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No difference in cycle pregnancy rate and incumulative live-birth rate between women withsurgically treated minimal to mild endometriosis andwomen with unexplained infertility after controlledovarian hyperstimulation and intrauterineinseminationErika Werbrouck, M.D., Carl Spiessens, Ph.D., Christel Meuleman, M.D., andThomas D’Hooghe, 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 poorlyunderstood. The clinical pregnancy rate (PR) per cycle after controlled ovarian hyperstimulation (COH) with orwithout intrauterine insemination (IUI) is reportedly lower in women with surgically untreated minimal to mildendometriosis than in women with unexplained infertility. It is possible that prior laparoscopic removal ofendometriosis has a positive effect on the clinical PR after COH and IUI. Therefore, we tested the hypothesis thatafter COH and IUI the PR per cycle and the cumulative live-birth rate (CLBR) are equal or higher in women withrecently surgically treated minimal to mild endometriosis when compared with women with unexplainedinfertility.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 withendometriosis (n � 58, 137 cycles) and unexplained infertility (n � 49, 122 cycles). All patients withendometriosis 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 (236cycles) 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% or18.9%, respectively) and in women with unexplained infertility (20.5%). The CLBR within four cycles of COHand IUI was also comparable in women with minimal endometriosis, mild endometriosis, and unexplainedinfertility (70.2%, 68.2 %, 66.5%, respectively).Conclusion(s): The data from our study suggest that COH and IUI shortly after laparoscopic excision ofendometriosis 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

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ntil today, the association between minimal to mild endo-etriosis (American Society for Reproductive Medicine

ASRM] [1]) and subfertility has been controversial. In aecent prospective cohort study (2), the probability of con-eiving naturally and carrying a pregnancy beyond 20 weeksas approximately 50% lower in women with surgicallyntreated minimal to mild endometriosis (15.7%) than inomen with unexplained infertility (23.6%). In addition,ther retrospective studies have indicated a lower monthly

eceived September 13, 2005; revised and accepted January 23, 2006.eprint requests: T. D’Hooghe, Leuven Unversity Centre, UZ Gasthuis-berg, Herestraat 49, B-3000 Leuven, Belgium (FAX: 32-16-344368;

sE-mail: thomas.dhooghe@uz.kuleuven.ac.be).

566 Fertility and Sterility� Vol. 86, No. 3, September 2006Copyright ©2006 American Society for Reproductive Medicine,

ecundity rate (MFR) in women with minimal to mild endo-etriosis than in women with unexplained infertility (3).lthough more prospective studies are needed to confirm

nd understand the mechanism of subfertility associated withinimal to mild endometriosis, many investigators have now

ccepted this association and have tested the hypothesis thatndometriosis-related infertility can be treated by surgery ory nonspecific fertility-enhancing therapy, including con-rolled ovarian hyperstimulation (COH) and intrauterinensemination (IUI).

The hypothesis that surgical removal of minimal to mildndometriosis improves fecundity has been confirmed by

ome (4, 5) but not by all (6, 7) investigators in mostly

0015-0282/06/$32.00Published by Elsevier Inc. doi:10.1016/j.fertnstert.2006.01.044

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etrospective controlled studies. Recently, in a randomized,ontrolled Canadian trial, the hypothesis was confirmed thataparoscopic resection or ablation of minimal to mild endo-etriosis and associated adhesions enhances fecundity (8).

n this study, the MFR and clinical pregnancy rate (PR) after6 weeks were twice as high after surgical removal of thendometriosis and associated adhesions (4.7% and 30.7%,espectively) than after diagnostic laparoscopy (2.4% and7.7%, respectively).

According to two prospective, randomized controlled tri-ls, nonspecific fertility enhancement using COH and IUIeportedly improves the monthly live-birth rate (11%) whenompared with expectant management (2%) in women withinimal to mild endometriosis (9, 10). However, not allomen had received an ablation of the endometriotic lesionsefore COH and IUI, and treatment with COH and IUI didot restore normal fertility in these women.

In contrast, recently randomized, controlled trials indi-ated that the clinical PR after COH and IUI (11) or afterOH only (12) was significantly lower in women withinimal to mild endometriosis (13% and 6.5%, respectively)

han in women with unexplained infertility (32% and 15%,espectively). However, in both randomized trials, endome-riosis had not been treated surgically before the onset ofreatment with COH and IUI. It is possible that treatmentith COH and IUI after surgical removal of endometriosisay result in a higher clinical PR after COH and IUI than

reatment with COH and IUI in women with surgicallyntreated endometriosis.

Therefore, the aim of the present study was to test theypothesis that the clinical pregnancy (live-birth) rate perycle, and the cumulative pregnancy (live-birth) rate afterOH and IUI are similar or higher in patients with previ-usly surgically removed minimal to mild endometriosishen compared with women with unexplained infertility.

