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Adenomyosis: a life-cycle approach

Reproductive BioMedicine Online, Volume 30, Issue 3, Pages 220 - 232

Editorial Comment

Adenomyosis has been linked to reduced pregnancy rates following embryo transfer, and there is limited evidence that gonadotrophin-releasing hormone agonist therapy for adenomyosis prior to embryo transfer can improve pregnancy rates. However, more studies are required to clarify the natural history of this condition, its prevalence in different phases of reproductive life including adolescence, and the best approach to screening. This manuscript discusses the life-cycle approach to adenomyosis and emphasizes the need for further research to answer a number of fundamental questions regarding adenomyosis.


The life-cycle approach to endometriosis highlighted unexpected features of the condition; the same approach was therefore applied to gain insight into the clinical features of adenomyosis and to draw a comparison with endometriosis. This is possible today thanks to new imaging techniques enabling non-invasive diagnosis of adenomyosis. The specificity and sensitivity of magnetic resonance imaging and transvaginal ultrasound remain uncertain. Unlike endometriosis, little information is available on the presence of classic adenomyosis in adolescents, except for rare cystic forms that may not represent the true disease. Adenomyosis is most likely to affect adult women, although most reported incidences are still based on post-hysterectomy studies, and are affected by diligence in histopathologic diagnosis and the adopted cut-off point. The traditionally accepted associations of adult adenomyosis, such as multiparity, a link to infertility and its effect on pregnancy are uncertain. Active adenomyosis has been found in pre- and peri-menopausal women and in postmenopausal women receiving tamoxifen. In conclusion, major diagnostic limitations and the systematic bias of hysterectomy make it difficult to draw firm conclusions from existing evidence. In addition, no information is available on the natural history of adenomyosis and no study has systematically evaluated its existence in adolescents.

Keywords: adenomyosis, adolescent, adult, post-menopausal, pregnancy.


Descriptions of ‘mucosal invasions’ of the peritoneal surface and organs were first published in the last part of the 19th century. With the exception of ovarian endometriosis, these structures were all considered to be adenomyomas (Benagiano et al., 2014a). In the 1920s, two separate conditions were identified: endometriosis and adenomyosis, with different clinical profiles (Frankl, 1925, Sampson, 1925a, Sampson, 1925b, and Sampson, 1927).

More recently, however, similarities between the two pathologies have led to a re-evaluation of the situation and to a theory that they may have a common origin (Benagiano, Brosens, 2011 and Brosens et al, 2013a). In particular, evidence shows that endometriosis and adenomyosis have in common an endometrial dysfunction involving both eutopic and heterotopic endometrium (Benagiano et al., 2014b). Although anomalies are not identical, they share the common feature of leading to increased invasiveness. In both conditions, there is also a reaction of the inner myometrium that, although more pronounced in the case of adenomyosis, is nonetheless also present in endometriosis (Kunz et al., 2000).

Research on endometriosis has progressed rapidly owing to the introduction in the late 1960s and 1970s of endoscopic techniques; however, the study of adenomyosis continued to be limited to the evaluation of surgical specimen (i.e. to symptomatic disease requiring hysterectomy). Fortunately, over the past 2 decades, the availability of new diagnostic modalities, such as magnetic resonance imaging (MRI) and high resolution three-dimensional transvaginal ultrasound (3D-TVU), made it possible to study adenomyosis in women not requiring, or who cannot have, a hysterectomy and therefore to begin to reconstruct its natural history. In particular, the identification and evaluation of the inner myometrium or myometrial junctional zone by Hricak et al. (1983) provided new, non-invasive diagnostic criteria for adenomyosis (Luciano et al, 2013 and Reinhold et al, 1996). This signalled the beginning of a new era, where comparative evaluation of the features of adenomyosis and endometriosis could be made, including both early and advanced stages. Also, the presence and frequency of the two conditions during the various stages of a woman's life can now be studied.

We have recently appraised endometriosis by applying a life-cycle approach (Brosens et al., 2013a). Here, we apply a similar approach to adenomyosis. Importantly, a life-cycle approach may allow the question of whether adenomyosis and endometriosis are linked to be re-visited, a concept that is not new and was proposed during the 1940s nd 1950s (Javert, 1951 and Novak, de Lima, 1948).

Although we have recently reviewed the pathophysiology of uterine adenomyosis (Benagiano et al., 2012), we wanted to assess whether further insight into its pathogenesis can be gained through understanding the disease in women not undergoing hysterectomy and by comparing features in different stages of life. This can now be done by applying the new, early, non-invasive diagnostic criteria for adenomyosis (Champaneria et al, 2010, Dueholm, 2006, Meredith et al, 2009, Novellas et al, 2011, and Tamai et al, 2006).

Materials and methods

In order to identify features of adenomyosis at different stages of a woman's life, and attempt a comparison between adenomyosis and endometriosis, areas in which differences and similarities had already been evaluated were selected (e.g. incidence, imaging diagnosis, infertility, parity and pregnancy).

Critical evaluation and comparison was only possible for adult women. Therefore, for this group of patients, we searched for all articles published over the past 20 years on adenomyosis using Scopus and PubMed searches. The cut-off point for our search was March 2014. For adenomyosis, 143 articles were identified on histopathologic features and incidence, 160 on imaging diagnosis, 18 on issues relating to parity, 69 on infertility and 81 on pregnancy-related issues. At this stage, analysis of publications was restricted to studies reporting findings in relation to age groups or a comparison with adenomyosis. Because of the variation in diagnostic criteria and in research methods, these studies do not lend themselves to meta-analysis and, although existing recent meta-analyses were used, a critical narrative review of published literature was opted for.

