Mifepristone for Prevention of Breakthrough Bleeding

描述(由申请人提供)：仅使用孕激素的避孕药，如醋酸去孕孕酮(DMPA)，是最有效的避孕药之一，但由于突破性出血，特别是在使用的第一年，停用率很高，这限制了避孕药的使用。米非司酮是一种竞争性孕激素受体拮抗剂。当给正常骑行的灵长类动物服用米非司酮时，就达到了接近闭经的状态。米非司酮已被证明可以减少使用左炔诺孕酮植入物的妇女的突破性出血。尽管服用米非司酮后雌激素受体的表达增加，但在子宫内膜中发现了一种矛盾的抗增殖作用。这使得一些研究人员得出结论，米非司酮可以通过非竞争性手段抑制雌激素受体的转录活性，如隔离雌激素受体转录辅助因子。其结果是子宫内膜缺乏增殖和发展为萎缩的子宫内膜状态。随着子宫内膜脱落的减少，出血减少，闭经随之而来。我们建议进行一项为期14个月的前瞻性、随机、双盲、安慰剂对照研究，对50名新开始服用DMPA的患者每两周服用50毫克米非司酮，共12个周期，以确定出血和排卵的发生率。将通过每周三次尿液采集监测每天的乳制品和排卵情况来收集出血数据。治疗前和治疗后获得的7例子宫内膜活检将使用免疫组织化学和定量RT-PCR方法进行分析，以评估雌激素和孕激素受体亚型的水平。活组织检查也将进行组织学评估。为了确定DMPA和米非司酮后雌激素受体的功能，我们将建立原代子宫内膜细胞培养，通过检测SRC、MIB-1和MMT等增殖标记物并将结果与活体活检标本相关联来检测雌激素功能。我们目前正在进行一项试验性研究，类似于拟议的收集初步数据和测试更大规模试验的可行性的研究。如果米非司酮被证明可以安全地降低突破性出血的发生率，更多的女性可能会继续进行DMPA，而不会将自己置于意外怀孕的风险中。

DESCRIPTION (provided by applicant): Progestin-only contraceptives such as depomedroxyprogesterone acetate (DMPA) represent one of the most effective classes of contraceptives but are limited by high discontinuation rates due to breakthrough bleeding especially during the first year of use. Mifepristone is a competitive progesterone receptor antagonist. When Mifepristone was given to normally cycling primates, a near-amenorrheic state was achieved. Mifepristone has been shown to decrease breakthrough bleeding in women using levonorgestrel implants. Although estrogen receptor expression increases after Mifepristone administration, a paradoxical anti-proliferative effect is seen in the endometrium. That has lead some investigators to conclude that mifeprisone can suppress estrogen receptor transcriptional activity through non-competitive means such as sequestration of estrogen receptor transcriptional cofactors. The result being lack of endometrial proliferation and development of an atrophic endometrial state. With less endometrial tissue to shed, bleeding diminishes and amenorrhea ensues. We propose to conduct a 14-month prospective, randomized, double-blind, placebo-controlled study of 50 mg of Mifepristone administered every 2 weeks for 12 cycles to 50 new starters of DMPA in order to determine the incidence of bleeding and ovulation. Bleeding data will be gathered with the use of daily dairies and ovulation monitored by thrice-weekly urine collections. Seven endometrial biopsies obtained pre- and post - treatment will be analyzed using immunohistochemical and quantitative RT-PCR methods to evaluate levels of estrogen and progesterone receptor isoforms. Biopsies will also be evaluated histologically. In order to determine the function of estrogen receptors following DMPA and Mifepristone we will establish primary endometrial cell culture and test estrogen function by measuring markers of proliferation such as SRC, MIB-1 and MMT and correlating results to in vivo biopsy samples. We are currently conducting a pilot study similar to the one proposed to gather preliminary data and to test the feasability of a larger trial. If Mifepristone is shown to safely decrease the incidence of breakthrough bleeding, more women may continue DMPA and not place themselves at risk of an unintended pregnancy.