ATERIALS AND METHODSatient Selectionll couples with unexplained infertility or minimal to mild

ndometriosis who participated in our program of COH andUI between 1994 and 2002 were identified from the data-ase of the Leuven University Fertility Center (LUFC).ecause the study was of a retrospective nature and all filesere searched electronically, it was not necessary to ask for

nstitutional Review Board (IRB) approval according to theuidelines of the Commission for Medical Ethics in ourospital.

In all patients, a complete workup, including surgery, waserformed within a period of 3 to 4 months after the initialisit and before the waiting period of 6 to 12 months,llowing spontaneous conception before the onset of treat-ent with COH and IUI. The complete infertility investiga-

ion at LUFC included a semen analysis; basal body tem-

erature records; basal hormonal analysis between day 3 and s

ertility and Sterility�

ay 5 of the cycle for FSH, LH, E2, prolactin, TSH, andndrogens; midluteal endometrial biopsy or P analysis; hys-eroscopy; and laparoscopy. Three patients had received �1reatment cycle with COH and IUI in another fertility centerefore being fully investigated at LUFC.

Patients with unexplained infertility were defined as cou-les with infertility associated with normal results for allreviously mentioned diagnostic investigations, with the ex-eption of luteal insufficiency. Patients with minimal to mildndometriosis were similar to patients with unexplained in-ertility, except for the presence of endometriotic lesions thatere staged as minimal to mild endometriosis according to

he ASRM classification system (1). Patients with minimalndometriosis or mild endometriosis had a score of 1–5 or–15 points, respectively, as defined in the revised ASRMlassification (1).These endometriotic lesions were all ex-ised or destroyed by laser surgery during the diagnosticaparoscopy. Histological confirmation of endometriosisi.e., presence of endometrial glands and stroma) was con-rmed in all patients in �1 biopsy. Luteal insufficiency wasresent if the histological dating of the endometrial biopsyas �2 days out of phase (13) or if midluteal P concentra-

ion was �10 ng/mL. Patients who conceived naturally afteraparoscopy and therefore did not participate in the programf COH and IUI were not followed up in our center; thus,heir number is not known.

Exclusion criteria included abnormal tuboovarian anat-my compromising tubal transport of gametes or embryos ormbrial oocyte pickup function (dense adnexal and/or ovar-

an adhesions due to pelvic inflammatory disease because ofrevious pelvic surgery for the treatment of moderate orevere endometriosis), abnormal ovulatory function (anovu-ation or oligoovulation due to polycystic ovary syndrome,yperprolactinemie, thyroid dysfunction, or luteinized un-uptured follicle syndrome), abnormal implantation due tondometrial polyps or submucosal myomas, and male factornfertility (semen analysis with �50% progressive motilitynd/or �20 � 106 spermatozoa/mL and/or �10% normalperm morphology, according to previously reported guide-ines (World Health Organization [WHO] [14, 15]).

In contrast with the male exclusion criteria, no hard cutoffalues were used for the female exclusion criteria becausehey were based on the medical diagnosis for each patientmmediately after the infertility investigation including hys-eroscopy and laparoscopy. This diagnosis was based onenerally accepted causes for female infertility (16).

Using the previously mentioned inclusion and exclu-ion criteria, we identified 107 patients who were treateduring 259 cycles of COH with IUI. Because this was aetrospective cohort study evaluating pregnancy outcomefter fertility treatment, neither specific approval by theRB nor informed consent by the patients was needed. Theetailed characteristics of patients and cycles are pre-

ented in Table 1.

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ontrolled Ovarian Hyperstimulationhe COH in preparation for IUI was performed either withlomiphene citrate (CC), in a dose of 50 or 100 mg/d fromay 3 to day 7 of the menstrual cycle (n � 23 cycles), or withuman menopausal gonadotropin (hMG) in a dose of 75 or50 IU IM/d (Humegon, Organon, Oss, the Netherlands oretrodin HP, Serono, Geneva, Switzerland) starting day 2 of

he cycle (n � 236 cycles). Ovarian response was monitoredy ultrasound and blood sampling for E2, P, LH, and FSH.uman chorionic gonadotropin in a dose of 5,000 or 10,000

U IM was administered when the leading follicle hadeached an average diameter of 17–18 mm. An IUI waserformed approximately 38 hours later. When the womenad two or more mature follicles (�14 mm) at the time ofCG injection, selective follicle aspiration was offered tohem, and usually one or two mature follicles were left intactfter this procedure.

perm Analysis and Preparationhe semen was collected by masturbation after 3 to 5 days ofexual abstinence. A semen analysis was performed follow-ng the WHO guidelines (14, 15). After liquefaction, spermamples were centrifuged over a discontinuous two-layerensity gradient (40%/80%) (Percoll, Amersham Pharmaciaiotech SA, Uppsala, Sweden or PureSperm, Nidacon Inter-ational AB, Göteborg, Sweden) followed by one wash withEPES-buffered Earle’s Balanced Salt Solution supple-ented with 0.3% human serum albumin (Sigma Chemical

TABLE 1Patient characteristics.

