Accepted Manuscript

Adenomyosis; A Clinical Review of a Challenging Gynecologic Condition

Jennifer Struble, MD, Shannon Reid, MD, Mohamed A. Bedaiwy, MD PhD

PII: S1553-4650(15)01559-9
DOI: 10.1016/j.jmig.2015.09.018
Reference: JMIG 2690

To appear in: The Journal of Minimally Invasive Gynecology

Received Date: 31 July 2015

Revised Date: 18 September 2015
Accepted Date: 19 September 2015

Please cite this article as: Struble J, Reid S, Bedaiwy MA, Adenomyosis; A Clinical Review of a
Challenging Gynecologic Condition, The Journal of Minimally Invasive Gynecology (2015), doi: 10.1016/
j.jmig.2015.09.018.

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 ACCEPTED MANUSCRIPT
Struble 1

Adenomyosis; A Clinical Review of a Challenging Gynecologic Condition

Jennifer Struble, MD1

Shannon Reid, MD3

Mohamed A. Bedaiwy, MD PhD2,3

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1
Department of Obstetrics & Gynecology, University of Saskatchewan, Saskatoon, SK, Canada

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2
Division of Reproductive Endocrinology and Infertility, University of British Columbia,

Vancouver, BC, Canada

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3
Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC,

Canada

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This review on adenomyosis highlights current clinical information regarding its
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epidemiology, risk factors, pathogenesis, clinical manifestations, diagnosis, imaging

findings, and treatment.

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Corresponding Author:
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Mohamed A Bedaiwy MD, PhD

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Division of Reproductive Endocrinology and Infertility

Department of Obstetrics and Gynaecology

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Faculty of Medicine

The University of British Columbia

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D415A - 4500 Oak Street

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Vancouver, BC V6H 3V4 Canada

Ph: 604 975 2588 F: 604 875 2987

Email: bedaiwymmm@yahoo.com
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Abstract

Adenomyosis is a heterogenous gynecological condition. Patients with adenomyosis can

have a range of clinical presentations. The most common presentation of adenomyosis is heavy

menstrual bleeding and dysmenorrhea, however patients can also be asymptomatic. Currently,

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there are no standard diagnostic imaging criteria and choosing the optimal treatment for patients

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is challenging. Women with adenomyosis often have other associated gynecological conditions,

such as endometriosis or leiomyomas, therefore making the diagnosis and evaluating response to

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treatment challenging. The objective of this review is to highlight current clinical information

regarding the epidemiology, risk factors, pathogenesis, clinical manifestations, diagnosis,

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imaging findings, and treatment of adenomyosis. Several studies support the theory that
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adenomyosis results from invasion of the endometrium into the myometrium causing alterations

in the junctional zone. These changes are commonly seen on imaging studies such as
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transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI). The second most
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common theory is that adenomyosis results from embryologic misplaced pleuripotent Mllerian
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remnants. Traditionally adenomyosis was only diagnosed after hysterectomy however studies

have shown that a diagnosis can be made with biopsies at hysteroscopy and laparoscopy. Non-
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invasive imaging can be used to help guide the differential diagnosis. The most common findings

on 2-D/3-D TVUS and MRI are reviewed. 2-D TVUS and MRI have a respectable sensitivity
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and specificity however recent studies indicate that 3-D TVUS is superior to 2-D TVUS for the
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diagnosis of adenomyosis and may allow for the diagnosis of early stage disease. Management

options for adenomyosis, both medical and surgical, are reviewed. Currently the only definitive

management option for patients is hysterectomy.

I. Introduction
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Adenomyosis is identified by uterine enlargement secondary to areas of endometrium,

both endometrial glands and stroma, located deep within the myometrium. These areas cause

hyperplasia and hypertrophy of the surrounding myometrium and clinically result in an enlarged

uterus. Ectopic areas of endometrium can be diffusely present throughout the myometrium or

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focal, forming a circumscribed nodular collection, an adenomyoma.1 Frequently it is found in the

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posterior uterine wall, less commonly in the anterior wall of the uterus, and infrequently in the

cornua or by the cervical os.1-3

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The degree of disease is determined by symptom severity, by the number of adenomyotic

foci, and by the distance of the deepest focus of ectopic endometrium from the lower border of

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the endometrium. Levgur et al4 created a grading system to describe the depth of adenomyotic
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foci such as deep (greater than 80%), intermediate (40-80%), and superficial (less than 40%).4

II. Prevalence & Incidence

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The true incidence of adenomyosis is unknown. Historically, a diagnosis of adenomyosis

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was made after hysterectomy in women later in their reproductive years, however the use of
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preoperative imaging has shown that adenomyosis may also occur in adolescents.5 The

prevalence has been reported to range from 1%6 to 70%; this large range is likely reflective of
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the lack of standard diagnostic criteria both by imaging modalities and pathological analyses.

There may also be variations in the literature because of factors such as potential bias by the
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pathologist in making the diagnosis because of knowledge of the patients history or differences
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in the number of tissue samples examined.7 The mean frequency of adenomyosis at hysterectomy

is between 20% to 30%.8,9 Cystic adenomyosis may be present in up to 24% of hysterectomy

specimen10 and is usually found in patients who are multiparous and over the age of 30.11

However cystic adenomyosis can also occur in young girls; this rare form of the disease is called
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juvenile cystic adenomyosis.12,13 Cases of juvenile cystic adenomyosis reported in the literature

are in women younger than 30, which is often used as a cutoff age to differentiate juvenile cystic

adenomyosis from adult cystic adenomyosis.13 Case reports describe young girls presenting with

lower abdominal pain and sever dysmenorrhea, refractory to medical treatment.12

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Surgical management is required for management12,13 and complete resection of the cystic

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adenomyoma can be done laparoscopically.13 Juvenile cystic adenomyosis can be misdiagnosed

as a non-communicating rudimentary horn.12

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III. Risk factors

The etiology of adenomyosis is unknown and various theories have been proposed.

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Support for the various theories comes from commonly identified risk factors such as exposure
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to estrogen, parity, and prior uterine surgery as summarized in Table 1.

It is thought that increased estrogen exposure may contribute to the disease.

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Adenomyosis is most commonly diagnosed in women during their forties and fifties, which is in
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keeping with clinical practice where hysterectomies are common in this age group and
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adenomyosis is then diagnosed at histology. However the increased rate of adenomyosis in this

age group may also be due to prolonged exposure to hormones over a womans lifetime.1 A
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study by Templeman et al14 compared 961 women with a surgically confirmed diagnosis of

adenomyosis to 79,329 women in their base cohort, to serve as the comparison group for
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adenomyosis analyses.14 They found that increasing parity, early menarche (10 years of age),
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short menstrual cycles (24 days in length), elevated BMI and oral contraceptive (OCP) use

were all statistically significant findings in patients with adenomyosis, thus suggesting an

association between adenomyosis and estrogen exposure (Table 1).14 It is not clear if

contraceptive use is a risk factor for adenomyosis, or if women were prescribed an OCP to
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manage symptoms of dysmenorrhea and heavy menstrual bleeding, which are common

symptoms in patients with adnomyosis.14 Parazzini et al8 studied 707 women, 150 of whom had

adenomyosis and found similar risk factors for adenomyosis. The frequency of adenomyosis was

greater in parous women (OR 3.1 for two or more births) and women who had a previous

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spontaneous abortion (OR 1.7), however they did not find a relationship between the risk of

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adenomyosis and the use of the OCP.8 They also found that women who smoked tended to be at

a decreased risk (OR 0.7 for current smokers).8 It is thought that cigarette smoking alters

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hormonal metabolism, leading to a reduced incidence of endometrial abnormalities.15,16

Additionally studies have shown increased rates of adenomyosis in patients who have received

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tamoxifen treatment. Tamoxifen binds to selective estrogen receptors and can stimulate both
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normal and ectopic endometrial tissue fostering the development of adenomyosis.17-19

Parity may be a risk factor as studies have shown an increased frequency of adenomyosis
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in multiparous patients.14 This may be due to the elevated levels of estrogen as described above
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or secondary to trophoblast invasion into the myometrium at implantation.1

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A similar mechanism may occur due to trauma during uterine surgery and therefore

explain the higher prevalence of adenomyosis in patients that have had prior uterine surgery.
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Levgur et al4 found that pregnancy termination was more common in women with adenomyosis

alone or adenomyosis with leiomyomas than in women with leiomyomas alone and women with
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neither (P < .01) thus supporting the theory of endometrial trauma as a cause of adenomyosis.4
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Parazzini et al8 also reported an increased risk of adenomyosis in women who had a history of

dilatation and curettage (OR 2.2). In a case control study by Riggs et al20 they studied 189

women with adenomyosis and 178 women without adenomyosis. They found in the group of

women with adenomyosis the rate of cesarean delivery was 25% compared to 14% in the group
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without adenomyosis. They concluded that there is a strong association between adenomyosis

and previous cesarean section, with an odds ratio of 2.08.20

Patients with adenomyosis may also have another disease process such as leiomyomas or

endometriosis. A study by Taran et al21 compared women who had pathologically confirmed

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diagnoses of leiomyoma (n=152) to adenomyosis (n=76). In this study, women with

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adenomyosis were more likely to be younger, have depression, infertility, dysmenorrhea,

dyspareunia, pelvic pain, and had prior uterine surgery.21

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IV. Pathogenesis

A diagnosis of adenomyosis is made when endometrial glands and stroma are present

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within the musculature of the uterus. Although the pathogenesis of adenomyosis is not known
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there are at least four proposed theories1,22 as summarized in Figure 1. The first theory is that

adenomyosis results from direct invasion of the endometrium into the myometrium. A second
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theory is that adenomyosis results from embryologic misplaced pleuripotent Mllerian remnants.
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Two other theories that are not as common are that adenomyosis is caused by invagination of the
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basalis along the intramyometrial lymphatic system or that adenomyosis results from bone

marrow stem cells.1

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IV.1 Invagination of the Endometrial Basalis

The first and most common theory of the pathogenesis of adenomyosis is that it develops
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from the downward invagination of the endometrial basalis layer into the myometrium. The
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mechanisms that stimulate deep myometrial invasion are unknown, but may be due to

myometrial weakness caused by prior pregnancy or surgery.22

IV.1.A Invagination due to Myometrial Weakness

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Pregnancy and trauma may cause a disruption of the myometrial-endometrial border,

which causes reactive hyperplasia of the basalis and penetration into the injured myometrium.22

Ostrzenski23 published a case report of a patient who had a laparoscopic myomectomy. At the

time of surgery the endometrium, myometrium and uterine serosa were not approximated and the

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patient developed iatrogenic adenomyosis three months postoperatively.23

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IV.1.B Invagination due to Altered Immunological Activity

Another potential mechanism that results in invagination of the basalis endometrium into

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the myometrium may be due to altered immunological activity at the endometrial-myometrial

interface. It has been shown that macrophage activated T and B cells produce antibodies and

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stimulate cytokines that alter the junction zone of the endomyometrium.24
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Although it is not clear what triggers the invagination process hormones likely play a role

in initiating and maintaining adenomyosis.22 Clinically women often develop adenomyosis

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during their reproductive years and the disease regresses after menopause. Some studies have
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shown that adenomyotic tissue exhibits higher expression of estradiol receptors and this
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increased response to estrogen may enhance the invagination and growth of endometriotic tissue

into the myometrium.22,25 Studies have shown that compared to normal adjacent myometrium,
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myometrium containing adenomyosis had higher levels of estrogen sulphatase and aromatase

activity, supporting the theory that a hyperestrogenaemia is required for the development and
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maintenance of adenomyosis.22 A study by Green et al19 found that mice exposed to estrogen by
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treatment with tamoxifen had increased rates of adenomyosis and abnormal myometrium.19

