Association between Uterine Adenomyosis and Infertility: Role of Axonemal Alteration in Apical Endometria

Uterine adenomyosis is a benign estrogen-dependent gynecological disease characterized by the presence of endometrial glands and stroma within the myometrium and may cause painful symptoms, abnormal uterine bleeding, and/or subfertility/infertility.[,] Although exact pathogenesis is still controversial, it is a common understanding that while endometriosis originates from the functionalis endometrium, adenomyosis develops as a downgrowth and invagination of the basalis endometrium into the myometrium.[,] A panel of mechanisms has been reported indicating tissue damage or injury at the endometrial-myometrial interface (EMI), leading to inflammation, local estrogen production, and development of adenomyosis.[] Adenomyosis commonly occurs during the fourth and fifth decades of life, and after the completion of childbearing activity, however, recent imaging modalities such as trans-vaginal ultrasonography and magnetic resonance imaging (MRI) have indicated that adenomyosis may occur in women of younger ages.[,] Endometriosis and adenomyosis are closely related diseases with variable coexistence rates depending on the endometriosis phenotype involved.[] Endometriosis and adenomyosis share a number of features in terms of symptomatology, histology, and molecular alterations,[] albeit, there are several differences in their pathogenesis and pathogenic mediators.[] The incidence rate of adenomyosis is widely variable. Histological examination of hysterectomy specimens revealed that the prevalence of adenomyosis varies between 5% and 70%. This variation may be due to the difference in diagnostic criteria used and the techniques used to procure myometrial samples.[] A separate study demonstrated that the estimated prevalence of adenomyosis among consecutive hysterectomy patients ranged from 8.8% to 61.5%.[] Adenomyosis appears in different configurations such as diffuse, focal, and rare cases of cystic adenomyoma, and is better detected by MRI.[,,] Recently, four subtypes of adenomyosis have been proposed based on the clinical experience and assessment by MRI/histology. Among them, intrinsic adenomyosis (subtype I) is considered a product of direct endometrial invasion involving inner-mid myometrium and extrinsic adenomyosis (subtype II) as endometriotic lesion coming from outside involving outer myometrium and is confirmed by a separate study from our laboratory.[,] Subtype III (intramural type) consists of adenomyosis that occurs solitarily without relationship to structural components. Adenomyosis that did not satisfy these criteria composed subtype IV (indeterminate type). Collectively, subtypes I–III were suggested as a product of direct endometrial invasion, endometriotic invasion from the outside, and de novo metaplasia, respectively. Subtype IV was a heterogeneous mixture of far-advanced diseases.[] Despite its prevalence and the severity of symptoms, little information is available on the etiology/pathogenesis of adenomyosis, and our knowledge is insufficient on the factors related to negative fertility outcome in women with adenomyosis. Updated information on the etiology and pathogenesis of adenomyosis is reported elsewhere.[] In this review article, we aim to summarize our current understanding on factors that might be associated with infertility. In this article, a comprehensive review was performed with a literature search using PubMed for all publications in English, related to adenomyosis and infertility, from inception to March 2024. ASSOCIATION WITH INFERTILITY Female infertility and subfertility are clinical conditions associated with a significant economic and psychosocial impact.[] There are many gynecological diseases that influence infertility, including endometriosis,[] ovulatory dysfunction,[] tubal factor,[] endocrine disruption,[] reduced endometrial receptivity,[,] and age-related infertility.[] Infertility is highly prevalent among women with endometriosis (25%–50%), its etiology is ambiguous, and the exact mechanisms driving infertility are unclear, as the majority of women with endometriosis are able to conceive but with reduced fertility.[,] Similarly, the mechanisms causing infertility or subfertility in women with adenomyosis are elusive, because a majority of women with adenomyosis are multiparous. Approximately, 20% of cases of adenomyosis involve women younger than 40%, and 80% are aged 40–50 years, when they almost complete their childbearing activity.[] Recently, however, an association between adenomyosis and infertility has emerged. With the advent of noninvasive diagnosis with MRI and transvaginal ultrasonography, the role of adenomyosis in infertility and early pregnancy was better recognized.[,] A potential concern exists in the majority of reported studies to find an association between adenomyosis and infertility as adenomyosis commonly coexists with other pathologic processes linked to infertility such as endometriosis, polyps, or leiomyomas.