Purpose
In a series of publications, we had developed the concept that uterine adenomyosis and pelvic endometriosis as well as endometriotic lesions at distant sites of the body share a common ...pathophysiology with endometriosis constituting a secondary phenomenon. Uterine auto-traumatization and the initiation of the mechanism of tissue injury and repair (TIAR) were considered the primary events in the disease process. The present MRI study was undertaken (1) to corroborate this concept by re-visiting, in view of discrepant results in the literature, the association of adenomyosis with endometriosis and (2) to extend our views concerning the mechanisms of uterine auto-traumatization.
Patients and methods
MRI was performed in 143 women attending our center, in whom, on the basis of transvaginal sonography (TVS) and historical data, such as documented endometriosis and dysmenorrhea of various degrees of severity, the presence of uterine adenomyosis was suspected. In addition to the measurement of the diameter of junctional zone (JZ) of the anterior and posterior walls in the mid-sagittal plane, the diagnosis of adenomyosis was based on visualization, in that all planes were analyzed with scrutiny. By this method of “visualization” all transient enlargement of the JZ, such as peristaltic waves of the archimyometrium and sporadic neometral contractions that might mimic adenomyotic lesions could be excluded. At the same time, this method allowed to lower the limit of detection in terms of thickness of the JZ for assured diagnosis of adenomyosis. Furthermore, the localizations of the individual lesions, their shapes and patterns were described.
Results
With the method of ‘visualization’, the diagnosis of uterine adenomyosis could be verified in 127 of the 143 patients studied. The prevalence of endometriosis in adenomyosis was 80.6 % and the prevalence of adenomyosis in endometriosis was 91.1 %. As concluded from their localization within the uterine wall, the adenomyotic lesions predominantly developed in the median region of the upper two-thirds of the uterine wall. Cystic cornual angle adenomyosis was a distinct phenomenon that was only observed in patients suffering from extreme primary dysmenorrhea. Aside from this, the majority of the patients complained of primary dysmenorrhea (80 %). On the basis of these findings and the fact that particularly extreme primary dysmenorrhea is associated with high intrauterine pressure, menstrual ‘archimetral compression by neometral contraction’ has to be considered as an important cause of uterine auto-traumatization in addition to uterine peristalsis and hyperperistalsis. Both mechanical functions of the non-pregnant uterus exert their strongest power in the upper region of the uterus, which is compatible with the predominant localization of the adenomyotic lesions.
Conclusions
The data confirm our previous results of a high association of adenomyosis with endometriosis and vice versa. Our view of the mechanism of uterine auto-traumatization by mechanical functions of the non-pregnant uterus has to be extended, in that ‘archimetral compression by neometral contractions’ could be realized as the predominant cause of mechanical strain to the non-pregnant uterus. The data of this study confirm our concept of the etiology and pathophysiology of adenomyosis and endometriosis in that the process of chronic proliferation and inflammation is induced at the level of the archimetra by chronic uterine auto-traumatization. Furthermore, with respect to the diagnosis of uterine adenomyosis (and consequently endometriosis) this study shows a high degree of accordance between the findings in real-time TVS and MRI.
Adenomyosis and endometriosis share a common origin as both of them result from the development of endometrial tissue outside the endometrium. Despite this, the 2 disorders were until recently ...considered as 2 different entities notably, because of their different epidemiology. Today, however, new findings regarding core similarities in pathophysiology and endometrial receptivity - not altered in assisted reproductive technology when using frozen embryo transfers - tend to reunite these 2 ailments as variants of 1 disorder.
Uterine adenomyosis was initially thought to be found only in parous women, and final diagnosis was made at histology after hysterectomy. With better imaging techniques and with women attending ...clinics at older ages, adenomyosis is diagnosed with increasing frequency in women attending infertility clinics. A dozen conservative interventions have been advocated, with variable reports of their impact on fertility. This presents a dilemma for clinicians managing such patients. Hence, this systematic review of adenomyosis was performed to determine (i) the prevalence in a subfertile population, (ii) the accuracy of diagnostic tests, (iii) the efficacy of fertility sparing treatment options and (iv) the reproductive and obstetric/perinatal outcomes in women with adenomyosis.
Systematic searches of various databases were performed independently by two reviewers, and data were extracted according to predefined criteria by two reviewers.
