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No difference in cycle pregnancy rate and in

cumulative live-birth rate between women with


surgically treated minimal to mild endometriosis and
women with unexplained infertility after controlled
ovarian hyperstimulation and intrauterine
insemination
Erika Werbrouck, M.D., Carl Spiessens, Ph.D., Christel Meuleman, M.D., and
Thomas DHooghe, M.D., Ph.D.
Leuven University Fertility Centre, University Hospital Leuven, Leuven, Belgium

Objective: The association between infertility and minimal to mild endometriosis is controversial and poorly
understood. The clinical pregnancy rate (PR) per cycle after controlled ovarian hyperstimulation (COH) with or
without intrauterine insemination (IUI) is reportedly lower in women with surgically untreated minimal to mild
endometriosis than in women with unexplained infertility. It is possible that prior laparoscopic removal of
endometriosis has a positive effect on the clinical PR after COH and IUI. Therefore, we tested the hypothesis that
after COH and IUI the PR per cycle and the cumulative live-birth rate (CLBR) are equal or higher in women with
recently surgically treated minimal to mild endometriosis when compared with women with unexplained
infertility.
Design: A retrospective, controlled cohort study.
Setting: Leuven University Fertility Centre, a tertiary academic referral center.
Patient(s): One hundred seven women treated during 259 cycles with COH and IUI including patients with
endometriosis (n 58, 137 cycles) and unexplained infertility (n 49, 122 cycles). All patients with
endometriosis had minimal (n 41, 100 cycles) or mild (n 17, 37 cycles) disease that had been laparoscopi-
cally removed within 7 months before the onset of treatment with COH and IUI.
Intervention(s): Controlled ovarian hyperstimulation using clomiphene citrate (23 cycles) or gonadotrophins (236
cycles) in combination with IUI.
Main Outcome Measure(s): Clinical PR per cycle and CLBR within four cycles of treatment with COH and IUI.
Result(s): The clinical PR per cycle was comparable in women with minimal or mild endometriosis (21% or
18.9%, respectively) and in women with unexplained infertility (20.5%). The CLBR within four cycles of COH
and IUI was also comparable in women with minimal endometriosis, mild endometriosis, and unexplained
infertility (70.2%, 68.2 %, 66.5%, respectively).
Conclusion(s): The data from our study suggest that COH and IUI shortly after laparoscopic excision of
endometriosis is as effective as COH and IUI in patients with unexplained subfertility. (Fertil Steril 2006;86:
566 71. 2006 by American Society for Reproductive Medicine.)
Key Words: Intrauterine insemination, controlled ovarian hyperstimulation, minimal to mild endometriosis,
unexplained infertility

Until today, the association between minimal to mild endo- fecundity rate (MFR) in women with minimal to mild endo-
metriosis (American Society for Reproductive Medicine metriosis than in women with unexplained infertility (3).
[ASRM] [1]) and subfertility has been controversial. In a Although more prospective studies are needed to confirm
recent prospective cohort study (2), the probability of con- and understand the mechanism of subfertility associated with
ceiving naturally and carrying a pregnancy beyond 20 weeks minimal to mild endometriosis, many investigators have now
was approximately 50% lower in women with surgically accepted this association and have tested the hypothesis that
untreated minimal to mild endometriosis (15.7%) than in endometriosis-related infertility can be treated by surgery or
women with unexplained infertility (23.6%). In addition, by nonspecific fertility-enhancing therapy, including con-
other retrospective studies have indicated a lower monthly trolled ovarian hyperstimulation (COH) and intrauterine
insemination (IUI).
Received September 13, 2005; revised and accepted January 23, 2006. The hypothesis that surgical removal of minimal to mild
Reprint requests: T. DHooghe, Leuven Unversity Centre, UZ Gasthuis-
berg, Herestraat 49, B-3000 Leuven, Belgium (FAX: 32-16-344368; endometriosis improves fecundity has been confirmed by
E-mail: thomas.dhooghe@uz.kuleuven.ac.be). some (4, 5) but not by all (6, 7) investigators in mostly

