**3. Pathogenesis**

Endometriosis and adenomyosis are closely linked diseases, but there are several differences in their pathogenesis. Four theories have been proposed to explain adenomyosis: heredity, trauma, hyperketonemia, and viral transmission. Although the exact cause is unknown, the most widely accepted theory of histogenesis was proposed by Meyer in 1900. Meyer postulated that the normal barrier between

the endometrium and myometrium is somehow attenuated. The most held theory regarding adenomyosis is the endometrial basalis layer invades through the end myometrial junctional zone (JZ) into the myometrium after trauma on the endometrium [3]. Estrogen and progesterone likely play a role in its development after invagination of the endometrium. Another theory is that adenomyosis is caused by metaplasia of the Müllerian tissue [4]. Ren et al. demonstrated that Belin 1 expression was decreased in eutopic endometrium, and negatively correlated with serum CA125 and pelvic pain. Belin 1, therefore, may play a role in the pathogenesis and progression of adenomyosis [5]. The tissue injury and repair (TIAR) mechanism is activated in response to tissue auto-traumatization. This mechanism leads to a specific physiological process that promoted local production of Bcl-2, and plays an important role in the occurrence and development of adenomyosis [6]. The levels of anti-smooth muscle antibody positive and collage I positive myofibroblasts are significantly higher in the JZ of women with adenomyosis than in those without [3], as the evidence of tissue microtrauma and activation of the TIAR mechanism.

Hyperestrogenism is suggested to result from increased local aromatization, and decreased local estrogen metabolism in the eutopic and ectopic endometrium of patients with adenomyosis. Hyperestrogenism may promote elevated mechanical strains and stresses that could injure cells in the junctional zone (JZ) [7, 8].

Recently, studies of embryonic pluripotent Müllerian remnants and differentiation of adult stem cells have also been reported [4, 9, 10]. Epithelial-mesenchymal transition (EMT) is biological process involved in embryological development, tissue repair, and cancer cell migration, but the mechanism triggering EMT in adenomyosis has not yet been elucidated [11].
