Adenomyosis: a life-cycle approach

REVIEW

Adenomyosis: a life-cycle approach

Giuseppe Benagiano a, Ivo Brosens b,*, Marwan Habiba c

a Department of Gynaecology, Obstetrics and Urology, Sapienza University, 00161 Rome, Italy; b Leuven and LeuvenInstitute 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. E-mail address: [email protected] (I Brosens).

Giuseppe Benagiano has been Professor at ‘la Sapienza’, University, Rome, since 1980 and directed the FirstInstitute of Obstetrics and Gynaecology and the Postgraduate School of Gynaecology and Obstetrics. Between1993 and 1997, he acted as Director of the Special Programme of Research in Human Reproduction of the WorldHealth 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 Obstet-rics. His postgraduate training was at Karolinska Institute, Stockholm and at Population Council, RockefellerUniversity, New York.

Abstract The life-cycle approach to endometriosis highlighted unexpected features of the condition; the same approach was there-fore applied to gain insight into the clinical features of adenomyosis and to draw a comparison with endometriosis. This is possibletoday thanks to new imaging techniques enabling non-invasive diagnosis of adenomyosis. The specificity and sensitivity of magneticresonance imaging and transvaginal ultrasound remain uncertain. Unlike endometriosis, little information is available on the pres-ence of classic adenomyosis in adolescents, except for rare cystic forms that may not represent the true disease. Adenomyosis ismost likely to affect adult women, although most reported incidences are still based on post-hysterectomy studies, and are af-fected by diligence in histopathologic diagnosis and the adopted cut-off point. The traditionally accepted associations of adult ad-enomyosis, such as multiparity, a link to infertility and its effect on pregnancy are uncertain. Active adenomyosis has been found inpre- and peri-menopausal women and in postmenopausal women receiving tamoxifen. In conclusion, major diagnostic limitationsand the systematic bias of hysterectomy make it difficult to draw firm conclusions from existing evidence. In addition, no informa-tion is available on the natural history of adenomyosis and no study has systematically evaluated its existence in adolescents.© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: adenomyosis, adolescent, adult, post-menopausal, pregnancy

Introduction

Descriptions of ‘mucosal invasions’ of the peritoneal surfaceand organs were first published in the last part of the 19th

century. With the exception of ovarian endometriosis, thesestructures were all considered to be adenomyomas (Benagiano

et al., 2014a). In the 1920s, two separate conditions were iden-tified: endometriosis and adenomyosis, with differentclinical profiles (Frankl, 1925; Sampson, 1925a, 1925b, 1927).

More recently, however, similarities between the two pa-thologies have led to a re-evaluation of the situation and toa theory that they may have a common origin (Benagiano and

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Brosens, 2011; Brosens et al., 2013a). In particular, evi-dence shows that endometriosis and adenomyosis have incommon an endometrial dysfunction involving both eutopicand heterotopic endometrium (Benagiano et al., 2014b). Al-though anomalies are not identical, they share the commonfeature of leading to increased invasiveness. In both condi-tions, there is also a reaction of the inner myometrium that,althoughmore pronounced in the case of adenomyosis, is none-theless also present in endometriosis (Kunz et al., 2000).

Research on endometriosis has progressed rapidly owingto the introduction in the late 1960s and 1970s of endo-scopic techniques; however, the study of adenomyosis con-tinued to be limited to the evaluation of surgical specimen(i.e. to symptomatic disease requiring hysterectomy). For-tunately, over the past 2 decades, the availability of new di-agnostic modalities, such as magnetic resonance imaging (MRI)and high resolution three-dimensional transvaginal ultra-sound (3D-TVU), made it possible to study adenomyosis inwomen not requiring, or who cannot have, a hysterectomyand therefore to begin to reconstruct its natural history. Inparticular, the identification and evaluation of the inner myo-metrium or myometrial junctional zone by Hricak et al. (1983)provided new, non-invasive diagnostic criteria for adenomyo-sis (Luciano et al., 2013; Reinhold et al., 1996). This sig-nalled the beginning of a new era, where comparativeevaluation of the features of adenomyosis and endometrio-sis could be made, including both early and advanced stages.Also, the presence and frequency of the two conditions duringthe various stages of a woman’s life can now be studied.

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

Although we have recently reviewed the pathophysiol-ogy of uterine adenomyosis (Benagiano et al., 2012), wewanted to assess whether further insight into its pathogen-esis can be gained through understanding the disease in womennot undergoing hysterectomy and by comparing features indifferent stages of life. This can now be done by applying thenew, early, non-invasive diagnostic criteria for adenomyo-sis (Champaneria et al., 2010; Dueholm, 2006; Meredith et al.,2009; Novellas et al., 2011; Tamai et al., 2006).

Materials and methods

In order to identify features of adenomyosis at different stagesof a woman’s life, and attempt a comparison between ad-enomyosis and endometriosis, areas in which differences andsimilarities had already been evaluated were selected(e.g. incidence, imaging diagnosis, infertility, parity andpregnancy).

