Watanabe Momoe, Kobayashi Yoichi, Ishida Manami, Tajima Atsushi, Tanigaki Shinji, Morisada Tohru
Department of Obstetrics and Gynecology, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka City, Tokyo, 181-8611, Japan.
Reprod Sci. 2025 Mar;32(3):702-715. doi: 10.1007/s43032-025-01795-w. Epub 2025 Feb 5.
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.
子宫内膜异位症和卵巢子宫内膜异位囊肿（OMA）会导致痛经和不孕。目前用于OMA治疗的激素疗法可能效果有限。激素治疗通过孕酮受体（PR）信号通路下调雌激素受体（ERs）发挥作用；因此，孕激素被用于治疗子宫内膜异位症。地诺孕素（DNG）是一种口服孕激素，对PRs具有高度选择性。此前我们已确定天青杀素与DNG耐药性有关。在此，我们旨在研究天青杀素对OMA的影响及其临床意义。我们使用人永生化子宫内膜上皮Emosis-CC/TERT1细胞系，研究了天青杀素对PR或ER的影响以及DNG对OMA中炎性细胞因子白细胞介素-6（IL-6）和白细胞介素-8（IL-8）的作用，并测量了人生物样本中的天青杀素水平。DNG在体外抑制IL-6和IL-8的产生，而在天青杀素存在的情况下这种抑制作用受到抑制。此外，炎性细胞因子IL-6和IL-8可增强天青杀素的产生。此外，天青杀素可诱导ER表达；与17β-雌二醇和天青杀素共同孵育后，EMosis-CC/TERT1细胞的增殖显著增加。总体而言，天青杀素通过促进ER表达增加雌激素敏感性，从而抑制DNG的作用并导致子宫内膜异位症。DNG治疗耐药患者血液和尿液中的天青杀素浓度高于其他患者。因此，天青杀素可能与OMA中的DNG耐药性有关。