566 Fertility and Sterility Vol. 86, No. 3, September 2006 0015-0282/06/$32.00
Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2006.01.044
retrospective controlled studies. Recently, in a randomized, day 5 of the cycle for FSH, LH, E2, prolactin, TSH, and
controlled Canadian trial, the hypothesis was confirmed that androgens; midluteal endometrial biopsy or P analysis; hys-
laparoscopic resection or ablation of minimal to mild endo- teroscopy; and laparoscopy. Three patients had received 1
metriosis and associated adhesions enhances fecundity (8). treatment cycle with COH and IUI in another fertility center
In this study, the MFR and clinical pregnancy rate (PR) after before being fully investigated at LUFC.
36 weeks were twice as high after surgical removal of the
endometriosis and associated adhesions (4.7% and 30.7%, Patients with unexplained infertility were defined as cou-
respectively) than after diagnostic laparoscopy (2.4% and ples with infertility associated with normal results for all
17.7%, respectively). previously mentioned diagnostic investigations, with the ex-
ception of luteal insufficiency. Patients with minimal to mild
According to two prospective, randomized controlled tri- endometriosis were similar to patients with unexplained in-
als, nonspecific fertility enhancement using COH and IUI fertility, except for the presence of endometriotic lesions that
reportedly improves the monthly live-birth rate (11%) when were staged as minimal to mild endometriosis according to
compared with expectant management (2%) in women with the ASRM classification system (1). Patients with minimal
minimal to mild endometriosis (9, 10). However, not all endometriosis or mild endometriosis had a score of 15 or
women had received an ablation of the endometriotic lesions 6 15 points, respectively, as defined in the revised ASRM
before COH and IUI, and treatment with COH and IUI did classification (1).These endometriotic lesions were all ex-
not restore normal fertility in these women. cised or destroyed by laser surgery during the diagnostic
In contrast, recently randomized, controlled trials indi- laparoscopy. Histological confirmation of endometriosis
cated that the clinical PR after COH and IUI (11) or after (i.e., presence of endometrial glands and stroma) was con-
COH only (12) was significantly lower in women with firmed in all patients in 1 biopsy. Luteal insufficiency was
minimal to mild endometriosis (13% and 6.5%, respectively) present if the histological dating of the endometrial biopsy
than in women with unexplained infertility (32% and 15%, was 2 days out of phase (13) or if midluteal P concentra-
respectively). However, in both randomized trials, endome- tion was 10 ng/mL. Patients who conceived naturally after
triosis had not been treated surgically before the onset of laparoscopy and therefore did not participate in the program
treatment with COH and IUI. It is possible that treatment of COH and IUI were not followed up in our center; thus,
with COH and IUI after surgical removal of endometriosis their number is not known.
may result in a higher clinical PR after COH and IUI than Exclusion criteria included abnormal tuboovarian anat-
treatment with COH and IUI in women with surgically omy compromising tubal transport of gametes or embryos or
untreated endometriosis. fimbrial oocyte pickup function (dense adnexal and/or ovar-
Therefore, the aim of the present study was to test the ian adhesions due to pelvic inflammatory disease because of
hypothesis that the clinical pregnancy (live-birth) rate per previous pelvic surgery for the treatment of moderate or
cycle, and the cumulative pregnancy (live-birth) rate after severe endometriosis), abnormal ovulatory function (anovu-
COH and IUI are similar or higher in patients with previ- lation or oligoovulation due to polycystic ovary syndrome,
ously surgically removed minimal to mild endometriosis hyperprolactinemie, thyroid dysfunction, or luteinized un-
when compared with women with unexplained infertility. ruptured follicle syndrome), abnormal implantation due to
endometrial polyps or submucosal myomas, and male factor
infertility (semen analysis with 50% progressive motility
MATERIALS AND METHODS and/or 20 106 spermatozoa/mL and/or 10% normal
Patient Selection sperm morphology, according to previously reported guide-
All couples with unexplained infertility or minimal to mild lines (World Health Organization [WHO] [14, 15]).
endometriosis who participated in our program of COH and
IUI between 1994 and 2002 were identified from the data- In contrast with the male exclusion criteria, no hard cutoff
base of the Leuven University Fertility Center (LUFC). values were used for the female exclusion criteria because
Because the study was of a retrospective nature and all files they were based on the medical diagnosis for each patient
were searched electronically, it was not necessary to ask for immediately after the infertility investigation including hys-
Institutional Review Board (IRB) approval according to the teroscopy and laparoscopy. This diagnosis was based on
guidelines of the Commission for Medical Ethics in our generally accepted causes for female infertility (16).
hospital.
Using the previously mentioned inclusion and exclu-
In all patients, a complete workup, including surgery, was sion criteria, we identified 107 patients who were treated
performed within a period of 3 to 4 months after the initial during 259 cycles of COH with IUI. Because this was a
visit and before the waiting period of 6 to 12 months, retrospective cohort study evaluating pregnancy outcome
allowing spontaneous conception before the onset of treat- after fertility treatment, neither specific approval by the
ment with COH and IUI. The complete infertility investiga- IRB nor informed consent by the patients was needed. The
tion at LUFC included a semen analysis; basal body tem- detailed characteristics of patients and cycles are pre-
perature records; basal hormonal analysis between day 3 and sented in Table 1.

