Review Article

Adenomyosis: What the Patient Needs

Giulia Alabiso, MD, Luigi Alio, MD, Saverio Arena, MD, Allegra Barbasetti di Prun, MD,
Valentino Bergamini, MD, Nicola Berlanda, MD, Mauro Busacca, MD, Massimo Candiani, MD,
Gabriele Centini, MD, Annalisa Di Cello, MD, Caterina Exacoustos, MD, Luigi Fedele, MD,
Eliana Fuggetta, MD, Laura Gabbi, MD, Elisa Geraci, MD, Ludovica Imperiale, MD,
Elena Lavarini, MD, Domenico Incandela, MD, Lucia Lazzeri, MD, Stefano Luisi, MD,
Antonio Maiorana, MD, Francesco Maneschi, MD, Luca Mannini, MD, Alberto Mattei, MD,
Ludovico Muzii, MD, Luca Pagliardini, MD, Alessio Perandini, MD, Federica Perelli, MD,
Serena Pinzauti, MD, Maria Grazia Porpora, MD*, Valentino Remorgida, MD,
Umberto Leone Roberti Maggiore, MD, Renato Seracchioli, MD, Eugenio Solima, MD,
Edgardo Somigliana, MD, Claudia Tosti, MD, Roberta Venturella, MD, Paolo Vercellini, MD,
Paola Vigan
o, MD, Michele Vignali, MD, Letizia Zannoni, MD, Fulvio Zullo, MD, and
Errico Zupi, MD, for the Endometriosis Treatment Italian Club
From the Department of Obstetrics and Gynecology, Macedonio Melloni Hospital (Drs. Alabiso, Barbasetti di Prun, Busacca, Vignali, and Solima),
Department of Obstetrics and Gynecology, Istituto Luigi Mangiagalli (Drs. Berlanda, Fedele, and Vercellini), Department of Obstetrics and Gynecology,
San Raffaele Hospital (Drs. Candiani, Pagliardini, Maggiore, and Vigan
o), University of Milan, Milan, Italy, Department of Obstetrics and Gynecology
(Drs. Alio, Incandela, and Maiorana), Civico Hospital, Palermo, Italy, Department of Obstetrics and Gynecology (Dr. Arena), Santa Maria della
Misericordia Hospital, Perugia, Italy, Department of Obstetrics and Gynecology (Drs. Bergamini, Lavarini, and Perandini), University of Verona, Verona,
Italy, Department of Obstetrics and Gynecology (Drs. Centini, Lazzeri, Luisi, Pinzauti, and Tosti), University of Siena, Siena, Italy, Infertility Unit
(Dr. Somigliana), Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy, Department of Obstetrics and Gynecology (Drs. Di Cello,
Venturella, and Zullo), University of Magna Graecia, Catanzaro, Italy, University of Tor Vergata (Drs. Exacoustos and Zupi), Rome, Italy, Department of
Obstetrics and Gynecology (Dr. Maneschi), Santa Maria Goretti Hospital, Latina, Italy, Department of Obstetrics and Gynecology (Drs. Mannini, Mattei
and Perelli), University of Florence, Florence, Italy, Department of Gynecology, Obstetrics and Urology (Drs. Fuggetta, Imperiale, Muzii, and Porpora),
‘‘Sapienza’’ University of Rome, Rome, Italy, Department of Obstetrics and Gynecology (Drs. Gabbi and Remorgida), University of Genova, Genova, Italy,
and Department of Obstetrics and Gynecology (Drs. Geraci, Seracchioli, and Zannoni), University of Bologna, Bologna, Italy.

ABSTRACT A panel of experts in the field of endometriosis expressed their opinions on management options in a 28-year-old patient,
attempting pregnancy for 1 year, with severe cyclic pelvic pain and with clinical examination and imaging techniques sug-
gestive of adenomyosis. Many questions this paradigmatic patient may pose to the clinician are addressed, and all clinical
scenarios are discussed. A decision algorithm derived from this discussion is also proposed. Journal of Minimally Invasive
Gynecology (2016) 23, 476–488 Ó 2016 AAGL. All rights reserved.
Keywords: Adenomyosis; Diagnosis; Pelvic pain; Pregnancy desire; Treatment

In 2013 a panel of Italian experts on endometriosis,

The authors declare that they have no conflict of interest.
Corresponding author: Maria Grazia Porpora, MD, Department of Gynecol-
ogy, Obstetrics and Urology, ‘‘Sapienza’’ University of Rome, Policlinico
Umberto I, Viale del Policlinico 155, 00161, Rome, Italy.
E-mail: mariagrazia.porpora@uniroma1.it
Submitted October 29, 2015. Accepted for publication December 31, 2015.
Available at www.sciencedirect.com and www.jmig.org
1553-4650/$ - see front matter Ó 2016 AAGL. All rights reserved.
http://dx.doi.org/10.1016/j.jmig.2015.12.017
adenomyosis, and pelvic pain disorders founded the Endo-
metriosis Treatment Italian Club, or ETIC. ETIC has the
primary scientific aim to identify any debatable issue in
the management of endometriosis, offering the reader a
complete review of the literature on that topic and trying
to elucidate its controversies. Endometriosis and adenomyo-
sis are considered as variants of the same disease and often-
coexisting conditions. Both diseases are characterized by the
Alabiso et al. Management of Adenomyosis 477

presence of endometrial glands and stroma outside their proposed. Recent studies suggest that estrogen-induced
normal locations [1]. This article focuses on the manage- epithelial to mesenchymal transition of endometrial cells
ment of a paradigmatic young patient, wishing to conceive, could play a role in the migration and invasion of endome-
with the suspicion of uterine adenomyosis. trial cells. Higher expression of estrogen receptor-b in endo-
metrium basalis and decreased expression of progesterone
Clinical Case receptors A and B may be related to development or progres-
sion of adenomyosis [17]. Angiogenesis deriving from
A 28-year-old woman presented for a gynecologic
unbalanced proangiogenic and antiangiogenic factors could
consultation. Her family, past medical, and surgical histories
increase the survival of endometrial implants in the myome-
were unremarkable. Menarche occurred at 12 years of age,
trium. Immune factors, such as cell surface antigens and
and the patient had irregular and heavy menstrual periods.
