The endometrial–myometrial junction: a fresh look at a busy crossing

Routine ultrasound examination of the uterus includes a detailed assessment of the morphological characteristics of the myometrium and endometrium. These two main functional components of the uterus display different acoustic properties, which facilitates their differentiation on ultrasound imaging. The majority of pathological entities that affect the myometrium differ in their pathogenesis and clinical significance from those that affect the endometrium and they tend to be analyzed separately on ultrasound examination. However, it is well known that, due to their anatomical proximity, some endometrial abnormalities tend to extend into the myometrium and vice versa. This can be documented only by a careful examination of the interface between the endometrium and myometrium, which is often referred to as the endometrial–myometrial junction (EMJ). Traditionally, assessment of the EMJ has been part of the magnetic resonance imaging (MRI) evaluation of the uterus, with changes in this area being a key component of the diagnosis of adenomyosis. Although the EMJ is visible on ultrasound, it has not played a major part in the sonographic evaluation of uterine pathology. In order to obtain clear images of the EMJ, high-resolution ultrasound equipment with three-dimensional (3D) imaging capability is often required, but this has only been available in recent years. In this Editorial we describe anatomical and physiological characteristics of the EMJ and discuss different abnormalities which can cause its disruption. We also summarize the role of 3D ultrasound in assessing the EMJ and describe novel diagnostic features which are demonstrated by this new technique. The myometrium consists of bundles of smooth muscular fibers, intermixed with areolar tissue, blood vessels, lymphatic vessels and nerves. Wetzstein and Renn3 found that the muscle fibers of the inner myometrium have a predominantly circular orientation, in contrast to both the intermediate and outer layers of the myometrium. The endometrium, the mucous membrane that lines the uterine cavity, is composed of a single layer of columnar epithelium. The EMJ is the transitional zone between the mucous membrane that is the endometrium and the outer smooth-muscle layer of the myometrium. The inner layer of myometrium that encircles the endometrium has been variously termed the uterine junctional zone2, the endometrial–subendometrial unit or stratum sub-vasculare1, the subendometrial myometrium4, the archimetra5 or archimyometrium6 and the inner myometrium7. While these terms are often used interchangeably, it is not always clear whether they are referring to exactly the same entity. The EMJ is structurally distinct from other mucosal–muscle interfaces within the human body in that it lacks a submucosal layer. Most tissues with a mucosa have a subjacent, histologically recognizable submucosa that protects the underlying tissue from mucosal invasion (e.g. stomach, intestine, trachea and bronchi8, 9). While the superficial and basal layers of the endo- metrium are clearly distinguishable on light microscopy, there is no histological distinction between the inner myometrium and the outer myometrium on light microscopy. Tetlow et al.10 demonstrated increased vascularity of the inner myometrium compared with the rest of the myometrium. It was also found that the muscle fibers of this zone were more densely packed compared with other zones of the myometrium. They concluded that these architectural findings would account for the hypoechoic appearance of the inner myometrium on both transvaginal ultrasound and MRI. It is not just an embryological origin that the endometrium and inner myometrium share. While physiologically distinct, they are both under the cyclical influence of ovarian sex steroids. The main function of the inner myometrium appears to be modulation of uterine peristalsis, an area that increasingly is believed to play a significant role in fertility. Uterine contractions emanating from the inner myometrium were first visualized and subsequently described by Birnholz11, who identified them on transabdominal ultrasound. Inner myometrial contractions vary in orientation, amplitude and frequency throughout the menstrual cycle, under the influence of estradiol and progesterone. Studies have shown that, in the follicular phase of the cycle, these contractions are predominantly cervicofundal in orientation and their amplitude and frequency increase significantly as ovulation approaches. There is evidence that this pattern of contractions facilitates sperm transport12. After ovulation there is a decrease in overall inner myometrial contractility under the influence of progesterone. Ijland et al.13 have suggested that this may help to facilitate implantation of the developing blastocyst while improving its supply of oxygen and nutrients. The uterus has been described as comprising three distinct zones on both MRI and transvaginal ultrasound. On MRI, the uterine zonal anatomy is best demonstrated on T2-weighted images. Generally, the endometrium is of high signal intensity and is therefore visualized as a thin white stripe. The inner myometrium is of uniformly low signal intensity, while the outer myometrium is of intermediate signal intensity14. Because of this observed contrast of the three uterine zones, MRI is very good at delineating and measuring the size of these zones. This is crucial in the MRI diagnosis of adenomyosis, which