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CHIEF EDITOR'SNOTE: This article is part of a series of continuing education activities in this Journal through which a total of
36 AMA PRA Category 1 Credits
TM
can be earned in 2016. Instructions for how CME credits can be earned appear on the last
page of the Table of Contents.
The Impact of Adenomyosis on
Women’s Fertility
Tasuku Harada, MD, PhD, DMSci,* Yin Mon Khine, MB, BS,†
Apostolos Kaponis, MD, PhD,‡Theocharis Nikellis, MD,§
George Decavalas, MD, PhD,∥and Fuminori Taniguchi, MD, PhD¶
*Professor and †Postgraduate Student, Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Tottori,
Japan; ‡Associate Professor, §Training Doctor, and ∥Professor, Department of Obstetrics and Gynecology, Patras University
School of Medicine, Patra, Greece; and ¶Associate Professor, Department of Obstetrics and Gynecology, Tottori University,
Faculty of Medicine, Tottori, Japan
Until recently, adenomyosis has been associated with multiparity, not impaired fertility. Currently,
adenomyosis is diagnosed with increasing frequency in infertile patients since women delay their first
pregnancy until their late 30s or early 40s. Although an association between adenomyosis and infertility
has not been fully established, based on the available information, recent studies suggested that
adenomyosis has a negative impact on female fertility. Several uncontrolled studies with limited data also
suggested that treatment of adenomyosis may improve fertility. This article discusses (i) the hypothesis
and epidemiology of adenomyosis, (ii) diagnostic techniques, (iii) clinical evidence of correlation between
adenomyosis and infertility, (iv) proposed mechanism of infertility in women with adenomyosis, (v) different
treatment strategies and reproductive outcomes, and (vi) assisted reproductive technology outcome in
women with adenomyosis.
Target Audience: Obstetricians and gynecologists, family physicians.
Learning Objectives: After completing this activity, the learner should be better able to: Recall the hypothesis
and epidemiology of adenomyosis; Evaluate the important findings on improved imaging techniques to diagnose
adenomyosis; Understand that the presence of adenomyosis may impair the reproductive outcomes in women
with adenomyosis; Explain the proposed mechanism of infertility in women with adenomyosis; Give the most ap-
propriate treatment for better reproductive outcomes in women with adenomyosis; and Advise patients that sur-
gery could be effective in women with adenomyosis with a history of IVF failure although latter finding could be
partly attributed to the higher rate of early miscarriage.
Adenomyosis is a benign uterine disorder character-
ized by the presence of heterotopic endometrial glands
and stroma in the myometrium and reactive fibrosis
of the surrounding smooth muscles cells of the myo-
metrium. For the past 80 years, a number of theories
have described how adenomyosis develops. Currently,
the most widespread hypothesis is that adenomyosis
originates from the invagination of the basalis of the
endometrium into the myometrium. According to a
second theory, this basalis invagination would pro-
ceed along the intramyometrial lymphatic system. A
third theory suggests that a metaplastic process initi-
ating from ectopic intramyometrial endometrial tis-
sue is produced de novo.
1–3
Reports show that approximately 20% of cases of
adenomyosis involve women younger than 40 years,
and 80% are 40 to 50 years old. The most severe symp-
toms are associated with the older group. Adenomyosis
All authorsand staff in a position to control the content of this CME
activity and their spouses/life partners (if any) havedisclosed that they
have no financial relationships with, or financial interests in, any com-
mercial organizations pertaining to this educational activity.
Correspondence requests to: Tasuku Harada, MD, PhD, DMSci,
Department of Obstetrics and Gynecology, Tottori University Faculty
of Medicine, 36-1 Nishicho, Yonago, Tottori, 683-8504, Japan.
E-mail: tasuku@med.tottori-u.ac.jp.
This is an open-access article distributed under the terms of the
Creative Commons Attribution-Non Commercial-No Derivatives
License 4.0 (CCBY-NC-ND), where it is permissible to download
and share the work provided it is properly cited. The work cannot be
changed in any way or used commercially.
www.obgynsurvey.com | 557
Volume 71, Numbe r 9
OBSTETRICAL AND GYNECOLOGICAL SURVEY
Copyright ©2016 Wolters Kluwer Health,
Inc. All rights reserved.
CME REVIEW ARTICLE
26
is completely asymptomatic in approximately one third
of cases. The most frequent symptoms in the remaining
two thirds are menorrhagia (50%), dysmenorrhea (30%),
and metrorrhagia (20%). Dyspareunia may also be
a complaint.
4,5
From the epidemiologic data, a large number of births,
spontaneous and induced abortions, and endometrial hy-
perplasia are related to increased risk of adenomyosis.
Other risk factors associated with adenomyosis are endo-
metriosis, smoking, and surgical trauma, such as cesar-
ean section or curettage.
6
Since adenomyosis has been
reported in 60% of postmenopausal women taking ta-
moxifen therapy for a long time, it seems to reactivate le-
sions of preexisting adenomyosis,
7
implying that this
condition is estrogen dependent.
DIAGNOSIS OF ADENOMYOSIS
Until recently, adenomyosis was thought to be found
only in parous women. With few physical findings,
diagnosis of adenomyosis relied on surgical resection
and pathological examination. With improved imag-
ing techniques, however, it is frequently encountered
in infertile patients. Hysterectomy has been advised
for women with severe symptoms from adenomyosis,
although alternative conservative treatment can pre-
serve the uterus. Therefore, the role of preoperative
diagnostic tools is important to avoid unnecessary
surgery. In patients with uterine masses and infertil-
ity, adenomyosis needs to be excluded before other
treatment options are given.
8
Hysterosalpingography was the first imaging tool used
to diagnose adenomyosis, but it is no longer used to eval-
uate patients because of its low overall accuracy.
9
Uterine enlargement without any features of fi-
broids and asymmetric thickening of anterior and
posterior myometrial walls are signs of adenomyosis
that transabdominal ultrasonography (TAU) can re-
veal.
10,11
In a retrospective review, Siedler et al.
10
exam-
ined 80 patients using TAU and diagnosed adenomyosis
with a sensitivity of 63%, a specificity of 97%, and a
positive predictive value of 71%. However, because
it is not possible to get sufficient image resolution to
visualize the myometrium, TAU cannot reliably diagnose
adenomyosis or differentiate it from leiomyoma.
10,11
In clinically suspected adenomyosis cases, trans-
vaginal sonography (TVS) should be considered as the
primary diagnostic tool. Fundamental TVS signs for
adenomyosis are heterogeneous and hypoechogenic
poorly described areas in the myometrium, those areas
with or without anechoic lacunae or cysts of varying
size, linear striation radiating out from the endometrium
into the myometrium, poor definition of the junctional
zone (JZ), and pseudo-widening of the endometrium
(enlargement of uterus with asymmetric thickening of
the anterior or posterior walls). Adenomyosis is most
often diagnosed in the presence of 3 or more sono-
graphic criteria.
8,12
On 3D TVS, features linked to adenomyosis were
JZmax 8 mm or greater, myometrial asymmetry, and
hypoechoic striations.
13
When at least 2 of the described
ultrasound features were present, the accuracy was 90%
(sensitivity, 92%; specificity, 83%; positive predictive
value, 99%; and negative predictive value, 71%).
