Reproductive BioMedicine Online (2014) 28, 590–598

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ARTICLE

Efficacy and safety of intrauterineinsemination in patientswith moderate-to-severe endometriosis

http://dx.doi.org/10.1016/j.rbmo.2014.01.0051472-6483/ª 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Lisette EE van der Houwen a,*, Anneke MF Schreurs a, Roel Schats a,Martijn W Heymans b, Cornelis B Lambalk a, Peter GA Hompes a,Velja Mijatovic a

a Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, VU University Medical Center,PO Box 7057, 1007MB Amsterdam, The Netherlands; b Department of Epidemiology and Biostatistics, VU UniversityMedical Center, PO Box 7057, 1007MB Amsterdam, The Netherlands* Corresponding author. E-mail address: l.vanderhouwen@vumc.nl (LEE van der Houwen).

Abstract Performing intr

Lisette van der Houwen is a PhD researcher in the Endometriosis Center, Division of Reproductive Medicine,Department of Obstetrics and Gynaecology, VU University Medical Centre in Amsterdam, the Netherlands. Herthesis is focusing on fertility in endometriosis patients. She will begin her gynaecology and obstetricsspecialization in 2014.

auterine insemination (IUI) in moderate-to-severe endometriosis patients is not implemented in interna-tional guidelines, as only limited data exist on treatment efficacy and safety. This retrospective study examined the efficacy andsafety of two IUI treatment strategies performed between January 2007 and July 2012 in moderate-to-severe endometriosispatients. Eight (40.0%) versus seven (15.6%) ongoing pregnancies were accomplished in patients undergoing IUI with ovarianstimulation (n = 20, 61 cycles) versus IUI without ovarian stimulation in the first three cycles followed by IUI with ovarian stimulation(IUI with natural/ovarian stimulation; n = 45, 184 cycles). Preceding long-term pituitary down-regulation tended to result in a higherongoing pregnancy rate (adjusted HR 1.8) and a higher chance of endometriosis recurrence (adjusted HR 2.3). Eight (40.0%) versus16 (35.6%) recurrences of endometriosis complaints were reported in patients receiving IUI with ovarian stimulation versus IUI withnatural/ovarian stimulation. IUI might be a valuable treatment in moderate-to-severe endometriosis patients and IUI with ovarianstimulation should be offered over IUI with natural/ovarian stimulation. Preceding long-term pituitary down-regulation mightpositively influence the ongoing pregnancy rate and can be considered. Whether this treatment strategy can be structurally offered

prior to IVF must be investigated in a randomized controlled trial. RBMOnline

ª 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: complication, endometriosis, GnRH agonist, intrauterine insemination, ongoing pregnancy rate, recurrence

IUI in moderate-to-severe endometriosis patients 591

Introduction

Fecundity is commonly impaired in patients with endometri-osis (Collins et al., 1995). Since its cause is still not unrav-elled, management of infertility in endometriosis patientsis widely debated in literature (de Ziegler et al., 2010).

In subfertile patients with moderate-to-severe endome-triosis, the anatomy of the pelvic cavity can be disturbedresulting in impaired ovum retrieval or diminished patencyof the Fallopian tubes, making IVF the first choice of fertilitytreatment (Kennedy et al., 2005). However, in patients withsurgically treated endometriosis in which normal function-ing ovum retrieval and patency of at least one Fallopiantube has been established, intrauterine insemination (IUI)can be provided prior to IVF.

According to the guidelines of both the European Societyof Human Reproduction and Endocrinology (Kennedy et al.,2005) and American Society for Reproductive Medicine(ASRM; Practice Committee of the American Society forReproductive Medicine, 2012), IUI is only recommended insubfertile women with minimal-to-mild endometriosis.Recommendations with regard to performing IUI inmoderate-to-severe endometriosis patients are notformulated, due to the absence of sufficient data (Macerand Taylor, 2012; Ozkan et al., 2008). Observational,noncomparative studies showed pregnancy rates of 4–32%per cycle (Dickey et al., 1991, 1992; Dodson and Haney, 1991;Goker et al., 2002; Lodhi et al., 2004; Tay et al., 2007;Vollenhovenet al., 1996; Yovich andMatson, 1988). In addition,two randomized controlled trials investigated the effect oflong-term pituitary down-regulation with a gonadotro-phin-releasing hormone (GnRH) agonist prior to IUI in moder-ate-to-severe endometriosis patients and showed increasedclinical pregnancy rates (Kim et al., 1996; Rickes et al., 2002).