is dependent on the increased thickness of the inner myometrium15. On ultrasound, the inner myometrium has been described as a regular hypoechoic band or 'halo' that encircles the endometrium16. While this zone is distinct from both the endometrium and the outer myometrium, the delineation of uterine zonal anatomy is less clear on sonography than it is on MRI. Ultrasound, however, has the ability to visualize very clearly the basal endometrial layer, which forms the actual interface between the inner myometrium and the endometrium. On two-dimensional (2D) ultrasound, the EMJ is best seen in the longitudinal section, which enables the examination of its anterior and posterior aspects. In this view, the EMJ is seen as consisting of two distinctive structures: basal endometrium and inner myometrium. In normal uteri, the basal endometrium is seen as a continuous uninterrupted hyperechoic line and in practical terms it represents the endometrial–myometrial interface (Figures 1 and 2). A longitudinal view of a normal uterus in the early proliferative phase of the cycle. The calipers are placed on the basal endometrial layer, which appears as a regular, continuous echogenic line. The surrounding inner myometrium appears hypoechoic in comparison to the outer endometrial layer. Schematic diagram of a uterus in transverse section showing the myometrial and endometrial layers (EMJ, endometrial–myometrial junction). The differences in the sonographic appearance of the inner and outer myometrium depend partially on the ovarian sex steroid hormone levels present at the time. Prepubertally, when the levels of the ovarian sex steroids are low, the inner and outer myometrium are indistinct on both ultrasound17 and MRI18. A similar pattern is also seen on MRI images obtained from healthy postmenopausal women7. Willms et al.19 noted an increase during pregnancy in the signal intensity of the inner myometrium on MRI, which gradually reverted to normal postpartum. Furthermore, serial MRI scans throughout menstrual cycles have shown an increase in EMJ size from the early proliferative phase through to the late luteal phase20, 21. There are no reported ultrasound studies of the cyclical changes within the EMJ. 3D transvaginal ultrasound is a relatively recent diagnostic modality, which allows detailed evaluation of the pelvic organs by collecting a series of sequential ultrasound images and converting them into an ultrasound volume. This information is digitally stored as a dataset which is reconstructed in such a way as to allow visualization of an organ from any chosen angle and in any arbitrary plane22. In the field of obstetrics and gynecology, 3D ultrasound has so far had the greatest impact on the diagnosis of uterine abnormalities. The ability to obtain a coronal uterine plane while simultaneously evaluating both the uterine cavity and the external contour of the uterine fundus has dramatically improved the ultrasound diagnosis of congenital uterine anomalies23. 3D diagnosis of these anomalies is much more accurate than is diagnosis by 2D B-mode ultrasound. It is also more reproducible and considerably less invasive compared with the previous gold standard of hysteroscopy and laparoscopy24. 3D ultrasound has therefore become accepted increasingly as the best method with which to diagnose congenital uterine anomalies. 3D reconstruction of uterine anatomy in the coronal plane provides new and unrivalled views of the EMJ. By obtaining panoramic views of the uterine cavity it is now possible to assess the lateral and fundal aspects of the EMJ, which are impossible to see clearly on standard 2D imaging. The ability to see the entire lateral borders of the EMJ in a single view greatly increases our ability to identify minor changes, which are essential for the diagnosis of subtle abnormalities, such as cavity strictures and early adenomyosis. Another advantage of 3D ultrasound is the much clearer visualization of the hypoechoic inner myometrium in comparison to that on 2D imaging (Figure 3a). Three-dimensional reconstructions of the uterus in the coronal plane showing: (a) the normal appearance of hyperechoic endometrium surrounded by hypoechoic inner myometrium, and (b) a diffusely thickened and cystic endometrium in a woman taking tamoxifen. The inner myometrium appeared normal. Abnormalities of the EMJ include both breaches of the basal endometrium and morphological changes to the inner myometrium. We have categorized these abnormalities as being congenital, acquired or iatrogenic. T-shaped uterus is a specific type of congenital uterine anomaly, which is seen in the female offspring of women treated with diethylstilbestrol during pregnancy. Features described on hysterosalpingography by Kaufman et al.25 include a small T-shaped uterus, constricting bands, hypoplasia, polypoid defects and synechiae. In some cases, the inner borders of the uterus were seen to have an 'irregular and shaggy' appearance. The majority of these features, including the T-shaped configuration of the uterus as well as the synechiae and irregular and shaggy appearance, cannot be visualized on 2D ultrasound and are very hard to assess, even at hysteroscopy. By using 3D ultrasound to create a reconstructed coronal plane of the uterus, the T-shaped configuration of the uterus can be documented clearly. In addition, 3D ultrasound allows the diagnosis of the herniations and strictures of the uterine cavity, which are visualized as irregularities of the EMJ26 (Figure 4). Three-dimensional