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Abstract |
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Key words: buserelin/ganirelix/GnRH agonist/GnRH antagonist/ICSI/IVF/ovarian stimulation/recombinant FSH
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Introduction |
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In current practice, GnRH agonists are used to suppress endogenous gonadotrophins during ovarian stimulation (Loumaye, 1990). However, agonists initially stimulate the release of gonadotrophins (flare-up), and complete pituitary suppression is only achieved after 23 weeks pretreatment when pituitary desensitization occurs due to receptor down-regulation.
The introduction of a GnRH antagonist such as ganirelix allows a short and simple treatment regimen for IVF patients undergoing ovarian stimulation, since antagonists immediately suppress gonadotrophins by blocking the GnRH receptor, and thus treatment may be restricted to those days when a premature LH surge is likely to occur. Studies in healthy female volunteers and IVF patients have shown that steady-state concentrations of ganirelix are reached within 23 days of treatment, and that maximal suppression of endogenous LH occurs about 4 h after each injection (Oberyé et al., 1999b). Moreover, after discontinuation, a rapid recovery of pituitary function (Gordon et al., 1990
) was observed, also due to the relative short elimination half-life (about 13 h) of ganirelix. The additional anticipated advantages of antagonist treatment in ovarian stimulation programmes are a reduction of the use of gonadotrophins, a lower risk for developing ovarian hyperstimulation syndrome (OHSS), and the ability to use a bolus injection of a GnRH agonist to trigger a midcycle LH surge for final follicular maturation (Olivennes et al., 1996
). Moreover, in cases of multiple follicles and excessively high oestradiol concentrations, the use of GnRH agonist instead of human chorionic gonadotrophin (HCG) is thought to prevent the clinical manifestation of OHSS (Itskovitz et al., 1991
). If nevertheless, the IVF cycle is cancelled, ganirelix treatment may be continued to prevent spontaneous ovulation as well as signs and symptoms of OHSS (De Jong et al., 1998
).
The third-generation GnRH antagonists cetrorelix and ganirelix have both been applied in a multiple-dose regimen in women undergoing ovarian stimulation. Clinical research of cetrorelix started off with relatively high daily dosages of 3 and 1 mg (Diedrich et al., 1994; Felberbaum et al., 1995
), but finally the lowest effective daily dose of cetrorelix appeared to be 0.25 mg (Albano et al., 1997
, 1999
). To select the minimal effective daily dose of ganirelix, a multicentre, double-blind, randomized, dose-finding study was performed in 333 women including six different dosages ranging between 0.0625 and 2 mg (Ganirelix dose-finding study group, 1998
; Itskovitz-Eldor et al., 1998
). In this study, patients were treated with a fixed dose of 150 IU rFSH for 5 days before starting ganirelix. The study revealed that a daily dose of 0.25 mg ganirelix prevented LH from rising above 10 IU/l during stimulation, and resulted in a good clinical outcome, i.e. the ongoing pregnancy rate was 34% per attempt (23/68) and 37% per transfer (23/62). Moreover, as in other studies (Fujimoto et al., 1997
; Oberyé et al., 1999b
), serum ganirelix concentrations increased in a linear dose-proportional manner, and serum LH decreased in a dose-proportional manner, indicating that the degree of pituitary suppression can be adjusted by changing the ganirelix dose.
In the current study the efficacy and safety of a multiple-dose regimen administering 0.25 mg ganirelix daily was assessed in a randomized study in women undergoing ovarian stimulation with rFSH for IVF or intracytoplasmic sperm injection (ICSI).
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Materials and methods |
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Study design
This trial was a phase III, multi-centre, open-label, randomized study to assess the efficacy and safety of the GnRH-antagonist ganirelix in women undergoing ovarian stimulation. Eligible patients were randomized by an interactive voice response system (IVRS) to either treatment with ganirelix (Orgalutran®, Org 37462; NV Organon, Oss, The Netherlands) or buserelin (Suprecur®; Hoechst, Frankfurt Am Main, Germany) in a ratio of 2:1. To improve balance, a minimization method was used for randomizing patients to treatment (Treasure and MacRae, 1999), stratifying for centre age, for primary or secondary infertility, and for IVF or ICSI.
