ADENOMYOSIS: DISEASE, UTERINE AGING PROCESS LEADING TO SYMPTOMS, OR BOTH? - FACTS, VIEWS & VISION IN OBGYN
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Facts Views Vis Obgyn, 2020, 12 (2): 91-104 Review
Adenomyosis: Disease, uterine aging process leading to
symptoms, or both?
A. ProtoPAPAs1, G. Grimbizis2, s. AthAnAsiou1, D. LoutrADis1
1st Department of Obstetrics & Gynecology of the Medical School of the National and Kapodistrian University of Athens,
1
Greece; 21st Department of Obstetrics & Gynecology of the Medical School of the Aristotle University of Thessaloniki,
Greece.
Correspondence at: Athanasios Protopapas, 3 Aisopou str, Marousi, 15122 Athens, Greece. Tel/fax: +30-
2108052252, Mobile: +30-6977408368. E-mail: prototha@otenet.gr
Abstract
For many decades adenomyosis has been a histological diagnosis in hysterectomy specimens. Traditionally,
it has been considered a disease of late reproductive and premenopausal years causing uterine enlargement,
dysmenorrhoea and menorrhagia. Recent advances in pelvic and uterine imaging techniques including
transvaginal sonography and magnetic resonance imaging were responsible for a shift towards a non-invasive
diagnosis and made a significant contribution to a better understanding of its pathogenesis, epidemiology,
histological spectrum, and clinical symptomatology. With these non-invasive tools it has been shown that
adenomyosis is probably a condition affecting much younger populations and is frequently asymptomatic at
an early stage of its development. Regarding symptomatic disease, the distribution and extent of adenomyotic
lesions do not correlate consistently with the various symptoms that are considered typical of adenomyosis.
More importantly, accurate diagnosis of adenomyosis suffers from a lack of consensus among experts on
imaging and even histological diagnostic criteria. Several pathogenetic theories have attempted to shed light on
the establishment, evolution and distribution of adenomyotic lesions within the uterine wall, including the tissue
injury and repair (TIAR) mechanism, metaplasia, and the more recent genetic-epigenetic theory. So far, none of
these can adequately and independently explain the appearance of all types of adenomyosis. This review paper
attempts a correlation between the proposed pathogenetic theories and the clinical and histological spectrum of
adenomyosis, in an effort to give a plausible explanation of the evolution of this condition from an asymptomatic
state to a disease, through synthesis of the existing data.
Keywords: Adenomyosis, diagnosis, epidemiology, pathogenesis symptoms
Introduction are diagnosed with non-invasive methods such as
transvaginal 2- or 3-dimensional sonography (2-D
Adenomyosis is a uterine condition that is TVS and 3-D TVS), or magnetic resonance imaging
histologically characterized by the presence of (MRI) (Andres et al., 2018; Tellum et al., 2020).
ectopic endometrial glands and stroma within the These imaging methods have been pivotal in
myometrium, surrounded by hypertrophic and clarifying the functional anatomy of the uterus,
hyperplastic myometrial changes (Garcia and changing our understanding of the natural history and
Isaackson, 2011). For several decades, the diagnosis the clinical spectrum of adenomyosis significantly.
of adenomyosis was made in hysterectomy The myometrium is composed of two separate layers;
specimens either coincidentally, or in women treated the inner myometrium or junctional zone (JZ), and
surgically for chronic pelvic pain and/or abnormal the outer myometrium, that are histologically and
uterine bleeding (Molitor, 1971). Over the past embryologically different (Brosens et al., 1995;
twenty years more and more cases of adenomyosis Fusi et al., 2006). The inner myometrium, like the
91endometrium, is of Müllerian origin, undergoes (symptoms OR presentation OR clinical spectrum),
cyclical changes in response to hormonal stimuli, and adenomyosis symptoms (Title) AND pathogenesis,
is involved in embryo implantation and placentation adenomyosis symptoms (Title) AND epidemiology
(Uduwela et al., 2000). This area according to the and adenomyosis symptoms (Title) AND diagnosis,
tissue injury and repair (TIAR) pathogenetic theory till December 2019. The title and abstract were
represents the original site of the development of screened and the full text of 245 possibly relevant
the adenomyotic process (Leyendecker et al., 2009). articles were assessed by two authors (AP and SA).
Other investigators have suggested that the so- A total of 89 articles were finally included in this
called endometrial-subendometrial unit disruption review. The main inclusion criterion was relevance
disease should be considered a separate entity from to the question posed in the title of our manuscript.
adenomyosis (Tocci, et al., 2008). Studies reporting on symptoms of adenomyosis
The histopathological spectrum of adenomyosis represented the core literature that had been
includes diffuse and circumscribed lesions that may initially built and carefully reviewed. Subsequently,
have a variable distribution and extent within the papers correlating symptoms with epidemiology,
myometrium. This histological variability probably pathogenesis, and diagnosis of adenomyosis
relates to the variety of clinical manifestations that both histological and imaging were reviewed
have been attributed to adenomyosis, including the and cross-referenced. There were no particular
absence of symptoms in many patients (Peric and exclusion criteria. Nevertheless, papers reporting
Frazer, 2006). The time of the 1st appearance and purely on imaging diagnosis without reference to
the age-related evolution of adenomyotic lesions is a symptoms, were included only after reading the
matter of controversy. A life-cycle approach to both abstract and/or text. Papers on surgical methods
endometriosis and adenomyosis has indicated that to treat adenomyosis were considered only if they
these two conditions, despite their common features, included data on pre- and postoperative symptoms.
have a different epidemiology (Benagiano et al., A hypothesis has also been formulated on the
2015). Adenomyosis until recently was considered evolution of symptoms attributed to adenomyosis,
a disease of older women. Nevertheless, advances from menarche to menopause, correlating it with
in imaging techniques have enabled the detection existing pathogenetic theories.