ultrasound imaging in the coronal plane showing two examples of T-shaped uteri. (a) Note the very narrow and irregular lower part of the uterine cavity due to severe strictures. The fundal aspect of the cavity os is short and wide, creating the typical T shape. A small intramural fibroid (F) is also visible in the left lateral wall of the uterus. In (b), the relatively short fundal part of the uterine cavity and strictures (*) are discernible. Herniations are also seen as mild protrusions of the endometrium into the inner myometrium. Adenomyosis is defined as the presence of endometrial glands and stroma within the myometrium. The etiology of adenomyosis is still debated, with risk factors including age and parity, and proposed causes including uterine hyperperistalsis16 and sharp curettage of the pregnant uterus27. It is, however, agreed that adenomyosis is a disease that regularly affects the EMJ. Many studies have illustrated that the sensitivity and specificity of transvaginal ultrasound in diagnosing adenomyosis are comparable to those of both MRI and histology28. Kepkep et al.29 assessed the accuracy of various transvaginal sonographic findings, including poor definition of the EMJ and the presence of subendometrial echogenic linear striations, in the diagnosis of adenomyosis. They found that subendometrial linear striations had the highest accuracy in its diagnosis (Figure 5). Longitudinal section of the uterus on two-dimensional ultrasound showing a poorly defined endometrial–myometrial border with hyperechoic endometrial tissue penetrating into the inner myometrium. One difficulty with 2D B-mode ultrasound is that the EMJ can only be assessed in one plane at the time. Ahmed et al.30 conducted a similar study to that of Kepkep et al.29 in which they also assessed the diagnostic accuracy of 'the presence of a hazy or ill-defined and irregular EMJ on 3D coronal plane of the uterus'. They reported a positive predictive value of 95.2% and an accuracy of 80% for this finding in diagnosing adenomyosis. Figure 6a shows a 3D ultrasound image of a uterus in the coronal plane. Protrusions of the endometrium into the inner myometrium can be seen at the fundal aspect of the uterus. A similar example is shown in Figure 6b. We hypothesize that these images illustrate migration of endometrial tissue into the myometrium, and that they could represent an early stage in the development of adenomyosis. These findings also suggest that adenomyosis is more likely to be caused by 'invasion' of endometrial tissue across the EMJ and into the myometrium than by endometrial tissue developing de novo within the myometrium. Three-dimensional ultrasound imaging in the coronal plane showing protrusions of the endometrium into the inner myometrium (arrows) in: (a) a normal uterus and (b) a unicornuate uterus. Note the irregular endometrial–myometrial junction at the lateral aspect of the uterine cavity suggestive of early adenomyosis. The medial aspect of the cavity is normal, with clearly defined hypoechoic inner myometrial echo. Verma et al.31 recently reported a novel feature of adenomyosis seen on saline contrast sonohysterography that would appear to corroborate the theory of adenomyosis as an 'invasive' disease. They were able to visualize breaches of the EMJ as the presence of 'ill-defined areas of fluid intravasation extending from the uterine cavity into the myometrium'. They proposed that these fluid tracks represented direct invasion of basal endometrium across the EMJ into the myometrium. However, it is difficult to be certain that these breaches are not simply caused by fluid leaking from the uterine cavity because of high instillation pressure. Ultrasound appears to be able to visualize features of early adenomyosis. Can it also monitor its progression? The images in Figure 7 are taken from the same patient, 5 years apart, and may provide some insight into the progression of adenomyosis. Figure 7a shows limited focal adenomyosis, manifested by the presence of myometrial cysts. These cysts can be seen to be in continuum with the endometrium, crossing the EMJ. In Figure 7b, taken 5 years later, the focal adenomyosis has progressed to severe diffuse disease. There are no myometrial cysts, but there is uterine enlargement, with asymmetrical thickening of the posterior myometrium and heterogeneous and poorly circumscribed areas within the myometrium with typical parallel shadowing. Ultrasound images from the same patient, showing the progression of adenomyosis. In (a) well-defined myometrial cysts are seen in the transverse view. In (b), 5 years later, in an oblique view there is extensive adenomyosis involving the posterior uterine wall. Calipers indicate the endometrial thickness. Uterine fibroids are classified as submucosal, intramural or subserous. They are submucosal if they distort the mucosal surface of the endometrial cavity. Submucosal fibroids are thought to be associated with reproductive dysfunction32 and menorrhagia33. Their size and the degree of protrusion into the endometrial cavity are the main factors determining the severity of clinical symptoms. Although there have been suggestions that all submucosal fibroids originate from the inner myometrium34, it is likely that in some cases distortion of the cavity is caused by relatively large fibroids that have originated from the outer myometrium. There is some evidence that submucosal fibroids originating from the inner myometrium grow faster35 and have greater expression of estrogen