IV.1.C Role of Hormones

Other hormones that may play a role include prolactin, follicle stimulating hormone and

progesterone. It is thought that elevated prolactin levels promote myometrial cell degeneration
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and invasion of endometrial stroma into the myometrium and progression to adenomyosis.26

Taran et al21 completed a case control study of 76 women undergoing hysterectomy with

adenomyosis and 152 women with uterine leiomyomas but no adenomyosis. They found that

adenomyosis was independently associated with a history of depression. Depression and the

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subsequent elevation in prolactin from antidepressant treatment is consistent with animal models

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of adenomyosis.21 In animal models elevated FSH and prolactin appear to induce

adenomyosis.27,28 In mice studies it has been found that mice who lack a fully functional FSH

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receptor developed uterine vascular pathology and adenomyosis which was not seen in the wild-

type mice.28 Further research using the FSH receptor deficient mice might allow for further

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understanding of genes involved in tissue patterning under conditions that produce hormonal,
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growth factor, and receptor imbalances that lead to conditions such as adenomyosis.28

Progesterone plays an important role in regulating the function and receptivity of the
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endometrial lining throughout the menstrual cycle. In women who have progesterone resistance
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their endometrium demonstrates an impaired decidualization response, and therefore they are
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unable to establish and maintain a successful pregnancy.29 The endometrium responds to

progesterone through its interaction with the progesterone receptor, which has two isoforms (PR-
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A and PR-B). The relative concentration of these two isoforms determines the downstream effect

of progesterone; PR-A promotes a pro-inflammatory state and PR-B promotes an anti-

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inflammatory state. Bedaiwy et al30 completed a case control study in women undergoing
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laparoscopic tubal ligation or diagnostic laparoscopy and obtained samples of endometrium from

all participants, 7 with histopathologically proven adenomyosis and 14 controls. They found that

PR-A was the predominant isoform detected in patients with adenomyosis. In eutopic

endometrium, levels of PR-A were significantly higher in patients with adenomyosis (p=.001).30
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IV.2 De novo from Embryologic Misplaced Pleuripotent Mllerian Remnants

Another common theory is that adenomyosis develops de novo from Mllerian rests. This

metaplasia theory is supported by findings of adenomyosis in locations outside the myometrium

such as the rectovaginal septum,1 by a case report of histologically confirmed adenomyosis in a

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patient with Rokitansky-Kuster-Hauser syndrome and therefore no functional endometrium,31

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and in studies demonstrating that ectopic endometrium in adenomyosis differs from eutopic

endometrium in both its proliferative and biological characteristics.1,30,32 Matsumoto et al33

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examined 23 patients with adenomyosis and found that the ectopic endometrium did not have the

same secretory pattern as eutopic endometrium and induction of apoptotic cells and bcl-2 gene

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expression was different in ectopic endometrium compared to eutopic endometrium. The
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adenomyotic tissue did not have the same cyclic changes as eutopic endometrium and was rarely

influenced by hormonal change, which suggests that adenomyotic lesions do not originate in the
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basal endometrium.33 Growth factors such as basic fibroblast growth factor and angiogenic
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growth factor have been found to be different between ectopic and eutopic endometrium, which
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may contribute to the pathogenesis of abnormal uterine bleeding as seen in some patients with

adenomyosis.34
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IV. 3&4. Invagination along the intramyometrial lymphatic system & displaced bone

marrow stem cells

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Two other less common theories are that adenomyosis develops by invagination of the
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basalis endometrium along the intramyometrial lymphatic system1 or it develops from displaced

bone marrow stem cells.35,36 It has been proposed that adenomyosis may develop

from invagination of the deepest portion of the endometrial mucosa along the intramyometrial

lymphatic system.25,32Adenomyosis can be found in hysterectomy specimens within

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intramyometrial lymphatics.25,37

Research has shown that endometrial repopulation can be driven by bone marrow derived

stem cells. Stem cells are thought to have a role in the cyclic regeneration of the endometrium

during each menstrual cycle and this has potential implications for the etiology of both

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endometriosis and adenomyosis. Supporters of this theory believe that the stem cells foster

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development of endometrium within the musculature of the uterus leading to adenomyosis.35,36

V. Clinical Manifestations

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V.1 Symptoms

The clinical presentation of adenomyosis is heterogeneous as summarized in Table 2.

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Abnormal uterine bleeding and dysmenorrhea are two of the most commonly reported symptoms
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in patients with adenomyosis; occurring in approximately 65% of patients.22,38 Symptom onset is

typically reported in women between the ages of 40 and 50.

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Heavy menstrual bleeding occurs in approximately 40-60% of patients. This may be

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secondary to the increased endometrial surface of the enlarged uterus or it may be secondary to
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the increased vascularization of the endometrial lining.39 Other proposed causes are improper

uterine contractions during menses, and overproduction of prostaglandin and estrogen.40 Levgur
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et al4 studied 36 patients with adenomyosis and found that there was no significant difference

between median numbers of adenomyotic foci in women with heavy menstrual bleeding
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compared to women without heavy menstrual bleeding, but the degree of myometrial invasion
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was statistically associated with heavy menstrual bleeding. Heavy menstrual bleeding occurred

in 36.8% of patients with deep foci and 13.3% with intermediate foci (P< .001). Heavy menstrual

bleeding was not associated with superficial foci.4

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Painful menstruation occurs in approximately 15-30% of patients with adenomyosis. This

may be secondary to bleeding and swelling of areas of endometrial tissue within the myometrium

or it may be secondary to the increased prostaglandin production in adenomyotic tissue

compared to normal myometrium.39 Studies have shown that there is increased production of

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prostaglandins within adenomyotic tissue compared to normal myometrium and that there is

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significantly more prostaglandin and eicoisanoid production in patients with severe

dysmenorrhea compared to patients who reported no dysmenorrhea.41 Levgur et al4 found that

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dysmenorrhea was associated with both the amount of adenomyotic foci and the depth of

invasion. The mean number of foci was 10 in women with dysmenorrhea and 4.5 in women

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without (P <.003). Dysmenorrhea was present in 77.8% of women with deep foci, 12.5% of
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women with intermediate myometrial foci (P<.001) and not associated with superficial foci.4

This study was limited to uteri specimens less than 280g. They decided that in larger uteri, the
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diagnosis of adenomyosis was not as common, possibly due to atrophy of foci due to large
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leiomyomas, and therefore large specimens were not suitable for accurate evaluation.4
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McCausland et al42 also found a statistically significant correlation between severity of heavy

menstrual bleeding and depth of adenomyosis.42

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Conversely, Sammour et al found that the spread of adenomyosis foci correlated

significantly with both pelvic pain (p=.02) and dysmenorrhea (p=.01) but not with heavy
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menstrual bleeding or dyspareunia.43 Other reported symptoms include dyspareunia, which can
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be present in 7-10% of patients39 and chronic pelvic pain.44

V.2 Signs

Diffuse uterine enlargement is frequently described as a globular uterus and is a common

finding on physical exam when a patient has adenomyosis. Often the uterus does not exceed the
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size of a 12 week gestational age pregnant uterus.45 The uterus enlarges globally secondary to

proliferation of the ectopic endometrial tissue, which causes smooth muscle cell hyperplasia and

hypertrophy.1 Adenomyosis can also be present in the endometrial cavity as a polypoid mass or it

can form adenomyomas which are focal areas of circumscribed nodular aggregates of smooth

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muscle.1,25,40 Some women may have a tender uterus on physical exam. Shrestha et al46

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completed a prospective case-control study comparing women undergoing a hysterectomy with a

histological diagnosis of sole adenomyosis without fibroid (n=78), women with both

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adenomyosis and fibroid (n=27), and women with only fibroid uterus (n=45). Women in the

adenomyosis group had significantly more uterine tenderness and chronic pelvic pain.46

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Infertility is found in 11-12% of patients.39 Other associated uterine abnormalities are common in
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women with adenomyosis such leiomyomas (50%), endometriosis (11%), and endometrial

polyps (7%).47
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VI. Diagnosis
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VI.1 Histology: Hysterectomy

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Historically the diagnosis of adenomyosis has been made by histological findings after a

hysterectomy. At hysterectomy, often the uterus is enlarged globally and the surface is smooth.
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When cut in half, the cut surface often appears spongy with areas of focal hemorrhage. On

microscopic examination, adenomyosis is identified when endometrial tissue is found inside the
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myometrium. The minimal distance required for a diagnosis has been debated but ranges from
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one-half to two low-power fields from the endomyometrial junction45 or a minimal depth of

invasion ranging from 1 to 4mm.4,6,7,22,25 Involvement of at least 25%25 to one third of

myometrial thickness is another criteria for diagnosis that has been used.40 No one criterion is
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universally accepted and this variation in diagnostic criteria has contributed to the variation in

prevalence rates published in the literature.48

VI.1.A Histology: Hysteroscopic Biopsy

A histological diagnosis of adenomyosis can also be obtained from hysteroscopic or

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laparoscopic myometrial biopsies.49 Fernandez et al49 published a case report of a patient with a

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preoperative diagnosis of hypermenorrhea secondary to adenomyosis and an endometrial polyp.

The patient had a hysteroscopy, resectoscopy, and polypectomy. During her procedure, three

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intramyometrial lacune were identified and blood came through the openings. These lacunae

were resected and sent for histology with the final diagnosis being adenomyosis.49 Adenomyosis

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does not have pathognomonic signs at hysteroscopy. However Molinas and Campo50 have shown
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that hysteroscopy is a useful tool as part of a patients investigations because it allows for

visualization of the uterine cavity, the ability to assess for other potential abnormalities, and it
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offers the possibility of obtaining endometrial or myometrial biopsies under direct visualization.
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Some evidence suggests that irregular endometrium with endometrial defects, cystic
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hemorrhagic lesions, and altered vascularization can be seen at hysteroscopy and that these

findings may be associated with adenomyosis.50 Conversely, McCausland42 completed

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hysteroscopy and myometrial biopsies in 90 patients; 50 of which had normal appearing cavities,

defined by the absence of polyps or submucous myomas, and identified significant adenomyosis,
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greater than 1mm, in 66% (n=33) of patients, as compared with controls with a depth of only
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0.8mm.42 It must be noted that a diagnosis of adenomyosis can be missed if the adenomyosis is

deeper than the biopsy samples taken or is located at sites that are not biopsied.1

VI.1.B Histology: Laparoscopic Biopsy

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Studies have also looked at the role of myometrial biopsies at laparoscopy for the

diagnosis of adenomyosis. Popp et al51 found that the sensitivity of a single myometrial sample

taken at laparoscopy was between 8 to 18.7%.51 Brosens et al52 also found that myometrial

needle biopsy has low sensitivity. They performed 8 needle biopsies on 27 hysterectomy

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specimens with adenomyosis and found that the sensitivity increased with the number of biopsies

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and the depth of adenomyosis. The calculated sensitivity of 2 random biopsies was between 2.3

and 56%.52

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As mentioned previously, often adenomatous tissue has an immature proliferative pattern

and is surrounded by a zone of myometrial hypertrophy and hyperplasia. The adenomyosis can

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be present diffusely throughout the myometrium or localized to discrete areas called an
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adenomyoma. Any area of the uterus may be involved, but the most commonly affected area is

the posterior wall of the uterus.45 These findings can be seen on imaging as described below.
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VI.2 Imaging
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Commonly the diagnosis of adenomyosis is made histologically, however the use of

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imaging can help to guide the differential diagnosis. The two most common modalities are

transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI).