Given the paucity of data, all articles dealing with young or menopausal women were summarized, including early studies. All articles on adult women dealing with the above-mentioned topics were systematically identified, and relevant articles selected.

Imaging diagnosis

The specificity of a preoperative diagnosis of adenomyosis based on clinical findings is poor (Bird et al., 1972), ranging from 2–26% (Azziz, 1989, Molitor, 1971, and Sammour et al, 2002). Meredith et al. (2009) analysed data from 14 selected published hysterectomy studies and found that adenomyosis was more common in women with heavy bleeding (31.9%), compared with all other hysterectomies (25.9%). The probability of adenomyosis in a woman with heavy bleeding and positive ultrasound features was 68.1%, compared with 65.1% probability in a woman with positive ultrasound if undergoing hysterectomy for any symptom. The investigators reported that the value of transvaginal ultrasound is weakened by the lack of uniform histopathologic and ultrasound criteria. Therefore, before a life-cycle approach can be applied to the natural history of adenomyosis, it is necessary to critically evaluate the accuracy of the new non-invasive diagnostic procedures.

In a systematic review and meta-analysis of the diagnostic accuracy of transvaginal ultrasound and MRI compared with histological standards (Champaneria et al., 2010), only three studies using MRI (Bazot et al, 2001, Dueholm et al, 2001, and Reinhold et al, 1996) and six comparing transvaginal ultrasound (Bazot et al, 2001, Bazot et al, 2002, Dueholm et al, 2001, Kepkep et al, 2007, Reinhold et al, 1996, and Vercellini et al, 1998), fulfilled quality criteria. Agreement was reached on three of the transvaginal ultrasound diagnostic features: the presence of myometrial cysts, a heterogeneous myometrium and focal abnormal echo-texture (Figure 1 and Figure 2). All studies except Dueholm et al. (2001) and Reinhold et al. (1996) included the presence of globular or asymmetrical uterus. Two studies (Bazot et al, 2002 and Kepkep et al, 2007) emphasized the diagnostic value of sub-endometrial linear striations; only one study used colour Doppler (Bazot et al., 2002). The study by Bazot et al. (2002) reported on the diagnostic value of individual features examined, but some features had a higher sensitivity than the overall assessment, which appears contradictory. The reported sensitivity, specificity, positive and negative predictive value for transvaginal ultrasound in the study by Kepkep et al. (2007) are the same as those reported for the sonographic feature of ‘heterogeneous myometrium’. Thus, the relative weight of individual features remains unclear. Sonography concurred with histopathology in assessing the depth of invasion in only 57% cases and in assessing the degree of involvement and lesion density in only 23% (Bazot et al., 2001). Reinhold et al. (1996) on the other hand, reported good agreement between transvaginal ultrasound and histology in depicting adenomyosis location (κ = 0.69) and maximum depth of involvement (κ = 0.81).


Figure 1 Ultrasound images of a uterus with adenomyosis. Panel A: grey scale image showing asymmetrically thickened posterior uterine wall with inhomogeneous, irregular myometrial echotexture with hyperechoic irregular myometrial areas and small cystic anechoic areas; panel B: power Doppler image showing diffusely spread small vessels (white arrow). source: (Courtesy of Dr. Caterina Exacoustos, Rome).


Figure 2 Ultrasound image of the uterus obtained using three-dimensional ultrasound and volume contrast imaging (VCI) with 4-mm slices. The multiplanar view shows transverse and coronal sections of the uterus on the left side of the image; a longitudinal section is shown on the right side of the image. Note the round cystic anechoic areas (white arrows) in the myometrium below the endometrium in the junctional zone. The coronal view of the uterus is shown with the junctional zone appearing as a dark halo outside the endometrium on the right and left side of the endometrial cavity (yellow arrow) and with distortion and infiltration by hyperechoic endometrial tissue on the fundus and left side of the image (red arrows). source: (Courtesy of Dr. Caterina Exacoustos, Rome).

In the review by Champaneria et al. (2010) referred to above, the pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio for transvaginal ultrasound were 72% (95% confidence interval [CI] 65 to 79), 81% (95% CI 77 to 85), 3.7 (95% CI 2.1 to 6.4) and 0.3 (95% CI 0.1 to 0.5) respectively; and for MRI were 77% (95% CI 67 to 85), 89% (95% CI 84 to 92), 6.5 (95% CI 4.5 to 9.3), and 0.2 (95% CI 0.1 to 0.4), respectively. Many important differences exist between the studies included in this review, including different cut-off points and differences in case ascertainment and the number of sections examined. Some investigators have described assessment of uterine weight, wall thickness, histological grade (depth), extent of disease or lesion density, but these were not analysed in the respective studies (Bazot et al, 2001, Bazot et al, 2002, and Kepkep et al, 2007).

In a prospective evaluation by Luciano et al. (2013) of the accuracy of 3D-TVU, features linked to adenomyosis were junctional zone (maximum 8 mm or over), myometrial asymmetry and hypo-echoic striations. When at least two of these features were present, 3D-TVU was 90% accurate (sensitivity [92%], specificity [83%], positive predictive value [99%] and negative predictive value [71%]). Naftalin et al. (2012) reported on the use of 3D-TVU in women who attended a general gynaecology clinic. In this study, the prevalence of adenomyosis was 20.9% (95% CI 18.5 to 23.6). Forty-five women subsequently underwent a hysterectomy. Once women with cancer or large fibroids were excluded, there was a fair level of agreement between 3D-TVU and histological adenomyosis (κ = 0.62; P = 0.001); 95% CI 0.324 to 0.912).

