Adenomyosis: a life-cycle approach

Reproductive BioMedicine Online (2015) 30, 220–232
w w w. s c i e n c e d i r e c t . c o m
w w w. r b m o n l i n e . c o m
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 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.
E-mail address: ivo.brosens@med.kuleuven.be (I Brosens).
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.
Abstract 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.
© 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 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, 1925b, 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 and
http://dx.doi.org/10.1016/j.rbmo.2014.11.005
1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
Adenomyosis: a life-cycle approach
Brosens, 2011; 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; 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 lifecycle 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; Novak and 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; 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 cutoff 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
221
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 abovementioned 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; 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;
Reinhold et al., 1996) and six comparing transvaginal ultrasound (Bazot et al., 2001, 2002; Dueholm et al., 2001; Kepkep
et al., 2007; Reinhold et al., 1996; 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 (Figures 1 and 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; 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
222
A
B
G Benagiano et al.
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
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). (Courtesy of Dr. Caterina
Exacoustos, Rome).
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 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, 2002; Kepkep et al., 2007).
In a prospective evaluation by Luciano et al. (2013) of the
accuracy of 3D-TVU, features linked to adenomyosis were
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, 1897; Holden, 1931; Javert, 1951; Philipp, 1954;
Albrecht, 1955; Erbslöh, 1955). 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).
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
Adenomyosis: a life-cycle approach
223
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). (Courtesy of Dr. Caterina Exacoustos, Rome).
60
53
Number of years
50
46
40
36
31
30
20
17
12
10
6
6
2
0
25
30
35
40
45
50
55
60
65
1
70
75
Age group (years)
Figure 3 Age distribution of 210 patients with adenomyosis at
hysterectomy. Adapted from Emge (1962).
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 nonresponsive 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
224
G Benagiano et al.
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 and Kjerulff,
1996; Siegler and Camilien, 1994). Thus, in adult women, the
Table 1
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 overdiagnosis (Gompel and Silverberg, 1985; 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 subbasalis’ was introduced to denote lesions within one low power
field (Bird et al., 1972; 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 and
Strickler, 1977; 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; Zaloudek and
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,
Different definitions of adenomyosis.
Reference
Novak and Woodruff, 1979
Parazzini et al., 1997
Zaloudek and Hendrickson, 2002
Gompel and Silverberg, 1985
Owolabi and Strickler, 1977
Hendrickson and Kempson, 1980
Shaikh and Khan, 1990
Bergholt et al., 2001
Levgur et al., 2000
Depth from endometrial–myometrial junction
>1 high-power field.
>0.5 of low-power field about 2.5 mm.
1 medium-power field (×100 lens)
>low-power field.
>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.
Penetration of more than one-third to one-quarter of the total thickness of the uterine wall
below the normal endometrial–myometrial junction.
Various analyses >1, > 3, or >5 mm, but recommended 3 mm as cut-off.
Depth of 2.5 mm or more.
Adenomyosis: a life-cycle approach
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.
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 uterotubal 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, 1998; 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; 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
225
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,
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).
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; 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; 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
226
Table 2
Clinical pregnancy rates in women with adenomyosis.
Study
MartínezConejero
et al., 2011
Chiang
et al., 1999
Mijatovic
et al., 2010
Thalluri and
Tremellen,
2012
Maubon
et al., 2010
Costello
et al., 2011
Salim et al.,
2012
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 (%)
Imaging-diagnosed
adenomyosis
Ovarian endometriosis
Normal group
Ultrasound-diagnosed
adenomyosis
Controls
Endometriosis but no
adenomyosis
Subgroup with endometriosis
and ultrasound-diagnosed
adenomyosis
Ultrasound-diagnosed
adenomyosis
Controls with no adenomyosis
Infertility and average
junctional zone <7 mm
Infertility and average
junctional zone >7 mm
Ultrasound-diagnosed
adenomyosis
No adenomyosis
Ovum
donation
IVF
152
>1
328
131/328 (39.9)
29.6
43/328 (13.1)
88/328 (26.8)
Unknown
242
331
Unknown
107/242 (44.2)
147/331 (44.4)
6/19 (31.6)
33.3
30.8
Unknown
15/242 (6.2)
24/331 (7.3)
4/19 (21.1)
92/242 (38.0)
123/331 (37.2)
2/19 (10.5)
Unknown
Unknown
38/144 (26.4)
30/54 (55.6)
Unknown
28.2
8/144 (5.6)
14/54 (25.9)
30/144 (20.8)
16/54(29.6)
Unknown
11/20 (55.0)
31
4/20 (20.0)
7/20 (35.0)
Unknown
12/38 (31.6)
Unknown
3/38 (7.9)
9/38 (23.7)
Unknown
87/175 (49.7)
71/113 (62.8)
Unknown
Unknown
9/175 (5.1)
Unknown
78/175 (44.6)
Unknown
Unknown
10/39 (25.6)
Unknown
Unknown
Unknown
31
13/31 (41.9)
15/53 (28.3)
2/13 (15.4)
11/37 (29.7)
139
60/139 (43.2)
65/206 (31.6)
16/59 (27.1)
42/161 (26.1)
4/18 (22.2)
6/32 (18.8)
2/18 (11.1)
2/18 (11.1)
108/229 (47.2)
123/419 (29.4)
Ultrasound-diagnosed
adenomyosis
Control group
IVF
144
54
1
20
38
1
175
113
>1
39
Women
undergoing
IVF and
ICSI
Women
undergoing
IVF–ICSI
cycles
37
1
164
19
256
1
18
229
3/229 (1.3)
105/229 (45.8)
G Benagiano et al.