adhesion molecules, have been shown to be altered in
She had been trying to conceive for 1 year and complained
adenomyosis. According to the most widely accepted theory,
of severe chronic pelvic pain (graded 90/100 on a 100-mm
the mechanical lesions to the endometrial–myometrial inter-
visual analog scale), severe dysmenorrhea (graded 95/100
face lead to disruption of the junctional zone (JZ) and invag-
on a 100-mm visual analog scale), and deep dyspareunia
ination of the basal endometrium into myometrium,
(graded 78/100 on a 100-mm visual analog scale) for 2 years.
probably due to a defect of regeneration, healing, and
The patient had never used oral contraceptives or other
re-epithelization of this site.
hormonal therapies. Gynecologic examination, pelvic ultra-
The incidence of adenomyosis is increased after uterine
sound, and magnetic resonance imaging (MRI) were sugges-
surgery, cesarean section, postpartum endometritis, preg-
tive of uterine adenomyosis. Given this background, the aim
nancy, uterine trauma, and surgery [18]. Thus, adenomyosis
of the current study was to discuss all potential criticisms
was initially thought to be a condition of parous women,
arising from this paradigmatic case of uterine adenomyosis
with poor association with infertility [19]. On the contrary,
to clarify the main issues potentially encountered during
in the last few years some authors linked this condition to
the management of this condition.
subfertility, because more and more women are delaying
Uterine adenomyosis is defined as the presence of endo-
childbearing due to social reasons and better imaging
metrial glands and stroma within the myometrium, and its
techniques have identified adenomyosis in women labeled
reported prevalence in literature is extremely variable
as having ‘‘unexplained infertility’’ [15].
(14%–66%) because of the histologic criteria adopted for
diagnosis and the technique used to obtain myometrial sam-
ples [2–6]. The definitive diagnosis of adenomyosis is based Histology
on histologic examination after hysterectomy. By tradition, a
No universally accepted criteria exist to define the histo-
histologic diagnosis is made when endometrial glands and
logic presence of adenomyosis. Definitions such as ‘‘foci
stroma are found at least 1 low-power field beneath the en-
domyometrial junction (R4 mm) [7], even if less restrictive located deeper than 25% of the myometrial thickness’’ or
‘‘glandular extensions greater than 1 to 3 mm below the
criteria were proposed [8,9].
endometrial layer’’ are commonly used. Most studies use a
Uterine adenomyosis may be asymptomatic in about 35%
cutoff of 2.5 mm below the basalis layer to define the mini-
of the cases [10], whereas 50% of women with symptoms
mal depth of invasion [5].
have menorrhagia, 30% have dysmenorrhea, and 20% have
The main histologic feature of adenomyosis is repre-
metrorrhagia [11,12]. Around 20% of patients experience
sented by the presence of endometrial glands and stroma
both menorrhagia and severe dysmenorrhea [13]. Dyspareu-
within the myometrium, and ‘‘ectopic’’ endometrium is
nia and chronic pelvic pain are less common symptoms [14].
Because as many as 80% of women with uterine adenomyo- generally associated with smooth muscle changes. These
modifications of uterine structure may range from simple
sis have coexisting pelvic disease, it is troublesome to distin-
thickening of the JZ . 12 mm to nodular or diffuse lesions
guish which symptoms are caused only by adenomyosis
involving the entire uterus. The JZ is the inner part of the
[14]. Furthermore, the association of uterine adenomyosis
myometrium involved in implantation and deep placentation
with infertility is still debated. It was deemed that adeno-
that, similarly to the endometrium, is of M€ullerian origin and
myosis was a typical condition of parous women. However,
from which the uterine peristaltic activity originates. The JZ
adenomyosis has become more relevant in the setting of
shows cycle-dependent changes in response to hormonal
infertility and assisted reproductive technologies due to the
improvement in imaging techniques and to the growing stimulation, with usual thickness ranging from 5 to 8 mm
in premenopausal women [20]. JZ hyperplasia (8–12 mm
number of women delaying their first pregnancy until late
of thickness) indicating inordinate proliferation of smooth
thirties or early forties [15,16].
muscle cells (myosis) is not necessarily linked to the
presence of heterotopic endometrium, even if many authors
Pathogenesis
claims that the disruption of the architecture of this myome-
The pathogenesis of ectopic endometrial implants in the trial layer leads to adenomyosis development [21].
myometrium is still debated. Four principal theories were Adenomyosis can be defined as diffuse or focal. Focal
478
adenomyosis, consisting of ectopic endometrium enclosed
in s smooth muscle nodule, is usually called adenomyoma.
Clinical Features
Clinical presentation of adenomyosis could be heteroge-
neous. Young women with mild disease could be highly symp-
tomatic, whereas older patients with very enlarged uteri may
present only small symptoms. Moreover, up to 80% of ad-
enomyotic uteri contain associated pathology, such as my-
omas that could have similar clinical presentations [22]. On
the other hand, about one-third of women suffering from endo-
metriosis have concomitant adenomyosis, with overlapping
and usually heavier symptoms [23]. Diagnosis of adenomyo-
sis is placed commonly in the fourth or fifth decade of life.