According to Dueholm et al. (2001),
12
magnetic res-
onance imaging (MRI) and TVS were equally good at
identifying patients with adenomyosis, but MRI was
superior to TVS to exclude the diagnosis of adenomyosis,
with equal sensitivity but a higher specificity (sensitivity:
MRI, 0.70 (0.46–0.87); and TVS, 0.68 (0.44–0.86)
(P= 0.66); specificity: MRI, 0.86 (0.76–0.93); and TVS
0.65 (0.50–0.77) (P= 0.03). The combination of TVS
and MRI had the highest sensitivity, but, surprisingly, it
also had the lowest specificity. In addition, measuring
the difference in junctional zone thickness may opti-
mize the MRI diagnosis. Gordts et al.
14
recently sug-
gested the following adenomyosis classification: simple
JZ hyperplasia (zone thickness >8 mm but <12 mm on
T2-weighed images, in women aged 35 years or youn-
ger); partial or diffuse adenomyosis (thickness >12 mm;
high signal intensity myometrial foci; involvement
of the outer myometrium <1/3, <2/3, and >2/3), adeno-
myoma (myometrial mass with indistinct margins with
primarily low signal intensity on all MRI sequences).
However, this classification still remains to be proved.
The consensus today is that adenomyosis can be
strongly considered when JZ thickness is greater than
12 mm, although there is no definable JZ on MRI in
approximately 20% of premenopausal women.
15
A
diagnosis can also be suspected when the thickness
of the JZ is between 8 and 12 mm; if other signs, such
as a relative thickening of JZ in a localized area, poor
definition of the JZ borders, or high signal foci on T2- or
T1-weighed sequences, are present.
9
Uterine Junctional Zone (JZ)
In 1983, Hricak et al.
16
first described the functional
uterine zone, which is the junction between the endo-
metrium and the inner myometrium. Today, in healthy
women of reproductive age, through T2-weighted im-
ages, 3 distinct layers were noted: (i) a high signal in-
tensity corresponding to the endometrial stripe, (ii) an
inner low signal intensity that is adjacent to the basal
endometrium, the JZ or subendometrial layer, and (iii)
an outer medium signal intensity subserosal zone, or
558 Obstetrical and Gynecological Survey
outer myometrium.
17
However, diffuse thickening of
the JZ should be carefully distinguished from normal
physiological change, since the thickness of JZ varies
considerably during the menstrual cycle.
18
de Souza
et al.
19
reported an incidence of 54% myometrial JZ hy-
perplasia (a clear sign of adenomyosis) in subfertile pa-
tients complaining of menorrhagia or dysmenorrhea.
Association With Infertility
Diagnosing adenomyosis was difficult until recently,
and in the past, it was associated with multiparous
women not with infertility. Indeed, women often delay
their first pregnancy, and adenomyosis is typically ob-
served in their late 30s and 40s. When nonsurgical diag-
nosis, such as TVS and MRI, became possible, the role
of adenomyosis in infertility and early miscarriage was
recognized.
20
CLINICAL EVIDENCE OF CORRELATION
BETWEEN ADENOMYOSIS AND
INFERTILITY
Dysfunctional Uterine JZ and Fertility Outcome
Chiang et al.
21
suggested the link between spontane-
ous abortion rate and uterine JZ dysfunction in infertile
patients undergoing in vitro fertilization (IVF) and
found that the spontaneous abortion rate was higher in
women with a diffusely enlarged uterus on ultrasound
imaging without distinct uterine masses compared with
those with a normal uterus. However, their pregnancy
rates were not statistically significant. Piver et al.
22
also proposed that MRI evaluation of JZ thickness is
the best negative predictive factor of implantation
failure, and an increase in JZ diameter is inversely
correlated to implantation rate. Implantation failure
was found to be high when the average junctional
zone was greater than 7 mm.
23
Achieving Pregnancy After Medical or
Surgical Therapy
Infertile women reportedly achieve pregnancy after
being treated for adenomyosis. Since 1993, published
case reports or small series report adenomyosis treated
with gonadotrophin-releasing hormone (GnRH) ana-
log alone, conservative surgery, or combined therapy
(Tables 1–3).
24–42
A live birth rate after treatment with
GnRH agonist (GnRH-a) for 5 months was first reported
by Silva et al.
25
In a case study by Nelson and Corson,
24
the patient with histologically diagnosed adenomyosis
who underwent a long-term course of GnRH-a con-
ceived shortly after cessation of treatment. It was also re-
ported that 2 cases of adenomyosis were conceived
within 6 months after a short course of GnRH therapy
with buserelin.
26
A small Japanese study, in which 3 of
4 infertile patients successfully conceived after using a
danazol IUD, is also additional evidence to link adeno-
myosis and infertility.
42
Furthermore, Fujishita et al.
29
described the modified
reduction surgical technique for adenomyosis; and in this
study, one patient conceived spontaneously 4 months af-
ter operation by H-incision technique. One prospective
study used a triple-flap method for reconstructing the
uterine wall for 104 patients with severe adenomyosis.
Of these, 4 of 26 women who wished to conceive became
pregnant after conservative surgery.
34
Uterus-sparing sur-
gery for adenomyosis-associated subfertile women were
also demonstrated by Kishi et al.
35
In the group aged
younger than 39 years, 60.8% of women with a history
of IVF failure achieved pregnancy after surgery, although
there was no clear benefit of surgery on fertility outcomes
TABLE 1
Successful Pregnancies After GnRH-a in Women With Adenomyosis
Reference N Treatment Period With GnRH-a Pregnancy Outcome Duration of Infertility
Interval Between Spontaneous
Pregnancy and
Completed Treatment
Nelson and
Corson
24
1 Over 3-year period Viable first-trimester pregnancy No infertility 1 month
Silva et al.
25
1 5 months Cesarean section at term 10 years 5 months
Huang et al.
26
2 3 months Term, healthy infant, vaginal and
cesarean section
2 years and 4 years 4 to 6 months
Wang et al.
27
37 6 months Cumulative 3-year pregnancy rate,
10.8% (4/37); cumulative 3-year
successful delivery rate,
8.1% (3/37)
>3 years <12 months
Al Jama et al.
28
22 6 months Spontaneous abortion, 1;
ectopic, 1; vaginal; term, 1
6–15 years 5–18 months
N, number of women who intended pregnancy.
559Impact of Adenomyosis on Women’s Fertility •CME Review Article
for patients older than 40 years. Wang et al.
30
also sug-
gested that laparoscopic cytoreductive surgery might be
suitable for women with localized adenomyosis who
failed the usual infertility treatments and assisted repro-
ductive technology (ART). They reported one sponta-
neous pregnancy that occurred 21 months after surgery.
Conservative surgery or combination treatment in
subfertile women with adenomyosis also had signifi-
cant benefits for not only controlling symptoms but
also for increasing the pregnancy rate compared with
GnRH-a alone.
27,28
The cumulative 3-year clinical
pregnancy rate and final successful delivery rate were
higher in adenomyotic women who underwent conser-
vative surgery with or without GnRH-a compared with
those who received GnRH-a alone for 6 months.
27
In one large prospective study, 55 of 165 patients with
adenomyosis became pregnant after surgery followed by
6-course GnRH treatment or surgery alone, with a clini-
cal pregnancy rate of 77.5%, and 49 women (69.0%) had
a successful delivery by the end of the 2-year follow-up
period.
33
The combination of microsurgical cytoreduc-
tion and GnRH-a treatment could be appropriate for
patients who failed GnRH-a alone or would not toler-
ate long-term GnRH-a treatment for presumed severe
adenomyosis.
