ESTROGEN-INDUCED NORMAL AND DYSPLASTIC UTERINE GROWTH

当仓鼠在新生儿时期接受合成雌激素治疗时， 己烯雌酚(DES)，她们的子宫一直表现出严重的 成年期雌激素的增生性/肿瘤性反应。两个中的一个 另一种工作假设应该解释这种现象：1)直接 行动--新生儿的细胞生理和/或成分 仓鼠的子宫被这种侮辱直接和永久地改变了 成年器官对雌激素的整体增殖反应 非典型的，或2)间接作用-子宫营养活性是由 雌激素主要通过或与其他不明原因的 因素，新生儿DES治疗永久改变水平或 这类因子的功能活动。检验这些假说将开始 (特定目标#1)通过监测新生儿子宫的形态发生 对照和DES处理的供体动物被移植到 对照和DES处理的成熟宿主的对侧颊囊 要么原封不动，要么失去雌激素，要么被雌激素替代。至 确认并扩展发现(具体目标2)、同型和 对照组子宫间质和上皮的异型重组 将进行DES处理的动物，它们的形态发生将 研究：a)在体外使用添加了子宫组织的培养液 来自用于特定目标#1的相同主群的提取物和/或血清 和b)活体内(在面颊囊内，使用与在 特指#L。最后(特指#3)，Northern杂交分析将 被用来考虑两个改变的表达的可能性 原癌基因(c-myc和c-fos)可能参与非典型癌的发生。 新生地鼠子宫对雌激素的反应性。 因为这种方法的组合依赖于很少(如果有的话)先验 假设和适应体内和体外观察，坚定 应该得出关于哪种替代假设最多的结论 有效。这样的信息应该对长期 目的了解雌激素如何调节子宫生长和 形态发生。这一目标在生物医学上很重要，因为：1) 成功的受孕和妊娠需要正常的子宫形态和 功能，2)雌激素依赖性子宫肿瘤负责 当代美国社会中相当大的发病率和死亡率。

When hamsters are treated neonatally with the synthetic estrogen, diethylstilbestrol (DES), their uteri consistently exhibit a severe hyperplastic/neoplastic response to estrogen in adulthood. One of two alternative working hypotheses should explain this phenomenon: 1) Direct Action - The cellular physiology and/or composition of the neonatal hamster uterus is directly and permanently altered by the DES insult such that the adult organ's overall proliferative response to estrogen becomes atypical, or 2) Indirect Action - Uterotrophic activity is mediated by estrogen primarily through or in conjunction with other unidentified factors, and neonatal DES treatment permanently alters the level or functional activity of such factors. Testing these hypotheses will begin (Specific Aim # 1) by monitoring the morphogenesis of neonatal uteri from control and DES-treated donor animals that are transplanted into the contralateral cheek pouches of control and DES-treated mature hosts that are either left intact, estrogen-deprived or estrogen-replaced. To confirm and extend the findings (Specific Aim #2), homotypic and heterotypic recombination of uterine stroma and epithelium from control and DES-treated animals will be performed and their morphogenesis will be studied: a) in vitro using media supplemented with uterine tissue extracts and/or serum from the same host groups used in Specific Aim # 1 and b) in vivo (within the cheek pouch, using the same host groups as in Specific Aim #l. Lastly (Specific Aim #3), Northern blot analysis will be used to consider the possibility that altered expression of two proto-oncogenes (c-myc and c-fos) may be involved in the atypical estrogen responsiveness of uteri in neonatally DES-exposed hamsters. Because this combination of approaches relies on few, if any, a priori assumptions and accommodates both in vivo and in vitro observations, firm conclusions should be reached about which alternative hypothesis is most valid. Such information should contribute significantly to the long-term objective of understanding how estrogen regulates uterine growth and morphogenesis. This objective is biomedically important because: 1) successful conception and gestation demands normal uterine form and function, and 2) estrogen-dependent uterine neoplasms are responsible for considerable morbidity and mortality in contemporary American society.