Project III: Selective Progesterone Receptor Modulators (SPRMs) represent a new class of progesterone receptor (PR) ligands that range from full PR antagonists to compounds with mixed agonist/antagonist activities on various progesterone target tissues in vivo. Due to diverse effects on the PR, specific PRMs are being investigated for multiple clinical applications in reproductive health care. Potential clinical applications of SPRMs include emergency contraception, long-term estrogen-free contraception and post-menopausal hormone therapy, and treatments for myomas, endometriosis and hormone-dependent tumors. The proposed studies combine molecular modeling, translational, and clinical studies to further investigate the clinical safety of CDB-2914 and characterize its effects at a cellular level on hormone target tissues.
Aim 1 : Establish and characterize responses of normal human mammary epithelial cells (HMEC) using primary culture models to: a) Determine characteristics of cell cycle kinetics after short and long term exposure to CDB-2914, in the presence of E2 and/or P4;b) Determine whether a proliferating population of stem and progenitor cells can be isolated for further study ex vivo to establish long-term safety of CDB-2914 on breast stem cells.
Aim 2 : Establish and characterize mouse mammary stem and progenitor cell populations as ex vivo models to study effects of CDB-2914 on the breast, studies with a focus on steroid receptor expression and function. Developing a long-term estrogen-free contraception using a PRM that would also prevent P action on the breast is potentially a contraceptive method with dual benefits, i.e., prevention of conception and breast disease. New findings on endometrial effects of PRMs justify further clinical evaluation.
Aim 3 : The first clinical study will explore the endometrial effects of CDB 2914 delivered from a vaginal ring at a dose blocking ovulation. Endometrial histology and proliferation markers will be determined over time. A second clinical study will evaluate whether sequential 2-week progestin courses after 12-week PRM ring use will reverse any endometrial changes. The third clinical study will evaluate the effects of low doses of CDB- 2914 applied using an intrauterine system to induce only a local effect while a normal ovulation is maintained.
Aim 4 : Establish a human endometrial epithelial cell (HEEC) model for molecular modeling studies and characterization of the effects of progestins compared to those of CDB-2914 and SPRMs on the endometrium: a) Determine cell cycle-related effects when estrogen is present or absent, comparing the activity of progestins (P4;medroxyprogesterone acetate, MPA) with that of CDB-2914 using several immortalized human endometrial carcinoma cells;b) Compare effects of SPRMs, progestin, estrogen, or sequential hormone exposure on HEEC functions, using gene expression and proteomic analyses. Project III combines basic, translational and clinical studies to further ascertain the safety of CDB-2914 for human use as well as characterization of this PRM's molecular mechanisms.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Population Council
New York
United States
Zip Code
Li, Linxi; Tang, Elizabeth I; Chen, Haiqi et al. (2017) Sperm Release at Spermiation Is Regulated by Changes in the Organization of Actin- and Microtubule-Based Cytoskeletons at the Apical Ectoplasmic Specialization-A Study Using the Adjudin Model. Endocrinology 158:4300-4316
Tung, Kenneth S K; Harakal, Jessica; Qiao, Hui et al. (2017) Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance. J Clin Invest 127:1046-1060
Gao, Ying; Chen, Haiqi; Lui, Wing-Yee et al. (2017) Basement Membrane Laminin ?2 Regulation of BTB Dynamics via Its Effects on F-Actin and Microtubule Cytoskeletons Is Mediated Through mTORC1 Signaling. Endocrinology 158:963-978
Chen, Haiqi; Li, Michelle W M; Yan Cheng, C (2017) Drebrin and Spermatogenesis. Adv Exp Med Biol 1006:291-312
Gao, Ying; Chen, Haiqi; Xiao, Xiang et al. (2017) Perfluorooctanesulfonate (PFOS)-induced Sertoli cell injury through a disruption of F-actin and microtubule organization is mediated by Akt1/2. Sci Rep 7:1110
Jesus, Tito T; Oliveira, Pedro F; Sousa, Mário et al. (2017) Mammalian target of rapamycin (mTOR): a central regulator of male fertility? Crit Rev Biochem Mol Biol 52:235-253
Kumar, Narender; Fagart, Jerôme; Liere, Philippe et al. (2017) Nestorone® as a Novel Progestin for Nonoral Contraception: Structure-Activity Relationships and Brain Metabolism Studies. Endocrinology 158:170-182
Gao, Ying; Mruk, Dolores; Chen, Haiqi et al. (2017) Regulation of the blood-testis barrier by a local axis in the testis: role of laminin ?2 in the basement membrane. FASEB J 31:584-597
Chen, Haiqi; Mruk, Dolores D; Lee, Will M et al. (2017) Regulation of spermatogenesis by a local functional axis in the testis: role of the basement membrane-derived noncollagenous 1 domain peptide. FASEB J 31:3587-3607
Oliveira, Pedro F; Cheng, C Y; Alves, Marco G (2017) Emerging Role for Mammalian Target of Rapamycin in Male Fertility. Trends Endocrinol Metab 28:165-167

Showing the most recent 10 out of 243 publications