Reproductive tract tumours: the scourge of woman reproduction ails Indian rhinoceroses
Endometriosis and assisted reproduction: the role for reproductive surgery
Transcript of Endometriosis and assisted reproduction: the role for reproductive surgery
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Endometriosis and assisted rep
roduction: the role forreproductive surgery?Annemieke De Hondt, Christel Meuleman, Carla Tomassetti, Karen Peeraer andThomas M. D’Hooghe
Purpose of review
The aim of this review paper is to discuss the relationship
between endometriosis and assisted reproductive
technology. More specifically, the following clinically
relevant issues will be discussed. (1) Does the presence of
endometriosis affect the outcome of assisted reproductive
technology? (2) Does surgical treatment for endometriosis
prior to or after assisted reproductive technology treatment
affect the outcome of assisted reproductive technology?
(3) Is assisted reproductive technology a risk factor for the
recurrence of endometriosis after medical or surgical
therapy?
Recent findings
The review is based on recently published review papers/
meta-analyses or international guidelines as published by
the European Society of Human Reproduction or the
American Society of Reproductive Medicine, updated with
a selective review of recent papers searching PubMed with
the key words ‘Endometriosis’, ‘Assisted Reproduction’,
‘IVF’, ‘IUI’ and ‘Reproductive Surgery’.
Summary
At the end of this review, a practical proposal for the clinical
management of women with endometriosis-associated
subfertility is proposed, based on our own experience.
Keywords
assisted reproduction, endometriosis, in-vitro fertilization,
intra-uterine insemination, reproductive surgery
Curr Opin Obstet Gynecol 18:374–379. � 2006 Lippincott Williams & Wilkins.
Leuven University Fertility Center, Department of Obstetrics and Gynaecology,University Hospital Gasthuisberg, Leuven, Belgium
Correspondence to Thomas M. D’Hooghe, MD, Department of Obstetrics andGynaecology, University Hospital, Gasthuisberg Herestraat 49, 3000 Leuven,BelgiumTel: +32 16 34 36 24; e-mail: [email protected]
Current Opinion in Obstetrics and Gynecology 2006, 18:374–379
Abbreviations
ART a
opyr
374
ssisted reproductive technology
ICSI in tracytoplasmatic sperm injection IUI in tra-uterine insemination IVF in -vitro fertilization� 2006 Lippincott Williams & Wilkins1040-872X
ight © Lippincott Williams & Wilkins. Unautho
IntroductionEndometriosis is an estrogen-dependent disease associ-
ated with subfertility and pelvic pain. In three recent
review papers [1–3] we have reviewed the association
between endometriosis, subfertility, miscarriage and
assisted reproductive technology (ART). There are many
arguments to support the hypothesis that there is a causal
relationship between the presence of endometriosis and
subfertility [1]. These arguments include:
(1) A
riz
n increased prevalence of endometriosis in subfer-
tile women when compared to women of proven
fertility.
(2) A
reduced monthly fecundity rate in baboons withmild to severe (spontaneous or induced) endometri-
osis when compared to those with minimal endo-
metriosis or a normal pelvis.
(3) A
trend towards a reduced monthly fecundity rate ininfertile women with minimal to mild endometriosis
when compared to women with unexplained
infertility.
(4) A
dose–effect relationship: a negative correlationbetween the revised American Fertility Society stage
of endometriosis and the monthly fecundity rate and
crude pregnancy rate.
(5) A
reduced monthly fecundity rate and cumulativepregnancy rate after donor sperm insemination in
women with minimal to mild endometriosis when
compared to those with a normal pelvis.
(6) A
reduced monthly fecundity rate after husbandsperm insemination in women with minimal to mild
endometriosis when compared to those with a
normal pelvis.
(7) A
reduced implantation rate per embryo after in-vitrofertilization (IVF) in women with moderate to severe
endometriosis when compared to women with a
normal pelvis.
(8) A
n increased monthly fecundity rate and cumulativepregnancy rate after surgical removal of minimal to
mild endometriosis.
Several different mechanisms have been suggested to
explain the impaired reproductive outcome in women
with endometriosis. According to a review document
written by the Practice Committee of the American
Society for Reproductive Medicine [4], these mecha-
nisms included: distorted pelvic anatomy that can impair
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Endometriosis and assisted reproduction De Hondt et al. 375
oocyte release from the ovary and inhibit ovum pickup or
transport; peritoneal fluid alterations in women with
endometriosis (increased volume of peritoneal fluid,
increased concentration of activated macrophages, and
increased peritoneal fluid concentrations of prostaglan-
dins, interleukin-1, tumor necrosis factor and proteases)
that may have adverse effects on the oocyte, sperm,
embryo or fallopian tube function; altered hormonal
and cell-mediated function in the endometrium
(increased IgG and IgA antibodies as well as lympho-
cytes) that may alter endometrial receptivity and embryo
implantation; endocrine and ovulatory abnormalities
such as the luteinizing unruptured follicle syndrome,
luteal phase dysfunction, abnormal follicular growth
and premature as well as multiple luteinizing surges;
impaired implantation due to disorders of the endo-
metrial function.