Treatment decision making, including aspects of efficacyand safety, is hard to make due to the lack of sufficientdata. Safety of IUI in moderate-to-severe endometriosispatients is reported in only one retrospective study(D’Hooghe et al., 2006), showing a significantly higher riskof developing endometriosis recurrence after IUI comparedwith IVF treatment. This observation might be explained bya monthly exposure to ovulation and retrograde menstrua-tion in women undergoing IUI. D’Hooghe et al. (2006) postu-lated that the exposure to retrograde menstruation mighteven be increased by ovarian hyperstimulation, negativelyaffecting the cumulative endometriosis recurrence rate(CERR). Comparison of IUI with and without ovarian stimula-tion could further clarify this, but, as far as known, it hasnot been investigated. Besides this, a possible favourablerole of long-term pituitary down-regulation with a GnRHagonist in this regard has not been investigated.

Therefore, this study investigated the efficacy and safety ofan IUI treatment strategy, comparing IUI with and without ovar-ian stimulation in patients with moderate-to-severe endometri-osis and the effect on efficacy and safety of long-term pituitarydown-regulation with a GnRH agonist prior to IUI.

Materials and methods

This study retrospectively analysed patients with surgicallyconfirmed moderate-to-severe endometriosis (ASRM stages

III and IV) with at least one patent Fallopian tube receivingIUI treatment. Patients were selected from the electronicpatient database of the IVF centre of the VU University Med-ical Centre, Amsterdam, The Netherlands. Only patientsundergoing their first IUI treatment between January 2007and July 2012 were selected. Up to a maximum of sixsubsequent IUI treatment cycles were included in the anal-ysis. IUI treatment cycles with donor spermatozoa wereexcluded. The database was validated and completed bytwo researchers (AS, LH). This study was formally exemptedfrom ethical approval granted by the Institutional ReviewBoard (reference no. 2013/1).

This fertility clinic is reluctant to perform IUI directlycombined with ovarian stimulation due to the fear thatovarian hyperstimulation may lead to an increase in orrecurrence of endometriosis complaints and also to preventmultiple pregnancies. Therefore, IUI treatments are usuallyperformed as follows: IUI without ovarian stimulation in thefirst three cycles followed by IUI with ovarian stimulation(IUI with natural/ovarian stimulation). Data are presentedfor the total study population and the two treatment strat-egies (IUI with ovarian stimulation versus IUI with natural/ovarian stimulation). The additional effect of long-termpituitary down-regulation with a GnRH agonist is evaluatedfor the total population as well as for both groups.

Long-term pituitary down-regulation with a GnRH agonist(Leuprolide 3.75 mg depot injections, Lucrin; Abbott, USA)was administered prior to IUI treatment in a subgroup ofpatients. Ovarian stimulation was accomplished by subcuta-neous administration of highly purified human menopausalgonadotrophin (Menopur; Ferring, Denmark) or recombinantFSH (Gonal-F; Merck Serono, Germany; or Puregon; MSD,USA) from cycle day 3, starting with 75 IU in the first IUItreatment cycle. In case of monofollicularity, the dosagewas increased in the next treatment cycle by 37.5 IU percycle. Follicle growth was measured by transvaginal ultra-sound. When a follicle reached the size of �17 mm,10,000 IU human chorionic gonadotrophin (Pregnyl; Orga-non, the Netherlands) was administered subcutaneouslyand 42 h later, insemination was performed. According tothis centre’s protocol, after three IUI treatment cycles, aclinical evaluation was performed and, if a pregnancy didnot occur, a diagnostic or therapeutic laparoscopy wasperformed.

