Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology.

Traditionally considered as an enigmatic disease, adenomyosis is a uterine disease that affects many women of reproductive age and is a contributing factor for pelvic pain, heavy menstrual bleeding (HMB), and subfertility. In this review, the new development in the pathogenesis and pathophysiology of adenomyosis has been summarized, along with their clinical implications. After reviewing the progress in our understanding of the pathogenesis and describing the prevailing theories, in conjunction with their deficiencies, a new hypothesis, called endometrial-myometrial interface disruption (EMID), which is backed by extensive epidemiologic data and demonstrated by a mouse model, is reviewed, along with recent data implicating the role of Schwann cells in the EMI area in the genesis of adenomyosis. Additionally, the natural history of adenomyotic lesions is elaborated and underscores that, in essence, adenomyotic lesions are fundamentally wounds undergoing repeated tissue injury and repair (ReTIAR), which progress to fibrosis through epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, and smooth muscle metaplasia. Increasing lesional fibrosis propagates into the neighboring EMI and endometrium. The increased endometrial fibrosis, with ensuing greater tissue stiffness, results in attenuated prostaglandin E2, hypoxia signaling and glycolysis, impairing endometrial repair and causing HMB. Compared with adenomyosis-associated HMB, the mechanisms underlying adenomyosis-associated pain are less understood but presumably involve increased uterine contractility, hyperinnervation, increased lesional production of pain mediators, and central sensitization. Viewed through the prism of ReTIAR, a new imaging technique can be used to diagnose adenomyosis more accurately and informatively and possibly help to choose the best treatment modality.