Typical presentation includes abnormal uterine bleeding
(AUB), with menorrhagia and metrorrhagia, representing 1
of the most common causes of AUB by the PALM-COEIN
(Polyp; Adenomyosis; Leiomyoma; Malignancy and hyper-
plasia; Coagulopathy; Ovulatory dysfunction; Endometrial;
Iatrogenic; and Not yet classified) International Federation
of Gynecology and Obstetrics classification [24]. Dysmenor-
rhea, dyspareunia, or chronic pelvic pain can be present, but
it is important to consider that up to 35% of women are asymp-
tomatic at the time of diagnosis [10]. In young women the most
common complaint is represented by severe dysmenorrhea
unresponsive to nonsteroidal anti-inflammatory drugs or to
oral contraceptives. Severity of symptoms may correlate to
the depth of uterine disease [25].
Diagnosis
Physical Examination
Suspicion for adenomyosis may arise from gynecologic
history, symptoms, and physical examination. Physical
examination includes inspection of the vagina and cervix
and a bimanual gynecologic examination. Establishing the
position, size, mobility, and tenderness of the uterus is essen-
tial to start the diagnostic process. An enlarged and tender
uterus, painful at mobilization, may suggest adenomyosis.
It is important to detect the possible presence of concomitant
endometriosis and/or uterine myomas. A fixed uterus may
suggest the presence of adhesions, whereas palpation of
adnexal masses, induration or retraction of uterosacral liga-
ments, and nodules in the rectovaginal septum may reveal
endometriosis. Examination during menses may help to
assess modifications in tenderness and uterine size. Instru-
mental diagnosis is mandatory to confirm the diagnosis.
Transvaginal ultrasound (TVUS) and MRI are the most use-
ful techniques to reveal the disease presence.
Ultrasound
Detection methods for adenomyosis remain a diagnostic
challenge. TVUS and MRI have shown high levels of accu-
Journal of Minimally Invasive Gynecology, Vol 23, No 4, May/June 2016
racy in the preoperative diagnosis [26]. Accuracy of
2-dimensional (2D) transvaginal sonography (TVS) in diag-
nosing adenomyosis is comparable with that of MRI and/or
histology, with a sensitivity of 75% to 88% and a specificity
of 67% to 93% [27–31]. However, TVUS compared with
MRI is better tolerated by patients, repeatable, less
expensive, and widely available.
The 2D sonograph describes features of adenomyosis as
alterations of the outer myometrium, whereas MRI has spe-
cific sign for adenomyosis evaluating the JZ. The 2D transva-
ginal sonographic evaluation of the JZ seems to be, also with
high-frequency probes (5–10 MHz), difficult and imprecise
because the sonographic differentiation of the inner and outer
myometrium is not always optimal. With 3-dimensional (3D)
TVSography, it is possible to better visualize the JZ due to
some post-processing arrangements [32–34].
2D Transvaginal Sonographic Features of Adenomyosis
Continuous improvements in the resolution of TVUS
have enabled a more detailed assessment of uterine architec-
ture and thus permits an accurate evaluation of ultrasound
myometrial features of adenomyosis. 2D transvaginal
sonographic features considered to be associated with
adenomyosis are defined as follows [26,29,35–38]:
 Globally enlarged uterus: The fundus of the uterus
appears to be enlarged.
 Asymmetrically enlarged uterus (e.g., anterior wall
thicker than posterior wall or vice versa) unrelated to leio-
myoma.
 Round cystic area within the myometrium: Power
Doppler can be used to distinguish myometrial cysts
from blood vessels.
 Inhomogeneous, irregular myometrial echotexture in an
indistinctly defined myometrial area with decreased or
increased echogenicity; hyperechogenic islands, suben-
dometrial lines, and buds.
 Myometrial hypoechoic linear striations seen as a radi-
ating pattern of thin acoustic shadows not arising from
echogenic foci or leiomyoma (fan-shaped shadowing).
 Indistinct, fuzzy endometrial–myometrial border (ill-
defined endometrial stripe).
 Presence of diffuse minimal vascularity seen as diffuse
spread of small vessels without the normal course of the
arcuate and radial arteries inside the myometrium. Uterine
leiomyomas manifest a circular flow along the myoma
capsule, whereas localized adenomyosis and adenomyo-
mas are characterized by diffusely spread vessels inside
the lesions.
 The ‘‘question mark sign’’ of uteri that is described when
the corpus uterus is flexed backward, the fundus of uteri is
facing the posterior pelvic compartment, and the cervix is
directed frontally toward the urinary bladder [39].
A recent meta-analysis of 14 trials and 1985 participants
reported sensitivity and specificity of ultrasound-diagnosed
Alabiso et al. Management of Adenomyosis 479

adenomyosis to be as high as 82.5 and 84.6%, respectively Fig. 1

[40]. 2D transvaginal sonographic findings are more likely
Ultrasound images of the uterus of our 28-year-old patient with adeno-
to be seen in advanced stages of disease, and most studies
myosis. (A) Two-dimensional gray scale image showing the longitudi-
on TVS and adenomyosis considered as diagnostic have at
nal section of the uterus with asymmetric thickening of the anterior wall
least 2 or 3 ultrasound features [33,41–44]. The presence unrelated to leiomyoma. (B) Asymmetric thickening of the uterus. The
of only 1 of the typical TVS features creates some anterior wall is thicker than the posterior wall with inhomogeneous,
concerns, especially in young women. The association of irregular myometrial echotexture due to hyperechoic and small cystic
these 2D ultrasound features of adenomyosis with anechoic areas (endometrial thickness). Note the ill-defined endometrial
symptoms like menometrorrhagia, dysmenorrhea, or stripe. (C) Power Doppler image showing diffusely spread vessels
infertility may improve the diagnostic accuracy [45]. Some without a circular flow along a capsule, typical for leiomyoma.
studies showed that these 2D ultrasound features of adeno-
myosis are significantly associated with the presence of
pelvic endometriosis, in particular of deep infiltrating
endometriosis [41,42,46].