ICSI = intracytoplasmic sperm injection.
IVF for
primary
infertility
IVF or
ICSI in
women
with
endometriosis
IVF
144
147
19
Live birth
rate or
ongoing
pregnancy (%)
Adenomyosis: a life-cycle approach
227
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.
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 and parity
Contrary to what happens with endometriosis, adenomyosis
diagnosed at hysterectomy has traditionally been linked to
multiparity (Vercellini et al., 1995, 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
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.
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).
228
Table 3
G Benagiano et al.
Pregnancy complications in patients with adenomyosis.
Study group
Intervention
Outcome
n = 151
Percentage with adenomyosis (17.8%).
Number with adenomyosis (n = 72)
Kim et al., 2006
Caesarean
hysterectomy
specimens
Review of
previously
published
case reports
Case report
Nikolaou et al., 2013
Case report
Reported complications: ectopic
pregnancies (n = 7), obstetric or surgical
complications (n = 29) uterine
perforation or rupture (n = 11).
Rapid growth of adenomyosis in early
pregnancy.
Spontaneous uterine rupture.
Wang et al., 1998
Case report
Ukita et al., 2011
Case report
Dim et al., 2009
Case report
Wada et al., 2006
Case report
Morimatsu et al., 2007
Case report
Juang et al., 2007
Case control
study
Shitano et al., 2013
Case report
Study
Sandberg and Cohn, 1962
Azziz, 1989
Huge enlargement between 13 and 18 weeks
gestation. Early pregnancy loss.
Uterine rupture and intrauterine fetal death
at 28 weeks’ gestation in an unscarred
uterus of a primigravida.
Emergency hysterectomy for severe
postpartum haemorrhage 20 days after
caesarean section.
Uterine rupture at 29 weeks’ gestation in a
primigravida.
Uterine rupture identified after delivery in a
primigravida.
Uterine rupture at 30 weeks’ gestation in a
twin pregnancy.
Uterine rupture at 28 weeks’ gestation after
onset of labour.
A: 104 with spontaneous preterm birth or
preterm rupture of membranes
B: 208 control.
Magnetic resonance imaging features during
pregnancy in three cases with adenomyosis.
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
Delayed postpartum haemorrhage.
Uterine rupture after
adenomyomectomy.
Uterine rupture after
adenomyomectomy.
Uterine rupture after
adenomyomectomy.
Uterine rupture after
adenomyomectomy.
Incidence of adenomyosis: 15.4% in
group A; 9.1% in group B.
Low signal intensity areas with
embedded bright foci that expanded to a
few millimetres in diameter.
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,
Adenomyosis: a life-cycle approach
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.
Conclusions
Today, the idea that adenomyosis and endometriosis share,
not only common features, but also a common origin, is gaining
momentum (Benagiano and Brosens, 2011; 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
229
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.
References
Albrecht, H., 1955. Die Endometriose. In: Seitz, L., Amreich, A.L.
(Eds.), Biologie und Pathologie des Weibes. Urban and
Schwarzenberg, West Berlin. pp. 192–203.
Ascher, S.M., Johnson, J.C., Barnes, W.A., Bae, C.J., Patt, R.H.,
Zeman, R.K., 1996. MR imaging appearance of the uterus in postmenopausal women receiving tamoxifen therapy for breast cancer:
histopathologic correlation. Radiology 200, 105–110.
Azziz, R., 1989. Adenomyosis: current perspectives. Obstet. Gynecol.
