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Adenomyosis - What The Patient Needs
Adenomyosis - What The Patient Needs
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
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 Journal of Minimally Invasive Gynecology, Vol 23, No 4, May/June 2016
adenomyosis, consisting of ectopic endometrium enclosed racy in the preoperative diagnosis [26]. Accuracy of
in s smooth muscle nodule, is usually called adenomyoma. 2-dimensional (2D) transvaginal sonography (TVS) in diag-
nosing adenomyosis is comparable with that of MRI and/or
Clinical Features histology, with a sensitivity of 75% to 88% and a specificity
of 67% to 93% [27–31]. However, TVUS compared with
Clinical presentation of adenomyosis could be heteroge- MRI is better tolerated by patients, repeatable, less
neous. Young women with mild disease could be highly symp- expensive, and widely available.
tomatic, whereas older patients with very enlarged uteri may The 2D sonograph describes features of adenomyosis as
present only small symptoms. Moreover, up to 80% of ad- alterations of the outer myometrium, whereas MRI has spe-
enomyotic uteri contain associated pathology, such as my- cific sign for adenomyosis evaluating the JZ. The 2D transva-
omas that could have similar clinical presentations [22]. On ginal sonographic evaluation of the JZ seems to be, also with
the other hand, about one-third of women suffering from endo- high-frequency probes (5–10 MHz), difficult and imprecise
metriosis have concomitant adenomyosis, with overlapping because the sonographic differentiation of the inner and outer
and usually heavier symptoms [23]. Diagnosis of adenomyo- myometrium is not always optimal. With 3-dimensional (3D)
sis is placed commonly in the fourth or fifth decade of life. TVSography, it is possible to better visualize the JZ due to
Typical presentation includes abnormal uterine bleeding some post-processing arrangements [32–34].
(AUB), with menorrhagia and metrorrhagia, representing 1
of the most common causes of AUB by the PALM-COEIN 2D Transvaginal Sonographic Features of Adenomyosis
(Polyp; Adenomyosis; Leiomyoma; Malignancy and hyper- Continuous improvements in the resolution of TVUS
plasia; Coagulopathy; Ovulatory dysfunction; Endometrial; have enabled a more detailed assessment of uterine architec-
Iatrogenic; and Not yet classified) International Federation ture and thus permits an accurate evaluation of ultrasound
of Gynecology and Obstetrics classification [24]. Dysmenor- myometrial features of adenomyosis. 2D transvaginal
rhea, dyspareunia, or chronic pelvic pain can be present, but sonographic features considered to be associated with
it is important to consider that up to 35% of women are asymp- adenomyosis are defined as follows [26,29,35–38]:
tomatic at the time of diagnosis [10]. In young women the most
common complaint is represented by severe dysmenorrhea Globally enlarged uterus: The fundus of the uterus
unresponsive to nonsteroidal anti-inflammatory drugs or to appears to be enlarged.
oral contraceptives. Severity of symptoms may correlate to Asymmetrically enlarged uterus (e.g., anterior wall
the depth of uterine disease [25]. thicker than posterior wall or vice versa) unrelated to leio-
myoma.
Round cystic area within the myometrium: Power
Diagnosis Doppler can be used to distinguish myometrial cysts
Physical Examination from blood vessels.
Inhomogeneous, irregular myometrial echotexture in an
Suspicion for adenomyosis may arise from gynecologic indistinctly defined myometrial area with decreased or
history, symptoms, and physical examination. Physical increased echogenicity; hyperechogenic islands, suben-
examination includes inspection of the vagina and cervix dometrial lines, and buds.
and a bimanual gynecologic examination. Establishing the Myometrial hypoechoic linear striations seen as a radi-
position, size, mobility, and tenderness of the uterus is essen- ating pattern of thin acoustic shadows not arising from
tial to start the diagnostic process. An enlarged and tender echogenic foci or leiomyoma (fan-shaped shadowing).
uterus, painful at mobilization, may suggest adenomyosis. Indistinct, fuzzy endometrial–myometrial border (ill-
It is important to detect the possible presence of concomitant defined endometrial stripe).
endometriosis and/or uterine myomas. A fixed uterus may Presence of diffuse minimal vascularity seen as diffuse
suggest the presence of adhesions, whereas palpation of spread of small vessels without the normal course of the
adnexal masses, induration or retraction of uterosacral liga- arcuate and radial arteries inside the myometrium. Uterine
ments, and nodules in the rectovaginal septum may reveal leiomyomas manifest a circular flow along the myoma
endometriosis. Examination during menses may help to capsule, whereas localized adenomyosis and adenomyo-
assess modifications in tenderness and uterine size. Instru- mas are characterized by diffusely spread vessels inside
mental diagnosis is mandatory to confirm the diagnosis. the lesions.