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Currently, there are no standard diagnostic imaging criteria for adenomyosis. This results

in inconsistent preoperative diagnosis, confusion among clinicians and patients, as well as a lack
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of common language used between various studies, making comparisons between published
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literature challenging as illustrated in Supplemental Table 1 and Supplemental Table 2 in the

appendix. Although there is no general consensus for the diagnosis of adenomyosis with

imaging, below are commonly described findings seen on imaging.

VI.2.A Transvaginal Ultrasound (TVUS)

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VI.2.A.i Two-dimensional Transvaginal Ultrasound (2-D TVUS)

The most common 2-D TVUS findings for adenomyosis are heterogenous myometrial

echotecture (Figure 2 A), poorly defined foci of abnormal myometrial echotexture, myometrial

cysts1 and a globular and/or asymmetric uterus (Figure 2 B).53 Although uterine enlargement

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(described as up to 12 cm in uterine length) has been reported as a sonographic finding

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associated adenomyosis,54 the majority of 2-D TVUS studies have not defined the criteria used

for uterine enlargement. In addition, the term globular uterus appears to be a diagnostic

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feature, which is subjectively interpreted by the ultrasound operator. Interestingly, a study by

Exacoustos et al55 found that a 2-D TVUS volume measurement [cm3], calculated by the

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ellipsoid formula (uterine longitudinal diameter x transverse diameter x anteroposterior diameter
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x 0.532), was higher for women without adenomyosis than those with adenomyosis confirmed at

histology.55 Other less commonly reported findings include lack of contour abnormality, absence
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of mass effect, ill-defined margins between normal and abnormal myometrium (Figure 2 C and
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D), and an elliptical myometrial abnormality.56 When the ectopic endometrium extends into the
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inner myometrium this can give the appearance of echogenic linear striations and when these are

not well defined they may give the appearance on ultrasound of poor definition of the
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endomyometrial junction or pseudowidening of the endometrium.56 The diffuse spread of small

vessels within the myometrium has also been described as a diagnostic feature of adenomyosis
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(Figure 2 C and D).55 An adenomyoma is a focal circumscribed nodular collection of ectopic

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endometrium commonly identified on the posterior uterine wall (Figure 2 E).1 Reinhold et al56

reported that areas of decreased echogenicity or heterogeneity of the myometrium are found in

approximately 75% of patients with adenomyosis. These findings represent areas of smooth

muscle hyperplasia or echogenic islands of heterotopic endometrial tissue surrounded by smooth

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muscle respectively.56 Myometrial cysts will be present in 50% of patients. Cysts are dilated

glands or hemorrhagic foci in the heterotopic endometrium. Commonly these are less than 5mm

in diameter. However in cystic adenomyosis, these can be larger (greater than 5mm in diameter).

These can appear as echogenic nodules on ultrasound because of the increased amount of

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hemorrhage within the ectopic endometrial glands.56

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VI.2.A.ii Three-dimensional Transvaginal Ultrasound (3D-TVUS)

As described previously alterations in the junctional zone such as thickening or hyperplasia have

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an important role in the pathogenesis, clinical presentation, and diagnosis of adenomyosis. 3D-

TVUS allows the junctional zone to be visualized more clearly compared to 2D-TVUS.57 In

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supporting the theory that adenomyosis arises from invasion of the endometrium across the
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junctional zone and into the myometrium 3D-TVUS may be advantageous in identifying early

adenomyosis because it allows for evaluation of the junctional zone. On the coronal view the
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junctional zone can be identified as a hypoechoic area around the endometrium and this
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junctional zone can be measured.57 Findings of adenomyosis are commonly described as a

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widened junctional zone, an ill-defined junctional zone, and a distortion or infiltration of the

hypoechoic inner myometrium.55,57

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VI.2.B Magnetic Resonance Imaging (MRI)

On MRI the most common described findings are a large, regular, asymmetric uterus
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without leiomyomas,53 abnormal myometrial signal intensity, thickening of the junctional zone,
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and myometrial foci of high signal intensity on T1 weighted images.38,56

Thickening of the junctional zone can be focal or diffuse, representing the smooth muscle

hyperplasia accompanying the heterotopic endometrial tissue. Reinhold et al58 completed a

prospective study of 119 patients in which 28 had adenomyosis confirmed by histopathology.

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They found that patients with adenomyosis had a mean junctional zone thickness of 15mm,

which was statistically different from patients without adenomyosis 7mm (P <.0001). They

concluded that adenomyosis could be diagnosed with a high degree of accuracy when the

maximal junctional zone thickness is 12mm or greater,58 and that a maximal junction zone

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thickness of 8mm or less usually ruled out adenomyosis.58 Junctional zone thickness can be

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altered secondary to hormone influences and therefore some MRI diagnoses, especially in

postmenopausal women, are made based on a ratio of the junctional zone to the myometrial wall

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thickness of 40%.59

In approximately 50% of patients, bright foci can be seen in areas of abnormal low signal

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intensity within the myometrium on T2-weighted images. These represent foci of heterotopic
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endometrial tissue, cystic dilatation of heterotopic glands or hemorrhagic foci.56 Conversely,

bright foci on T1 weighted images correspond to areas of hemorrhage and are seen less
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commonly. Cystic adenomyosis can result when the degree of hemorrhage is large. This appears
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as well-circumscribed, cystic lesions in the myometrium that show hemorrhage in varying stages
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of organization. On T2-weighted images, these areas have a low-signal intensity rim.56

Other findings that can be seen on MRI include linear striations of increased signal
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intensity radiating from the endometrium into the myometrium on T2-weighted images. These

represent invasion of the basal endometrium into the myometrium. Pseudowidening of the
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endometrium occurs when these striations become less defined. Other signs of adenomyosis on
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MRI include lack of contour abnormality or mass effect, ill-defined margins between normal and

abnormal myometrium, and an elliptical shape of a low-signal-intensity myometrial

abnormality.56

VI.2.C Diagnostic Accuracy

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Many studies have been done to determine the diagnostic accuracy of TVUS and MRI as

summarized in Table 3. Reinhold et al60 completed a prospective study by preforming TVUS on

100 women undergoing hysterectomy for a variety of conditions and correlated imaging findings

with histologic examination. TVUS correctly identified 25 of 29 pathologically proven cases of

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adenomyosis and ruled it out in 61 of 71 patients. They concluded that TVUS could be used to

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accurately diagnose adenomyosis.60 A prospective study by Brosens et al61 performed TVUS on

56 women with heavy menstrual bleeding and dysmenorrhea and compared the sonographic

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diagnosis of adenomyosis to histological findings after hysterectomy (n = 34, 15 of whom had a

diagnosis of adenomyosis) or to the appearances on MRI (n=22; 13 of whom had a diagnosis of

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ademonyosis). TVUS demonstrated sensitivity, specificity, positive and negative predictive
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values of 86%, 50%, 86%, and 77% respectively. They concluded that TVUS had good

sensitivity but poor specificity.61

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Exacoustos et al55 compared 2D-TVUS to 3D-TVUS in 72 women prior to hysterectomy

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and correlated sonographic findings of adenomyosis to histological findings. The histological

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prevalence of adenomyosis was 44.4% and overall accuracy of 2D-TVUS was 83%, sensitivity

75%, specificity 90%, positive predictive value 86%, and negative predictive value 82%. They
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found the most specific finding on 2D-TVUS was the presence of myometrial cysts with a

specificity of 98% and accuracy of 78%. The most sensitive finding was heterogeneous
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myometrium with a sensitivity of 88% and an accuracy of 75%.55 The overall accuracy for 3D-
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TVUS was higher than 2D-TVUS at 89% and was found to have a sensitivity of 91%, specificity

of 88%, positive predictive value of 85% and negative predicative value of 92%.55 Findings on

3D-TVUS that had high sensitivity and accuracy were when the difference between the maximal

junctional zone thickness and the minimal junctional zone was greater than or equal to 4 mm,
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and findings of junctional zone infiltration and distortion.55 Exacoustos et al concluded that when

using 3D-TVUS, the coronal section of the uterus allows for accurate evaluation and

measurement of the junctional zone and has good diagnostic accuracy for adenomyosis.55

Compared to MRI Reinhold et al58 concluded that there was no statistically significant

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difference between the sensitivities (P=.65) and specificities (P=.75) of TVUS and MRI, after

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completing a prospective study on 119 patients who had a TVUS and MRI prior to hysterectomy.

Of the 119 patients, 28 had confirmed adenomyosis.58 Bazot et al53 also found that TVUS was

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just as accurate in women with adenomyosis who did not have other uterine pathology. They

prospectively studied 120 patients, 40 (33.0%) of whom had adenomyosis, by comparing

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transabdominal ultrasounds, transvaginal ultrasound and MRI for the diagnosis of adenomyosis
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and correlating these findings with histological findings. They found the sensitivity, specificity,

and positive and negative predictive values of TVUS and MRI to be 65.0% and 77.5%, 97.5%
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and 92.5%, 92.8% and 83.8%, and 88.8% and 89.2% respectively and concluded that in women
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who do not have a leiomyoma TVUS is as efficient as MRI in diagnosing adenomyosis, whereas
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in women who have an associated leiomyoma the sensitivity was lower in TVUS and therefore

MRI may be recommended in these patients.53

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Conversely, Ascher et al62 prospectively compared TVUS and MRI for the diagnosis of

adenomyosis in 20 women with a clinical suspicion of adenomyosis. All cases were confirmed
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by pathology; 17 were found to have adenomyosis. The sensitivity was 53% and 88%; specificity
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of 66% and 66% for TVUS and MRI respectively. They concluded that MRI was significantly

better (P= .02) than TVUS in the diagnosis of adenomyosis.62 Dueholm et al63 also found that

MRI was superior to TVUS in a study of 106 women who had TVUS and MRI prior to

hysterectomy, 22 of which had adenomyosis.

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MRI has been shown to be highly accurate in the diagnosis of adenomyosis. Togashi et

al64 correlated MRI findings with surgical/pathological findings in 93 patients who had an

enlarged uterus. The cause of the enlarged uterus was due to leiomyoma (n=71), ademonyosis

(n=16), leiomyoma and adenomyosis (n=6). The cause of uterine enlargement was correctly

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diagnosed by MRI in 92 of the 93 cases.64 More recently, Champaneria et al65 completed a

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systematic review to compare the diagnostic accuracy of MRI and ultrasound. They included 23

articles, involving 2,312 women and found that TVUS had a pooled sensitivity of 72% (95% CI

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65-79%), specificity of 81% (95% CI 77-85%), positive likelihood ratio of 3.7 (95% CI 2.1-6.4)

and negative likelihood ratio of 0.3 (95% CI 0.1-0.5). MRI had a pooled sensitivity of 77% (95%

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CI 67-85%), specificity of 89% (95% CI 84-92%), positive likelihood ratio of 6.5 (95% CI 4.5-
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9.3), and negative likelihood ratio of 0.2 (95% CI 0.1-0.4). They concluded that both TVUS and

MRI had high levels of accuracy in diagnosing adenomyosis, but that the correct diagnosis was
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reached more often by MRI.65

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VII. Treatment
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Historically the standard treatment for adenomyosis has been hysterectomy. However this

is not always an option for patients, especially those women who want to maintain fertility
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options, or who are not good surgical candidates because of other comorbidities.1 Treatment

options for adenomyosis include both medical and surgical management. However determining
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the optimal treatment for patients can be difficult. As described above there are no agreed upon
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diagnostic imaging criteria. Patients symptoms can be heterogeneous, adenomyosis can be

associated with other gynecological conditions, and there are few high quality randomized

controlled trials.66 Much of the published literature includes only case reports, retrospective

studies, or studies with small numbers of participants. Because there are no agreed upon 2-D/3-D
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TVUS and MRI diagnostic criteria, it is challenging to monitor treatment effect objectively after

medical management or to compare between studies where different imaging criteria has been

used. The accuracy of ultrasound is also dependent on the population that is studied, if there is

additional pathology present such as endometriosis or leiomyomas, operator skill and experience,

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quality of the ultrasound machine, and post image processing of 3D acquisition.66

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Determining the effect of treatment on patients symptoms is also challenging as

concurrent benign gynecologic pathology such as leiomyomas, endometriosis, or polyps can lead

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to significant bias when studying the effect of treatment on adenomyosis-related symptoms such

as heavy menstrual bleeding and dysmenorrhea.66 Some medical therapies have shown

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regression of disease short-term.1 Unfortunately there are limited medical options for patients
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that alleviate their symptoms but allow for conception as summarized in Table 4.

