Dual suppression of estrogenic and inflammatory activities for targeting of endometriosis

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Science Translational Medicine  21 Jan 2015:
Vol. 7, Issue 271, pp. 271ra9
DOI: 10.1126/scitranslmed.3010626

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Fewer Lesions, More Little Mice

Endometriosis is a poorly understood disorder of the female reproductive system, where collections of tissue that normally lines the uterus appear outside the uterus as well. These tissue deposits can be found anywhere in the abdominal cavity, where they cause inflammation and pain, and often also decreased fertility. Although some hormonal treatments for endometriosis exist, they are not always effective, have numerous side effects, and also suppress fertility. Now, Zhao et al. present some mechanistic explanations for the inflammatory phenomena seen in endometriosis. Even more importantly, the authors identified two new estrogen receptor ligands that can suppress endometriosis in mouse models safely and effectively, without disrupting the animals’ reproductive cycles and fertility.


Estrogenic and inflammatory components play key roles in a broad range of diseases including endometriosis, a common estrogen-dependent gynecological disorder in which endometrial tissue creates inflammatory lesions at extrauterine sites, causing pelvic pain and reduced fertility. Current medical therapies focus primarily on reducing systemic levels of estrogens, but these are of limited effectiveness and have considerable side effects. We developed estrogen receptor (ER) ligands, chloroindazole (CLI) and oxabicycloheptene sulfonate (OBHS), which showed strong ER-dependent anti-inflammatory activity in a preclinical model of endometriosis that recapitulates the estrogen dependence and inflammatory responses of the disease in immunocompetent mice and in primary human endometriotic stromal cells in culture. Estrogen-dependent phenomena, including cell proliferation, cyst formation, vascularization, and lesion growth, were all arrested by CLI or OBHS, which prevented lesion expansion and also elicited regression of established lesions, suppressed inflammation, angiogenesis, and neurogenesis in the lesions, and interrupted crosstalk between lesion cells and infiltrating macrophages. Studies in ERα or ERβ knockout mice indicated that ERα is the major mediator of OBHS effectiveness and ERβ is dominant in CLI actions, implying involvement of both ERs in endometriosis. Neither ligand altered estrous cycling or fertility at doses that were effective for suppression of endometriosis. Hence, CLI and OBHS are able to restrain endometriosis by dual suppression of the estrogen-inflammatory axis. Our findings suggest that these compounds have the desired characteristics of preventive and therapeutic agents for clinical endometriosis and possibly other estrogen-driven and inflammation-promoted disorders.

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