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The Impact of Adenomyosis on Women's Fertility

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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 appropriate treatment for better reproductive outcomes in women with adenomyosis; and Advise patients that surgery 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.
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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.
13
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.
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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 (0.460.87); and TVS, 0.68 (0.440.86)
(P= 0.66); specificity: MRI, 0.86 (0.760.93); and TVS
0.65 (0.500.77) (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 13).
2442
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
615 years 518 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.
32,4346
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,
4345
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 15 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
(319 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 2050 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 IIIIV; 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 (322 months)
Al Jama et al.
28
18 Combined therapy (with GnRH a) Spontaneous abortion, 2; cesarean section, 6 615 years 430 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).
8183
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.
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568 Obstetrical and Gynecological Survey
... 6 Adenomyosis has also been associated with an increased risk for obstetrical complications including preeclampsia, hypertensive disorders, placentary abnormalities and preterm delivery. 7,8 However, the exact mechanism of these associations is not yet fully grasped, but it is thought that disruptions at the endometrial-myometrial junction, and abnormal placentation, are central. 9 Particularly high resolution transvaginal ultrasound, and magnetic resonance imaging (MRI), the non-invasive diagnosis of adenomyosis has improved greatly. 10 However, diagnostic challenges remain in low resource settings where such technologies are not available. ...
... 6 Data also suggest a relationship to an increased risk of miscarriage and hypertensive disorders of pregnancy. 7 However, these findings, along with the heterogeneity in diagnostic criteria and study designs, have led to inconsistent literature. 12 In Bangladesh, adenomyosis is underdiagnosed due to lack of healthcare resources and awareness. ...
Article
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Background: Adenomyosis is a serious reproductive difficulty caused by aberrant endometrial tissue within the myometrium. It can induce infertility and predispose women to hypertensive problems, preeclampsia, and preterm birth. However, the influence of adenomyosis on fertility and obstetric outcomes has not been extensively explored, particularly in resource-limited settings. This study aimed to investigate the effect of adenomyosis on fertility and obstetric outcomes in women who visited a tertiary care hospital in Dhaka, Bangladesh. Methods: A case control study was conducted in Shahabuddin Medical College Hospital and one IVF center from June 2023 to May 2024. The study included 100 women divided into two groups: A case group of 50 with adenomyosis and 50 in the control group without. Two groups were compared in terms of baseline characteristics, fertility outcomes, obstetric complications, and delivery outcomes. SPSS software statistical analysis was performed. Results: Obstetric complications such as hypertensive disorders (32% versus 6%, p=0.001), preeclampsia (16% versus 2%, p=0.01) and preterm delivery (26% versus 8%, p=0.01) were more frequent in the adenomyosis group. The adenomyosis group also had a higher caesarean delivery rate (62% versus 34%), p<0.05. Outcomes in fertility, namely implantation rates and live birth rates were not different (p>0.05). Conclusions: Early diagnosis and careful management of adenomyosis are important because adenomyosis is associated with increased obstetric complications and higher caesarean delivery.
... while focal adenomyosis lesions, particularly those in the vicinity of the cystic uterine glands, are less frequently observed (4). When the diameter of the single or fused lumen of the cystic space exceeds 1 cm, the condition is termed cystic adenomyosis (CA) (3), also known as cystic adenomyoma or adenomyotic cyst (5). So far, less than 50 cases of CA have been reported in the literature (6). ...
... Along with chronic pelvic pain and abnormal uterine bleeding, infertility is the third characteristic clinical sign accompanying adenomyosis due to an abnormal uterine environment and aberrant utero-tubal transport because of an increased arrhythmic peristalsis 2 ; together, these last two conditions may alter sperm transport and embryo implantation. 3 It has been reported that up to 25% of women visiting gynecologic clinics, including those with ongoing in vitro fertilization (IVF) cycles, present uterine adenomyotic features. 4,5 Also, previous reports have described that up to 70% of women diagnosed with adenomyosis are over 40 years of age. ...