There is little data on the epidemiology of adenomyosis associated with subfertility. Both magnetic resonance imaging and ultrasound are non-invasive tests with equivalent accuracy in diagnosing adenomyosis (area under curve 0.91 and 0.88, respectively). Most studies on treatments have been uncontrolled and outcomes are usually reported in the form of case series. Hence, the true impact of various treatments on fertility is not known. There are variable reports of the impact of adenomyosis on the success of IVF. Increased incidence of preterm labour and premature rupture of membranes has been reported in women with adenomyosis.
Further studies are needed to determine the natural history of adenomyosis and implications for fertility and reproductive outcomes, with and without treatment. Currently, there is no evidence that we should find and treat adenomyosis in patients who wish to conceive.
Abstract
The epithelial to mesenchymal transition (EMT) has been implicated in the development of adenomyosis, along with dysregulated immune responses. Inflammation potentially induces Notch ...signaling, which could promote this EMT. The objective of this study was to investigate the involvement of immune cells and Notch1-mediated EMT in the development of adenomyosis. Adenomyosis was induced in 18 CD-1 mice by neonatal oral administration of tamoxifen (TAM group), while 18 neonates received vehicle only (Control group). Their uteri were sampled at 30, 60 or 90 days of age. Immune cell markers (Cd45, Ly6c1, Cd86, Arginine1, Cd19, Cd4, Cd8), Notch1 and its target genes (Hey1, Hey2, Hes1, Hes5) and biomarkers of EMT (E-Cadherin, Vimentin, Tgfb, Snail1, Slug, Snail3) were analyzed by quantitative RT-PCR and immunohistochemistry. Activated-Notch1 protein was measured by western blot. Aberrant expression of immune cell markers was observed in the uteri of mice as they developed adenomyosis. The expression of inflammatory cell markers, notably M1 macrophages and natural killer cells, was increased from Day 30 in the TAM group compared to controls, followed by an increase in the Cd4 marker (T cells) at Day 60. Conversely, expression of the Cd19 marker (B cells) was significantly reduced at all of the stages studied. Notch1 signaling was also highly activated compared to controls at Day 30 and Day 60. Concomitantly, the levels of several markers for EMT were also higher. Therefore, the activation of Notch1 coincides with aberrant expression of immune and EMT markers in the early development of adenomyosis.
STUDY QUESTION
Is the presence of adenomyosis associated with menorrhagia?
SUMMARY ANSWER
There was no significant association between adenomyosis and menorrhagia, but there was a significant ...positive correlation between the severity of adenomyosis on ultrasound and the amount of menstrual loss estimated using pictorial blood loss assessment charts.
WHAT IS KNOWN ALREADY
There is no consensus in the literature with regards to the association between adenomyosis and menorrhagia. Previous studies have been limited to retrospective studies of highly selected populations which mainly included women who underwent hysterectomy. There are no large prospective studies evaluating the association between adenomyosis and menorrhagia, either in the general population of women or in a general gynaecology clinic setting.
STUDY DESIGN, SIZE, DURATION
This was a prospective observational study set in the general gynaecology clinic of a university teaching hospital between January 2009 and January 2010.
PARTICIPANTS/MATERIALS, SETTING, METHODS
There were 714 consecutive premenopausal women who attended the clinic and underwent structured clinical and transvaginal ultrasound examination in accordance with the study protocol. Morphological features of adenomyosis were systematically recorded on ultrasound scan. Menorrhagia was determined subjectively by direct questioning and objectively by completion of pictorial blood loss analysis charts.
MAIN RESULTS AND THE ROLE OF CHANCE
A diagnosis of adenomyosis was made in 157/714 women 22.0% (95% CI: 19.1–25.2%). Multivariable analysis showed significant associations between submucous fibroids OR 5.60 (95% CI: 2.69–11.6), any fibroids OR 1.53 (95% CI: 0.91–2.58) and endometrial polyps OR 2.81 (95% CI: 1.15–11.7) and menorrhagia. There were also significant associations between increasing gravidity and BMI and menorrhagia (P < 0.01). There was no significant association between adenomyosis and menorrhagia in the study population, when adenomyosis was assessed as a binary outcome. When severity of adenomyosis was assessed by counting the number of morphological features of adenomyosis in each woman, we found a significant 22% increase in menstrual loss for each additional feature of adenomyosis OR 1.21 (95% CI: 1.04–1.40).
LIMITATIONS, REASONS FOR CAUTION
A classification of severity of adenomyosis based on the number of ultrasound features present is a novel concept that should be prospectively evaluated in different populations.
WIDER IMPLICATIONS OF THE FINDINGS
A better understanding of the relationship between adenomyosis and menorrhagia can help improve counselling of women regarding the significance of this common condition and facilitate future studies assessing the effectiveness of different conservative treatments protocols.