3D Transvaginal Sonographic Features of Adenomyosis

3D transvaginal sonographic signs of adenomyosis are
based on the evaluation of the JZ on the acquired volume
of the uterus to obtain the sagittal, transverse, and coronal
planes as shown in a standardized multiplanar view
[32,33,38]. The JZ may be regular, irregular, interrupted,
not visible, and not assessable or may manifest more than
1 feature (e.g., irregular and interrupted). Any irregularity
in the JZ can be described (e.g., cystic areas,
hyperechogenic dots, hyperechogenic buds and lines) in
each location in the uterus (anterior, posterior, lateral left,
lateral right, fundus) [33,34,38].
In addition to subjective morphologic evaluation of the
JZ, objective parameters as thickness measurements, simi-
larly used in MRI, have been proposed [33,47,48]. The
maximum thickness of the JZ (JZmax) is measured at the
area where the JZ appears to be at its thickest and the
minimum thickness (JZmin) where it appears to be at its
thinnest. The total myometrial wall thickness can be
measured perpendicular to the endometrium on the same
section. The magnitude of a JZ irregularity is expressed as
the difference between the maximal and minimal JZ
thickness: (JZmax)2(JZmin) 5 JZdif. The extent of JZ
irregularity can reported as the subjective estimation of the
percentage of the JZ that is irregular (,50% or R50%)
[33,38,47]. It was shown that JZ thickness JZmax R 6 to
8 mm and (JZmax)2(JZmin) R 4 mm were significantly
more associated with histologically proven adenomyosis
than other 2D features [33,47]. Also, the subjective
evaluation of infiltration and disruption by endometrial
tissue in the JZ represents an accurate tool for the
diagnosis of adenomyosis [32,33,47]. 3D TVS evaluation
of the JZ could probably detect initial adenomyosis [49]
(Figs. 1 and 2). It has been observed that pelvic
endometriosis, especially in severe stages, is also strongly
associated with JZ thickening and adenomyosis [33,47,50]. more than one 2D ultrasound features in our 28-year-old
2D and 3D TVUS have reached a high level of accuracy, patient permits a diagnosis of adenomyosis also without his-
and a high agreement between ultrasound diagnosis of tologic confirmation. 3D ultrasound evaluation of the JZ and
adenomyosis and histologic findings has been demonstrated. its alterations seems to be very important, especially in
The number of different morphologic features in an individ- patients with suspicion of pelvic endometriosis and with
ual woman could confirm the diagnosis. The presence of associated symptoms [51].
480
Fig. 2
Coronal view of the uterus of our 28-year-old patient obtained using
3-dimensional ultrasound. An ill-defined with focal hyperechoic infil-
tration of junctional zone is seen on the right side (three arrows) and
a normal junctional zone is seen on the left side (two arrows).
MRI
The diagnostic accuracy of MRI in the diagnosis of
adenomyosis has long been established [52]. MRI is consid-
ered more accurate than TVS for the diagnosis of the disease,
although studies have shown that the 2 techniques may be
comparable when a 3D-TVS is performed [53–55].
Moreover, TVS could be useful in identifying those
patients who should consider an additional MRI evaluation
to confirm the diagnosis. This selection can obviously
reduce medical costs. MRI findings are linked to
thickening or hyperplasia of the JZ in association with the
disruption of the normal JZ architecture [53,54].
The standard MRI protocol combines sagittal and axial
views on T2-weighted and spin echo sequences and
T1-weighted axial sequences with and without fat saturation
[56]. On MRI, adenomyosis appears as an ill-demarcated
low-signal-intensity area on T2-weighted images. Addition-
ally, on T2-weighted MRI, small high-signal-intensity areas
refer to ectopic endometrium. Small cysts may also appear
as high-signal-intensity spots on T2-weighted images. The
presence of methemoglobin could be detected as a hyperin-
tense signal on T1-weighted images with fat saturation in
some of these areas, and it is a quite specific sign of adeno-
myosis [48].
Three features on MRI have been considered diagnostic
of adenomyosis: (1) thickening of the JZ to at least
8 to 12 mm [28], (2) ratio JZ maximum-to-total
myometrium over 40% [49], and (3) difference between
the maximum and the minimum thickness of the JZ
(JZmax2Zmin 5 JZdif) . 5 mm [28]. The first 2 criteria
have been criticized because JZ thickness is influenced by
hormonal status and menstrual cycle phase [28], whereas
JZdif appears to be more independent from hormonal status
Journal of Minimally Invasive Gynecology, Vol 23, No 4, May/June 2016
because it is the difference between 2 measurements taken
in the same hormonal phase.
The sensitivity and specificity of MRI in diagnosing
adenomyosis range from 88% to 93% and from 67% to
91%, respectively [29]. However, some factors, such as the
use of gonadotropin-releasing hormone (GnRH) agonists
or the presence of menstrual bleeding, could alter the typical
appearance aspect of the JZ. In fact, during menstruation the
myometrium is frequently contracted and thickened, and this
transient physiologic event could simulate an abnormal JZ
[57]. Adenomyoma (focal adenomyosis) appears as a round
lesion, which is separated from the JZ and included in the
myometrium; therefore, it can often be confused with uterine
leiomyoma. Adenomyoma and leiomyoma are both charac-
terized by low-signal intensity on T2-weighted imaging, but
adenomyomas frequently present high-intensity foci,
whereas leiomyomas are characterized by the presence of
large peripheral vessels [29].