Fertility and Sterility 567


TABLE 1
Patient characteristics.

Minimal Mild Unexplained


Characteristic endometriosis endometriosis infertility

No. of patients 41 17 49
Age (y) 30.6 3.3 31.0 2.2 32.6 4.1
No. of insemination cycles 100 37 122
No. with primary subfertility (%) 82 (82) 33 (89) 72 (59)
No. with secundary subfertility (%) 18 (18) 4 (11) 50 (41)
No. with LI 16 4 20
Time interval between cycles (years) 0.191 0.15 0.159 0.042 0.229 0.277
Duration of subfertility (years) 2.726 1.95 2.654 0.796 2.278 1.007
Time interval laparoscopy/first IUI (years) 0.651 0.464 0.848 0.411 0.760 0.707
No. of CC cycles 20 1 2
Start-dose (mg) 63 22 50 1 100 0
No. of hMG cycles 80 36 120
Start-dose (N ampuls 75 IU per day) 10 10 11
No. of follicles 1.94 1.15 1.62 1.14 1.64 1.64
Endometrial thickness (mm) 8.7 1.59 8.69 1.94 8.86 1.97
Note: Values are means SD. CC clomiphere citrate; hMG human menopausal gonadotropin; LI luteal
insufficiency.
Werbrouck. COH and IUI are effective in endometriosis. Fertil Steril 2006.

Controlled Ovarian Hyperstimulation (MediCult, Copenhagen, Denmark). The samples were re-
The COH in preparation for IUI was performed either with suspended in IVF medium and subsequently incubated at
clomiphene citrate (CC), in a dose of 50 or 100 mg/d from 37C and 5% CO2. After 1 hour, the motility was evaluated
day 3 to day 7 of the menstrual cycle (n 23 cycles), or with and the sperm count was determined. The samples were
human menopausal gonadotropin (hMG) in a dose of 75 or centrifuged just before insemination, and the pellets were
150 IU IM/d (Humegon, Organon, Oss, the Netherlands or resuspended in a volume of 0.25 mL IVF medium.
Metrodin HP, Serono, Geneva, Switzerland) starting day 2 of
the cycle (n 236 cycles). Ovarian response was monitored
by ultrasound and blood sampling for E2, P, LH, and FSH. Intrauterine Insemination
Human chorionic gonadotropin in a dose of 5,000 or 10,000 The IUI was performed using an intrauterine catheter (Kre-
IU IM was administered when the leading follicle had mer Delafontaine; Prodimed, Neuilly-en-Thelle, France)
reached an average diameter of 1718 mm. An IUI was with a 1- or 2-mL syringe. The catheter was gently passed
performed approximately 38 hours later. When the women through the cervical canal, and the sperm suspension was
had two or more mature follicles (14 mm) at the time of expelled into the uterine cavity. Insemination volumes
hCG injection, selective follicle aspiration was offered to ranged from 0.52.0 mL. The women remained supine for 20
them, and usually one or two mature follicles were left intact minutes after IUI. A pregnancy test on blood was performed
after this procedure. 12 days after IUI. If the test was positive, the pregnancy was
confirmed by ultrasonography 3 weeks later. Pregnancies
were followed up for the occurrence of miscarriage, ectopic
Sperm Analysis and Preparation pregnancy, multiple pregnancy, and live birth.
The semen was collected by masturbation after 3 to 5 days of
sexual abstinence. A semen analysis was performed follow-
ing the WHO guidelines (14, 15). After liquefaction, sperm Statistical Analysis
samples were centrifuged over a discontinuous two-layer On the cycle level, pregnancy outcome was defined as clin-
density gradient (40%/80%) (Percoll, Amersham Pharmacia ical PR (presence of a gestational sac on ultrasound at 7
Biotech SA, Uppsala, Sweden or PureSperm, Nidacon Inter- weeks of amenorrhea), implantation rate (number of em-
national AB, Gteborg, Sweden) followed by one wash with bryos with positive fetal heart rate on ultrasound), and live-
HEPES-buffered Earles Balanced Salt Solution supple- birth rate per cycle of COH and IUI. Differences in these
mented with 0.3% human serum albumin (Sigma Chemical endpoints between groups were statistically evaluated by the
Co., St Louis, MO) and a second wash using IVF medium 2 test. The cumulative live-birth rate (CLBR) within four