Semen was prepared by this centre’s protocol. In sum-mary, after liquefaction, semen was centrifuged through aPureSperm 70% gradient (Nidacon, Molndal, Sweden)HEPES-human tubal fluid (HTF; Lonza, Basel, Switserland)medium supplemented with human serum albumin (HSA;Albuman, Sanquin, Amsterdam, The Netherlands) at 710gfor 15 min. The pellet was washed with HTF/HSA mediumat 270g for 7 min. After removal of the supernatant, a max-imum of 50 · 106 spermatozoa were resuspended with0.5–5 ml HTF/HSA medium and incubated at room temper-ature (5% CO2). Prior to insemination, one last wash stepwas performed (200g for 7 min). The pellet was concen-trated to a volume of 250 ll. Insemination was performedwith a total motile sperm count of 0.5 · 106 up to a maxi-mum of 50 · 106 spermatozoa.

The primary outcome measure was the ongoing preg-nancy rate (OPR), which was calculated as the total numberof ongoing pregnancies divided by the total number of

592 LEE van der Houwen et al.

patients included as well as a cumulative OPR calculated bylife-table analysis. Secondary outcomes included total num-ber of complications and recurrences as well as the CERRand time to pregnancy including all ongoing pregnanciesafter treatment (including IUI and IVF) and natural concep-tion up to 1 year after start of IUI treatment. An ongoingpregnancy was defined as a vital intrauterine pregnancyvisualized by transvaginal ultrasound at 12 weeks of gesta-tion. Ovarian hyperstimulation syndrome, infection or hos-pital admittance occurring within 1 month after treatmentwere defined as complications. Recurrence of or increasein a patient’s complaint within 12 months after the last IUItreatment suspected to be based on endometriosis wasstated as endometriosis recurrence.

Baseline measurements included female age, body massindex, type of infertility (primary/secondary), duration ofinfertility, duration since last therapeutic procedure andthe presence of deep infiltrating endometriosis. The pres-ence of deep infiltrating endometriosis was based on MRIfindings and included rectovaginal or colorectal endometri-osis or endometriosis of the urinary tract.

Statistical analysis

Statistical analysis was performed using SPSS version 20.0(IBM SPSS, USA). Data were expressed as mean ± standarddeviation (SD) or n (%). Nonparametric data were expressedas medians with range. Differences between the two groupswere evaluated using the Students’ t-test (continuous data)or Mann–Whitney U-test in case of nonparametric data andchi-squared or Fishers’ exact tests for categorical data. AP-value < 0.05 was considered significant.

Life-table analysis was used to calculate the cumulativeongoing pregnancy rate and CERR. Both the number ofcycles and duration in the months since first IUI treatmentcycle were used as time parameters. The date of entrywas the date of the first IUI treatment cycle. Up to a max-imum of six subsequent cycles were included. Patients werefollowed up to 1 year after finishing their last IUI treatment

Patients in electronic patient data file undergoing IUI

(n = 1585)

Patients in electronic patient database withthe notification of ‘endometriosis’

(n = 380)

E‘e

Patients with surgically confirmed endometriosis ASRM III / IV prior to start

of IUI treatment(n = 65)

E

Patients receiving three times IUI without ovarian stimulation followed by up to

three times IUI with ovarian stimulation (n = 45)

P

Figure 1 Flowch

cycle. For measuring the CERR, the endpoint of the studywas 12 months after the last IUI treatment cycle, the dateof endometriosis recurrence, the date of positive pregnancytest (in ongoing pregnant patients) or the date of patient’slast visit (in case of loss to follow up). To plot the time topregnancy, the endpoint was stated at 12 months after startof IUI treatment. The log rank test was used to compareboth groups in cumulative ongoing pregnancy rate and theCERR. Cox regression analysis was performed to estimatehazard ratios (HR) for treatment strategy and long-termpituitary down-regulation on ongoing pregnancy and endo-metriosis recurrence rates.

Results

This retrospective study selected 65 patients receiving 245IUI treatment cycles from the electronic databasewho met the inclusion criteria (Figure 1). Forty-fivepatients (69.2%) were assigned to the combined IUI withnatural/ovarian stimulation treatment strategy. In thisgroup, 125 natural and 59 stimulated IUI treatment cycleswere performed. The remaining 20 patients (30.8%) wereassigned immediately to IUI with ovarian stimulation andreceived 61 stimulated IUI treatment cycles.

At baseline, all patient characteristics were not statisti-cally different between the treatment groups (Table 1). ForIUI with natural/ovarian stimulation versus IUI with ovarianstimulation, 31 and 42 patients were surgically treatedwithin 6 and 12 months, respectively, before commencingIUI treatment (not significant).

