Endometrial Inflammation and Impaired Spontaneous Decidualization: Insights into the Pathogenesis of Adenomyosis

Abstract

Adenomyosis is an estrogen-dependent gynecologic disease characterized by the myometrial invasion of the endometrial tissue. This review summarized the current understanding and recent findings on the pathophysiology of adenomyosis, focusing on repeated menstruation, persistent inflammation, and impaired spontaneous decidualization. A literature search was performed in the PubMed and Google Scholar databases from inception to 30 April 2022. Thirty-one full-text articles met the eligibility criteria. Repeated episodes of physiological events (i.e., endometrial shedding, damage, proliferation, differentiation, repair, and regeneration) during the menstrual cycle are associated with inflammation, angiogenesis, and immune processes. The decidualization process in humans is driven by the rise in progesterone levels, independently of pregnancy (i.e., spontaneous decidualization). Adenomyotic cells produce angiogenic and fibrogenic factors with the downregulation of decidualization-associated molecules. This decidualization dysfunction and persistent inflammation are closely related to the pathogenesis of adenomyosis. Recently, it has been found that the reproductive tract microbiota composition and function in women with adenomyosis differ from those without. An increase in opportunistic pathogens and a decrease in beneficial commensals may promote impaired defense mechanisms against inflammation and predispose women to uncontrolled endometrial inflammation. However, currently, there is no direct evidence that adenomyosis is linked to pre-existing inflammation and impaired spontaneous decidualization. Overall, persistent inflammation, impaired spontaneous decidualization, and microbiota dysbiosis (i.e., an imbalance in the composition and function of endometrial microbiota) may be involved in the pathophysiology of adenomyosis.

Proposal for targeted, neo-evolutionary-oriented, secondary prevention of early-onset endometriosis and adenomyosis. Part I: pathogenic aspects

“…In this context, repetitive ovulation and menstruation without prolonged periods of amenorrhoea induced by multiple pregnancies and prolonged lactation may be considered a maladaptive reproductive trait that may also increase the risk of diseases such as endometriosis and adenomyosis ( Renfree, 2012 ; Fathalla, 2019 ; Pei et al , 2022 ). In other words, it cannot be excluded that the exposure to repeated menstruation-related and blood-mediated tissue injury and repair and monthly transtubal mentrual reflux may be greater than the female immune system has genetically evolved to handle at the endo-myometrial junction or within the pelvic environment, respectively ( Guo, 2020 ; Maruyama et al , 2020 ; Kobayashi, 2023 ).…”

“…The hypothesis of an effect of ROM on the risk of endometriosis and adenomyosis maybe even more plausible if one considers not only the number of events, in terms of the mere total amount of displaced endometrial tissue and thus its probabilistic chance of survival at ectopic sites, but also the quality of such events, in terms of a possible transition from a state of acute and self-limited inflammation to a state of chronic and self-perpetuating inflammation ( Guo, 2018 , 2020 , 2023 ; Bulun et al , 2019 , 2021 ; Kobayashi, 2023 ; Kobayashi et al , 2023 ). In this context, both ovulation and menstruation can be considered as a source of acute inflammation with a risk of chronicity if relentlessy repeated ( Jarrell and Arendt-Nielsen, 2016 ; Jarrell, 2018 ).…”

“…Under physiological conditions, menstruation-associated inflammation is self-limited and does not lead to persistent inflammation with the consequences of tissue destruction, fibrotic replacement, and potential loss of function ( Critchley et al , 2020b ). However, some researchers have suggested that ROM may sometimes induce chronic inflammation, uterine hypercontractility, and fibrotic scarring due to repeated myometrial injury and repair ( Bulun et al , 2021 ; Guo, 2023 ; Kobayashi, 2023 ).…”

“…Repetitious menstrual episodes also imply reiterative intrauterine tissue hypoxia and necrosis, myometrial contractions, and rapid angiogenesis and regenerative processes ( Bulun et al , 2021 ; Guo, 2023 ; Kobayashi, 2023 ). These events may disrupt the endo-myometrial junction, favouring intra-myometrial invagination of basal endometrium fragments and the development of adenomyosis ( Jarrell, 2018 ; Bulun et al , 2021 ).…”

“…However, despite the criticisms of our view described above, it is undeniable that menstruators from Palaeolithic to pre-industrial times spent the first decade after menarche in a relatively stable hormonal environment, characterized by infrequent ovulatory menstruation, prolonged progesterone exposure and long periods of hypoestrogenism, whereas menstruators from Western, industrialized, high-income nations now experience recurrent gonadal hormone fluctuations, characterized by repetitious ovulatory menstruation, prolonged oestrogen exposure, and the absence of hypoestrogenic phases. Indeed, Renfree (2012) suggests that reiterative menstruation is an iatrogenic disorder of modern societies, potentially causing ‘ diseases of nulliparity ’, and several investigators support the notion of endometriosis and adenomyosis as disorders initiated by ROM in susceptible individuals, promoted by a mitogenic and pro-inflammatory hyper-oestrogenic local and systemic milieu, and alleviated by amenorrhoea and long-term, stable, low-oestrogen, and high-progesterone exposure ( Kruitwagen, 1993 ; D’Hooghe and Debrock, 2002 ; Lousse et al , 2009 ; Donnez et al , 2016 ; Bulun et al , 2019 , 2021 , 2023 ; Guo, 2020 , 2023 ; Maruyama et al , 2020 ; Koninckx et al , 2021c ; Bulun, 2022 ; Yovich et al , 2020; Kobayashi, 2023 ; Kobayashi et al , 2023 ; Wyatt et al , 2023 ).…”