of subtle adenomyotic lesions in very young
asymptomatic populations, and this has raised Results
reasonable doubts on whether adenomyosis - or at
Pathogenesis and distribution of lesions
least some of its forms - is a true disease, or a normal
process related to, and aggravated by, uterine aging. In common with endometriosis, it is difficult to
The purpose of this paper is to review the existing cover all cases of adenomyosis under the same
data correlating the clinical presentation with the pathogenetic umbrella. The TIAR theory suggests
histological and imaging features of adenomyosis, to that both conditions are the result of trauma which
examine how symptoms may evolve with age, and is induced by chronic uterine peristaltic activity
to attempt a correlation of clinical manifestations of or phases of hyperperistalsis at the endometrial-
adenomyosis with existing theories of pathogenetic myometrial interface activating a mechanism of
mechanisms. Using a systematic approach, we tissue injury and repair (Leyendecker et al., 2009).
formulated a hypothesis that considers adenomyosis This in the case of adenomyosis is followed by
to be a multi-faceted entity which, in accordance invasion of the endometrium into the myometrium
with all principal pathogenetic theories, may be and development of chronic inflammation. Despite
diagnosed throughout a woman’s life, acquiring being an attractive theory, TIAR may explain many
the characteristics of a morbid condition, when but not all ectopic lesions. Variable depth of lesions
significant molecular changes occur and symptoms in particular may indicate either the operation of
develop. This transformation may or may not be different pathogenetic mechanisms, or different
age-related and will depend on the type of lesion, the stages of the disease process (Leyendecker et al.,
mechanism of its initial development in an ectopic 2015). Invasion of the breached junctional zone
location, and the sustained action of important risk by hyperplastic endometrium and sustained hyper-
factors contributing to its evolution and spread. peristaltic activity, at least initially, would result
in superficially located lesions (Garcia-Solares et
Materials and Methods al., 2018). There is no solid proof that the same
process can result in adenomyotic lesions up to the
A comprehensive search was performed on PubMed, distant outer myometrium. Probably, the theory of
EMBASE, Web of science, and Science Direct for de novo development of adenomyotic lesions from
studies reporting on adenomyosis (Title) AND metaplasia either as a result of Müllerian remnants,
92 Facts Views Vis Obgynor from external invasion of progenitor epithelial and even before menarche to their early postmenopausal
stromal cells derived from endometrial menstrual years. Such a study does not exist so far, and it
debris is more appropriate to explain lesions far would be difficult if not impossible to conduct in
distant from basal endometrium and close to the the future. In contrast to what is really necessary to
uterine serosa (Garcia-Solares et al., 2018; Gargett, further elucidate the pathogenesis of adenomyosis,
2016). Kishi Y et al., have suggested an MRI-based our assumptions are actually based on studies that
classification of adenomyosis into four subtypes, currently offer captures of the adenomyotic process,
according to involvement or not of the inner and in women of different age groups.
outer layers of myometrium, and separating cases
Diagnosis of adenomyosis: an urgent need for solid
with lesions occurring alone unrelated to structural
criteria
components, and those not satisfying the above
criteria (Kishi et al., 2012). Similarly, Bazot M, Traditionally, the diagnosis of adenomyosis had been
and Darai E, classified lesions into internal and a histological one made at hysterectomy specimens.
external adenomyosis, and structural-related At present time, the evolution of imaging tools
adenomyoma subtypes, but underlined that all three and especially ultrasound and MRI, has permitted
types can be present alone or in association in the accurate non-invasive diagnosis, using well
same patient (Bazot and Darai, 2018). These two described morphological myometrial alterations,
proposed classifications indicate the operation of at measurement of the thickness, and assessment of
least two different pathogenetic mechanisms that the outline of the JZ, or a combination of all these
may act independently of each other, but at times parameters (Bazot and Darai, 2018, Tellum et
together on the same subject, giving rise to the al., 2020). Nevertheless, diagnostic criteria, both
complex histological profile of adenomyosis. Co- histological and imaging, have been variable in the
existence of endometriosis may act as the bridging existing literature, and this variability could explain
factor between internal and external adenomyosis, to a certain extent significant differences in the
with the TIAR mechanism acting to promote observed prevalence of this condition, in groups of
simultaneous appearance of both conditions, during patients with similar epidemiological and clinical
the initial stages of their development (Leyendecker characteristics.
et al., 2009). At a more advanced stage external
A. Histological diagnosis
infiltration of the myometrium by endometriotic
stem cells and metaplasia especially in cases with Unfortunately, even today, no universally acceptable
deep endometriosis, may result in the active distant histological criteria exist. The histological diagnosis
myometrial lesions that constitute the typical commonly relies on the minimum distance from the
adenomyotic foci of the outer myometrium. endometrial-myometrial junction that ectopic lesions
The location of ectopic lesions within the different are found within the myometrium, but this varies
layers of the myometrium no matter how they end from 1-3mm in reported series. Accordingly, a low
up there, may have significant implications on the or a high-power field (LPF-HPF) has been used as
appearance of symptoms, their quality, and their marking reference of depth (Garcia and Isaackson,
timing along the natural history of adenomyosis (Bird 2011; Benagiano et al., 2015). This lack of solid
et al., 1972; Levgur M, et al., 2000; Sammour et al., histological criteria would significantly affect the
2002; Li et al., 2014). The recent genetic-epigenetic reported prevalence and incidence of adenomyosis
theory initially proposed to explain pathogenesis of in different patient populations. Equally, it would
the different forms of endometriosis (Koninckx et affect any subsequent clinical correlations.
al., 2019), can be equally applied to adenomyosis, In their important study Bird et al. (1972) proposed
as these two conditions share many molecular, a histological classification of adenomyosis based
immunological and biochemical alterations of the on the depth of myometrial invasion and the
eutopic and ectopic endometrium (Benangiano and number of ectopic lesions within the myometrium.