The role of reproductive surgery versus ART in the
treatment of endometriosis-associated subfertility is con-
troversial. Therefore, the aim of this paper is to present an
overview regarding the effect of untreated endometriosis
and surgically treated endometriosis on the outcome of
infertility treatment with ART techniques. Furthermore,
we will address the question whether ART treatment
itself alters the course of endometriosis: is it safe to treat a
woman with endometriosis with ovulation induction,
intra-uterine insemination (IUI), IVF or intracytoplas-
matic sperm injection (ICSI), or could this possibly
worsen the pre-existent disease? At the end of this
review, a practical proposal for the clinical management
of women with endometriosis-associated subfertility is
proposed.
Does the presence of endometriosis affectthe success rate of assisted reproductivetechnology?Following artificial reproduction technologies and their
relationship with endometriosis, we will discuss ovarian
stimulation, ovulation induction, IUI, IVF and ICSI.
Assisted reproductive technology using ovarian
stimulation or ovulation induction
Ovulatory or anovulatory patients with minimal to mild
endometriosis can be treated with ovarian stimulation or
with ovulation induction, respectively. In these patients,
ovarian stimulation or induction using gonadotrophins
results in higher fecundity rates than no treatment [5],
but the clinical pregnancy rate after treatment is still
significantly lower in the endometriosis group (6.5%) than
in women with unexplained infertility (15%) [6].
Intra-uterine insemination in combination with
controlled ovarian stimulation
Whereas sufficient data support the statement that IUI
with ovarian stimulation is an effective treatment, the
opyright © Lippincott Williams & Wilkins. Unauth
role of unstimulated IUI is uncertain for endometriosis-
associated subfertility [7��]; at the same time, it is clear
that both the monthly fecundity rate and the cumula-
tive pregnancy rate are significantly reduced in women
with minimal to mild endometriosis when compared
with women with a normal pelvis [8–10]. When con-
trolled ovarian stimulation is used in combination
with IUI, gonadotrophins are more effective than clomi-
phene citrate for mild male subfertility and for
unexplained subfertility [11�], but no data are avail-
able regarding the best ovarian stimulation protocol
to be used in combination with IUI in women with
endometriosis.
In-vitro fertilization or intracytoplasmatic sperm
injection followed by embryo transfer
IVF can be considered to be an effective treatment
for endometriosis-associated subfertility [12]. Further-
more, the continuously ameliorating results of IVF and
ICSI, the coverage by insurance companies, and the
social acceptability of ART in general have led to the
situation that many women with endometriosis-associ-
ated subfertility receive IVF treatment. A meta-
analysis by Barnhart et al. [13] in 2002 pooled data from
22 nonrandomized studies regarding IVF success rates in
patients with endometriosis versus control patients with-
out endometriosis and with tubal infertility. When
adjusted for confounding variables, there was a signifi-
cantly negative association between endometriosis and
IVF outcome. Not only pregnancy rates, but also fertili-
zation rates, implantation rates, peak estradiol concen-
trations and the number of retrieved oocytes were
significantly lower in women with endometriosis than
in controls, and these parameters were negatively cor-
related with the degree of endometriosis. Indeed, im-
plantation rates, peak estradiol concentrations and the
number of retrieved oocytes were significantly lower in
women with stage III–IV endometriosis when compared
to women with stage I–II endometriosis. Overall, the
authors of this meta-analysis concluded that there was a
54% reduction in pregnancy rate after IVF in patients
with endometriosis and that the success was even poorer
when the staging of endometriosis was higher. Apart from
this meta-analysis, there are no other reliable data
(reviewed by De Hondt et al. [2]).
A number of researchers have hypothesized that IVF
with ICSI may improve oocyte and embryo quality
in women with endometriosis. Indeed, there is no
evidence that the presence and extent of endometrio-
sis has a negative effect on implantation and pregnancy
rates in patients treated with ICSI, but this observa-
tion is based on only two retrospective studies [14,15]
(reviewed by De Hondt et al. [2]) Clearly, randomized
trials are needed before this hypothesis can be
accepted.