Critical evaluation and comparison was only possible foradult women. Therefore, for this group of patients, wesearched for all articles published over the past 20 years onadenomyosis using Scopus and PubMed searches. The cut-off point for our search was March 2014. For adenomyosis, 143articles were identified on histopathologic features and in-cidence, 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 studiesreporting findings in relation to age groups or a comparisonwith adenomyosis. Because of the variation in diagnosticcriteria and in research methods, these studies do not lendthemselves to meta-analysis and, although existing recentmeta-analyses were used, a critical narrative review of pub-lished literature was opted for.

Given the paucity of data, all articles dealing with youngor menopausal women were summarized, including earlystudies. All articles on adult women dealing with the above-mentioned topics were systematically identified, and rel-evant articles selected.

Imaging diagnosis

The specificity of apreoperativediagnosis of adenomyosis basedon clinical findings is poor (Bird et al., 1972), ranging from2–26% (Azziz, 1989; Molitor, 1971; Sammour et al., 2002).Meredith et al. (2009) analysed data from 14 selected pub-lished hysterectomy studies and found that adenomyosis wasmore common in women with heavy bleeding (31.9%), com-pared with all other hysterectomies (25.9%). The probabilityof adenomyosis in a woman with heavy bleeding and positiveultrasound features was 68.1%, compared with 65.1% prob-ability in a womanwith positive ultrasound if undergoing hys-terectomy for any symptom. The investigators reported thatthe value of transvaginal ultrasound is weakened by the lackof uniform histopathologic and ultrasound criteria. There-fore, before a life-cycle approach can be applied to the naturalhistory of adenomyosis, it is necessary to critically evaluatethe accuracy of the new non-invasive diagnostic procedures.

In a systematic review and meta-analysis of the diagnos-tic accuracy of transvaginal ultrasound and MRI compared withhistological standards (Champaneria et al., 2010), only threestudies using MRI (Bazot et al., 2001; Dueholm et al., 2001;Reinhold et al., 1996) and six comparing transvaginal ultra-sound (Bazot et al., 2001, 2002; Dueholm et al., 2001; Kepkepet al., 2007; Reinhold et al., 1996; Vercellini et al., 1998),fulfilled quality criteria. Agreement was reached on three ofthe transvaginal ultrasound diagnostic features: the pres-ence of myometrial cysts, a heterogeneous myometrium andfocal abnormal echo-texture (Figures 1 and 2). All studiesexcept Dueholm et al. (2001) and Reinhold et al. (1996) in-cluded the presence of globular or asymmetrical uterus. Twostudies (Bazot et al., 2002; Kepkep et al., 2007) empha-sized the diagnostic value of sub-endometrial linear stria-tions; only one study used colour Doppler (Bazot et al., 2002).The study by Bazot et al. (2002) reported on the diagnosticvalue of individual features examined, but some features hada higher sensitivity than the overall assessment, which appearscontradictory. The reported sensitivity, specificity, positiveand negative predictive value for transvaginal ultrasound inthe study by Kepkep et al. (2007) are the same as those re-ported for the sonographic feature of ‘heterogeneous myo-metrium’. Thus, the relative weight of individual featuresremains unclear. Sonography concurred with histopathologyin assessing the depth of invasion in only 57% cases and in as-sessing the degree of involvement and lesion density in only23% (Bazot et al., 2001). Reinhold et al. (1996) on the otherhand, reported good agreement between transvaginal

221Adenomyosis: a life-cycle approach

ultrasound and histology in depicting adenomyosis location(κ = 0.69) and maximum depth of involvement (κ = 0.81).

In the review by Champaneria et al. (2010) referred toabove, the pooled sensitivity, specificity, positive likeli-hood ratio and negative likelihood ratio for transvaginal ul-trasound 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 0.1to 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 existbetween the studies included in this review, including dif-ferent cut-off points and differences in case ascertainmentand the number of sections examined. Some investigators havedescribed assessment of uterine weight, wall thickness, his-tological grade (depth), extent of disease or lesion density,but these were not analysed in the respective studies (Bazotet al., 2001, 2002; Kepkep et al., 2007).

In a prospective evaluation by Luciano et al. (2013) of theaccuracy of 3D-TVU, features linked to adenomyosis were

junctional zone (maximum 8 mm or over), myometrial asym-metry and hypo-echoic striations. When at least two of thesefeatures were present, 3D-TVU was 90% accurate (sensitiv-ity [92%], specificity [83%], positive predictive value [99%] andnegative predictive value [71%]). Naftalin et al. (2012) re-ported on the use of 3D-TVU in women who attended a generalgynaecology clinic. In this study, the prevalence of adeno-myosis was 20.9% (95% CI 18.5 to 23.6). Forty-five women sub-sequently underwent a hysterectomy. Once women withcancer or large fibroids were excluded, there was a fair levelof agreement between 3D-TVU and histological adenomyo-sis (κ = 0.62; P = 0.001); 95% CI 0.324 to 0.912).

In conclusion, although the difficulties involved in this kindof trial can be appreciated, the fact remains that, despitemuch promise, studies of the role of ultrasound and MRI indiagnosing adenomyosis suffer from methodological weak-nesses. This is primarily due to the lack of agreed diagnosticstandards.