At MRI, our patient presented a large area of alteration
signal that affected the left side of the corpus-fundus portion,
characterized in T2-weighted sequences by high hypointen-
sity and some glandulocystic areas with a predominantly sub-
endometrial location. Two of these areas showed shaded
hyperintensity of signal on Thrive sequences. This wide area
presented a maximum transverse diameter of about 5.5 mm.
In addition, a thickening with shaded limits of JZ was observed
(Figs. 3–5).
Hysteroscopy
A direct visualization of the uterine cavity by means of an
outpatient diagnostic hysteroscopy with the utilization of a
miniature hysteroscope with a 3.5-mm sheath and saline
uterine distension may offer more accurate information
Fig. 3
Magnetic resonance appearance of adenomyosis. Axial T2-weighted
TSE (Turbo spin echo) image: Ill-defined, large area of mixed signal in-
tensity involving the anterior wall of the uterus. It is mainly hypointense
with associated several small hyperintense regions representing ectopic
endometrium. On the right ovary there is a high-signal 2-cm cystic mass
representing a functional cyst.
Alabiso et al. Management of Adenomyosis 481

Fig. 4 [59]. Sometimes, a millimeter lacuna may be observed in

the uterine wall. The excision of superficial openings, cystic
Coronal T2-weighted TSE (Turbo spin echo) image. It confirms an
lesions, and lacuna by operative hysteroscopy is suggested to
extensive area of altered signal intensity involving the anterior wall of
obtain an adequate specimen [60]. The histologic diagnosis
the uterus.
of adenomyosis requires the visualization of glandular
extension in the myometrium . 1 mm [61].
Few data on the diagnostic accuracy of hysteroscopy in
the diagnosis of adenomyosis are available; however, office
hysteroscopy may add information in young patients with
irregular bleeding [62], and it is indicated in patients under-
going in vitro fertilization (IVF). If adenomyosis is sus-
pected, a hysteroscopic loop resection of the lesion is
indicated to obtain the pathologic specimen and, in some
patients, to treat the intracavitary adenomyosis. Office
hysteroscopy in this patient showed a regular uterine cavity
and a regular endometrium.

Impact of Adenomyosis on Fertility Status and IVF

Outcomes
Mechanisms that account for a negative impact of adeno-
myosis on fertility may include the following:
 Impairment of the uterine system of sperm transport,
possibly due to the destruction of the normal myometrial
architecture. Indeed, there is a close relationship between
about the intracavitary pathology [58]. Although adenomyo- the occurrence of adenomyosis and structural and func-
sis represents a rare finding, particularly in young women, tional defects in eutopic endometrium and myometrial
some suggestive hysteroscopic images have been described uterine JZ. The loss of nerve fibers at the endometrium–
[59]. Irregular endometrium with superficial openings myometrium interface and the absence of uterotubal
and/or cystic lesions with a dark blue color can be found transport after the uterine application of radionuclides
associated with adenomyosis support this view [63].
 Uterine dysperistalsis that may be responsible for a reduced
embryo implantation. This effect is, however, controver-
Fig. 5
sial, with 4 studies performed in IVF patients supporting
T1-weighted GE (gradient echo) image with FS (Fat Saturated). There is a detrimental effect and 6 reports against this idea [64].
a high signal intensity area that is consistent with a stromal element. The
 Abnormal concentrations of free radicals in the uterine
findings are in keeping with an active adenomyosis.
environment. Available evidence suggests that generation
of nitric oxide, superoxide, and other free radicals is
increased in women with adenomyosis. Because low
concentrations of free radicals are believed to create a
favorable environment for embryonic development, alter-
ations in the expression of these negative factors may
impair early embryo development and/or increase risk
of early miscarriage [65].
 Altered endometrial vascularization. Indeed, in adeno-
myosis patients mean and total surface area and total num-
ber of capillaries have been shown to be significantly
increased in both proliferative and secretory phases
compared with fertile women. More specifically, the total
surface area of capillaries per mm2 can rise by more than
10 times. Clinically, the abnormal vascularization of the
endometrium is closely related to hypermenorrhea [65].
Notwithstanding the relationship between these mecha-
nisms and infertility seems to be well established, we cannot
exclude that other factors may contribute to the infertility
482
status. Thus, the assessment of the current infertility condi-
tion, including evaluation of the ovarian reserve, hystero-
scopic evaluation of the uterine cavity, and the
investigation of the male factor, should be suggested.
Because our paradigmatic patient is very young, it should
be also suggested that she to proceed with an explorative
laparoscopy to exclude pelvic unfavorable conditions (i.e.,
endometriosis, adhesions) not visible on the ultrasound
[16]. If the laparoscopy identifies and eliminates other detri-
mental pelvic findings, potentially affecting fertility, and
other factors are excluded, the patient should be counseled
for another year of spontaneous childbearing. Otherwise,
after the intervention she could be referred to an IVF
procedure.
In relation to the association between adenomyosis and
infertility, it should be considered that, according to a recent
meta-analysis from some researchers from this group,
adenomyosis is associated with a 28% (95% confidence
interval [CI], 5–45) reduction in the probability of clinical
pregnancy derived from assisted reproduction technology
procedures [66]. However, quantitative heterogeneity
among studies was shown to be high (p 5 .03). Adenomyo-
sis was also associated with a more than double risk of
miscarriage, thus suggesting a causal relationship. Relative
risk was 2.12 (95% CI, 1.20–3.75). Live birth rate was
reported to be reduced by 30%. This decreased probability
of achieving a viable pregnancy should be discussed with
the patient.
On the other hand, patients should also be informed that
the available information should be integrated with several
other variables. In the context of the IVF procedure, suppres-
sion of adenomyosis by long-term down-regulation with
GnRH agonists has to be considered to improve the outcome.