568 Werbrouck et al. COH and IUI are effective in endometriosis Vol. 86, No. 3, September 2006
FIGURE 1 women with recently surgically treated minimal to mild
endometriosis and in women with unexplained infertility.
Classification of patients with minimal to mild These data are in contrast with earlier reports that demon-
endometriosis. strated a significantly lower PR after COH, with or without
IUI, in patients with surgically untreated minimal to mild
endometriosis when compared with those with unexplained
infertility (11, 12). Furthermore, in our study, the 20% PR
per cycle after COH and IUI in women with minimal to mild
endometriosis was higher than the 6% (11) or 13% (12) PRs
reported previously. The fact that there was no surgical
treatment of endometriosis before therapy with COH and IUI
in these studies (11, 12) could contribute to these lower PRs.
Collectively, these data suggest that surgical treatment be-
fore COH and IUI restores the clinical PR after COH and IUI
in women with minimal to mild endometriosis to the same
level as reached in women with unexplained infertility.
Werbrouck. COH and IUI are effective in endometriosis. Fertil Steril 2006.
To our knowledge, only one other investigation (17) has
evaluated the outcome of superovulation and IUI in patients
cycles of COH and IUI was analyzed using life table anal-
with treated minimal to mild endometriosis compared with
ysis, and subgroups were compared using Kaplan-Meier
those with unexplained infertility, but it concluded that
analysis.
women with endometriosis had lower PRs than those with
unexplained infertility. However, that study (17) cannot be
RESULTS compared with our study because the patients were older
General Patient Characteristics (average age, 37.4 years) than in our study and included not
General patient group characteristics (107 women, 259 cy- only patients with minimal or mild endometriosis but also a
cles) and the distribution of endometriosis scoring points (5) subgroup with mild adnexal disease, including distal tubal
among the patients with minimal to mild endometriosis are disease and adnexal adhesions, which are known to cause a
listed in Table 1 and Figure 1, respectively. The subgroups less favorable fertility prognosis (3). In our study, no statis-
with minimal endometriosis, mild endometriosis, and unex- tical difference was found between the cumulative live-birth
plained infertility were similar, except for the duration of rate of patients with minimal and mild endometriosis and
infertility, which was significantly lower in women with unexplained infertility (70.2%, 68.2%, and 66.5%, respec-
unexplained infertility compared with women with minimal tively). In another retrospective cohort study performed at
endometriosis (P.0053). None of the patients developed LUFC (18), a lower CLBR of 52.8% was found within four
ovarian hyperstimulation. cycles of COH and IUI in couples with normozoospermia. A
possible explanation for the discrepancies in results is the
Cycle Level difference in patient selection in the study. The previously
published trial (18) evaluated the CLBR in a group of
The average clinical PR per cycle was 20.4% and was
women whose male partners had normozoospermia, but the
similar in women with minimal endometriosis (21%), mild
group was heterogeneous with respect to the severity of
endometriosis (18.9%), and unexplained infertility (20.5%)
endometriosis, abnormal ovulatory function, abnormal tubo-
(Table 2). The results were also similar between groups for
ovarian anatomy, and other factors (18).
all the other clinical outcome data (Table 2).
A longer duration of infertility (Table 1) was observed in
Life Table Analysis patients with minimal endometriosis when compared with
couples with unexplained infertility. This may be explained
The cumulative live-birth rate within four cycles was similar
by our policy of expectant management (after full infertility
in patients with minimal endometriosis (70.2%), mild endo-
workup before surgery) during 6 to 12 months after surgical
metriosis (68.2%), and unexplained infertility (66.5 %) (Fig.
treatment of endometriosis to allow spontaneous conception;
2). A spontaneous pregnancy occurred during the time in-
it was demonstrated in a multicenter, Canadian randomized
terval between two treatment cycles with COH and IUI in six
controlled study that surgical removal of endometriotic le-
couples with minimal endometriosis (n 3), mild endome-
sions and endometriosis-related adhesions in women with
triosis (n 1), and unexplained infertility (n 2). These
minimal to mild endometriosis increased the spontaneous PR
pregnancies were not included in the life table analysis.
(8). This longer duration of infertility in the endometriosis
group when compared to the unexplained infertility group is
DISCUSSION unlikely to have influenced the results significantly. Indeed,
The results of our study confirm our hypothesis that, after any bias introduced would have favored a lower PR in the
COH and IUI, the clinical PR and CLBR are similar in endometriosis group than in the unexplained infertility group

