C

Endometriosis and assisted rep

roduction: the role for

reproductive 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: Thomas.Dhooghe@uz.kuleuven.ac.be

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 with

mild 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 in

infertile women with minimal to mild endometriosis

when compared to women with unexplained

infertility.

(4) A

dose–effect relationship: a negative correlation

between the revised American Fertility Society stage

of endometriosis and the monthly fecundity rate and

crude pregnancy rate.

(5) A

reduced monthly fecundity rate and cumulative

pregnancy 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 husband

sperm 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-vitro

fertilization (IVF) in women with moderate to severe

endometriosis when compared to women with a

normal pelvis.

(8) A

n increased monthly fecundity rate and cumulative

pregnancy 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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C

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

rized reproduction of this article is prohibited.

C

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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C

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 endometriotic

cysts 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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3 Tomassetti C, Meuleman C, Pexsters A, et al. Endometriosis, recurrentmiscarriage and implantation failure: is there an immunological link? ReprodBiomed Online 2006; in press.

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��Kennedy S, Bergqvistg Q, Chapron C, et al., on behalf of the ESHRE SpecialInterest Group for Endometriosis and Endometrium. ESHRE guideline for thediagnosis and treatment of endometriosis. Hum Reprod 2005; 20:2698–2704.

Excellent practical guide for daily clinical use.

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Discussion: will IVF make IUI obsolete?

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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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