Treatment outcomes, recurrences and complications arepresented in Table 2. Significantly fewer treatment cycleswere performed in patients assigned to IUI with ovarianstimulation (P = 0.045). In 13 (28.9%) patients assigned toIUI with natural/ovarian stimulation, completing six IUItreatment cycles was considered to be ineffective: IVFwas offered in 10 (22.2%) patients and treatment was com-pletely discontinued in three (6.7%). In six (30.0%) patients

xclusion of patients without the notification of ndometriosis’ in the electronic patient database

Excluded: (n = 1205)

xclusion of patients without surgically confirmed endometriosis ASRM stage III/IV

Excluded: (n = 315)

atients receiving IUI with ovarian stimulation up to a maximum

of six cycles (n = 20)

art of patients.

Table 1 Patient characteristics.

x Total (n = 65) IUI with natural/ovarianstimulation (n = 45)

IUI with ovarianstimulation (n = 20)

Age (years) 33.2 ± 3.8 33.4 ± 3.3 32.8 ± 4.7BMI (kg/m2) 23.4 ± 3.6 23.4 ± 3.5 23.4 ± 3.8

x xxxxASRM grade xxxIII 26/65 (40.0) 17/45 (37.8) 9/20 (45.0)IV 39/65 (60.0) 28/45 (62.2) 11/20 (55.0)

x xxxxSubfertility (months) 26 (3–56) 27 (3–56) 22 (6–51)

x xxxxType of subfertility xxxPrimary 43/65 (66.2) 30/45 (66.7) 13/20 (65.0)Secondary 22/65 (33.8) 15/45 (33.3) 7/20 (35.0)

x xxxxDeep infiltrating endometriosisa 15/20 (75.0) 8/12 (66.7) 7/8 (87.5)

Values are mean ± SD or n/total (%). Differences were tested using the Students’ t-test or chi-squared test unless otherwise stated. Therewere no statistically significant differences between the groups.ASRM = American Society for Reproductive Medicine; BMI = body mass index.aFisher’s exact test.

Table 2 Treatment outcomes, recurrences and complications.

x Total (n = 65) IUI with natural/ovarianstimulation (n = 45)

IUI with ovarianstimulation (n = 20)

P-value

Lucrin prior to first IUI 31/65 (47.7) 20/45 (44.4) 11/20 (55.0) NSNo. of treatment cycles per patient 3 (1–6) 4 (1–6) 3 (1–6) 0.045Ongoing pregnancy 15/65 (23.1) 7/45 (15.6) 8/20 (40.0)a NSb

Live birth 12/65 (18.5) 6/45 (13.3)c 6/20 (30.0)d NSb

Recurrence 24/65 (36.9) 16/45 (35.6) 8/20 (40.0) NSComplication 2/65 (3.1) 1/45 (2.2) 1/20 (5.0) NSb

Values are n/total (%). Differences were tested using the Students’ t-test or chi-squared test unless otherwise stated.NS = not statistically significant.aOne pregnancy concerned a twin pregnancy.bFisher’s exact test.cOne lost to follow up.dTwo preterm deliveries (one single and one twin pregnancy).

IUI in moderate-to-severe endometriosis patients 593

assigned to IUI with ovarian stimulation, completing six IUItreatment cycles was considered to be ineffective. In allof them, IVF was offered. Four patients discontinued IUItreatment for personal reasons (IUI with natural/ovarianstimulation: n = 2 (4.4%); IUI with ovarian stimulation:n = 2 (10.0%)).

Primary outcome

In total, 15 ongoing pregnancies (OPR 6.1% per cycle and23.1% per patient) were accomplished after IUI treatment:seven (OPR 3.8% per cycle and 15.6% per patient) for IUIwith natural/ovarian stimulation and eight (OPR 13.1% percycle and 40.0% per patient) for IUI with ovarian stimula-tion, respectively (P = 0.014 per cycle).

