Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.
Clinical Laboratory, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.
Biol Reprod. 2023 May 10;108(5):791-801. doi: 10.1093/biolre/ioad014.
Increasing evidences showed that ovulatory dysfunction, possibly caused by luteinized unruptured follicular follicle syndrome (LUFS), is one of the reasons for endometriosis-related infertility. The present study was conducted to explore the potential effect of elevated progesterone in follicular fluid (FF) on ovulation in endometriosis. A prospective study including 50 ovarian endometriosis patients and 50 control patients with matched pairs design was conducted with alterations in FF and peritoneal fluid (PF) components identified by metabolomics analyses and differentially expressed genes in granulosa cells (GCs) identified by transcriptome analysis. Patients with endometriosis exhibited a significantly higher progesterone level in serum, FF, and PF. Granulosa cells from endometriosis patients revealed decreased expression of HPGD, COX-2, and suppressed NF-ĸB signaling. Similarly, progesterone treatment in vitro downregulated HPGD and COX2 expression and suppressed NF-ĸB signaling in granulosa tumor-like cell line KGN (Bena Culture Collection, China) and primarily cultured GCs, as manifested by decreased expressions of IL1R1, IRAK3, reduced pIĸBα/IĸBα ratio, and nucleus translocation of p65. On the contrary, TNF-α treatment increased expression of IL1R1, IRAK3, pIĸBα, p65, and HPGD in GCs. One potential p65 binding site was identified in the promoter region of HPGD by chromatin immunoprecipitation. In conclusion, we found that intrafollicular progesterone might downregulate HPGD and COX-2 in GCs via suppressing the NF-ĸB signaling pathway, shedding light on the mechanism underlying the endometriosis-related ovulatory dysfunction.
越来越多的证据表明，排卵功能障碍可能是由黄体未破裂卵泡黄素化综合征（LUFS）引起的，这是子宫内膜异位症相关不孕的原因之一。本研究旨在探讨卵泡液（FF）中孕酮水平升高对子宫内膜异位症排卵的潜在影响。采用配对设计的前瞻性研究，纳入 50 例卵巢子宫内膜异位症患者和 50 例配对对照患者，通过代谢组学分析鉴定 FF 和腹腔液（PF）成分的变化，通过转录组分析鉴定颗粒细胞（GC）中的差异表达基因。子宫内膜异位症患者血清、FF 和 PF 中的孕酮水平明显升高。子宫内膜异位症患者的颗粒细胞显示 HPGD、COX-2 表达降低，NF-κB 信号受到抑制。同样，孕酮在体外处理颗粒细胞瘤样细胞系 KGN（Bena Culture Collection，中国）和原代培养的 GC 时下调 HPGD 和 COX2 的表达并抑制 NF-κB 信号，表现为 IL1R1、IRAK3 的表达减少，pIκBα/IκBα 比值降低，p65 核易位。相反，TNF-α 处理增加了 GC 中 IL1R1、IRAK3、pIκBα、p65 和 HPGD 的表达。染色质免疫沉淀法在 HPGD 启动子区域鉴定到一个潜在的 p65 结合位点。总之，我们发现卵泡内孕酮可能通过抑制 NF-κB 信号通路下调 GC 中的 HPGD 和 COX-2，这为子宫内膜异位症相关排卵功能障碍的发病机制提供了新的见解。
