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. Similar content being viewed by others Data Availability The datasets used and analysed in the current study are from the corresponding author on reasonable request. Code Availability Not applicable.

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We are very grateful to Ms. Manami Ishida for her excellent technical assistance. Funding This study was partly supported by a Grant-in-Aid for Scientific Research (C), Grant number 18K09236. Author information Authors and Affiliations Corresponding author Ethics declarations Ethics Approval The study was approved by our institution’s IRB (IRB No. H28-037_673-03). Consent for Publication All authors read the final version of the manuscript and consented to its publication. Consent to Participate Informed consent was obtained from all participants included in the study. Competing Interests The authors declare no competing interests. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Watanabe, M., Kobayashi, Y., Ishida, M. et al. Azurocidin is Associated with Dienogest-resistance in Ovarian Endometriotic Cysts. Reprod. Sci. 32, 702–715 (2025). https://doi.org/10.1007/s43032-025-01795-w Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-025-01795-w