Clin. North Am. 16, 221–235.
Bazot, M., Cortez, A., Darai, E., Rouger, J., Chopier, J., Antoine,
J.-M., Uzan, S., 2001. Ultrasonography compared with magnetic
resonance imaging for the diagnosis of adenomyosis: correlation
with histopathology. Hum. Reprod. 16, 2427–2433.
Bazot, M., Darai, E., Rouger, J., Detchev, R., Cortez, A., Uzan, S.,
2002. Limitations of transvaginal sonography for the diagnosis of
adenomyosis, with histopathological correlation. Ultrasound
Obstet. Gynecol. 20, 605–611.
Benagiano, G., Brosens, I., 2011. Adenomyosis and endometriosis have
a common origin. J. Obstet. Gynecol. India 133, 146–153.
Benagiano, G., Brosens, I., 2012. The endometrium in adenomyosis. Womens Health 8, 301–312.
Benagiano, G., Habiba, M., Brosens, I., 2012. The pathophysiology
of uterine adenomyosis: an update. Fertil. Steril. 98, 572–579.
Benagiano, G., Brosens, I., Lippi, D., 2014a. The history of endometriosis. Gynecol. Obstet. Invest. 78, 1–9.
Benagiano, G., Brosens, I., Habiba, M., 2014b. Structural and molecular features of the endomyometrium in endometriosis and adenomyosis. Hum. Reprod. Update 20, 386–402.
Bergholt, T., Eriksen, L., Berendt, N., Jacobsen, M., Hertz, J.B., 2001.
Prevalence and risk factors of adenomyosis at hysterectomy. Hum.
Reprod. 16, 2418–2421.
Bird, C.C., McElin, T.W., Manalo-Estrella, P., 1972. The elusive adenomyosis of the uterus-revisited. Am. J. Obstet. Gynecol. 112,
583–593.
Brosens, I., Kunz, G., Benagiano, G., 2012. Is adenomyosis the neglected phenotype of an endomyometrial dysfunction syndrome? Gynecol. Surg. 9, 131–137.
Brosens, I., Puttemans, P., Benagiano, G., 2013a. Endometriosis: a
life cycle approach? Am. J. Obstet. Gynecol. 209, 307–316.
Brosens, I., Gordts, S., Benagiano, G., 2013b. Endometriosis in
adolescents is a hidden, progressive and severe disease that
deserves attention, not just compassion. Hum. Reprod. 28, 2026–
2031.
Brosens, I., Gordts, S., Habiba, M., Benagiano, G., 2014. Myometrial cystic adenomyosis: a young people disorder. J. Pediatr.
Adolesc. Gynecol. In press.
230
Campo, S., Campo, V., Benagiano, G., 2012. Adenomyosis and infertility. Reprod. Biomed. Online 24, 35–46.
Champaneria, R., Abedin, P., Daniels, J., Balogun, M., Khan, K.S.,
2010. Ultrasound scan and magnetic resonance imaging for the
diagnosis of adenomyosis: systematic review comparing test accuracy. Acta Obstet. Gynecol. Scand. 89, 1374–1384.
Chiang, C.H., Chang, M.Y., Shiau, C.S., Hou, H.C., Hsieh, T.T., Soong,
Y.K., 1999. Effect of a sonographically diffusely enlarged uterus
without distinct uterine masses on the outcome of in vitro
fertilization-embryo transfer. J. Assist. Reprod. Genet. 16, 369–
372.
Cohen, I., Beyth, Y., Tepper, R., Figer, A., Shapira, J., Cordoba, M.,
Yigael, D., Altaras, M.M., 1995. Adenomyosis in postmenopausal
breast cancer patients treated with tamoxifen: a new entity?
Gynecol. Oncol. 58, 86–91.
Cohen, I., Beyth, Y., Shapira, J., Tepper, R., Fishman, A., Cordoba,
M., Bernheim, J., Yigael, D., Altaras, M.M., 1997. High frequency of adenomyosis in postmenopausal breast cancer patients treated with tamoxifen. Gynecol. Obstet. Invest. 44, 200–
205.
Costello, M.F., Lindsay, K., McNally, G., 2011. The effect of adenomyosis on in vitro fertilisation and intra-cytoplasmic sperm injection treatment outcome. Eur. J. Obstet. Gynecol. Reprod. Biol.
158, 229–234.
de Ziegler, D., Borghese, B., Chapron, C., 2010. Endometriosis and
infertility: pathophysiology and management. Lancet 376, 730–
738.