40,41
Effect of Adenomyosis on Reproductive Outcome
After Endometriosis Surgery
The impact of adenomyosis on pregnancy rates fol-
lowing surgery for both rectovaginal and colorectal en-
dometriosis was reviewed in five articles from 2005 to
2010.
32,43–46
Diagnosis of uterine adenomyosis based
on TVS,
44
MRI,
32
andbothTVSandMRI.
43,45,46
Among
the five selected studies, the criteria for the presence
of adenomyosis were described in only one.
32
Although fertility was not their primary study end
point, in Landi et al.
32
in 2008, a significantly higher
pregnancy rate was recorded in women with endometri-
osis, but without adenomyosis, compared with those
with concurrent endometriosis and adenomyosis after
laparoscopic excision of deep, infiltrated endometriosis
(Table 2). One prospective study evaluated the cumu-
lative pregnancy rate after intracytoplasmic sperm
injection (ICSI)/IVF in patients with colorectal en-
dometriosis. Cumulative pregnancy rates in patients
with associated adenomyosis was 19%, and in those
who had endometriosis only, it was 82%, revealing
that adenomyosis was associated with decreased cu-
mulative pregnancy rate (Fig. 1).
47
Presurgical hormone treatment (GnRH agonists for
3months)wasusedin2studies.
45,46
Surgery was per-
formed in 3 studies with laparoscopy
32,44,45
and with
laparotomy or laparoscopy in 2 studies.
44,46
In 3 of 5 studies,
43–45
no pregnancy occurred in
women older than 35 years, and in the study by Darai
et al.,
46
only1of24womenwhoconceivedwasolder
than 35 years. Moreover, the percentage of women
with adenomyosis seeking pregnancy was 4 of 18 in
Darai et al.,
45
8 of 17 in Ferrero et al.,
43
11 of 20 in
Darai et al.,
46
and 10 of 20 in Stepniewska et al.
44
ART (IVF/ICSI) Outcome in Patients
With Adenomyosis
Many studies reported reproductive outcome after
ART in women with adenomyosis.
21,48,49
Most con-
cluded that adenomyosis causes infertility, but more
TABLE 2
Successful Pregnancies After Conservative Surgery in Women With Adenomyosis
Reference N Treatment Pregnancy Outcome Duration of Infertility
Interval Between
Spontaneous
Pregnancy and
Completed Treatment
Fujishitaetal.
29
6 Conservative surgery Spontaneous clinical pregnancy, 1 —~4 months
Wang et al.
30
1 Conservative surgery Cesarean section at term 4 years secondary infertility 30 months
Takeuchi et al.
31
8 Conservative surgery +
hysteroplasty
Spontaneous clinical pregnancy, 2 1–5 years Not mentioned
Landi et al.
32
26 Laparoscopic surgery
treated for endometriosis
Spontaneous clinical pregnancy, 3 —<30 months
Wang et al.
33
51 Conservative surgery Clinical pregnancy, 20 (74.1%);
successful delivery, 17 (63%)
—<24 months
(3–19 months)
Osada et al.
34
26 Conservative surgery Spontaneous clinical pregnancy, 4 —Unknown
Kishi et al.
35
102 Conservative surgery Clinical pregnancy rate, 41.3% in
women aged 39 years or younger;
and 3.7% in women aged 40 years
or older
3 years to 6 years <92 months
Saremi et al.
36
70 Conservative surgery Spontaneous pregnancy, 7/21 (33.33%) ~6 years 20–50 months
N, number of women who intended pregnancy.
560 Obstetrical and Gynecological Survey
prospective studies with a large population should be
performed to further evaluate this causal interaction and
unravel the mechanisms responsible for this negative
effect. One of the first studies that connect the thickness
of JZ in women with adenomyosis with embryo implan-
tation failure came from Maubon et al.
23
Two recent
large population studies confirmed lower pregnancy
rates in women with adenomyosis who underwent
IVF.
48,49
There are significantly lower clinical preg-
nancy rates in women with adenomyosis diagnosed by
ultrasound (23.6%) compared with the nonadenomyosis
group (44.6%) after stimulation with a GnRH antago-
nist protocol for IVF. Possibly, the age factor in older
women with adenomyosis may be related to a lower
pregnancy rate. This difference was still significant
(P= 0.031) even after normalization of groups for age
using regression analysis.
49
In a study by Tremellen
et al.,
50
4 patients with adenomyosis who previously
had multiple unsuccessful IVF cycles promptly resulted
in successful pregnancy with ART after prolonged
down-regulation with GnRH-a.
However, Costello et al.
51
investigated the effect of
TVS-diagnosed adenomyosis on subsequent IVF/ICSI
outcome. After a single cycle of IVF/ICSI, reproductive
outcome was compared in women with and women
without adenomyosis excluding patients with severe en-
dometriosis. There was no difference in live birth rate
per patient (cycle) between the 2 groups. Mijatovic
et al.
52
also showed reproductive outcome in infertile pa-
tients with surgically proven endometriosis who were
pretreated with more than 3 months of long-term pitu-
itary down-regulation (GnRH-a) before IVF/ICSI. No
significant differences in IVF/ICSI outcome were ob-
served between women with and women without
adenomyosis. However, in this study, the authors point
out that endometriosis was an important confounder,
and 90.4% of the patients with endometriosis were sur-
gically staged with moderate to severe endometriosis
(revised American Society of Reproductive Medicine
stages III–IV; Figs. 1, 2). Having a study population
of asymptomatic women with adenomyosis undergoing
IVF attempts, Benaglia et al.
53
failed to show a detri-
mental effect of the disease in the pregnancy rate of these
women. The authors proposed that GnRH-a pretreatment
might have a therapeutic effect on adenomyosis.
Association With Early Miscarriage
Two recent prospective studies concluded that
adenomyosis reduces implantation and number of em-
bryos transferred, clinical pregnancy rate, and ongoing
pregnancy rate in women undergoing IVF. The first tri-
mester miscarriage rate was also higher in women with
TABLE 3
Successful Pregnancies After Combined Therapy in Women With Adenomyosis
Reference N Treatment Pregnancy Outcome Duration of Infertility
Interval Between
Spontaneous Pregnancy
and Completed Treatment
Hirata et al.
37
1 Combined therapy (with GnRH a) Spontaneous abortion at 10 weeks' gestation 4 years 4 months
Strizhakov et al.
38
8 Combined therapy Spontaneous clinical pregnancy, 4 —<12 months
Wang et al.
27
28 Conservative surgery or combined Cumulative 3-year pregnancy rate, 46.4% (13/28);
cumulative 3-year successful delivery rate,
32.1% (9/28)
>3 years 36 months
Ozaki et al.
39
1 Combined therapy (with danazol) Cesarean section at term 5 years secondary infertility ~3 months
Wang et al.
40
3 Combined therapy (with GnRH a) Delivered viable infants 5 years 3 months to 12 months
Wang et al.
30
1 Combined therapy (with danazol) Cesarean section at term 9 years secondary infertility 21 months
Wang et al.
33
114 Combined therapy (with GnRH a) Clinical pregnancy, 35 (79.5%); successful
delivery, 32 (72.7%)
—<24 months (3–22 months)
Al Jama et al.
28
18 Combined therapy (with GnRH a) Spontaneous abortion, 2; cesarean section, 6 6–15 years 4–30 months
Huang et al.