Characteristic end

No. of patientsAge (y) 30No. of insemination cyclesNo. with primary subfertility (%)No. with secundary subfertility (%)No. with LITime interval between cycles (years) 0.1Duration of subfertility (years) 2.7Time interval laparoscopy/first IUI (years) 0.6No. of CC cycles

Start-dose (mg)No. of hMG cycles

Start-dose (N ampuls 75 IU per day)No. of follicles 1.Endometrial thickness (mm) 8Note: Values are means � SD. CC � clomiphere citra

insufficiency.

Werbrouck. COH and IUI are effective in endometriosis. Fertil Steril 2006.

o., St Louis, MO) and a second wash using IVF medium �

568 Werbrouck et al. COH and IUI are effective in endomet

MediCult, Copenhagen, Denmark). The samples were re-uspended in IVF medium and subsequently incubated at7°C and 5% CO2. After 1 hour, the motility was evaluatednd the sperm count was determined. The samples wereentrifuged just before insemination, and the pellets wereesuspended in a volume of 0.25 mL IVF medium.

ntrauterine Inseminationhe IUI was performed using an intrauterine catheter (Kre-er Delafontaine; Prodimed, Neuilly-en-Thelle, France)ith a 1- or 2-mL syringe. The catheter was gently passed

hrough the cervical canal, and the sperm suspension wasxpelled into the uterine cavity. Insemination volumesanged from 0.5–2.0 mL. The women remained supine for 20inutes after IUI. A pregnancy test on blood was performed

2 days after IUI. If the test was positive, the pregnancy wasonfirmed by ultrasonography 3 weeks later. Pregnanciesere followed up for the occurrence of miscarriage, ectopicregnancy, multiple pregnancy, and live birth.

tatistical Analysisn the cycle level, pregnancy outcome was defined as clin-

cal PR (presence of a gestational sac on ultrasound at 7eeks of amenorrhea), implantation rate (number of em-ryos with positive fetal heart rate on ultrasound), and live-irth rate per cycle of COH and IUI. Differences in thesendpoints between groups were statistically evaluated by the

imaltriosis

Mildendometriosis

Unexplainedinfertility

1 17 493.3 31.0 � 2.2 32.6 � 4.1

0 37 122(82) 33 (89) 72 (59)(18) 4 (11) 50 (41)6 4 20

0.15 0.159 � 0.042 0.229 � 0.2771.95 2.654 � 0.796 2.278 � 1.0070.464 0.848 � 0.411 0.760 � 0.707

0 1 222 50 � 1 100 � 0

0 36 1200 1 � 0 1 � 11.15 1.62 � 1.14 1.64 � 1.641.59 8.69 � 1.94 8.86 � 1.97

hMG � human menopausal gonadotropin; LI � luteal

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ycles of COH and IUI was analyzed using life table anal-sis, and subgroups were compared using Kaplan-Meiernalysis.

ESULTSeneral Patient Characteristicseneral patient group characteristics (107 women, 259 cy-

les) and the distribution of endometriosis scoring points (5)mong the patients with minimal to mild endometriosis areisted in Table 1 and Figure 1, respectively. The subgroupsith minimal endometriosis, mild endometriosis, and unex-lained infertility were similar, except for the duration ofnfertility, which was significantly lower in women withnexplained infertility compared with women with minimalndometriosis (P�.0053). None of the patients developedvarian hyperstimulation.

ycle Levelhe average clinical PR per cycle was 20.4% and wasimilar in women with minimal endometriosis (21%), mildndometriosis (18.9%), and unexplained infertility (20.5%)Table 2). The results were also similar between groups forll the other clinical outcome data (Table 2).

ife Table Analysishe cumulative live-birth rate within four cycles was similar

n patients with minimal endometriosis (70.2%), mild endo-etriosis (68.2%), and unexplained infertility (66.5 %) (Fig.

). A spontaneous pregnancy occurred during the time in-erval between two treatment cycles with COH and IUI in sixouples with minimal endometriosis (n � 3), mild endome-riosis (n � 1), and unexplained infertility (n � 2). Theseregnancies were not included in the life table analysis.

ISCUSSIONhe results of our study confirm our hypothesis that, after

FIGURE 1

Classification of patients with minimal to mildendometriosis.

Werbrouck. COH and IUI are effective in endometriosis. Fertil Steril 2006.