Davies, A.P., Oram, D., 1994. Exacerbation of adenomyosis in a postmenopausal woman taking tibolone associated with an elevation in serum CA 125. Br. J. Obstet. Gynaecol. 101, 632–633.
Dieterich, J., 2010. An update on adenomyosis in the adolescent. Curr.
Opin. Obstet. Gynecol. 22, 388–392.
Dim, C.C., Agu, P.U., Dim, N.R., Ikeme, A.C., 2009. Adenomyosis and
uterine rupture during labour in a primigravida: an unusual obstetric emergency in Nigeria. Trop. Doct. 39, 250–251.
Dreyfuss, M.L., 1940. Pathologic and clinical aspects of adenomyosis and endometriosis: a survey of 224 cases. Am. J. Obstet.
Gynecol. 39, 95–99.
Dueholm, M., 2006. Transvaginal ultrasound for diagnosis of adenomyosis: a review. Best Pract. Res. Clin. Obstet. Gynaecol. 20, 569–
582.
Dueholm, M., Lundorf, E., Hansen, E.S., Sorensen, J.S., Ledertoug,
S., Olesen, F., 2001. Magnetic resonance imaging and transvaginal ultrasonography for the diagnosis of adenomyosis. Fertil. Steril.
76, 588–594.
Emge, L.A., 1962. The elusive adenomyosis of the uterus. Am.
J. Obstet. Gynecol. 83, 1541–1563.
Erbslöh, J., 1956. Roentgen picture of adenomyosis uteri (text in
German). Zentralbl Gynäk 78, 1121–1129.
Frankl, O., 1925. Adenomyosis uteri. Am. J. Obstet. Gynecol. 10, 680–
684.
Frontino, G., Bianchi, S., Ciappina, N., Restelli, E., Borruto, F., Fedele,
L., 2009. The unicornuate uterus with an occult adenomyotic rudimentary horn. J. Minim. Invasive Gynecol. 16, 622–625.
Gompel, C., Silverberg, S.G., 1985. Pathology in Gynecology and Obstetrics. Lippincott, Philadelphia, pp. 149–277.
Habiba, M.A., 1994. Radionuclide migration through the genital tract
in infertile women with endometriosis. Hum. Reprod. 9, 1193–
1195.
Hendrickson, M.R., Kempson, R.L., 1980. Endometrial epithelial metaplasias: proliferations frequently misdiagnosed as adenocarcinoma. Report of 89 cases and proposed classification. Am. J. Surg.
Pathol. 4, 525–542.
Holden, F.C., 1931. Adenomyoma of the uterus. Am. J. Obstet.
Gynecol. 22, 801.
Hricak, H., Alpers, C., Crooks, L.E., Sheldon, P.E., 1983. Magnetic
resonance imaging of the female pelvis: initial experience. AJR
Am. J. Roentgenol. 141, 1119–1128.
G Benagiano et al.
Igarashi, S., Sato, N., Tanaka, H., Tanaka, T., 2002. Involvement of
catalase in the endometrium of patients with endometriosis and
adenomyosis. Fertil. Steril. 78, 804–809.
Itam, S.P., 2nd, Ayensu-Coker, L., Sanchez, J., Zurawin, R.K., Dietrich,
J.E., 2009. Adenomyosis in the adolescent population: a case report
and review of the literature. J. Pediatr. Adolesc. Gynecol. 22,
e146–e147.
Javert, C.T., 1951. Observations on the pathology and spread of endometriosis based on the theory of benign metastasis. Am.
J. Obstet. Gynecol. 62, 477–487.
Juang, C.-M., Chou, P., Yen, M.-S., Twu, N.-F., Horng, H.-C., Hsu,
W.-L., 2007. Adenomyosis and risk of preterm delivery. Br.
J. Obstet. Gynaecol. 114, 165–169.
Kepkep, K., Tuncay, Y.A., Göynümer, G., Tutal, E., 2007. Transvaginal sonography in the diagnosis of adenomyosis: which
findings are most accurate? Ultrasound Obstet. Gynecol. 30, 341–
345.
Kim, S.H., Kim, J.K., Chae, H.D., Kim, C.H., Kang, B.M., 2006. Rapidly
growing adenomyosis during the first trimester: magnetic resonance images. Fertil. Steril. 85, 1057–1058.
Kishi, Y., Yabuta, M., Taniguchi, F., 2014. Who will benefit from
uterus-sparing surgery in adenomyosis-associated subfertility?
Fertil. Steril. 102, 802–807.e1. doi:10.1016/j.fertnstert.