41
9 Combined therapy (with GnRH a) Clinical pregnancy, 3; cesarean section at term, 2 >3 years 62 months to 83 months
N, number of women who intended pregnancy.
561Impact of Adenomyosis on Women’s Fertility •CME Review Article
adenomyosis compared with the control group.
48,54
Martínez-Conejero et al.
55
examined the endometrium
of women with adenomyosis undergoing oocyte dona-
tion and found a similar endometrial gene expression
pattern in both the adenomyosis and the control group.
The implantation and clinical pregnancy rates were not
different in all groups, but the miscarriage rate was sig-
nificantly higher in the adenomyosis group (13.1%)
than adenomyosis + endometriosis group (6.1%) and
the controls (7.2%). The term pregnancy rate was also
lower in the adenomyosis group (26.8%) than in the
adenomyosis + endometriosis (38%) and the control
group (37.1%), showing that implantation is not af-
fected by adenomyosis. However, the higher rate of
miscarriages associated with this condition led to
lower term pregnancy rates, indicating a negative ef-
fect on the final outcome of oocyte donation.
Lifelong Primary Infertility in Baboons
After assessing their necropsy records, 37 baboons
diagnosed with adenomyosis and 38 baboons with nor-
mal uteri histology were compared in one case-
control study. The authors analyzed the association
FIG. 1. Clinical pregnancies in women with adenomyosis.
FIG. 2. Ongoing pregnancies in women with adenomyosis.
562 Obstetrical and Gynecological Survey
between adenomyosis, primary infertility, and the
presence of coexisting endometriosis. They found
that adenomyosis is strongly associated with lifelong
infertility (P< 0.001) and was maintained even after
excluding coexisting endometriosis cases (N = 17).
The weakness in that study lies in the selection of
the negative controls. Unless uteri are exhaustively
sectioned, adenomyosis cannot be excluded. How-
ever, this study showed that adenomyosis is strongly
associated with the presence of endometriosis and
lifelong infertility.
56
PROPOSED MECHANISM OF INFERTILITY
IN PATIENTS WITH ADENOMYOSIS
Abnormal Uterotubal Transport
Intrauterine Abnormalities
Anatomical distortion of the uterine cavity may be
one important factor leading to infertility, although
the mechanism by which uterine adenomyoma has a
detrimental effect on reproductive function remains
unknown. Adenomyoma that distorts the uterine cav-
ity may obstruct the tubal ostia and interfere with
sperm migration and embryo transport. Several stud-
ies have demonstrated that submucosal and intramural
fibroids in the presence of endometrial cavity distor-
tion are associated with reduced implantation and preg-
nancy rates.
57,58
Disturbed Uterine Peristalsis and Sperm Transport
Using transabdominal ultrasound, the presence of
distinct contraction waves in the myometrium can be
seen. This peristaltic activity originates solely from
the JZ, whereas the outer myometrium remains inac-
tive.
59
Directed sperm transport toward the peritoneal
opening of the tubes on the side of dominant follicle
by uterine peristalsis is fundamental to the early repro-
ductive process, and it depends on the architecture of
the myometrial wall with circular muscular fibers.
60
In women with adenomyosis, normal architecture
of the “archimyometrium”(JZ myometrium) was
destroyed owing to invagination of the endometrial
glands and stroma. This gives rise to the develop-
ment of hyperplastic muscular tissue that causes dys-
functional uterine hyperperistalsis with increased
intrauterine pressure.
61
It seems reasonable to sup-
pose that those changes may affect fertility in patients
with adenomyosis. Increased uterine JZ activity just
before embryo transfer in IVF is also associated with
a reduced pregnancy rate and increased frequency of
ectopic pregnancy.
62
Destruction of Normal Myometrial
Architecture and Function
Mehasseb et al.
63
studied the ultrastructural features of
myometrium in the presence or absence of adenomyosis.
Myocytes of adenomyosis uteri are ultrastructurally
different from those of normal uteri. In the presence
of adenomyosis, JZ showed cellular and nuclear hy-
pertrophy, abnormal nuclear and mitochondrial shape,
abundant myelin bodies, and other abnormalities. This
suggests that those ultrastructural abnormalities may
cause a disturbance in normal calcium cycling in affected
myocytes, with subsequent loss of normal rhythmic con-
traction, eventually affecting uterotubal transport.
Altered Endometrial Function and Receptivity
Aberrant Endometrial Metabolism
Altered Endometrial Steroid Metabolism. Kitawaki
et al.
64
demonstrated the expression of aromatase cy-
tochrome P450 (P450arom) protein and mRNA only
in adenomyotic tissues and the eutopic endometrium
of patients with adenomyosis, but not in the normal en-
dometrium of women without adenomyosis. P450arom
is an enzyme that catalyzes the conversion of andro-
gens to estrogens. Takahashi et al.
65
found menstrual
blood estradiol levels were highest in women with
adenomyosis, whereas they were within normal levels
in peripheral blood, suggesting that local estrogen pro-
duction may increase estrogen concentration in the
menstrual blood of women with adenomyosis. Lessey
et al.
66
also showed that overexpression of P450 aroma-
tase increases local estrogen production within the en-
dometrium. Clinical pregnancy rates were statistically
lower in women with high endometrial P450arom
mRNA levels,
67
and they suggest that P450arom
mRNA expression can identify women at increased risk
of IVF failure. Moreover, treatment with GnRH agonist
or danazol decreased expression of P450arom in the
eutopic endometrium of women with adenomyosis.
68
Abnormal Inflammatory Response. Macrophages
have the capacity to produce not only proinflamma-
tory cytokines, such as TNF-αand IL-1, but also reac-
tive oxygen species that can be toxic to embryos.
69,70
Tremellan et al.
70
reported women with severe adeno-
myosis who, after a failed implantation, have signifi-
cantly greater stromal macrophage density than the
nonadenomyosis controls. Additionally, IL-6 mRNA
expression was increased in macrophage-cocultured
endometriotic stromal cells in adenomyosis.
71
Wang
et al.
72
have shown that IL-10 staining intensity in
women with adenomyosis was higher in epithelial cells
563Impact of Adenomyosis on Women’s Fertility •CME Review Article
of both eutopic and ectopic endometrium than controls,
suggesting that an abnormal inflammatory response
may impair fertility (Fig. 3).
Altered Expression of Estrogen and Progesterone Re-
ceptors. Since IL-6 can activate the estrogen receptor
in breast cancer cells,
73
overexpressed IL-6 could
lead to an increased estrogen receptor expression in
adenomyosis women. Progesterone has antiproliferative
activity through its receptors. Within the adenomyotic
tissue, there was reduction in the expression of proges-
terone receptors (A and B) in all layers,
74,75
resulting
in up-regulation of ER-α, since down-regulation of es-
trogen receptor-αis one of the primary functions of pro-
gesterone. Overexpression of ER-αreduces β-3 integrin
secretion and alters uterine receptivity.
76
Altered Uterine Oxidative Stress Environment
A low oxygen environment in the uterus needs to be
maintained for implantation of fertilized eggs because
an excessive free radical environment may damage fer-
tilized eggs and interfere with embryo development.
77
In a normal woman, concentrations of nitric oxide syn-
thase, xanthine oxidase, superoxide dismutase are low
during the proliferative phase and increase during
the early and midsecretory phases.
