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 #
5U54HD029990-23
Application #
8720029
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Population Council
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10017
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
Li, Nan; Mruk, Dolores D; Lee, Will M et al. (2016) Is toxicant-induced Sertoli cell injury in vitro a useful model to study molecular mechanisms in spermatogenesis? Semin Cell Dev Biol 59:141-156
Gao, Ying; Lui, Wing-Yee; Lee, Will M et al. (2016) Polarity protein Crumbs homolog-3 (CRB3) regulates ectoplasmic specialization dynamics through its action on F-actin organization in Sertoli cells. Sci Rep 6:28589
Li, Nan; Mruk, Dolores D; Chen, Haiqi et al. (2016) Rescue of perfluorooctanesulfonate (PFOS)-mediated Sertoli cell injury by overexpression of gap junction protein connexin 43. Sci Rep 6:29667
Chen, Haiqi; Mruk, Dolores D; Lee, Will M et al. (2016) Planar Cell Polarity (PCP) Protein Vangl2 Regulates Ectoplasmic Specialization Dynamics via Its Effects on Actin Microfilaments in the Testes of Male Rats. Endocrinology 157:2140-59
Tang, Elizabeth I; Lee, Will M; Cheng, C Yan (2016) Coordination of Actin- and Microtubule-Based Cytoskeletons Supports Transport of Spermatids and Residual Bodies/Phagosomes During Spermatogenesis in the Rat Testis. Endocrinology 157:1644-59
Wen, Qing; Cheng, C Yan; Liu, Yi-Xun (2016) Development, function and fate of fetal Leydig cells. Semin Cell Dev Biol 59:89-98
Jesus, Tito T; Oliveira, Pedro F; Silva, Joaquina et al. (2016) Mammalian target of rapamycin controls glucose consumption and redox balance in human Sertoli cells. Fertil Steril 105:825-833.e3

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