[] Endometriosis is reported to occur in 54%–90% of cases with adenomyosis.[,] Therefore, we cannot avoid the bias that the cause of infertility is due to concurrent endometriosis rather than adenomyosis because endometriosis is a well-known condition to cause infertility.[] However, a study with baboons showed a strong association between histological adenomyosis and lifelong infertility even in cases when coexisting endometriosis was excluded.[] This was confirmed in another study of women who received embryos created through oocyte donation. In this study, the miscarriage rate was significantly higher in groups of women who had adenomyosis alone versus those with coexisting endometriosis or controls.[] A recent meta-analysis further concluded that adenomyosis has a detrimental effect on clinical outcomes of in vitro fertilization (IVF).[] PROPOSED MECHANISMS A recent trend is that women delay their first pregnancy until they are aged in their late 30s or early 40s and as such adenomyosis has been diagnosed with increasing frequency in infertile women.[] Although the exact mechanism behind the relationship between adenomyosis and infertility is still unclear, a number of factors have been proposed and focused on four putative pathways: (i) intrauterine abnormities and increased uterine peristalsis causing abnormal uterotubal sperm transport. Intrauterine anatomical distortion caused by uterine hyperperistalsis and inflammation-induced adnexal adhesion may block the tubal ostia and potentially impair sperm migration and embryo transport. The abnormal myometrial contraction waves lead to abnormal sperm transport through the uterine cavity and may also lead to intrauterine pressure.[] (ii) Abnormal endometrial steroid metabolism, increased inflammatory response, and increased intrauterine oxidative stress environment leading to altered endometrial function and receptivity.[,] The increased density of macrophages (Mφ) increases the inflammatory response of the endometrium and release of reactive oxygen species that are thought to be embryotoxic.[] (iii) Impairment of implantation may result from inflammation, a lack of adequate expression of adhesion molecules (integrins), reduced expression of implantation markers such as leukemia inhibitory factor, and altered function of the gene for embryonic development (HOXA10).[] (iv) Occurrence of chronic endometritis (CE) resulting from intrauterine microbial infection may be associated with negative fertility outcome in women with adenomyosis.[] Recent studies have shown a correlation between CE and reproductive failures such as recurrent implantation failures after IVF and embryo transfer, recurrent miscarriage, and unexplained infertility.[,] The major cause of CE is microbial infection in the uterine cavity. This is supported by the fact that treatment with antibiotics is effective to eliminate plasma cells in the affected patients.[] A multicenter cohort study in Japan reported a higher incidence of uterine infection in patients with diffuse adenomyosis that may result in the occurrence of CE in these women.[] Although it is controversial about the causality between CE and embryo implantation failure, reports suggest that CE negatively affects reproductive outcome. A recent study provides the first piece of clinical evidence that a variable rate of CE occurs in women with different types of adenomyosis such as focal/diffuse adenomyosis and intrinsic/extrinsic adenomyosis.[] These findings indicated that a variable occurrence of CE in different types of adenomyosis may be involved in negative fertility outcome. Similar to endometriosis where inflammation is a common factor associated with infertility and chronic pelvic pain, a similar inflammatory response of the endometrium may play a significant role in the adverse reproductive outcome in women with adenomyosis.[] In contrast to women with endometriosis, adenomyosis has not yet been shown to have an adverse influence on oocyte function or folliculogenesis.[] In patients with endometriosis, different inflammatory markers (Mφ, prostaglandins, interleukin-1 [IL-1], IL-6, and tumor necrosis factor α) were increased in the peritoneal fluid and their high concentrations may negatively affect oocyte function.[] However, no association has been found so far between adenomyosis and oocyte quality and/or function. ROLE OF MICROVILLI AND AXONEMAL ALTERATION A successful spontaneous conception requires normal function of the endometrium and fallopian tube, and this contributes to a physiologically optimized environment for fertilization and early embryonic development. This provides a conduit for the gametes to convene and for the embryo to reach the uterine cavity.[] The successful capture and/or migration of sperm and embryo may be achieved by the efficient microtubule-mediated movement of microvilli in the apical surface of the endometrium.[] Adenomyosis-induced local inflammation is one of the biological bases for the negative impact of adenomyosis on fertility.