Adenomyosis

Aaron Budden and Jason Abbott, School of Women’s and Children’s Health UNSW, Sydney, Australia
© 2018 Elsevier Inc. All rights reserved.

Glossary
Extirpative Complete removal or eradication of an organ or tissue.
Multiparous Two or more pregnancies resulting in birth by any means, where the child is > 400 g or > 20 weeks gestation.
Parity The number of children delivered by a woman by any means where the child is > 400 g or > 20 weeks gestation.

Adenomyosis is a structural uterine pathology specifically denoted in the FIGO PALM-COIEN classification system for abnormal
uterine bleeding (AUB-A). The principle symptoms of the pathology are pelvic pain and heavy menstrual bleeding (HMB) and
confirmation of adenomyosis requires histological diagnosis. The prevalence of adenomyosis either in the general community
or a subgroup of women with these symptoms has therefore been difficult to accurately assess. As accuracy and availability of
medical imaging modalities including transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI) have become
more widely available, there has been an increase in image-based diagnosis with high correlation to histological disease when per-
formed by experts. The debate regarding the accuracy of these imaging techniques, which modality to use, and the classification of
disease continues to be important factors in this increasingly recognized uterine pathology.

Epidemiology and Etiology

Diagnosis of adenomyosis may only be truly made after invasive extirpative surgery and complete sectioning, or a positive myome-
trial biopsy with histological demonstration of endometrium or endometrium-like structures within the myometrium and associ-
ated smooth muscle hypertrophy or hyperplasia. Given the difficulty in noninvasive diagnosis, the prevalence of adenomyosis is
variably reported from as few as only a few percent of women through to 70%, although many studies suggest a 20%–35% prev-
alence (Vercellini et al., 1995) when post-hysterectomy specimens are examined histologically.
Increasing parity has been commonly associated with an increased risk of adenomyosis and multiparous women who undergo
caesarean delivery are reported to be up to five times more likely to develop adenomyosis, although this association is variably re-
ported within these studies (Vercellini et al., 1995). It is hypothesized that breach of the endometrial junction leads to glandular
elements growing within the myometrium, which accounts for the increased association with multiparity as well as women who
have received curettage at uterine surgery, termination of pregnancy, and caesarean delivery (Parazzini et al., 1997), although these
factors are again variably reported.
Endometriosis is commonly noted in the presence of adenomyosis both during imaging and at the time of surgery. As there are
similar pathogenic pathways for both diseases, it has been hypothesized that these diseases may occur on a continuum, although
current data to support this is lacking. Other risk factors identified include advancing age and tamoxifen use whilst smoking may be
protective (Parazzini et al., 1997).
There are a number of pathophysiological theories thought to contribute to adenomyosis, however as for endometriosis, there
are likely multiple factors involved including:
1. Infolding of the endometrium with direct penetration into the myometrium
2. Damage to the endometrial–myometrial interface by pregnancy, myometrial incision, or development of leiomyomas
3. Increasing age with cellular damage and repair and
4. Vascular spread
Recent cell biology studies have demonstrated a genetic role in developing adenomyosis. From a well conducted case-control study,
down regulation of DNA methyltransferase 3 alpha (DNMT3A) was reported to be significantly decreased in women with adeno-
myosis compared to women with eutopic endometrium (Zou et al., 2017) and may be responsible for ectopic endometrial cell
proliferation and invasion. From separate work, researchers investigated RhoA and ROCK-I messenger RNA and protein expression,
which is responsible for various cellular functions including cell migration and proliferation and normally has cyclical expression in
concert with menstrual cycles. In women with adenomyosis, the authors reported higher levels of RhoA and ROCK-I messenger
RNA and protein expression throughout the menstrual cycle with loss of normal upgrade and downgrade of protein expression
(Wang et al., 2016).
Whilst there is are common threads in the aetiological theories of adenomyosis with endometriosis and other benign diseases of
the reproductive tract there, the complex epigenetic, hormonal, and reproductive factors are not yet fully defined and continues to
be an area of research and progress in this field.