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376 Minimally invasive gynecologic procedures
Does previous surgical treatment ofendometriosis change the success rate ofassisted reproduction techniques?Surgically treating an asymptomatic patient before refer-
ring her to ART treatment is only justified as long as
the treatment is beneficial, since laparoscopy for endo-
metriosis can be very difficult, time-consuming and
high risk, with significant postprocedure morbitity and
long revalidation.
Surgical treatment and spontaneous conception
Several authors have reported on the influence of laparo-
scopic surgery for stage I or II endometriosis on spon-
taneous pregnancy [16,17]. The Canadian multicenter
study [16] revealed that the monthly fecundity rate
doubles after surgical removal of endometriotic lesions
and endometriosis-related adhesions in this patient popu-
lation, and appears to be of higher quality in terms of
study design, study power and statistical analysis than the
Italian study [17] where these data were not confirmed.
Although the usefulness of a meta-analysis evaluating
these two heterogeneous trials can be debated, there is
consensus that surgery is effective in treating the inferti-
lity associated with minimal to mild endometriosis: for
every 12 patients having stage I or II endometriosis
diagnosed at laparoscopy, there will be one additional
successful pregnancy if ablation or resection of visible
endometriosis is performed, compared to no treatment
[12,18,19]. The benefit of surgical therapy for subfertility
associated with moderate to severe endometriosis is
generally accepted, but has never been studied in
randomized trials.
Surgical treatment prior to controlled ovarian
stimulation and intra-uterine insemination
If surgical treatment of minimal to mild endometriosis
increases the likelihood of spontaneous conception, then
it is also possible that prior surgical treatment of minimal
to mild endometriosis increases the fecundability follow-
ing treatment with controlled ovarian stimulation and
IUI. This hypothesis has never been tested in random-
ized controlled trials, but indirect evidence suggests that
this may be a valid assumption. Indeed, in a recent
publication [20], we reported a similar cycle pregnancy
rate and cumulative live birth rate in women with surgi-
cally treated minimal to mild endometriosis and women
with unexplained infertility after controlled ovarian
stimulation and IUI. These data suggest that, if an
operative laparoscopy with complete removal of all endo-
metriotic lesions, is performed within 6 months of the
onset of treatment with IUI, the fecundability in endo-
metriosis patients is increased up to the level of patients
with unexplained subfertility. In contrast, women with
surgically untreated endometriosis are reported to have
a lower fecundability than women with unexplained
subfertility. These data are in line with the effect of
opyright © Lippincott Williams & Wilkins. Unautho
reproductive surgery for endometriosis on spontaneous
conception, as reviewed in the previous section.
Surgical treatment prior to in-vitro fertilization
In one retrospective study [21] investigators measured
how reproductive outcome after IVF/embryo transfer was
affected by surgery for endometriosis performed prior to
IVF/embryo transfer. The study group consisted of
patients with endometriosis, but excluded patients with
persistent or recurrent endometriomas of more than 3 cm
at the time of IVF. Patients were divided into two groups
based on the interval between the most recent surgical
intervention and oocyte aspiration (more or less than
6 months). No significant difference was found between
these two groups with regard to results of ovarian stimu-
lation, number of oocytes retrieved and ongoing preg-
nancy rates. The authors concluded that possibly the
pregnancy-enhancing effect of surgery on spontaneous
conception is overcome by the inherently greater impact
of IVF-embryo transfer on implantation and pregnancy.
In another retrospective case–control study [22] the
authors concluded that removal of endometriomas prior
to IVF does not improve fertility outcomes. The study
was recently criticized [23�], however, since the diagnosis
of endometriomas in the control group was only based on
ultrasound criteria, since complete resection of the endo-
metriotic cyst wall was impossible in some case and since
the authors did not mention if peritoneal endometriosis,
known to be copresent with ovarian endometriomas, was
surgically excised at the same time.
In summary, the simple truth is that we do not know and
that randomized trials are desperately needed to solve
this issue.
Surgical treatment after in-vitro fertilization
Recently, an interesting study has stirred the debate
whether reproductive surgery should be performed
before or after the onset of IVF [23�]. In this study,
29 patients with at least one failed IVF cycle were
laparoscopically treated for endometriosis by a senior
surgeon and 22 of them subsequently conceived, includ-
ing 15 non-IVF pregnancies (13 after spontaneous con-
ception and three after IUI treatment) and seven IVF
pregnancies. In this study, great care was taken to treat
patients radically: all endometriotic lesions were ablated
or excised, complete adhesiolysis was performed and
endometriomata were ‘appropriately managed’. The
authors admit that the approach towards endometriomata
varied based on the intra-operative assessment of the
pathophysiology or the type of the endometrioma, but
from their description we understand that endometrio-
mata were completely removed, not just coagulated, and
care was taken not to damage the healthy ovarian tissue.
