Suppression of Breakthrough Bleeding in LNG-IUS Users

描述(由申请人提供)：Mirena(C)(Leiras，Oy，芬兰)是一种宫内系统(IUS)，释放左旋诺孕酮(LNG)，为妇女提供为期5年的高效避孕措施。然而，可能会发生严重的突破性出血(BTB)，导致许多患者停止治疗。在使用Norants皮下避孕药的妇女中，BTB可以通过间歇性抗孕激素治疗和米非司酮来抑制。NICHD有一种新的抗孕激素CDB-2914，比米非司酮更有效。这项提案的目的是确定CDB-2914是否能够抑制与LNG-IUS相关的BTB。临床前研究将首先在安装了LNG-IUS的恒河猴身上进行，所获得的信息将被传输给爱丁堡大学的希拉里·克里奇利教授，她将从每年接受LNG-IUS避孕的400多名女性中挑选150名女性进行测试。CDB-2914的止血剂量和时间表在猕猴身上效果良好，将被调整用于女性。本工作包括两个主要目标：目的1：建立CDB 2914在猕猴体内的有效止血剂量方案，并评估出血相关因子在子宫内膜中的时空表达。目的2：进行一项随机、安慰剂对照试验，以评估CDB-2914对安装了LNG-IUS的女性BTB的抑制作用；并为增加价值，开发一份问卷，以评估女性对拟议治疗的接受性。这项建议涉及在赠款的时间范围内将从猕猴基础研究中获得的信息转化为妇女的临床实践。在英国苏格兰爱丁堡大学进行这项临床工作是至关重要的，因为在美国，没有一家诊所有如此多的女性患者人口配备LNG-IUS用于避孕。猕猴模型为人类研究提供了极好的预测性，布伦纳博士和克里奇利博士在最近的几篇论文中联合发表了来自猕猴和女性的数据。这项提案将基础科学家和临床医生聚集在一起，采用“从板凳到床边”的方法，促进妇女的健康，改进避孕技术。

DESCRIPTION (provided by applicant): The Mirena(c) (Leiras, OY, Finland) is an intrauterine system (IUS) that releases levonorgestrel (LNG) and provides women with highly effective contraception for 5 years. However, serious breakthrough bleeding (BTB) can occur that leads many patients to discontinue treatment. In women using subcutaneous Norplant contraception, BTB can be suppressed by intermittent antiprogestin therapy with mifepristone. NICHD has a new antiprogestin, CDB-2914, that is more potent than mifepristone. The goal of this proposal is to determine whether CDB-2914 can suppress the BTB associated with the LNG-IUS. Preclinical studies will be done first in rhesus macaques fitted with an LNG-IUS and the information gained will be transmitted to Professor Hilary Critchley, University of Edinburgh, who will select a test population of 150 women from a pool of over 400 who are being fitted annually with an LNG-IUS for contraception. The bleeding-suppressive dose and schedule of CDB-2914 that works well in macaques will be adapted for use in women. The work consists of two major aims: Aim 1: to establish an effective, bleeding-suppressive dose schedule of CDB 2914 in macaques, and to assess spatio-temporal expression of bleeding-associated factors in the endometrium. Aim 2: to conduct a randomized, placebo controlled trial to evaluate CDB-2914 suppression of BTB in women being fitted with the LNG-IUS; and for added value, to develop a questionnaire to assess acceptability of the proposed treatment to women. This proposal involves translation of the information gained from basic research with macaques into clinical practice in women within the time frame of the grant. It is essential to conduct the clinical work at the University of Edinburgh, Scotland, UK, because no clinic in the USA has such a large patient population of women being fitted with the LNG-IUS for contraception. The macaque model provides excellent predictability for human studies, and Drs. Brenner and Critchley have published collaboratively on data from macaques and women in several recent papers. The proposal brings basic scientists and clinicians together for a "bench to bedside" approach that will advance women's health and improve contraceptive technology.