Transvaginal ultrasound (TVUS) and MRI are the most use- The ‘‘question mark sign’’ of uteri that is described when
ful techniques to reveal the disease presence. the corpus uterus is flexed backward, the fundus of uteri is
facing the posterior pelvic compartment, and the cervix is
Ultrasound directed frontally toward the urinary bladder [39].
Detection methods for adenomyosis remain a diagnostic A recent meta-analysis of 14 trials and 1985 participants
challenge. TVUS and MRI have shown high levels of accu- reported sensitivity and specificity of ultrasound-diagnosed
Alabiso et al. Management of Adenomyosis 479
status. Thus, the assessment of the current infertility condi- induce an endometrial atrophy either by a local action (levo-
tion, including evaluation of the ovarian reserve, hystero- norgestrel intrauterine system) or by a systemic action both
scopic evaluation of the uterine cavity, and the on the endometrium and on the hypothalamic-pituitary-
investigation of the male factor, should be suggested. ovarian axis (progestogens, danazol, GnRH agonists). There
Because our paradigmatic patient is very young, it should are, however, very few well-conducted clinical studies on the
be also suggested that she to proceed with an explorative pharmacologic treatment of adenomyosis, and no reports on
laparoscopy to exclude pelvic unfavorable conditions (i.e., novel compounds are being developed.
endometriosis, adhesions) not visible on the ultrasound Intrauterine systems diffusing 20 mg/day levonorgestrel
[16]. If the laparoscopy identifies and eliminates other detri- are commonly used in women with AUB due to adenomyo-
mental pelvic findings, potentially affecting fertility, and sis. The efficacy of levonorgestrel–intrauterine systems in
other factors are excluded, the patient should be counseled the treatment of adenomyosis-related pain and heavy men-
for another year of spontaneous childbearing. Otherwise, strual bleeding could be explained by different mechanisms:
after the intervention she could be referred to an IVF (1) a direct progestogenic effect on ectopic adenomyosis
procedure. foci, (2) decidualization and atrophy of the eutopic endome-
In relation to the association between adenomyosis and trium, and (3) modulation of endometrial factors altered in
infertility, it should be considered that, according to a recent adenomyosis [68].
meta-analysis from some researchers from this group, Adenomyosis is characterized by a decreased expression
adenomyosis is associated with a 28% (95% confidence of progesterone receptors A and B in ectopic endometrial le-
interval [CI], 5–45) reduction in the probability of clinical sions, possibly related to epigenetic changes [69]. This pro-
pregnancy derived from assisted reproduction technology gesterone resistance in adenomyosis could potentially lead
procedures [66]. However, quantitative heterogeneity to an abnormal expression of progesterone receptor–related
among studies was shown to be high (p 5 .03). Adenomyo- genes, to a reduced expression of implantation-related
sis was also associated with a more than double risk of genes, and to a resistance to progestogens treatment [70].
miscarriage, thus suggesting a causal relationship. Relative Danazol, a derivative of 17a-ethinyl-testosterone, has
risk was 2.12 (95% CI, 1.20–3.75). Live birth rate was been described to act by inducing apoptosis in ectopic endo-
reported to be reduced by 30%. This decreased probability metrial implants and to reduce aromatase expression in the
of achieving a viable pregnancy should be discussed with eutopic endometrium [71]. Literature on the use of danazol
the patient. for the treatment of adenomyosis is very scarce. In a report
On the other hand, patients should also be informed that on 14 women with adenomyosis, treatment with a danazol-
the available information should be integrated with several loaded intrauterine systems induced an important reduction
other variables. In the context of the IVF procedure, suppres- in dysmenorrhea and hypermenorrhea [72].