VII.1 Medical Management

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VII.1.A Non-steroidal Anti-inflammatory Drugs (NSAIDs)

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Women with dysmenorrhea have elevated levels of prostaglandins, which can result in
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painful cramps. Women may experience symptom improvement by taking non-steroidal anti-

inflammatory drugs, which inhibit cyclooxygenase, the enzyme involved in the production of
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prostaglandins. Marjoribanks et al67 completed a review comparing all non-steroidal anti-

inflammatory drugs to placebo in the treatment of primary dysmenorrhea. They concluded that
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NSAIDs are significantly more effective for pain relief than placebo in women with
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dysmenorrhea (OR 7.91, 95% CI 5.65 to 11.09). However the overall adverse effect was also

increased (OR 1.52 95% CI 1.09 to 2.12). Women must understand these potential adverse

effects and if willing may try treatment with NSAIDs as a option for symptoms of

dysmenorrhea.67
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VII.1.B Oral Contraceptive Pills and Progestins

Patients may show symptomatic improvement of dysmenorrhea and heavy menstrual

bleeding when taking oral contraception continuously or from use of a high-dose progestin such

as continuous oral norethindrone acetate or subcutaneous depot medroxyprogesterone. These

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medications help improve symptoms by inducing amenorrhea and for a short period of time may

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also induce regression of adenomyosis,1 however randomized control trials are lacking and some

experts believe that these therapies are ineffective in treating adenomyosis.22

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VII.1.C Levonorgestrel Intrauterine Device

The levonorgestrel intrauterine device (Mirena) is an effective treatment for

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adenomyosis. It acts by releasing 20 mcg of levonorgestrel per day for up to 5 years.
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Symptomatic improvement is thought to occur secondary to two mechanisms. Firstly, it causes

decidualization of the endometrium resulting in decreased menstrual flow. Secondly, it is thought

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to act on adenomyotic foci by causing a down regulation of the estrogen receptors. This causes
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the ectopic foci of endometrium to reduce in size, allowing the uterus to contract more
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efficiently, reducing menstrual blood loss, and resulting in decreased prostaglandin production,

improving dysmenorrhea.6,68 Various studies have been published reporting improvements in

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symptoms of heavy menstrual bleeding and dysmenorrhea, as well as radiologic changes after

the insertion of the LNG-IUD.38,68-70

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Fedele et al69 studied 25 women who had TVUS diagnosed adenomyosis and recurrent
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heavy menstrual bleeding. Each patient had a levonorgestel 20mcg/day IUD inserted and

completed a pictorial blood loss assessment chart each month and had TVUS examinations at 3,

6, and 12 months post insertion. One patient requested the IUD be removed after 4 months

because of persistent irregular bleeding and another patient had expulsion of the IUD after 2
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months. Of the remaining 23 women, they found a reduced uterine volume, decreased blood loss,

and a significant increase in hemoglobin, hematocrit, and serum ferritin one year after

insertion.69

Bragheto et al38 studied 29 women who suffered from heavy menstrual bleeding and

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dysmenorrhea secondary to adenomyosis diagnosed by MRI. Women were evaluated at baseline

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and then at 3 and 6 months post LNG-IUD insertion. They found a significant reduction in

junctional zone thickness (24.2% p < .0001), however there was no reduction in uterine volume.

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There was also a significant decrease in pain scores and the most common pattern of bleeding

was oligomenorrhea.38

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Sheng et al70 studied the efficacy of the LNG-IUD in 94 women with moderate or severe
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dysmenorrhea associated with adenomyosis diagnosed by TVUS. They followed women for 3

years and found a significant improvement in scores of dysmenorrhea; mean baseline score of
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77.9 decreased to 11.8, 36 months after insertion (p <.001). They also found a decrease in uterine
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volume and serum CA 125 levels. Overall patient satisfaction rate was 72.5%.70 Cho et al71 also
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studied the long-term clinical effects of LNG-IUD in 47 women diagnosed with adenomyosis.

They found that pain scores and pictorial blood loss assessment chart scores decreased in 6
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months and showed significant decreases after 36 months. However there was a significant

increase in uterine volume, pain scores, and pictorial blood loss assessment chart scores at 36
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months compared with 12 months post insertion. They concluded that the LNG-IUD is effective
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at reducing uterine volume with improvement of vascularity and patients symptoms, however

this benefit may be limited to 2 years post insertion.71

Ozdegirmenci et al72 completed a randomized study in 75 women with a clinical

suspicion of adenomyosis complaining of heavy menstrual bleeding and/or dysmenorrhea.

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Women who had TVUS and MRI findings consistent with adenomyosis were randomized to

either levonorgestrel intrauterine system (LNG-IUD) or hysterectomy. In addition to monitoring

blood loss and hemoglobin levels, the authors also studied the impact of treatment on the

participants quality of life. For quality of life (QOL) evaluation, they used the World Health

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Organization Quality of Life-Short Form, Turkish Version (WHOQOL-BREF TR). This

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questionnaire has 26 questions that relate to four domains: physical health, psychological health,

social relationships, and environment. The version they used included a national environment

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item (environmental-TR), which contributes to the environmental domain of the scale to

calculate a national-environmental domain score. National environment items supplement the

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core WHOQOL and reflect special aspects of quality of life not included in the core WHOQOL
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because they are not universally valued. The participants scored each item, illustrating how they

felt in the past 2 weeks; a higher score indicated a better quality of life. They found that
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hemoglobin levels were significantly increased in both treatment groups at 6 months and 1year
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post-treatment and there was no statistical difference between the two groups. When
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pretreatment and post treatment quality of life scores were compared, they found women who

had a hysterectomy showed improvement in three domains (environmental, environmental-TR,

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and physical) whereas women who had the LNG-IUD showed improvement in all 5 domains

(environmental, environmental-TR, physical, physiological, and social).72 They concluded that

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LNG-IUD may be a promising therapy for adenomyosis with results similar to hysterectomy in
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terms of managing heavy menstrual bleeding and hemoglobin levels and superior to

hysterectomy with respect to physiologic, social well-being, and quality of life at one-year

follow-up.72
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Generally women experience significant symptom improvement with the LNG-IUD, and

this may provide a medical treatment that allows them to retain future fertility options. The most

frequent problem with the LNG-IUD is irregular spotting during the initial months post insertion;

however this usually resolves within 3 months.6 Other potential side effects that Sheng et al70

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found were weight gain (28.7%), simple ovarian cyst formation (22.3%) and lower abdominal

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pain (12.8%).70 Headache, breast tenderness, acne69 and transient depressive episodes have also

been reported.72

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VII.1.D Danazol

Danazol acts by suppressing pituitary release of FSH and LH and therefore causes

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atrophy of both normal and ectopic endometrial tissue. Systemic treatment with Danazol has
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been shown to decrease expression of aromatase cytochrome P450 in disease eutopic

endometrium; this may contribute to improvement of symptoms and reduced uterine size in
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patients treated with danazol.73 However, it is not well tolerated by many patients because of its
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side effect profile which can include acne, depression, deepening of the voice, hirsutism, hot
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flashes, decreased high-density lipoprotein levels, increased liver enzyme concentrations, oily

skin, muscle cramps, reduced breast size, and weight gain.1

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Novel ways of treating adenomyosis with danazol are being studied such as intracervical

injections and with IUDs. These methods allow local delivery of hormones in an attempt to
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minimize systemic side effects. Takebayashi et al74 studied patients receiving cervical danazol
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suspension injections and reported that all women had subjective improvement of symptoms by

the 24th week.74 Igarashi et al75 studied 14 women with dysmenorrhea, heavy menstrual bleeding,

or infertility diagnosed with adenomyosis, confirmed by bimanual examination, transvaginal

ultrasonography, and magnetic resonance imaging (MRI). Each patient had a danazol-loaded
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IUD inserted. They found that serum danazol levels remained below the level of detection during

the study, unlike in patients receiving oral danazol and therefore the danazol IUD did not cause

any of the side effects typically observed with oral therapy. During their study 9 patients had

complete remission of dysmenorrhea, reduction of symptoms was reported in 4 patients, and 1

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patient reported no change in symptoms. Heavy menstrual bleeding resolved in 12 patients, and

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no change in 2 patients. There was a reduction of the maximal thickness of the myometrium in 9

patients. Additionally after the danazol IUD was removed 3 of the 4 infertile patients

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successfully conceived.75

Shawki et al76 prospectively studied 21 women with heavy menstrual bleeding,

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dysmenorrhea and adenomyosis diagnosed by TVUS and hysteroscopic guided endomyometrial
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biopsies. All women had a 400mg loaded danazol IUD placed for 6 months. They found that

menstrual related pains and dysmenorrhea resolved in 17 women (80.9%). Improvement in

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bleeding and regular menstrual blood flow occurred in 16 women (76%), and there was
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significant increase in hemoglobin levels during treatment. Two women achieved spontaneous
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pregnancy within 6 months after removal of the IUD out of 9 infertile women. There was only

once case of spontaneous expulsion and no systemic side effects known with danazol were
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reported during the study. In keeping with other studies, serum levels of danazol were

undetectable.76 This remains an experimental treatment and is not readily available for patient
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use.
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VII.1.E GnRH Agonists

GnRH agonists cause a suppression of pituitary gonadotropins and thus induce ovarian

quiescence, resulting in a medical menopausal, hypoestrogenic state.39 The first report of using a

GnRH analogue in the management of adenomyosis was published by Grow et al77 in 1991.
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They reported a 65% reduction in uterine volume after 4 months of treatment as well as

amenorrhea and improvement in severe dysmenorrhea.77 Huang et al39 reported 2 cases of

women with infertility suspected to be secondary to adenomyosis. Both women had biopsy

proven adenomyosis and had 3-month treatment of buserelin acetate nasal spray, 600mg/d in

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divided doses. In the first case, the patients symptoms of heavy menstrual bleeding and

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dysmenorrhea completely resolved and her uterine volume decreased from 344cm3 to 180cm3.