78,79
In women with
adenomyosis, levels do not fluctuate during the men-
strual cycle and are overexpressed.
80
Abnormal levels
of intrauterine free radicals seem to cause infertility
in women with adenomyosis.
Some studies with animal models demonstrated that
excess or deficient levels of free radicals mediated by
inflammatory factors in reproductive tissue may inhibit
both embryo development in vitro and implantation in
vivo, resulting in a low pregnancy rate (Fig. 3).
81–83
Impaired Implantation
Lack of Expression of Adhesion Molecules. Several cell
adhesion molecules (integrin, selectin, and cadherin)
expressed by the endometrium are necessary for embryo
and endometrium interaction. Integrins are the best stud-
ied markers of endometrial receptivity.
84
Abnormal en-
dometrial expression of integrin subtype α-5 and β-3
takes place in patients with IVF failure despite good
embryo quality.
85
Osteopontin (OPN) is a small integrin-
binding ligand, N-linked glycoprotein in the endometrium.
It binds to integrin 3, giving rise to speculation that it
may mediate trophoblast endometrial interaction during
implantation.
86
Integrin β-3 and OPN levels were sig-
nificantly lower in patients with adenomyosis than in
controls. Dysregulation of both integrin β-3 and OPN
mRNA and protein in the endometrium during the im-
plantation window suggests that adenomyosis is associ-
ated with impaired implantation.
87
Reduced Expression of Implantation Markers. Another
factor associated with endometrial receptivity, leukemia
inhibitory factor (LIF),
88
is present during the implanta-
tion window. Leukemia inhibitory factor is an essential
cytokine for successful egg implantation during human
reproduction.
89
In addition, adenomyotic endometrium
shows abnormalities in the production of LIF, which
may contribute to altering uterine receptivity.
90
Leuke-
mia inhibitory factor concentrations in uterine flushing
are lower in women with infertility than in controls. Ad-
ditionally, LIF expression is lower in the endometrium
of women with adenomyosis during the midsecretory
phase.
89
Leukemia inhibitory factor and IL-6 expres-
sion is controlled in endometrial cells by nuclear factor
kappa B (NF-kB) activation. Nuclear factor kappa B is
a transcription factor and critical regulator of innate im-
mune response and inflammation. Ponce et al.
91
reported
that NF-kB binding, phosphorylated NF-kB, and IL-6
expression were down-regulated in the late secretory
phase in the eutopic endometrium of women with endo-
metriosis. Nuclear factor kappa B activities in the
eutopic endometrium of patients with adenomyosis
are an intriguing target for future investigation.
FIG. 3. Implantation factors showing altered concentration in adenomyosis-associated infertility.
564 Obstetrical and Gynecological Survey
Altered Function of the Gene for Embryonic Develop-
ment. HOXA 10 gene, essential for embryonic uterine
development and proper adult endometrial growth
during the menstrual cycle, may be involved in creat-
ing an impairment of implantation in women with
adenomyosis.
92
Its expression is necessary for endome-
trial receptivity, and it is significantly lower in the endo-
metrial stroma of women with adenomyosis compared
with fertile controls.
93
PHARMACOLOGICAL AND SURGICAL
TREATMENT OF ADENOMYOSIS
Hormonal Treatments
GnRH Agonists
A lack of randomized, controlled trials exploring
the impact of GnRH-a treatment on fertility hinders
our understanding of adenomyosis. One case study
reported that treatment of severe adenomyosis with
GnRH-afor16weeksresultedinthelivebirthofa
healthy male infant.
39
Progestogens
Women with adenomyosis are characterized by a
lower expression of progesterone receptors (A and
B) in endometrial lesions, but also in the outer and inner
layers of myometrium. The treatment of adenomyosis
with progesterone may be restricted owing to the abnor-
mal expression of progesterone receptors.
94
Dienogest
Dienogest (progestin) has been used to treat adeno-
myosis pharmacologically. Dienogest directly inhibited
cellular proliferation and induced apoptosis in human
adenomyotic stromal cells.
95
Two nonrandomized stud-
ies on a small number of patients have been published,
but neither refers to the patients' fertility. The first study
compared 2 groups of approximately 20 subjects
treated with danazol and dienogest for adenomyosis.
96
That study did not clearly describe the effectiveness
of the therapeutic protocols. Adenomyosis patients
treated with dienogest are at higher risk of discontin-
uation owing to uterine bleeding. The second study
presented a correlation of 3 factors: age younger than
38 years, lower hemoglobin levels before the starting
point of the therapeutic protocol, and estradiol levels
after 3 months of dienogest therapy.
97
Levonorgestrel Intrauterine System
Levonorgestrel intrauterine system (LNG-IUS) is ap-
proved for treating womenwith adenomyosis who have
completed their childbearing. Levonorgestrel intrauter-
ine system treatment is accompanied by decreased pain
and heavy uterine bleeding, which could be explained
by the following mechanisms: (i) a progestogenic influ-
ence on adenomyosis foci; (ii) atrophy of the eutopic
endometrium; and (iii) controlling of endometrial fac-
tors that changed during adenomyosis. Choi et al.
98
de-
scribed decreased expression of growth factor and the
related receptors in women with heavy bleeding and
adenomyosis after LNG-IUS treatment. In another
randomized study, Maia et al.
99
described a positive
effect of LNG-IUS in approximately 100 women with
adenomyosis experiencing heavy menstrual bleeding.
Exploring Surgery Treatments and
Pregnancy Rates
Conservative Surgery Alone
The results of conservative surgery, which consists
of laparoscopy or laparotomy, are based on 3 studies
in women with a diagnosis with adenomyosis. Two
studies reported birth rate,
31,100
and one reported preg-
nancy rate.
38
The surgical techniques presented in all
the studies consisted of excision of the adenomyoma
and hysteroplasty using laparoscopy or laparotomy.
The overall average birth rate reached 36.2% (21 of
58) in women who had this surgery.
Comparison of 2 Surgical Techniques
A retrospective study of 104 patients undergoing
conservative surgery compared the classical adenomy-
omectomy with a new technique, the H-incision sur-
gery. The classical technique was performed in 5
women with adenomyosis who were selected retro-
spectively among 104 patients. The newer technique
wasusedin6of83patientswhodesiredtopreserve
fertility. The classical technique involves incision of the
uterine wall and a stepwise resection of adenomyomatic
tissue. The newer technique consists of an H-shape inci-
sion and excision of the adenomyomatic tissue. In this
study, the newer technique resulted in one spontaneous
pregnancy 4 months after operation compared with no
pregnancy in women undergoing the classical technique.
(Classical technique pregnancy rate, 0.14 [95% confi-
dence interval].) Time between surgery and pregnancy
was 4 to 6 months followed by a live birth, with one con-
tinuing pregnancy at the time the study finished.
29
Adenomyomectomy
When women experience the severe symptoms of ad-
vanced adenomyosis, hysterectomy has been advised.
However, the more conservative adenomyomectomy
565Impact of Adenomyosis on Women’s Fertility •CME Review Article
preserves the uterus. One study reported that from a
pool of 103 patients, 55.34% presented with infertility,
and of those, 16.50% had IVF failure, 8.74% had recur-
rent miscarriages, and 19.42% had abnormal uterine
bleeding. Of the 103 patients, 70 attempted pregnancy,
21 naturally through intercourse, and 49 through
IVF. Pregnancy outcomes were 30% pregnancy, with
23% live births. The symptoms of dysmenorrhea/
hypermenorrhea lessened after surgery. Only one pa-
tient had a recurrence of adenomyosis.