Brosens, 2011; Vannuccini et al., 2017). According In a series of 200 hysterectomies, they showed
to this theory, ectopic adenomyotic lesions of that the incidence of adenomyosis would increase
variable origin, bearing genetic and epigenetic from 31% to 38.5% if they used 6 extra sections
stigmata, will become a disease after exposure to a to their routine histological assessment, and more
toxic environment that will inflict further crucial hits importantly, by including sub-basal lesions (Grade
and molecular changes. I disease, or adenomyosis sub-basalis, according
To appropriately study the clinical course and to their definition), the incidence would rise to an
imaging evolution of adenomyosis in the aging impressive 61.5% (Bird et al., 1972).
female we would possibly need to follow-up closely Similarly, in a more recent study, Bergholt et al.
a large cohort of young asymptomatic women from (2001) reporting on 486 hysterectomised patients,
ADENOMYOSIS: DISEASE, AGING PROCESS, OR BOTH? – PROTOPAPAS et AL. 93found that by increasing the depth of myometrial population. Using very strict exclusion criteria
invasion from 1mm to 3mm, and including Pinzauti et al. (2015) applied 2D and 3D TVS on
myometrial hyperplasia as essential criteria for the 156 young women (18-30 years old) attending
diagnosis of adenomyosis, its prevalence in their a contraception clinic. Their ultrasonographic
cohort would drop from 18% to 10%. Therefore, it criteria had been previously tested and evaluated.
is clear that the application of stricter histological Surprisingly, they found a prevalence of diffuse
criteria for the diagnosis of adenomyosis would adenomyosis of 33% (53/156) in a group of women
significantly affect its reported epidemiology. not seeking advice for symptoms. Understandably,
no hysterectomies were performed in this cohort of
B. Imaging diagnosis
patients.
The development of high-resolution imaging The Morphological Uterus Sonographic
techniques has profoundly affected both our Assessment (MUSA) group, have recently reported
understanding of adenomyosis and the frequency of on the sonographic features and use of terminology
its diagnosis. But it has also created more problems for describing the two most common myometrial
that need to be addressed. Criteria for the diagnosis lesions (fibroids and adenomyosis) and uterine
of this condition have been established by several smooth muscle tumours. Regarding adenomyosis,
groups for all 3 modalities; two and three dimensional they have concluded that this condition may be
transvaginal ultrasonography (2D-TVS and 3D- difficult to diagnose with ultrasound. Although
TVS), and magnetic resonance imaging (MRI) different ultrasound features have been suggested
(Reinhold et al., 1996; Bazot et al., 2001; Dueholm, to be associated with adenomyosis, at present, it is
2006; Exacoustos et al., 2011; Stamatopoulos et al., not clear which of the various ultrasound criteria
2012; Tellum et al., 2019). It is beyond the scope are most important for diagnosis. Some features
of this article to perform a systematic review of may carry a greater diagnostic weight than others
existing studies and discuss the reliability of their and the presence of more than one ultrasound
diagnostic criteria. On average, they have a good feature associated with adenomyosis might increase
reported sensitivity of 70-80%, and an even better the likelihood of the diagnosis. They did not
specificity of 80-90% (Champaneria et al., 2010). include in their consensus statement the so called
In evaluating their performance in the diagnosis ‘question-mark sign’, suggested to be typical of
of adenomyosis, these modalities have initially adenomyosis, because this sign occurs when there is
been compared with a histological diagnosis made also deep infiltrating endometriosis in the posterior
at hysterectomy, which is considered the gold compartment. (Van den Bosch et al., 2015).
standard. This has three weaknesses: a) the number MRI has been shown to be equally effective
of women finally submitted to hysterectomy usually – if not better – compared with ultrasound in the
represents a minority of the total cohort, b) the diagnosis of adenomyosis, (Bazot and Darai, 2018;
number of the imaging criteria considered essential Tellum et al., 2020), but it is an expensive tool,
for establishment of a non-invasive diagnosis and its routine use cannot be justified especially
may vary significantly between studies, and c) the in asymptomatic populations. Nevertheless, the
histological criteria as explained above are also prevalence of adenomyosis in asymptomatic women
subject to variation. has been examined using MRI criteria in two studies.
An additional drawback of non-invasive diagnosis In the first study, Hauth et al. (2007) performed MRI
is that the population of women subjected to an in 100 women and found adenomyosis in 12%,
imaging study and the indication for it. Naftalin et whereas Juang et al. (2007) reported on the incidence
al. (2012) studied a cohort of 986 women visiting of adenomyosis postpartum in women with term and
a general gynaecology clinic with a variety of preterm deliveries and found an incidence in these
complaints with 2D and 3D TVS. They applied two populations of 9.4% and 13.2%, respectively.
seven ultrasonographic criteria for a diagnosis In symptomatic women in whom MRI could
and found a prevalence of 21% of adenomyosis be much more easily justified, the prevalence of
in their population. Only 45 women were finally adenomyosis appears significantly different. Four
subjected to a hysterectomy and of these 18 (40%) large prospective studies have compared MRI
had co-morbidities such as uterine malignancies or performance with histopathology for the diagnosis
multiple fibroids that complicated assessment of of adenomyosis (Reinhold et al., 1996; Bazot et al.,
the specimen and were excluded from comparison 2001; Dueholm et al., 2001; Tellum et al., 2019).