The second patient also had improvement in her symptoms and a decrease in uterine volume

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from 330cm3 to 178cm3 following a 3-month treatment. Both patients went on to conceive within

6 months of stopping treatment. This study showed that GnRH analogues can be an effective for

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patients with heavy menstrual bleeding and dysmenorrhea secondary to adenomyosis and can
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result in a reduction in uterine size. However treatment is often limited to short duration because

of undesirable side effects that occur with long course treatment, such as hot flushes, vaginal
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atrophy and accelerated bone demineralization.39 Additionally, after discontinuation of therapy,

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symptoms may return and uterine volumes may increase to pretreatment size.1 Further research is
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required to determine the duration of GnRH analogue treatment that will result in symptomatic

improvement while minimizing risk of long-term side effects and delay in patients wanting to
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conceive.39

More recently Akira et al78 published a case report of a patient on low-dose buserelin
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acetate treatment for 2 years without side effects of low estrogen. The patient had adenomyosis
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complicated by deep vein thrombosis. The deep vein thrombosis was confirmed by leg

venography and treated with thrombolytic therapy. The patient wanted to conserve her uterus and

it was decided to treat her adenomyosis, which was causing chronic pelvic pain, dysmenorrhea

and anemia due to hypermenorrhea, with a low-dose GnRH agonist. She was started on 450
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microg/day of buserelin acetate nasally. Her anemia, leg numbness and chronic pelvic pain

resolved and she did not have symptoms of estrogen deficiency for more than 2 years on

treatment.78

VII.1.F Aromatase Inhibitors

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Aromatase cytochrome P-450 converts androgens to estrogens and its expression has

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been observed in both eutopic and ectopic endometrium in patients with endometriosis. It is

thought that aromatase P450 expression in the endometrium is limited to women with

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proliferative reproductive tract disorders such as adenomyosis, endometriosis, and

leiomyomata.79,80 Studies have shown an improvement in mean pain scores, lesion size and

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quality of life scores in patients with endometriosis treated with aromatase inhibitors81 and
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therefore patients with adenomyosis may similarly benefit from treatment with aromatase

inhibitors.6 Further research is required to determine the role of aromatase inhibitors for the
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treatment of adnomyosis.1
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VII.2 Surgical
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VII.2.A Endometrial Ablation and Hysteroscopic Resection

Endometrial ablation can be used as a treatment option in patients who have completed
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childbearing. Typically ablation procedures are classified as being either non-resectoscopic such

as bipolar radiofrequency, cryotherapy, circulating hot water, microwave, and thermal balloon or
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as resectoscopic including wire loop resection, laser or roller ball ablation. A common concern
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with ablation and resection procedures is that the depth of the adenomyotic lesions limits the

success of the treatment. Deep ectopic endometrium can become trapped behind the ablated edge

resulting in pain and bleeding.1 Resection is often limited to superficial lesions as there is risk of
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causing significant bleeding from arteries present approximately 5 mm below the myometrial

surface.82

McCausland et al83 examined 50 patients diagnosed with adenomyosis up to 3.5 years

after endometrial ablation and found that patients with superficial adenomyosis (<2mm) had

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good results, whereas patients with deep adenomyosis (>2mm) had poor outcomes after ablation.

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They reported that the rollerball electrode has a coagulation effect approximately 2 to 3 mm into

the myometrium, and can therefore destroy the endometrium and surrounding hypertrophic

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dysfunctional smooth muscle. However as the ectopic endometrium penetrates further into the

myometrium there is less complete destruction of the tissue.83 They also found that patients with

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post-ablation bleeding responded well to treatment with progesterone if they had superficial
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adenomyosis, however progesterone therapy was often ineffective in patients with deep

adneomyosis.83
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El Nashar et al84 completed a retrospective study of 816 women who had a global
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endometrial procedure with either a thermal balloon ablation or radio frequency ablation. They
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found that 16% of patients had treatment failure requiring hysterectomy or re-ablation because of

bleeding or pain. The overall amenorrhea rate, defined as cessation of bleeding for at least 12
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months post procedure, was 23%. Predictors of amenorrhea were age greater than 45, uterine

length less than 9cm, endometrial thickness less than 4mm and the use of radio-frequency
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ablation instead of thermal balloon ablation.84 Predictors of treatment failure included age
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younger than 45 years, parity of 5 or greater, prior tubal ligation, and history of dysmenorrhea.84

These factors should be considered as many women with adenomyosis are multiparous and

suffer from dysmenorrhea and therefore may be more likely to fail this treatment option. A
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repeat procedure can be considered in patients who do not have a satisfactory result after their

initial surgery.85

More recently Gordts et al86 published a paper on two patients with cystic adenomyosis

and illustrated the role of hysteroscopy in both the diagnosis and excision of myometrial cystic

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adenomyosis by using mechanical dissection and ablative bipolar current. They explained that at

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hysteroscopy the cystic adenomyosis may appear as a bulge into the cavity, or one may see

abnormal vascularization or fibrosis in the endometrium overlying the cyst.86 Visualization of the

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cystic structures is improved by lowering the intrauterine pressure. In addition to being able to

visualize the cavity directly, another benefit of this approach is that it allows for biopsies under

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direct visualization and/or ultrasound guidance. In their first case the patient was found to have a
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bulging area of abnormal vascularization at hysteroscopy. This area was opened using

hysteroscopic scissors and a brownish fluid came from the area. On inspection of this cyst the
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authors noted a fibrotic wall and areas of endometrial-like tissue. The lesion was resected and the
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histological findings were in keeping with cystic adenomyosis.86 In the second case, Gordts et
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al86 described a patient known to have an intramural cyst diagnosed on MRI. At hysteroscopy the

cavity appeared normal however using ultrasound guidance the cystic lesion was localized and
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they used a spirotome to create a channel into the cyst. The inner cystic wall was coagulated and

follow up hysteroscopy 10 week later revealed a slightly inflamed endometrial cavity and a
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normal uterine cavity with no adhesions. The patient went on to have GnRH-A therapy and IVF
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therapy that was unsuccessful and had recurrence of heavy menstrual bleeding. Follow up MRI

illustrated a focal enlargement of the junctional zone present at the mid-third of the uterine

corpus. They concluded that hysteroscopy allowed for direct visualization of the cavity and the

ability to treat cystic adenomyosis by mechanical dissection or bipolar ablative surgery while
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causing minimal tissue damage, leaving the outer myometrium intact, preserving fertility, and

avoiding an abdominal scar.86 However it is noted that this approach is not an option for diffuse

adenomyosis and when patients have larger cystic adenomyotic structures localized in the outer

intramural third a laparoscopic approach is better.86

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VII.2.B Uterine Artery Embolization

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Uterine artery embolization is another method for managing symptoms secondary to

dysmenorrhea. Patients report improvement in symptoms following uterine artery embolization87

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with significant improvement in symptoms of heavy menstrual bleeding and dysmenorrhea (p

<.001).88 In a review article by Popovic et al89 they found that in 511 women from 15 studies,

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where long-term data was available, improvements were reported by 387 patients (75.7%). They
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concluded that uterine artery embolization for adenomyosis had significant clinical and

symptomatic improvements at both a short-term and long-term follow-up. The median follow-up
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from these studies was 26.9 months.89 However commonly reported side effects include pelvic
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pain, nausea, and fever due to ischemic necrosis.90 Nearly 5% of patients suffer a major
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complication such as infection, hemorrhage, or unplanned surgical procedure.91 Additionally

there are reports of decreased ovarian function following uterine artery embolization.90
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Jha et al87 studied 30 patients with adenomyosis diagnosed by MRI prior to uterine artery

embolization. Follow-up MRI one year after UAE showed changes such as areas of
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devascularization of adenomyosis. The three patients with pure adenomyosis and 6 patients with
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adenomyosis and uterine fibroids, but where adenomyosis was the dominant disease, reported an

improvement in symptoms.87 Kim et al88 completed a retrospective study on women who

underwent UAE for adenomyosis, excluding patients with fibroids. Of the 66 patients, 54

patients had a follow-up period of 3 years or longer and were enrolled in the study. Thirty-one
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(57.4%) of these women had long-term success.88 They concluded that UAE was an option for

patients, however women should be informed of the risks of treatment failure (7.4%), recurrence

(35%), and the potential need for hysterectomy (26%).88

VII.2.C Myometrium or Adenomyoma excision

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Excision of adenomyotic foci can be completed if the ectopic endometrium is well

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identified. However the lesions often are not clearly defined and the adenomyosis is present

diffusely throughout the myometrium. Subsequently the success following excisional treatment

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is low at 50%.82 Wang et al92 prospectively studied 165 women who had conservative

adenomyomectomy and compared outcomes of patients who had surgery alone (n=51) versus

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women who had surgery and then had a postoperative 6 course treatment of GnRH agonist
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(n=114). After treatment there was a significant decrease in dysmenorrhea scores and heavy

menstrual bleeding for both treatment groups. Women who were more likely to have symptom
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relapse following 2 year follow up were those with a higher preoperative serum CA125 as well
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as higher baseline heavy menstrual bleeding and dysmenorrhea compared to those women who
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did not have symptom relapse.92 Additionally this study showed promising reproductive

outcomes following treatment; 71 women were sexually active and did not use contraception and
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55 of these women became pregnant. Clinical pregnancy rate was 77.5% and 49 women (69.0%)

had a successful delivery. There was no statistical difference between the two groups.92
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Fedele et al93 also evaluated reproductive outcomes in 28 women who had conservative
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surgery for uterine adenomyoma. Patients (n=18) wanting children were followed for a mean of

53.2 months. Thirteen (72.2%) women conceived and there were 18 pregnancies. Of these, there

were 9 (50%) term deliveries, 7 (38.8%) spontaneous abortions, 1 (5.6%) ectopic pregnancy, and

1 (5.6%) pre-term delivery with neonatal death. Although excision may provide an option for
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symptomatic patients wanting to become pregnant, it should be noted that this rate of

spontaneous abortion is higher than the general population possibly due to scar tissue formation

and therefore patients should be counseled appropriately.93

VII.2.D Myometrial Electrocoagulation

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Myometrial electrocoagulation by laparoscopy or hysteroscopy can cause a decrease in

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adenomyosis secondary to necrosis. This method has been used in both diffuse and localized

disease and may be an option in symptomatic patients with extensive adenomyosis, who have

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failed medical therapy, where excision is not possible, and they want to preserve there uterus but

do not wish to conceive. Wood et al82 reported 2 cases that had improvement in dysmenorrhea

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and bleeding 2 years after treatment. The procedure is completed by using unipolar or bipolar
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needles at 50 W coagulation and the extent of treatment is controlled by current strength and

duration of time the needles are in place. The depth of coagulation is predetermined by the
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thickness of disease found on preoperative MRI. Limitations to myometrial electrocoagulation

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are that this approach may be less accurate than surgical excision because the extent of abnormal
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tissue being treated cannot be confirmed during the time of surgery. Secondly, the treated areas

form scar tissue and this may decrease the strength of the uterus. Patients may be at risk of
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uterine rupture and therefore permanent contraception should be offered. Wood et al82 reported a

case of uterine rupture at 12 weeks gestational age in a patient treated with myometrial
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electrocoagulation and therefore felt that this procedure should be offered to women over the age
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of 40 who have completed childbearing, and who want to avoid a larger surgery such as excision

or hysterectomy.82

The published reports of myometrial electrocoagulation are limited, and the success of

treatment ranges from 55% to 70%.1 Wood et al94 reported 7 patients treated by myometrial
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electrocoagulation. Four (57.1%) of these patients were considered cured, meaning they had

relief of heavy menstrual bleeding and dysmenorrhea requiring no further treatment.94 Phillips et

al95 studied 10 patients with symptomatic adenomyosis diagnosed by MRI and had laparoscopic

bipolar coagulation for management. Twelve months after surgery, 7 (70.0%) patients had either

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resolution or significant reduction of dysmenorrhea and heavy menstrual bleeding. One patient