sion of adenomyosis by long-term down-regulation with After an initial stimulatory effect, continuous prolonged
GnRH agonists has to be considered to improve the outcome. treatment with GnRH analog induces a central down-
Indeed, in 2 studies in which a long down-regulation proto- regulation with a deep suppression of gonadotropin secre-
col was used, heterogeneity was absent and no difference tion. This inhibition of the hypothalamic-pituitary-ovarian
was observed in clinical pregnancy rate (relative risk, 1.05; axis suppresses ovarian function and induces profound
95% CI, .75–1.48). Conversely, in 4 studies in which a short hypoestrogenism. GnRH receptors have been found in endo-
GnRH agonist protocol was applied, a major difference was metriosis, adenomyosis lesions, and leiomyomas; GnRH
observed (relative risk. .58; 95% CI, .38–.88), but heteroge- analog could therefore also exert a direct antiproliferative
neity was moderate to high. If the patient will finally undergo action within the myometrium. GnRH analog decreases
an IVF procedure, a possible approach could include an macrophages and microvessel density and increases
ovarian hyperstimulation with high gonadotropin doses apoptosis in the eutopic endometrium and the myometrium
and embryo freezing [67]. The transfer could be postponed but does not seem to have the same impact on ectopic lesions
after 2 to 4 months of GnRH agonist therapy with hormone in women with adenomyosis [73]. Although in many in-
replacement therapy used in frozen–thawed cycles. All this stances medical therapy may be the preferred choice for a
is done with the aim to take advantage of the ability of symptomatic patient, in particular with diffuse adenomyosis,
GnRH agonist to reduce disease activity. Considering the in a patient currently seeking pregnancy, such as the one
patient’s age, this general strategy is likely to solve the infer- described in this article, currently available medical thera-
tility problem in the short term. If not, other factors should be pies have no indication.
investigated, including the infertility workup for recurrent
implantation failure and a preimplantation diagnosis.
Surgical Treatment
In symptomatic young women desiring to conceive, the
Medical Treatment
concept of conservative, uterine-sparing surgery for adeno-
The medications most commonly used to treat bleeding myosis is acquiring more and more consensus; nevertheless,
and pain in adenomyosis are hormonal treatments that conservative surgery has not become the standard treatment
Alabiso et al. Management of Adenomyosis 483
with thermal injury of the sciatic nerve. Very rare severe malignant neoplasms originating from adenomyosis seems
complications reported include temporary acute renal failure extremely rare. This is precisely why a 28-year-old nullipa-
and intestinal perforation [87]. 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
Uterine Artery Embolization
[102]. The authors collected all published reports of malig-
UAE represents a minimally invasive procedure origi- nant tumors arising from adenomyosis, describing only 44
nally described in 1995 by Ravina et al [88] for women cases. The most frequent histologic subtype was endome-
with symptomatic leiomyomas. It might be an alternative trioid adenocarcinoma. Most of the reported cases occurred
to surgery for women with adenomyosis [89]. UAE could in postmenopausal women, whereas malignant transforma-
be proposed to women with symptomatic adenomyosis tion of adenomyosis in premenopausal women with normal
(bleeding, pain, dysmenorrhea, menorrhagia, increased uter- endometrium was extremely rare. All the uteri described in
ine volume). MRI has been suggested to predict the response this review showed no evidence of endometrial malignancy
to UAE [90]. in the endometrial cavity; this clearly confirms that the
Although UAE might act similarly for these 2 indications, neoplasm primitively originates from adenomyosis with a
there are some technical differences when it is used for ad- normal endometrium.
enomyosis. At angiography and histology, adenomyosis Colman and Rosenthal [103] proposed the 3 following
shows a reduction in arterial pattern but an increase in micro- strict criteria to define carcinomas developing from adeno-
vessel density compared with normal myometrium [91,92]. myosis by modifying Sampson criteria for ovarian cancer
The most used embolic agent is nonspherical PVA originating from endometriosis:
(polyvinyl alcohol) particles ranging from 255 to 900 mm
The carcinoma must not be situated in the endometrium or
that can pass in the microcatheter without clogging it and
elsewhere in the pelvis.
can embolize adenomyosis microvessels [93]. Kim et al
The carcinoma must be seen to arise from the epithelium
[94] have developed a 1-2-3 protocol with nonspherical
of adenomyosis and not to have invaded from another
PVA (polyvinyl alcohol) agents with saline solution and
source.
