The Pathogenesis of Adenomyosis vis-à-vis Endometriosis

Abstract

Adenomyosis is used to be called endometriosis interna, and deep endometriosis is now called adenomyosis externa. Thus, there is a question as to whether adenomyosis is simply endometriosis of the uterus, either from the perspective of pathogenesis or pathophysiology. In this manuscript, a comprehensive review was performed with a literature search using PubMed for all publications in English, related to adenomyosis and endometriosis, from inception to June 20, 2019. In addition, two prevailing theories, i.e., invagination-based on tissue injury and repair (TIAR) hypothesis-and metaplasia, on adenomyosis pathogenesis, are briefly overviewed and then critically scrutinized. Both theories have apparent limitations, i.e., difficulty in falsification, explaining existing data, and making useful predictions. Based on the current understanding of wound healing, a new hypothesis, called endometrial-myometrial interface disruption (EMID), is proposed to account for adenomyosis resulting from iatrogenic trauma to EMI. The EMID hypothesis not only highlights the more salient feature, i.e., hypoxia, at the wounding site, but also incorporates epithelial mesenchymal transition, recruitment of bone-marrow-derived stem cells, and enhanced survival and dissemination of endometrial cells dispersed and displaced due to iatrogenic procedures. More importantly, the EMID hypothesis predicts that the risk of adenomyosis can be reduced if certain perioperative interventions are performed. Consequently, from a pathogenic standpoint, adenomyosis is not simply endometriosis of the uterus, and, as such, may call for interventional procedures that are somewhat different from those for endometriosis to achieve the best results.

Keywords: adenomyosis; endometrial-myometrial interface disruption; endometriosis; pathogenesis; pathophysiology; repeated tissue injury and repair.

Figure 1

The key molecular signaling events initiated by the tissue injury and repair (TIAR) that leads to the increased local production of estradiol, as proposed by Leyendecker et al. [29,30]. Gene/protein names: COX-2: cyclooxygenase-2; E₂: 17β-estradial; ERβ: estrogen receptor β; IL-1β: interleukin-1β; P450 aromatase: aromatase; PGE₂: prostaglandin E2; StAR: steroidogenic acute regulatory protein.

Figure 2

Leyendecker’s model of tissue injury and repair (TIAR) that initiates the genesis of adenomyotic lesions [29,30]. Briefly, microtraumatization in the endometrial–myometrial interface causes tissue injury, which subsequently induces upregulation of COX-2 and increased production of PGE₂, which, in turn, induces the expression of genes critical to estrogen production such as StAR and aromatase, resulting in increased local estrogen production. The elevated estrogen levels would activate both ERα and ERβ, leading to the induction of the OT/OTR signaling and subsequent increased uterine peristalsis and increased angiogenesis and proliferation. The increased peristalsis would further exacerbate uterine hyperperistalsis and thus TIAR, causing endometrial invagination and ultimately the formation of adenomyotic lesions. Gene/protein names: COX-2: cyclooxygenase-2; E₂: 17β-estradial; ERα: estrogen receptor α; ERβ: estrogen receptor β; IL-1β: interleukin-1β; P450 aromatase: aromatase; OT: oxytocin; OTR: oxytocin receptor; PGE₂: prostaglandin E2; StAR: steroidogenic acute regulatory protein.

Figure 3

Schematic illustration of the formation of adenomyotic lesions due to the endometrial–myometrial interface disruption (EMID). Iatrogenic procedures causes disruption at the endometrial–myometrial interface (EMI), which leads to platelet aggregation and the induction of HIF-1α, effectively causing tissue hypoxia. Uterine hyperperistalsis may also induce EMI disruption (shown in dashed arrow). As a result, genes involved in estrogen production are upregulated, resulting in increased local production of estrogen and subsequent induction of both ERα and ERβ, which, in turn, leads to the induction of the OT/OTR signaling and increased uterine peristalsis. In addition, tissue hypoxia activates TGF-β1, VEGF, PDGF, COX-2, and SDF-1 signaling pathways, leading to increased angiogenesis, vascularature, and the recruitment of BMDSCs to the wounding site. The induction of COX-2 would also increase the production of PGH₂ and TXA₂, which also enhances uterine peristalsis. Moreover, the TGF-β1 signaling pathway induces EMT, leading to the invasion of endometrial epithelial cells to the EMI and further down to the myometrium. Tissue injury also would activate the HPA axis, leading to the release of catecholamines and PGE₂, which collectively result in impaired cell-mediated immunity and, as such, enhances the survival of displaced and dispersed endometrial cells within the myometrium. All these events ultimately lead to the formation of adenomyotic lesions in the myometrium. Abbreviations used: BMDSC: bone marrow derived stem cells; COX-2: cyclooxygenase-2; E₂: 17β-estradial; EMI: endometrial-myometrial interface; EMT: epithelial-mesenchymal transition; ERα: estrogen receptor α; ERβ: estrogen receptor β; HIF-1α: hypoxia-inducible factor 1α; HPA: hypothalamic-pituitary-adrenal; P450 aromatase: aromatase; PDGF: platelet-derived growth factor; OT: oxytocin; OTR: oxytocin receptor; PGE₂: prostaglandin E2; PGH₂: prostaglandin H2; SDF-1: stromal cell-derived factor 1; SF-1: steroidogenic factor-1; StAR: steroidogenic acute regulatory protein; TGF-β1: transforming growth factor β1; TXA₂: thromboxane A2; VEGF: vascular endothelial growth factor.