Suppression of Breakthrough Bleeding in LNG-IUS Users

描述（由申请人提供）：曼月乐（c）（Leiras，OY，芬兰）是一种宫内系统（IUS），可释放左炔诺孕酮（LNG），为女性提供5年的高效避孕。然而，可能发生严重突破性出血（BTB），导致许多患者停止治疗。使用皮下Norplant避孕的妇女，BTB可以通过米非司酮间歇性抗孕激素治疗来抑制。NICHD有一种新的抗孕激素，CDB-2914，比米非司酮更有效。该提案的目标是确定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的恒河猴中进行，所获得的信息将传输给爱丁堡大学的Hilary Critchley教授，他将从每年装有LNG-IUS避孕的400多名女性中选择150名女性作为测试人群。在猕猴中效果良好的CDB-2914的止血剂量和时间表将适用于女性。该工作包括两个主要目的：目的1：在猕猴中建立CDB 2914的有效的出血抑制剂量方案，并评估子宫内膜中出血相关因子的时空表达。目标二：进行随机、安慰剂对照试验，以评价CDB-2914对安装LNG-IUS的女性中BTB的抑制;并且为了增加价值，开发调查问卷以评估所提议的治疗对女性的可接受性。这项建议涉及在赠款期限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开展临床工作至关重要，因为美国没有一家诊所拥有如此庞大的女性患者人群，这些患者都安装了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，Brenner和Critchley博士在最近的几篇论文中合作发表了来自猕猴和女性的数据。该提案将基础科学家和临床医生聚集在一起，采取“从工作台到床边”的方法，促进妇女健康，改善避孕技术。

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.