HORMONAL CONTROL OF FEMALE REPRODUCTIVE TRACT GROWTH

卵巢雌二醇(E)刺激大鼠卵巢细胞增殖 人子宫内膜；黄体分泌期 孕酮(P)进一步抑制E诱导的血管内皮细胞增殖 腔上皮。这种啮齿动物被广泛用作 激素控制子宫生长的模型。在 去卵巢(Ovxd)啮齿类动物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、E预处理的动物中，E刺激有丝分裂 子宫间质(上皮下)的活性。大剂量孕激素 治疗子宫内膜增生症和子宫内膜的方法 癌症。据推测，这起案件的行动模式 治疗方法是抑制E驱动的细胞事件。然而，最近 在啮齿动物身上的证据表明，磷抑制子宫上皮 在没有雌激素的情况下正在进行的DNA合成。分成两份 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。的目标是 目前的建议是研究以下机制：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处理动物；3)E刺激子宫和阴道 上皮细胞增殖。因为孕激素和糖皮质激素 抑制啮齿类动物的子宫上皮，出现了两个问题：1)做 糖皮质激素抑制人子宫上皮细胞增殖 P或糖皮质激素对子宫的抑制是由 孕激素受体(PR)还是糖皮质激素受体？这个 第一个问题将通过检查以下人员的回答来回答 异种移植中人组织对糖皮质激素的作用(无菌小鼠)。 第二个问题将通过执行多个 两类诉讼模式的比较研究 E刺激和E非依赖模型中的类固醇 啮齿类动物子宫上皮DNA合成。建议的研究 将：1)检查“E-独立”模型的迹象 激活的雌激素机制，即雌激素的状态 受体(胞浆与细胞核的比例)和PR含量；2) 确定孕激素和孕激素的细胞周期特异性 糖皮质激素反应；3)比较相对结合亲和力 以及几种不同类型类固醇的剂量反应曲线 糖皮质激素和孕激素活性的程度；以及4)比较 3种不同程度的抗孕激素的疗效观察 抗糖皮质激素活性。上皮细胞之间可能的相互作用 和间质在测定细胞增殖活性中的作用 荷尔蒙的影响也将被检查。上皮细胞消融术 SITE将确定该组织是否是必要组件 P处理的子宫对E的间质反应。异型 上皮和间质组织重组体将定义组织 激素(E或E+P)产生的信号来源 管理。病毒癌基因细胞同源物的表达 (C-onc)在E-刺激和P-抑制将被检测。 要使用的组织分离技术提供了一种定义的系统 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.