A diagrammatic representation of the applied treatment regimens is shown in Figure 1. Injections of rFSH (Puregon®; NV Organon) and ganirelix were given in the morning. In the ganirelix group, treatment with rFSH was started in patients on day 2 or 3 of the menstrual cycle by a once-daily s.c. injection. After 5 days of rFSH treatment, ganirelix treatment was started by daily s.c. administration in the upper leg. Ganirelix treatment was continued up to and including the day of HCG administration.
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In both treatment groups, ovarian stimulation was started with a fixed daily dose of 150 IU rFSH for the first five treatment days. From day 6 onwards, the dose of rFSH was adapted depending on the ovarian response as monitored via ultrasonography. On the day of HCG, rFSH was not administered.
HCG (10 000 IU, Pregnyl®; NV Organon) was administered when at least three follicles of 17 mm diameter were observed, and 3036 h thereafter oocyte retrieval was performed. Oocyte retrieval was followed by IVF or ICSI, and no more than three embryos were to be replaced 25 days thereafter. Luteal phase support was given according to the clinics' routine practice, and was started no later than the day of embryo transfer.
Assessments
In the ganirelix group prior to the start of rFSH, and in the buserelin group prior to the start of buserelin, an HCG test was to be performed to exclude pregnancy. When bleeding did not occur within 2 weeks after starting buserelin treatment, an additional HCG test was performed. Just before the first injection of rFSH, a blood sample was taken for hormone assessment and ultrasonography (USS) was performed. From rFSH treatment day 6 up to and including HCG administration, the patient returned to the clinic for USS and blood sampling before ganirelix administration once every 2 days. Serum FSH, LH, oestradiol and progesterone were assessed by a central laboratory by means of fluoro-immunoassay (Delfia®, Wallac OY, Finland).
Local tolerance was assessed by the patient at 1, 4 and 24 h after each ganirelix injection. The subject was asked to record on a diary card the score (none, mild, moderate or severe) for five different parameters, i.e. bruising, swelling, pain, itching and redness.
Statistical methods
The study was designed as a non-inferiority trial to test whether the combination of efficacy, safety and convenience of ganirelix treatment was clinically equivalent to the current care, i.e. GnRH agonist treatment in a long protocol. As a large previous study with Puregon and intranasal buserelin in a long protocol had an excellent clinical outcome (Out et al., 1995), this regimen was selected as the reference treatment in the current study. Data from the intent-to-treat (ITT) group were used for efficacy analysis, and data from the all-subjects-treated (AST) group were used for safety analysis. The ITT group and the AST group consisted of all patients randomized who started treatment. Patients in the ITT group were grouped according to the treatment they should have received by randomization, whereas patients in the AST group were grouped according to the actual treatment they received.
Efficacy analysis
A total of 701 subjects started treatment with rFSH or buserelin and was included in the ITT group. Of the treated subjects, 463 were randomized to the ganirelix group and 238 to the buserelin group. One subject was randomized to buserelin, but was treated with the ganirelix regimen, and one subject was randomized to buserelin and received during buserelin treatment also three injections of ganirelix. Since both subjects were intended to receive buserelin, they were included in the ITT group of buserelin. One subject with a spontaneous pregnancy who started buserelin treatment was also included in the ITT group. Main efficacy parameters were treatment failure, number of cumulusoocyte complexes, number of good quality embryos, and ongoing pregnancy rate. For patients treated with both IVF and ICSI, oocyte quality was not analysed.
The estimated difference of ganirelix and buserelin in ongoing pregnancy rate was compared with the margin of 5%. For cumulusoocyte complexes, the lower one-sided 97.5% confidence limit of the treatment difference was compared with the equivalence margin of 3 oocytes. For continuous efficacy variables, adjusted-for-centre treatment means and their differences were calculated, using a weighted average over the centres based on the CochranWhitehead method (Whitehead and Whitehead, 1991). For the ongoing pregnancy outcome the CochranMantelHaenszel weights (Cochran, 1954
) were used. Lower one-sided 97.5% confidence limits of the adjusted-for-centre treatment differences between ganirelix and buserelin were calculated for the number of oocytes, good quality embryos, and the ongoing pregnancy rate. For the rate of study medication treatment failure in each group, a one-sided 97.5% confidence limit was calculated based on the binomial distribution.
