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Hum. Reprod. Advance Access originally published online on March 14, 2006
Human Reproduction 2006 21(6):1408-1415; doi:10.1093/humrep/del030
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study

J.A. Huirne1, J.N. Hugues2, C. Pirard3, F. Fischl4, J.C. Sage5, J.L. Pouly6, A. Obruca7, D.M. Braat8, A.C.D. van Loenen1 and C.B. Lambalk1,9

1 Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands, 2 Hôpital Jean Verdier, Reproductive Medicine Center, University Paris XIII, Paris, France, 3 Universite Catholique de Louvain, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium, 4 Allgemeines Krankenhaus, Universitätsklinik für Frauenheilkunde Abteilung Gynäkologischen Endocrinologie und Reproduktions Medicin Spitalgasse 23, Vienna, Austria, 5 Tour Belledonne, Boulevard Maréchal Leclerc 23, Grenoble, 6 Polyclinique Hotel Dieu, Boulevard Charles-de-Gaulle 13, Clermont-Ferrand, France, 7 Kinderwunschzentrum Wien, Lazarettgasse 16–18, Vienna, Austria and 8 University Hospital Nijmegen, AZ St Radboud, Obstetrecs-Gynaecology, Geert Grootenplein Zuid 1b, GA Nijmegen, The Netherlands

9 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Centre, PO Box 7075, 1007 MB Amsterdam, The Netherlands. E-mail: cb.lambalk{at}vumc.nl


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: The aim of this study was to assess the non-inferiority of an oral contraceptive (OC)-pretreated cetrorelix regimen and a buserelin regimen in IVF/ICSI patients treated with r-hFSH in terms of total number of oocytes retrieved. METHODS: Multicentre, randomized study. One hundred and eighty two patients were randomized to receive cetrorelix with OC pretreatment (n = 91) or to receive buserelin (n = 91). The cetrorelix group started with daily OCs on cycle day 5 and continued for 21–28 days. Cetrorelix (0.25 mg) was given daily from stimulation day 6 up to and including the day of r-hCG administration. The buserelin group started with buserelin (500 µg/day) for at least 10 days until down-regulation was achieved, after which the dose was reduced to daily 200 µg up to and including the day of r-hCG administration. r-hFSH was started in both groups on a Friday, in the cetrorelix group 5 days after the last OC pill intake. Both regimens were followed by a standard IVF or ICSI procedure. The primary efficacy endpoint was the number of oocytes retrieved per patient. RESULTS: Number of oocytes, cancellation rates, r-hFSH requirements, number of oocyte retrievals during the weekend or public holiday and number of pregnancies were similar in both groups. Both treatment regimens were well tolerated. CONCLUSIONS: Cetrorelix pretreated with OCs resulted in similar number of oocytes retrieved compared with a long buserelin protocol. Both regimens were well tolerated and allowed scheduling of the oocyte retrieval, with only small number of retrievals falling on a weekend or public holiday.

