Suppression of Breakthrough Bleeding in LNG-IUS Users

描述（由申请人提供）：Mirena(c) （Leiras， OY, Finland）是一种宫内系统（IUS），释放左炔诺孕酮（LNG），为妇女提供5年高效避孕。然而，严重的突破性出血（BTB）可能会发生，导致许多患者停止治疗。在使用诺普兰皮下避孕的妇女中，BTB可以通过米非司酮间歇抗黄体酮治疗来抑制。NICHD有一种新的抗黄体酮，CDB-2914，比米非司酮更有效。本提案的目的是确定CDB-2914是否可以抑制与LNG-IUS相关的BTB。临床前研究将首先在装有LNG-IUS的恒河猴身上进行，获得的信息将传递给爱丁堡大学的希拉里·克里奇利（Hilary Critchley）教授，她将从每年使用LNG-IUS避孕的400多名女性中选择150名作为测试人群。CDB-2914的止血剂量和时间表在猕猴中效果良好，将适用于女性。这项工作包括两个主要目的：目的1：建立CDB 2914在猕猴体内有效的出血抑制剂量计划，并评估子宫内膜出血相关因子的时空表达。目标2：开展一项随机、安慰剂对照试验，以评估CDB-2914对使用LNG-IUS的女性BTB的抑制作用；此外，还应编制一份调查问卷，以评估拟议的治疗对妇女的可接受性。该提案涉及在拨款的时间框架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临床工作是至关重要的，因为在美国没有一家诊所有如此大的患者群体使用LNG-IUS进行避孕。猕猴模型为人类研究提供了极好的可预测性。布伦纳和克里奇利在最近的几篇论文中合作发表了关于猕猴和女性的数据。该提案将基础科学家和临床医生聚集在一起，采用“从实验室到床边”的方法，促进妇女健康并改进避孕技术。

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.