Freezethaw cycles
Embryos were frozen in 18 out of the 20 IVF centres; in two German centres only two-pronuclear (2PN) oocytes were frozen which were not included in this analysis. Data were collected for all patients (n = 126) who did not become pregnant after replacement of fresh embryos, and for whom spare embryos were cryopreserved. By June 1999, 53 of these patients had had at least one embryo transfer using thawed embryos. The outcome of these first freezethaw cycles is presented.
Safety analysis
Analysis was performed by means of frequency distributions of the incidence of adverse events, local tolerance outcome, clinically significant abnormal laboratory values and vital signs. For patients treated with the ganirelix regimen, analysed data included all days of stimulation, thus also the first 5 days of rFSH treatment when patients were not yet exposed to ganirelix.
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Results |
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Duration of GnRH analogue treatment and total dose of rFSH
The median (range) duration of GnRH analogue treatment was 5 (214) days in the ganirelix group, and 26 (1844) days in the buserelin group. The total amount of GnRH analogue administered was 1.25 versus 16.2 mg. The median (range) duration of rFSH treatment was 9 (618) and 10 (619) days respectively. The total amount of rFSH administered was in total 1500 (9005400) IU and 1800 (9006450) IU, and the median daily dose was 150 IU/day and 178 IU/day in the ganirelix and buserelin groups respectively.
LH rises (10 IU/l) before and during ganirelix treatment
Early LH rises at day 6 of stimulation, before the first ganirelix administration, were observed in 20 patients (4.3%). In these patients serum LH values ranged between 10.4 and 33.4 IU/l and concomitant rises of serum progesterone >1 ng/ml were observed in seven out of these 20 patients. On day 6 of stimulation, this subset of patients had on average 6.8 follicles 11 mm diameter, and their median serum oestradiol concentration was 856 (range 3481900) pg/ml, indicating that most of these patients were high responders. Due to initiation of ganirelix treatment, endogenous LH rises were effectively cut-down in all 20 patients. Out of the 20 patients, 19 had embryo transfer, and in three patients an ongoing pregnancy was established.
After the day of the first ganirelix injection, 13 women (2.8%) had an LH value 10 IU/l. Peak LH values ranged between 10.1 and 58.1 IU/l, and concomitant rises (>1 ng/ml) of serum progesterone were observed in six patients (1.5%). Seven patients were discontinued before embryo transfer, and none of the other patients became pregnant. In the buserelin group, three patients (1.3%) had an LH rise to
10 IU/l during stimulation. Of these, one patient was discontinued and one patient became pregnant.
Miscarriage did not occur in any of the patients with an early or late rise of serum LH after confirmation of an early clinical pregnancy.
Follicle growth
The mean (± SD) number of follicles 11 mm diameter measured on days 6, 8 and 10 of stimulation for patients with at least 9 days of stimulation are presented in Figure 2
. The number and size of follicles measured at the day of HCG administration are summarized in Table III
.
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Serum hormone concentrations
Median serum FSH, LH, oestradiol and progesterone concentrations measured at days 1, 6, 8 and 10 of stimulation for patients with at least 9 days of stimulation are presented in Figure 3. At the start of rFSH stimulation (day 1), serum hormone concentrations were higher in the ganirelix group than in the buserelin group, and represented normal levels as measured at day 2 to 3 of the menstrual cycle and after pituitary down-regulation respectively. On day 6 of stimulation, serum FSH and LH concentrations had become similar in both treatment groups, probably due to a negative feedback by initial rising oestradiol concentrations in the ganirelix group. Median serum oestradiol concentrations rose from 38 pg/ml on day 1 to 358 pg/ml on day 6 of stimulation in the ganirelix group, and from 19 pg/ml to 160 pg/ml in the buserelin group. This increase was in accordance with the number of growing follicles in each group. From day 6 to the day of HCG, serum FSH increased by 0.5 IU/l in the ganirelix group and by 1 IU/l in the buserelin group. Predose concentrations of serum LH in patients treated with ganirelix were comparable with those measured in the buserelin group. After day 6 of stimulation up to the day of HCG, serum oestradiol concentrations followed the pattern of follicular growth in that on day 8 the oestradiol concentrations were only 128 pg/ml higher in the ganirelix group than in the buserelin group, whereas on the day of HCG (see Table III
) the opposite was observed, with serum oestradiol concentration being about 500 pg/ml lower in the ganirelix group than in the buserelin group (1190 versus 1700 pg/ml). Finally, serum oestradiol content per follicle (
11 mm) was lower in the ganirelix group than in the buserelin group.