In conclusion, although the difficulties involved in this kind of trial can be appreciated, the fact remains that, despite much promise, studies of the role of ultrasound and MRI in diagnosing adenomyosis suffer from methodological weaknesses. This is primarily due to the lack of agreed diagnostic standards.

Nonetheless, it is today possible to identify adenomyosis through a careful analysis of the endo-myometrial junctional zone, and therefore to identify the presence of unsuspected adenomyosis in women not undergoing a hysterectomy. Unfortunately, such a study has yet to be conducted.

Adenomyosis in young women

At the beginning of the 20th century, Meyer (1903) examined 100 uteri from fetuses, newborn children and girls up to the age of 14 years. He found that a mucosal invasion of the myometrium was seldom visible and concluded that ‘adenomyoma’ was a disease of adult life. Emge (1962), referred to the report by Meyer in 1897 of the identification of adenomyosis in a fetus at term, and the reports by Albrecht, Erbslöh, Holden, Javert, and Philipp of the existence of adenomyosis in autopsies of children between the ages of 4 and 14 years (Meyer, 2009, Holden, 1931, Javert, 1951, Philipp, 1954, Albrecht, 1955, and Erbslöh, 1956). Emge (1962) considered this to support the existence of a type of ‘congenital adenomyosis’ present before cyclic ovarian activities. Emge (1962) also cited cases of persistent primary dysmenorrhoea that were later found to have adenomyosis and advocated ‘further search of the evidence in premenarchial uteri obtainable at autopsies’. It is a fact that early literature contains no reports of adenomyosis in pubertal or teenage girls: Lewinski (1931) identified one case at autopsy among five cases in women aged 20–30 years, and Dreyfuss (1940) found three cases among 152 hysterectomy specimens of women aged 21–30 years. Even Emge (1962), in his work, indicated that he could not find any case below 25 years of age (Figure 3).


Figure 3 Age distribution of 210 patients with adenomyosis at hysterectomy. source: Adapted from Emge (1962).

Contrary to the case with endometriosis, and despite the availability of non-invasive diagnostic tools, to this day information on adenomyosis in adolescent girls remains limited. A recent review (Dieterich, 2010) found a heterogeneous group of uterine pathology, including adenomyosis, adenomyotic cysts, focal adenomyosis and adenomyoma. Among young women, the most common complaint was severe dysmenorrhoea unresponsive to non-steroidal anti-inflammatory drugs or to combined oral contraceptives.

Cases of classic adenomyosis seem rare and even dubious: Itam et al. (2009) diagnosed adenomyosis using MRI in two adolescents aged 16 years. In one case, a low signal area in the caudal aspect of the uterus was interpreted as focal adenomyosis. In the other, the diagnosis was based on a poorly defined junctional zone.

A variant of adenomyosis that seems specific to young women is the so-called myometrial cystic adenomyosis (Brosens et al., 2014), in which young patients present with non-responsive severe dysmenorrhoea. Diagnosis is usually delayed, but when MRI is carried out, it easily shows a cyst up to 3 cm in diameter with haemorrhagic content; histologically, these cysts are lined with an endometrial-like layer. Characteristically, the smooth muscle cells surrounding the cyst show hyperplasia, macrophage infiltration and haemosiderin pigmentation.

Another variant was described in two adolescents with severe dysmenorrhoea and a normal uterine contour on ultrasonography and MRI (Frontino et al., 2009); at hysteroscopy, a single cervical canal was observed, but the uterine cavity resembled a unicornuate uterus with a left tubal ostium. Laparoscopy demonstrated a right uterine nodule or rudimentary horn which contained a small cavity with endometrium, haematometra and adenomyotic foci.

The rarity of adolescent adenomyosis can also be inferred from the study by Lee et al. (2013) who compared patient characteristics and clinical associations in women with laparoscopically confirmed endometrioma. The incidence of myomas or adenomyosis diagnosed at surgery or preoperative ultrasound in four age groups (20 years or younger, 21–30 years, 31–40 years and 41–45 years), was 0, 14%, 31% and 47%, respectively. Similarly, the California Teachers Study (Templeman et al., 2008) found that, at the time of diagnosis, women with adenomyosis were on average 10 years older (mean, 53; SD, 10) compared with those with endometriosis (mean, 44, SD, 6). In this study, however, the diagnosis of adenomyosis may have been substantially delayed as it was surgically based.

Interesting comparative results have been obtained by Kunz et al. (2007) who carried out an MRI evaluation of the uterus in 227 women with and without endometriosis, and related the results to the age of the women and the subsequent appearance of adenomyosis. They subdivided women into four age-groups (17–24, 25–29, 30–34, and over 34 years), and found that an increased diameter of the dorsal junctional zone of the uterus (a feature considered indicative of the invasion of basal endometrium into the junctional zone and therefore of incipient adenomyosis), had already commenced early in the third decade. In women with endometriosis, this phenomenon progressed steadily, whereas, in those without endometriosis, there was almost no sign of adenomyosis up to the age of 34 years. In both groups of women, however, a marked increase in the incidence of adenomyosis could be observed beyond the age of 34 years. This study identified three important features: endometriosis usually becomes clinically evident at an age lower than that of adenomyosis; the alterations leading to adenomyosis may start early, but usually become manifest only after the age of 30 years; and, in a fair number of cases, adenomyosis and endometriosis may coexist.

In conclusion, at present, little, if any, evidence is available on the presence of adenomyosis in adolescence; however, as previously mentioned, before we can conclude that the process leading to the disease or mild forms of it does not exist in adolescent and young women, a systematic search should be undertaken using MRI or 3D-TVU.