The value of this study [23�] is criticized in the same issue
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Endometriosis and assisted reproduction De Hondt et al. 377
of Fertility and Sterility [24�–26�] because of the study
design: it is a retrospective, nonblinded study, with
patients being operated or not depending on their own
motivation, suggesting that symptomatic patients were
operated and asymptomatic patients not, and there was
no uniform approach to the patients’ treatment. In his
comment, Adamson [25�] gives a synthesis of ‘pros and
cons’: laparoscopy is probably efficient to augment preg-
nancy rates, does not increase the risk of multiple birth,
may help achieve more than one pregnancy and helps
alleviate pain problems. On the other hand, it is costly,
recovery time is needed, as well as time to allow spon-
taneous conception, skilled surgeons are hard to find and
the operative risk can be high. IVF has the advantage that
it can treat multiple infertility problems at the same
time (both male and female) and that one cycle only
takes 2–3 months. It is also costly, however, and the risk
of multiple pregnancy is high. This latter disadvantage is
relative and dependent on the number of embryos trans-
ferred: recent Belgian legislation with a restrictive
embryo transfer policy has resulted in a 3-fold drop in
multiple pregnancy rates from 25 to 8% [27��].
Do artificial reproduction techniques augmentthe cumulative recurrence rate ofendometriosis after surgery or is assistedreproductive technology safe in patientswith endometriosis?When conducting a Medline search on complications of
endometriosis, a lot of hits will lead to articles discussing
the risk of multiple births after ART treatment in women
with endometriosis [28]. In the very recent publication,
‘The science behind 25 years of ovarian stimulation for
IVF’ [29], several complications of ovarian stimulation for
IVF are mentioned: more common and usually relatively
mild complications like infection and bleeding, anesthe-
sia problems, discomfort such as weight gain, headache,
mood swings, breast tenderness, abdominal pain, and
sometimes diarrhea and nausea. More serious compli-
cations are more elaborately discussed: ovarian hyper-
stimulation syndrome, venous thromboembolism, mul-
tiple pregnancy and long-term maternal risks associated
with ovarian stimulation. Under this last section, the
authors conclude that although recent large cohort
follow-up studies linked to National Cancer Registries
have to date shown no causative association between
ovarian stimulation with exogenous gonadotrophins
and increased risk of malignant or benign ovarian disease,
data from studies with longer follow-up periods in well-
defined and characterized populations is required, with
adequate controls for potential confounders.
When thinking about endometriosis as an estrogen-
related and recurrent disease, the assumption can be
made that hyperestrogenism following hormonal stimu-
lation will augment the cumulative risk for recurrence of
opyright © Lippincott Williams & Wilkins. Unauth
endometriosis after surgery or increase the progression
rate of endometriosis in patients who have not been
surgically treated. Nowhere in the literature, however,
do we find any trials to support or reject this hypothesis.
Only a few case reports have been published related to
this topic. In a first report, the case is described of a
patient presenting with an acute renal colic after ovarian
stimulation [30]. In the second paper [31], four cases are
presented with severe digestive complications due to the
rapid growth of sigmoid endometriosis under ovarian
stimulation for IVF. In three patients, sigmoid endo-
metriosis was diagnosed at laparoscopy for sterility.
Due to the absence of digestive symptoms or repercus-
sion on the bowel, no bowel resection was performed
prior to ovarian stimulation. All patients experienced
severe digestive symptoms during ovarian stimulation
and a segmental sigmoid resection had to be performed.
On the other hand, a retrospective cohort study [32]
conducted in our center was unable to document an
increased cumulative recurrence rate of endometriosis
after ovarian stimulation for IVF (higher estradiol levels)
when compared to ovarian stimulation for IUI (lower
estradiol levels), suggesting that the estrogen levels were
not the most determining factor in the recurrence of
endometriosis. Further research as to which hyperstimu-
lation regimens have the least risk of causing recurrence
or worsening of endometriosis is therefore indispensable.