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The clinical outcome of all patients receiving embryo transfer, expressed per attempt and per embryo transfer, is shown in Table V. Although a similar number of embryos was replaced in each group, the implantation rate (number of gestational sacs divided by the number of replaced embryos) was relatively lower in the ganirelix group (15.7 versus 21.8%), whereas the miscarriage rate per clinical pregnancy was comparable (12.0 versus 13.9%). Accordingly, the vital and ongoing pregnancy rate tended to be lower in the ganirelix group than in the buserelin group. For the ITT group, the ongoing pregnancy rate per attempt was 20.3% in the ganirelix group and 25.7% in the buserelin group (including one spontaneous pregnancy in the buserelin group). The estimated difference for the ongoing pregnancy rate was at the margin of 5%. When comparing the ongoing pregnancy rate per study site, this difference ranged from 26.3% in favour of ganirelix to 28.6% in favour of buserelin. The ongoing pregnancy rate per attempt for patients (n = 337) treated at study sites (n = 10) that had previous experience with the ganirelix regimen was similar, i.e. 24.2% in the ganirelix group and 23.6% in the buserelin group, whereas this rate was respectively 16.5 and 27.5% for patients (n = 363) treated in study sites (n = 10) that had applied the ganirelix regimen for the first time.
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Outcome of subsequent freezethaw cycles
The mean (± SD) number of embryos frozen was 1.1 ± 2.3 and 1.3 ± 2.5 in the ganirelix and buserelin groups respectively. The first frozenthawed embryo cycles (n = 53) performed within one year after study completion resulted in three miscarriages, one induced abortion and 10 ongoing pregnancies (1216 weeks after embryo transfer). Seven pregnancies (20.0%) were established in patients previously treated with ganirelix, and three pregnancies (16.7%) were established in patients treated with buserelin. The overall ongoing pregnancy rate was 18.9% (see Table VI).
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The incidence of OHSS was two-fold lower in the ganirelix group than in the buserelin group. Eleven subjects (2.4%) in the ganirelix group and 14 subjects in the buserelin group (5.9%) experienced signs and symptoms related to OHSS. For two pregnant patients in the ganirelix group OHSS was graded as severe; all other cases were of moderate or mild intensity.
The local tolerance outcome indicated that ganirelix administered daily by the s.c. route was well tolerated. The percentage of patients with at least one moderate or severe local tolerance reaction (skin redness, swelling, bruising, pain or itching) during ganirelix treatment was 16.6, 2.0 and 2.7%, at 1, 4 and 24 h after the injection respectively. Most frequently reported were moderate or severe skin redness (9.5%) or swelling (9.5%) at 1 h after injection, but by 4 h after injection these reactions had mostly disappeared. At 24 h after injection, bruising (moderate or severe) was most frequently reported (2.5%). None of the patients had to discontinue ganirelix treatment because of a hypersensitivity reaction or because of a drug-related adverse experience.
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Discussion |
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Ganirelix is used to prevent premature LH surges occurring during ovarian stimulation. However, in the literature no clear definition on an LH surge has been provided, and therefore data analysis was based primarily on the incidence of LH rises 10 IU/l and additionally on concomitant rises of serum progesterone 1 ng/ml, indicating premature luteinization. During ganirelix treatment the overall incidence of LH rises was 2.8%, and only in 1.5% of the cases was a concomitant rise in progesterone concentration observed, demonstrating the effective suppression of endogenous LH during ovarian stimulation.
