Etiology
The exact etiology and pathogenesis of adenomyosis remains unclear. Multiple hypotheses have been suggested to explain its development; theories include:[13][14][15]
Infiltration of basalis endometrial cells into the myometrium due to the activation of tissue injury and repair processes (tissue injury and repair theory [TIAR]).
Transformation of displaced embryonic pluripotent Müllerian remnants into adenomyotic tissue (metaplasia).
Differentiation of embryonic stem/progenitor cells.
Endometrial cell migration.
Enhanced proliferation and survival of endometrial cells.
Numerous risk factors for the development of the condition have been documented, including multiparity, early menarche, prior uterine surgery, and a history of ectopic pregnancy.[9] The coexistence of uterine leiomyoma and adenomyosis has been reported in 15% to 57% of women undergoing hysterectomy for leiomyomas.[9][16] A history of endometriosis is also associated with increased risk of adenomyosis, which has been found in approximately 65% of women with histologically proven endometriosis.[17] The use of tamoxifen has also been associated with a higher incidence of adenomyosis.[18][19]
Pathophysiology
Local hyperestrogenism appears to be a significant factor in the development of adenomyosis.
In patients with adenomyosis, both the eutopic and ectopic endometrial tissues experience increased estrogen production and higher estrogen levels due to heightened local aromatization and reduced estrogen metabolism.[20]
This is primarily attributed to the inactivation of the 17beta-hydroxysteroid dehydrogenase type 2 (HSD17β2) gene in the eutopic cells, which inhibits conversion of estradiol to less potent estrone.[21]
Adenomyosis also involves progesterone resistance, likely caused by reduced immunoreactivity of progesterone receptor-B (PRB) due to promoter hypermethylation.[22]
Consequently, the counteractive effect of progesterone against estrogen-driven proliferation in a healthy endometrium is diminished or lost, exacerbating the estrogen-dependent growth in adenomyosis.[22]
Additionally, the presence of high estrogen levels in adenomyosis may contribute to increased uterine activity mediated by oxytocin.[23][24]
Heightened uterine activity can lead to elevated mechanical strains and stresses, which have the potential to cause damage to cells in the junctional zone (JZ) near the fundocornual raphe; the tissue injury and repair (TIAR) mechanism can be triggered when tissue self-injury occurs, leading to an increase in inflammation. This inflammatory response, in turn, stimulates the production of more estrogen.[23][24]
Elevated levels of estrogen further contribute to hyperperistalsis by inducing the expression of estrogen receptor-alpha (ER-alpha), which promotes the activation of the oxytocin/oxytocin receptor (OT/OTR) system.[25]
Chronic hyperperistalsis occurring at the JZ contributes to repetitive self-injury, leading to the breakdown of muscular fibers in the JZ. Over time, this can cause the invagination of the basal layer of the endometrium into the myometrium, ultimately leading to the development of adenomyosis. This biologic phenomenon at the endometrial-myometrial interface has recently been termed endometrial-myometrial interface disruption (EMID).[25]
Moreover, there are elevated levels of matrix metalloproteinases (MMPs) -2 and -9 observed in the eutopic endometrium of adenomyotic lesions when compared with the levels found in the endometrium of women without the disease. These MMPs are believed to play a role in the process of intramyometrial endometrial invagination, contributing to the development of adenomyosis.[26]
An alternative theory suggests that adenomyotic lesions may arise de novo from the metaplasia of displaced embryonic pluripotent Müllerian remnants.[27][28]
The Müllerian structures comprise surface epithelium and the underlying urogenital ridge mesenchyme, which have the potential to generate ectopic endometrial tissue within the myometrial wall, giving rise to adenomyotic lesions.[29]
This theory, known as the Müllerian metaplasia theory, is supported by case reports demonstrating confirmed adenomyosis in the rudimentary muscular uterine wall of patients with Rokitansky-Kuster-Hauser syndrome.[30][31]
Another hypothesis proposes that endometrial epithelial progenitor and mesenchymal stem cells (eMSCs), found within the endometrium, can migrate to the uterine wall during menstruation and differentiate into endometrial gland and stromal cells.[14]
These stem cells play a critical role in the regeneration of the endometrium following menstruation. Retrograde menstruation (menstrual blood flowing backward into the uterus) can result in the transfer of these adult progenitor stem cells.
When they differentiate into endometrial glands and stroma, this leads to the development of new intramyometrial endometrial implants.[32] Moreover, tissue injury activates stem cells, and the microtrauma to the JZ and endometrial basalis layer can alter the stem cell niche, causing abnormal movement toward the myometrium instead of the endometrial functionalis.[27][33]
A newer group of stem cells, referred to as pale cells due to their appearance under electron microscopy, has been discovered at the endometrial-myometrial interface in adenomyotic patients.
These cells, located eccentrically in the epithelial glands of the basal endometrium, exhibit reduced attachment to their surrounding epithelial cells (loss of desmosomal junctions) and display more pseudopods compared with observations in disease-free women.
It is believed that these cells can acquire motile properties and migrate toward the stromal compartment and then to the myometrium, where they can develop into new adenomyotic lesions.[34] This process can be further facilitated by the elevated expression of MMP-2 and -9 in the eutopic endometrium of patients with adenomyosis.[26]
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