Key words: GnRH agonist/GnRH antagonist/IVF/oral contraceptive/programming


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
GnRH antagonists have recently been introduced in assisted reproduction cycles to prevent premature luteinization. The third generation antagonists are safe with low histamine releasing properties and a lower number of side effects in comparison with the long agonist protocols (European and Middle East Orgalutran Study Group, 2001Go; Fluker et al., 2001Go). Owing to the ability of GnRH antagonists to inhibit gonadotrophin secretion rapidly without exerting any stimulation, less injections are required in comparison with the long agonist protocol which improves patient convenience (Huirne and Lambalk, 2001Go). Although this antagonist regimen seems to be an attractive alternative to the long agonist protocol, several drawbacks became clear in the first comparative phase III studies. The pregnancy rates were not different in the various individual studies. But a meta-analysis, including the first five comparative studies indicated that the number of clinical pregnancies might possibly be lower in the antagonist-only protocols (Al-Inany and Aboulghar, 2002Go). In the individual studies, the number of oocytes was lower with antagonist treatment (Albano et al., 2000Go; Borm and Mannaerts, 2000Go; European and Middle East Orgalutran Study Group, 2001Go; Fluker et al., 2001Go; Al-Inany and Aboulghar, 2002Go). Therefore, we hypothesized that the higher number of oocyts retrieved in the agonist groups may play a role in the possibly higher pregnancy rates. Number of oocytes retrieved may be related to improved pregnancy rates, possibly via better embryo selection (Templeton and Morris, 1998Go). Furthermore, the initiation of FSH administration in a GnRH antagonist regimen is cycle dependent. It is mostly started on day 2 or 3 of the natural cycle, which makes the treatment planning and scheduling difficult (Huirne and Lambalk, 2001Go) and increases the clinical site workload. Therefore, we postulated that oral contraceptive (OC) pills could be used to improve the results of the GnRH antagonist protocols in terms of number of oocytes and treatment scheduling. A few publications have addressed outcomes of GnRH antagonist cycles in combination with OCs. All confirmed the feasibility and the convenience of this regimen (Obruca et al., 2000Go; Huirne et al., in pressGo). Using estradiol (E2) or OCs, the endogenous FSH rise which normally occurs during the luteo-follicular transition in a natural cycle can be attenuated (de Ziegler et al., 1998Go; van Heusden and Fauser, 1999Go; Fanchin et al., 2003Go). In a previous study, we demonstrated that OC pretreatment induces a more homogeneous follicular cohort resulting in delayed hCG administration, thus an extended FSH window leading to more oocytes retrieved in comparison with a GnRH antagonist-only regimen (Huirne et al., in pressGo). We hypothesized that the OC pretreatment in GnRH antagonist cycles will improve follicular homogeneity and number of oocytes rendering these regimen equal to the long agonist protocol in terms of IVF results. The additional advantage of OC pretreatment is that a withdrawal bleeding can be induced to adjust the treatment cycle to the patient’s and centre’s time plan. In a previous study, we demonstrated that the IVF results were independent of the duration of OCs pretreatment in GnRH antagonist cycles (Huirne et al., in pressGo). We further hypothesized that OC pretreatment in GnRH antagonist cycles allows oocyte retrieval scheduling with only minor numbers of oocyte retrievals during the weekend or public holiday comparable with the long agonist protocol.

The aim of this study was to assess the non-inferiority of cetrorelix in patients pretreated with OCs with a long buserelin protocol in terms of number of oocytes retrieved in IVF/ICSI patients treated with r-hFSH. In addition, we assessed the number of oocyte retrievals occurring on weekends/holidays as well as safety aspects.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Study design and patient’s characteristics
This randomized controlled phase IIIb study was conducted in eight European IVF centres. The protocol was approved in all centres by the respective Ethics Committees. One hundred and eighty two patients were randomly allocated to undergo an OC treatment followed by a GnRH antagonist regimen (cetrorelix group) or a GnRH agonist long protocol without OC (buserelin group). The treatment assigned to each patient was determined according to a computer-generated concealed randomization list. Randomization was performed by centre. Patients needed to have a regular IVF/ICSI indication, a male partner with viable sperm in the ejaculate (testicular biopsy or epididymal sperm was not allowed), aged between 18 and 39 and given their informed consent. Patients with any previous assisted reproduction treatment (ART) cycles with less than three oocytes or three or more consecutive ART cycles without a clinical pregnancy or patients with any contraindication to ART, gonadotrophins or OC pills were excluded from the study. Patients with a significant systemic disease were also excluded.