[] Negative fertility outcome in women with adenomyosis could be due to tissue inflammation of the endometrium and/or the toxic effect of chemical mediators as released by different immune cells.[] If these embryotoxic chemical mediators diffuse to the apical endometrial cells, they may cause structural damage to the apical microvilli and its core bundles of microtubules.[] In fact, inflammation-induced damage of the mucosal cilia in the fallopian tube has been described in women with ectopic pregnancy and salpingitis.[] A longitudinal bundle of microtubules is encased at the core of the microvilli ultrastructure, known as axoneme. Similar to the fallopian tube, these microtubules are arranged in a 9 + 2 pattern in which nine peripheral microtubule doublets surround a core of two central single microtubules.[] Each doublet microtubule consists of an A and a B component. Extending from each A microtubule to the B microtubule of the adjacent doublet is a dynein arm; these dynein arms, depending on whether they anchor to the inner or outer side of the A microtubule, are called inner dynein arm or outer dynein arm (ODA), respectively. The energy required for microvilli or cilia movement is derived from adenosine triphosphate (ATP) hydrolysis through the ATPs activity of ODA causing the transformation of chemical energy from ATP into a mechanical movement of the single microvillus.[,] The sliding movements between peripheral doublets are transmitted through a different ultrastructural component, called radial spokes, to the central part of the axoneme (central microtubules), resulting in microvilli bending.[] It can be noted that any abnormality in the 9 + 2 arrangement of microtubules in the microvilli or its core component may impair ciliary/microvilli movement of the fallopian tube or endometrium. An ultrastructural diagrammatic representation of an axoneme with a 9 + 2 arrangement of microtubules and axonemal arrangement in the apical endometria is shown in Figure 1. In an attempt to find an association between endometrial inflammation, microvilli damage, and an axonemal alteration in the apical endometria, a recent prospective cohort study was performed using the endometria derived from women with and without adenomyosis.[] An in-depth evaluation with transmission electron microscopy found that compared to control endometria, the number of microvilli on the apical epithelial cells of the endometria collected from women with focal and diffuse adenomyosis was significantly decreased in response to endometrial inflammation [Figure 2].[] As a mechanistic basis of microvilli damage, an abnormal distribution of microtubules was observed on the ipsilateral side of focal adenomyosis and the anterior or posterior wall of diffuse adenomyosis [Figure 3].[] These findings were consistent with strong tissue inflammatory reaction in the endometria collected from women with focal and diffuse adenomyosis compared to that of control women with both fibroids and cervical intraepithelial neoplasia grade 3 (CIN3).[] In fact, significantly less tissue infiltration Mφ was observed in the endometria of women with CIN3 than in the endometria of women with focal adenomyosis and diffuse adenomyosis.[] Interestingly, the endometria collected from symptomatic women with focal adenomyosis showed significantly increased tissue inflammatory reaction compared to that of asymptomatic women.[] These biological and ultrastructural abnormal findings in the endometria may be associated with negative fertility outcome in women with adenomyosis. The distribution of abnormal axonemal arrangements was more frequently observed in women with symptomatic adenomyosis than that in asymptomatic women. The detailed distribution of normal and abnormal microtubules in the apical endometria of women with and without adenomyosis is shown in Table 1. An Italian study demonstrated that clinical pregnancy rate, implantation rate, and live birth rate are not impaired in asymptomatic women with adenomyosis compared to groups of women without adenomyosis in IVF cycles.[] On the other hand, a systemic review and meta-analysis targeting IVF outcome suggested that women with symptomatic adenomyosis have a 28% reduction in the likelihood of clinical pregnancy rate (relative risk [RR] = 0.72; 95% confidence interval [CI], 0.55–0.95) and a two-fold increase in the risk of miscarriage (RR = 2.12; 95% CI, 1.20–3.75).[] These findings indicate that complaints of symptoms may be associated with a causal link between adenomyosis and infertility. Our findings may support the mechanistic basis of these ART clinical trials.[,] In addition to other mechanistic links as mentioned above, the ultrastructural abnormalities of microvilli and microtubules in the apical endometria in response to tissue inflammatory reaction may clarify the possible association between negative fertility outcome and adenomyosis. The possible mechanisms that might be involved in infertility in women with adenomyosis are shown in Figure 4.