between ultrasound and hysterectomy. These studies give a sensitivity of between 70% to
Another important prospective study published 93% and a specificity of 86 to 93%, with a prevalence
by an experienced Italian Group produced very of adenomyosis of 21 to 33%. Nevertheless, not all
interesting results reporting on a much different these reports agreed in regarding the usefulness
94 Facts Views Vis Obgynof different diagnostic criteria (thickness and the different symptoms reported by their patients. appearance of JZ, and morphological alterations They found that menorrhagia was more common of myometrium). JZ thickness ≥12mm, a finding in patients with Grade I disease in comparison commonly used to diagnose adenomyosis has been with those with deeper disease affecting the middle disputed recently by Tellum et al. (2019) who and more distant myometrium – Grades 2 and 3 reported that presence of JZ irregularity rather than disease (60% vs. 42%, respectively). The severity thickness, and specific morphological criteria such of involvement, indicated by the number of glands as cysts and adenomyomas provide the highest per LPF, was significantly associated with the specificity for diagnosing adenomyosis. frequency of menorrhagia. When >10 glands/LPF In their meta-analysis comparing the diagnostic were found, menorrhagia was present in 82% of performance of MRI and TVS, Champaneria et al. cases, compared to 58% (4-9 glands/LPF), and (2010) reported that MRI had a pooled sensitivity 23% (1-3 glands/LPF), of a lesser myometrial of 77% (95% confidence interval (CI) 67–85), involvement. On the contrary, the rates of severe a specificity of 89% (95% CI 84–92), a positive dysmenorrhea increased proportionally, according likelihood ratio of 6.5 (95% CI 4.5–9.3), and a to the depth of myometrial involvement (4.3% negative likelihood ratio of 0.2 (95% CI 0.1–0.4). vs. 42.4% vs. 83.3%). Increasing disease severity The authors concluded that MRI performs more defined by the number of ectopic lesions within the favourably than TVS in the presence of associated myometrium also significantly affected the rates uterine leiomyomas. However, while MRI is of dysmenorrhea (13.3% vs. 26.7% vs. 58.8%). less operator-dependent than TVS, expertise is Nevertheless, only 18.7% of their patients had both required. Little data are available on the value of menorrhagia and severe dysmenorrhea – the classic MRI to determine the location, severity and extent symptom complex. Their findings underscore the of adenomyosis in comparison with histology potential significance of lesion depth and location (Reinhold et al., 1996; Dueholm et al., 2001; (inner vs. outer myometrium), on the type and Rasmussen et al., 2019). severity of symptoms accompanying the presence The above data underline the difficulty in of adenomyosis, and possibly the timing of their attempting to make clinical correlations when no appearance during the evolution of the adenomyotic solid criteria for the diagnosis of adenomyosis have process. been agreed upon among pathologists and imaging In a more recent study, Levgur et al. (2000) experts. Furthermore, the type of population reported on 111 uteri weighing
menorrhagia and dyspareunia, with the spread of the symptoms, nor did it become clear how many should adenomyotic lesions. constitute a certain diagnosis of adenomyosis, taking In a large Chinese study, which included 770 cases into account the wide variability of their presence of adenomyosis diagnosed at hysterectomy out of a in patients with a diagnosis of this disease (from total of 1690 patients, Li et al. (2014) reported on the 1.3-26.8%). Kepkep et al. (2007) in their study correlation of symptoms attributed to adenomyosis of 70 patients correlating ultrasonographic and with the age of 1st appearance, and their severity. histological diagnosis of adenomyosis, found that They found that dysmenorrhea was the most imaging characteristics have variable sensitivities, common symptom reported by 81.7% of patients specificities, and negative and positive predictive either alone or in combination with other complaints. values. Severe dysmenorrhea in particular, was found to be In agreement with the above findings, Pinzauti significantly associated with a younger age of 1st et al. (2015) in their study on much younger diagnosis of adenomyosis, appearance of symptoms nulligravid patients (mean age: 24 years, IQR: 23- at a lower age, its presence as a sole symptom, and 27) attending a contraception clinic found that the with a longer duration of symptoms. Menorrhagia number of ultra-sonographic findings suggestive of appeared later in life affecting women in their adenomyosis at 2D-TVS, and the thickness of the mid-40s and was commonly associated with other JZ on a coronal section at 3D-TVS, both correlated symptoms, and in particular severe dysmenorrhea. significantly with the severity of dysmenorrhea Asymptomatic women with adenomyosis (only and menorrhagia assessed by visual analogue 4.5% in this series) were predominantly of the late scale (VAS) and pictorial blood loss analysis premenopausal age range. In this study the size chart (PBAC) scores, respectively. Nevertheless, of the uterus did not differ significantly between the mere diagnosis of adenomyosis using the symptomatic and asymptomatic women, in presence of a single ultrasonographic feature was agreement with the findings of a previous study by not associated with the subjective symptom of Molitor et al. (1971). In contrast, Bird et al. (1972) menorrhagia. Although the obvious weakness of had found that adenomyotic uteri were on average this study is the lack of histological confirmation heavier than normal. of the diagnosis of adenomyosis, finding evidence The above correlations should be viewed with of diffuse adenomyosis in a significant proportion caution for the simple reason that patients with (1:3) of young nulligravid women without obvious adenomyosis submitted to a hysterectomy are classic risk factors (previous pregnancy and labor, commonly of the older age group and complain of miscarriage, uterine surgery, IUCD use), casts more severe symptoms, have more co-morbidities doubt on the true pathogenetic pathways leading to causing similar symptoms, and probably are not development of this disease. representative of the true clinical spectrum of this Recently, Exacoustos et al. (2019) reported on 108 disease. Furthermore, differences in methodology patients with ultrasonographic signs of adenomyosis such as criteria for the histological diagnosis (mean age 37.7±7.7 years) who were classified of adenomyosis and number of sections used, according to a proposed scoring system that graded indications and threshold for hysterectomy, and the type of adenomyosis (diffuse vs. focal) and its the impact of the healthcare system may have extension inside the myometrial wall. Women with significantly affected the above correlations. ultrasound diagnosis of diffuse adenomyosis were It is clear that patients with adenomyotic changes older (p= 0.04) and had heavier menstrual bleeding diagnosed with imaging methods may tell a different (p=0.04) than women with focal disease, however story regarding adenomyosis-related symptoms. no statistically significant differences were found Naftalin et al. published two subsequent studies regarding the presence and severity of dyspareunia on practically the same patient population of a and dysmenorrhea. Higher values of menstrual general gynaecology clinic (mean age: 38 years, bleeding were found for severe diffuse adenomyosis inter-quantile range - IQR: 30-43), in an attempt to and the highest values were found in those with correlate TVS findings suggestive of adenomyosis adenomyomas. with both dysmenorrhea and menorrhagia (Naftalin An important relevant issue is whether et al., 2014; Naftalin et al., 2016). They found ultrasonography can correctly identify the grade that the increasing number of a panel of seven or degree of adenomyosis. Bazot et al. (2002) ultrasonographic criteria present in each case in an older study, reported concurrence between was significantly associated with a worsening histopathology and TVS in only 57% of cases, when dysmenorrhea and with the severity of menorrhagia. assessing the depth of presence of endometrium Nevertheless, not all ultrasonographic characteristics within the myometrium, and in only 23% of cases, had the same importance regarding the severity of when assessing the degree of involvement and lesion 96 Facts Views Vis Obgyn
density. This relative weakness of ultrasonography endometriosis and other pathologies such as fibroids
would probably negatively affect any effort to that can also have a negative impact on fertility.
