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

Abstract

Adenomyosis is a benign uterine disease and 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 to 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.

Perioperative Suppression of Schwann Cell Dedifferentiation Reduces the Risk of Adenomyosis Resulting from Endometrial–Myometrial Interface Disruption in Mice

“…More remarkably, the EMID hypothesis successfully predicted that the risk of developing adenomyosis depends on the mode and severity of EMID, and that the risk can be mitigated by perioperative intervention [ 12 ]. Importantly, the finding that EMID induces adenomyosis has also been independently confirmed very recently in another mouse model [ 13 ]. Thus, our mouse model also provides a perfect explanation of why iatrogenic uterine procedures are a risk factor for adenomyosis.…”

“…The involvement of SCs in EMID-induced adenomyosis is supported by a recent study demonstrating that EMID induces the activation of signal transducer and activator of transcription 3 (STAT3) right after the injury, which persisted throughout the entire course of adenomyosis progression [ 13 ]. Indeed, STAT3 is activated after nerve injury [ 79 ], and it supports SC survival and is essential for the long-term maintenance of the phenotype of differentiated SCs [ 80 ].…”

Current perspectives on endometrial receptivity: A comprehensive overview of etiology and treatment

“…Another recent study using a mouse model of trauma‐induced uterine adenomyosis also suggested that excessive STAT3 activation might be responsible for the pathogenesis of adenomyosis via increased epithelial proliferation, 43,44 which, in turn, could abrogate embryo invasion through the abovementioned mechanism 24,25,41 . In addition, the hyperinflammatory uterine environment elicits an enhanced proliferative activity in the endometrial epithelia, and pro‐inflammatory cytokines, such as interleukin (IL)‐1β, IL‐6, and IL‐8, have been reported to be significantly upregulated in the eutopic endometria of patients with adenomyosis, 45–48 inducing endometrial epithelial proliferation through STAT3 43,44 . Also, the hyperinflammatory environment itself may adversely affect embryo implantation through the alteration of the immune cell population 49 or the emission of embryotoxic cytokines from the immune cells 50,51 .…”

“…40 Moreover, previous reports indicated that mutant KRAS downregulated the expression of progesterone receptors through epigenetic silencing, leading to progesterone resistance in patients with adenomyosis, which could induce endometrial epithelial proliferation and retention during the window of implantation (WOI), 24,25,41 thereby hindering trophectoderm invasion into the stroma. 42 Another recent study using a mouse model of trauma-induced uterine adenomyosis also suggested that excessive STAT3 activation might be responsible for the pathogenesis of adenomyosis via increased epithelial proliferation, 43,44 which, in turn, could abrogate embryo invasion through the abovementioned mechanism. 24,25,41 In addition, the hyperinflammatory uterine environment elicits an enhanced proliferative activity in the endometrial epithelia, and pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and IL-8, have been reported to be significantly upregulated in the eutopic endometria of patients with adenomyosis, [45][46][47][48] inducing endometrial epithelial proliferation through STAT3.…”

“…24,25,41 In addition, the hyperinflammatory uterine environment elicits an enhanced proliferative activity in the endometrial epithelia, and pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and IL-8, have been reported to be significantly upregulated in the eutopic endometria of patients with adenomyosis, [45][46][47][48] inducing endometrial epithelial proliferation through STAT3. 43,44 Also, the hyperinflammatory environment itself may adversely affect embryo implantation through the alteration of the immune cell population 49 or the emission of embryotoxic cytokines from the immune cells. 50,51 The abovementioned findings put forward a possible link between the etiology of adenomyosis and reduced endometrial receptivity.…”