Hiraoka Takehiro, Hirota Yasushi, Aikawa Shizu, Iida Rei, Ishizawa Chihiro, Kaku Tetsuaki, Hirata Tomoyuki, Fukui Yamato, Akaeda Shun, Matsuo Mitsunori, Shimizu-Hirota Ryoko, Takeda Norihiko, Osuga Yutaka
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Internal Medicine, Center for Preventive Medicine, School of Medicine, Keio University, Tokyo, Japan.
Endocrinology. 2022 May 1;163(5). doi: 10.1210/endocr/bqac044.
Adenomyosis is a benign uterine disease that causes dysmenorrhea, heavy menstrual bleeding, and infertility; however, its pathophysiology remains unclear. Since signal transducer and activator of transcription 3 (STAT3) is crucial for endometrial regeneration, we hypothesized that STAT3 participates in adenomyosis pathophysiology. To investigate the influence of STAT3 on adenomyosis development, this study was performed using a novel mouse model of adenomyosis and human specimens of eutopic endometria and adenomyosis lesions. We established a novel mouse model of adenomyosis by puncturing entire mouse uterine layers with a thin needle. Mouse eutopic and ectopic endometria showed a positive immunoreactivity for phosphorylated STAT3 (pSTAT3), the active form of STAT3. Decreased numbers of adenomyotic lesions and reduced expression of Cxcl1, Icam1, and Spp1, which are associated with immune cell chemotaxis and tissue regeneration, were observed in uterine Stat3-deficient mice compared with the controls. In humans, pSTAT3 was intensely expressed at both the eutopic endometrium and the adenomyotic lesions regardless of the menstrual cycle phases. Conversely, it was limitedly expressed in the eutopic endometrium during the menstrual and proliferative phases in women without adenomyosis. Our findings indicate that continuous STAT3 activation promotes adenomyosis development. STAT3 inhibition can be a promising treatment strategy in patients with adenomyosis.
子宫腺肌病是一种良性子宫疾病，可导致痛经、月经过多和不孕；然而，其病理生理学仍不清楚。由于信号转导和转录激活因子3（STAT3）对子宫内膜再生至关重要，我们推测STAT3参与了子宫腺肌病的病理生理过程。为了研究STAT3对子宫腺肌病发展的影响，本研究使用了一种新型子宫腺肌病小鼠模型以及人在位子宫内膜和子宫腺肌病病变标本。我们通过用细针穿刺小鼠整个子宫层建立了一种新型子宫腺肌病小鼠模型。小鼠在位和异位子宫内膜对磷酸化STAT3（pSTAT3，STAT3的活性形式）呈阳性免疫反应。与对照组相比，在子宫Stat3缺陷小鼠中观察到子宫腺肌病病变数量减少，以及与免疫细胞趋化和组织再生相关的Cxcl1、Icam1和Spp1表达降低。在人类中，无论月经周期阶段如何，pSTAT3在位子宫内膜和子宫腺肌病病变中均强烈表达。相反，在没有子宫腺肌病的女性中，pSTAT3在月经和增殖期在位子宫内膜中表达有限。我们的研究结果表明，持续的STAT3激活促进子宫腺肌病的发展。抑制STAT3可能是子宫腺肌病患者一种有前景的治疗策略。