In this efficacy trial, ganirelix treatment was started on day 6 of stimulation, since the previous dose-finding study (Ganirelix dose-finding study group, 1998) demonstrated that during the first days of stimulation, median serum LH concentrations decrease and nadir LH concentrations are reached at day 5 of stimulation. This initial suppression of endogenous LH is thought to be established by a negative feedback of rising oestradiol concentrations during the first days of stimulation. When follicular growth is progressing and oestradiol concentrations become as high as in the late follicular phase of the normal menstrual cycle, then the reverse occurs and the risk for a premature LH surge becomes imminent (Filicori et al., 1986
). In the current study, early LH rises before the first ganirelix administration occurred in 20 patients who were high responders, i.e. stimulation resulted in more rapid initial follicular growth and in a more pronounced rise of serum oestradiol as compared with the overall treatment group. Even though the clinical outcome of this small subset of patients was good, early LH rises may be prevented by starting ganirelix treatment on day 5 instead of day 6 of stimulation. On the other hand, 13.2% of all patients did not show any follicles
11 mm diameter at day 6 of stimulation; in these lower responders exposure to ganirelix may be limited by delaying the start of treatment up to the moment of actual follicle growth.
In the current study, duration of treatment was short, i.e. on average 9 days with rFSH including 5 days of ganirelix treatment. Since initial growth of follicles was more rapid and endogenous FSH concentrations were only partly suppressed (during the late follicular phase), the duration of rFSH treatment was one day shorter and the amount of rFSH required was lower in the ganirelix group. Since the number of subjects without any follicles 11 mm diameter on day 6 of stimulation was twice as high in the long protocol of buserelin, the ganirelix regimen might be of special benefit for poor-responders, who are frequently treated with a short flare-up protocol of GnRH agonist (Frydman et al., 1988
).
Comparison of the number and size of follicles indicated that, in the ganirelix group, initial follicular growth was faster but the final cohort of growing follicles was smaller and produced on average less oestradiol, which is explained by the different endocrine status of the patient at the start of stimulation. In view of this different follicular pattern, rFSH dose adjustments in patients treated with the ganirelix regimen should be based on the number and size of growing follicles, rather than on the amount of circulating oestradiol. The smaller cohort of follicles and the lower oestradiol concentrations are in good agreement with the lower incidence (less than half) of OHSS in the ganirelix group.
The possible direct effect of GnRH antagonists on follicle growth, steroidogenesis, oocyte or embryo quality or implantation is of specific interest, since GnRH receptors have been identified in human granulosa-lutein cells (Latouche et al., 1989; Brus et al., 1997
), and might be present in uterine endometrial tissue (Raga et al., 1998
), although their function and interaction with GnRH or GnRH analogues is not (yet) understood (Ikeda et al., 1997
). Recent studies in vitro with human granulosa cells have demonstrated that neither ganirelix nor cetrorelix exert any significant action on ovarian steroidogenesis (Ortmann et al., 1999
; Verbost et al., 1999
), and in the ganirelix dose-finding study no difference was noted in the number or size of follicles of patients treated in the six different dose groups (Ganirelix dose-finding study group, 1998
).
In comparison with buserelin treatment in a long protocol, the ganirelix regimen resulted in one preovulatory follicle less and, as a consequence, one cumulusoocyte complex less was recovered at oocyte retrieval. This difference is within the preset equivalence margin of 3 oocytes, and is thought to be related to the short regimen rather than ganirelix per se. The recovery of fewer oocytes is a well-described phenomenon of the short protocol of GnRH agonists in comparison with the long protocol (Tan et al., 1992; Cramer et al., 1999
). Overall, the ganirelix regimen resulted in the recovery of good quality oocytes as reflected by the percentage of metaphase II oocytes in ICSI patients (83% in each group), the high fertilization rate (62.1% in each group), and the number of good quality embryos, which was comparable with the reference group. The latter finding suggests a higher recovery of good quality embryos in the ganirelix regimen than in the buserelin group, which is in good agreement with the outcome of a previous small study which compared the antagonist Nal-Glu (5 mg/day) with the agonist leuprolide acetate (Minaretzis et al., 1995
). The recovery of good quality oocytes and embryos is further supported by the good success rates of replaced frozen embryos collected in the dose-finding study of ganirelix (Kol et al., 1999
), as well as in this study.