Fertility and Sterility 569


TABLE 2
Clinical PR and live-birth rate per cycle after treatment with COH and IUI in women with
endometriosis and women with unexplained infertility.

Minimalmild Minimal Mild Unexplained


Characteristic Total endometriosis endometriosis endometriosis infertility

Patients 107 58 41 17 49
Cycles 259 137 100 37 122
No. of pregnancies/no. 20% 20% 21% 19% 20%
of cycles (53/259) (28/137) (21/100) (7/37) (25/122)
No. of implantations/ 23% 23% 25% 19% 23%
no. of cycles (60/259) (32/137) (25/100) (7/37) (28/122)
No. of multiple
pregnancies/no. of 11% 14% 19% 0 12%
clinical pregnancies (6/53) (4/28) (3/21) (0/7) (3/25)
Twins 0/7 3/25
Triplets 2/21 0/7 0/25
1/21a
No. of miscarriages/
no. of clinical 11% 11% 19% 0 12%
pregnancies (6/53) (3/28) (3/21) (0/7) (3/25)
Ectopic pregnancies/ 4% 4% 5% 0 4%
clinical pregnancies (2/53) (1/28) (1/21) (0/7) (1/25)
No. of live births/no. of 85% 85% 81% 100% 84%
pregnancies (45/53) (24/28) (17/21) (7/7) (21/25)
No. of multiple live
births/no. of live 11% 7% 9% 0 12%
births (5/45) (2/28) (2/21) (0/7) (3/25)
a
Single delivery was achieved after embryo reduction of a triplet pregnancy.
Werbrouck. COH and IUI are effective in endometriosis. Fertil Steril 2006.

because it is well known that the PR after fertility treatment tion rate of 44% was observed in patients with unexplained
is negatively correlated with the duration of infertility. infertility in a randomized prospective trial (11) because the
multiple pregnancy rate per cycle was much higher in that
In our study, the implantation rate per cycle was 23%; it
study (11) than in our study (11%). The multiple pregnancy
was similar in women with endometriosis and in women
rate in our study is comparable to the rate reported in our
with unexplained infertility. In contrast, a higher implanta-
previously published study (18), still higher than in our
current practice (19), but lower than what is generally re-
ported after COH with gonadotrophins and IUI (20 22).
FIGURE 2 This observation, together with the high cumulative live-
birth rate of nearly 70% within four cycles, suggest that
Cumulative birth rate.
COH and IUI should be a first line of treatment in patients
who have not become pregnant within 6 months to 1 year
after surgical treatment of minimal to mild endometriosis
and who have no other fertility reducing factors.

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