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Objective The primary objective of this study was to assess if uterine adenomyosis impacts live birth rate per euploid embryo transfer. The secondary objectives included addressing obstetric and perinatal outcomes in the study group. Methods This was a multicenter and retrospective cohort study in which 228 patients diagnosed with adenomyosis undergoing single euploid embryo transfer between 2016 and June 2023 were included and matched on 1:1 ratio to control patients without ultrasonographic diagnostic criteria for adenomyosis. Results A significant higher live birth rate per embryo transfer was observed in controls compared to women with adenomyosis: 107/228 (46.9%) versus 56/228 (24.6%), respectively (odds ratio (OR) = 2.71, 95% confidence interval [CI]: 1.73–4.13, p < 0.001). When dividing adenomyotic patients regarding the nature of the disease, a higher live birth rate per transfer was described in diffuse adenomyosis compared to focal adenomyosis: 47/166 (28.3%) versus 9/62 (15%), respectively (OR = 2.32, 95% CI: 1.03–5.78, p = 0.034). Described differences were constant even when correcting for multiple variables. There was no statistically significant difference in childbirth delivery method (vaginal vs. cesarean section) between the adenomyosis and control groups. Mean gestational age at the time of delivery, newborn size and weight, and incidences of low birth weight, preterm birth, and admission to the neonatal intensive care unit did not differ between the two groups. In addition, in vitro fertilization (IVF) and perinatal outcomes were similar in patients with diffuse compared with focal adenomyosis. Conclusion Adenomyosis, especially focal adenomyosis, affects clinical but may not affect perinatal outcomes after single euploid embryo transfer.
... Qalan üçdə ikisində ən çox görülən simptomlar menorragiya (50%), dismenoreya (30%) və metrorragiyadır (20%). Disparuniya da şikayət olaraq qeyd oluna bilər [4,5,6]. ...
Article
Bu tədqiqatın öyrənilməsi zamanı adenomiozlu 30-50 yaş arası (orta yaş – 42,0±1,8 il) 224 xəstə üzərində hərtərəfli klinik, laborator və instrumental perspektiv müayinə aparılmışdır. Nəzarət qrupu 84 nəfərdən ibarət idi nisbətən sağlam reproduktiv yaşda olan, müntəzəm ovulyasiya dövrü olan və ginekoloji xəstəlikləri olmayan qadınlar. Aparılmış tədqiqatlar müəyyən etmişdir ki, ən böyük qrup 36-40 yaşlı xəstələrdir - əsas qrupda - 92 qadın, 41,1±3,3%, nəzarət qrupunda isə 37 qadın, bu da 44,0± 5,4%.Aparılmış tədqiqatlar müəyyən etmişdir ki, adenomiyozun erkən diaqnostikası üçün meyarların olmaması diaqnostikada gecikmələrə və çətinliklərə səbəb olur. Mövcud tibbi sənədlərin təhlili zamanı göstərilmişdir ki, xəstəliyin ilk əlamətlərinin yaranmasına dair anamnez toplanması və düzgün diaqnozun qoyulmasında orta hesabla 5,3±1,8 il “gecikmə” olur. Eyni zamanda, araşdırmalarımız göstərdi ki, daha ətraflı anamnez toplanması, yeniyetməlik dövründə dismenoreya və ağrı sindromunun təfsiri və erkən reproduktiv yaşda olan qadınlarda vizual analoq miqyasında şiddəti, həmçinin mövcudluğu və şiddəti menstruasiya olmayan ağrılara daha diqqətli yanaşmaq lazımdır. Bütün bunlar həm də vaxtında diaqnostikaya kömək edəcəkdir.