2014.05.028; S0015-0282(14)00491-9[pii].
Kissler, S., Hamscho, N., Zangos, S., Wiegratz, I., Schlichter, S.,
Menzel, C., Doebert, N., Gruenwald, F., Vogl, T.J., Gaetje, R.,
Rody, A., Siebzehnruebl, E., Kunz, G., Leyendecker, G., Kaufmann, M., 2006. Uterotubal transport disorder in adenomyosis and
endometriosis – a cause for infertility. Br. J. Obstet. Gynaecol.
113, 902–908.
Koot, Y.E., Teklenburg, G., Salker, M.S., Brosens, J.J., Macklon, N.S.,
2012. Molecular aspects of implantation failure. Biochim. Biophys.
Acta 1822, 1943–1950.
Krause, A., Gerber, B., 1994. Postmenopausal hemorrhage and endometrial cancer in tamoxifen therapy [Postmenopausenblutungen
und endometriumkarzinom unter tamoxifen-therapie]. Zentralbl.
Gynäkol. 116, 44–47, (in German).
Kunz, B., Beil, D., Huppert, P., Leyendecker, G., 2000. Structural
abnormalities of the uterine wall in women with endometriosis
and infertility visualized by vaginal sonography and magnetic resonance imaging. Hum. Reprod. 15, 76–82.
Kunz, G., Beil, D., Huppert, P., Noe, M., Kissler, S., Leyendecker,
G., 2005. Adenomyosis in endometriosis – prevalence and impact
on fertility. Evidence from magnetic resonance imaging. Hum.
Reprod. 20, 2309–2316.
Kunz, G., Herbertz, M., Beil, D., Huppert, G., Leyendecker, G., 2007.
Adenomyosis as a disorder of the early and late human reproductive period. Reprod. Biomed. Online 15, 681–685.
Le Bouëdec, G., Kauffmann, P., Pingeon, J.M., de Latour, M., Lemesle,
P., Dauplat, J., 1991. Post-menopausal endometriosis developed during tamoxifen treatment [Endométriose postménopausique développée sous tamoxifène]. Rev. Fr. Gynecol.
Obstet. 86, 407–410, (in French).
Lee, D.-Y., Kim, H.J., Yoon, B.-K., Choi, D., 2013. Clinical Characteristics of Adolescent Endometrioma. J. Pediatr. Adolesc. Gynecol.
26, 117–119.
Lessey, B.A., 2013. Endometrial assessment: a clinical guide. Womens
Health 9, 415–417.
Levgur, M., Abadi, M.A., Tucker, A., 2000. Adenomyosis: symptoms, histology, and pregnancy terminations. Obstet. Gynecol.
95, 688–691.
Lewinski, H., 1931. Contribution to questions about adenomyosis
[Beitrag zur Frage der Adenomyosis]. Zentralbl. Gynäkol. 55, 2163–
2166, (in German).
Lister, J.E., Kane, G.J., Ehrmann, R.L., Benacerraf, B.R., 1988. Ultrasound appearance of adenomyosis mimicking adenocarcinoma in a postmenopausal woman. J. Clin. Ultrasound 16, 519–
521.
Adenomyosis: a life-cycle approach
Luciano, D.E., Exacoustos, C., Albrecht, L., Lamonica, R., Proffer,
A., Zupi, E., Luciano, A.A., 2013. Three-dimensional ultrasound
in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus. J. Minim. Invasive Gynecol.
20, 803–810.
Lundberg, S., Wramsby, H., Bremmer, S., Lundberg, H.J., Asard, P.E.,
1997. Radionuclide hysterosalpingography does not distinguish
between fertile women, before tubal sterilization, and infertile
women. Hum. Reprod. 12, 275–278.
Lundberg, S., Wramsby, H., Bremmer, S., Lundberg, H.J., Asard,
P.E., 1998. Radionuclide hysterosalpingography is not predictive in the diagnosis of infertility. Fertil. Steril. 69, 216–220.
Maheshwari, A., Gurunath, S., Fatima, F., Bhattacharya, S., 2012.
Adenomyosis and subfertility: a systematic review of prevalence, diagnosis, treatment and fertility outcomes. Hum. Reprod.
Update 18, 374–392.
Martínez-Conejero, J.A., Morgan, M., Montesinos, M., Fortuño, S.,
Meseguer, M., Simón, C., Horcajadas, J.A., Pellicer, A., 2011. Adenomyosis does not affect implantation, but is associated with miscarriage in patients undergoing oocyte donation. Fertil. Steril. 96,
943–950.