106 Encyclopedia of Reproduction, 2nd edition, Volume 4 https://doi.org/10.1016/B978-0-12-801238-3.64528-2

 Medical Conditions j Adenomyosis 107

Diagnosis

Whilst histology is considered the ultimate manner by which the diagnosis of adenomyosis may be made, even the variations in the
pathological definitions thwart a clear determination of what is ‘disease’. The presence of glandular and stromal tissue within the
myometrium is generally agreed upon, however, the depth at which this occurs from eutopic endometrium in the absence of a base-
ment membrane is more problematic. Specific pathological problems include angle of specimen sectioning, specimen preparation,
and the natural irregularity of the endometrial–myometrial border. In addition, the requirement for endometrium to be connected
directly to the basalis is fiercely debated since isolated cystic lesions deep in the myometrium, separate to the endometrium, are well
recorded. These difficulties have lead to a number of reported definitions which are based on boundary disruption, depth of pene-
tration, and distribution within the uterus.
It should be clear from the aforementioned problems, that these histological definitions require the uterus to be removedda fact
that is not acceptable for women who desire current or future fertility. Less invasive methods assessing histology through specific
biopsy tools are reported however they each have potential specimen collection and diagnostic issues. For example, given that
a biopsy may only sample part of the uterine muscle, this is problematic for accurate histological diagnosis. A small prospective
study compared TVUS alone versus TVUS guided needle biopsy prior to performing a hysterectomy and reported adenomyosis
in 29/102 (28%) of those women (Vercellini et al., 1998). The sensitivity for TVUS was 83% and just 45% for biopsy with a spec-
ificity of 67% and 96% respectively. In a large cross-sectional study involving 292 women examining the use of hysteroscopic biopsy
(Dakhly et al., 2016), diagnosis by inspection of the endometrial cavity had a sensitivity of 41% and the endomyometrial biopsy
had a sensitivity of 54% compared to the TVUS with a sensitivity of 84%. Specificity of these instruments was 47%, 54%, and 60%
respectively.
The diagnostic capabilities of magnetic resonance imaging (MRI) have evolved substantially and are now able to differentiate
three distinct layers of the functional zone between the endometrium and myometrium. Thickening of the junctional zone to
> 12 mm is a reported surrogate diagnostic marker of adenomyosis on MRI or 3D ultrasound, however the normal physiological
change that occurs in the zone with the menstrual cycle has limited its interpretation and variations in both this thickness and this
finding in isolation as truly representative of disease continued to be debated.