Indeed, in 2 studies in which a long down-regulation proto-
col was used, heterogeneity was absent and no difference
was observed in clinical pregnancy rate (relative risk, 1.05;
95% CI, .75–1.48). Conversely, in 4 studies in which a short
GnRH agonist protocol was applied, a major difference was
observed (relative risk. .58; 95% CI, .38–.88), but heteroge-
neity was moderate to high. If the patient will finally undergo
an IVF procedure, a possible approach could include an
ovarian hyperstimulation with high gonadotropin doses
and embryo freezing [67]. The transfer could be postponed
after 2 to 4 months of GnRH agonist therapy with hormone
replacement therapy used in frozen–thawed cycles. All this
is done with the aim to take advantage of the ability of
GnRH agonist to reduce disease activity. Considering the
patient’s age, this general strategy is likely to solve the infer-
tility problem in the short term. If not, other factors should be
investigated, including the infertility workup for recurrent
implantation failure and a preimplantation diagnosis.
Medical Treatment
The medications most commonly used to treat bleeding
and pain in adenomyosis are hormonal treatments that
Journal of Minimally Invasive Gynecology, Vol 23, No 4, May/June 2016
induce an endometrial atrophy either by a local action (levo-
norgestrel intrauterine system) or by a systemic action both
on the endometrium and on the hypothalamic-pituitary-
ovarian axis (progestogens, danazol, GnRH agonists). There
are, however, very few well-conducted clinical studies on the
pharmacologic treatment of adenomyosis, and no reports on
novel compounds are being developed.
Intrauterine systems diffusing 20 mg/day levonorgestrel
are commonly used in women with AUB due to adenomyo-
sis. The efficacy of levonorgestrel–intrauterine systems in
the treatment of adenomyosis-related pain and heavy men-
strual bleeding could be explained by different mechanisms:
(1) a direct progestogenic effect on ectopic adenomyosis
foci, (2) decidualization and atrophy of the eutopic endome-
trium, and (3) modulation of endometrial factors altered in
adenomyosis [68].
Adenomyosis is characterized by a decreased expression
of progesterone receptors A and B in ectopic endometrial le-
sions, possibly related to epigenetic changes [69]. This pro-
gesterone resistance in adenomyosis could potentially lead
to an abnormal expression of progesterone receptor–related
genes, to a reduced expression of implantation-related
genes, and to a resistance to progestogens treatment [70].
Danazol, a derivative of 17a-ethinyl-testosterone, has
been described to act by inducing apoptosis in ectopic endo-
metrial implants and to reduce aromatase expression in the
eutopic endometrium [71]. Literature on the use of danazol
for the treatment of adenomyosis is very scarce. In a report
on 14 women with adenomyosis, treatment with a danazol-
loaded intrauterine systems induced an important reduction
in dysmenorrhea and hypermenorrhea [72].
After an initial stimulatory effect, continuous prolonged
treatment with GnRH analog induces a central down-
regulation with a deep suppression of gonadotropin secre-
tion. This inhibition of the hypothalamic-pituitary-ovarian
axis suppresses ovarian function and induces profound
hypoestrogenism. GnRH receptors have been found in endo-
metriosis, adenomyosis lesions, and leiomyomas; GnRH
analog could therefore also exert a direct antiproliferative
action within the myometrium. GnRH analog decreases
macrophages and microvessel density and increases
apoptosis in the eutopic endometrium and the myometrium
but does not seem to have the same impact on ectopic lesions
in women with adenomyosis [73]. Although in many in-
stances medical therapy may be the preferred choice for a
symptomatic patient, in particular with diffuse adenomyosis,
in a patient currently seeking pregnancy, such as the one
described in this article, currently available medical thera-
pies have no indication.
Surgical Treatment
In symptomatic young women desiring to conceive, the
concept of conservative, uterine-sparing surgery for adeno-
myosis is acquiring more and more consensus; nevertheless,
conservative surgery has not become the standard treatment
Alabiso et al. Management of Adenomyosis
for adenomyosis yet. This is mainly because adenomyotic
tissue invades the uterine muscle layer with unclear borders,
determining the absence of a surgical cleavage plane, so
complete excision of the affected area remains inaccurate
and often causes heavy blood loss [18]. Moreover, the
excision of adenomyotic tissue is always accompanied by
excision of myometrium, so it is partly destructive for the
uterine wall. Therefore, the advantages of removing an
affected area must be balanced against the disadvantages
of leaving a possibly defective uterine wall.
In 1952 the term ‘‘hysteroplasty’’ was used to describe
uterine-sparing surgery in young women with extensive ad-
enomyosis [74]. The currently available uterine-preserving
surgical options for adenomyosis could be classified as com-
plete excision of adenomyosis (preferably used in case of
localized adenomyosis), debulking surgery/partial adeno-
myomectomy (preferably used in case of diffuse adenomyo-
sis), and nonexcisional techniques, used when removal of
adenomyotic tissue is not included (i.e., uterine artery liga-
tion, electrocoagulation of myometrium, hysteroscopic and
nonhysteroscopic endometrial resection/ablation). A recent
review concluded that uterine-sparing surgery for adenomyo-
sis appears to be feasible and satisfactory: After complete
excision, the dysmenorrhea reduction, menorrhagia control,
and pregnancy rates were found to be 82.0%, 68.8%, and
60.5%, respectively. After partial excision, the dysmenorrhea
reduction, menorrhagia control, and pregnancy rates were
81.8%, 50.0%, and 46.9%, respectively [18].
It should be underlined that today the true impact of
various treatments on fertility outcomes of adenomyosis-
associated subfertility has not been fully clarified, because
most studies on treatments have been uncontrolled, and out-
comes are usually reported in the form of case series [15].