Adult adenomyosis

Classically, adenomyosis is defined by the presence of heterotopic endometrial glands and stroma in the myometrium. Relevant diagnostic features are the depth of stromal and glandular penetration and myometrial hypertrophy or hyperplasia. Hendrickson and Kempson (1980) described myometrial changes as a collar of hypertrophic smooth muscle around adenomyotic foci, but no objective definition of myometrial hypertrophy and hyperplasia is availalbe. Clinically, adult women with adenomyosis show a number of differences compared to women with endometriosis; here we will analyse the most characteristic of such differences.

Histopathologic features and incidence

The endometrial–myometrial interface or intersection does not have a submucosa, and endometrial–myometrial interface irregularity is almost universal (Seidman, Kjerulff, 1996 and Siegler, Camilien, 1994). Thus, in adult women, the diagnosis relies on assessment of the degree of deviation of myometrial infiltration from that of mucosal irregularity in uteri considered to be normal. This leads to major variations in estimating the incidence of adenomyosis, which, in one study, varied from 12–58% between hospitals and 10–88% between pathologists (Seidman and Kjerulff, 1996). The variation was attributed to differences in diagnostic criteria and case ascertainment. In view of this, many pathologists have argued for a conservative cut-off point to avoid over-diagnosis (Gompel, Silverberg, 1985 and Vercellini et al, 1995). This approach remains arbitrary (Bird et al., 1972), and can overlook early stages and the possible contribution of less extensive disease to symptoms. The term ‘adenomyosis sub-basalis’ was introduced to denote lesions within one low power field (Bird et al, 1972 and Sammour et al, 2002) or less than 1 high power field (Vercellini et al., 1995) below the basal endometrium. This variety, however, may well be considered an initial form of classic adenomyosis, as no data are available on disease progression and even minimal-depth lesions have been linked to symptoms (Bird et al, 1972, Owolabi, Strickler, 1977, and Sammour et al, 2002).

Classically, incidence of adenomyosis has been calculated in hysterectomy studies; therefore, the reported incidence is necessarily affected by the diligence in diagnosis, because effect on the uterus is not uniform (Table 1). Yet, some studies have relied on as few as two random sections (Zaloudek and Hendrickson, 2002). Dreyfuss (1940) reported on 1807 surgically removed uteri, and found ‘adenomyosis and endometriosis’ in 224 instances; in 152 cases (8.4% of the total), the lesion was localised within the myometrium (therefore we should assume that these were cases of adenomyosis). Three decades later, Bird et al. (1972) reported adenomyosis in 31% of 200 consecutive hysterectomies examined routinely; this rose to 38.5% when six additional blocks were examined, and to 61.5% when sub-basal lesions were included. It is still controversial whether the posterior wall is the most affected (Sammour et al, 2002 and Zaloudek, Hendrickson, 2002). Adopted cut-off points of depth of gland and stromal invasion into the myometrium vary. In one study, the incidence varied from 18.2% using 1-mm to 11.5% using 5-m cut-off and was lower if myometrial hyperplasia was a diagnostic requirement (Bergholt et al., 2001). Therefore, despite numerous studies, many important questions relevant to adult adenomyosis remain unanswered, mainly because of methodological factors and reliance on case studies of women undergoing hysterectomy together with incomplete correlation between clinical and pathological findings. Finally, it is likely that future studies that rely on examination of hysterectomy specimens as the diagnostic gold standard will become increasingly constrained because of the tendency for more conservative treatment options.

Table 1 Different definitions of adenomyosis.

Reference Depth from endometrial–myometrial junction
Novak and Woodruff, 1979 >1 high-power field.
Parazzini et al., 1997
Zaloudek and Hendrickson, 2002
>0.5 of low-power field about 2.5 mm.
Gompel and Silverberg, 1985 1 medium-power field (×100 lens)
Owolabi and Strickler, 1977 >low-power field.
Hendrickson and Kempson, 1980 >one-quarter of the total thickness of the uterine wall away from the deepest point of the apparently normal endometrial–myometrial intersection. They state that they are loath to make a diagnosis of adenomyosis in the premenopausal uterus unless there is associated smooth muscle hypertrophy.
Shaikh and Khan, 1990 Penetration of more than one-third to one-quarter of the total thickness of the uterine wall below the normal endometrial–myometrial junction.
Bergholt et al., 2001 Various analyses >1, > 3, or >5 mm, but recommended 3 mm as cut-off.
Levgur et al., 2000 Depth of 2.5 mm or more.
Adenomyosis and infertility

In their review, de Ziegler et al. (2010) concluded that, endometriosis and infertility are associated clinically and that medical and surgical treatments produce different effects. Available data indicate that surgery at any stage of endometriosis enhances the chances of natural conception. On the other hand, evidence of the role of conservative surgery in adenomyosis is limited (Kishi et al., 2014).

In spite of some therapeutic success, questions remain on the nature of the association between adenomyosis, endometriosis and infertility. Kunz et al. (2005) carried out MRI in women with (n = 160) and without (n = 67) endometriosis, taking into account age, disease stage and partner's sperm count. Adenomyosis was identified in 79% of cases with endometriosis, rising to 90% in the subgroup aged younger than 36 years who had a fertile partner compared with 19 out of 67 (28%) in the infertile group with no endometriosis. They concluded that adenomyosis causes infertility, presumably by impairing sperm transport. In the same cohort, an increased junctional zone thickness in women with endometriosis compared with controls was reported in all age groups (17–24, 25–29, 30–34, and >34), but was statistically significant only for the two older groups. With the use of MRI and hysterosalpingosonography, endometriosis and adenomyosis were linked to hyperperistaltic and dysperistaltic utero-tubal transport, but reduced fertility was linked to adenomyosis in women with patent tubes (Kissler et al., 2006). This study should be interpreted with caution, first because of the unusually high incidence of adenomyosis and the lack of clear diagnostic criteria. Second, and perhaps most importantly, because of the use of a controversial test for tubal function. Indeed, many of the images produced by HSSG may be artefacts (Habiba, 1994), and studies have shown inconsistency of radioactive-labelled particle transport (Lundberg et al, 1997, Lundberg et al, 1998, and Wånggren et al, 2011).

