Editors' ChoiceReproductive Biology

Fewer lesions, more baby mice

Science Signaling  27 Jan 2015:
Vol. 8, Issue 361, pp. ec21
DOI: 10.1126/scisignal.aaa7461

Endometriosis is a disorder characterized by collections of tissue that normally line the uterus appearing outside the uterus. These aberrantly located tissue deposits cause inflammation and pain, and often also decrease fertility. Current treatments usually involve reducing estrogen, but they are not always effective, have numerous side effects, and reduce fertility. Zhao et al. tested two estrogen receptor (ER) ligands—chloroindazole (CLI), which has ERβ-dependent activity, and oxabicycloheptene sulfonate (OBHS), which exhibits preferential binding toward ERα—in a mouse model of endometriosis. Administration of either drug reduced the establishment of ectopically engrafted uterine tissue. When given with E2 estrogen, the drugs reduced markers of estrogen-stimulated proliferation and vascularization and the abundance of proangiogenic proteins at the site of engraftment. Administration of either drug also produced regression of lesions from established engrafted tissue along with similar effects on proliferative markers and neovascularization markers without compromising fertility. Either drug reduced the abundance of inflammatory cytokines and the prostaglandin biosynthesis enzyme COX2, reduced the activation of the proinflammatory transcription factor NF-κB, and reduced the recruitment of T cells and macrophages to and sensory innervation at sites of the engrafted tissue lesions. Recipient mice in which macrophages were depleted exhibited less effective inhibition of lesion growth in response to either drug. Consistent with their ER specificities, CLI was least effective in inhibiting growth of ectopic lesions in ERβ-knockout recipient mice and OBHS was least effective in ERα knockout recipient mice. Thus, these data suggest that, although estrogen stimulates growth of the lesions, estrogen-dependent inflammatory responses are important for the disease.

Y. Zhao, P. Gong, Y. Chen, J. C. Nwachukwu, S. Srinivasan, C. Ko, M. K. Bagchi, R. N. Taylor, K. S. Korach, K. W. Nettles, J. A. Katzenellenbogen, B. S. Katzenellenbogen, Dual suppression of estrogenic and inflammatory activities for targeting of endometriosis. Sci. Transl. Med. 7, 271ra9 (2015). [Abstract]

W. B. Nothnick, Endometriosis: Bright future for a cloudy past? Sci. Transl. Med. 7, 271fs2 (2015). [Abstract]