The cumulative ongoing pregnancy rate after six cycles inthe total population is shown in Figure 2A. Significantly

higher cumulative ongoing pregnancy rates were found inpatients assigned to IUI with ovarian stimulation (45.8%)compared with patients assigned to IUI with natural/ovarianstimulation (19.5%, P = 0.016; Figure 2B). Univariate Coxregression analysis showed a HR of 3.2 (95% CI 1.1–8.8,P = 0.027), reflecting a significantly higher chance of ongo-ing pregnancy in patients receiving IUI with ovarian stimula-tion. Multivariate Cox regression analysis showed thatlong-term pituitary down-regulation with a GnRH agonistcould not be identified as a confounding variable in thisregard. In patients pretreated with long-term pituitarydown-regulation (n = 31), the cumulative ongoing pregnancyrate was 35.0% compared with 21.3% in women (n = 34) whodirectly started with IUI treatment (Figure 2C). UnivariateCox regression analysis showed a HR of 2.0 (95% CI 0.7–5.5).Adjusted for treatment strategy (IUI with natural/ovarianstimulation or IUI with ovarian stimulation), the HR was1.8 (95% CI 0.6–5.1).

Figure 2 Kaplan–Meier curves of cumulative ongoing pregnancy rates according to IUI treatment cycle for the total population(A), IUI with natural/ovarian stimulation versus IUI with ovarian stimulation (B, P = 0.016) and with/without GnRH-agonist treatment(C).

594 LEE van der Houwen et al.

Secondary outcomes

The time to pregnancy at 1 year after start of IUI treatmentis presented in Figure 3. The cumulative ongoing pregnancyrate, including only ongoing pregnancies accomplished byIUI treatment, was significantly higher in the patientsassigned to IUI with ovarian stimulation (41.3%) comparedwith IUI with natural/ovarian stimulation (16.8%, P = 0.014;Figure 3A). In patients assigned to IUI with natural/ovarianstimulation, two naturally conceived pregnancies wereachieved up to 1 year after start of IUI treatment. Sixteen(35.6%) patients underwent at least one IVF attempt, result-ing in four ongoing pregnancies. With IUI with ovarian stim-ulation, no naturally conceived pregnancies were achieved,and up to 1 year after start of IUI treatment, seven (35.0%)patients underwent at least one IVF attempt. Three ongoingpregnancies after IVF were described. The cumulative ongo-ing pregnancy rate 1 year after start of IUI treatment,including naturally conceived and IVF, ongoing pregnancieswas significantly higher in patients assigned to IUI with

ovarian stimulation (58.9%) compared to IUI withnatural/ovarian stimulation (31.8%, P = 0.008; Figure 3B).

As shown in Table 2, 24 patients developed a recurrenceof endometriosis complaints. Two (3.1%) patients reportedrecurrence of their endometriosis complaints, but did notreceive an intervention. Five (7.7%) patients started on oralcontraception, eight (12.3%) patients started with a GnRH

agonist and discontinued IUI treatment and four (6.2%)patients underwent surgery for their endometriosis. Eleven

patients had a laparoscopy after three IUI treatment cycles.Cystectomy of endometrioma or extensive adhesiolysis wasperformed in five (7.7%) and those were considered asrecurrences of endometriosis.

The CERR was 60.4% for the total population (Figure 4A).Twelve months after start of first IUI treatment, the CERRwas 36.5% for IUI with natural/ovarian stimulation versus72.3% for IUI with ovarian stimulation (Figure 4B). Univari-ate Cox regression analysis showed a HR of 2.6 (95% CI1.1–6.3, P = 0.03), reflecting a significantly higher chanceof endometriosis recurrence in patients receiving IUI with

Figure 3 Kaplan–Meier curves of cumulative ongoing pregnancy rates according to time after start of treatment for IUI withnatural/ovarian stimulation versus IUI with ovarian stimulation for only IUI-conceived ongoing pregnancies (A, P = 0.014) andincluding naturally and IVF-conceived ongoing pregnancies (B, P = 0.008).

IUI in moderate-to-severe endometriosis patients 595

ovarian stimulation versus patients receiving IUI withnatural/ovarian stimulation. Adjusted for the confounderlong-term pituitary down-regulation with a GnRH agonist,the HR became 2.2 (95% CI 0.9–5.3).