Ultrasound and MRI

With an increasing desire for uterine retention and improvement in imaging techniques, noninvasive diagnosis of adenomyosis has
received greater attention and study. The Morphological Uterus Sonographic Assessment (MUSA) Group reported a consensus state-
ment describing the terms, definitions and measurements that may be used in the sonographic description of uterine diseases
including adenomyosis (Van den Bosch et al., 2015). The authors state that ultrasound of the myometrium may be performed using
a transabdominal (TAS) or transvaginal (TVS) approach though the resolution of TVS is preferred as it allows for detailed assessment
of the myometrium. When assessing the myometrium, the authors recommend measuring the uterine corpus separate to the entire
length of the uterus (corpus and cervix) and the fundal length (fundal serosal surface to the fundal tip of the endometrial cavity) and
endometrial cavity (fundal tip of the endometrial cavity to the internal os) should also be measured separately. Serosal contour
should be reported as either regular or lobulated, the myometrial walls reported as symmetrical or asymmetrical, and the overall
echogenicity as homogenous or heterogeneous. If a lesion is visualized it should be described as well-defined or ill-defined and
its location specific as well as the ratio of the thickness of the lesion to the uterine wall thickness measured on the same image.
Finally the presence or absence of cysts should be reported and where present the number, maximum diameter, and appearance
of cyst fluid included.
When evaluating the use of imaging techniques in the diagnosis of adenomyosis, the changes in imaging technology and tech-
niques must be considered. Older studies reported poor diagnostic accuracy of adenomyosis at sonography however with changes
in 2D transvaginal ultrasound technology, diagnostic accuracy has improved and more recent studies conducted using expert sonol-
ogists and well-defined criteria report very high accuracy (Luciano et al., 2013; Exacoustos et al., 2011). In a prospective study
involving 54 symptomatic women scheduled for hysterectomy, 3D ultrasound mapping was undertaken prior to taking full thick-
ness serosa to endometrium biopsies from areas suspected of adenomyosis (Luciano et al., 2013). This resulted in a sensitivity of
92% and a specificity of 83% when compared to histology after hysterectomy. Importantly from this study, women who had
previous endometrial ablation or were receiving medical treatment had substantial reductions in diagnostic accuracy reflecting
the changes in the endometrial myometrial interface that may occur in these circumstances.
In another small prospective evaluation of women, 2D and 3D TVUS was performed prior to hysterectomy and histological diag-
nosis (Exacoustos et al., 2011). The presence of myometrial cysts was the most specific 2D TVUS feature and a heterogeneous myo-
metrium was the most sensitive. For 2D TVUS and 3D TVUS, respectively, the sensitivity was 75% and 91%, the specificity was 90%
and 88%. It must be recognized that these data occurred in studies with strict methodology but it demonstrates what the best
possible accuracy is in the noninvasive diagnosis of adenomyosis.
The increased access to MRI and its relatively less dependence on operator experience has lead to considerable investigation
in its diagnostic capabilities of adenomyosis. MRI has been compared to ultrasound in a number of studies, again with changes
in the diagnostic accuracy over time of both modalities. From a meta-analysis published in 2010, 2312 women from 23 studies
examining ultrasound and MRI concluded that both techniques have a high accuracy for the noninvasive diagnosis of
108 Medical Conditions j Adenomyosis

adenomyosis, although MRI was determined to more often result in the correct diagnosis (Champaneria et al., 2010). The
pooled sensitivity of ultrasound from this assessment was 72% and specificity 81% compared to MRI with a sensitivity of
77% and specificity of 89%.
With improvement in imaging technology and more reliable interpretation of findings from images, data support a high accu-
racy for the noninvasive diagnosis of adenomyosis with either ultrasonography or MRI. Whilst MRI may be more accessible than
previously, it continues to be both more expensive and less available than transvaginal ultrasound and this may be driving factors in
the choice of imaging for women with suspected adenomyosis.

Symptoms
A woman’s clinical presentation is the usual starting point for a differential diagnosis list and therefore remains an essential part of
the clinical process. However, the reliance of the clinical symptoms usually associated with the presentation of suspected adeno-
myosis is neither sensitive nor specific. Broadly speaking, abnormal uterine bleeding (AUB), pelvic pain (dysmenorrhoea and
noncyclical pelvic pain), and infertility are three main symptoms that women with adenomyosis may present with to their care
provider.
Heavy menstrual bleeding (HMB) does not appear to be highly predictive for all forms of adenomyosis, although increasing
severity of disease may increase the likelihood of this symptom. Likewise, dysmenorrhoea and other noncyclical pelvic pain present
in a variety of gynecological conditions and there is no evidence about pain quality or site that differentiates it from other conditions
such as endometriosis or leiomyomas.
Adenomyosis is increasingly being diagnosed during investigations of the subfertile or infertile couple. MRI studies in women
with adenomyosis have demonstrated uterotubal disturbance and substantial dysperistalsis when diffuse forms of the disease occur.
Increased symptoms such as dysmenorrhoea may represent worsening of these disco-ordinated contractions of the reproductive
musculature and may contribute to poorer sperm transportation for spontaneous pregnancy and increased implantation failure
for advanced reproductive technology (ART) cycles (Vercellini et al., 2014).