and progesterone receptors than do those originating from the periphery36. Studies of the relationship between the EMJ and submucosal fibroids might help to identify the site of their origin. Fibroids originating from the inner myometrium should cause a disruption of its uniform hypoechoic echotexture adjacent to the basal endometrium, whilst the fibroids originating from the outer myometrium should cause a displacement and distortion of the EMJ without affecting its morphological appearance. So far, no attempts have been made to differentiate between these two types of submucosal fibroids on ultrasound. The two examples illustrated in Figure 8 show that this might be possible. The ability to determine the site of origin of submucosal fibroids within the myometrium may help to counsel patients with small early fibroids as to the likely speed of their growth and the risk of developing clinical symptoms in the future. Three-dimensional ultrasound images of the uterus suggesting the possibility of sonographic differentiation between submucosal fibroids originating from the inner and from the outer myometrium. (a) Type submucosal fibroid (F) in the lateral aspect of the cavity. The part of the fibroid into the cavity is by a hypoechoic layer of tissue which represents inner myometrium. (b) Submucosal fibroid (F) at the uterine The fibroid is only by a thin endometrial layer which might be of its origin from the inner myometrium. are focal of endometrial They are with an in the of women of They are often but they can also cause uterine and they have been associated with On ultrasound, endometrial are seen as hyperechoic that the endometrial echo. They do not or the EMJ as they are endometrial however, their vessels, which are visible on transvaginal ultrasound in can be seen to the EMJ on examination (Figure 9). imaging in a of large endometrial from the fundal aspect of the uterine cavity. A well-defined is seen crossing the endometrial–myometrial is the to the any endometrial that is or a of the EMJ, this stage being defined as an endometrial that has less than one of the myometrial thickness. myometrial invasion has a of the definition of the EMJ is of the of myometrial invasion is as it both and the of the MRI is the with a reported sensitivity of It is, however, limited in and for some The accuracy of transvaginal 2D B-mode ultrasound has been and one of the reported an accuracy of in myometrial of 2D ultrasound include in all and the degree of on the of imaging. These are less to 3D ultrasound and there are suggestions that this might the ultrasound diagnosis of endometrial However, a careful examination of the EMJ on 2D ultrasound might be in an early invasive endometrial Figure shows a of an early by an appearance of the EMJ. examination (Figure was in showing blood vessels penetrating the EMJ as to a single which is typical of a Ultrasound imaging in a of an early endometrial as a polypoid (a) Note the normal thin endometrium and an endometrial–myometrial junction the posterior and fundal aspect of the cavity the EMJ is not visible and the is into the myometrium (b) examination of the same blood vessels penetrating the EMJ at the site of is a estrogen used in the of it has a on the uterus and has been associated with an increased risk of endometrial endometrial and There is a and between the and of the endometrium in patients taking tamoxifen. et described a of all of had the ultrasound appearance of a cystic endometrium, but at hysteroscopy had only endometrium, which was by of One for this found is that accurate assessment of endometrial thickness is by the that the EMJ is often found to be poorly defined and irregular in these patients (Figure Another possible for this is that the ultrasound changes seen in patients represent a subendometrial While this is not a MRI studies to the that the cysts seen in these patients are endometrial–myometrial or subendometrial in The presence of cysts within the myometrium is, of one of the ultrasound diagnostic for adenomyosis. It is whether the presence of these cysts represents new or adenomyosis or a of cystic contrast sonohysterography has been used to the assessment of the endometrial cavity in patients to have endometrial on ultrasound. The advantage of saline contrast sonohysterography is its ability to the endometrial to differentiate endometrial from myometrial pathology. et found that of patients to have a thickened endometrium on ultrasound, using as a had no on saline contrast hysteroscopy and endometrial in two patients and in ultrasound has been found to have in assessing the of and 3D ultrasound appears to be more accurate in the type and of One of 2D ultrasound is its to visualize clearly the lateral and fundal of the endometrial cavity. of on 3D ultrasound enables detailed studies of the of in to the EMJ. We have noted that the of the and by the EMJ in a large of cases, extending into the outer myometrium (Figure a small of 3D images of in our that the of these extend into the myometrium in more than of This of myometrial by is of clinical It is to with the of the but in some cases it might be the cause of uterine which is reported by The assessment of the degree of the into the myometrium might be to of the with clear evidence of the extending into the outer myometrium might be as is likely to be more difficult and more in these It to be seen whether the disruption of the of the EMJ by the of might play a role in the development of adenomyosis. Three-dimensional ultrasound imaging