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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD043209-02
Application #
6667348
Study Section
Special Emphasis Panel (ZHD1-DRG-D (16))
Program Officer
Mackay, H Trent
Project Start
2002-09-27
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$397,500
Indirect Cost
Name
Oregon Health and Science University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Warner, P; Guttinger, A; Glasier, A F et al. (2010) Randomized placebo-controlled trial of CDB-2914 in new users of a levonorgestrel-releasing intrauterine system shows only short-lived amelioration of unscheduled bleeding. Hum Reprod 25:345-53
Brenner, Robert M; Slayden, Ov D; Nath, Anita et al. (2010) Intrauterine administration of CDB-2914 (Ulipristal) suppresses the endometrium of rhesus macaques. Contraception 81:336-42
Nayak, Nihar R; Slayden, Ov D; Mah, Kunie et al. (2007) Antiprogestin-releasing intrauterine devices: a novel approach to endometrial contraception. Contraception 75:S104-11
Cao, W; Mah, K; Carroll, R S et al. (2007) Progesterone withdrawal up-regulates fibronectin and integrins during menstruation and repair in the rhesus macaque endometrium. Hum Reprod 22:3223-31
Critchley, Hilary O D; Kelly, Rodney W; Baird, David T et al. (2006) Regulation of human endometrial function: mechanisms relevant to uterine bleeding. Reprod Biol Endocrinol 4 Suppl 1:S5
Brenner, Robert M; Slayden, Ov D (2005) Progesterone receptor antagonists and the endometrial antiproliferative effect. Semin Reprod Med 23:74-81