Tocci et al. (2008) argued that the distinct epidemiological features of junctional zone thickening as seen on MRI compared with histological adenomyosis indicate that the ‘subendometrial-myometrial unit disruption disease’ is distinct from adenomyosis. Whether junctional zone thickening is truly a distinct entity, or simply an early manifestation of adenomyosis, it is still not known; also unknown is whether it may have relevance for fertility. Epidemiological differences between those with and without the disease are constrained by method of diagnosis; in addition, the genesis of the MRI features of the junctional zone is still unclear (Mehasseb et al, 2011 and Zangos et al, 2004).

Similar to the case of endometriosis, the effect of adenomyosis on fertility has been assessed through examining its prevalence in infertility clinics or its effect on outcomes of assisted conception. Unfortunately, until recently, no convincing data on the pathogenesis of adenomyosis-related infertility had been obtained. In a recent review of the evidence, Campo et al. (2012) mentioned a series of pathogenetic hypotheses: The first was proposed by (Kunz et al, 2005) and (Kunz et al, 2007), who argued that disruption and thickening of the myometrial junctional zone can result in perturbed uterine peristalsis, which, in the non-pregnant uterus, originates exclusively from the juncitonal zone. The second hypothesis stresses that a number of biochemical and functional alterations have been identified in both eutopic and heterotopic endometrium in individuals with adenomyosis (Benagiano and Brosens, 2012); these may lead to lower receptivity, as suggested by the presence of ‘implantation marker’ defects. The final hypothesis proposes that the presence of an abnormal concentration of intrauterine free radicals (Igarashi et al., 2002) and of altered decidualization (Ota et al., 1999), is also suggestive of altered receptivity.

Campo et al. (2012) concluded that a negative effect on implantation was likely. Martínez-Conejero et al. (2011) evaluated the outcome of ovum donation in three groups: women with ultrasound-diagnosed adenomyosis (including cases with endometriosis); women with ovarian endometriosis, but no adenomyosis; and controls with no identified pathology. The investigators concluded that the implantation rates did not differ between the groups (Table 2). At the same time, a statistically significantly higher spontaneous abortion rate was observed in the group with adenomyosis. The investigators suggested a link between spontaneous abortion and junctional zone dysfunction. A higher spontaneous abortion rate was also reported by Chiang et al. (1999).

Table 2 Clinical pregnancy rates in women with adenomyosis.

Study Study group: women with: Intervention Number of women Number of cycles per woman Total number of cycles Clinical pregnancy n (%) Implantation rate (per embryos transferred) (%) Spontaneous abortions (%) Live birth rate or ongoing pregnancy (%)
Martínez-Conejero et al., 2011 Imaging-diagnosed adenomyosis Ovum donation IVF 152 >1 328 131/328 (39.9) 29.6 43/328 (13.1) 88/328 (26.8)
Ovarian endometriosis 144 242 107/242 (44.2) 33.3 15/242 (6.2) 92/242 (38.0)
Normal group 147 331 147/331 (44.4) 30.8 24/331 (7.3) 123/331 (37.2)
Chiang et al., 1999 Ultrasound-diagnosed adenomyosis IVF for primary infertility 19 Unknown Unknown 6/19 (31.6) Unknown 4/19 (21.1) 2/19 (10.5)
Controls 144 Unknown 38/144 (26.4) Unknown 8/144 (5.6) 30/144 (20.8)
Mijatovic et al., 2010 Endometriosis but no adenomyosis IVF or ICSI in women with endometriosis 54 1 Unknown 30/54 (55.6) 28.2 14/54 (25.9) 16/54(29.6)
Subgroup with endometriosis and ultrasound-diagnosed adenomyosis 20 Unknown 11/20 (55.0) 31 4/20 (20.0) 7/20 (35.0)
Thalluri and Tremellen, 2012 Ultrasound-diagnosed adenomyosis IVF 38 1 Unknown 12/38 (31.6) Unknown 3/38 (7.9) 9/38 (23.7)
Controls with no adenomyosis 175 Unknown 87/175 (49.7) Unknown 9/175 (5.1) 78/175 (44.6)
Maubon et al., 2010 Infertility and average junctional zone <7 mm IVF 113 >1 71/113 (62.8) Unknown Unknown Unknown
Infertility and average junctional zone >7 mm 39 Unknown 10/39 (25.6) Unknown Unknown Unknown
Costello et al., 2011 Ultrasound-diagnosed adenomyosis Women undergoing IVF and ICSI 37 1 31 13/31 (41.9) 15/53 (28.3) 2/13 (15.4) 11/37 (29.7)
No adenomyosis 164 139 60/139 (43.2) 65/206 (31.6) 16/59 (27.1) 42/161 (26.1)
Salim et al., 2012 Ultrasound-diagnosed adenomyosis Women undergoing IVF–ICSI cycles 19 1 18 4/18 (22.2) 6/32 (18.8) 2/18 (11.1) 2/18 (11.1)
Control group 256 229 108/229 (47.2) 123/419 (29.4) 3/229 (1.3) 105/229 (45.8)

ICSI = intracytoplasmic sperm injection.