In the current trial, on average only 2.2 embryos were replaced, which is in line with the current standard practice in several European IVF centres not to replace more than two good quality embryos, in order to prevent multiple pregnancies. In comparison with a large previous multi-centre study of Puregon, using the same stimulation regimen with buserelin, the ongoing pregnancy rate per attempt was very similar to the outcome of the ganirelix regimen (Out et al., 1995). Although the clinical outcome is considered good (ongoing pregnancy rate per attempt was 20.3%), in the current study the pregnancy rate tended to be higher in the reference group. In view of the limited study power, it cannot be excluded that this tendency is related to chance. However, using the same multiple dose regimen and also intranasal buserelin in a long protocol as control, others (Felberbaum, 1999
) reported a vital pregnancy rate per transfer of 27% (compared with 25% in this study) in patients treated with human menopausal gonadotrophin (HMG) and 0.25 mg GnRH antagonist cetrorelix (n = 188) and of 33% (cf. 32% in this study) in patients treated with the agonist (n = 85). Therefore, several other factors that may influence clinical outcome should be considered. For instance, study sites that participated in the previous ganirelix dose-finding study provided a favourable outcome more often for the ganirelix regimen compared with study sites who participated for the first time. This indicates that some clinical experience with the new ganirelix regimen might contribute positively to the success rate. In addition, the regimen applied has not been selected based on prospective research, and further optimization of the regimen might appear beneficial. In the current applied regimen, stimulation was started on day 2 or 3 of the follicular phase; thus serum gonadotrophin and steroid concentrations were higher than after down-regulation in the reference group. High concentrations of serum hormones are especially established in patients who receive the GnRH-agonist flare-up protocol, and these were reported to have a lower clinical pregnancy rate, which is thought to be related to a higher oestradiol concentration before HCG administration, and a higher production of oestradiol per oocyte recovered (Cramer et al., 1999
). In the ganirelix group, the opposite was shown in that before HCG administration oestradiol concentrations were lower, and also the oestradiol production per follicle was lower in the ganirelix group than in the buserelin group. Although in the current study neither serum LH nor oestradiol concentrations appeared to be predictive factors for pregnancy (Loumaye et al., 1997
), it cannot be excluded that the hormonal milieu of the current ganirelix regimen is less favourable for a certain subset of patients. If so, patients might benefit from postponing HCG administration and allowing follicles to grow larger, or to pretreat patients with oral contraceptives which would also allow patient scheduling. Thus, further optimization of treatment, as well as clinical experience with the antagonist regimen, might further optimize clinical outcome in the near future.
Overall, it may be concluded that ganirelix introduces a new treatment option for patients undergoing ovarian stimulation for IVF or ICSI which is safe, short and simple. The clinical outcome was good, and the ongoing pregnancy rate was within the range of pregnancy rates of a long-protocol GnRH-agonist, the latter being supported by many years of clinical experience.
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Notes |
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* T.Åbyholm (Kvinneklinikken, Rikshospitalet, Oslo, Norway); D.Barlow (John Radcliffe Hospital, Oxford, UK); P.Devroey (Academic Hospital, Free University Brussels, Brussels, Belgium); K.Diedrich (Medizinische Universität zu Lübeck, Lübeck, Germany); J.Donnez (Clinique Universitair Brussels, Belgium); V.von Düring (Regionsykehuset I Trondheim, Trondheim, Norway); B.Fauser (Dijkzigt Academic Hospital, Rotterdam, The Netherlands); L.Hamberger (Sahlgrenska Sjukhuset, Götenborg, Sweden); T.Hillensjö (Fertilitets Centrum, Carlanderska Sjukhuset, Götenborg, Sweden); J.N.Hugues (Hôpital Jean Verdier, Bondy, France); C.Jansen (Diaconessenhuis, Voorburg, The Netherlands); J.Kahn (The Fertility Clinic Ciconia, Copenhagen, Denmark); J.Blaabjerg (Herlev Hospital, Herlev, Denmark); F.Olivennes (Hôpital Antoine Béclère, Clamart, France); A.Pellicer (Instituto Valenciano de Infertilidad, Valencia, Spain); S.Pavlou (Mitera Fertility and IVF Unit, Athens, Greece); T.Rabe (Universitätsklinikum, Heidelberg, Germany); A.Rutherford (Leeds General Infirmary, Leeds, UK); B.Tarlatzis (Infertility IVF Centre `Geniki Cliniki', Thessaloniki, Greece); L.Westergaard (Odense Sygehus, Odense, Denmark); B.Mannaerts and G.Borm (Research and Development, NV Organon, Oss, The Netherlands)
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Submitted on December 22, 1999; accepted on March 30, 2000.