Treatment protocol
On cycle days 1–5 of menses, patients were randomized to receive either OC pretreatment (cetrorelix group) or not (buserelin group) (Figure 1). In the cetrorelix group, patients started with daily OC pills (Microgynon 30®, Schering, Berlin, Germany, containing 30 µg ethinyl E2 and 150 µg levenorgestrel), within 5 days of menses onset and was continued for 21–28 days, stopping on a Sunday. In this group, daily cetrorelix, Serono International, Geneva, Switzerland (0.25 mg, Serono International, Geneva, Switzerland subcutaneously) was started on stimulation day 6 and continued up to and including the day of r-hCG administration. The buserelin group started with daily buserelin, Advantis Pharma, Frankfurt, Germany (500 µg, subcutaneously) at the mid-luteal phase of a natural menstrual cycle (on days 18–22 of the pre-ART cycle) for at least 10 days until down-regulation was achieved, after which the dose was reduced to 200 µg/day. Daily administration was continued up to and including the day of r-hCG administration. r-hFSH (Gonal-F®, Serono, Inetrnational, Geneva, Switzerland) was started on the fifth day (Friday) after the last OC pill in the cetrorelix group. In the buserelin group, r-hFSH was started on a Friday as soon as down-regulation was achieved. In both groups, r-hFSH was administered daily, subcutaneously, up to the day of hCG administration. The starting dose of r-hFSH 150–225 IU, according to the study centre’s standard practice, was maintained for 5 days, after which it could be adjusted by steps of 75 IU, according to the ovarian response up to a maximal dose of 450 IU/day. r-hCG 250 µg (=6500 IU) (Ovitrelle®, Serono, Inetrnational, Geneva, Switzerland) was injected as soon as the largest follicle reached a mean diameter ≥18 mm and at least two other follicles of a mean diameter ≥16 mm. A transvaginal oocyte retrieval was performed 34–38 h after r-hCG administration under ultrasound guidance, followed by a standard IVF or ICSI procedure. No more than 2–3 embryos were replaced either 2–3 days or 5–6 (blastocyst transfer) days after oocyte retrieval, according to centre’s standard procedure and country regulations. Remaining embryos were cryopreserved if the quality was sufficient enough. After oocyte retrieval, intravaginal natural progesterone (three times daily 200 mg Progestan®, Organon, Oss, The Netherlands) was started as luteal support. This was continued up to a negative pregnancy test or during the first 3 weeks of pregnancy.


Figure 1
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  		Figure 1. Treatment schedule. Schematic overview of the treatment regimens. In the cetrorelix group, daily 0.25 mg cetrorelix was pretreated with daily oral contraceptive (OC) pills starting within 5 days of menses onset and was to be continued for 21–28 days, stopping on a Sunday; the Buserelin group started with daily Buserelin (500 µg) at the mid-luteal phase of a spontaneous menstrual cycle [on days 18–22 of the pre-assisted reproduction treatment (ART) cycle] for at least 10 days until down-regulation was achieved, after which the dose was reduced to 200 µg/day. All patients were undergoing ovarian stimulation with r-hFSH. S1, stimulation day 1; S6, stimulation day 6.

 

Assessments
Not more than 3 months before randomization, gynaecological, physical and ultrasound examination was performed to test eligibility. After giving written consent, a transvaginal ultrasound was performed on cycle day 2 or 3 to measure the antral follicular count and to exclude the presence of ovarian cysts or other abnormalities. A blood sample was taken to perform a pregnancy test. On stimulation day 1, 6 and on each day thereafter that the patient was seen in the clinic while undergoing ovarian stimulation and on the day of r-hCG administration, blood samples were taken in the morning before any drugs were given, to assess E2 levels. On the same day, transvaginal ultrasounds was performed to monitor the number and size of the follicles and the endometrial thickness. The oocyte and embryo quality assessment was based on morphological criteria. In case of ICSI, the cumulus cells were removed to assess nuclear maturity. Date, time, dose of r-hFSH injections were recorded daily on personal diary cards as were the side effects or local skin reactions. On days 15–20 after r-hCG administration, a blood sample was taken to assess hCG value: if >10 IU/l, the test was repeated 2–4 days later to confirm pregnancy. Pregnancy was defined as continuing increase in serum hCG. In that case, 4 and 10 weeks after embryo transfer, ultrasound was performed to assess the number of fetal sacs and heart activity. Clinical pregnancy was defined as the presence of a fetal sac, with or without heart activity. Ongoing pregnancy as a positive heart activity at a gestational age of 12 weeks. The results from cryopreserved embryos were not included in this study.

Statistics
The primary efficacy endpoint was the number of oocytes retrieved per patient. Secondary endpoints were total number of oocyte retrievals performed on weekend or public holiday, cancellation rate, drug requirements, total number of (good quality) embryos, implantation and pregnancy rates.

