HORMONAL CONTROL OF FEMALE REPRODUCTIVE TRACT GROWTH

卵巢雌二醇（E）刺激细胞增殖， 人子宫内膜;在分泌期黄体 孕酮（P）进一步抑制E诱导的细胞增殖。 腔上皮 这种啮齿动物被广泛用作 荷尔蒙控制子宫生长的模型。 在 卵巢切除（ovxd）啮齿动物E刺激DNA合成， 子宫、宫颈和阴道上皮; P阻断E刺激， 子宫和宫颈上皮，而不是阴道上皮。 糖皮质激素也阻断E对子宫生长的影响， 啮齿动物 在用P预处理的动物中，E刺激有丝分裂 子宫基质（上皮下）的活性。 大剂量雷公藤红素 治疗用于治疗子宫内膜增生和子宫内膜异位症。 carcinoma. 据推测，在这种情况下， 治疗是抑制E驱动的细胞事件。 但最近的 啮齿类动物的证据表明，P抑制子宫上皮细胞 在没有雌激素的情况下进行的DNA合成。 在两 雌激素非依赖性子宫上皮生长模型， 孕激素和糖皮质激素抑制DNA合成。 的目标 目前的建议是调查的机制：1） 孕激素和糖皮质激素对子宫上皮细胞的抑制作用 增殖; 2）E刺激子宫基质DNA合成， P处理的动物; 3）E刺激子宫和阴道 上皮增生 因为孕激素和糖皮质激素 抑制啮齿类动物子宫上皮，出现两个问题：1） 糖皮质激素抑制人子宫上皮细胞增殖？ （二） P或糖皮质激素对子宫的抑制作用是否由 孕激素受体（PR）或糖皮质激素受体？ 的 第一个问题将通过检查的反应来回答 人组织与异种移植物（无胸腺小鼠）中糖皮质激素。 第二个问题将通过执行一些 比较两类药物作用方式的研究 类固醇在E-刺激，和E-独立的模型， 啮齿类动物子宫上皮DNA合成。 拟定研究 将：1）检查“E独立”模型的迹象， 激活雌激素机制，即雌激素的状态 受体（胞质与核部分）和PR含量; 2） 确定该蛋白的细胞周期特异性， 糖皮质激素反应; 3）比较相对结合亲和力 和剂量反应曲线的几种类固醇与不同 糖皮质激素和孕酮活性的程度;和4）比较 3种不同程度的抗孕激素的作用 抗糖皮质激素活性 上皮细胞之间可能的相互作用 和间质在确定增殖活性下 还将检查激素的影响。 上皮消融术 原位将确定该组织是否是必要成分 间质对E的反应。 异型 上皮和基质组织重组体将定义组织 激素（E或E + P）产生的信号源 管理。 病毒癌基因的细胞同源物的表达 将检查E-刺激和P-抑制期间的（c-onc）。 所使用的组织分离技术提供了一个确定的系统 其中检查c-onc与 荷尔蒙刺激

Ovarian estradiol (E) stimulates cellular proliferation in the human endometrium; during the secretory phase luteal progesterone (P) inhibits further E-induced proliferation of the luminal epithelium. The rodent has been used extensively as a model of hormonal control of uterine growth. In the ovariectomized (ovxd) rodent E stimulates DNA synthesis in uterine, cervical, and vaginal epithelia; P blocks E stimulation of uterine and cervical epithelia but not vaginal epithelium. Glucocorticoids also block the effect of E on uterine growth in rodents. In animals pretreated with P, E stimulates mitotic activity of the uterine stroma (subepithelial). High-dose progestin therapy is used to treat endometrial hyperplasia and endometrial carcinoma. It has been assumed that the mode of action in this therapy is to inhibit E-driven cellular events. However, recent evidence in rodents indicates that P inhibits uterine epithelial DNA synthesis that is ongoing in the absence of estrogen. In two models of estrogen-independent uterine epithelial growth, progestins and glucocorticoids inhibit DNA synthesis. The goal of the present proposal is to investigate the mechanisms of: 1) progestin and glucocorticoid inhibition of uterine epithelial proliferation; 2) E stimulation of uterine stromal DNA synthesis in P treated animals; 3) E stimulation of uterine and vaginal epithelial proliferation. Since both progestins and glucocorticoids inhibit uterine epithelium of rodents, two questions arise: 1) Do glucocorticoids inhibit human uterine epithelial proliferation? 2) Is P or glucocorticoid inhibition of the uterus mediated by the progesterone receptor (PR) or the glucocorticoid receptor? The first question will be answered by examining the response of human tissue to glucocorticoids in xenograft (athymic mouse). The second question will be answered by performing a number of studies comparing the modes of action of the two classes of steroids in the E-stimulated, and the E-independent models of uterine epithelial DNA synthesis in rodents. Proposed studies will: 1) examine the "E-independent" models for signs of activated estrogenic mechanisms, i.e. the state of the estrogen receptor (cytosolic vs. nuclear fraction) and PR content; 2) determine the cell cycle specificities of the progestin and glucocorticoid responses; 3) compare relative binding affinities and dose response curves for several steroids with differing degrees of glucocorticoid and progestin activity; and 4) compare the effects of 3 antiprogestins with differing degrees of antigulcocorticoid activity. Possible interactions of the epithelia and stroma in determining the proliferative activity under hormonal influence will also be examined. Epithelial ablation in situ will determine whether that tissue is a necessary component of the stromal response to E in P-treated uterus. Heterotypic epithelial and stromal tissue recombinants will define the tissue source of the signal produced by hormones (E or E + P) administered. Expression of cellular homologs of viral oncogenes (c-onc) during E-stimulation and P-inhibition will be examined. Techniques of tissue separation to be used offer a defined system in which to examine the possible correlation of c-onc with hormonal stimulation.