Biomarkers
Despite general advancement in the field of cellular biology and the use of specific biomarkers for diagnostics, studies of potential
biomarkers for adenomyosis have been limited. Many of the biomarkers being studies are linked to etiology and are nonspecific,
leading to issues in terms of differentiation from both gynecological disease and other systemic disease.
One of the more promising biomarkers for diagnosis of adenomyosis is MALDI-TOF-MS which has been associated with both
adenomyosis and endometriosis but unfortunately does not differentiate between these diseases (Long et al., 2013). Another prom-
ising biomarker is Moesin, a protein overexpressed in adenomyosis and whilst it is still being developed there is a potential for
determine the extent of disease within the myometrium (Ohara et al., 2014).
Given the current issues with utility of biomarkers for the diagnosis of adenomyosis, none are currently in use clinically and
should only be examined in the framework of appropriate clinical research studies.

Classification

Most classification systems for adenomyosis to date have relied on histopathological assessment of the uterus with or without
imaging criteria. In part due to an increased desire to diagnose women without performing extirpative surgery, there has been
a call for a standardized classification system to aid in diagnosis and management. Previous reviews, studies and consensus meet-
ings have proposed several systems to improve clinical and research descriptions although not as yet has been universally adopted
(Grimbizis et al., 2014). One of the problems of these classification systems is the primary focus on histological findings, specifically
relating to depth and/or severity of disease. One small study has reported a classification based on MRI appearance however of the
163 women included only 40 underwent hysterectomy for complete histological comparison (Kishi et al., 2012). The main classi-
fication systems are presented in Table 1.

Treatment

Women suffering from AUB and dysmenorrhoea have commonly been managed with extirpative surgery with adenomyosis diag-
nosed retrospectively based on histopathological findings. As previously discussed, this method of treatment is not ideal to every
women and available management strategies will depend on specific symptoms, for example dysmenorrhoea or noncyclical pelvic
pain, AUB or infertility as well as the desire for current or future fertility. As both the understanding of the disease and diagnosis has
improved, the available treatment options has improved and includes medical treatments, surgical options, radiologic or sono-
graphic interventions or combinations of these choices.
 Medical Conditions j Adenomyosis 109

Table 1 Classification systems for adenomyosis

Depth Severity Other histopathology MRI

Siegler and Camilien (1994)a Siegler and Camilien (1994)a Grimbizis et al. (2014) Kishi et al. (2012)
Grade 1: inner 1/3rd Mild: 1–3 islets on low Diffuse: extensive disease with Type I: adenomyosis affects only the
Grade 2: 2/3rd of myometrium powered field (LPF) endometrial mucosa scattered inner layer of the myometrium and
Grade 3: entire myometrium Moderate: 4–9 islets throughout uterine musculature not other areas
Severe: >10 islets Focal: Hypertrophic and distorted Type II: adenomyosis affects only the
Hulka et al. (2002) endometrium within the myometrium outer layer of the myometrium
Sammour et al. (2002) Mild: microscopic foci present Polypoid: circumscribed masses of Type III: isolated adenomyomas
or only inner 1/3 involved glands and stroma that is without a relationship to other
1.<25% Focal: focal adenomyosis predominantly smooth muscle structural components
2.25–50% Severe Other: endocervical type and Type IV: any other variation that
3.51–75% retroperitoneal forms does not satisfy these variations
4.>75% of myometrial
thickness
Penetration ratio: depth of
penetration to myometrial Vercellini et al. (2006)b
thickness Grade 1: 1–3 islets at LPF
Grade 2: 4–10 islets
Vercellini et al. (2006)b Grade 3: >10 islets Vercellini et al. (2006)b
Mild: <1/3 deep Configuration of lesion:
Moderate: 1–2/3rd deep
Severe: >2/3rd 1.Focal
2.Nodular
Diffuse

a
System includes both depth and severity.
b
System include depth, severity, and configuration (other).

