Unveiling the Pathogenesis of Adenomyosis through Animal Models

Abstract

Background: Adenomyosis is a common gynecological disorder traditionally viewed as “elusive”. Several excellent review papers have been published fairly recently on its pathogenesis, and several theories have been proposed. However, the falsifiability, explanatory power, and predictivity of these theories are often overlooked. Since adenomyosis can occur spontaneously in rodents and many other species, the animal models may help us unveil the pathogenesis of adenomyosis. This review critically tallies experimentally induced models published so far, with a particular focus on their relevance to epidemiological findings, their possible mechanisms of action, and their explanatory and predictive power. Methods: PubMed was exhaustively searched using the phrase “adenomyosis and animal model”, “adenomyosis and experimental model”, “adenomyosis and mouse”, and “adenomyosis and rat”, and the resultant papers were retrieved, carefully read, and the resultant information distilled. All the retrieved papers were then reviewed in a narrative manner. Results: Among all published animal models of adenomyosis, the mouse model of adenomyosis induced by endometrial–myometrial interface disruption (EMID) seems to satisfy the requirements of falsifiability and has the predictive capability and also Hill’s causality criteria. Other theories only partially satisfy Hill’s criteria of causality. In particular, animal models of adenomyosis induced by hyperestrogenism, hyperprolactinemia, or long-term exposure to progestogens without much epidemiological documentation and adenomyosis is usually not the exclusive uterine pathology consequent to those induction procedures. Regardless, uterine disruption appears to be a necessary but not sufficient condition for causing adenomyosis. Conclusions: EMID is, however, unlikely the sole cause for adenomyosis. Future studies, including animal studies, are warranted to understand how and why in utero and/or prenatal exposure to elevated levels of estrogen or estrogenic compounds increases the risk of developing adenomyosis in adulthood, to elucidate whether prolactin plays any role in its pathogenesis, and to identify sufficient condition(s) that cause adenomyosis.

Perioperative Suppression of Schwann Cell Dedifferentiation Reduces the Risk of Adenomyosis Resulting from Endometrial–Myometrial Interface Disruption in Mice

“…To be fair, it is very challenging, if not ethically restrictive, to directly prove causal relationships in pathogenesis in humans. Since adenomyosis can and does occur in mouse spontaneously or by induction, mouse models of adenomyosis can be capitalized to aid our research into pathogenesis, especially when the EMID model is backed by ample epidemiological data [ 5 ]. In addition, it is also helpful not to be fixated on a particular culprit, as in any complex forensic investigations, but instead to have an open mind and cast a wider net whenever possible and practical [ 5 ].…”

“…Despite its first description by the German pathologist Carl von Rokitans over 160 years ago [ 2 ], its pathogenesis and etiology are still poorly understood [ 3 ]. While invagination and metaplasia are the two most popular theories [ 4 ], unfortunately, neither of them has much support from either epidemiological or experimental data [ 5 ].…”

Pathogenesis of Human Adenomyosis: Current Understanding and Its Association with Infertility

“…As chemical mediators, estrogen and estromedin (estrogen regulated) growth factors, such as HGF at EMI, may trigger the sequential cellular cascades of EMT. Since, adenomyosis can also occur spontaneously in many animal species, the role of EMID in the pathogenesis of adenomyosis has been recently confirmed in an animal model to strengthen the validity and feasibility of findings in human study [ 203 ]; (ii) De nevo metaplasia of displaced pluripotent embryonic Mullerian remnants or differentiation of adult stem cells; (iii) There are also genetic, epigenetic and environmental factors that may trigger the pathogenic process of adenomyosis; (iv) The recently discovered epithelial mutations that mostly affect the KRAS gene and are seen in both the glandular endometrium and adjacent adenomyosis provide high quality evidence that adenomyotic gland islands arise from the basalis layer of the endometrium. (v) Multiple epigenetic alterations, such as DNA methylation, histone modification, and differential expression profiles of microRNAs (miRNAs), may be involved in the occurrence of endometriosis and adenomyosis.…”

Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology

“…Despite the appeal, unfortunately, so far there have been no experimental data whatsoever to support or refute either of the theories or the TIAR hypothesis (Wang et al 2022b). Of particular note is that neither theory seems to be backed by any epidemiological data.…”

“…In spite of its long history, adenomyosis is a underresearched disease (Wang et al 2022b), but the seemingly neglect may be changing. In the last 10 years, there has been a growing interest in adenomyosis as seen by a swell of excellent reviews on the pathogenesis and pathophysiology of adenomyosis in recent years (Benagiano et al 2012, Vannuccini et al 2017, Garcia-Solares et al 2018, Vannuccini & Petraglia 2019, Zhai et al 2020, Bulun et al 2021, Donnez et al 2021, Stratopoulou et al 2021b, Khan et al 2022.…”