Constant Activation of STAT3 Contributes to the Development of Adenomyosis in Females

• Published in: Endocrinology (Philadelphia) Vol. 163; no. 5; p. 1
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-05-2022
• Subjects: Adenomyosis - genetics; Adenomyosis - metabolism; Adenomyosis - pathology; Analysis; Animals; Chemotaxis; Endocrinology; Endometriosis; Endometriosis - metabolism; Endometrium; Endometrium - metabolism; Epidermal growth factor; Female; Humans; Immune system; Immunoreactivity; Infertility; Intercellular adhesion molecule 1; Lesions; Menstrual cycle; Menstruation; Mice; Pathophysiology; Regeneration (physiology); Stat3 protein; STAT3 Transcription Factor - metabolism; Thin films; Tissue engineering; Uterine Diseases; Uterus; Japan; myometrium; uterus; mouse model; signal transducer and activator of transcription 3 (STAT3); adenomyosis
• ISSN: 0013-7227; 1945-7170
• 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.