Nonetheless, it is today possible to identify adenomyosisthrough a careful analysis of the endo-myometrial junc-tional zone, and therefore to identify the presence of unsus-pected 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) exam-ined 100 uteri from fetuses, newborn children and girls up tothe age of 14 years. He found that a mucosal invasion of themyometrium was seldom visible and concluded that ‘adeno-myoma’ was a disease of adult life. Emge (1962), referred tothe report by Meyer in 1897 of the identification of adeno-myosis in a fetus at term, and the reports by Albrecht, Erbslöh,Holden, Javert, and Philipp of the existence of adenomyosisin autopsies of children between the ages of 4 and 14 years(Meyer, 1897; Holden, 1931; Javert, 1951; Philipp, 1954;Albrecht, 1955; Erbslöh, 1955). Emge (1962) considered thisto support the existence of a type of ‘congenital adenomyo-sis’ present before cyclic ovarian activities. Emge (1962) alsocited cases of persistent primary dysmenorrhoea that werelater found to have adenomyosis and advocated ‘further searchof the evidence in premenarchial uteri obtainable at autop-sies’. It is a fact that early literature contains no reports ofadenomyosis in pubertal or teenage girls: Lewinski (1931) iden-tified one case at autopsy among five cases in women aged20–30 years, and Dreyfuss (1940) found three cases among 152hysterectomy specimens of women aged 21–30 years. EvenEmge (1962), in his work, indicated that he could not find anycase below 25 years of age (Figure 3).

Contrary to the case with endometriosis, and despite theavailability of non-invasive diagnostic tools, to this day in-formation on adenomyosis in adolescent girls remains limited.A recent review (Dieterich, 2010) found a heterogeneous groupof uterine pathology, including adenomyosis, adenomyoticcysts, focal adenomyosis and adenomyoma. Among youngwomen, the most common complaint was severe dysmenor-rhoea unresponsive to non-steroidal anti-inflammatory drugsor to combined oral contraceptives.

Cases of classic adenomyosis seem rare and even dubious:Itam et al. (2009) diagnosed adenomyosis using MRI in twoadolescents aged 16 years. In one case, a low signal area in

A

B

Figure 1 Ultrasound images of a uterus with adenomyosis. PanelA: grey scale image showing asymmetrically thickened poste-rior uterine wall with inhomogeneous, irregular myometrialechotexture with hyperechoic irregular myometrial areas and smallcystic anechoic areas; panel B: power Doppler image showing dif-fusely spread small vessels (white arrow). (Courtesy of Dr. CaterinaExacoustos, Rome).

222 G Benagiano et al.

the caudal aspect of the uterus was interpreted as focaladenomyosis. In the other, the diagnosis was based on a poorlydefined junctional zone.

A variant of adenomyosis that seems specific to youngwomen is the so-calledmyometrial cystic adenomyosis (Brosenset 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 cmin diameter with haemorrhagic content; histologically,these cysts are lined with an endometrial-like layer.

Characteristically, the smooth muscle cells surrounding thecyst show hyperplasia, macrophage infiltration andhaemosiderin pigmentation.

Another variant was described in two adolescents withsevere dysmenorrhoea and a normal uterine contour onultrasonography and MRI (Frontino et al., 2009); at hyster-oscopy, a single cervical canal was observed, but theuterine cavity resembled a unicornuate uterus with a left tubalostium. Laparoscopy demonstrated a right uterine nodule orrudimentary horn which contained a small cavity with endo-metrium, haematometra and adenomyotic foci.

The rarity of adolescent adenomyosis can also be in-ferred from the study by Lee et al. (2013) who comparedpatient characteristics and clinical associations in women withlaparoscopically confirmed endometrioma. The incidence ofmyomas or adenomyosis diagnosed at surgery or preopera-tive ultrasound in four age groups (20 years or younger, 21–30 years, 31–40 years and 41–45 years), was 0, 14%, 31% and47%, respectively. Similarly, the California Teachers Study(Templeman et al., 2008) found that, at the time of diagno-sis, 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 ad-enomyosis may have been substantially delayed as it was sur-gically based.

Interesting comparative results have been obtained by Kunzet al. (2007) who carried out an MRI evaluation of the uterusin 227 women with and without endometriosis, and relatedthe results to the age of the women and the subsequent ap-pearance of adenomyosis. They subdivided women into fourage-groups (17–24, 25–29, 30–34, and over 34 years), and

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

Num

ber

of y

ears

60

50

40

30

20

10

0

6

12

36

53

46

31

17

62 1

Age group (years)

25 30 35 40 45 50 55 60 65 70 75

Figure 3 Age distribution of 210 patients with adenomyosis athysterectomy. Adapted from Emge (1962).


found that an increased diameter of the dorsal junctional zoneof the uterus (a feature considered indicative of the inva-sion of basal endometrium into the junctional zone and there-fore of incipient adenomyosis), had already commenced earlyin the third decade. In women with endometriosis, this phe-nomenon progressed steadily, whereas, in those without en-dometriosis, there was almost no sign of adenomyosis up tothe age of 34 years. In both groups of women, however, amarked increase in the incidence of adenomyosis could be ob-served beyond the age of 34 years. This study identified threeimportant features: endometriosis usually becomes clini-cally evident at an age lower than that of adenomyosis; thealterations leading to adenomyosis may start early, but usuallybecome manifest only after the age of 30 years; and, in a fairnumber of cases, adenomyosis and endometriosis may coexist.