As this was a non-inferiority study, the patient population used for the analyses of the primary efficacy endpoint was defined as all randomized patients who received at least one injection of buserelin or took OCs, without major deviation to the protocol (per protocol). For the analysis of the secondary endpoints, all patients allocated were included in the intention to treat (ITT) population.

As the randomization was stratified by centre, it was taken into account in the analyses of the non-inferiority testing. If no convergence of the statistical model could be achieved because of sparse data, pooling of centres was performed. The centre factor was used either as a covariate for parametric models or as a strata variable for non-parametric methods. The treatment by covariate interactions were assessed, and if one of these terms was significant, then the overall comparison of the treatments was interpreted with caution and separate analyses for each strata of the covariate was done. Binary endpoints were compared using Cochran–Mantel–Haenszel (CMH) test of general association or a two-sided Fisher’s exact test, depending on the distribution of the variable. Continuous and discrete endpoints were analysed using analysis of variance (ANOVA). If deemed appropriate to include a covariate, analysis of covariance (ANCOVA) was used. Categorical parameters may have been investigated by using CMH testing or Fisher’s exact tests, whichever was appropriate. All statistical tests were performed two sided at the significance level of 5%, with the exception of the primary endpoint (the number of ooyctes retrieved) which was performed using a one-sided 97.5% confidence interval.

Sample size calculation
The number of oocytes retrieved was the primary efficacy endpoint of the study. Sample size calculation was performed, under the assumptions that the non-inferiority margin (also called clinically irrelevant difference) is equal to three oocytes and the estimated standard deviation is equal to 5.9 (obtained from previous studies in which the number of oocytes retrieved was calculated and a one-sided alpha level of 0.025 is used (which was used to compute the overall 97.5% confidence interval of the difference between the two treatment groups). With the objective to demonstrate that the difference in average number of oocytes retrieved between the cetrorelix and the buserelin groups would not exceed three, the power for a comparison between the two groups would be equal to 87% for 75 evaluable patients in each treatment groups (for an allocation of 1:1 and a total sample size of 150). To allocate at least 150 patients per protocol, an additional 10% to cover possible dropping out were planned to allocate. However, recruitment was concurrently carried out in eight centres, with each having complete blocks, making it impossible to stop the recruitment exactly after the allocation of 165 patients.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Baseline characteristics and cancellations
A total of 216 patients were screened for eligibility, and 182 patients were enrolled in the study (Figure 2) and received at least one dose of either OC’s or buserelin’s; 91 received OC pills and 91 received buserelin. In the cetrorelix group, two patients did not start with r-hFSH after OC intake; one patient turned out to be hepatitis B positive, and another patient was excluded because of non-compliance before first cetrorelix dose. In the buserelin group, six patients did not start with r-hFSH after buserelin administration; two patients became pregnant before rFSH administration, in three patients desensitization failed and one patient decided to withdraw because of failed confidence in buserelin. One hundred and seventy patients received r-hCG. In the cetrorelix group, one patient did not receive r-hCG for personal reasons, and two others had insufficient follicular response and did not reach the r-hCG criteria of which one patient received r-hCG followed by IUI. In the buserelin group, one patient stopped r-hFSH because of stimulation failure. All together, 169 patients had an oocyte retrieval, 85 in the cetrorelix and 84 in the buserelin group. In the cetrorelix group, 81 patients had embryos transferred, one patient had no mature oocytes and three had no viable embryos. In the buserelin group, 79 patients had an embryo transfer, three patients had no (mature) oocytes and two patients had no fertilization (Figure 2). Overall, the number of patients receiving hCG, oocyte retrieval and an embryo transfer were comparable in both arms.


Figure 2
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  		Figure 2. Flow diagram, showing the flow of the participants through each stage of the trial.

 

The mean age of the study population was 32.5 (±4.0) years, with a range of 20–39 years. The two treatment groups were similar with regard to demographics and baseline characteristics except for body mass index which was slightly higher in the cetrorelix group (Table I). All P values are adjusted for the centre effect.