Maubon, A., Faury, A., Kapella, M., Pouquet, M., Piver, P., 2010.
Uterine junctional zone at magnetic resonance imaging: a predictor of in vitro fertilization implantation failure. J. Obstet.
Gynaecol. Res. 36, 611–618.
McCluggage, W.G., Desai, V., Manek, S., 2000. Tamoxifen-associated
postmenopausal adenomyosis exhibits stromal fibrosis, glandular dilatation and epithelial metaplasias. Histopathology 37, 340–
346.
Mehasseb, M.K., Bell, S.C., Brown, L., Pringle, J.H., Habiba, M., 2011.
Phenotypic characterisation of the inner and outer myometrium
in normal and adenomyotic uteri. Gynecol. Obstet. Invest. 71, 217–
224.
Meredith, S., Sanchez-Ramos, L., Kaunitz, A., 2009. Diagnostic accuracy of transvaginal sonography for the diagnosis of adenomyosis: systematic review and metanalysis. Am. J. Obstet. Gynecol.
201, e1–e6.
Meyer, R., 1897. Ueber die genese der cystadenome und adenomyome
des uterus, mit demonstrationene. Ztschr Geburtsh Gynäkol 37,
327–335.
Meyer, R., 1903. On the the adenomatous mucosal growths in the
uterus – and tubal wall and their pathological-anatomical features [Über adenomatöse Schleimhautwucherungen in der Uterus
– und Tubenwand und ihre pathologisch-anatomische Bedeutung].
Virchows Arch. Pathol. Anat. Physiol. Klin. Med. 172, 394–409, (in
German).
Mijatovic, V., Florijn, E., Halim, N., Schats, R., Hompes, P., 2010.
Adenomyosis has no adverse effects on IVF/ICSI outcomes in women
with endometriosis treated with long-term pituitary downregulation before IVF/ICSI. Eur. J. Obstet. Gynecol. Reprod. Biol.
151, 62–65.
Molitor, J.J., 1971. Adenomyosis: a clinical and pathologic appraisal. Am. J. Obstet. Gynecol. 110, 275–282.
Morimatsu, Y., Matsubara, S., Higashiyama, N., Kuwata, T., Ohkuchi,
A., Izumi, A., Shibahara, H., Suzuki, M., 2007. Uterine rupture
during pregnancy soon after a laparoscopic adenomyomectomy.
Reprod. Med. Biol. 6, 175–177.
Naftalin, J., Hoo, W., Pateman, K., Mavrelos, D., Holland, T., Jurkovic,
D., 2012. How common is adenomyosis? A prospective study of
prevalence using transvaginal ultrasound in a gynaecology clinic.
Hum. Reprod. 27, 3432–3439.
Nikolaou, M., Kourea, H.P., Antonopoulos, K., Geronatsiou, K.,
Adonakis, G., Decavalas, G., 2013. Spontaneous uterine rupture
in a primigravid woman in the early third trimester attributed to
adenomyosis: a case report and review of the literature. J. Obstet.
Gynaecol. Res. 39, 727–732.
Novak, E., de Lima, O.A., 1948. A correlative study of adenomyosis
and pelvic endometriosis, with special reference to the
231
hormonal reaction of ectopic endometrium. Am. J. Obstet.
Gynecol. 56, 634–644.
Novak, E.R., Woodruff, J.D., 1979. Novak’s Gynecologic and Obstetric Pathology: with Clinical and Endocrine Relations. Saunders,
Philadelphia.
Novellas, S., Chassang, M., Delotte, J., Toullalan, O., Chevallier, A.,
Bouaziz, J., Chevallier, P., 2011. MRI characteristics of the uterine
junctional zone: from normal to the diagnosis of adenomyosis. AJR
Am. J. Roentgenol. 196, 1206–1213.
Ota, H., Igarashi, S., Hatazawa, M., Tanaka, T., 1999. Immunohistochemical assessment of superoxide dismutase expression inthe
endometrium in endometriosis and adenomyosis. Fertil. Steril. 72,
129–134.
Owolabi, T.O., Strickler, R.C., 1977. Adenomyosis. A neglected diagnosis. Obstet. Gynecol. 50, 424–426.
Özkan, Z.S., Kumbak, B., Cilgin, H., Simsek, M., Turk, B.A., 2012.
Coexistence of adenomyosis in women operated for benign gynecological diseases. Gynecol. Endocrinol. 28, 212–215.