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

Adult adenomyosis

Classically, adenomyosis is defined by the presence of het-erotopic endometrial glands and stroma in the myome-trium. Relevant diagnostic features are the depth of stromaland glandular penetration and myometrial hypertrophy or hy-perplasia. Hendrickson and Kempson (1980) described myo-metrial changes as a collar of hypertrophic smooth musclearound adenomyotic foci, but no objective definition of myo-metrial hypertrophy and hyperplasia is availalbe. Clinically,adult women with adenomyosis show a number of differ-ences compared to women with endometriosis; here we willanalyse the most characteristic of such differences.

Histopathologic features and incidenceThe endometrial–myometrial interface or intersection doesnot have a submucosa, and endometrial–myometrial inter-face irregularity is almost universal (Seidman and Kjerulff,1996; Siegler and Camilien, 1994). Thus, in adult women, the

diagnosis relies on assessment of the degree of deviation ofmyometrial infiltration from that of mucosal irregularity inuteri considered to be normal. This leads to major varia-tions in estimating the incidence of adenomyosis, which, inone study, varied from 12–58% between hospitals and 10–88% between pathologists (Seidman and Kjerulff, 1996). Thevariation was attributed to differences in diagnostic criteriaand case ascertainment. In view of this, many pathologistshave argued for a conservative cut-off point to avoid over-diagnosis (Gompel and Silverberg, 1985; Vercellini et al., 1995).This approach remains arbitrary (Bird et al., 1972), and canoverlook early stages and the possible contribution of less ex-tensive disease to symptoms. The term ‘adenomyosis sub-basalis’ was introduced to denote lesions within one low powerfield (Bird et al., 1972; Sammour et al., 2002) or less than 1high power field (Vercellini et al., 1995) below the basal en-dometrium. This variety, however, may well be consideredan initial form of classic adenomyosis, as no data are avail-able on disease progression and even minimal-depth lesionshave been linked to symptoms (Bird et al., 1972; Owolabi andStrickler, 1977; Sammour et al., 2002).

Classically, incidence of adenomyosis has been calcu-lated in hysterectomy studies; therefore, the reported inci-dence 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) re-ported on 1807 surgically removed uteri, and found ‘adeno-myosis and endometriosis’ in 224 instances; in 152 cases (8.4%of the total), the lesion was localised within the myome-trium (therefore we should assume that these were cases ofadenomyosis). Three decades later, Bird et al. (1972) re-ported adenomyosis in 31% of 200 consecutive hysterecto-mies examined routinely; this rose to 38.5% when six additionalblocks were examined, and to 61.5% when sub-basal lesionswere included. It is still controversial whether the posteriorwall is the most affected (Sammour et al., 2002; Zaloudek andHendrickson, 2002). Adopted cut-off points of depth of glandand stromal invasion into the myometrium vary. In one study,the incidence varied from 18.2% using 1-mm to 11.5% using5-m cut-off and was lower if myometrial hyperplasia was adiagnostic requirement (Bergholt et al., 2001). Therefore,

Table 1 Different definitions of adenomyosis.

ReferenceDepth from endometrial–myometrial junction

Novak and Woodruff, 1979 >1 high-power field.Parazzini et al., 1997Zaloudek 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 tomake a diagnosis of adenomyosis in the premenopausal uterus unless there is associatedsmooth muscle hypertrophy.

Shaikh and Khan, 1990 Penetration of more than one-third to one-quarter of the total thickness of the uterine wallbelow 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.


despite numerous studies, many important questions rel-evant to adult adenomyosis remain unanswered, mainlybecause of methodological factors and reliance on case studiesof women undergoing hysterectomy together with incom-plete correlation between clinical and pathological find-ings. Finally, it is likely that future studies that rely onexamination of hysterectomy specimens as the diagnostic goldstandard will become increasingly constrained because of thetendency for more conservative treatment options.

Adenomyosis and infertilityIn their review, de Ziegler et al. (2010) concluded that, en-dometriosis and infertility are associated clinically and thatmedical and surgical treatments produce different effects.Available data indicate that surgery at any stage of endome-triosis enhances the chances of natural conception. On theother hand, evidence of the role of conservative surgery inadenomyosis is limited (Kishi et al., 2014).

In spite of some therapeutic success, questions remain onthe nature of the association between adenomyosis, endo-metriosis and infertility. Kunz et al. (2005) carried out MRIin women with (n = 160) and without (n = 67) endometrio-sis, taking into account age, disease stage and partner’s spermcount. Adenomyosis was identified in 79% of cases with en-dometriosis, rising to 90% in the subgroup aged younger than36 years who had a fertile partner compared with 19 out of67 (28%) in the infertile group with no endometriosis. Theyconcluded that adenomyosis causes infertility, presumably byimpairing sperm transport. In the same cohort, an increasedjunctional zone thickness in women with endometriosis com-pared with controls was reported in all age groups (17–24, 25–29, 30–34, and >34), but was statistically significantonly for the two older groups. With the use of MRI andhysterosalpingosonography, endometriosis and adenomyosiswere linked to hyperperistaltic and dysperistaltic utero-tubal transport, but reduced fertility was linked to adeno-myosis in women with patent tubes (Kissler et al., 2006). Thisstudy should be interpreted with caution, first because of theunusually high incidence of adenomyosis and the lack of cleardiagnostic criteria. Second, and perhaps most importantly,because of the use of a controversial test for tubal func-tion. Indeed, many of the images produced by HSSG may beartefacts (Habiba, 1994), and studies have shown inconsis-tency of radioactive-labelled particle transport (Lundberget al., 1997, 1998; Wånggren et al., 2011).

