Pathogenesis of Adenomyosis
Adenomyosis most likely develops through direct invagination of endometrial basalis tissue into the myometrium following repeated microtrauma and disruption at the endometrial-myometrial interface (EMI), though metaplasia of Müllerian remnants or stem cell differentiation represents an alternative mechanism. 1, 2
Primary Pathogenic Theory: Endometrial Invagination
The dominant theory proposes that adenomyosis results from downward invasion of the endometrial basalis layer through a damaged endometrial-myometrial interface, driven by tissue injury and repair mechanisms. 1, 3, 4
Key Mechanistic Steps:
Microtrauma at the EMI serves as the initiating event, creating pathways for endometrial tissue to penetrate into the myometrium. 2, 4
Epithelial-mesenchymal transition (EMT) plays a critical role in the early stages of invasion, allowing endometrial epithelial cells to acquire migratory and invasive properties. 1, 4
Collective cell migration appears to drive later stages of invasion, suggesting that adenomyosis progression involves time-dependent combinations of different cellular migration mechanisms rather than a single process. 1
Hepatocyte growth factor (HGF), functioning as an estrogen-regulated factor, promotes EMT either alone or in combination with estrogen, facilitating the invagination process. 4
Once ectopic endometrial glands and stromal fibroblasts establish within the myometrium, they elicit hyperplasia and hypertrophy of surrounding smooth muscle cells, creating the characteristic pathological features. 2, 4
Alternative Theory: Metaplasia and Stem Cell Differentiation
A competing hypothesis suggests that adenomyotic lesions arise de novo from metaplasia of displaced embryonic pluripotent Müllerian remnants or from differentiation of adult stem cells within the myometrium. 1, 2, 3
This theory proposes that pluripotent cells already present in the myometrium transform into endometrial-like tissue rather than migrating from the endometrial cavity. 3
Endometrial stem/progenitor cells within the myometrium may differentiate into adenomyotic lesions under appropriate hormonal and inflammatory stimuli. 2, 4
Hormonal and Molecular Drivers
Estrogen Dependence and Progesterone Resistance:
Adenomyosis is fundamentally an estrogen-dependent disease occurring on a background of progesterone resistance, similar to endometriosis. 5, 6
The disease maintains itself through autonomous local estrogen synthesis independent of ovarian production, which explains why systemic hormonal suppression alone may be insufficient for treatment. 5
Additional Pathogenic Factors:
Aberrant local steroid and pituitary hormones can induce adenomyotic lesion formation. 2
Genetic and epigenetic modifications affecting abnormal uterine development contribute to disease susceptibility. 2, 4
MicroRNAs may play regulatory roles in adenomyosis development, though their exact contributions require further elucidation. 4
Somatic mutations in target genes have been proposed as contributing factors. 4
Pathophysiological Consequences
Once established, adenomyotic lesions trigger a cascade of pathological processes:
Chronic inflammation develops within both endometrial and myometrial components. 2, 6
Neurogenesis occurs, contributing to the pain symptoms characteristic of adenomyosis. 2
Angiogenesis supports the growth and maintenance of ectopic endometrial tissue. 2, 6
Contractile abnormalities in the myometrium result from smooth muscle hyperplasia and altered architecture. 2
Fibrosis develops as part of the chronic inflammatory response. 6
Clinical Pitfalls and Caveats
The exact pathogenesis remains incompletely understood despite significant research advances, and multiple mechanisms may operate simultaneously in different patients. 2, 3
Adenomyosis frequently coexists with endometriosis and uterine fibroids, complicating the clinical picture and suggesting shared pathogenic pathways. 6
Different phenotypes exist (diffuse versus focal, intrinsic versus extrinsic), which may reflect different pathogenic mechanisms or stages of disease progression. 4, 6
Recent transmission electron microscopy studies indicate that microvilli damage and axonemal alterations in the apical endometrium, secondary to endometrial inflammation, may contribute to infertility in adenomyosis patients. 4
The theory that retrograde menstrual effluent infiltrates the uterine wall from the serosal side represents another proposed mechanism, though this is less widely accepted. 2