Hormonal Regulation of the Cervix During Pregnancy

怀孕期间子宫颈的荷尔蒙调节

• 批准号: 6623700
• 负责人: ORRIN David SHERWOOD
• 金额: $ 25.78万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623700
• 关键词: apoptosis; cell proliferation; cervix; electron microscopy; estrogens; hormone regulation /control mechanism; immunocytochemistry; induced labor; laboratory mouse; laboratory rat; mifepristone; pregnancy; progesterone; proliferating cell nuclear antigen; prostaglandin E; relaxin; terminal nick end labeling

The three objectives of this proposal will examine the regulation of both growth and softening of the cervix during pregnancy. In the rat, cervical growth is accompanied by an accumulation of epithelial and stromal cells. The first objective is to determine the influence of relaxin, estrogen and progesterone on the rates of apoptosis and proliferation of cervical cells. At three-day intervals throughout the second half of pregnancy, relaxin's action will be neutralized with a monoclonal antibody for rat relaxin, estrogen's action will be blocked with the estrogen antagonist ICI 182,780, and progesterone's action will be blocked with the progesterone antagonist RU 486. The rates of apoptosis will be determined immunohistochemically by employing the terminal deoxynucleotidyl transferase-mediated UTP end-labeling (TUNEL) method. Electron microscopy will be used to evaluate treatment effects on percent of cell types undergoing apoptosis, stromal collagen, and epithelium functional complexes. Light microscopy immunohistochemistry will be used also to evaluate treatment effects on epithelium functional complexes. Rates of cell proliferation will be determined immunohistochemically by measuring the rate of incorporation of 5-bromo-2-deoxyuridine (BrdU) into proliferating cells and also by measuring the expression of proliferating cell nuclear antigen (PCNA). RU 486 induces delivery and promotes cervical softening at term in women and other species. The second objective will test the hypothesis that relaxin is more effective than RU 486 in promoting cervical softening near term. To accomplish this, the effects of RU 486 and relaxin on cervical extensibility will be determined at term in relaxin-deficient rats in which endogenous relaxin is immunoneutralized throughout the second half of pregnancy. Morphometric analysis will also be done to compare the effects of RU 486 and relaxin on the histological characteristics of the cervix. This proposal will also examine a novel procedure for both inducing delivery and softening the cervix. Induction of labor more than doubled to 19% between 1989 and 1998. The success of labor induction is influenced by the state of the cervix. The active component of the two approved agents for cervical softening (Prepidil and Cervidil) is PGE2, and this prostaglandin causes uterine hyperstimulation in a significant percentage of patients. Relaxin has potential advantages over PGE2 because relaxin not only promotes rapid and marked growth and softening of the cervix, but also reduces uterine contractility. The third objective will test the hypothesis that the administration of RU 486 for induction of delivery in combination with relaxin for induction of cervical softening is more effective in promoting rapid and safe delivery in pregnant rats than is the administration of RU 486 alone. Treatment with RU 486 alone and in combination with exogenous relaxin will be done at term with relaxin-deficient rats.

本提案的三个目标将检查在怀孕期间宫颈的生长和软化的调节。在大鼠中，宫颈生长伴随着上皮细胞和基质细胞的积累。第一个目的是确定松弛素、雌激素和孕酮对宫颈细胞凋亡率和增殖率的影响。在妊娠后半期，每隔三天用大鼠松弛素单克隆抗体中和松弛素的作用，用雌激素拮抗剂ICI 182780阻断雌激素的作用，用孕激素拮抗剂RU 486阻断孕激素的作用。凋亡率将采用末端脱氧核苷酸转移酶介导的UTP末端标记（TUNEL）方法进行免疫组织化学测定。电子显微镜将用于评估治疗对发生凋亡的细胞类型、基质胶原和上皮功能复合物百分比的影响。光镜免疫组织化学也将用于评估治疗对上皮功能复合物的影响。通过测量5-溴-2-脱氧尿苷（BrdU）掺入增殖细胞的速率以及测量增殖细胞核抗原（PCNA）的表达，免疫组织化学方法可以确定细胞增殖率。ru486诱导分娩，促进妇女和其他物种足月宫颈软化。第二个目标将检验松弛素在促进近期颈椎软化方面比RU 486更有效的假设。为了实现这一目标，在松弛素缺乏的大鼠中，内源性松弛素在妊娠后半期免疫中和，将在足月确定RU 486和松弛素对宫颈延伸性的影响。形态计量学分析也将做比较ru486和松弛素对宫颈组织学特征的影响。本提案还将研究一种既能诱导分娩又能软化宫颈的新方法。1989年至1998年间，引产率增加了一倍多，达到19%。引产的成功与否受宫颈状态的影响。两种经批准的宫颈软化药物（Prepidil和Cervidil）的活性成分是PGE2，这种前列腺素在很大比例的患者中引起子宫过度刺激。与PGE2相比，松弛素具有潜在的优势，因为松弛素不仅能促进宫颈的快速和明显的生长和软化，还能降低子宫的收缩性。第三个目的将检验一个假设，即与单独使用RU 486相比，使用RU 486诱导分娩与使用松弛素诱导颈椎软化在促进妊娠大鼠快速安全分娩方面更有效。RU 486单独或联合外源性松弛素对松弛素缺乏大鼠进行足月治疗。