Tocci et al. (2008) argued that the distinct epidemiologi-cal features of junctional zone thickening as seen on MRI com-pared with histological adenomyosis indicate that the‘subendometrial-myometrial unit disruption disease’ is dis-tinct from adenomyosis. Whether junctional zone thicken-ing is truly a distinct entity, or simply an early manifestationof adenomyosis, it is still not known; also unknown is whetherit may have relevance for fertility. Epidemiological differ-ences between those with and without the disease are con-strained by method of diagnosis; in addition, the genesis ofthe MRI features of the junctional zone is still unclear(Mehasseb et al., 2011; Zangos et al., 2004).

Similar to the case of endometriosis, the effect of adeno-myosis on fertility has been assessed through examining itsprevalence in infertility clinics or its effect on outcomes ofassisted conception. Unfortunately, until recently, no con-vincing data on the pathogenesis of adenomyosis-related

infertility had been obtained. In a recent review of the evi-dence, Campo et al. (2012) mentioned a series of pathoge-netic hypotheses: The first was proposed by Kunz et al. (2005,2007), who argued that disruption and thickening of the myo-metrial junctional zone can result in perturbed uterine peri-stalsis, which, in the non-pregnant uterus, originatesexclusively from the juncitonal zone. The second hypoth-esis stresses that a number of biochemical and functional al-terations have been identified in both eutopic and heterotopicendometrium in individuals with adenomyosis (Benagiano andBrosens, 2012); these may lead to lower receptivity, as sug-gested by the presence of ‘implantation marker’ defects. Thefinal hypothesis proposes that the presence of an abnormalconcentration of intrauterine free radicals (Igarashi et al.,2002) and of altered decidualization (Ota et al., 1999), is alsosuggestive of altered receptivity.

Campo et al. (2012) concluded that a negative effect onimplantation was likely. Martínez-Conejero et al. (2011) evalu-ated the outcome of ovum donation in three groups: womenwith ultrasound-diagnosed adenomyosis (including cases withendometriosis); women with ovarian endometriosis, but noadenomyosis; and controls with no identified pathology. Theinvestigators concluded that the implantation rates did notdiffer between the groups (Table 2). At the same time, a sta-tistically significantly higher spontaneous abortion rate wasobserved in the group with adenomyosis. The investigatorssuggested a link between spontaneous abortion and junc-tional zone dysfunction. A higher spontaneous abortion ratewas also reported by Chiang et al. (1999).

On the other hand, implantation rate in adenomyosis wasmarginally lower compared with women with endometrio-sis, which is traditionally associated with impaired receptiv-ity (Lessey, 2013). In addition, in individuals with adenomyosis,no differences were observed in genes relevant for implan-tation (Martínez-Conejero et al., 2011), but the latter studydid not control for the various down-regulation protocols. Theirterm pregnancy rate (84% of clinical pregnancies) for thecontrol group is remarkable, compared with 76% in the groupwith adenomyosis (Martínez-Conejero et al., 2011; Vila-Viveset al., 2012). In conclusion, at present it cannot be ruled outthat defects in implantation or in mechanisms relevant toembryo selection may play a role (Koot et al., 2012; Salkeret al., 2012).

Mijatovic et al. (2010) reported no significant differ-ences for any IVF or intracytoplasmic sperm injection cycle(ICSI) outcome between women with and without adenomyo-sis. They also reported IVF–ICSI outcomes of 74 women withendometriosis, including 90.4% with rASRM stage III-IV disease,and 27% with ultrasound diagnosed adenomyosis. All out-comes were comparable, and the implantation rates weresimilar in the presence or absence of adenomyosis. Butgonadotrophin-releasing hormone agonist down-regulation mayhave modified the effect of adenomyosis. In contrast to this,another study involving women with ultrasound-diagnosed ad-enomyosis reported a statistically significant lower clinicalpregnancy rate (Thalluri and Tremellen, 2012). The same grouplinked the outcomes to differences in stromal leukocyte popu-lation, but the effect of exogenous steroids was not consid-ered (Tremellen and Russell, 2012). Maubon et al. (2010)reported higher implantation failure when the average junc-tional zone was greater than 7 mm. The proportion with junc-tional zone thickness greater than 7 was comparable in the


Table 2 Clinical pregnancy rates in women with adenomyosis.