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had unresolved symptoms requiring hysterectomy and 2 patients with recurrent heavy menstrual

bleeding required endomyometrium resection. Another patient had continued heavy menstrual

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bleeding but refused further treatment.95

VII.2.E Myometrial reduction

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Myometrial reduction is an approach to treating patients with diffuse adenomyosis by
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removing the abnormal tissue and then completing metroplasty during laparoscopy or

laparotomy.1 Three approaches have been described. A classical reduction method where the
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uterus is dissected longitudinally in the midline and there is resection of the anterior and
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posterior portions of the myometrium.1 Nishida et al96 described covering the remaining part of
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the uterus with myometrium. They found this method was not very successful as women

developed adenomyosis and required hysterectomy within 1 year.96

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Fujishita et al97 describe a second method; in their modified method a transverse H

incision is completed. They compared two methods in 11 women (classical reduction, n=5 and
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transverse H incision, n =6). Between the two methods there was no difference in operation time,
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blood loss, and volume of specimen removed. The modified group had a greater improvement in

pain and there was 1 successful pregnancy in this treatment group. No patients became pregnant

in the classical group. A major complication of this method is perforation during surgery, which

occurred in 2 patients (40%) by the classical method and in only 1 patient (17%) by the H
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incision technique.97

Nishida et al96describe a third method of conservative surgical management for diffuse

uterine adenomyosis. They preformed this in 44 patients with diffuse adenomyosis. Following

surgery menstruation resumed in all women within 3 months, and there was an improvement in

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dysmenorrhea, menstrual blood loss, and anemia. Additionally 2 women became pregnant after

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surgery; one had an interstitial pregnancy and the other was still pregnant after IVF/ET during

the time of publication.96

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Removing diffuse adenomyosis is problematic in patients who want to become pregnant

because excision of the disease results in a reduced uterine volume. This is a concern for future

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pregnancies because the reduction of myometrium may predispose to spontaneous abortion or
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premature labour. Additionally this method causes uterine scaring, which may contain small

areas of adenomyosis leading to decreased uterine wall strength and increased risk of uterine
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rupture.82,85,96 Although pregnancy rates following these procedures have been low, these small
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studies have shown an improvement in dysmenorrhea and heavy menstrual bleeding, and
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therefore these conservative surgeries may be an option for patients with symptomatic diffuse

adenomyosis who want to preserve their uterus.96

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VII.2.F MRI-guided focused ultrasound surgery for adenomyosis

Removing areas of adenomyosis in patients wanting to maintain their fertility is

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challenging. As described previously, conservative surgery can cause scarring and negatively
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affect fertility. Therefore magnetic resonance guided focused ultrasound surgery may provide an

alterative treatment for patients with adenomyosis wanting to preserve fertility. The treatment

causes cell death and necrosis of the targeted adenomyotic tissue, preserving the surrounding

myometrium and uterine walls.98 The ultrasound beams are focused on the target and cause
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thermal coagulation and consequent necrosis. With the use of MRI guided ultrasound surgery

there is excellent anatomic resolution and high thermal imaging sensitivity.90 Complications of

this procedure include risk of skin burn, nausea and vomiting, and sciatic nerve palsy.1

Most of the published data is only of small case series and reports. Fukunishi et al99

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looked at 20 cases and found after treatment patients had a significantly smaller mean uterine

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volume and lower scores related to heavy menstrual bleeding and bulk during a period of 3 to 6

months post treatment.99 In another study dysmenorrhea was assessed 3 months post treatment in

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78 patients; complete relief was reported in 39.1% of patients, significant relief in 37.7%, and

partial relief in 13.0%.100 Exacerbation of pain did not occur.100

VII.2.G Hysterectomy
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Hysterectomy provides definitive treatment for patients with adenomyosis and

historically was the primary diagnostic and therapeutic option for patients. Commonly it is the
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treatment of choice for patients with significant symptoms who have completed childbearing.
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This procedure can be completed by laparoscopy, vaginally or abdominally.

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Among these options, vaginal hysterectomy is preferable to an abdominal hysterectomy because

of faster recovery and lower morbidity.101 However Furuhashi et al102 found that patients with
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adenomyosis undergoing vaginal hysterectomy had an increased risk of bladder injury. They

reviewed 1246 vaginal hysterectomies and compared complication rates between patient with
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leiomyomas n=893 and women with adenomyosis n=535. They found there was no significant
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difference between operative time and estimated blood loss when analyzed by uterine weight

between the two groups. However adenomyosis was associated with an increased risk of bladder

injury, which occurred in 0.7% of patients in the leiomyoma group and 2.3% of patients in the
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adenomyosis group. They thought this may be due to difficulty in identifying the supravaginal

septum and the vesicovaginal or vesicocervical planes.102

The role of laparoscopy assisted vaginal hysterectomy was studied to see if this approach

could decrease the risk of bladder injury. However in a study by Meikle et al103 there was no

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significant difference in the rate of bladder injury or bowel and ureteral injuries between

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laparoscopy assisted vaginal hysterectomy and vaginal hysterectomy.103

Further to this, laparoscopic hysterectomy is thought to allow better dissection of

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anatomic planes and therefore prevent injury.1 It also has shown to have other benefits compared

to vaginal hysterectomy. Candiani104 prospectively studied 60 patients randomized to either

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vaginal hysterectomy or laparoscopic hysterectomy and then followed for 12 months. Patients
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who had the laparoscopic hysterectomy had a shorter hospital stay (2.7days vs. 3.2 days, p =

<.001), less blood loss (83 mL vs. 178 mL, p =.004), and less postoperative pain (p =.023).104
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Decreased postoperative pain following laparoscopic hysterectomy compared to vaginal

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hysterectomy was also found by Ghezzi et al105 in a prospective randomized trial comparing
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laparoscopic and vaginal hysterectomy in 82 patients.105

As mentioned previously hysterectomy is commonly offered to patients as definitive

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treatment in women with significant symptoms who have completed childbearing. However, it

should be noted that there is a possibility that patients may still experience pelvic pain
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following hysterectomy. In a study by Stovall et al106 they looked at the long-term outcomes of
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99 women who had hysterectomy (vaginal or abdominal) for pelvic pain of at least 6 months

duration. Patients were excluded from the study if they had symptoms, signs, previously

documented findings, or findings at the time of surgery of extrauterine disease. Histopathologic

studies found adenomyosis in 20.2%, leiomyomata in 12.1%, and both leiomyomata and
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adenomyosis in 2.02%.106 Patients were followed for an average of 21.6 months after surgery

and 77.8% showed significant improvement. However 22.2% had persistent pelvic pain. Of those

patients with adenomyosis, 22.2% had persistent pelvic pain after the hysterectomy.106

VIII. Conclusion

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Adenomyosis is present when endometrial tissue is abnormally located within the

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myometrium. The true incidence of this disease is not known but advancements in imaging are

allowing women to be identified more frequently. Risk factors for the disease include exposure

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to estrogen, parity and prior uterine surgery. There are numerous proposed theories of

pathogenesis, but the two most commonly described theories are that adenomyosis develops

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from invagination of the endometrial basalis, secondary to either myometrial weakness (due to
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pregnancy or surgery), or altered immunological activity at the endometrial-myometrial

interface. The second commonly proposed theory is that adenomyosis occurs from Mllerian
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rests; this theory is supported by studies that show ectopic endometrium has different
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proliferative and biological characteristics compared to eutopic endometrium.

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The two most common symptoms of adenomyosis are heavy menstrual bleeding and

dysmenorrhea. Other reported symptoms include dyspareunia and chronic pelvic pain. On exam
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patients often have an enlarged uterus that may be tender to palpation. Traditionally a diagnosis

was only made histologically after hysterectomy. However studies have shown that a diagnosis
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can be made with biopsies obtained during hysteroscopy and laparoscopy. Non-invasive imaging
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can also be used to help guide in the differential diagnosis. The two most commonly studied

imaging modalities are TVUS and MRI. Many studies have shown that TVUS and MRI have

respectable sensitivities and specificities for adenomyosis, however there is a lack of common

diagnostic language in the literature. The most commonly reported findings on TVUS are
 ACCEPTED MANUSCRIPT
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heterogenous myometrial echotexture, ill-defined foci of abnormal myometrial echotexture,

myometrial cysts, and a globular, asymmetric uterus. Recent studies indicate that the use of 3-D

TVUS is superior to 2-D TVUS for the diagnosis of adenomyosis, and may allow for the

diagnosis of early stage disease. The most common findings on MRI include a large, regular,

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asymmetric uterus without leiomyomas, abnormal myometrial signal intensity, junctional zone

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thickening, and myometrial foci of high signal intensity on T1weighted images, as summarized

in Figure 3.

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Management for patients can include medical options such as NSAIDs, oral contraceptive

pills, progestins, levonorgestrel IUD, danazol, GnRH agonists, and aromatase inhibitors or

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surgical options such as endometrial ablation and resection, uterine artery embolization,
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myometrium or adenomyoma excision, myometrial electrocoagulation, myometrial reduction,

MRI-guided focused ultrasound surgery, and for definitive management, hysterectomy, as

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summarized in Figure 4. The lack of properly randomized trials accounts for the insufficient
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evidence to support one treatment over another. Factors that should be considered while making
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treatment decisions include age, severity of symptoms, desire of future fertility, and associated

comorbidities such as endometriosis and fibroids.

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85. Pepas L, Deguara C, Davis C. Update on the surgical management of adenomyosis.
Current Opinion in Obstetrics and Gynecology. 2012;24(4):259-264.
86. Gordts S, Campo R, Brosens I. Hysteroscopic diagnosis and excision of myometrial
cystic adenomyosis. Gynecol Surg. 2014;11(4):273-278.
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87. Jha RC, Takahama J, Imaoka I, et al. Adenomyosis: MRI of the uterus treated with
uterine artery embolization. AJR. American journal of roentgenology.
2003;181(3):851-856.
88. Kim MD, Kim S, Kim NK, et al. Long-term results of uterine artery embolization for
symptomatic adenomyosis. AJR. American journal of roentgenology.
2007;188(1):176-181.
89. Popovic M, Puchner S, Berzaczy D, Lammer J, Bucek RA. Uterine artery embolization

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for the treatment of adenomyosis: a review. Journal of vascular and interventional
radiology : JVIR. 2011;22(7):901-909; quiz 909.
90. Rabinovici J, Stewart EA. New interventional techniques for adenomyosis. [Review]

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91. Taran FA, Stewart EA, Brucker S. Adenomyosis: Epidemiology, risk factors, clinical

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92. Wang PH, Liu WM, Fuh JL, Cheng MH, Chao HT. Comparison of surgery alone and
combined surgical-medical treatment in the management of symptomatic uterine

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adenomyoma. Fertil Steril. 2009;92(3):876-885.
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93. Fedele L, Bianchi S, Zanotti F, Marchini M, Candiani GB. Fertility after conservative
surgery for adenomyomas. Human Reproduction. 1993;8(10):1708-1710.
94. Wood C, Maher P, Hill D. Biopsy diagnosis and conservative surgical treatment of
adenomyosis. The Journal of the American Association of Gynecologic Laparoscopists.
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1994;1(4 Pt 1):313-316.
95. Phillips DR, Nathanson HG, Milim SJ, Haselkorn JS. Laparoscopic bipolar coagulation
for the conservative treatment of adenomyomata. Journal of the American
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Association of Gynecologic Laparoscopists. 1996;4(1):19-24.