36
CONCLUSIONS
In summary, adenomyosis is a common gynecolog-
ical disorder with unclear etiology. Several studies
have demonstrated that the presence of adenomyosis
may impair the fertility by affecting the uterotubal
transport and altering endometrial function and recep-
tivity. Some indirect proofs have shown that women
with adenomyosis have poor reproductive outcomes
compared with those without adenomyosis. Based on
limited available evidence, it has been reported that in-
fertile women who experience adenomyosis achieved
pregnancy after being treated with different strategies,
indirectly revealing poor reproductive outcomes in
women with adenomyosis. Furthermore, surgery could
be effective in women with adenomyosis with a history
of IVF failure, although latter finding could be partly at-
tributed to the higher rate of early miscarriage.
However, in the clinical situation, it is still difficult to
determine whether adenomyosis is the cause of the in-
fertility or not because, as previous studies have made
us aware, unknown or as yet undiagnosed cases of en-
dometriosis may be present in both cases and controls.
Additionally, studies on treatment are limited to case se-
ries and a retrospective data without control groups.
Better studies are needed to determine the molecular
mechanism of implantation failure in women with adeno-
myosis and the impact of adenomyosis on infertile
women with or without endometriosis.
REFERENCES
1. Moll R, Levy R, Czernobilsky B, et al. Cytokeratins of normal
epithelia and some neoplasms of the female genital tract.
Lab Invest. 1983;49:599–610.
2. Sahin AA, Silva EG, Landon G, et al. Endometrial tissue in
myometrial vessels not associated with menstruation. Int J
Gynecol Pathol. 1989;8:139–146.
3. Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod
Update. 1998;4:312–322.
4. Benson RC, Sneeden VD. Adenomyosis: a reappraisal of symp-
tomatology. Am J Obstet GynecoI. 1958;76:1044–1057; discus-
sion 1057–61.
5. Nishida M. Relationship between the onset of dysmenorrhea
and histologic findings in adenomyosis. Am J Obstet Gynecol.
1991;165:229–231.
6. Vercellini P, Viganò P, Somigliana E, et al. Adenomyosis: epide-
miological factors. Best Pract Res Clin Obstet Gynaecol. 2006;
20:465–477.
7. Bergeron C, Amant F, Ferenczy A. Pathology and physiopathol-
ogy of adenomyosis. Best Pract Res Clin Obstet Gynaecol.
2006;20:511–521.
8. Dueholm M. Transvaginal ultrasound for diagnosis of
adenomyosis: a review. Best Pract Res Clin Obstet Gynaecol.
2006;20:569–582.
9. Reinhold C, Tafazoli F, Wang L. Imaging features of adenomyosis.
Hum Reprod Update. 1998;4:337–349.
10. Siedler D, Laing FC, Jeffrey RB Jr, et al. Uterine adeno-
myosis. A difficult sonographic diagnosis. J Ultrasound Med.
1987;6:34–39.
11. Arnold LL, Ascher SM, Schruefer JJ, et al. The nonsurgical diag-
nosis of adenomyosis. Obstet Gynecol. 1995;86:461–465.
12. Dueholm M, Lundorf E, Hansen ES, et al. Magnetic resonance
imaging and transvaginal ultrasonography for the diagnosis of
adenomyosis. Fertil Steril. 2001;76:588–594.
13. Luciano DE, Exacoustos C, Albrecht L, et al. Three-dimensional
ultrasound in diagnosis of adenomyosis: histologic correlation
with ultrasound targeted biopsies of the uterus. JMinimInvasive
Gynecol.2013;20:803–810.
14. Gordts S, Brosens JJ, Fusi L, et al. Uterine adenomyosis: a need
for uniform terminology and consensus classification. Reprod
Biomed Online. 2008;17:244–248.
15. Novellas S, Chassang M, Delotte J, et al. MRI characteristics of
the uterine junctional zone: from normal to the diagnosis of
adenomyosis. AJR Am J Roentgenol. 2011;196:1206–
1213.
16. Hricak H, Alpers C, Crooks LE, et al. Magnetic resonance imaging
of the female pelvis: initial experience. AJR Am J Roentgenol.
1983;141:1119–1128.
17. Tamai K, Koyama T, Umeoka S, et al. Spectrum of MR fea-
tures in adenomyosis. Best Pract Res Clin Obstet Gynaecol.
2006;20:583–602.
18. Masui T, Katayama M, Kobayashi S, et al. Changes in
myometrial and junctional zone thickness and signal intensity:
demonstration with kinematic T2-weighted MR imaging. Radiol-
ogy. 2001;221:75–85.
19. de Souza NM, Brosens JJ, Schwieso JE, et al. The potential
value of magnetic resonance imaging in infertility. Clin Radiol.
1995;50:75–79.
20. Devlieger R, D'Hooghe T, Timmerman D. Uterine adenomyosis
in the infertility clinic. Hum Reprod Update.2003;9:139–147.
21. Chiang CH, Chang MY, Shiau CS, et al. Effect of a sonogra-
phically diffusely enlarged uterus without distinct uterine masses
on the outcome of in vitro fertilization-embryo transfer. J Assist
Reprod Genet. 1999;16:369–372.
22. Piver P. Uterine factors limiting ART coverage. J Gynecol Obstet
Biol Reprod (Paris).2005;34:5S30–5S33.
23. Maubon A, Faury A, Kapella M, et al. Uterine junctional zone at
magnetic resonance imaging: a predictor of in vitro fertilization
implantation failure. J Obstet Gynaecol Res. 2010;36:611–618.
24. Nelson JR, Corson SL. Long-term management of adenomyosis
with a gonadotropin-releasing hormone agonist. Fertil Steril.
1993;59:441–443.
25. Silva PD, Perkins HE, Schauberger CW. Live birth after treat-
ment of severe adenomyosis with a gonadotropin-releasing hor-
mone agonist. Fertil Steril. 1994;61:171–172.
26. Huang FJ, Kung FT, Chang SY, et al. Effects of short-course
buserelin therapy on adenomyosis. A report of two cases.
JReprodMed. 1999;44:741–744.
27. Wang PH, Fuh JL, Chao HT, et al. Is the surgical approach
beneficial to subfertile women with symptomatic extensive
adenomyosis? J Obstet Gynaecol Res. 2009;35:495–502.
28. Al Jama FE. Management of Adenomyosis in subfertile women
and pregnancy outcome. Oman Med J.2011;26:178–181.
29. Fujishita A, Masuzaki H, Khan KN, et al. Modified reduction sur-
gery for adenomyosis. A preliminary report of the transverse H
incision technique. Gynecol Obstet Invest.2004;57:132–138.
566 Obstetrical and Gynecological Survey
30. Wang CJ, Yuen LT, Chang SD, et al. Use of laparoscopic
cytoreductive surgery to treat infertile women with localized
adenomyosis. Fertil Steril. 2006;86:462.e5–462.e8.
31. Takeuchi H, Kitade M, Kikuchi I, et al. Laparoscopic
adenomyomectomy and hysteroplasty: a novel method. J Minim
Invasive Gynecol. 2006;13:150–154.
32. Landi S, Mereu L, Pontrelli G, et al. The influence of adeno-
myosis in patients laparoscopically treated for deep endometri-
osis. J Minim Invasive Gynecol. 2008;15:566–570.