StudyStudy group:women with:

Intervention Numberof women

Numberof cyclesper woman

Totalnumberof cycles

Clinicalpregnancyn (%)

Implantationrate (perembryostransferred) (%)

Spontaneousabortions (%)

Live birthrate orongoingpregnancy (%)

Martínez-Conejeroet al., 2011

Imaging-diagnosedadenomyosis

OvumdonationIVF

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)

Chianget al., 1999

Ultrasound-diagnosedadenomyosis

IVF forprimaryinfertility

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., 2010Endometriosis but noadenomyosis

IVF orICSI inwomenwithendometriosis

54 1 Unknown 30/54 (55.6) 28.2 14/54 (25.9) 16/54(29.6)

Subgroup with endometriosisand ultrasound-diagnosedadenomyosis

20 Unknown 11/20 (55.0) 31 4/20 (20.0) 7/20 (35.0)

Thalluri andTremellen,2012


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., 2010Infertility and averagejunctional zone <7 mm

IVF 113 >1 71/113 (62.8) Unknown Unknown Unknown

Infertility and averagejunctional zone >7 mm

39 Unknown 10/39 (25.6) Unknown Unknown Unknown

Costelloet al., 2011


WomenundergoingIVF andICSI

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


WomenundergoingIVF–ICSIcycles

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.

226GBenagiano

etal.

group with endometriosis, male infertility, anovulation or tubalfactor infertility, and lower compared with those with un-explained infertility. This is at variance with the high inci-dence of junctional zone thickening previously reported inendometriosis (Kissler et al., 2006).

No differences were found in live birth rates betweenwomen with or without adenomyosis diagnosed by transvagi-nal ultrasound among women undergoing IVF–ICSI who re-ceived gonadotrophin-releasing hormone down-regulation(Costello et al., 2011). In another report, the clinical andongoing pregnancy rates were lower in adenomyosis com-pared with controls (Salim et al., 2012). The review byMaheshwari et al. (2012) found few data on the epidemiol-ogy of adenomyosis associated with subfertility, as most studieshave been uncontrolled, small retrospective case series in-volving heterogeneous patients and treatments. Thus con-vincing evidence is lacking to support treatments targeted toadenomyosis. A recent meta-analysis by Vercellini et al. (2014)concluded that adenomyosis has a negative effect on theoutcome of IVF–ICSI, leading to reduced rates of clinical preg-nancy and implantation and an increased risk of early preg-nancy loss. Given this, screening for adenomyosis beforestarting assisted reproduction procedures is to be consid-ered. Although there seems to be a protective effect of longdown-regulation protocols, more data are required before afirm conclusion can be drawn. The controversy suggests thatfuture research needs to adopt more robust methodology.

Adenomyosis and parityContrary to what happens with endometriosis, adenomyosisdiagnosed at hysterectomy has traditionally been linked tomultiparity (Vercellini et al., 1995, 2006), pregnancy termi-nation and uterine curettage, especially if this was carriedout after pregnancy.

The notion of a link with parity is longstanding but notcertain. Bird et al. (1972) reported that the average parityof women with adenomyosis was 3.2 compared with 2.5 forall hysterectomies, and that 89.5% of women with adeno-myosis were parous. This was taken to support pre-existingreports linking adenomyosis and parity. Molitor (1971) iden-tified adenomyosis in 281 uteri, 93.6% of whom were parous,and took this to indicate a link. In another study, adenomyo-sis 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 andgreater than 4, respectively (Shaikh and Khan, 1990). The dif-ference between parous and nulliparous women was statis-tically significant. But 97.9% of the group were parous, andthe possible interaction between age, parity and the indica-tion for hysterectomy was not considered.

In a retrospective study, the incidence of adenomyosis innulliparous women was not significantly different comparedwith women who had one or more children (Vercellini et al.,1995). In a prospective follow-up study, after adjusting forage, the odds ratio for adenomyosis in primiparous and mul-tiparous women was 1.8 (95% CI 0.9 to 3.4), and 3.1 (95% CI1.7 to 5.5) compared with nulliparous women (Parazzini et al.,1997). In the study by Vavilis et al. (1997), adenomyosis wasidentified in 116 out of 594 (19.5%) hysterectomy speci-mens, and was more common in parous (114/554 [20.6%]),compared with nulliparous (2/40 [5.0%]) women. The analy-sis provided, however, does not account for confoundingfactors, such as age and presenting symptoms. The lower

incidence in older women has not been consistently demon-strated, but may be an indication that symptomatic adeno-myosis leads to hysterectomy at younger age. In a retrospectivestudy involving 549 women who underwent hysterectomy, en-dometrial hyperplasia was the only factor demonstrated tobe significantly associated with adenomyosis and there wasno association with age or parity (Bergholt et al., 2001).

Kunz et al. (2005) reported a statistically significantly highergravidity and parity, but not age in women with adenomyo-sis 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’ pregnan-cies (50/5015 [1.0%]). The low overall incidence is attribut-able to the reliance on histological diagnosis in 96% of cases.Although these figures may point to a link with parity, ad-enomyosis was not ruled out in the control group, and the in-terplay between symptoms, parity and the desire for children– an important driver influencing uptake of hysterectomy –was not considered. In the large retrospective study byPanganamamula et al. (2004), comprising 873 complete recordsof hysterectomies, 412 patients (47.2%) had adenomyosis.These women had significantly higher gravidity (P < 0.001) andparity (P = 0.004) compared with women hysterectomised forother benign conditions. The analysis provided, however, doesnot account for confounding factors in relation to parity, suchas age and presenting symptoms.