... The pathogenic mechanisms of adenomyosis are not fully elucidated, but in recent years it has been observed that inflammatory molecules, extracellular matrix enzymes, sex hormone receptors, as well as neuroangiogenic factors and growth factors play an important role [6]. Adenomyosis is considered to originate from the basal invagination of the endometrium into the myometrium, an invagination that occurs along the intramyometrial lymphatic system [7]. Another theory is that the condition may arise de novo from a metaplastic process starting from intramyometrial endometrial tissue [8]. ...
Article
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Background and aims Adenomyosis is a heterogeneous disease, which differs from patient to patient. The objective of our study was to evaluate the risk factors that influence the occurrence of adenomyosis, more precisely to highlight aspects that may be used in practice. In addition, the in vitro impact of levonorgestrel (a possible predisposing factor in the occurrence of adenomyosis) on MDA-MB-231 cells was evaluated, trying to obtain a link between adenomyosis and mammary cancer. Methods Clinical and demographic data of patients diagnosed with adenomyosis hospitalized between January and September 2023 in the Obstetrics-Gynecology Clinic were analyzed. For the in vitro assays, the MTT and LDH method was used to investigate the effect on cell viability and the potential cytotoxic effect of LG on MDA-MB-23 cells. Results Out of a total of 99 hysterectomies performed, the diagnosis of adenomyosis was confirmed by ultrasound in 28 cases. Among our patients, we could observe that most of cases of adenomyosis developed in women between 40 and 45 years old. Multiple pregnancies can influence the development of this uterine pathology, along with a history of uterine surgery and abortions. It was also found that treatment with sex hormones can increase the risk of adenomyosis. Our in vitro study has showed that LG stimulates the proliferation of MDA-MB-231 cells depending on the dose and time. Conclusions Personal history along with progestin treatment may influence myometrial lesions, leading to diffuse or focal adenomyosis. Moreover, in vitro, LG has been shown to stimulate the proliferation of breast cancer cells.
Article
Adenomyosis is a benign uterine disorder characterized by the infiltration of endometrial tissue into the myometrium, often associated with debilitating symptoms such as heavy menstrual bleeding, severe pelvic pain and infertility. Traditionally viewed as a condition affecting older, multiparous women, recent studies highlight its prevalence among younger women with primary infertility, emphasizing its significant impact on reproductive health. Emerging evidence underscores the importance of accurate diagnosis and effective management to improve patients’ outcomes, particularly in the context of assisted reproductive technologies (ART). This review synthesizes findings from recent literature (January-November 2024), focusing on diagnostic advancements, treatment modalities, and implications for infertility management. Diagnostic strategies, particularly transvaginal ultrasound (TVUS) and three-dimensional TVUS (3D-TVUS), have improved with revised MUSA criteria, enhancing the identification of direct and indirect adenomyosis markers. Despite these advances, challenges remain in achieving diagnostic consistency and in minimizing overdiagnosis. The therapeutic approaches are evolving, with hormonal therapies, minimally invasive procedures, and targeted treatments addressing inflammation and uterine abnormalities. For women undergoing ART, interventions such as oxytocin receptor antagonists and tailored GnRH protocols show promise in improving pregnancy outcomes. However, the role of conservative surgical treatments and emerging molecular therapies warrants further investigation. Additionally, this review highlights the critical need for patient-centered care, integrating emotional support with evidence-based interventions. Adenomyosis not only disrupts physical well-being, but also profoundly impacts the patients’ emotional health, necessitating a holistic approach to management. Advancements in diagnostic techniques and treatment strategies offer hope for enhancing fertility outcomes and overall quality of life for women with adenomyosis. Further research is essential to establish standardized guidelines and optimize patients’ care in this complex and multifaceted condition.
