OR44-4 Novel Estrogen Receptor Ligands with Anti-estrogenic and Anti-inflammatory Activity for Prevention and Treatment of Endometriosis: Studies in a Mouse Model

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR44-Female Reproductive Endocrinology
Basic/Translational
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 10:00 AM
Room 256 (Moscone Center)
Yuechao Zhao*1, Ping Gong1, Yiru Chen1, Milan K Bagchi1, Robert N Taylor2, Kendall W Nettles3, John A Katzenellenbogen4 and Benita S Katzenellenbogen1
1University of Illinois at Urbana-Champaign, Urbana, IL, 2Wake Forest Schl of Med, Winston-Salem, NC, 3Scripps Florida, Jupiter, FL, 4Univ of Illinois, Urbana, IL
Endometriosis is an estrogen-dependent and inflammatory gynecological disorder associated with pelvic pain and infertility. Current therapies for this common disease focus on reducing systemic levels of estrogens; however, these treatments are not fully effective and are associated with side effects and frequent recurrence. Developed by us as novel estrogen receptor (ER) antagonists, chloroindazole (CLI) and oxabicycloheptene sulfonate (OBHS) showed strong ER-dependent anti-inflammatory activity, thus making them attractive candidates for possible treatment of endometriosis. In this study, prevention and therapeutic models were used. Surgical endometriosis was induced in ovariectomized mature immunocompetent mice supplemented with estradiol (E2). Endometriotic lesion establishment, including cell proliferation, cyst formation, vascularization and lesion growth, were greatly reduced by co-treatment with CLI or OBHS with E2 for 2 weeks. Strikingly, the E2-induced inflammatory response was also suppressed during endometriosis progression by either ligand, based on: (1) greatly reduced production of cytokines and chemokines in endometriotic lesions (i.e., IL6, IL1B, IL10, and RANTES), known to be highly stimulated in human endometriosis; (2) suppression of NF-κB activation in endometriotic cells; and (3) markedly inhibited infiltration of immune cells (i.e., T cells and macrophages) into endometriotic lesions. In normal eutopic host uterine tissues, anti-estrogenic effects of CLI and OBHS were displayed by hypoplastic uterine morphology and inactive angiogenesis and cell proliferation. Therefore, these observations indicate the great potential of CLI and OBHS for preventing recurrence of the disease. To further evaluate the therapeutic effects of these ligands, CLI or OBHS alone was administrated to intact animals beginning after 2 weeks of lesion establishment. Marked lesion regression and suppressed inflammation with decreased levels of cytokines and chemokines were observed. Importantly, neither ligand caused stimulation of reproductive tissues or alteration of estrus cycling. Hence, CLI and OBHS have strong ability not only to restrain endometriosis progression but also to elicit regression of established lesions by acting as potent anti-estrogenic and anti-inflammatory ligands. Our observations suggest that these compounds may have good potential as novel preventive and therapeutic agents for endometriosis treatment in humans.

Nothing to Disclose: YZ, PG, YC, MKB, RNT, KWN, JAK, BSK

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by NIH U54 HD055787 as part of the Eunice Kennedy Shriver NICHD/NIH Centers Program in Reproduction and Infertility Research, by NIH DK015556 and by NIH DK077085.