Adenomyosis during pregnancyFew data are available on the epidemiology of adenomyosisin pregnancy, although pregnancies are not rare after spon-taneous or assisted conception (Table 3). Sandberg and Cohn(1962) analysed 151 caesarean hysterectomies, and found ad-enomyosis in 17.8% of the specimens. Azziz (1989) pub-lished a comprehensive report of 72 pregnancies in womenwith adenomyosis; 14 cases where published before 1930 andtherefore probably refer to ‘adenomyoma’, a term that en-compasses both adenomyosis and endometriosis. Azziz (1989),however, states that he excluded cases where the distinc-tion was not made. Seven ectopic pregnancies occurred; ob-stetric or surgical complications were described in 29 reportsand uterine perforation or rupture in 11.

Today, complications are rare, and may include rapidgrowth in pregnancy (Kim et al., 2006), spontaneous ruptureof an unscarred uterus (Nikolaou et al., 2013) and delayedpostpartum haemorrhage (Wang et al., 1998). Uterine ruptureduring pregnancy may occur after adeno-myomectomy (Ukitaet al., 2011).

In a study involving 104 cases and 208 controls, Juang et al.(2007) evaluated the incidence of adenomyosis in women withspontaneous preterm delivery or preterm rupture of mem-branes. Adenomyosis was identified by ultrasound, MRI, orboth, in 16 (15.4%) women who delivered before 37 weekscompared with 19 (9.1%) of those delivered at term. They re-ported a link between adenomyosis and preterm birth, buttheir study design cannot support such a conclusion. They iden-tified adenomyosis in 19 women who delivered at term andin 16 women who had preterm delivery. Although the figuresdo not reach statistical significance, the odds ratio after ad-justing for age, BMI, smoking and previous preterm deliveryis reported as 1.96 (95% CI 1.23 to 4.47).


Recently, Shitano et al. (2013) reported on MRI featuresduring pregnancy in three cases with adenomyosis. Low signalintensity areas with embedded bright few millimetre diam-eter intramyometrial foci were attributed to decidualization.

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

Post-menopausal adenomyosis

The presence of adenomyosis in post-menopausal women iswell documented. At autopsy, Lewinski (1931) reported ad-enomyosis in 26 out of 49 women over 50 years of age and inthree out of five cases over 70 years of age. In the study byDreyfuss (1940), 13 women out of a total of 152 (8.6%) withadenomyosis were over 50 years of age. Dreyfuss (1940) madean important observation: ‘the adenomyotic structures wereof the resting type in women who were not menstruating anymore’. A total of 55 out of 119 (46.2%) postmenopausal womenwere included in the study by Reinhold et al. (1996) and 23%in the study by Kepkep et al. (2007). In a study of 1334 con-secutive women undergoing hysterectomy, adenomyosis was

diagnosed in 332 (24.9%) of all cases and in 132 (24.3%) of thepostmenopausal cohort (n = 544) (Vercellini et al., 1995). Inthe California Teachers Study (Templeman et al., 2008), ad-enomyosis was linked to the pre- or peri-menopause, and tothe use of postmenopausal hormone replacement therapy.Contrary to the case in premenopausal women, overweightor obesity was not associated with increased risk of adeno-myosis in the postmenopause, but case selection may haveinfluenced the conclusions of this study.

Vavilis et al. (1997) identified adenomyosis in 116 out of594 (19.5%) hysterectomy uterine specimens. These com-prised 61 out of 295 (20.7%) women younger than 50 yearsof age; 39 out of 136 (28.7%) women aged 50–59 years; andin 16 out of 163 (9.8%) women aged 60 years or over. The dif-ference between the latter group and the other two was sta-tistically significant. Postmenopausal adenomyosis was anincidental finding in most reported cases. Lister et al. (1988)described a case of post-menopausal adenomyosis with an ap-parent thickening of the endometrium mimicking a carci-noma. Davies and Oram (1994) described a case of one womenwho had a flare-up of symptoms and elevated CA125 in re-sponse to post-menopausal tibolone hormone replacementtherapy. In a retrospective study of 137 perimenopausalwomen who had undergone hysterectomies, symptoms weresimilar in those with (48%) and without adenomyosis. The in-vestigators concluded that adenomyosis is a physiologicalvariant (Weiss et al., 2009). This relatively small study,

Table 3 Pregnancy complications in patients with adenomyosis.

StudyStudy group Intervention Outcome

Sandberg and Cohn, 1962 Caesareanhysterectomyspecimens

n = 151 Percentage with adenomyosis (17.8%).

Azziz, 1989 Review ofpreviouslypublishedcase reports

Number with adenomyosis (n = 72) Reported complications: ectopicpregnancies (n = 7), obstetric or surgicalcomplications (n = 29) uterineperforation or rupture (n = 11).

Kim et al., 2006 Case report Huge enlargement between 13 and 18 weeksgestation. Early pregnancy loss.

Rapid growth of adenomyosis in earlypregnancy.

Nikolaou et al., 2013 Case report Uterine rupture and intrauterine fetal deathat 28 weeks’ gestation in an unscarreduterus of a primigravida.

