Azurocidin is Associated with Dienogest-resistance in Ovarian Endometriotic Cysts

Endometriosis and ovarian endometrioma (OMA) cause dysmenorrhea and infertility. Current hormonal therapies for OMA treatment, may exhibit limited effectiveness. Hormonal treatments function by downregulate estrogen receptors (ERs) via progesterone receptor (PR) signaling; therefore, progestins are used for the treatment of endometriosis. Dienogest (DNG), an oral progestin, is highly selective for PRs. Previously we identified the association of azurocidin with DNG resistance. Herein, we aimed to examine the effect of azurocidin on OMAs and its clinical significance. We examined the effect of azurocidin on PR or ER and the action of DNG on the inflammatory cytokines IL-6 and IL-8 in OMAs used the human immortalized endometriotic epithelial Emosis-CC/TERT1 cell line, and measured azurocidin levels in human biological samples. DNG inhibited IL-6 and IL-8 production in vitro, which was suppressed in the presence of azurocidin. Additionally, the inflammatory cytokines IL-6 and IL-8 enhanced azurocidin production. Furthermore, azurocidin induced ER expression; the proliferation of EMosis-CC/TERT1 cells increased significantly upon incubation with 17β-estradiol and azurocidin. Overall, azurocidin inhibits the action of DNG by increasing estrogen sensitivity via promoting ER expression and endometriosis. Azurocidin concentrations in the blood and urine were higher in patients resistant to DNG therapy than in other patients. Thus, azurocidin may be associated with DNG resistance in OMAs.