On the other hand, implantation rate in adenomyosis was marginally lower compared with women with endometriosis, which is traditionally associated with impaired receptivity (Lessey, 2013). In addition, in individuals with adenomyosis, no differences were observed in genes relevant for implantation (Martínez-Conejero et al., 2011), but the latter study did not control for the various down-regulation protocols. Their term pregnancy rate (84% of clinical pregnancies) for the control group is remarkable, compared with 76% in the group with adenomyosis (Martínez-Conejero et al, 2011 and Vila-Vives et al, 2012). In conclusion, at present it cannot be ruled out that defects in implantation or in mechanisms relevant to embryo selection may play a role (Koot et al, 2012 and Salker et al, 2012).

Mijatovic et al. (2010) reported no significant differences for any IVF or intracytoplasmic sperm injection cycle (ICSI) outcome between women with and without adenomyosis. They also reported IVF–ICSI outcomes of 74 women with endometriosis, including 90.4% with rASRM stage III-IV disease, and 27% with ultrasound diagnosed adenomyosis. All outcomes were comparable, and the implantation rates were similar in the presence or absence of adenomyosis. But gonadotrophin-releasing hormone agonist down-regulation may have modified the effect of adenomyosis. In contrast to this, another study involving women with ultrasound-diagnosed adenomyosis reported a statistically significant lower clinical pregnancy rate (Thalluri and Tremellen, 2012). The same group linked the outcomes to differences in stromal leukocyte population, but the effect of exogenous steroids was not considered (Tremellen and Russell, 2012). Maubon et al. (2010) reported higher implantation failure when the average junctional zone was greater than 7 mm. The proportion with junctional zone thickness greater than 7 was comparable in the group with endometriosis, male infertility, anovulation or tubal factor infertility, and lower compared with those with unexplained infertility. This is at variance with the high incidence of junctional zone thickening previously reported in endometriosis (Kissler et al., 2006).

No differences were found in live birth rates between women with or without adenomyosis diagnosed by transvaginal ultrasound among women undergoing IVF–ICSI who received gonadotrophin-releasing hormone down-regulation (Costello et al., 2011). In another report, the clinical and ongoing pregnancy rates were lower in adenomyosis compared with controls (Salim et al., 2012). The review by Maheshwari et al. (2012) found few data on the epidemiology of adenomyosis associated with subfertility, as most studies have been uncontrolled, small retrospective case series involving heterogeneous patients and treatments. Thus convincing evidence is lacking to support treatments targeted to adenomyosis. A recent meta-analysis by Vercellini et al. (2014) concluded that adenomyosis has a negative effect on the outcome of IVF–ICSI, leading to reduced rates of clinical pregnancy and implantation and an increased risk of early pregnancy loss. Given this, screening for adenomyosis before starting assisted reproduction procedures is to be considered. Although there seems to be a protective effect of long down-regulation protocols, more data are required before a firm conclusion can be drawn. The controversy suggests that future research needs to adopt more robust methodology.

Adenomyosis and parity

Contrary to what happens with endometriosis, adenomyosis diagnosed at hysterectomy has traditionally been linked to multiparity (Vercellini et al, 1995 and Vercellini et al, 2006), pregnancy termination and uterine curettage, especially if this was carried out after pregnancy.

The notion of a link with parity is longstanding but not certain. Bird et al. (1972) reported that the average parity of women with adenomyosis was 3.2 compared with 2.5 for all hysterectomies, and that 89.5% of women with adenomyosis were parous. This was taken to support pre-existing reports linking adenomyosis and parity. Molitor (1971) identified adenomyosis in 281 uteri, 93.6% of whom were parous, and took this to indicate a link. In another study, adenomyosis was diagnosed in 5 out of 18 (27.8%), 150 out of 264 (56.8%), and 82 out of 137 (59.9%) in women with parity of 0, 1–4 and greater than 4, respectively (Shaikh and Khan, 1990). The difference between parous and nulliparous women was statistically significant. But 97.9% of the group were parous, and the possible interaction between age, parity and the indication for hysterectomy was not considered.

In a retrospective study, the incidence of adenomyosis in nulliparous women was not significantly different compared with women who had one or more children (Vercellini et al., 1995). In a prospective follow-up study, after adjusting for age, the odds ratio for adenomyosis in primiparous and multiparous women was 1.8 (95% CI 0.9 to 3.4), and 3.1 (95% CI 1.7 to 5.5) compared with nulliparous women (Parazzini et al., 1997). In the study by Vavilis et al. (1997), adenomyosis was identified in 116 out of 594 (19.5%) hysterectomy specimens, and was more common in parous (114/554 [20.6%]), compared with nulliparous (2/40 [5.0%]) women. The analysis provided, however, does not account for confounding factors, such as age and presenting symptoms. The lower incidence in older women has not been consistently demonstrated, but may be an indication that symptomatic adenomyosis leads to hysterectomy at younger age. In a retrospective study involving 549 women who underwent hysterectomy, endometrial hyperplasia was the only factor demonstrated to be significantly associated with adenomyosis and there was no association with age or parity (Bergholt et al., 2001).

Kunz et al. (2005) reported a statistically significantly higher gravidity and parity, but not age in women with adenomyosis compared with those without it. Templeman et al. (2008) reported a higher incidence of adenomyosis in parous (791/56502 [1.4%]) compared with nulligravid (116/16947 [0.68%]) women or to women with ‘previous, but non-term’ pregnancies (50/5015 [1.0%]). The low overall incidence is attributable to the reliance on histological diagnosis in 96% of cases. Although these figures may point to a link with parity, adenomyosis was not ruled out in the control group, and the interplay between symptoms, parity and the desire for children – an important driver influencing uptake of hysterectomy – was not considered. In the large retrospective study by Panganamamula et al. (2004), comprising 873 complete records of hysterectomies, 412 patients (47.2%) had adenomyosis. These women had significantly higher gravidity (P < 0.001) and parity (P = 0.004) compared with women hysterectomised for other benign conditions. The analysis provided, however, does not account for confounding factors in relation to parity, such as age and presenting symptoms.