Spontaneous uterine rupture.

Wang et al., 1998 Case report Emergency hysterectomy for severepostpartum haemorrhage 20 days aftercaesarean section.

Delayed postpartum haemorrhage.

Ukita et al., 2011 Case report Uterine rupture at 29 weeks’ gestation in aprimigravida.

Uterine rupture afteradenomyomectomy.

Dim et al., 2009 Case report Uterine rupture identified after delivery in aprimigravida.


Wada et al., 2006 Case report Uterine rupture at 30 weeks’ gestation in atwin pregnancy.


Morimatsu et al., 2007 Case report Uterine rupture at 28 weeks’ gestation afteronset of labour.


Juang et al., 2007 Case controlstudy

A: 104 with spontaneous preterm birth orpreterm rupture of membranesB: 208 control.

Incidence of adenomyosis: 15.4% ingroup A; 9.1% in group B.

Shitano et al., 2013 Case report Magnetic resonance imaging features duringpregnancy in three cases with adenomyosis.

Low signal intensity areas withembedded bright foci that expanded to afew millimetres in diameter.


however, did not involve asymptomatic controls or unified di-agnostic criteria. Özkan et al. (2012) compared women whounderwent hysterectomy for non-malignant indications. Thosewho had surgery because of fibroids (n = 98) were comparedwith those with adenomyosis (n = 106); overall, 41% were post-menopausal. Women with adenomyosis were statistically sig-nificantly older and of higher parity; although the presentingsymptoms of the group are provided separately and these showlittle difference between the two groups, the data suggestthat, in a sizable proportion, adenomyosis was an incidentalfinding. In a case-control blinded comparison, Mehasseb et al.(2011) reported higher cell density, total nuclear area andmuscle mass, but not nuclear size in the inner compared withthe outer-myometrium in uteri with and without adenomyo-sis, but the difference between adenomyosis and controls wasnot statistically significant in postmenopausal uteri.

Tamoxifen use has been linked to postmenopausal adeno-myosis and to an endometrioma in one case report (Le Bouëdecet al., 1991), and to adenomyosis and an adenomyomatousendometrial polyp in another (Ugwumadu et al., 1993); in astudy (n = 8) of endometrial pathology during tamoxifentherapy, one had adenomyosis (Krause and Gerber, 1994).Cohen et al. (1995) reported adenomyosis in eight (57.1%) outof 14 women who had a hysterectomy while receivingtamoxifen. Seven had small microscopic foci, and one casewas a large fundal adenomyotic lump. Cohen et al. (1997) re-ported adenomyosis in 15 (54%) women with breast cancerreceiving tamoxifen compared with only two out of 11 womennot receiving tamoxifen, pointing to an association. A com-parative histopathologic evaluation concluded that intamoxifen-associated cases, a cystic dilatation of glands, fi-brosis of the stroma and various epithelial metaplasias weremore often found, indicating a higher proliferation(McCluggage et al., 2000). Tamoxifen also induces distinct MRIpatterns in the postmenopausal uterus. Most have heteroge-neous endometrial signal intensity on T2-weighted images(mean 1.8 cm), with enhanced endometrial–myometrialinterface, coexisting sub-endometrial cysts, nabothiancysts, leiomyoma, and adenomyosis (Ascher et al., 1996). Itis unclear whether adenomyosis can develop de novo in thepost-menopause.

Conclusions

Today, the idea that adenomyosis and endometriosis share,not only common features, but also a common origin, is gainingmomentum (Benagiano and Brosens, 2011; Brosens et al.,2012). Use of a life-cycle approach, however, has mani-fested a number of important differences. Indeed, the evi-dence gathered here indicates that, contrary to what happenswith endometriosis, adenomyosis is a disease of the adultwoman. Whereas endometriosis can manifest itself in youngadolescents and even before menarche (Brosens et al., 2013a)and can progress rapidly (Brosens et al., 2013b), the rare ju-venile cases are characterised by a localized cyst, rather thanthe presence of classic features (Brosens et al., 2014).

Available evidence points to the fact that when the pres-ence of adenomyosis is observed in the post-menopause, thedisease had started earlier, during the woman’s fertile age.The finding of adenomyosis in women taking tamoxifen isinteresting: on the one hand, it is not clear whether the

phenomenon is a result of reactivation of pre-existing diseaseor de-novo development. On the other hand, observed casespoint to the possibility of a flaring-up of a silent conditionunder the influence of tamoxifen with its well-known oes-trogenic effect on the endometrium.

What is apparent from this review it that considerable un-certainties remain about the disease, including its clinical pre-sentations and its impact. Research into adenomyosis has beenhampered by the many methodological challenges posed bythe inability, until recently, to diagnose the condition throughnon-invasive means and because much of the research hasrelied on retrospective reviews with little attempt to corre-late clinical presentation with gross or macroscopic fea-tures. Except in women treated with hormone replacementtherapy, adenomyosis becomes silent in most cases past themenopause.

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Declaration: The authors report no financial or commercial con-flicts of interest.

Received 17 July 2014; refereed 12 November 2014; accepted 12November 2014.














































































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Adenomyosis: a life-cycle approach