classify adenomyosis and its severity with imaging, The possible underlying pathogenetic mechanisms of
and subsequently any clinical correlations, made infertility in women with adenomyosis involve not
important by previous studies reporting on only molecular changes of the eutopic endometrium
histopathological diagnosis (Bird et al., 1972; that may affect implantation, (Benangiano et al.,
Bergholt et al., 2001). Unfortunately, few recent 2012; Benangiano et al., 2014b) but also abnormal
studies using modern imaging (ultrasound and MRI) peristaltic activity of the inner myometrium that may
equipment have attempted correlations between interfere with sperm transport (Kissler et al., 2007).
detailed imaging and extensive histological sections There is current ample evidence that the presence
in large hysterectomy populations. Rasmussen et of adenomyosis is associated with the dysregulation
al. (2019) have recently reported on 110 patients of a large number of implantation-associated factors
submitted either to hysterectomy or transcervical (HOXA10, LIF, MMP2, IL-6, cytochrome 450,
resection of the endometrium (TCRE) for menstrual and RCAS1), immune factors, pro-inflammatory
pain and bleeding. They examined with preoperative mediators (IL-1β, CRH), markers of apoptosis and
2D and 3D ultrasound predominantly morphology proliferation, and mediators of oxidative stress,
of JZ (normal vs. serrated vs. adenomyosis of inner leading to low uterine receptivity (Campo et al.,
myometrium). They found that an ultrasonographic 2012, Vannuccini et al., 2017). Additionally,
diagnosis of adenomyosis of the inner myometrium adenomyosis in common with endometriosis is
by 2D-TVS was not confirmed by histopathology in associated with the development of progesterone
19 of 42 (45%) women, and 17 (90%) of these had resistance (Campo et al., 2012; DeZiegler et al.,
a serrated JZ. A 3D-TVS diagnosis of adenomyosis 2010; Vannuccini et al., 2017). As a result of
of the inner myometrium was not confirmed by persistent local hyper-estrogenism dysregulated
histopathology in 11 of 33 (33%) women, and eight uterine peristalsis mediated by endometrial oxytocin
(73%) of these had a serrated JZ. Thus, most false and its receptors ensues, causing further trauma and
positive cases had a serrated JZ. However, there endometrial invasion of the junctional zone (Garcia-
were fewer women with a serrated JZ diagnosed as Solares et al., 2018; Shaked et al., 2015). The altered
adenomyosis of the inner myometrium by 3D-TVS eutopic endometrium displays a dysregulation
(n=8) than with 2D-TVS (n=17). Their findings of immune factors, markers of apoptosis or
regarding internal adenomyosis obviously cannot proliferation, inflammatory mediators, and oxidative
be extrapolated to disease expanding to deeper stress resulting in low uterine receptivity (Campo et
myometrium, and further studies are needed. al., 2012).
Although many consider an increased thickness
Adenomyosis and subfertility
of JZ a sign of early adenomyosis, this has been
The relation of adenomyosis to infertility and disputed by Tocci et al. (2008) who believe that JZ
subfertility also remains uncertain. This uncertainty disruption disease is a different pathological entity.
partly relates to the fact that infertility is frequently The normal JZ itself when diffusely thickened and
multifactorial. Due to a large number of cofounders, not irregular should be carefully distinguished from
large populations are needed in order to determine normal physiological thickness variability that
this association. On the other hand, the long- occurs throughout the cycle in response to a varying
standing concept of adenomyosis being a disease hormonal environment (Brosens et al., 1995; Fusi
of late reproductive and premenopausal years et al.; 2006; Kishi et al., 2017). There is no doubt
has recently been challenged and instead of that establishing universally accepted imaging
hysterectomy, imaging techniques are currently criteria for JZ thickness normality unrelated to early
used for its diagnosis in the majority of suspect cases adenomyosis is crucial to avoid overdiagnosis of
(Bajot and Darai, 2018, Tellum et al., 2020). As a this condition and false clinical correlations.
result, the recognition that adenomyosis may affect A relatively good model for prospectively
much younger populations led to investigation of its studying the effect of adenomyosis on conception
potential negative impact on female fertility. and early pregnancy has been assisted reproduction.
Despite the theoretical impact of the presence The potential detrimental effect of a thickened JZ
of adenomyosis on female fertility, and its many at imaging on implantation and evolution of early
molecular similarities with endometriosis, an pregnancy has been suggested by several authors.
established infertility factor, it is difficult to correlate Unfortunately, many of these studies report on
the presence and clinical severity of this condition small numbers of patients. Chiang et al. (1999)
with the probability of spontaneous conception. suggested a link between miscarriage and uterine
Furthermore, adenomyosis frequently co-exists with JZ dysfunction in infertile patients undergoing IVF
ADENOMYOSIS: DISEASE, AGING PROCESS, OR BOTH? – PROTOPAPAS et AL. 97and found that the spontaneous abortion rate was the severity and extent of adenomyosis would be
higher in women with a diffusely enlarged uterus on of utmost importance to evaluate the prognosis
ultrasound imaging without distinct uterine masses of patients with this condition undergoing ART,
compared with those with a normal uterus (66.7% assisting in the design of randomized studies
vs. 21%, p=0.04). However, their clinical pregnancy evaluating different IVF protocols (Gordts et al.,
rates were not statistically different (31.6% vs. 2018). Park et al. (2016) reported on 214 IVF cycles
26.4%). Piver (2005) proposed that evaluation in women with adenomyosis, comparing the IVF
of JZ thickness with MRI is the best negative outcomes of fresh embryo transfer (ET) cycles with
predictive factor of implantation failure, and an (N=147 – group A), or without (N=105 – group B)
increase in JZ diameter is inversely correlated to gonadotropin-releasing hormone (GnRH) agonist
implantation rate. Implantation failure was found pre-treatment, and of frozen-thawed embryo transfer
to be high when the average JZ was greater than (FET) cycles following GnRH agonist treatment
7mm, possibly setting an upper limit of normality (N=43 – Group C). The clinical pregnancy rate in
which is lower than the usual reported threshold for group C (39.5%) tended to be higher than those in
diagnosis of adenomyosis. Similarly, Maubon et al. groups B (30.5%) and A (25.2%) (Park et al., 2016).