STUDY FUNDING/COMPETING INTEREST(S)
The authors have no competing interests. The study was not supported by an external grant.
The availability of non-invasive diagnostic tests is an important factor in the renewed interest in adenomyosis, as the disease can now be more accurately mapped in the uterus without a need for ...hysterectomy. An agreed system for classifying and reporting the condition will enhance our understanding of the disease and is envisaged to enable comparison of research studies and treatment outcomes. In this review, we assess previous and more recent attempts at producing a taxonomy, especially in view of the latest proposal for subdivision of adenomyosis into an internal and an external variant. In this context, we also explore the uncertainties linked to classifying involvement of the uterovesical pouch, the pouch of Douglas and lesions in the outer myometrium. Two opposing hypotheses are forwarded to explain the pathogenesis of these variants, namely that disease localized in these areas originates from an invasion by uterine adenomyosis of peritoneal organs; alternatively, that lesions present in the outer myometrium originate from peritoneal endometriosis. At the root of debates around these opposing theories of pathogenesis is fragmentary evidence. Because of the limitations of currently available evidence, and until this issue is resolved, broad agreement on a hypothesis to underpin any proposed classification is unlikely.
To determine whether the presence of focal adenomyosis of the outer myometrium (FAOM) at preoperative magnetic resonance imaging is associated with the severity of deep infiltrating endometriosis.
...Observational cross-sectional study involving 255 symptomatic deep infiltrating endometriosis patients. Comparisons were performed according to the presence of FAOM.
University hospital.
Women with a preoperative magnetic resonance imaging and complete surgical exeresis of endometriotic lesions with histologically documented deep infiltrating endometriosis.
Surgical management for deep infiltrating endometriosis.
The presence of multiple deep infiltrating endometriosis lesions, the mean number and location of deep infiltrating endometriosis lesions, and the mean total revised American Society for Reproductive Medicine scores.
The prevalence of FAOM at preoperative magnetic resonance imaging in the 255 patients with deep infiltrating endometriosis was 56.5%. The mean number of deep infiltrating endometriosis lesions was significantly higher in the FAOM(+) group than in the FAOM(-) group: 3.5 ± 2.1 vs. 2.2 ± 1.5. The mean total revised American Society for Reproductive Medicine score was higher in case of FOAM coexisting with deep infiltrating endometriosis. After adjusting for confounding factors, the presence of FAOM was significantly associated with multiple deep lesions.
FAOM was significantly associated with greater deep infiltrating endometriosis severity. This needs to be integrated into the management strategy. Furthermore, a pathogenic link between deep infiltrating endometriosis and FAOM cannot be excluded.
Endometriosis and adenomyosis: Similarities and differences Donnez, Jacques; Stratopoulou, Christina Anna; Dolmans, Marie-Madeleine
Best practice & research. Clinical obstetrics & gynaecology,
February 2024, 2024-Feb, 2024-02-00, 20240201, Volume:
92
Journal Article
Peer reviewed
Deep endometriosis and uterine adenomyosis are two frequently encountered conditions affecting approximately 200 million women worldwide. They are closely related, showing similar histological ...patterns and multiple common pathogenic features, and share the same symptoms. It is therefore not surprising that they are often thought to have a common developmental origin. Indeed, both deep endometriosis and adenomyosis appear to derive from estrogen-dependent overproliferation of endometrial tissue and its subsequent implantation in ectopic sites.
Although the scientific community has shown increasing interest in these diseases over recent years, neither pathogenesis has yet been elucidated, so there are currently no efficient treatment options. Understanding the mechanisms underlying disease development, as well as discerning their relationship, are key to improving clinical management for millions of patients.
The aims of this review are to summarize current knowledge on deep endometriosis and adenomyosis pathogeneses and discuss the possibility that these two entities are actually differential phenotypes of the same disease.
•MRI data confirm frequent coexistence of deep endometriotic nodules and uterine adenomyosis.•An inflammatory response driven by aberrant macrophage accumulation is involved in pathogeneses.•Endometrial cells in both diseases resist cell death mechanisms (apoptosis and autophagy).•Progesterone resistance is involved in both disease pathogeneses.•Deep endometriosis and adenomyosis do indeed share multiliple pathogenic features.