A significantly higher 12-month CERR was found inpatients who were treated with a GnRH agonist prior tothe first IUI treatment cycle (n = 31) versus patients withouta GnRH pretreatment ((n = 34; 68.0% versus 26.6%;Figure 4C). Univariate Cox regression analysis showed aHR of 2.6 (95% CI 1.1–6.0, P = 0.024), reflecting a signifi-cantly higher chance of endometriosis recurrence inpatients treated with long-term pituitary down/regulationwith a GnRH agonist. Adjusted for the confounder treat-ment strategy, the HR became 2.3 (95% CI 0.98–5.3).

Two complications were reported (3.1%): one patienthad to be admitted to the hospital for an infected endome-triosis cyst and another patient had to be admitted becauseof an infection of unknown origin (Table 2).

Discussion

This study demonstrates that IUI treatment in the total pop-ulation of moderate-to-severe endometriosis patientsresults in a cumulative ongoing pregnancy rate calculatedby life-table analysis of 28% after six subsequent IUI treat-ment cycles with low complication and modest cumulativeendometriosis recurrence rates. A significantly higher cumu-lative ongoing pregnancy rate calculated by life-table anal-ysis is found in patients receiving IUI with ovarianstimulation versus IUI with natural/ovarian stimulation.Although, as far as is known, this is the first study comparingboth IUI treatment strategies in moderate-to-severe endo-metriosis patients, this observation was not contrary toexpectations, since similar results have been reported forminimal-to-mild endometriosis (Nulsen et al., 1993) andunexplained infertility (Veltman-Verhulst et al., 2012). Atthe same time, the CERR is significantly higher in patientsreceiving IUI with ovarian stimulation versus IUI with

natural/ovarian stimulation. This result supports thehypothesis, stated by D’Hooghe et al. (2006), that a monthlyexposure to ovulation and retrograde menstruation is thebasis of an increased risk of endometriosis recurrence,which might be facilitated by ovarian hyperstimulation.

This study’s 1-year CERR after IUI with ovarian stimula-tion is in line with the reported 1-year CERR of 70% byD’Hooghe et al.(2006); however that study used a differentdefinition of endometriosis recurrence (i.e. surgically con-firmed or cytologically proven endometriosis). In total, nineof the current study’s patients (13.8%) were surgicallytreated with confirmation of recurrence of endometriosis.Since the development of endometriosis complaints(presumably based on recurrence of endometriosis) is animportant factor in the possibility of continuing IUI treat-ment, this study used this broad definition of recurrenceof endometriosis to calculate the CERR. In a future prospec-tive study, the use of validated questionnaires would berecommended (Jones et al., 2006).

An important advantage of calculating the CERR by usinglife-table analysis is achieved by the opportunity to take thevariable ‘time of follow up’ into account (Olive and Lee,1986). However, one assumption in life-table analysis is thatcensored patients have the same risk of endometriosisrecurrence as noncensored patients (Daya, 2005). A discrep-ancy between cumulative and absolute number can beexplained by a large number of early censored patients. Inthis study, the high discrepancy between the CERR andabsolute number of endometriosis recurrence can beexplained by, in particular, early censored pregnantpatients. For them, the endpoint was stated as the dateof a positive pregnancy test. This conforms with the defini-tion used by D’Hooghe et al. (2006). However, thesepatients presumably have a lower risk of endometriosisrecurrence (Busacca et al., 2006), meaning that the CERRis an overestimation of the endometriosis recurrence risk.

This study also investigated the additional effect oflong-term pituitary down-regulation with a GnRH agonistprior to the first IUI treatment cycle, which resulted in

Figure 4 Kaplan–Meier curves of cumulative endometriosis recurrence rate (CERR) per month after start of IUI treatment for thetotal population (A), IUI with natural/ovarian stimulation versus IUI with ovarian stimulation (B, P = 0.021) and with/withoutGnRH-agonist treatment (C, P = 0.016).

596 LEE van der Houwen et al.

nonsignificantly higher odds of achieving an ongoing preg-nancy. This observation is in line with two randomized con-trolled trials investigating the effect of GnRH administrationprior to IUI. Rickes et al. (2002) investigated the effect oflong-term pituitary down-regulation with a GnRH agonistfor 6 months after surgery before commencing IUI treat-ment in patients with endometriosis ASRM stages II–IV. Theyfound a significantly higher pregnancy rate in the long-termpituitary down-regulation group (89%) versus no prior GnRHtreatment group (61%). Kim et al. (1996) compared standarddown-regulated IUI cycles (2 weeks GnRH agonist) versus anultralong down-regulated IUI cycle (6 weeks GnRH agonist)and found a significantly increased clinical pregnancy rate.Before long-term pituitary down-regulation with a GnRHagonist for 3–6 months prior to IUI can be routinely offered,a well-powered randomized controlled trial should beperformed.