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  		Table I. Baseline characteristics

 

Efficacy results
The mean duration of OC intake in the cetrorelix group was 24 (±2.7) days, with a range of 15–31 days. The mean duration of cetrorelix administration was 5.3 (±1.8) days, with a range of 2–10 days. Duration of GnRH agonist administration was 25.4 ± 4.4 days (range 14–38 days). The stimulation period and FSH requirement were similar in both groups (Table II). Also no differences were observed between the two groups in number of follicles ≥11 mm, ≥16 mm or the endometrial thickness on S1, S6 and day of hCG. All P values were >0.58 (Figures 3 and 4). The number of patients having oocyte retrievals at the weekend or on public holidays was low and similar in both groups, 5 (5.9%) in the cetrorelix and 6 (7.1%) in the buserelin group (P = 0.74).


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  		Table II. Drug requirements

 

Figure 3
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  		Figure 3. Endometrial thickness. Mean endometrial thickness, with standard deviations (error bars) on stimulation day 1 (S1), 6 (S6) and day of hCG administration (r-hCGd). Analyses were performed on an intention to treat (ITT) basis, and P values were all >0.05.

 

Figure 4
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  		Figure 4. Follicular growth pattern. Number of follicles ≥11 mm and ≥16 mm on stimulation day 1 (S1), stimulation day 6 (S6) and on the day of r-hCG administration (r-HCGd). Values are mean with standard deviations (error bars). Analyses were performed on an intention to treat basis, and P values were all >0.05.

 

In the per protocol data set, there was no significant difference between the two treatment groups in the number of oocytes retrieved. The mean number of oocytes retrieved was 11.2 (±7.1) for the cetrorelix and 11.3 (±6.8) for the buserelin group. As the lower boundary of the one-sided 97.5% confidence interval for the difference between the two treatment groups was –2.19, the two treatment groups were declared as non-inferior. Results for the ITT data set were also similar: the two treatment groups were not statistically different for the number of oocytes retrieved [11.4 (±7.3)] in the cetrorelix group and [10.9 (±10.9)] in the buserelin group. The estimate was 0.47, with the lower boundary of the one-sided 97.5% confidence interval for the difference between the two groups is of –1.51.

Number of intact oocytes, number of metaphase II oocytes, the number of embryos obtained, the mean number of embryos transferred and the number of patients in which blastocysts were transferred were not different between the two groups (Table III). We could not observe differences between the two groups with respect to implantation, clinical and ongoing pregnancy rates although this study was not powered to assess these points in detail (Table III). Overall, multiple clinical pregnancies (all twin) occurred in 11 of 52 pregnant patients (21.2%) and were similar in both groups, six in the cetrorelix group and five in the buserelin group. There were three clinical miscarriages reported (one in the cetrorelix group and two in the buserelin group); one of these was a partial miscarriage of a twin pregnancy. Of the 37 ongoing pregnancies, there were three patients who had adverse pregnancy outcomes, all in the buserelin group. One patient suffered a fetal death in utero; in one patient, trisomy 21 was diagnosed, and the pregnancy was aborted. One patient with a twin pregnancy had a fetus selectively removed by embryo reduction because of trisomy 21 but also lost the second fetus because of an immature delivery. Finally, there were 34 births, 17 in each treatment group, resulting in 43 live babies, 23 from the cetrorelix-treated women and 20 from buserelin-treated women.


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  		Table III. IVF outcome

 

The E2 level on hCG day were significantly lower in the cetrorelix group compared with the buserelin group, 5439 (±4743) versus 9443 (±6789) pmol/l, respectively (P < 0.001). The E2 levels on S1 and S6 were not different (Figure 5).


Figure 5
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  		Figure 5. Mean estradiol (E2) levels (pmol/l) on stimulation day 1 (S1), 6 (S6) and the day of r-hCG administration (r-hCGd). The error bars represent the standard deviation. Analyses were performed on an intention to treat (ITT) basis. *P < 0.05.

