Hormonal Regulation of the Cervix During Pregnancy

怀孕期间子宫颈的荷尔蒙调节

• 批准号: 6660223
• 负责人: ORRIN David SHERWOOD
• 金额: $ 1.08万
• 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/6660223
• 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.

该提案的三个目标将检查怀孕期间子宫颈生长和软化的调节。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、雌激素和孕激素对宫颈细胞凋亡和增殖率的影响。在整个妊娠后半期，每隔三天，松弛素的作用将被大鼠松弛素的单克隆抗体中和，雌激素的作用将被雌激素拮抗剂ICI 182，780阻断，孕酮的作用将被孕酮拮抗剂RU 486阻断。细胞凋亡率将通过采用末端脱氧核苷酸转移酶介导的UTP末端标记（TUNEL）方法以化学方法测定。电子显微镜将用于评价处理对发生细胞凋亡的细胞类型、基质胶原蛋白和上皮功能复合物百分比的影响。还将使用光学显微镜免疫组织化学来评价对上皮功能复合物的处理效果。通过测量5-溴-2-脱氧尿苷（BrdU）掺入增殖细胞的速率以及通过测量增殖细胞核抗原（PCNA）的表达，以化学方法测定细胞增殖速率。RU 486诱导分娩并促进妇女和其他物种足月子宫颈软化。第二个目的是检验松弛素在促进宫颈软化方面比RU 486更有效的假设。为了实现这一点，RU 486和松弛素对宫颈伸展性的影响将在松弛素缺乏大鼠中测定，其中内源性松弛素在整个妊娠后半期被免疫中和。还将进行形态测定分析，以比较RU 486和松弛素对宫颈组织学特征的影响。这项建议也将研究一种新的程序，既诱导分娩和软化子宫颈。1989年至1998年，引产率增加了一倍多，达到19%。引产的成功与否受宫颈的状态影响。两种批准的宫颈软化剂（Prepidil和Cervidil）的活性成分是PGE 2，这种前列腺素会导致相当比例的患者子宫过度刺激。松弛素具有优于PGE 2的潜在优势，因为松弛素不仅促进宫颈的快速和显著生长和软化，而且降低子宫收缩力。第三个目的是检验以下假设：与RU 486单独给药相比，RU 486诱导分娩与松弛素诱导宫颈软化联合给药在促进妊娠大鼠快速和安全分娩方面更有效。在松弛素缺乏大鼠的足月时，单独使用RU 486和与外源性松弛素联合使用RU 486进行治疗。