33. Wang PH, Liu WM, Fuh JL, et al. Comparison of surgery alone
and combined surgical-medical treatment in the management
of symptomatic uterine adenomyoma. Fertil Steril. 2009;92:
876–885.
34. Osada H, Silber S, Kakinuma T, et al. Surgical procedure to con-
serve the uterus for future pregnancy in patients suffering from
massive adenomyosis. Reprod Biomed Online. 2011;22:94–99.
35. Kishi Y, Yabuta M, Taniguchi F. Who will benefit from uterus-
sparing surgery in adenomyosis-associated subfertility? Fertil
Steril. 2014;102:802.e1–807.e1.
36. Saremi A, Bahrami H, Salehian P, et al. Treatment of
adenomyomectomy in women with severe uterine adenomyosis
using a novel technique. Reprod Biomed Online. 2014;28:753–760.
37. Hirata JD, Moghissi KS, Ginsburg KA. Pregnancy after medical
therapy of adenomyosis with a gonadotropin-releasing hor-
mone agonist. Fertil Steril. 1993;59:444–445.
38. Strizhakov AN, Davydov AI. Myometrectomy—amethodof
choice for the therapy of adenomyosis patients in the reproduc-
tive period [In Russian]. Akush Ginekol (Mosk).1995;5:31–33.
39. Ozaki T, Takahashi K, Okada M, et al. Live birth after conserva-
tive surgery for severe adenomyosis following magnetic reso-
nance imaging and gonadotropin-releasing hormone agonist
therapy. Int J Fertil Womens Med. 1999;44:260–264.
40. Wang PH, Yang TS, Lee WL, et al. Treatment of infertile women
with adenomyosis with a conservative microsurgical technique
and a gonadotropin-releasing hormone agonist. Fertil Steril.
2000;73:1061–1062.
41. Huang BS, Seow KM, TsuiKH, et al. Fertility outcomeof infertile
women with adenomyosis treated with the combination of a
conservative microsurgical technique and GnRH agonist: long-
term follow-up in a series of nine patients. Taiwan J Obstet
Gynecol. 2012;51:212–216.
42. Igarashi M, Abe Y, Fukuda M, et al. Novel conservative medical
therapy for uterine adenomyosis with a danazol loaded intra-
uterine device. Fertil Steril. 2000;74:412–413.
43. Ferrero S, Anserini P, Abbamonte LH, et al. Fertility after bowel
resection for endometriosis. Fertil Steril.2009;92:41–46.
44. Stepniewska A, Pomini P, Scioscia M, et al. Fertility and clinical
outcome after bowel resection in infertile women with endome-
triosis. Reprod Biomed Online. 2010;20:602–609.
45. Daraï E, Marpeau O, Thomassin I, et al. Fertility after laparo-
scopic colorectal resection for endometriosis: preliminary re-
sults. Fertil Steril. 2005;84:945–950.
46. Daraï E, Carbonnel M, Dubernard G, et al. Determinant factors of
fertility outcomes after laparoscopic colorectal resection for endo-
metriosis. Eur J Obstet Gynecol Reprod Biol. 2010b;149:210–214.
47. Ballester M, d'Argent EM, Morcel K, et al. Cumulative pregnancy
rate after ICSI-IVF in patients with colorectal endometriosis: re-
sults of a multicentre study. Hum Reprod. 2012;27:1043–1049.
48. Salim R, Riris S, Saab W, et al. Adenomyosis reduces pregnancy
rates in infertile women undergoing IVF. Reprod BioMed Online.
2012;25:273–277.
49. Thalluri V, Tremellen KP. Ultrasound diagnosed adenomyosis has
a negative impact on successful implantation following GnRH an-
tagonist IVF treatment. Hum Reprod. 2012;27:3487–3492.
50. Tremellen K, Russell P. Adenomyosis is a potential cause of re-
current implantation failure during IVF treatment. Aust N Z J
Obstet Gynaecol. 2011;51:280–283.
51. Costello MF, Lindsay K, McNally G. The effect of adenomyosis on
in vitro fertilisation and intra-cytoplasmic sperm injection treatment
outcome. Eur J Obstet Gynecol Reprod Biol. 2011;158:229–234.
52. Mijatovic V, Florijn E, Halim N, et al. Adenomyosis has no ad-
verse effects on IVF/ICSI outcomes in women with endometri-
osis treated with long-term pituitary down-regulation before
IVF/ICSI. Eur J Obstet Gynecol Reprod Biol. 2010;151:62–65.
53. Benaglia L, Cardellicchio L, Leonardi M, et al. Asymptomatic
adenomyosis and embryo implantation in IVF cycles. Reprod
Biomed Online. 2014;29:606–611.
54. Vercellini P, Consonni D, Dridi D, et al. Uterine adenomyosis and
in vitro fertilization outcome: a systematic review and meta-
analysis. Hum Reprod. 2014a;29:964–977.
55. Martínez-Conejero JA, Morgan M, Montesinos M, et al.
Adenomyosis does not affect implantation, but is associated
with miscarriage in patients undergoing oocyte donation. Fertil
Steril. 2011;96:943–950.
56. Barrier BF, Malinowski MJ, Dick EJ Jr, et al. Adenomyosis in the
baboon is associated with primary infertility. Fertil Steril. 2004;82
(Suppl 3):1091–1094.
57. Farhi J, Ashkenazi J, Feldberg D. Effect of uterine leiomyomata
on the results of in-vitro fertilization treatment. Hum Reprod.
1995;10:2576–2578.
58. Stovall DW, Parrish SB, Van VoorhisBJ. Uterine leiomyomas re-
duce the efficacy of assisted reproduction cycles: results of a
matched follow-up study. Hum Reprod. 1998;13:192–197.
59. Birnholz JC. Ultrasonic visualization of endometrial movements.
Fertil Steril. 1984;41:157–158.
60. Kunz G, Beil D, Deininger H, et al. The dynamics of rapid sperm
transport through the female genital tract: evidence from vaginal
sonography of uterine peristalsis and hysterosalpingoscintigraphy.
Hum Reprod. 1996;11:627–632.
61. Kunz G, Beil D, Huppert P, et al. Structural abnormalities of the
uterine wall in women with endometriosis and infertility visual-
ized by vaginal sonography and magnetic resonance imaging.
Hum Reprod. 2000;15:76–82.
62. Lesny P, Killick SR. The junctional zone of the uterus and its
contractions. BJOG. 2004;111:1182–1189.
63. Mehasseb MK, Bell SC, Pringle JH, et al. Uterine adeno-
myosis is associated with ultrastructural features of altered
contractility in the inner myometrium. Fertil Steril. 2010;93:
2130–2136.
64. Kitawaki J, Noguchi T,Amatsu T, et al. Expression of aromatase
cytochrome P450 protein and messenger ribonucleic acid inhu-
man endometriotic and adenomyotic tissues but not in normal
endometrium. Biol Reprod. 1997;57:514–519.
65. Takahashi K, Nagata H, Kitao M. Clinical usefulness of deter-
minationof estradiol level in the menstrual blood for patients
with endometriosis. Nihon Sanka Fujinka Gakkai Zasshi.
1989;41:1849–1850.
66. Lessey BA, Palomino WA,Apparao KB, et al. Estrogen receptor-
alpha (ER-alpha) and defects in uterine receptivity in women.