Article
Objective. We aimed to demonstrate the importance of prenatal diagnosis in the management of phenylketonuria (PKU). Materials and method. This study enrolled 90 pregnant women from 69 families, based on the fact that either the first child of the pregnant woman, or any other family member was diagnosed with classical phenylketonuria. Families with known mutant phenylalanine hydroxylase (PAH) alleles were accepted for the prenatal diagnosis program of the Hacettepe University, Ankara, Türkiye, over a ten-year period. Eighteen families who refused to undergo prenatal diagnosis were excluded from study. Seventy-two pregnant women (including one twin) from 51 families underwent chorionic villus sampling (CVS). Genomic DNA was extracted from chorionic villus samples. Polymerase chain reaction (PCR) was performed to identify the disease-causing mutations, if any, in the study subjects. We screened the study subjects for IVS10 and R261Q mutations of PAH. In the cases where mutations were not known, haplotype analyses were carried out by restriction fragment length polymorphism (using restriction enzymes such as MspI, BgIII, XmnI, PvuIIa, and PvuIIb) and variable number tandem repeats. Results. Of the 73 fetuses investigated in the study, 55 were healthy or disease-free carriers, and 18 were affected with the disease. Three families chose to terminate the pregnancy after the diagnosis for PKU was positive. On the contrary, 15 neonates with phenylketonuria were delivered. Unfortunately, there was one case of misdiagnosis. A neonate was found to be affected with PKU, although the prenatal diagnosis had given a negative result. Conclusions. Prenatal diagnosis and early detection are possible and important for a better management of neonatal phenylketonuria.
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This review discusses uterine adenomyosis as a (co-)factor in female subfertility. The clinical presentation of adenomyosis uteri is reviewed as well as recent developments in non-invasive imaging modalities for the condition. Different treatment options are discussed, focusing on conservative management in patients who wish to maintain their childbearing capacity.
Article
Forty patients with adenomyosis were referred for conservative surgical treatment. The technique, described by R. Musset (1971), consists in sagittal hysterotomy resection of the pathologic myometre and suture. Thirty six of the patients were infertile and have been studied in this paper. Their age is 28-45 (mean age: 36). The mean parity is 0.17. 17 cases (47%) had primary infertility, 19 cases (53%) had a secondary infertility. The uterine size was subnormal (< 12 cm high) in 4 cases (12%), medium (12-16 cm) in 14 cases (39%) and severe (> 16 cm) in 18 cases (50%). Twenty-one patients (58%) were pregnant, 15 (42%) had full term deliveries, 6 (16%) had a spontaneous abortion. The surgical resection of adenomyosis is an easy technique which can enhance the fertility of women with adenomyosis.
Article
The immunohistochemical distribution of superoxide dismutase (SOD) was examined in the human endometrium throughout the menstrual cycle. Surface and glandular epithelia showed positive staining throughout the menstrual cycle except just prior to the menstruation. Staining activity was more intense in the cytoplasm than that in the nucleus. Specific immunostaining of SOD was demonstrated in sub- and supranuclear vacuoles of glandular epithelia, and intraglandular substances during the early and mid secretory phases; i.e., the preand peri-implantation periods. Meanwhile, stromal cells showed weaker staining activity than surface and glandular epithelia throughout the menstrual cycle until the 22th day. Once the predecidual change occurred in stromal cells on the 23th day, predecidual cells came to show intensive staining. However, specific staining was shown neither in predecidual cells nor in surface or glandular epithelia just prior to the menstruation. In addition, SOD activity was also shown in the decidual cells of 8 weeks gestation and in the reserve cells of the endocervix. Collectively, the present immunohistochemical recults suggest that SOD may play an important role not only in the protection of developing embryos from superoxide anion radicals but also in the local defense mechanism against tissue damages resulting from inflammation in the uterine cavity, and that the expression of SOD may be regulated by sex steroids, especially progestorone. Furthermore, SOD could be a useful indicator to clinically diagnose the degree of predecidualization and the luteal phase defect.
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HOX genes are transcriptional regulators that play an essential role in determining tissue identity during embryonic development. HOX genes are involved in the development of the Mullerian system and then continue to be expressed in the adult uterus. Two HOX genes have been demonstrated necessary for uterine receptivity in knock-out mice. We have recently elucidated the expression patterns and regulation of HOX genes in the development of the human endometrium during the menstrual cycle. HOX genes are likely key regulators of human implantation. This paper will review the role of HOX genes in the reproductive tract, specifically the evidence that HOX genes are important for human endometrial development and receptivity.