Regarding the effect of age in fertility outcomes, uterine-
sparing surgery for adenomyosis showed to be a clear benefit
for women % 39 years but not for women R 40 years,
according to clinical pregnancy rates of 41.3% and 3.7%,
respectively [75].
Finally, the perinatal complications related to uterine-
sparing surgery for adenomyosis deserve to be mentioned.
Placenta accreta and uterine rupture during pregnancy or
labor have been described [76]. Placenta accreta is probably
due to small perforations of the endometrium, which may
become a crucial cause of invasion of the placenta into the
outer myometrium through the defected subendometrial
myometrium [75]. Uterine rupture in the presence of uterine
adenomyosis may be related to the fact that myocites are
widely separated by a loose connective tissue matrix filled
with less elastic collagen fibrils [77,78]. This structural
change may cause a decline in tissue elasticity so that the
repaired uterine wall could be lower in tensile strength,
which may increase the risk of uterine ruptures. Currently,
there is no clear evidence regarding finding and treating
adenomyosis in patients who wish to conceive.
Conversely, conservative surgery could be considered to
reduce dysmenorrhea and menorrhagia.
483
Alternative Treatments
Alternative treatments such as high-intensity focused
ultrasound (HIFU) and uterine artery embolization (UAE)
have been proposed for the treatment of selective cases of
adenomyosis. Their role is still controversial; data on preg-
nancy outcome are scanty. Therefore, at presently alternative
treatments should be proposed only in women with no desire
for pregnancy and who are unresponsive to medical treat-
ments.
High-Intensity Focused Ultrasound
HIFU, or focused ultrasound surgery (FUS), is a nonsur-
gical therapeutic treatment for adenomyosis; this technique
consists of focusing high-intensity ultrasound at the target
to induce thermal ablation and destroy the lesion. The
main histologic change in adenomyotic lesion after treat-
ment is represented by coagulative necrosis associated
with vascular damage and no hemorrhage. Microscopic
examination confirmed a typical coagulation necrosis within
the treated tissue.
MRI-guided HIFU (MRgHIFU), or MRI-guided FUS
(MRgFUS), is a novel technique founded in the 1990s as a
new and innovative method of treatment of some malignant
solid tumors and uterine myomas [79–82]. Over the last few
years, these noninvasive new techniques have also been used
in treating adenomyosis. About 10 years ago, a few groups
began to use MRgHIFU/MRgFUS to treat patients with
adenomyosis. Subsequently, other groups reported their
results showing that MRgHIFU/MRgFUS was feasible
and safe in treating symptomatic adenomyosis [83–85].
During the same period, other authors reported that
ultrasonography-guided HIFU was also safe and effective
in ablating adenomyotic lesion and in alleviating its symp-
toms [86,87].
Currently, MRI or ultrasound can be used for guidance.
MRI has excellent anatomic resolution, and MRI-based ther-
mal mapping offers real-time temperature monitoring during
HIFU or FUS treatment. Ultrasound is the alternative tech-
nique introduced to monitor HIFU treatment. Compared
with MRgHIFU/MRgFUS, ultrasonography-guided HIFU is
less costly; ultrasound also offers a real-time anatomic moni-
toring imaging, and a gray scale change during treatment rep-
resents a reliable indicator in monitoring the response to
HIFU. In addition, ultrasound is simple to use and does not
require the patient to be enclosed in a confined space. Exclu-
sion criteria are diffuse adenomyosis, no desire for pregnancy,
and general contraindications to HIFU/FUS (giant pelvic
scars, suspect of malignancy, uncontrolled general diseases).
With the improvement of the technique and increase of
physicians’ experience, the rate of adverse effects has
decreased dramatically. Mild adverse effects include small
vaginal discharge and lower abdominal pain; these side
effects subsided in most patients in 7 days. Serious adverse
effects are abdominal skin burns and leg pain associated
484
with thermal injury of the sciatic nerve. Very rare severe
complications reported include temporary acute renal failure
and intestinal perforation [87].
Uterine Artery Embolization
UAE represents a minimally invasive procedure origi-
nally described in 1995 by Ravina et al [88] for women
with symptomatic leiomyomas. It might be an alternative
to surgery for women with adenomyosis [89]. UAE could
be proposed to women with symptomatic adenomyosis
(bleeding, pain, dysmenorrhea, menorrhagia, increased uter-
ine volume). MRI has been suggested to predict the response
to UAE [90].
Although UAE might act similarly for these 2 indications,
there are some technical differences when it is used for ad-
enomyosis. At angiography and histology, adenomyosis
shows a reduction in arterial pattern but an increase in micro-
vessel density compared with normal myometrium [91,92].
The most used embolic agent is nonspherical PVA
(polyvinyl alcohol) particles ranging from 255 to 900 mm
that can pass in the microcatheter without clogging it and
can embolize adenomyosis microvessels [93]. Kim et al
[94] have developed a 1-2-3 protocol with nonspherical
PVA (polyvinyl alcohol) agents with saline solution and
contrast agent consisting of 3 different steps: injecting parti-
cles of 150 to 250 mm (first injection), then of 250 to 355 mm
(second injection), and finally of 355 to 500 mm (third injec-
tion) to achieve complete occlusion of the myometrial micro-
vessel (no blood flow for 10 cardiac beats). However, there
are no available data to recommend a specific embolic agent
to treat adenomyosis [95].
Commonly reported side effects of UAE are represented
by the so-called postembolization syndrome consisting in
pelvic pain, nausea, and fever due to ischemic necrosis and
hematoma at the femoral artery puncture site. Moreover,
the exposition to radiation (approximately 20 cGy) should
be taken into account [95]. Some patients can experience ma-
jor complications, including hemorrhage, unplanned surgical
procedures, and infections. Finally, an age-related impair-
ment of ovarian function has been reported in older women
(.40 years) [96]. Although the clinical outcome and
follow-up after UAE have been analyzed for myomas by
different authors [97–99], the available data for the efficacy
of UAE in ‘‘symptomatic’’ adenomyosis are less clear.