ConclusionEndometriosis is associated with pain and subfertility,
and can predominantly be found in women of reproduc-
tive age, between 20 and 45 years old. The majority of
these women will desire to become pregnant, actively or
passively, at the moment of the diagnosis of endo-
metriosis, whether this diagnosis is made as part of a clin-
ical investigation of pain or subfertility, or both. A small
subset of women will be diagnosed with endometriosis at
the end of their reproductive lifespan, in their 40s or 50s,
and will not be interested in fertility. Following this
observation, it is mandatory that for all medical or surgical
treatment in nearly all women with endometriosis, the
conservation or improvement of fertility should be a
fundamental concern for all patients and clinicians. As
a consequence, it is important that these women get the
best possible clinical care, integrating both fertility and
pain issues in a combined management. Ideally, this
treatment should be carried out in a center or network
of excellence where the best available skills in reproduc-
tive surgery and ART are present. Indeed, as described in
a recent opinion paper [33], centers/networks of excel-
lence are the only way forward to ensure that women with
endometriosis receive consistent, evidence-based care,
ensuring excellence, continuity of care, multidisciplin-
arity, research, training and cost-effectiveness. Clinical
excellence should be achieved by proper training,
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378 Minimally invasive gynecologic procedures
adherence to evidence-based guidelines, quality manage-
ment and continuous measurement of patient outcome as
a central focus, including a full registry of complications
and recurrences over many years. To ensure continuity of
care, the first step is to assign to each patient a ‘central
gynecologist’ who must have continuously updated
knowledge regarding all diagnostic and management
options for endometriosis, and who must set priorities
and realistic expectations together with the woman using
a long-term multidisciplinary treatment plan. Scientific
research within and scientific collaboration between
centers/networks of excellence will create the critical
mass of patients and tissue samples that is needed to
make progress. Centers/networks of excellence should be
accredited as training centers by professional bodies.
They should aim at improving the cost-effectiveness of
the management of endometriosis by a reduction in the
time to diagnosis, a reduction in the time before indi-
vidualized specialist care is invoked, a reduction of
expensive ‘hit and miss’ treatments, and a reduction in
expensive fertility treatments, if the disease is under
control before fertility is impaired [33].
Practically, we have adopted the following guidelines in
the Leuven University Fertility Center, as part of our ISO
9001–2000 Certificate for Quality Management of
couples with subfertiliy, and these are based on scientific
data, personal experience and common sense.
All female patients with a regular cycle, whose male
partner has normal sperm concentration and motility,
and all female patients with pain (dysmenorrhea, dyspa-
reunia, chronic pelvic pain) are advised to have a com-
plete laparoscopic and hysteroscopic evaluation under
general anesthesia (day surgery), and endometriosis
(mostly minimal to mild, sometimes moderate) is found
and surgically treated in at least 50%. All female patients,
regardless of the cause of subfertility, are advised to have
a complete laparoscopic and hysteroscopic evaluation
under general anesthesia (day surgery) before they start
hormonal treatment with IUI. All patients with pre-
sumed adnexal pathology (according to clinical examin-
ation or after ultrasound) and all patients with suspected
endometriotic cysts measuring 3 cm or more are offered
the same evaluation, combined with complete and
radical excision of peritoneal endometriosis, ovarian
endometriotic cysts and deeply infiltrative disease, if
present.
If patients are counseled to IVF as their primary sub-
fertility treatment due to age, duration of subfertility,
male factor infertility or due to other reasons, those who
do not conceive after one cycle of IVF could be offered a
full laparoscopic evaluation, certainly if there is coex-
istent pain or if they have risk factors to develop endo-
metriosis (i.e. heavy menstrual flow, short cycles).
opyright © Lippincott Williams & Wilkins. Unautho
The following clinical questions are desperately in need
of randomized research:
(1) D
riz
oes surgical treatment of peritoneal lesions and
associated adhesions prior to IVF increase the success
rate of IVF?
(2) W
hich hyperstimulation regimens (for IUI and IVF)have the lowest risk of causing endometriosis recur-
rences or worsening of the disease?
(3) D
oes surgical treatment of ovarian endometrioticcysts prior to IVF increase the success rate of IVF?
We think these studies can only be done in centers where
excellence in both reproductive surgery and ART treat-
ment is available, and where sufficient numbers of pat-
ients are treated.
References and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as:� of special interest�� of outstanding interest
Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (pp. 464–465).
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23
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�Diamond MP. Challenges of evaluating surgical outcomes. Fertil Steril 2005;84:1581.
Reaction on [22].
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�Adamson GD. Laparoscopy, in vitro fertilization, and endometriosis: anenigma. Fertil Steril 2005; 84:1582–1584.
Reaction on [22].
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Reaction on [22].
27
��Debrock S, Spiessens C, Meuleman C, et al. New Belgian legislation limitingthe number of transferable embryos after In Vitro Fertilization results in athreefold reduction of the multiple pregnancy rate without significantly redu-cing the pregnancy rate at the Leuven University Fertility Center. Fertil Steril2005; 83:1572–1574.
This article depicts how the Belgian system can reduce the number of multiplepregnancies after IVF and cuts down on cost and neonatal complications.
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orized reproduction of this article is prohibited.