96. Nishida M, Takano K, Arai Y, Ozone H, Ichikawa R. Conservative surgical
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management for diffuse uterine adenomyosis. Fertility & Sterility. 2010;94(2):715-

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technique. Gynecologic and Obstetric Investigation. 2004;57(3):132-138.

98. Rabinovici J, Inbar Y, Eylon SC, Schiff E, Hananel A, Freundlich D. Pregnancy and live
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99. Fukunishi H, Funaki K, Sawada K, Yamaguchi K, Maeda T, Kaji Y. Early results of
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magnetic resonance-guided focused ultrasound surgery of adenomyosis: analysis of

20 cases. J Minim Invasive Gynecol. 2008;15(5):571-579.
100. Zhou M, Chen JY, Tang LD, Chen WZ, Wang ZB. Ultrasound-guided high-intensity
focused ultrasound ablation for adenomyosis: the clinical experience of a single
center. Fertil Steril. 2011;95(3):900-905.
101. Dicker RC, Greenspan JR, Strauss LT, et al. Complications of abdominal and vaginal
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102. Furuhashi M, Miyabe Y, Katsumata Y, Oda H, Imai N. Comparison of complications of

vaginal hysterectomy in patients with leiomyomas and in patients with
adenomyosis. Arch Gynecol Obstet. 1998;262(1-2):69-73.
103. Meikle SF, Nugent EW, Orleans M. Complications and recovery from laparoscopy-
assisted vaginal hysterectomy compared with abdominal and vaginal hysterectomy.
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e361-367.
105. Ghezzi F, Uccella S, Cromi A, et al. Postoperative pain after laparoscopic and vaginal

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Gynecol. 2010;203(2):118 e111-118.
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presumed uterine etiology. Obstetrics and gynecology. 1990;75(4):676-679.

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Table 1: Risk Factors
Risk Factor Statistical significance
Exposure to estrogen:

Age: 40s and 50s

Average age of women 46.5 years; average age of women
diagnosed with adenomyosis and
adenomyosis plus leiomyomas
found at hysterectomy n=364
41.0 6.4 women with
adenomyosis vs 44.4 4.8
women with leiomyoma p<.00121

Early menarche (10 POR = 1.59; 95% CI, 1.262.01
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years of age) POR = 1.46; 95% CI, 1.131.89

Short menstrual cycles POR 1.54; 95% CI, 1.28-1.85
(24 days in length) o POR 1.30; 95% CI,

Past oral contraceptive 1.11-1.51
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use o POR 1.35; 95% CI,

Elevated BMI 1.12-1.62
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o 25-29.9
o 30

Tamoxifen17,18 Adenomyosis was histologically
diagnosed in 53.6% of tamoxifen
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treated patients and 18.2% of
patients who had not had
tamoxifen treatment (p = .019)18
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Patient who had been treated with
tamoxifen were followed; of the
patient who had a hysterectomy
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for various reasons, 57.1% were
found to have adenomyosis17
Parity POR = 1.80; 95% CI, 1.472.2014
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OR 3.1 95% CI 1.7-5.5 in women
reporting 2 or more births P<.018
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Pregnancy termination OR of women with adenomyosis
vs women with neither
adenomyosis nor leiomyomas
4.35 CI 1.19-15.99
P= .034
1 spontaneous abortions vs.none
OR 1.7 (95% CI 1.1-2.6)8
Study
Levgur et al4 total n=111;
adenomyosis alone: n=17;
adenomyosis + leiomyomas
n=19; leiomyomas alone n=39,
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neither adenomyosis or
leiomyomas n=36
Taran et al21 compared women
who had pathologically
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confirmed diagnoses of
leiomyoma (n=152) to
adenomyosis (n=76).
Templeman et al14 surgical
diagnosis of adenomyosis n=961
compared with disease-free
women in the same age range
n=79,495
Cohen et al18 compared 28
postmenopausal breast cancer
patients with tamoxifen and 11
similar patients without
tamoxifen treatment
Cohen et al17 14 patient had an
abdominal hysterectomy and
bilateral salpingo-oophorectomy
for various reasons, 8 of these
women had adenomyosis
Templeman et al14 surgical
diagnosis of adenomyosis n=961
compared with disease-free
women in the same age range
n=79,495
Parazzini et al8 707 women had a
hysterectomy; adenomyosis was
identified in 150 subjects
(21.2%)8
Levgur et al4 total n=111;
adenomyosis alone: n=17;
adenomyosis + leiomyomas
n=19; leiomyomas alone n=39,
neither adenomyosis or
leiomyomas n=36
Parazzini et al8 707 women had a
hysterectomy; adenomyosis was
identified in 150 subjects
(21.2%)8
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Prior uterine surgery
60.5% women with adenomyosis
vs 26.1% of women with
leiomyoma P=.03921
Taran et al21 compared women
who had pathologically
confirmed diagnoses of
leiomyoma (n=152) to
adenomyosis (n=76).

OR 2.2; 95% CI 1.4-4.0 in Parazzini et al8 707 women had a

women who reported dilatation hysterectomy; adenomyosis was

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and curettage compared to those identified in 150 subjects
who did not8 (21.2%)8
POR, prevalence odds ratio; CI, confidence interval; OR, odds ratio

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Table 2: Symptoms and Signs of Adenomyosis

% Affected Study n= subjects
Symptom

Heavy menstrual bleeding 40-50% Huang et al39 expert opinion
40-50% Levgur et al4 111 uterine
specimens; adenomyosis
alone n=17, adenomyosis
and leiomyomas n=19,

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leiomyomas alone n=39,
neither n=36

Deep Foci* 36.8% Levgur et al4

Intermediate foci* 13.3% Levgur et al4

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Dysmenorrhea 15-30% Huang et al39 expert opinion
15-30% Levgur et al4

Deep foci* 77.8% Levgur et al4

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Intermediate foci* 12.5% Levgur et al4

Chronic pelvic pain 76.9% Shrestha et al46 prospective
case-control n=78 women
with adenomyosis without

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fibroid

Asymptomatic 33%
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Dyspareunia 7% Huang et al39 expert opinion

Signs

Uterine enlargement 30%4 Levgur et al4
Slightly enlarged uterus in Ozdegirmenci et al72 75
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most cases72 women who had TVUS and

MRI imaging consistent with
adenomyosis were treated
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with either LNG-IUD or

hysterectomy

Tender uterus Significantly more tender Huang et al39 expert opinion
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uterus was found in Shrestha et al46 prospective

adenomyosis group case-control

Infertility 11-12% Huang et al39 expert opinion
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Associated uterine abnormalities McElin et al47

Leiomyomas47
50%

Endometriosis47
11%

Endometrial polyp47
7%
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Abnormalities at hysteroscopy: These findings may be Molinas and Campo50 expert

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irregular endometrium with associated with adenomyosis opinion

endometrial defects, cystic
hemorrhagic lesions, altered
vascularization.50

*Adenomyosis was defined as endometrial glands or stroma within the myometrium at a depth of 2.5 mm or
more. Adenomyosis foci within the myometrium, expressed as percentage of myometrial thickness, and
graded as deep (exceeding 80%), intermediate (4080%), and superficial (under 40%).4
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Table 3: Diagnostic Accuracy of TVUS and MRI

Study Study Design Sensitivity Specificity PPV NPV Notes
Ultrasound
Reinhold et TVUS was 86% 86% 71% 94% TVUS identified
al60 completed on 100 25 of 29
patients prior to pathologically
hysterectomy; 29 proved cases of
cases had adenomyosis.

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adenomyosis

Brosens et Performed TVUS on 86% 50% 86% 77%

al61 56 women with

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heavy menstrual
bleeding and
dysmenorrhea and
compared the

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sonographic
diagnosis of
adenomyosis to
histological findings

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after hysterectomy
(n = 34, 15 of whom
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had a diagnosis of
adenomyosis) or to
the appearances on
MRI (n=22; 13 of
whom had a
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diagnosis of
ademonyosis).
Levgur45 Review article 50-87%
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Exacoustos Completed 2D- 2D-TVUS: 2D-TVUS: 2D- 2D-TVUS: The overall

et al55 TVUS and 3D-TVS 75% 90% TVUS: 82% accuracy of 2D-
on 72 women prior 86% TVUS was 83%
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to hysterectomy and 3D-TVUS: The overall

correlated 3D- 3D- 3D- 92% accuracy for
sonographic TVUS:91% TVUS:88% TVUS: 3D-TVUS was
findings of 85% higher than 2D-
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adenomyosis to TVUS at 89%

histological findings
MRI
Togashi et Correlated MRI The cause of
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al64 findings with uterine

surgical/pathological enlargement
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findings in 93 was correctly

patients who had an diagnosis by
enlarged uterus. The MRI in 92 of
cause of the the 93 cases.64
enlarged uterus was
due to leiomyoma
(n=71),
ademonyosis
(n=16), leiomyoma
and adenomyosis
(n=6).
Ultrasound versus MRI
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Reinhold et Prospectively TVUS: 89% TVUS: 98% TVUS: TVUS: No statistically

al58 studied 119 patients 71% 96% significant
undergoing difference
hysterectomy. MRI: 89% between the
Imaging (TVUS and MRI: 89% MRI: 65% MRI: sensitivities (P =
MRI) findings were 95% .65) and
compared with those specificities (P
at histopathologic = .75) of TVUS

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examination. and MRI
28 patients had
histopathologic
diagnosis of

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adenomyosis
Bazot et al53 Prospectively TVUS: 65% TVUS: TVUS:92. TVUS:
studied 120 patients, 97.5% 8% 88.8%
40 (33.0%) of whom

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had adenomyosis,
by comparing MRI: 77.5% MRI: 92.5% MRI: MRI:
transabdominal 83.8% 89.2%
ultrasounds,

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transvaginal
ultrasound and MRI
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for the diagnosis
adenomyosis and
correlating these
findings with
histological findings
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Dueholm et 106 patients TVUS: 0.68 TVUS: 0.65

al63 underwent (0.44 0.86) (0.50 0.77)
hysterectomy; each
patient had a MRI: 0.70 MRI: 0.86
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preoperative TVUS (0.46 0.87) (0.76 0.93)

and MRI. Each
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uterus had
pathologic analysis;
22 specimens had
adenomyosis
Ascher et 20 patients; 17 were TVUS: 53% TVUS: 66% MRI is
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al62 found to have significantly

adenomyosis. MRI: 88% MRI: 66% better (P<.02)
than TVUS in
the diagnosis of
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adenomyosis
Reinhold et Review article TVUS: 80- TVUS: 50- The overall
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al56 86% 96% accuracy of

TVUS: 68%
MRI: 86- MRI: 86- 86%
100% 100% The overall
accuracy of
MRI: 85%
90.5%
Outwater et Review paper Ultrasound: Ultrasound:
al107 53-89% 50-89%

MRI: 88- MRI: 66-

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93% 91%
Champaneria Systematic review TVUS: 72% TVUS: 81% TVUS: TVUS:
et al65 including 23 articles (95% CI 65- (95% CI 77- positive negative
(2,312 women) 79%) 85%) likelihood likelihoo
ratio of 3.7 d ratio of
(95% CI 0.3 (95%
2.1-6.4) CI 0.1-
MRI: 0.5)

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specificity of MRI:
MRI: 77% 89% (95% positive MRI:
(95% CI 67- CI 84-92%) likelihood negative
85%) ratio of 6.5 likelihoo

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(95% CI d ratio of
4.5-9.3) 0.2 (95%
CI 0.1-
0.4)

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Table 4: Medical Management Options for Adenomyosis

Mechanisms Dose Duration Possible Effect
NSAIDs Reversible Various options Prostaglandins are
inhibition of COX-1 i.e. ibuprofen 400 known to cause
and COX-2 to 600mg q 4- cramping abdominal
enzymes, which 6hrs or 800mg q pain67
results in decreased 8hrs to a
formation of maximum dose

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prostaglandin of 2400mg per
precursors day, starting with
the onset of
symptoms or

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menses, and
continue for 2 to
3 days
Combination oral Mechanism of Take as directed May use Reduced menstrual

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contraceptives & Estrogen-progestin continuously flow and
progestin-only contraceptives: improvement and
regimens Suppression of dysmenorrhea
hypothalamic

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GnRH and pituitary
gonadotropin
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secretion,
suppression of
ovarian
folliculogenesis,
suppression of
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ovarian steroid
production

Mechanisms due to
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progestin:
endometrial
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decidualization and
atrophy
Levonorgestrel- Mechanisms:6, 68 It releases 20 Can be left in 1. Reduced
releasing 1. Decidualization mcg/day of LNG place for 5 years menstrual flow
intrauterine system of the endometrium into the uterine 2. Improvement in
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2. Down regulation cavity for up to a Benefit may be heavy

of estrogen 5-year period limited to 2 years menstrual
receptors on post insertion71 bleeding and
adenomyotic foci dysmenorrhea
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causing:
i. A reduction
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in foci size
thus allowing
the uterus to
contract more
efficiently
leading to a
reduction in
menstrual
blood loss
ii. A reduction
in
prostaglandin
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production
and therefore
an
improvement
in
dysmenorrhea
Danazol Suppression of 400mg PO daily Improvement of
pituitary release of symptoms and

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FSH and LH reduction of uterine
causing atrophy of size
both normal and
ectopic endometrial

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tissue.