OH and IUI, the clinical PR and CLBR are similar in e

ertility and Sterility�

omen with recently surgically treated minimal to mildndometriosis and in women with unexplained infertility.hese data are in contrast with earlier reports that demon-trated a significantly lower PR after COH, with or withoutUI, in patients with surgically untreated minimal to mildndometriosis when compared with those with unexplainednfertility (11, 12). Furthermore, in our study, the 20% PRer cycle after COH and IUI in women with minimal to mildndometriosis was higher than the 6% (11) or 13% (12) PRseported previously. The fact that there was no surgicalreatment of endometriosis before therapy with COH and IUIn these studies (11, 12) could contribute to these lower PRs.ollectively, these data suggest that surgical treatment be-

ore COH and IUI restores the clinical PR after COH and IUIn women with minimal to mild endometriosis to the sameevel as reached in women with unexplained infertility.

To our knowledge, only one other investigation (17) hasvaluated the outcome of superovulation and IUI in patientsith treated minimal to mild endometriosis compared with

hose with unexplained infertility, but it concluded thatomen with endometriosis had lower PRs than those withnexplained infertility. However, that study (17) cannot beompared with our study because the patients were olderaverage age, 37.4 years) than in our study and included notnly patients with minimal or mild endometriosis but also aubgroup with mild adnexal disease, including distal tubalisease and adnexal adhesions, which are known to cause aess favorable fertility prognosis (3). In our study, no statis-ical difference was found between the cumulative live-birthate of patients with minimal and mild endometriosis andnexplained infertility (70.2%, 68.2%, and 66.5%, respec-ively). In another retrospective cohort study performed atUFC (18), a lower CLBR of 52.8% was found within fourycles of COH and IUI in couples with normozoospermia. Aossible explanation for the discrepancies in results is theifference in patient selection in the study. The previouslyublished trial (18) evaluated the CLBR in a group ofomen whose male partners had normozoospermia, but theroup was heterogeneous with respect to the severity ofndometriosis, abnormal ovulatory function, abnormal tubo-varian anatomy, and other factors (18).

A longer duration of infertility (Table 1) was observed inatients with minimal endometriosis when compared withouples with unexplained infertility. This may be explainedy our policy of expectant management (after full infertilityorkup before surgery) during 6 to 12 months after surgical

reatment of endometriosis to allow spontaneous conception;t was demonstrated in a multicenter, Canadian randomizedontrolled study that surgical removal of endometriotic le-ions and endometriosis-related adhesions in women withinimal to mild endometriosis increased the spontaneous PR

8). This longer duration of infertility in the endometriosisroup when compared to the unexplained infertility group isnlikely to have influenced the results significantly. Indeed,ny bias introduced would have favored a lower PR in the

ndometriosis group than in the unexplained infertility group

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ecause it is well known that the PR after fertility treatments negatively correlated with the duration of infertility.

In our study, the implantation rate per cycle was 23%; itas similar in women with endometriosis and in womenith unexplained infertility. In contrast, a higher implanta-

FIGURE 2

Cumulative birth rate.

TABLE 2Clinical PR and live-birth rate per cycle after treaendometriosis and women with unexplained infe

Characteristic TotalMinimal–mildendometrios

Patients 107 58Cycles 259 137No. of pregnancies/no. 20% 20%

of cycles (53/259) (28/137)No. of implantations/ 23% 23%

no. of cycles (60/259) (32/137)No. of multiple

pregnancies/no. of 11% 14%clinical pregnancies (6/53) (4/28)

TwinsTriplets

No. of miscarriages/no. of clinical 11% 11%pregnancies (6/53) (3/28)

Ectopic pregnancies/ 4% 4%clinical pregnancies (2/53) (1/28)

No. of live births/no. of 85% 85%pregnancies (45/53) (24/28)

No. of multiple livebirths/no. of live 11% 7%births (5/45) (2/28)

a Single delivery was achieved after embryo reduction of

Werbrouck. COH and IUI are effective in endometriosis. Fertil Steril 2006.

Werbrouck. COH and IUI are effective in endometriosis. Fertil Steril 2006.

570 Werbrouck et al. COH and IUI are effective in endomet

ion rate of 44% was observed in patients with unexplainednfertility in a randomized prospective trial (11) because theultiple pregnancy rate per cycle was much higher in that

tudy (11) than in our study (11%). The multiple pregnancyate in our study is comparable to the rate reported in ourreviously published study (18), still higher than in oururrent practice (19), but lower than what is generally re-orted after COH with gonadotrophins and IUI (20–22).his observation, together with the high cumulative live-irth rate of nearly 70% within four cycles, suggest thatOH and IUI should be a first line of treatment in patientsho have not become pregnant within 6 months to 1 year

fter surgical treatment of minimal to mild endometriosisnd who have no other fertility reducing factors.

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(1/21) (0/7) (1/25)81% 100% 84%

(17/21) (7/7) (21/25)

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