然而，这个模型与人类口服避孕药相关的肝肿瘤的发展之间的相似之处是显而易见的。这是可能的，一些女性有潜伏的“启动”细胞，分裂速度比周围的肝细胞对雌激素的反应更快。
The administration of estrogens to humans has been associated with the development of benign and possibly malignant hepatocellular neoplasms. This study was designed to investigate the mechanism of this association. We present a rat model that demonstrates that stilbestrol (DES) and ethinyl estradiol promote the development of hepatic neoplasms in rats previously initiated with diethylnitrosamine (DEN). Eighty male and 12 female Fischer-344 rats were given a single intraperitoneal injection of either DEN (200 mg. per kg. of body weight) or saline. Beginning 4 weeks after injection, the rats were given an estrogen or corn oil twice weekly for up to 50 weeks. Treatments were stopped at the time of sacrifice or 11 to 29 weeks prior to sacrifice. Estrogen treatments included high dose DES (5 mg. per dose), low dose DES (0.5 mg. per dose), and ethinyl estradiol (0.2 mg. per dose). Male and female rats given both DEN and high dose DES developed grossly visible hepatic hyperplastic nodules (mean, 9.1 per liver) after 20 weeks of DES. Nodules also developed if the onset of DES treatment was delayed until 28 weeks after initiation. Rats given DEN alone or DES alone did not develop nodules after 20 weeks. Microscopic hyperplastic foci also developed in rats given DEN plus DES, DES alone, and DEN alone. The foci in rats given DES alone were largely reversible on cessation of estrogen therapy. Mitotic activity in foci and nodules was prominent during estrogen therapy but declined markedly after cessation of therapy. Similar promoting activity of ethinyl estradiol was observed. Low dose DES was not effective in promoting tumor formation. The data indicate that estrogens promote hepatic neoplasia, perhaps by increasing hepatocyte mitotic activity and thereby facilitating the evolution of previously initiated cells into neoplastic clones. Comparison with human disease should be made with caution, especially because the estrogenic dose administered was approximately 200-fold the usual contraceptive dose in humans. However, the analogy between this model and the development of human oral contraceptive-associated hepatic tumors is evident. It is possible that some women have latent "initiated" cells that divide faster than the surrounding hepatocytes in response to estrogens.