Medical Treatment
Medical options are often first line treatments and are of particular benefit where women desire uterine conservation to allow for
pregnancy to occur. Options include:
1. Nonhormonal medical to control symptoms of AUB and pain
2. Oral hormonal control such as a combined oral contraceptive pill, oral progestins, GnRHa, danazol, and aromatase inhibitors
3. Intrauterine progestin
In women who complain of symptoms of heavy menstrual bleeding (HMB) are commonly offered options that include nonste-
roidal anti-inflammatories, antifibrinolytic agents, and/or the combined oral contraceptive pill. Whilst these agents may be success-
ful to reduce symptoms of HMB in some forms of AUB, there few data to support adenomyosis (AUB-A) specific outcomes for these
options. In comparison, pharmacological agents used to suppressed endometrial growth including GnRHa, danazol, oral progestins
and aromatase inhibitors are reported to be efficacious for the treatment of adenomyosis (Fawzy and Mesbah, 2015). These agents
have also been shown to be efficacious in women with adenomyosis and infertility, although numbers of women involved in high
quality studies are few and comparative data are lacking at this time. When considering these agents for HMB or infertility, the
benefit of such medication versus the potential side effects must be evaluated carefully as the side effects may be equally unaccept-
able to the woman compared to the systems experienced by adenomyosis.
The use of the Levonogestrol intrauterine device (LNG-IUD) has received the most attention in studies examining the efficacy of
medication to reduce symptoms of AUB and pain in women with adenomyosis. In a recent randomized controlled trial (RCT) 75
women who received either the LNG-IUD or hysterectomy (Ozdegirmenci et al., 2011) were assessed for changes in quality of life
(QOL) over 1 year. The authors reported LNG-IUD improved hemoglobin levels of the first 6 months compared to hysterectomy
and had a superior effect in the psychological and social life domains of the QOL scores. This has supported previous cohort studies
which demonstrated improvement in dysmenorrhoea and high rates of satisfaction.

Surgical Treatment
Surgical management for adenomyosis may be:
1. “Definitive” or “curative” where hysterectomy is performed. Whilst hysterectomy resolves adenomyosis and its associated symp-
toms of HMB and pain, it is a major surgery and is not appropriate in women wanting future fertility or to maintain their uterus.
2. Conservative excisional surgery where the intent is to maintain the uterus in an intact and functional capacity with the aim for
future fertility.
3. Conservative ablative surgery where there is no intent of fertility (and pregnancy would then be contra-indicated).
110 Medical Conditions j Adenomyosis

One of the difficulties commonly faced when considering surgical options is understanding the depth and extent of disease and
what type of surgery could reasonably give symptomatic benefit. When considering conservative excisional surgery it is extremely
important to perform reliable imaging studies to facilitate informed discussion with the patient regarding outcomes and expecta-
tions in addition to accurate preoperative planning. Fertility sparing surgery may be accomplished by:

• Hysteroscopic endomyometrial resection

• Local hysteroscopic resection
• Local laparoscopic resection
• Laparoscopic or ultrasound directed radiofrequency ablation
Hysteroscopic endomyometrial resection requires a high degree of skill and excellent preoperative imaging. Where clinical settings
offer such expertise this procedure is reported to be successful with one prospective study reporting good outcomes with superficial
adenomyosis. Unfortunately, in women with deep disease, the procedure had much higher failure rates to achieve improvement in
symptoms. A recent meta-analysis of 1049 women which evaluated women undergoing hysteroscopic resection, in those where
complete surgical removal of disease was reported there was a reduction of dysmenorrhea of 82%, HMB reduction of 69%, and
a postoperative pregnancy rate of 60%. Where only partial excision was possible, these results are all reduced at 82%, 50%, and
47% respectively (Grimbizis et al., 2014). A particular challenge with these procedures is intraoperative heavy bleeding leading
to increased operating time and decreased resection rates. As such, adjuvant procedures such as temporary uterine artery occlusion
or preoperative GnRHa have been suggested to facilitate the procedure however there is currently insufficient evidence to support
these approaches.
Similar to hysteroscopic resection, a laparoscopic approach aims to resect local disease whilst retaining a functional uterine
corpus but likewise requires a high degree of skill. Most recently a retrospective study of 179 women who underwent laparoscopic
uterine artery occlusions and resection of adenomyosis (Liu et al., 2014) reported uterine volume reduction of 58% at 3 years and
a significant improvement in QOL scores. This is consistent with older and smaller studies and suggests there is some benefit to this
approach.