AND FUTURE PERSPECTIVE With the elapse of more than 150 years since the report of Von Rokitansky in 1860, most of the literature still claims that the pathogenesis and pathophysiology of endometriosis and adenomyosis are unclear. Despite abundant publications,[,,] lack of standardized histopathologic criteria for diagnosis and the variable number of histologic tissue samples evaluated per hysterectomy lag behind exact information on the true incidence rate of adenomyosis. However, the bulk of recent evidence has improved our knowledge greatly on the pathogenesis and supports that among many hypotheses, adenomyosis most commonly results from direct invasion of gland cells of the endometrial basalis layer deep into the myometrium by repeated tissue injury and repair at the endo-myometrial interface.[] Most of the studies investigating adenomyosis as a possible cause of infertility have focused on the comparison of clinical outcomes of ART procedures between affected and nonaffected infertile women. The rationale for this approach is that it allows evaluating the influence of adenomyosis on embryo implantation. The biological basis for a negative impact of adenomyosis on fertility may include one of the following: adenomyosis-induced local inflammation, impairment of uterotubal sperm transport, altered endometrial function/receptivity, and dysregulation of local hormonal metabolism leading to hyperestrogenic milieu. According to our most recent information,[] an endometrial inflammation-induced microvilli damage and an axonemal alteration in the apical endometria may clarify a link between adenomyosis and negative fertility outcome. These recent findings may be clinically useful during counseling with symptomatic patients with adenomyosis who are planning for future pregnancy. Unfortunately, there are several factors that make it difficult to investigate the relationship between adenomyosis and infertility: (i) the incidence of adenomyosis is not correctly known, (ii) universally accepted diagnostic criteria for adenomyosis are still lacking, and (iii) adenomyosis often coexists with endometriosis and/or uterine fibroids. There is an unmet need for adequately designed prospective studies to improve our knowledge of this polymorphic disease, consequently establish more effective therapeutic strategies, and to evaluate the cause–effect relationship between adenomyosis and infertility. Author contribution statement KNK contributes to conceptualization, study design, supervision, data interpretation and manuscript writing and editing. Data availability statement The data underlying this article will be shared on reasonable request to the corresponding author. Financial support and sponsorship This work was supported in part by Grants-in-Aid for Scientific Research (Grant Nos. 24592474, 15K10675, 18K09268 to KNK) from the Japan Society for the Promotion of Science. Conflicts of interest There are no conflicts of interest. Acknowledgment The authors thank Dr. Akira Fujishita of Saiseikai Nagasaki Hospital, Nagasaki, and Prof. Taisuke Mori/Dr. Akemi Koshiba of Kyoto Prefectural University of Medicine, Kyoto, or their kind assistance in collecting biopsy samples and stimulating discussion. The authors thank Prof. Masahiro Nakashima and Dr. Katsuya Matsuda of the Department of Molecular and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Nagasaki, Japan, for their kind assistance in sample preparation, experiments, and discussion. The authors thank Dr. Takashi Suematsu of Central Electron Microscopy Laboratory, Nagasaki University Graduate School of Biomedical Sciences in Nagasaki, for his kind assistance in sample preparation and electron microscopic study. The authors thank Prof. Satoshi Teramukai and Dr. Go Horiguchi of the Department of Biostatistics, Kyoto Prefectural University of Medicine, for their excellent assistance in data analysis and interpretation. The authors also thank Prof. Kyoko Itoh and Ms. Miyuki Mori of the Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, for their excellent technical assistance and discussion on histological and immunohistological findings.

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