(2010) in a prospective study of 152 infertile women
Adenomyosis and pregnancy-related complications
who had a pelvic MRI prior to IVF, measured the
average and maximum JZ thickness and correlated Epidemiologic studies have also shown that in
implantation outcomes both with JZ thickness and women with adenomyosis the course of pregnancy
causes of infertility (endometriosis, tubal infertility, may be complicated by several adverse events such as
anovulation, male factor, and unexplained infertility) preterm labour with or without rupture of membranes
(48). The implantation failure rates in their series (PPROM), placental abruption, pre-eclampsia and
were 95.8% vs. 37.5% in the groups with a JZ > small for gestational age (SGA) (Buggio et al.,
7mm vs. < 7mm, respectively. Surprisingly, in this 2018; Hashimoto et al., 2018). Delivery may be
study the highest pregnancy rate (59.3%), was in the complicated by placental malpositions, postpartum
endometriosis group, known from other studies to be haemorrhage, and caesarean hysterectomy (Vigano
associated with the thickest JZ (Kunz et al., 2005). et al., 2015; Vlahos et al., 2017). It is unclear
In a recent metanalysis Younes and Tulandi however, what the real impact of adenomyosis
(2015) examined the impact of adenomyosis on on pregnancy-related complications is, as in the
IVF outcome, including the effect on implantation. majority of cases the diagnosis is made postnatally.
They found that patients with adenomyosis had In a very recent metanalysis of 6 studies Razavi
significantly lower pregnancy (OR 0.70, 95%CI et al. (2019) reporting on 322 adenomyosis cases
0.60-0.90), and implantation (OR 0.66, 95%CI 0.49- and 9420 controls attempted to shed light on the
0.88) rates, compared with those without. They also important question i.e. whether adenomyosis is
observed that patients with diffuse adenomyosis associated with adverse pregnancy outcomes. In
have a tendency for lower pregnancy rates than those all included studies the diagnosis of adenomyosis
with focal disease (OR 1.36, 95%CI 0.67-2.75). was made with TVS, MRI, or a combination of the
In another interesting study, Mavrelos et al. two imaging modalities. Despite having different
(2017) found that IVF patients with ultrasound objectives in terms of the adverse pregnancy
findings of adenomyosis had significantly decreased outcome(-s) studied in relation to the presence
clinical pregnancy rates, (29.2% vs. 42.6%, p=0.044, or absence of adenomyosis, their observational
OR 0.68, 95%CI 0.47-1.00), and that the presence nature, differences in selection of controls, and the
of ≥4 ultrasound features was a negative predictor potential effect of previous obstetric history and
for clinical pregnancy (OR 0.35, 95%CI 0.15-0.82), other risk factors on pregnancy complications that
compared with those with no adenomyosis features. were not eliminated through multivariate analysis,
Their findings indicate that the more severe the this metanalysis produced interesting conclusions:
disease, the higher is the possibility of decreased women with adenomyosis had an increased
pregnancy rates. Unfortunately, in the majority of likelihood of preterm birth (OR, 3.05; 95%CI, 2.08-
reported studies on the effect of adenomyosis on 4.47; phad an increased risk of both preterm delivery (OR 343(48.3%) had adenomyosis alone, 158(22.3%) of 3.09 (95% CI; 1.88-5.09)) and SGA (OR: 3.23, adenomyosis and endometriosis, 129(18.2%), 95% CI; 1.71-6.09). Studies on adenomyosis were adenomyosis and fibroids, and 80(11.3%) all much less in number compared with those reporting three conditions combined. It appears that hyper- on endometriosis, therefore firm conclusions could oestrogenism is the common denominator of all not be drawn from this metanalysis other than to these conditions (Bergeron et al., 2006; Vercellini suggest close monitoring of these patients during et al., 2014; Reis et al., 2016). pregnancy. The prevalence of adenomyosis in symptomatic The pathogenetic mechanism underlying these cases with histologically proven endometriosis, adenomyosis-related pregnancy complications has been reported to be 40% in a recent study probably involves several different aspects. Preterm (Lazzeri et al., 2014). Naftalin et al. (2012) labour with or without PPROM may be caused by an have reported that 48.7% of patients with deep activated systematic or uterine inflammatory process infiltrative endometriosis, are also diagnosed with or infection. Levels of prostaglandins and cytokines adenomyosis. Endometriosis has a spectrum of in the peritoneal fluid are higher among women with symptoms similar to that of adenomyosis including adenomyosis than among controls (Juang et al., chronic pelvic pain and abnormal uterine bleeding. 2007). Local and systematic inflammation triggers It is also a significant factor of female subfertility. myometrial vasoconstriction and stimulates cervical Co-existence of endometriosis and adenomyosis in ripening (Vannuccini et al., 2016). Additionally, an the same patient is always a source of controversy implantation and a placentation defect commonly regarding the attribution of specific symptoms underlies pre-eclampsia, preterm delivery and foetal to each condition. Although they share several growth restriction. In the case of adenomyosis, pathogenetic and clinical characteristics they also pronounced changes of the endometrium- have considerable differences, for example, in myometrium interface possibly interferes with terms of molecular characteristics of the eutopic normal placentation through impaired spiral artery endometrium, such as the leukocyte population and remodelling (Brosens et al., 2010; Brosens et al., apoptosis markers. There is also some evidence of 2013). Furthermore, it has been suggested that an differences in cytokines and inflammatory mediators additional cause of SGA in cases with adenomyotic (Benangiano et al., 2014). uteri may be the increased blood flow shift towards There is recent evidence that adenomyosis may the adenomyotic lesion rather than the placenta develop earlier in life in women with endometriosis (Yorifuji et al., 2013). (Kunz et al., 2007; Chapron et al., 2017). Kunz et Unfortunately, no prospective comparative study al. (2007) performed MRI on 227 women with and exits correlating the depth and extent of adenomyosis without endometriosis who were stratified into 4 with the probability of developing pregnancy age groups (17-24, 25-29, 30-34, and >35 years). complications. Such a study should obviously rely They demonstrated that increasing thickness of the on imaging diagnosis and taking into account what dorsal JZ (an equivalent of adenomyosis according has been discussed above should necessarily include to their definition), commenced early in the third cases with adenomyosis of the inner myometrium decade of life, and progressed steadily during the that have an increased potential to develop impaired fourth decade in patients with endometriosis. On placentation. As with infertility and other clinical the contrary, women without endometriosis showed correlations, the true effect of adenomyosis on almost no sign of adenomyosis up to the age of 34 pregnancy-related complications relies largely upon years (average JZ thickness >11 vs.
