**1. Introduction**

Adenomyosis consists of a term that describes the presence of endometrial glands in a layer deep in the myometrium, in a random arrangement and similar histological lesions can be also appeared outside of the uterus, such as the area of the rectal septum [1–3]. Pathogenesis and etiology of adenomyosis development have not been elucidated thoroughly.

Studies in humans and experiments in animals support the hypothesis of endometrial insertion from the myometrium, although the development of adenomyosis from Müller's duct debris at locations outside the uterus is possible from the outset.

The conditions for the development of adenomyosis can be either some "weakness" of the smooth muscle fibers of the myometrium or the increased pressure in the uterine cavity or both. To maintain adenomyosis, relatively high concentrations of estrogen and impaired control of the development of the ectopic endometrium, which is associated with the immune system, may be necessary. Hyperplasia and hypertrophy of smooth muscle fibers are a reflection of the reactive changes in the proliferation of ectopic endometrium. The definitive diagnosis is made after hysterectomy, although efforts have been made to confirm the diagnosis preoperatively with magnetic resonance imaging and endometrial biopsies [4–6].

#### **1.1 Genetic predisposition**

Adenomyosis, one of the most common diseases in gynecology with a frequency ranging between 5% and 70%, can significantly affect the quality of life of women with clinical symptoms such as menorrhagia, dysmenorrhea and infertility [7–9]. There are two prevailing theories concerning the origin of adenomyosis. One supports "migration", which concerns the penetration of the endometrium into the myometrium, while the other is based on the metaplastic differentiation of the remaining endometrial stem cells in the myometrium. Mutations that have been observed, almost exclusively, in the KRAS genes, in the presence of adenomyosis, underscore the importance of these genes in the pathogenesis of the disease at the genetic level. This discovery of the cause-effect relationship between the presence of mutations in the aforementioned [7–9]. KRAS genes and adenomyosis refuted the recent theory that the reported molecular abnormalities in adenomyosis are mainly epigenetic or associated with abnormal expression in different genes [7–9]. Most recognized abnormalities regarding gene expression, were associated with excess estrogen formation, progesterone resistance and were related to steroid hormone receptors and other transcription factors. More specifically, mutations have been found, such as the following two P129R, M427I/L429M, which are the most predominant ones, in the ESR1 gene of the estrogen receptor α (ERa) located on chromosome 6q25.1 and appear to be involved in the etiology of adenomyosis [7–9]. It has also been described an association between adenomyosis and deregulation of mechanisms involved in the transition process of epithelial to mesenchymal cells, as occurs in cases of decreased expression of Cadherin-1 (CDH1) protein, as well as in cases of increased Notch I and TGF-β levels [7–9]. Regarding epigenetic factors, it has been suggested that Class I histone deacetylases (HDACs) are involved in promoting gene transcription, as well as DNA methyltransferase (DNMT) proteins involved in DNA methylation are associated with adenomyosis. High levels of HDAC1 and HDAC3 as well as DNMT1 and DNMT3B were found in cases of adenomyosis at the ectopic endometrium. Consequently, epigenetic alterations seem to play an important role in the pathogenesis of adenomyosis, which along with the other aforementioned genetic factors provides knowledge that could potentially lead to advances in the diagnosis and treatment of the disease [7–9].