Reprod Biol Endocrinol. 2006;4(Suppl 1):S9.
67. Brosens J, Verhoeven H, Campo R, et al. High endometrial aro-
matase P450mRNA expression is associated with poor IVF out-
come. Hum Reprod. 2004;19:352–356.
68. Ishihara H, Kitawaki J, Kado N, et al. Gonadotropin-releasing
hormone agonist and danazol normalize aromatase cytochrome
P450 expression in eutopic endometrium from women with en-
dometriosis, adenomyosis, or leiomyomas. Fertil Steril. 2003;79
(Suppl 1):735–742.
69. Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in fe-
male reproduction. Reprod Biol Endocrinol. 2005;3:28.
70. Tremellen KP, Russell P. The distribution of immune cells and
macrophages in the endometrium of women with recurrent re-
productive failure. II: adenomyosis and macrophages. J Reprod
Immunol. 2012;93:58–63.
71. Yang JH, Wu MY, Chang DY, et al. Increased interleukin-6
messenger RNA expression in macrophage-cocultured en-
dometrial stromal cells in adenomyosis. Am J Reprod Immunol.
2006;55:181–187.
72. Wang F, Li H, Yang Z, et al. Expression of Interleukin-10 in pa-
tients with adenomyosis. Fertil Steril. 2009;91:1681–1685.
567Impact of Adenomyosis on Women’s Fertility •CME Review Article
73. Fontanini G, Campani D, Roncella M, et al. Expression of inter-
leukin 6 (IL-6) correlates with oestrogen receptor in human
breast carcinoma. Br J Cancer. 1990;80:579–584.
74. Fung HY, Wong YL, Wong FW, et al. Study of oestrogen and
progesterone receptors in normal human endometrium during
the menstrual cycle by immunocytochemical analysis. Gynecol
Obstet Invest. 1994;38:186–190.
75. Fang Z, Yang S, Lydon JP, et al. Intact progesterone receptors
are essential to counteract the proliferative effect of estradiol in
a genetically engineered mouse model of endometriosis. Fertil
Steril. 2004;82:673–678.
76. Franco HL, Jeong JW, Tsai SY, et al. In vivo analysis of proges-
terone receptor action in the uterus during embryo implantation.
Semin Cell Dev Biol. 2008;19:178–186.
77. Noda Y, Matsumoto H, Umaoka Y, et al. Involvement of super-
oxide radicals in the mouse two-cell block. Mol Reprod Dev.
1991;28:356–360.
78. Narimoto K, Noda Y, Shiotani M, et al. Immunohistochemical
assessment of super oxide dismutase expression in human en-
dometrium throughout the menstrual cycle. Acta Histochem
Cytochem. 1990;23:487–497.
79. Telfer JF, Lyall F, Norman JE, et al. Identification of nitric oxide
synthase in human uterus. Hum Reprod. 1995;10:19–23.
80. Ota H, Igarashi S, Hatazawa J, et al. Immunohistochemical assess-
ment of superoxide dismutase expression in the endometrium in
endometriosis and adenomyosis. Fertil Steril. 1999;72:129–134.
81. Barroso RP, Osuamkpe C, Nagamani M, et al. Nitric oxide in-
hibits development of embryos and implantation in mice. Mol
Hum Reprod. 1998;4:503–507.
82. Biswas S, Kabir SN, Pal AK. The role of nitric oxide in the pro-
cess of implantation in rats. J Reprod Fertil. 1998;114:157–161.
83. Ota H, Igarashi S, Oyama N, et al. Optimal levels of nitric ox-
ide are crucial for implantation in mice. Reprod Fertil Dev.
1999;11:183–188.
84. Lessey BA, Castelbaum AJ, Buck CA, et al. Further characteri-
zation of endometrial integrins during the menstrual cycle and
in pregnancy. Fertil Steril. 1994a;62:497–506.
85. Surrey ES, Minjarez DA, Schoolcraft WB. The incidence of aber-
rant endometrial α-β3 vironectin expression in high risk infertility
population: could prolonged GnRH agonist therapy play a role?
J Assist Reprod Genet. 2001;24:553–556.
86. Wei Q, St Clair JB, Fu T, et al. Reduced expression of bio-
markers associated with the implantation window in women
with endometriosis. Fertil Steril. 2009;91:1686–1691.
87. Xiao Y, Li T, Xia E, et al. Expression of integrin β3 and osteo-
pontin in the eutopic endometrium of adenomyosis during
the implantation window. Eur J Obstet Gynecol Reprod Biol.
2013;170:419–422.
88. Mikolajczyk M, Wirstlein P, Skrzypczak J. Leukaemia inhibitory
factor and interleukin 11 levels in uterine flushings of infertile pa-
tients with endometriosis. Hum Reprod. 2006;21:3054–3058.
89. Takahashi Y, Takahashi M, Carpino N, et al. Leukemia inhib-
itory factor regulates trophoblast giant cell differentiation via
Janus kinase 1-signal transducer and activator of transcription
3-suppressor of cytokine signaling 3 pathway. Mol Endocrinol.
2008;22:1673–1681.
90. Xiao Y, Sun X, Yang X, et al. Leukemiainhibitory factor is dysreg-
ulated in the endometrium and uterine flushing fluids of patients
with adenomyosis during implantation window. Fertil Steril.
2010;94:85–89.
91. Ponce C, Torres M, Galleguillos C, et al. Nuclear factor kappaB
pathway and interleukin-6 are affected in eutopic endometrium
of women with endometriosis. Reproduction. 2009;13:727–737.
92. Taylor HS. The role of HOX genes in human implantation. Hum
Reprod Update.2000;6:75–79.
93. Fischer CP, Kayisili U, Taylor HS. HOXA10 expression is de-
creased in endometrium of women with adenomyosis. Fertil
Steril. 2011;95:1133–1136.
94. Mehasseb MK, Panchal R, Taylor AH, et al. Estrogen and pro-
gesteron e receptor isoform distribution through the menstrual
cycle in uteri with and without adenomyosis. Fertil Steril.
2011;95:2228–2235.
95. Yamanaka A, Kimura F, Kishi Y, et al. Progesterone and syn-
thetic progestin, dienogest, induce apoptosis of human primary
cultures of adenomyotic stromal cells. Eur J Obstet Gynecol
Reprod Biol. 2014;179:170–174.
96. Sasa H, Imai K, Suzuki A, et al. Comparison of low-dose
dienogest with low-dose danazol for long-term treatment of
adenomyosis. Obstet Gynecol. 2014;123:97S–98S.
97. Nagata C, Yanagida S, Okamoto A, et al. Risk factors of treat-
mentdiscontinuation due to uterine bleeding in adenomyosis
patients treated with dienogest. J Obstet Gynaecol Res. 2012;
38:639–644.
98. Choi YS, Cho S, Lim KJ. Effects of LNG-IUS on nerve growth fac-
tor and its receptors expression in patients with adenomyosis.
Growth Factors. 2010;28:452–460.
99. Maia H Jr, Maltez A, Coelho G, et al. Insertion of mirena after en-
dometrial resection in patients with adenomyosis. JAmAssoc
Gynecol Laparosc. 2003;10:512–516.
100. Tadjerouni A, Henry-Suchet J, Loysel T, et al. Adenomyosis
and infertility surgical treatment. Gynecol Rev Gynecol.1995;3:
380–386.
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