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.
