Mifepristone for Prevention of Breakthrough Bleeding

描述（由申请人提供）：仅孕激素避孕药，如醋酸去甲羟孕酮（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，其停药率很高。米非司酮是一种竞争性黄体酮受体拮抗剂。当给予正常循环的灵长类动物米非司酮时，达到了近乎闭经的状态。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。尽管米非司酮给药后雌激素受体表达增加，但在子宫内膜中发现了一种矛盾的抗增殖作用。这使得一些研究者得出结论，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，发展为子宫内膜萎缩状态。随着子宫内膜组织的减少，出血减少，闭经随之而来。我们建议对50例DMPA新患者进行为期14个月的前瞻性、随机、双盲、安慰剂对照研究，每2周给药50mg米非司酮，共12个周期，以确定出血和排卵的发生率。出血数据将通过使用每日奶瓶收集，并通过每周三次尿液收集监测排卵情况。我们将使用免疫组织化学和定量RT-PCR方法对治疗前后的7个子宫内膜活检进行分析，以评估雌激素和孕激素受体同种异构体的水平。活检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，我们将建立原发性子宫内膜细胞培养，并通过测量增殖标志物如SRC、mb -1和MMT以及体内活检样本的相关结果来测试雌激素功能。我们目前正在进行一项与提议的研究类似的试点研究，以收集初步数据并测试进行更大规模试验的可行性。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，更多的妇女可能会继续使用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.