Article
The objectives of this study were to evaluate the effects of a nitric oxide (NO) donor on embryo development in vitro and on implantation of embryos in vivo in mice. Mouse embryos (2-cell) were incubated in media containing different concentrations of diethylenetriamine/NO (DETA/NO), a nitric oxide donor, and development was monitored daily for 4 days. Specificity of NO effects was assessed by using DETA without NO or 48 h preincubated DETA/NO. In in-vivo studies, mated mice were continuously infused, subcutaneously, with various concentrations of DETA/NO or DETA through mini-osmotic pumps (from day 1 of pregnancy), and implantations in the uterus were assessed on day 6. None of the embryos progressed beyond 4-cell stage when exposed to 0.1 or 1.0 mM DETA/NO compared with 94.5% of control embryos that developed beyond the morula stage by day 4. Embryo development was unaffected by lower (0.001 and 0.01 mM) concentrations of DETA/NO, 48 h preincubated DETA/NO, or DETA only. Infusion of DETA/NO to mice caused inhibition of embryo implantation in a dose-dependent manner. No implantation sites were observed in mice infused with a daily dose of 20 mmol DETA/NO rate, compared with an implantation rate of 81.8% in control or DETA-treated mice. This study demonstrates for the first time that higher concentrations of NO inhibit both embryo development in vitro and implantation in vivo in mice.
Article
To determine whether local estrogen production takes place in endometriotic or adenomyotic tissues, in eutopic endometrium from patients with endometriosis or adenomyosis, and in normal endometrium, tissue specimens were examined by immunohistochemistry, catalytic activity, and mRNA expression for aromatase cytochrome P450 (P450arom). P450arom was immunohistochemically localized in the cytoplasm of glandular cells of endometriotic and adenomyotic tissues, and of eutopic endometrium from patients with the respective diseases, whereas estrogen receptors and progesterone receptors were localized in the nuclei of the glandular cells and stroma. Aromatase activity in the microsomal fraction of adenomyotic tissues was inhibited by the addition of danazol, aromatase inhibitors, and anti-human placental P450arom monoclonal antibody (mAb3-2C2) in a manner similar to such inhibition in other human tissues. Reverse transcription polymerase chain reaction and Southern blot analysis also revealed P450arom mRNA in these tissues. However, neither P450arom protein activity nor mRNA was detected in endometrial specimens obtained from normal menstruating women with cervical carcinoma in situ but without any other gynecological disease. These results suggest that at a local level, endometriotic and adenomyotic tissues produce estrogens, which may be involved in the tissue growth through interacting with the estrogen receptor.
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This review focuses on non-invasive imaging techniques that have proven useful in diagnosing adenomyosis, including hysterosalpingography, transabdominal and endovaginal ultrasound, as well as magnetic resonance imaging. An understanding of the histopathological features of this disease is crucial when attempting to interpret the associated imaging findings. The muscular hyperplasia accompanying the heterotopic endometrial tissue actually produces the typical gross appearance of adenomyosis and corresponds to areas of decreased echogenicity or signal intensity on ultrasound and magnetic resonance imaging respectively. The heterotopic endometrial tissue also contributes to the imaging appearance of adenomyosis, and with the advent of high resolution imaging techniques, these changes are being detected with increasing frequency, including the presence of myometrial nodules, linear striation, poor definition and nodularity of the endo-myometrial junction, pseudowidening of the endometrium, and myometrial cysts or haemorrhagic foci. The purpose of this review is to (i) present the spectrum of imaging findings of adenomyosis, (ii) illustrate potential pitfalls in diagnosis and (iii) review the accuracy and role of currently available noninvasive imaging techniques.