hysterectomy cases treated for adenomyosis and/ forms of this disease under this heading (Grimbizis
or fibroids found a significantly higher incidence et al., 2014). Focal forms of adenomyosis such as
of D-SMS in patients with adenomyosis alone adenomyomas including the less common cystic
(p=0.008). However, no significant differences were variables (adult and juvenile adenomyomas)
observed for the occurrence of hypermenorrhoea, possibly have a non-TIAR pathogenetic mechanism
menorrhagia/metrorrhagia, dysmenorrhea, pain, or of development and exhibit distinct imaging and
dyspareunia, between the three groups of patients. clinical profiles (Gordts et al., 2018).
Their results strengthen the doubt of what really Focal adenomyomas of the nodular type most
constitutes D-SMS in adenomyosis. On the other frequently develop in patients in their late 30s (Gilks
hand, technical issues may also complicate the et al., 2000; Grimbizis et al., 2008). Their size may
diagnosis. In the study of Naftalin et al. (2012) of vary considerably, and it has been reported to range
20 cases who underwent hysterectomy within 2 from 0.3-17cm in a series of 30 cases treated with
years from imaging diagnosis of adenomyosis, 4 hysterectomy (Gilks et al., 2000). They commonly
(20%) patients with multiple fibroids were excluded present with worsening dysmenorrhea that may be
from comparison between ultrasound and histology accompanied by menorrhagia or meno-metrorrhagia.
diagnosis, due to the difficulty to obtain systematic Occasionally, they may be diagnosed on the
representative sections from every part of the occasion of a pregnancy complication (Grimbizis
specimen to study adenomyosis. et al., 2008). Their appearance on both TVS and
The same investigators, in their group of 157 MRI is similar to that of fibroids and especially
cases with adenomyosis reported a prevalence those exhibiting cystic degenerative changes, and
of 27.4% of intramural/subserous fibroids, 6.4% although experienced groups on both imaging
submucous fibroids, and 1.9% endometrial polyps. modalities have reported on specific characteristics
Their multivariate analysis for subjective assessment that facilitate the differential diagnosis (Exacoustos
showed that all three pathologies were significantly et al., 2014; Song et al., 2011), it is frequently
associated with menorrhagia, but not dysmenorrhea made during fertility-sparing surgery. The adult
(Naftalin et al., 2014; Naftalin et al., 2016). On cystic variety is a rare form of focal adenomyosis,
the contrary, Li et al. (2014) in their group of 710 and few of these cases may present as giant cystic
adenomyosis cases using a logistic regression model tumours arising from the uterus from a narrow
demonstrated that the presence of fibroids was not pedicle. Several cases with this type of adult cystic
associated positively with either complaint, whereas adenomyomas are completely asymptomatic and are
presence of endometriosis in their series was misdiagnosed as adnexal cysts. On the contrary, the
positively associated with dysmenorrhea and chronic juvenile type commonly presents with debilitating
pelvic pain, and negatively with menorrhagia. dysmenorrhea dating as early as menarche requiring
It is therefore possible that in several women prompt management. The majority of women with
with other uterine and pelvic diseases that are adult cystic adenomyomas are also significantly
not subjected to hysterectomy, the diagnosis younger compared with those bearing diffuse
of adenomyosis will be missed, and symptoms adenomyosis (Protopapas et al., 2008).
caused by it will be attributed to other causes that Brosenset al. (2015) analyzed all cases of cystic
are easier to identify with non-invasive tools. adenomyosis that had been reported until 2012.
Additionally, differences in study populations The most striking characteristic in the majority of
(age, presence and severity of symptoms), method these patients was indeed their significantly younger
of final diagnosis (imaging, histology), and design age at diagnosis. The majority had an early onset
of studies (prospective, retrospective), may well of symptoms, predominantly severe dysmenorrhea
be responsible for discrepancies in the results of that dated since the patients’ onset of menstruation.
clinical correlations in patients diagnosed with Menorrhagia and irregular uterine bleeding were by
adenomyosis. far less common.
Polypoid adenomyomas on the other hand
Symptomatology and the wider spectrum of
represent an even rarer form of focal lesion that
adenomyosis
also develops more commonly in younger patients.
What has been discussed above refers predominantly They invariably protrude into the uterine cavity or
to diffuse adenomyosis defined as the extensive form the endocervical canal and present with abnormal
of the disease, characterized by foci of endometrial uterine bleeding. They are frequently misdiagnosed
mucosa (glands and stroma) scattered throughout as endometrial polyps and are treated as such (Mikos
the uterine musculature (Grimbizis et al., 2014). et al., 2019, Protopapas et al., 2016). Occasionally,
Grimbizis G, et al., proposed a new classification in they may co-exist with other forms of adenomyosis
an attempt to include all common and uncommon that will complicate the clinical picture causing
100 Facts Views Vis Obgynchronic pelvic pain symptoms (Protopapas et al., rates were similar in both groups (21.1 vs. 21.7%).