Although positive effects of long-term pituitarydown-regulation with a gonadotrophin-releasing hormone(GnRH) agonist on pregnancy rate after IUI (Kim et al.,

1996; Rickes et al., 2002) and IVF (Sallam et al., 2006)have been described, data on endometriosis recurrenceis limited. D’Hooghe et al. (2006) postulated thatshort-term administration of GnRH analogues might pro-tect against recurrence of endometriosis. Against all odds,in the current study, long-term pituitary down-regulationwith a GnRH agonist resulted in a nonsignificant 2.3-foldincrease in the adjusted odds on endometriosis recur-rence. It is inconceivable that GnRH agonists directlyincrease the risk on endometriosis recurrence, since GnRHagonists have positive effects on endometriosis complaintsby lowering the oestrogen concentrations (Brown et al.,2010). Indirectly, cessation of GnRH-agonist suppressiontherapy can result in a quick relapse of endometriosissymptoms (Waller and Shaw, 1993), which can explainthe higher amount of recurrences in this group of patients.Besides this, patients receiving long-term pituitarydown-regulation with a GnRH agonist probably had moresevere complaints of endometriosis prior to start ofGnRH-agonist treatment.

IUI in moderate-to-severe endometriosis patients 597

Due to the retrospective design of this study, a selectionbias might be achieved by the uncertainty about the assign-ment of patients to one of the two treatment groups. How-ever, both groups had comparable baseline patientcharacteristics. Still, it is possible that the included patientsrepresent a negative selected group, because patients witha strong suspicion of endometriosis without a surgical con-firmation were not included. Those patients may havestarted IUI with or without ovarian stimulation before theyare scheduled for a laparoscopic therapeutic procedure. Incase of an ongoing pregnancy, those patients were missingin the database.

This study showed that patients assigned to IUI with ovar-ian stimulation not only conceived more but also had ashorter time to pregnancy compared with patients receivingIUI with natural/ovarian stimulation. Although the numberof patients who discontinued IUI treatment and startedIVF was not different between the groups, patients receiv-ing IUI with ovarian stimulation switched to IVF earlier,which resulted in a higher cumulative ongoing pregnancyrate at 1 year after start of IUI treatment. This might beexplained by this centre’s standard evaluation after threeIUI with ovarian stimulation cycles of whether or not to stoptreatment, continue IUI with ovarian stimulation or switchto IVF.

From these data, it is concluded that IUI might be a valu-able treatment for achieving an ongoing pregnancy in thisgroup of patients. IUI with ovarian stimulation should beoffered over IUI with natural/ovarian stimulation, since thisstudy found a significantly higher cumulative ongoing preg-nancy rate in patients immediately starting ovarian stimula-tion. Taking into account an acceptable cumulativerecurrence rate at 6 months after start of treatment, IUIwith ovarian stimulation should be offered with a maximumof three cycles, providing that IUI treatment is completedwithin half a year after start of treatment. Long-term pitu-itary down-regulation with a GnRH agonist prior to the firstIUI treatment cycle might positively influence the ongoingpregnancy rate and can be considered. Although conclusionscan only be made with some degree of uncertainty, theresults highlight the need for prospective trials with regardto the efficacy and safety of IUI in moderate-to-severeendometriosis. Since IUI is less radical and less expensivethan an IVF procedure, the possibility to offer IUI with ovar-ian stimulation in patients with at least one patent Fallopiantube, for a maximum of three cycles prior to start of IVFtreatment, should be further investigated in a randomizedcontrolled trial, taking into account the efficacy, safetyand cost-effectiveness of both treatment strategies.

Acknowledgements

The authors would like to thank Jan-Willem Lens for hisassistance in using the electronic patient database of theIVF centre of the VU University Medical Centre.

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Declaration: The authors report no financial or commercialconflicts of interest.

Received 19 July 2013; refereed 7 January 2014; accepted 16January 2014.