Adenomyosis during pregnancy

Few data are available on the epidemiology of adenomyosis in pregnancy, although pregnancies are not rare after spontaneous or assisted conception (Table 3). Sandberg and Cohn (1962) analysed 151 caesarean hysterectomies, and found adenomyosis in 17.8% of the specimens. Azziz (1989) published a comprehensive report of 72 pregnancies in women with adenomyosis; 14 cases where published before 1930 and therefore probably refer to ‘adenomyoma’, a term that encompasses both adenomyosis and endometriosis. Azziz (1989), however, states that he excluded cases where the distinction was not made. Seven ectopic pregnancies occurred; obstetric or surgical complications were described in 29 reports and uterine perforation or rupture in 11.

Table 3 Pregnancy complications in patients with adenomyosis.

Study Study group Intervention Outcome
Sandberg and Cohn, 1962 Caesarean hysterectomy specimens n = 151 Percentage with adenomyosis (17.8%).
Azziz, 1989 Review of previously published case reports Number with adenomyosis (n = 72) Reported complications: ectopic pregnancies (n = 7), obstetric or surgical complications (n = 29) uterine perforation or rupture (n = 11).
Kim et al., 2006 Case report Huge enlargement between 13 and 18 weeks gestation. Early pregnancy loss. Rapid growth of adenomyosis in early pregnancy.
Nikolaou et al., 2013 Case report Uterine rupture and intrauterine fetal death at 28 weeks' gestation in an unscarred uterus of a primigravida. Spontaneous uterine rupture.
Wang et al., 1998 Case report Emergency hysterectomy for severe postpartum haemorrhage 20 days after caesarean section. Delayed postpartum haemorrhage.
Ukita et al., 2011 Case report Uterine rupture at 29 weeks' gestation in a primigravida. Uterine rupture after adenomyomectomy.
Dim et al., 2009 Case report Uterine rupture identified after delivery in a primigravida. Uterine rupture after adenomyomectomy.
Wada et al., 2006 Case report Uterine rupture at 30 weeks' gestation in a twin pregnancy. Uterine rupture after adenomyomectomy.
Morimatsu et al., 2007 Case report Uterine rupture at 28 weeks' gestation after onset of labour. Uterine rupture after adenomyomectomy.
Juang et al., 2007 Case control study A: 104 with spontaneous preterm birth or preterm rupture of membranes
B: 208 control.
Incidence of adenomyosis: 15.4% in group A; 9.1% in group B.
Shitano et al., 2013 Case report Magnetic resonance imaging features during pregnancy in three cases with adenomyosis. Low signal intensity areas with embedded bright foci that expanded to a few millimetres in diameter.

Today, complications are rare, and may include rapid growth in pregnancy (Kim et al., 2006), spontaneous rupture of an unscarred uterus (Nikolaou et al., 2013) and delayed postpartum haemorrhage (Wang et al., 1998). Uterine rupture during pregnancy may occur after adeno-myomectomy (Ukita et al., 2011).

In a study involving 104 cases and 208 controls, Juang et al. (2007) evaluated the incidence of adenomyosis in women with spontaneous preterm delivery or preterm rupture of membranes. Adenomyosis was identified by ultrasound, MRI, or both, in 16 (15.4%) women who delivered before 37 weeks compared with 19 (9.1%) of those delivered at term. They reported a link between adenomyosis and preterm birth, but their study design cannot support such a conclusion. They identified adenomyosis in 19 women who delivered at term and in 16 women who had preterm delivery. Although the figures do not reach statistical significance, the odds ratio after adjusting for age, BMI, smoking and previous preterm delivery is reported as 1.96 (95% CI 1.23 to 4.47).

Recently, Shitano et al. (2013) reported on MRI features during pregnancy in three cases with adenomyosis. Low signal intensity areas with embedded bright few millimetre diameter intramyometrial foci were attributed to decidualization.

This raises the question about what advice could be given to pregnant women with adenomyosis. Given that most women with adenomyosis will have uneventful pregnancies, and that the effect of the disease on the course of pregnancy is unclear, together with the lack of specific interventions, it may be best that available information be given to pregnant women in a way that would avoid raising unnecessary anxiety.

Post-menopausal adenomyosis

The presence of adenomyosis in post-menopausal women is well documented. At autopsy, Lewinski (1931) reported adenomyosis in 26 out of 49 women over 50 years of age and in three out of five cases over 70 years of age. In the study by Dreyfuss (1940), 13 women out of a total of 152 (8.6%) with adenomyosis were over 50 years of age. Dreyfuss (1940) made an important observation: ‘the adenomyotic structures were of the resting type in women who were not menstruating any more’. A total of 55 out of 119 (46.2%) postmenopausal women were included in the study by Reinhold et al. (1996) and 23% in the study by Kepkep et al. (2007). In a study of 1334 consecutive women undergoing hysterectomy, adenomyosis was diagnosed in 332 (24.9%) of all cases and in 132 (24.3%) of the postmenopausal cohort (n = 544) (Vercellini et al., 1995). In the California Teachers Study (Templeman et al., 2008), adenomyosis was linked to the pre- or peri-menopause, and to the use of postmenopausal hormone replacement therapy. Contrary to the case in premenopausal women, overweight or obesity was not associated with increased risk of adenomyosis in the postmenopause, but case selection may have influenced the conclusions of this study.

