Mechanisms Underlying Adenomyosis-Related Fibrogenesis

Adenomyosis is a common gynecologic disorder defined by the presence of endometrial glands and stroma within the uterine myometrium. This review focusses on: (1) current understanding of cellular and molecular mechanisms of adenomyosis-related fibrogenesis, (2) transforming growth factor beta (TGF-β)-dependent or TGF-β-independent mediators of fibrogenesis, and (3) the origin of fibrogenic myofibroblasts. We collected a literature search from PubMed and EMBASE database up to December 2018. First, causative factors of adenomyosis are classified into exogenous traumatic damage (surgical interventions, including curettage, normal delivery, or cesarean section) and endogenous traumatic damage (mechanical strain or myometrial hyperperistalsis). The mechanical forces and injury (microdehiscences) are fundamental regulators of cell behavior and central to our understanding of disease pathogenesis. Adenomyosis is characterized by abnormal response to injury and activation of myofibroblasts in the myometrium through altered barrier function of the endometrial-myometrial junctional zone (EMJZ). Second, we summarize recent advances on the molecular mechanism of fibrosis. Two distinct populations of myofibroblasts, highly myogenic cells, and nonmyogenic cells arise possibly through the TGF-β-dependent and TGF-β-independent processes. TGF-β-independent mechanisms are still intriguing and far from clear. Third, the importance and implications of resident fibroblasts, bone-marrow stem cells-derived fibrocytes, and epithelial-mesenchymal transition-derived myofibroblasts in fibrosis remain uncertain. Finally, originally adenomyosis was believed to be the single entity, but this disorder is composed of multiple heterogeneous subtypes. Key mediators of fibrogenesis may vary widely and largely depend on adenomyosis subtype. In conclusion, both cyclic mechanical strain and EMJZ weakness (microdehiscences) may be a prerequisite for adenomyosis fibrogenesis through the mechanotransduction process. Since there are significant molecular variations among affected individuals, the approach to identify key mediators of fibrosis remains challenging.