Radiologic or Sonographic Interventions as Treatment

In alignment with the development of treatment delivery using interventional radiology in a wide range of diseases, there is
increased interest in these procedures to deliver a nonsurgical option for women with adenomyosis. Evidence on techniques remain
largely retrospective, with few prospective trials and two randomized controlled trials that report on specific adjuvant treatments to
the principal intervention rather than comparing between techniques. Currently these techniques are too diverse to compare directly
and known studies are summaried in Table 2.

Table 2 Sonographic and interventional radiological techniques for treating adenomyosis

Authors and year Methodology Outcome(s)

Kim et al. (2011) Retrospective cohort study Significant improvement in QOL scores at 6 months
35 women with symptomatic adenomyosis treated with
magnetic resonance guided focused ultrasound (MRfFUS)
Liang et al. (2012) Retrospective cohort Reduction in dysmenorrhoea in 75% of women at
17 women with symptomatic adenomyosis treated by UAE 6 months
Resolution of pain in 56%
Mean reduction in uterine volume of 50%
Smeets et al. (2012) Retrospective cohort Significant improvement in QOL in 72% at 5 years
40 women with symptomatic adenomyosis treated by UAE Hysterectomy in 18% for ongoing symptoms
Long et al. (2015) Prospective study Significant reduction in uterine volume
47 women with symptomatic adenomyosis and uterine Significant reduction in dysmenorrhoea at 12 months and
volumes greater than 200 cm3 treated by USgHIFU improvement in QOL
Chen et al. (2015) Retrospective cohort 95% of women had successful treatment
2549 women with symptomatic adenomyosis treated by Mean volume ablation rate 73%
USgHIFU 10% adverse outcome (majority were minor-abdominal
pain, vaginal discharge)
Ferrari et al. (2016) Prospective trial There was a reduction in uterine volume for most women
18 women with symptomatic adenomyosis treated by 83% of women had a junctional zone thickness
MRgFUS of <12 mm at 1 year post-treatment

7 women with diffuse disease

11 women with focal disease
Hai et al. (2017) Prospective trial Mean volume reduction 40.8% at 6 months, 41.2% at
87 women with symptomatic adenomyosis treated by TVUS 12 months. Dysmenorrhoea statistically declined
guided transcervical radiofrequency ablation 2 women with intrauterine adhesions
 Medical Conditions j Adenomyosis 111

Infertility and Reproduction

The impact of adenomyosis on female infertility and reproduction is becoming increasingly appreciated. The symptomatic manage-
ment of women with AUB and pain who wish to conserve fertility has been outlined above however there is evidence to suggest the
disease may impact on spontaneous pregnancy and ART efficacy as well as possible complication of pregnancy.
The possible association of adenomyosis to infertility continues to be debated. Whilst transvaginal Imaging studies have shown
an increased spontaneous miscarriage rate in women with diffusely enlarged uterus but without distinct uterine masses this it did
not affect the pregnancy rate. In contrast, a current meta-analysis review of women with adenomyosis undergoing IVF demonstrated
a lower clinical pregnancy rate in women with adenomyosis (40.5% vs. 49.8%) (Vercellini et al., 2014) though there was significant
heterogeneity between studies. This review also reported on higher miscarriage rate among women with adenomyosis (32% vs.
14%). Subsequent to this systematic review, studies continue to report on clinical pregnancy rates in women with adenomyosis
undergoing IVF however the most important outcome, live birth rate, still remains under reported.
In women who are able to conceive there are several studies that report increased complications of pregnancy in women with
adenomyosis. From a large case-control study of 2138 women, those diagnosed with adenomyosis were more likely to have prema-
ture delivery (OR 1.84) or premature rupture of membranes (OR 1.98) (Juang et al., 2007).

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Relevant Website

https://www.endometriosisaustralia.org/single-post/2016/11/08/Adenomyosis-%E2%80%93-sister-to-endometriosis-or-distant-cousin – Endometriosis Australia.