contrast agent consisting of 3 different steps: injecting parti-
Endometrial adenomyotic stromal cells should be sur-
cles of 150 to 250 mm (first injection), then of 250 to 355 mm
rounding the aberrant glands to support the diagnosis of
(second injection), and finally of 355 to 500 mm (third injec-
adenomyosis.
tion) to achieve complete occlusion of the myometrial micro-
vessel (no blood flow for 10 cardiac beats). However, there Adenomyosis can also be involved with endometrial ade-
are no available data to recommend a specific embolic agent nocarcinomas arising from eutopic endometrium. Several
to treat adenomyosis [95]. previous studies have documented coexistent adenomyosis
Commonly reported side effects of UAE are represented and endometrial cancer, with a reported incidence ranging
by the so-called postembolization syndrome consisting in from 10% to 70% in hysterectomy specimens [104]; when
pelvic pain, nausea, and fever due to ischemic necrosis and an endometrial carcinoma and adenomyosis coexist in the
hematoma at the femoral artery puncture site. Moreover, same uterus, adenomyosis is invaded by the carcinoma only
the exposition to radiation (approximately 20 cGy) should in 25% of the cases [105]. It has been clearly shown that
be taken into account [95]. Some patients can experience ma- the presence of adenomyosis invaded by endometrial adeno-
jor complications, including hemorrhage, unplanned surgical carcinoma does not appear to worsen the prognosis [106].
procedures, and infections. Finally, an age-related impair- Although the occurrence of neoplastic transformation of
ment of ovarian function has been reported in older women adenomyosis is a rare event, the diagnosis could be sometimes
(.40 years) [96]. Although the clinical outcome and difficult, possibly significantly delaying treatment as reported
follow-up after UAE have been analyzed for myomas by by Boes et al [107]. The authors reported a woman with post-
different authors [97–99], the available data for the efficacy menopausal vaginal bleeding. Although hysteroscopic evalu-
of UAE in ‘‘symptomatic’’ adenomyosis are less clear. ation of the endometrial cavity was initially negative, biopsies
UAE might be a good alternative to surgery because it is from a second hysteroscopy performed 1 year later for persist-
more cost-effective, has a shorter hospitalization, and is less ing bleeding revealed a well-differentiated endometrioid
invasive [95]. However, because of the lack of high-quality endometrial carcinoma. Pathologic examination of the hyster-
data, randomized controlled studies with longer follow-up ectomy specimen revealed an atrophic endometrium and a
are mandatory to determine UAE importance in the field well-differentiated endometrioid endometrial carcinoma
of therapeutic options for women with adenomyosis [100]. originating from nodular adenomyosis.
nulliparous. In these patients symptoms may differ from out the presence of adhesions and/or endometriosis that may
those present in older women. In this review we discussed contribute to pain symptoms. One year after the laparoscopic
the case of a 28-year-old patient with irregular and heavy treatment of adhesions or/and endometriosis lesions, IVF is
menstrual periods, severe cyclic pelvic pain, dysmenorrhea, the best option if pregnancy has not been achieved.
and deep dyspareunia, attempting pregnancy for 1 year. The choice of treatment in patients with adenomyosis
Clinical examination and imaging techniques were sugges- depends on several variables: age of the patient, kind of symp-
tive of adenomyosis. A decision algorithm derived from toms (AUB, pain, infertility), pregnancy desire, and associa-
this discussion is proposed in Fig. 6. tion with other gynecologic diseases. In women complaining
Because of the patient’s young age and a desire for preg- of severe AUB and/or pain with no more reproductive desire,
nancy, medical therapy is contraindicated and an infertility the definitive treatment is hysterectomy. For those who wish
workup should be performed. Because of a lack of other to preserve fertility but not currently seeking pregnancy, med-
infertility factors, the available therapeutic options and the ical therapy is the best choice of treatment.
possibility of undergoing laparoscopy or IVF should be dis- Progestogens, in particular levonorgestrel–intrauterine
cussed with the patient. Laparoscopy is also indicated to rule systems, are considered the first-line therapy to reduce
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.
486 Journal of Minimally Invasive Gynecology, Vol 23, No 4, May/June 2016
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