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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DRG-H)
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Population Council
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Chen, Haiqi; Mruk, Dolores D; Xia, Weiliang et al. (2016) Effective Delivery of Male Contraceptives Behind the Blood-Testis Barrier (BTB) - Lesson from Adjudin. Curr Med Chem 23:701-13
Tang, Elizabeth I; Mruk, Dolores D; Cheng, C Yan (2016) Regulation of microtubule (MT)-based cytoskeleton in the seminiferous epithelium during spermatogenesis. Semin Cell Dev Biol 59:35-45
Venkatesh, Deepak; Mruk, Dolores; Herter, Jan M et al. (2016) AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function. Am J Pathol 186:270-84
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