UAE might be a good alternative to surgery because it is
more cost-effective, has a shorter hospitalization, and is less
invasive [95]. However, because of the lack of high-quality
data, randomized controlled studies with longer follow-up
are mandatory to determine UAE importance in the field
of therapeutic options for women with adenomyosis [100].
Oncologic Risk of Adenomyosis
Although malignant transformation of endometriosis
occurs in up to 1% of women [101], the occurrence of
Journal of Minimally Invasive Gynecology, Vol 23, No 4, May/June 2016
malignant neoplasms originating from adenomyosis seems
extremely rare. This is precisely why a 28-year-old nullipa-
rous woman with a diagnosis of adenomyosis should be
reassured about her risk of malignancy.
A literature review was reported in 2012 by Koike et al
[102]. The authors collected all published reports of malig-
nant tumors arising from adenomyosis, describing only 44
cases. The most frequent histologic subtype was endome-
trioid adenocarcinoma. Most of the reported cases occurred
in postmenopausal women, whereas malignant transforma-
tion of adenomyosis in premenopausal women with normal
endometrium was extremely rare. All the uteri described in
this review showed no evidence of endometrial malignancy
in the endometrial cavity; this clearly confirms that the
neoplasm primitively originates from adenomyosis with a
normal endometrium.
Colman and Rosenthal [103] proposed the 3 following
strict criteria to define carcinomas developing from adeno-
myosis by modifying Sampson criteria for ovarian cancer
originating from endometriosis:
 The carcinoma must not be situated in the endometrium or
elsewhere in the pelvis.
 The carcinoma must be seen to arise from the epithelium
of adenomyosis and not to have invaded from another
source.
 Endometrial adenomyotic stromal cells should be sur-
rounding the aberrant glands to support the diagnosis of
adenomyosis.
Adenomyosis can also be involved with endometrial ade-
nocarcinomas arising from eutopic endometrium. Several
previous studies have documented coexistent adenomyosis
and endometrial cancer, with a reported incidence ranging
from 10% to 70% in hysterectomy specimens [104]; when
an endometrial carcinoma and adenomyosis coexist in the
same uterus, adenomyosis is invaded by the carcinoma only
in 25% of the cases [105]. It has been clearly shown that
the presence of adenomyosis invaded by endometrial adeno-
carcinoma does not appear to worsen the prognosis [106].
Although the occurrence of neoplastic transformation of
adenomyosis is a rare event, the diagnosis could be sometimes
difficult, possibly significantly delaying treatment as reported
by Boes et al [107]. The authors reported a woman with post-
menopausal vaginal bleeding. Although hysteroscopic evalu-
ation of the endometrial cavity was initially negative, biopsies
from a second hysteroscopy performed 1 year later for persist-
ing bleeding revealed a well-differentiated endometrioid
endometrial carcinoma. Pathologic examination of the hyster-
ectomy specimen revealed an atrophic endometrium and a
well-differentiated endometrioid endometrial carcinoma
originating from nodular adenomyosis.
Conclusions
Adenomyosis has long been considered a typical condi-
tion of parous women, although it may occur in young
Alabiso et al. Management of Adenomyosis
nulliparous. In these patients symptoms may differ from
those present in older women. In this review we discussed
the case of a 28-year-old patient with irregular and heavy
menstrual periods, severe cyclic pelvic pain, dysmenorrhea,
and deep dyspareunia, attempting pregnancy for 1 year.
Clinical examination and imaging techniques were sugges-
tive of adenomyosis. A decision algorithm derived from
this discussion is proposed in Fig. 6.
Because of the patient’s young age and a desire for preg-
nancy, medical therapy is contraindicated and an infertility
workup should be performed. Because of a lack of other
infertility factors, the available therapeutic options and the
possibility of undergoing laparoscopy or IVF should be dis-
cussed with the patient. Laparoscopy is also indicated to rule
Fig. 6
Decision algorithm derived from the discussion. MRI, magnetic resonance imaging; IVF, in vitro fertilization; LNG-IUD, Levonorgestrel-Intrauterine
Dispositive; GnRH, Gonadotropin Releasing Hormone.
485
out the presence of adhesions and/or endometriosis that may
contribute to pain symptoms. One year after the laparoscopic
treatment of adhesions or/and endometriosis lesions, IVF is
the best option if pregnancy has not been achieved.
The choice of treatment in patients with adenomyosis
depends on several variables: age of the patient, kind of symp-
toms (AUB, pain, infertility), pregnancy desire, and associa-
tion with other gynecologic diseases. In women complaining
of severe AUB and/or pain with no more reproductive desire,
the definitive treatment is hysterectomy. For those who wish
to preserve fertility but not currently seeking pregnancy, med-
ical therapy is the best choice of treatment.
Progestogens, in particular levonorgestrel–intrauterine
systems, are considered the first-line therapy to reduce
486
pain and AUB. In some patients progestogens may not lead
to resolution of symptoms; in particular, the occurrence of
irregular bleeding frequently causes interruption of treat-
ment. In these cases GnRH agonists or, alternatively, oral
or intravaginal danazol may be used as a second-line treat-
ment. Progestogens are also the treatment of choice for
long-term therapy. In selected cases GnRH analog associ-
ated with add-back therapy may be prescribed. In cases
with symptoms resistant to medical therapy, conservative
surgery with resection of adenomyoma or adenomyotic tis-
sue can be performed in specialized centers with experi-
enced surgeons trained in these surgical techniques.
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