2017). They may also present with histological No significant differences were observed between
atypia or co-exist with endometrial hyperplasia and groups regarding natural conception and ART with
adenocarcinoma (Grimbizis et al., 2017; Protopapas or without GnRH agonist pre-treatment.
et al., 2016). It is therefore evident, that adenomyosis may indeed
be responsible for all the afore-mentioned types
Conservative surgery and symptomatic relief
of symptoms and signs that can be alleviated to a
In symptomatic patients that are subjected to varying extent with surgery. There is also a chance
conservative surgery for adenomyosis it is easier of improvement in the reproductive outcomes which
to make clinical correlations. The effect of surgery is less for diffuse disease (Kunz et al., 2005; Mikos
on symptoms relief, at least in theory, is a clear et al., 2020). Occasionally, this will come at a price,
indicator of the morbidity caused preoperatively by i.e. the rare risk of uterine rupture during pregnancy
the disease, especially in patients without co-existing due to a defective scar, which has been reported to
pathologies. Additionally, a histological diagnosis be of the order of 6.8% in cases with diffuse disease
of adenomyosis will be made despite weaknesses (0% in focal) (Tan et al., 2018). There is no doubt
and lack of universally accepted criteria. that a solid system of preoperative classification of
In a recent metanalysis, Mikos et al. (2020) the extent and severity of adenomyosis correlating
analysed the results of 19 studies and a total it with symptoms and potential pregnancy
of 1843 patients submitted to fertility-sparing complications, would considerably assist decision-
surgery for adenomyosis. They have shown that making during conservative surgery in order to
complete resection of the disease was related with avoid unnecessary radicality.
improvements in pain and menorrhagia, and a
Can existing pathogenetic theories explain
reduction in uterine volume by a factor of 6.2, 3.9,
discrepancies in clinical profiles?
and 2.3, respectively. Regarding the same outcomes,
partial excision was related with improvements of There is no doubt that we still have a long way to
symptoms and size reduction by a factor of 5.9, 3.0, go regarding the clarification of the natural history
and 2.9, respectively. In studies with mixed volume of adenomyosis. The reasons rest mainly on the
of patients, (complete and partial excision) the inability to make a firm non-invasive diagnosis from
corresponding factor-figures were 4.0, 6.3, and 5.1, early reproductive life and the huge difficulties in
respectively. properly following up a large asymptomatic cohort
It also appears that patients with focal of young women to their menopause. Nevertheless,
adenomyosis have the best chances of symptom we believe that a correlation between the proposed
improvement or resolution after fertility-sparing pathogenetic theories and the clinical spectrum of
surgery. Percentages of pain reduction has been adenomyosis can be attempted based on existing
reported to range from 45-80% with reductions in studies.
dysmenorrhea reported as high as 98%. Percentage Present data indicate that adenomyosis may indeed
reductions in uterine bleeding are in general less appear as an asymptomatic entity in genetically and
pronounced and range from 59-75%. Patients with epigenetically predisposed females. Those women
diffuse and extensive disease have a significant developing symptoms from menarche possibly
variability of pain reduction (18-91%), with an bear lesions that rest in ectopic locations since
average of 60% (46% for dysmenorrhea). A their embryonic life. The appearance of symptoms
reduction of uterine bleeding after surgery in such during adolescence and early reproductive life
cases has been reported to reach an average of may indicate both a congenital aetiology and an
60% (48-71%). This variability in the later cases epigenetic mechanism of early change of lesions
probably reflects different operative techniques and that possesses a progressive character leading
the extent of surgery applied in cases with diffuse to the gradual deterioration of menstrual pain in
adenomyosis (Berlanda et al., 2016). particular. Menarche will obviously result in onset
In another recent systematic review of 18 studies of dysmenorrhea in intra-myometrial isolated
and 1396 infertile patients Tan et al. (2018) analysed non-communicating with the endometrial cavity
the effects of surgical treatment of adenomyosis on ectopic lesions bearing functional endometrium.
reproductive outcomes. They demonstrated that Early disease involving the JZ will present with
overall, the reproductive outcome was better in increased menstrual loss that may not have a rapid
cases with focal adenomyosis compared to those progressive nature due to the repair mechanism that
with diffuse disease, in particular total pregnancy will temporarily isolate minor lesions from eutopic
rates (52.7 vs 34.1%), and successful delivery rates endometrium, and possibly prevent cross-talk. A
(43.5 vs. 25.0%). On the contrary, miscarriage thickened JZ may be considered an early stage of
ADENOMYOSIS: DISEASE, AGING PROCESS, OR BOTH? – PROTOPAPAS et AL. 101the TIAR mechanism when no permanent changes internal adenomyosis, whereas infiltrative disease
of the inner myometrium have occurred. Whether is commonly found together with severe external
it will evolve to typical adenomyotic lesions, will adenomyosis. Progressive JZ thickening occurs
depend on the longevity of the insult, subsequent from mid-30s - though to a lesser extent - also in
molecular and genetic changes, and the operation of unaffected women indicating that adenomyosis may
risk factors such as pregnancy and uterine surgery. also be a process related to uterine aging. Despite the
Therefore, recognition of JZ thickening may be fact, that the classic complex of adenomyosis-related
considered an indicator of an increased risk for symptoms and their timing during its evolution has
developing adenomyosis in later life. recently been challenged, the majority of studies
Dysmenorrhea that has a more constant relation indicate that severe dysmenorrhea remains the most
with disease severity and extent, will be gradually reliable indicator of its severity and extent.
aggravated by further changes of lesions resting Although significant work has been done so far by
in deeper myometrium – a more distant and many experts in both fields, an urgent need to further
foreign to the lesion’s environment. Development clarify the criteria for both imaging and histological
of deeper lesions in the mid-reproductive years diagnosis of adenomyosis and develop a universally
when dysmenorrhea usually appears first, may be accepted classification of its spectrum, extent,
associated with both a TIAR mechanism and/or and severity still exists. This should also take into
metaplasia of progenitor stem cells. The frequent account clinical correlations relating adenomyosis
co-existence of endometriosis in this age group to severity of clinical symptoms such as pain and
commonly causing worsening dysmenorrhea abnormal uterine bleeding, and its potential negative
and sharing similar pathogenetic pathways with effect on fertility. Well-designed prospective studies
adenomyosis may be an important contributor are urgently needed to clarify the potential evolution
to pain symptoms. Menorrhagia may re-appear of adenomyosis from an asymptomatic state to a
in late reproductive and premenopausal years in disease.
relation to the evolution of adenomyosis severity
- by involving more myometrium and increasing
its vascularity - and as a result of the operation of References
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