 

Safety evaluation
Over the course of the study, 88 of the 182 patients (48.4%) reported at least one adverse event (AE). About 41.8% in the cetrorelix group and 54.9% in the buserelin group (P = 0.10). Before the stimulation with r-hFSH, significantly less AEs were reported in the cetrorelix group versus the buserelin group (Table IV). The number of patients with at least one reported AE during stimulation, and up to 30 days after r-hCG injection were similar in the cetrorelix and buserelin group. The majority of the AEs were mild in severity (237 of 259 events) and possibly related to study drug (146 of 259 events). The reported possibly related AEs were significantly less in the cetrorelix group (15) compared with the buserelin group (37) (P < 0.001). The probably-related AEs were similar in both groups (11 in cetrorelix group and 10 in buserelin group). When the AEs were examined by both severity and drug relationship, significantly fewer patients in the cetrorelix group (14.3%) had mild, possibly related AEs compared with the buserelin group (39.6%) (P < 0.001). Three serious AEs were reported in both groups: in each treatment group, there was one patient with moderate ovarian hyperstimulation syndrome (OHSS), one patient with an ectopic pregnancy and one patient with abdominal pain. Additionally, in three patients, mild OHSS was reported, one in the cetrorelix and two in the buserelin group. There were no cancellations because of risk of OHSS recorded during the study. The most affected system organ classes with 10 or more reported AEs in the total study are summarized in Table IV. The main reported AEs were gastrointestinal disorders (21.4%), like nausea, abdominal discomfort, distension, pain, constipation and nausea, followed by nervous system disorders (20.9%) which was mainly headache. Some patients reported dizziness. Reported general disorders and administration site condition (18.7%) were fatigue, injection site bruising and pruritus. Reported reproductive system and breast disorders (13.7%) were breast tenderness and enlargement, ovarian cyst formation and enlargement. Reported musculoskeletal disorders were arthralgia and back pain. Reported psychiatric disorders mainly occurred in the buserelin group and varied widely, including abnormal dreams, aggression, crying, mood alterations, sleep disorders, decreased libido and depression. In the cetrorelix group, there were significantly fewer AEs from the nervous system class and the reproductive system and breast disorders class compared with the buserelin group (Table IV). The other organ class systems with less then 10 reported AEs were ear, eye, immune system, infections, musculoskeletal, respiratory and vascular organ class.


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  		Table IV. Adverse events occurring during the study by organ system affected

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
The aim of this study was to assess the non-inferiority of an OC-pretreated cetrorelix regimen compared with a long agonist buserelin regimen in terms of efficacy (total number of oocytes), number of oocyte retrievals on weekend or public holidays and safety in IVF/ICSI patients treated with r-hFSH.

We have demonstrated that in terms of length of stimulation, follicle and oocyte, yield the combination of OC with a GnRH antagonist was comparable with a long GnRH agonist treatment. Several phase III studies consequently report significantly less oocytes retrieved in the GnRH antagonist groups compared with the long agonist protocols (Albano et al., 2000Go; Borm and Mannaerts, 2000Go; European and Middle East Orgalutran Study Group, 2001Go; Fluker et al., 2001Go; Huirne and Lambalk, 2001Go; Al-Inany and Aboulghar, 2002Go). The timing of gonadotrophin suppression was totally different in these regimens, and this has probably played a role in follicular development and number of oocytes retrieved. GnRH analogue administration is usually started in the luteal phase of the preceding cycle in the long agonist protocol. Desensitization resulting in profound suppression of the endogenous gonadotrophins allows early antral follicles to grow more synchronized, when exogenous gonadotrophins are being given with more simultaneous maturation as result. In GnRH antagonist-only protocols, endogenous FSH during luteo-follicular transition is not suppressed because the antagonist administration is mostly started from stimulation day 6 onwards. If the endogenous FSH rise is not suppressed, marked follicular size discrepancies will lead to the administration of hCG dependent on the size of the leading follicle(s) while a number of follicles is still immature. Thus consequently, a shorter stimulation period and lower number of oocytes at time of retrieval is a feature of GnRH antagonist IVF/ICSI cycles as shown in the various phase III studies (Albano et al., 2000Go; Borm and Mannaerts, 2000Go; European and Middle East Orgalutran Study Group, 2001Go; Fluker et al., 2001Go; Al-Inany and Aboulghar, 2002Go). Not only GnRH agonists but also estrogens alone and estrogens in combination with progestagens in the form of OCs are able to suppress and attenuate the endogenous FSH rise (de Ziegler et al., 1998Go; van Heusden and Fauser, 1999Go). E2 or OC pretreatment are therefore possible tools in the prevention of untimely and uncoordinated development of the follicular cohort in GnRH antagonist regimens (Fanchin et al., 2003Go; Huirne et al., in pressGo). This study confirms that OC-pretreated regimens are feasible with similar efficacy in terms of number oocytes compared with a long GnRH agonist protocol. The three-oocyte margin at the time selected for this study was based on discussion between the investigators and European and US regulatory authorities. The results of this study do not indicate any difference in pregnancy rates. With the number of oocytes selected as primary endpoint, this study has only limited value with respect to pregnancy and implantation rates, but it can be of use in future meta-analyses. Our results are in agreement with the findings of a study comparing the same strategies in polycystic ovary syndrome (PCOS) patients (Hwang et al., 2004Go) and another study comparing an OC-pretreated flexible GnRH antagonist protocol to a long GnRH agonist protocol, showing similar number of oocytes, embryos and pregnancy rates (Barmat et al., 2005Go). A very recent study comparing a fixed GnRH antagonist regimen with or without OC pretreatment reported a significantly higher early pregnancy loss after OC pretreatment (Kolibianakis et al., 2006Go). So far, only a few studies assessed the effect of GnRH antagonists versus GnRH agonists on endometrial development and reported conflicting results (Saadat et al., 2004Go; Simon et al., 2005Go). Further studies are needed to study the effect of OC pretreatment on endometrial development, and proper designed meta-analyses and future adequately powered studies are needed to proof the idea that the combined OC-antagonist strategy overcomes the possible disadvantage of antagonist use over agonist use in terms of pregnancy outcome and its effect on implantation.