Vavilis et al. (1997) identified adenomyosis in 116 out of 594 (19.5%) hysterectomy uterine specimens. These comprised 61 out of 295 (20.7%) women younger than 50 years of age; 39 out of 136 (28.7%) women aged 50–59 years; and in 16 out of 163 (9.8%) women aged 60 years or over. The difference between the latter group and the other two was statistically significant. Postmenopausal adenomyosis was an incidental finding in most reported cases. Lister et al. (1988) described a case of post-menopausal adenomyosis with an apparent thickening of the endometrium mimicking a carcinoma. Davies and Oram (1994) described a case of one women who had a flare-up of symptoms and elevated CA125 in response to post-menopausal tibolone hormone replacement therapy. In a retrospective study of 137 perimenopausal women who had undergone hysterectomies, symptoms were similar in those with (48%) and without adenomyosis. The investigators concluded that adenomyosis is a physiological variant (Weiss et al., 2009). This relatively small study, however, did not involve asymptomatic controls or unified diagnostic criteria. Özkan et al. (2012) compared women who underwent hysterectomy for non-malignant indications. Those who had surgery because of fibroids (n = 98) were compared with those with adenomyosis (n = 106); overall, 41% were postmenopausal. Women with adenomyosis were statistically significantly older and of higher parity; although the presenting symptoms of the group are provided separately and these show little difference between the two groups, the data suggest that, in a sizable proportion, adenomyosis was an incidental finding. In a case-control blinded comparison, Mehasseb et al. (2011) reported higher cell density, total nuclear area and muscle mass, but not nuclear size in the inner compared with the outer-myometrium in uteri with and without adenomyosis, but the difference between adenomyosis and controls was not statistically significant in postmenopausal uteri.

Tamoxifen use has been linked to postmenopausal adenomyosis and to an endometrioma in one case report (Le Bouëdec et al., 1991), and to adenomyosis and an adenomyomatous endometrial polyp in another (Ugwumadu et al., 1993); in a study (n = 8) of endometrial pathology during tamoxifen therapy, one had adenomyosis (Krause and Gerber, 1994). Cohen et al. (1995) reported adenomyosis in eight (57.1%) out of 14 women who had a hysterectomy while receiving tamoxifen. Seven had small microscopic foci, and one case was a large fundal adenomyotic lump. Cohen et al. (1997) reported adenomyosis in 15 (54%) women with breast cancer receiving tamoxifen compared with only two out of 11 women not receiving tamoxifen, pointing to an association. A comparative histopathologic evaluation concluded that in tamoxifen-associated cases, a cystic dilatation of glands, fibrosis of the stroma and various epithelial metaplasias were more often found, indicating a higher proliferation (McCluggage et al., 2000). Tamoxifen also induces distinct MRI patterns in the postmenopausal uterus. Most have heterogeneous endometrial signal intensity on T2-weighted images (mean 1.8 cm), with enhanced endometrial–myometrial interface, coexisting sub-endometrial cysts, nabothian cysts, leiomyoma, and adenomyosis (Ascher et al., 1996). It is unclear whether adenomyosis can develop de novo in the post-menopause.


Today, the idea that adenomyosis and endometriosis share, not only common features, but also a common origin, is gaining momentum (Benagiano, Brosens, 2011 and Brosens et al, 2012). Use of a life-cycle approach, however, has manifested a number of important differences. Indeed, the evidence gathered here indicates that, contrary to what happens with endometriosis, adenomyosis is a disease of the adult woman. Whereas endometriosis can manifest itself in young adolescents and even before menarche (Brosens et al., 2013a) and can progress rapidly (Brosens et al., 2013b), the rare juvenile cases are characterised by a localized cyst, rather than the presence of classic features (Brosens et al., 2014).

Available evidence points to the fact that when the presence of adenomyosis is observed in the post-menopause, the disease had started earlier, during the woman's fertile age. The finding of adenomyosis in women taking tamoxifen is interesting: on the one hand, it is not clear whether the phenomenon is a result of reactivation of pre-existing disease or de-novo development. On the other hand, observed cases point to the possibility of a flaring-up of a silent condition under the influence of tamoxifen with its well-known oestrogenic effect on the endometrium.

What is apparent from this review it that considerable uncertainties remain about the disease, including its clinical presentations and its impact. Research into adenomyosis has been hampered by the many methodological challenges posed by the inability, until recently, to diagnose the condition through non-invasive means and because much of the research has relied on retrospective reviews with little attempt to correlate clinical presentation with gross or macroscopic features. Except in women treated with hormone replacement therapy, adenomyosis becomes silent in most cases past the menopause.


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Giuseppe Benagiano has been Professor at ‘la Sapienza’, University, Rome, since 1980 and directed the First Institute of Obstetrics and Gynaecology and the Postgraduate School of Gynaecology and Obstetrics. Between 1993 and 1997, he acted as Director of the Special Programme of Research in Human Reproduction of the World Health Organization, and between 1997 and 2001 as Director General of the Italian National Institute of Health. Between 1997 and 2003 he was Secretary General of the International Federation of Gynaecology and Obstetrics. His postgraduate training was at Karolinska Institute, Stockholm and at Population Council, Rockefeller University, New York.


a Department of Gynaecology, Obstetrics and Urology, Sapienza University, 00161 Rome, Italy

b Leuven and Leuven Institute for Fertility and Embryology, Catholic University, 3000 Leuven, Belgium

c Reproductive Sciences Section, University of Leicester, University Hospitals of Leicester, Leicester LE2 7LX, UK

* Corresponding author.