Decrease expression
of aromatase

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cytochrome P450 in
disease eutopic
endometrium73
GnRH agonist/ Decreases Buserelin acetate 3 months39 Reduces the size of

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analogue gonadotropin nasal spray 600 adenomyosis;
secretion leading to mg/d in divided improvement in
doses39
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ovarian quiescence dysmenorrhea and
and inducing a heavy menstrual
pseudomenopausal, bleeding
hypoestrogenic Long course
state39 (>6months) is
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limited due to side

effects: hot flashes,
vaginal atrophy,
accelerated bone
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demineralization
Buserelin acetate 2 years Case report n= 178
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450 microg/day Anemia, leg

nasally numbness and
chronic pelvic pain
resolved; no
estrogen deficiency
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symptoms for more

than 2 years on
treatment.
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http://www.AAGL.org/jmig-23-1-JMIG-D-15-00460

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Supplemental Table 1: Standardized Terminology for Findings Consistent with Adenomyosis

Described in the Literature during TVUS
Description used in Study Type Author Clinical
study Correlation
1. Heterogenous myometrial echotexture
-Distorted and Review article Garcia et
heterogenous al1
myometrial

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echotexture1
-Abnormal echo 106 patients underwent Dueholm
texture hysterectomy; each patient et al63
-Presence of had a preoperative TVUS

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heterogeneity and MRI. Each uterus had
-Increased or pathologic analysis; 22
decreased areas of specimens had
echogenicity adenomyosis

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-Decreased or TVUS was completed on Reinhold
increased echogenicity 100 patients prior to et al60
or heterogeneous hysterectomy; 29 cases

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echotexture had adenomyosis
-Areas of decreased Review article Reinhold -Represents areas
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echogenicity Review article et al56 of smooth muscle
-Heterogeneity of the hyperplasia
myometrium -Represents
echogenic islands
of heterotopic
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endometrial tissue,
surrounded by
smooth muscle
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Thickening and Review article Outwater

asymmetry of the et al107
anterior or posterior
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uterine walls, focal or

diffuse myometrial
thickening, an
increased or decreased
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echogenicity of the
myometrium, a poorly
defined area of
heterogenous
myometrium
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Heterogeneous Prospectively studied 120 Bazot et Defined by the

myometrium; distorted patients, 40 (33.0%) of al53 presence of an
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and heterogeneous whom had adenomyosis indistinctly

myometrial marginated
echotexture myometrial area
with decreased or
increased
echogenicity
Heterogenous Completed 2D-TVS and Exacoustos Heterogeneous
myometrium 3D-TVS on 72 women et al55 myometrium was
prior to hysterectomy and the most sensitive
correlated sonographic (sensitivity, 88%;
findings of adenomyosis accuracy, 75%).
 ACCEPTED MANUSCRIPT

to histological findings

2. Ill-defined foci of abnormal myometrial echotexture

Poorly defined foci of Review article Garcia et
abnormal myometrial al1
echotexture
Presence of focal areas 106 patients underwent Dueholm

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with not well-defined hysterectomy; each patient et al63
borders had a preoperative TVUS
and MRI. Each uterus had
pathologic analysis; 22

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specimens had
adenomyosis
Focal heterogeneous Review article Reinhold
et al56

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myometrial
echotexture
Poorly defined focus Prospectively studied 120 Bazot et
of abnormal patients, 40 (33.0%) of al53
myometrial whom had adenomyosis

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echotexture
3. Myometrial cysts
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Myometrial cysts (1 to Review article Garcia et
7 mm round anechoic al1
areas)
Presence of Dueholm
et al63
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myometrial cysts
Myometrial cysts TVUS was completed on Reinhold
100 patients prior to et al60
hysterectomy; 29 cases
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had adenomyosis
Small myometrial Reinhold Represent: dilated
cysts (usually <5 mm et al56 cystic glands or
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in diameter); cystic hemorrhagic foci

adenomyosis can result in the heterotopic
in discrete echogenic endometrium
nodules (5 mm in
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diameter) within the

myometrium

Myometrial cysts Review article Outwater

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et al107
Myometrial cyst Prospectively studied 120 Bazot et -Defined as a
al53
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patients, 40 (33.0%) of round anechoic

whom had adenomyosis area of 17 mm
diameter
-The most
sensitive and
specific TVUS
criterion
Myometrial cysts Completed 2D-TVUS and Exacoustos Presence of
3D-TVUS on 72 women et al55 myometrial cysts
prior to hysterectomy and was the most
correlated sonographic specific 2D-TVUS
findings of adenomyosis feature; specificity
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to histological findings55 was 98% and

accuracy 78%
4. Globular and/or Asymmetric uterus
Globular and/or Prospectively studied 120 Bazot et Defined as a
asymmetric uterus patients, 40 (33.0%) of al53 regular enlarged
whom had adenomyosis uterus with
possible
myometrial

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asymmetry
unrelated to
leiomyoma
5. Other TVUS Poor definition of Reinhold

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signs endomyometrial et al56
junction
Relative absence
of mass effect

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Poor definition of
lesion borders
Elliptical
myometrial

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abnormality
Echogenic nodules
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or linear striations
Pseudowidening
of the
endometrium
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hypoechoic N =1; case report Fernandez

lacunae et al49
Findings on 3D-TVUS
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Description used in Study Type Author Clinical

study Correlation
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1. Widened junctional zone

Junctional zone Review article Exacoustos
thickness as used on et al57
MRI
Junctional zone
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Completed 2D-TVUS and Exacoustos The 3D-TVUS

maximum 8mm 3D-TVUS on 72 women et al55 markers junctional
junctional zone prior to hysterectomy and zone thickness 4
max minus correlated sonographic mm had high
findings of adenomyosis sensitivity (88%)
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junctional zone
min 4mm to histological findings and the best
junctional zone accuracy (85%)
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ratio 50%
2. Ill-defined junctional zone
Ill-defined junctional Review article Exacoustos
zone et al57
3. Distortion and infiltration of the hypoechoic inner myometrium
Distortion and Review article Exacoustos
infiltration of the et al57
hypoechoic inner
myometrium by
hyperechoic
endometrial tissue
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Supplemental Table 2: Standardized Terminology for Findings Consistent with Adenomyosis

Described During MRI

Classification Description used in study Study Type Author Clinical Correlation

1. Large, regular, asymmetric uterus without leiomyomas

A large, regular, asymmetric Prospectively Bazot et
al53

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uterus without leiomyomas studied 120
patients, 40
(33.0%) of
whom had

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adenomyosis
2. Abnormal myometrial signal intensity
Focal not well-demarcated 22 patients Dueholm Represents: Focal adenomyosis
high or low intensity areas in et al63

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the myometrium
Bright foci can been seen in Review paper Reinhold Represent: heterotopic
areas of abnormal low signal et al56 endometrial tissue, cystic
intensity within the dilatation of heterotopic glands

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myometrium on T2-weighted
images
-Areas of decreased signal
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intensity compared to the
outer myometrium.
-Foci of increased signal
intensity seen on T2 weighted
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or hemorrhagic foci
Review paper Outwater These foci represent islands of
et al107 endometrial glands and stroma
within the hypertrophied
myometrium. They enhance
with administration of IV

sequences contrast and add specificity to

the diagnosis

An ill-defined, low-signal- Prospectively Bazot et

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intensity myometrial area studied 120 al53

distinguished from well- patients, 40
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circumscribed masses related (33.0%) of

to myoma whom had
adenomyosis
Punctate high-intensity Prospectively Bazot et
myometrial foci studied 120 al53
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patients, 40
(33.0%) of
whom had
adenomyosis
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3. Junctional zone thickening

-Junctional zone between 12- 22 patients63 Dueholm -Represents: Focal adenomyosis
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15mm and a nonuniform, et al63 -Represents: Diffuse

thickened junctional zone adenomyosis
-Thickest area of the
junctional zone in sagittal
slice >15mm
Junctional zone greater than Review paper Outwater Diffuse adenomyosis
12mm et al107
Abnormal widening of the Review paper Reinhold
junctional zone et al56
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-Thickening of the junctional Review paper Garcia et

zone from 8 to 12mm al1
-An abnormal ratio of
junctional zone to
myometrial thickness greater
than 40%
-Junctional zone of at least 12
Prospectively Bazot et
mm studied 120 al53

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-Maximal junctional zone patients, 40
thickness to myometrial (33.0%) of
thickness ratio of >40% whom had
adenomyosis

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4. Myometrial foci of high signal intensity on T1weighted images
-Bright foci on T1-weighted Review paper Reinhold Represent: areas of hemorrhage
images et al56

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- Well-circumscribed, cystic
myometrial lesion that
demonstrates hemorrhage in
different stages of

U
organization on T1-weighted.
On T2-weighted images a
low-signal-intensity rim
AN
High signal intensity in the Review paper Outwater Represents hemorrhage
glands on T1-weighted et al 107
images
Small hypointense spots Prospectively Bazot et
M

within the myometrium on studied 120 al53

gadolinium enhanced T1- patients, 40
weighted images were (33.0%) of
attributed to adenomyosis whom had
D

adenomyosis
5. Other findings
TE

A large asymmetric uterus Review article Garcia et

without leiomyomas al1
Linear striations Review Reinhold
Pseudowidening of Article et al56
the endometrium
EP

Lack of contour
abnormality
Absence of mass
effect
C

Poor definition of
lesions borders
AC

Elliptical
myometrial
abnormality
Focal thickening Review article Outwater Are more specific signs of
Spiculated masses et al107 adenomyosis than diffuse
The interface thickening
between the Both unlike what is seen with
surrounding leiomyomas
myometrium is ill-
defined and
infiltrative
 ACCEPTED MANUSCRIPT

Adenomyosis
appears to wrap
around the
endometrium with
relatively mild
distortion of its
shape

PT
RI
SC
U
AN
M
D
TE
EP
C
AC