Panganamamula, U.R., Harmanli, O.H., Isik-Akbay, E.F., Grotegut,
C.A., Dandolu, V., Gaughan, J.P., 2004. Is prior uterine surgery
a risk factor for adenomyosis? Obstet. Gynecol. 104, 1034–
1038.
Parazzini, F., Vercellini, P., Panazza, S., Chatenoud, L., Oldani, S.,
Crosignani, P.G., 1997. Risk factors for adenomyosis. Hum. Reprod.
12, 1275–1279.
Philipp, E., 1954. International Congress of Gynecology and Obstetrics. FIGO, Geneva 492.
Reinhold, C., McCarthy, S., Bret, P.M., Mehio, A., Atri, M., Zakarian,
R., Glaude, Y., Liang, L., Seymour, R.J., 1996. Diffuse adenomyosis: comparison of endovaginal US and MR imaging with histopathologic correlation. Radiology 199, 151–158.
Salim, R., Riris, S., Saab, W., Abramov, B., Khadum, I., Serhal, P.,
2012. Adenomyosis reduces pregnancy rates in infertile women
undergoing IVF. Reprod. Biomed. Online 25, 273–277.
Salker, M.S., Nautiyal, J., Steel, J.H., Webster, Z., Sućurović, S.,
Nicou, M., Singh, Y., Lucas, E.S., Murakami, K., Chan, Y.W., James,
S., Abdallah, Y., Christian, M., Croy, B.A., Mulac-Jericevic, B.,
Quenby, S., Brosens, J.J., 2012. Disordered IL-33/ST2
activation in decidualizing stromal cells prolongs uterine
receptivity in women with recurrent pregnancy loss. PLoS ONE 7,
e52252.
Sammour, A., Pirwany, I., Usubutun, A., Arseneau, J., Tulandi, T.,
2002. Correlations between extent and spread of adenomyosis and
clinical symptoms. Gynecol. Obstet. Invest. 54, 213–216.
Sampson, J.A., 1925a. Heterotopic or misplaced endometrial tissue.
Am. J. Obstet. Gynecol. 10, 649–664.
Sampson, J.A., 1925b. Inguinal endometriosis (often reported as endometrial tissue in the groin, adenomyoma in the groin, and adenomyoma of the round ligament). Am. J. Obstet. Gynecol. 10,
462–503.
Sampson, J.A., 1927. Peritoneal endometriosis due to the menstrual 6. dissemination of endometrial tissue into the peritoneal
cavity. Am. J. Obstet. Gynecol. 14, 422–469.
Sandberg, E.C., Cohn, F., 1962. Adenomyosis in the gravid uterus at
term. Am. J. Obstet. Gynecol. 84, 1457–1465.
Seidman, J.D., Kjerulff, K.H., 1996. Pathologic findings from the Maryland Women’s Health Study: practice patterns in the diagnosis of
adenomyosis. Int. J. Gynecol. Pathol. 15, 217–221.
Shaikh, H., Khan, K.S., 1990. Adenomyosis in Pakistani women: four
year experience at the Aga Khan University Medical Centre,
Karachi. J. Clin. Pathol. 43, 817–819.
Shitano, F., Kido, A., Fujimoto, K., Umeoka, S., Himoto, Y., Kiguchi,
K., Kondoh, E., Mikami, Y., Konishi, I., Togashi, K., 2013.
Decidualized adenomyosis during pregnancy and post-delivery:
three cases of magnetic resonance imaging findings. Abdom.
Imaging 38, 851–857.
Siegler, A.M., Camilien, L., 1994. Adenomyosis. J. Reprod. Med. 39,
841–853.
232
Tamai, K., Koyama, T., Umeoka, S., Saga, T., Fujii, S., Togashi, K.,
2006. Spectrum of MR features in adenomyosis. Best Pract. Res.
Clin. Obstet. Gynaecol. 20, 583–602.
Templeman, C., Marshall, S.F., Ursin, G., Horn-Ross, P.L., Clarke,
C.A., Allen, M., Deapen, D., Ziogas, A., Reynold, P., Cress, R.,
Anton-Culver, H., West, D., Ross, R.K., Bernstein, L., 2008. Adenomyosis and endometriosis in the California Teachers Study.
Fertil. Steril. 90, 415–424.
Thalluri, V., Tremellen, K.P., 2012. Ultrasound diagnosed adenomyosis has a negative impact on successful implantation following GnRH antagonist IVF treatment. Hum. Reprod. 27, 3487–
3492.