Another relative disadvantage of GnRH antagonist-only protocols in IVF is the limited ability to plan the start of the treatment which is cycle dependent. When stimulation is started on cycle day 2 or 3, it turns out that both initiation of treatment and oocyte retrieval occurred equally distributed on all week days (Huirne et al., 2005Go). The current study clearly indicates that OC pretreatment allows accurate planning of the initiation of FSH treatment, such that weekend retrievals occurred only in a very limited number of patients, comparable with the long GnRH agonist schedule. Another way of preventing oocyte retrieval from occurring at the weekend in GnRH antagonist cycles by delaying the hCG injection does not seem an attractive option since it was demonstrated that one day delay was associated with lower pregnancy rates (Kolibianakis et al., 2004Go). Therefore, planning by scheduling a withdrawal bleeding with OC pretreatment in combination with timely injected hCG could be advantageous.

Both treatment regimens in our study were well tolerated, with a similar duration of the stimulation period, but with significantly lower number of GnRH analogue injections with significant less reported side effects in the cetrorelix group before rFSH is started.

In conclusion, it seems that the combination of OC with antagonist largely overcomes several disadvantages of GnRH antagonist application in IVF that were claimed in the past compared with long agonist regimens. The mean number of oocytes retrieved were similar in OC-pretreated cetrorelix group and the long buserelin group with only a small number of oocyte retrievals occurring at the weekend or on public holidays. In our opinion, this combined strategy, in particular given the significant reduction of required injections and in part as a result of the significant reduction in reported side effects before stimulation, provides a good alternative for the long GnRH agonist protocol in the prevention of premature luteinization in ART.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors thank Serono for their support of the study, in particular R. Percival, C. Howles and L. O’Dea for the clinical aspects of the study design, D.W. Warne and S. Robson-Lasserre for the statistical design and analysis, J. Griffiths and R. Duran for data management, V. Hild and G. Decosterd for the study management and M. Leynaert and A. Zrener for the study monitoring.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Albano C, Felberbaum RE, Smitz J, Riethmuller-Winzen H, Engel J, Diedrich K, Devroey P and The European Cetrorelix Study Group (2000) Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)-antagonist cetrorelix and the LHRH-agonist buserelin. Hum Reprod 15,526–531.[Abstract/Free Full Text]

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Submitted on October 24, 2005; resubmitted on January 1, 2006; accepted on January 11, 2006.


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