Adenomyosis is associated with dysmenorrhea, infertility, and lesional fibrosis. The pathogenesis of adenomyosis is still unclear. Plasminogen activator inhibitor 1 (PAI-1) plays important roles in ...pathological activities like tumor metastasis and endometriosis. Our objective was to investigate the expression and localization of PAI-1 in eutopic and ectopic endometrium with adenomyosis and in endometrium without adenomyosis. We also sought to determine the relationship between PAI-1 immunoreactivity and the severity of dysmenorrhea and the extent of lesional fibrosis in adenomyosis. PAI-1 expression was significantly higher in the ectopic endometrium of patients with adenomyosis than in both the eutopic endometrium of patients with adenomyosis and the endometrium of controls. Ectopic PAI-1 expression correlated positively with dysmenorrhea visual analog scale (VAS) scores and the extent of lesional fibrosis in adenomyosis. High PAI-1 expression increased the likelihood of moderate to severe dysmenorrhea in adenomyosis. These results suggest that PAI-1 is involved in the adenomyosis-associated dysmenorrhea and lesional fibrosis, which provide a potential target in treating symptomatic adenomyosis.
Abstract
BACKGROUND
Adenomyosis, characterized by the presence of islands of endometrial tissue surrounded by hypertrophic smooth muscle cells within the myometrium, is one of the most challenging ...uterine disorders in terms of diagnosis and management. Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia and infertility. The relative contributions of abnormal endometrial tissue and myometrial smooth muscle cells to the development and growth of adenomyosis are not well understood. Moreover, there is continuing debate on the origins of adenomyosis; two competing theories describe the invagination of basal endometrium into the myometrium or the metaplastic differentiation of remnant endometrial stem/progenitor cells within the myometrium.
OBJECTIVE AND RATIONALE
A recent series of next-generation sequencing (NGS) studies have provided the best scientific evidence thus far regarding the cellular origins of adenomyosis and the contributions of new signaling pathways to its pathogenesis, survival, and growth. These seminal studies on endometrium, adenomyosis and endometriosis demonstrate or support the following key points. (i) Mutations of KRAS map to both intracavitary endometrial tissue and proximally located adenomyotic samples, supporting the invagination theory of pathogenesis. Driver mutations found in smooth muscle cells of uterine fibroids are absent in adenomyosis. (ii) KRAS and other less frequent mutations are limited to endometrial-type epithelial cells. They are also observed in endometriosis, indicating that the disease process in adenomyosis is similar to that in endometriosis and distinct from that of uterine fibroids. (iii) Activating mutations of KRAS stimulate specific pathways to increase cell survival and proliferation and are associated with progesterone resistance in adenomyosis. Together, these findings suggest that distinct cell populations in eutopic endometrial tissue play key roles in the etiology of adenomyosis. Dependence on ovarian steroids and ovulatory cycles for disease severity is a unique feature of adenomyosis. In this context, common patterns of aberrant gene expression have been reported both in adenomyosis and endometriosis. These include pathways that favor increased estrogen biosynthesis, decreased estradiol metabolism, a unique estrogen receptor beta (ESR2)-driven inflammatory process, and progesterone resistance due to decreased progesterone receptor expression. Since adenomyosis exhibits a uniquely estrogen-driven inflammatory process and progesterone resistance, we discuss the interactions between these molecular characteristics and signaling pathways induced by the newly discovered KRAS mutations.
SEARCH METHODS
We conducted a comprehensive search using PubMed for human and animal studies published until 2020 in the following areas: adenomyosis, endometriosis, endometrium, NGS, whole-exome sequencing, whole-genome sequencing, RNA sequencing, targeted deep sequencing, epigenetics, driver mutation, KRAS, progesterone resistance, estrogen action and steroid production.
OUTCOMES
Targeted deep sequencing analyses of epithelial cells in adenomyosis and adjacent basalis endometrial glands demonstrated recurring KRAS mutations in both cell types. This finding suggests that adenomyosis originates from basalis endometrium. Epithelial cells of the endometrium, adjacent adenomyosis and co-occurring endometriosis also share identical KRAS mutations. These findings suggest both adenomyosis and endometriosis are oligoclonal tissues that arise from endometrial cell populations carrying a specific driver mutation that most commonly affects the KRAS gene.
WIDER IMPLICATIONS
Adenomyosis usually follows an event such as pregnancy that has disrupted the integrity of the endometrial–myometrial junction followed by repetitious menstrual episodes that increase the likelihood of the entrapment of the basalis endometrium within the myometrium. Glandular epithelial cells carrying KRAS mutations and located within the deep crypts of basalis endometrium may become entrapped and invade myometrial tissue to give rise to adenomyosis. Evidence suggests that KRAS mutations may be responsible, in part, for previously observed phenomena such as prolonged cell survival and progesterone resistance in adenomyosis.
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