Tocci, A., Greco, E., Ubaldi, F.M., 2008. Adenomyosis and
‘endometrial-subendometrial myometrium unit disruption disease’
are two different entities. Reprod. Biomed. Online 17, 281–
291.
Tremellen, K.P., Russell, P., 2012. The distribution of immune cells
and macrophages in the endometrium of women with recurrent
reproductive failure. II: adenomyosis and macrophages. J. Reprod.
Immunol. 93, 58–63.
Ugwumadu, A.H., Bower, D., Ho, P.K., 1993. Tamoxifen induced adenomyosis and adenomyomatous endometrial polyp. Br. J. Obstet.
Gynaecol. 100, 386–388.
Ukita, S., Koshiyama, M., Yamaguchi, A., Ueda, M., Ukita, M.,
Hishikawa, K., Kakui, K., Kim, T., 2011. Total uterine rupture
during pregnancy after an adenomyomectomy. Am. J. Case Rep.
15, 106–109. art. no. 881914.
Vavilis, D., Agorastos, T., Tzafetas, J., Loufopoulos, A., Vakiani, M.,
Constantinidis, T., Patsiaoura, K., Bontis, J., 1997. Adenomyosis at hysterectomy: prevalence and relationship to operative findings and reproductive and menstrual factors. Clin. Exp. Obstet.
Gynecol. 24, 36–38.
Vercellini, P., Parazzini, F., Panazza, S., Oldani, S., Bramante, T.,
Crosignani, P.G., 1995. Adenomyosis at hysterectomy: a study on
frequency distribution and patient characteristics. Hum. Reprod.
10, 1160–1162.
Vercellini, P., Cortesi, I., De Giorgi, O., Merlo, D., Carinelli, S.G.,
Crosignani, P.G., 1998. Transvaginal ultrasonography versus uterine
needle biopsy in the diagnosis of diffuse adenomyosis. Hum.
Reprod. 13, 2884–2887.
Vercellini, P., Viganò, P., Somigliana, E., Daguati, R., Abbiati, A.,
Fedele, L., 2006. Adenomyosis: epidemiological factors. Best Pract.
Res. Clin. Obstet. Gynaecol. 20, 465–477.
G Benagiano et al.
Vercellini, P., Consonni, D., Dridi, D., Bracco, B., Frattaruolo, M.P.,
Somigliana, E., 2014. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis. Hum.
Reprod. 29, 964–977.
Vila-Vives, J.M., Martínez-Conejero, J.A., Pellicer, A., 2012. Effect
of adenomyosis on implantation. Reprod. Biomed. Online 24, 584.
Wada, S., Kudo, M., Minakami, H., 2006. Spontaneous uterine rupture
of a twin pregnancy after a laparoscopic adenomyomectomy: a
case report. J. Minim. Invasive Gynecol. 13, 166–168.
Wang, P.-H., Pang, Y.-P., Chao, H.-T., Lai, C.-R., Juang, C.-M., Yuan,
C.-C., Ng, H.-T., 1998. Delayed postpartum hemorrhage in adenomyosis: a case report. Chin. Med. J. (Taipei) 61, 492–495.
Wånggren, K., Wramsby, H., Bremmer, S., Lundberg, S., Jacobsson,
H., 2011. Radionuclide hysterosalpingography is not a reliable tool
for investigation of fallopian tube transport – a controlled randomized study using particles of two sizes during three different parts of the menstrual cycle. Gynecol. Obstet. Invest. 72,
20–24.
Weiss, G., Maseelall, P., Schott, L.L., Brockwell, S.E., Schocken, M.,
Johnston, J.M., 2009. Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of
Women’s Health Across the Nation (SWAN). Fertil. Steril. 91, 201–
206.
Zaloudek, C., Hendrickson, M.R., 2002. Mesenchymal Tumors of the
Uterus. Blaustein’s Pathology of the Female Genital Tract. R. J.
Kurman. Springer, New York; Berlin, pp. 561–616.
Zangos, S., Kissler, S., Mueller, A., Siebzehnruebl, E., Kaufmann, M.,
Hamscho, N., Grünwald, F., Eichler, K., Herzog, C., Marquardt,
F., Peters, J., Jacobi, V., Mack, M.G., Vogl, T.J., 2004. Uterine
adenomyosis in infertile patients: MR imaging findings and clinical conclusions [MRT der uterinen adenomyose bei infertilen
patientinnen: ergebnisse und klinische rückschlüsse]. Rofo 176,
1641–1647, (in German).
Declaration: The authors report no financial or commercial conflicts of interest.
Received 17 July 2014; refereed 12 November 2014; accepted 12
November 2014.