Ulipristal Acetate (UPA, previously named CDB-2914, a progesterone receptor modulator developed by the National Institutes of Child Health and Human Development (NICHD)), has potential use in contraception, treatment of fibroids and other gynecological indications [1]. UPA binds strongly to the progesterone receptor (PR), and delays ovulation in fertile women. It has been recently approved by the FDA and the European Medicine Agency as a single oral dose for emergency contraception [2]. In the previous grant period, we proposed the development of a novel estrogen-free, bleed-free long-term contraceptive method employing a UPA contraceptive vaginal ring (CVR) which would deliver the PRM continuously for a 3-month period. We identified the effective dose to suppress ovulation first in animal models in preclinical studies and then in women. The results justify further development. In the current cycle, we propose to study the endometrial safety and contraceptive efficacy of a sequential regimen consisting of a UPA vaginal ring (UPA CVR) in combination with a single oral dose of progestin treatment every month. A reformulated 3-month vaginal ring with an innovative design will be tested for a 6-month study. We will also pursue the development of an intrauterine system (IUS) delivering low daily doses of UPA to decrease endometrial thickness and bleeding, without blocking ovulation. It is anticipated that this novel approach may lead to a long-acting contraceptive with no monthly bleed while ovulation is maintained. Molecular mechanisms underlying potential health benefits of the UPA CVR on target tissues will be evaluated using novel techniques with the objective to demonstrate the potential protective effects benefiting breast health and assuring safety for endometrial tissue. Key novel target genes of interest have been identified as potential mediators underlying the proposed breast protection and health benefits of the UPA CVR. We will focus on detailed analyses of these genes and their downstream molecular signaling pathways in the proposed funding cycle. A new multiplex flow cytometry screening tool is under development for use in contraceptive R&D. It is anticipated that new targets for next generation contraceptives will be identified.

Public Health Relevance

The concept of an estrogen-free contraceptive using a progesterone receptor modulator (PRM) should offer a safer method of contraception, which in addition, could help to suppress the proliferation and emergence of abnormal breast cells, an additional potential benefit of high medical impact.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD029990-22
Application #
8549281
Study Section
Special Emphasis Panel (ZHD1-DRG-H)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
22
Fiscal Year
2013
Total Cost
$748,468
Indirect Cost
$533,450
Name
Population Council
Department
Type
DUNS #
071050090
City
New York
State
NY
Country
United States
Zip Code
10017
El-Etr, Martine; Rame, Marion; Boucher, Celine et al. (2015) Progesterone and nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex. Glia 63:104-17
Huang, YongMei; Jensen, Jeffrey T; Brache, Vivian et al. (2014) A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception. Contraception 90:565-74
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Xiao, Xiang; Mruk, Dolores D; Wong, Elissa W P et al. (2014) Differential effects of c-Src and c-Yes on the endocytic vesicle-mediated trafficking events at the Sertoli cell blood-testis barrier: an in vitro study. Am J Physiol Endocrinol Metab 307:E553-62
Gungor-Ordueri, N Ece; Celik-Ozenci, Ciler; Cheng, C Yan (2014) Fascin 1 is an actin filament-bundling protein that regulates ectoplasmic specialization dynamics in the rat testis. Am J Physiol Endocrinol Metab 307:E738-53

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