in the coronal view in cases of (a) A of a with into the lateral and fundal myometrium. (b) A of a into the with the of the penetrating the lateral of the uterus at the of the while relatively are a cause of They can any but they curettage of a recently pregnant well as they can cause pelvic and The type of the myometrium, disruption of the EMJ. On 2D ultrasound, the uterine cavity appears with focal or of endometrium. The EMJ is with of the of the basal endometrium (Figure The reported sensitivity of 2D transvaginal ultrasound in et and et reported of 80% and This with the sensitivity reported by et it be noted that their study only has been the used imaging for diagnosing but it has It is more invasive than is transvaginal ultrasound and it a high of in the presence of other such as is also limited in its ability to the endometrial cavity when in the lower uterine cavity instillation of contrast Three-dimensional ultrasound is to the sensitivity of ultrasound in However, by a panoramic view of the uterine cavity it provides information their and severity (Figure Ultrasound imaging in a of (a) On two-dimensional ultrasound these were visualized as a focal of the endometrial–myometrial with a of the functional endometrium at the same (b) imaging in the coronal view a clear of the of the affecting the cavity. Another involving the EMJ is subendometrial which should not be with It an such as and The changes are of the at is by the presence of echogenic in the basal endometrial layer, whilst the superficial layers of the endometrium appear normal (Figure The inner myometrium is normal in cases of mild but in severe cases, in women with a of there is evidence of extending into the inner and even into the outer myometrium (Figure is often seen at the of the os in women with a of uterine The clinical significance of subendometrial is and there is no evidence to suggest an on endometrial function or fertility. Three-dimensional ultrasound imaging in the coronal view in a of mild subendometrial in the lateral aspect of the uterine cavity longitudinal view of the uterus showing evidence of extensive subendometrial in a woman with a previous of of has been used to describe two different the presence and of within the and of endometrial is due to of endometrial caused by or a clinical however, the distinction is as both cause similar symptoms. is with an of It can be but has also been with a of including pelvic and menstrual The tissue is often described as an on ultrasound and is thought to have a similar of to an in (Figure The tissue often breaches the EMJ and within the myometrium. It is thought that the to which the uterine cavity is is of clinical should be to the EMJ to assess the of myometrial and uterine cavity of the tissue, as this determine both the and the of any In the of any other appears to of the view in a of with hyperechoic with posterior within the uterine cavity and at the of the The presence of facilitates diagnosis between and uterine section were identified on ultrasound in more than of women with a of single or In the majority of cases the present as thin hypoechoic lines extending from the endometrium, crossing the EMJ and extending through the outer myometrium to the anterior surface of the uterus (Figure In of the defects are wide, with a of more than of the myometrial Although in the majority of cases the are at the of the of are at the uterine are by a large in the EMJ, with of functional endometrium and inner myometrium. In some menstrual blood is within the which causes (Figure The of functional endometrium in at the the of is to be the main the of to into the myometrium, the EMJ, when are into a is the for which even when these early in the first which the are often by which is a significant cause of severe and The diagnosis of myometrial is relatively early in the first of pregnancy and is on the visualization of the which into the myometrium the EMJ. On the blood supply to the pregnancy is more than in cases of normal Ultrasound imaging in cases of section (a) A lower uterine section seen as a thin hypoechoic line the endometrial–myometrial junction (b) A of section with a thin layer of myometrium and of menstrual blood within the uterine cavity. may also be found in women with no of previous section or other uterine In these cases, only a part of the might be to the myometrium. This may not be of the when are with the of the The is often with one or two being within the uterus. The diagnosis of is made on ultrasound examination by the tissue penetrating through the EMJ into the outer myometrium (Figure imaging in a of an a at tissue is partially by the myometrium the endometrial–myometrial junction and into the outer myometrium. uterine cavity. in diagnostic ultrasound have to significant in the diagnosis of uterine abnormalities. In cases of congenital uterine 3D reconstructions of uterine anatomy in the coronal plane have a and views of the uterine cavity have also improved visualization of the EMJ. The ability to the entire contour of the uterine cavity facilitates of minor irregularities of the EMJ. This has the to significantly the diagnosis of early adenomyosis and it may help to to the of this and often A detailed assessment of the EMJ may also help to assess the origin and clinical significance of submucosal Another area in which 3D imaging might be of is the diagnosis of early invasive endometrial is to assess the impact of these diagnostic on the clinical of these and other less uterine abnormalities.