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Abstract |
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Key words: ganirelix/GnRH antagonist/ovarian stimulation/recombinant FSH/triptorelin
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Introduction |
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In current practice, GnRH agonists are used to prevent premature LH surges during ovarian stimulation (Seibel , 1997; Diedrich et al., 1998). Several disadvantages associated with either the initial flare-up (such as ovarian cyst formation) or the down-regulation of gonadotrophin release (e.g. vaginal spotting, hot flushes, headaches, tiredness, and dizziness) are related to the use of GnRH agonists (Caspi et al., 1989
; Barbieri and Friedman , 1991
). The mechanism of action of GnRH agonists requires a long period (23 weeks) of pretreatment to get pituitary suppression before stimulation with FSH can be started (Conn , 1986
). Furthermore, the recovery of the pituitary gland occurs more slowly after treatment with GnRH agonists than after treatment with GnRH antagonists (Oberye et al., 1999b
).
In contrast to GnRH agonist treatment, GnRH antagonists block GnRH receptors by competitive binding resulting in immediate gonadotrophin suppression, which enables a short treatment regimen for ovarian stimulation. Previous studies have shown that steady state concentrations of ganirelix are reached within 23 days of treatment and that maximal suppression of endogenous LH production occurs shortly (4 h) after each injection (Oberyé et al., 1999). Due to its mechanism of action and its relatively short half-life (13 h), rapid and complete recovery of pituitary suppression has been observed after discontinuation of ganirelix treatment (Oberyé et al., 1999). In a dose-finding study in women undergoing ovarian stimulation, it was shown that 0.25 mg of ganirelix effectively prevented LH surges and resulted in the highest pregnancy rates (Ganirelix dose-finding study group , 1998). In the current trial, the efficacy and safety of 0.25 mg ganirelix was compared to a long protocol with triptorelin.
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Materials and methods |
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Study design
An open-label, randomized trial was performed to investigate the efficacy, safety and tolerability of treatment with ganirelix in women undergoing ovarian stimulation.
A schematic overview of the treatment regimens is given in Figure 1. In the ganirelix group, recombinant (r)FSH treatment (Puregon®; NV Organon, The Netherlands) was given from day 2 or 3 of menses onwards by a daily s.c. injection (150 IU in 0.5 ml solvent) until the day of human chorionic gonadotrophin (HCG) administration. From day 6 of rFSH treatment, ganirelix (0.25 mg in 0.5 ml) was administered daily s.c. in the upper leg until and including the day of HCG administration.
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For subjects in both treatment regimens, ovarian stimulation was started by a fixed daily dose of rFSH (150 IU daily) for the first 5 treatment days. From day 6 onwards, the daily dose of rFSH could be adjusted and individualized per subject based on the follicular growth as observed by ultrasonography. On the day of HCG administration, no treatment with rFSH was applied.
HCG (Pregnyl®, NV Organon, The Netherlands, 10 000 IU in 1 ml saline) was administered when at least three follicles 17 mm were measured by ultrasound. About 3036 h after HCG administration, oocyte retrieval was performed followed by IVF or ICSI. No more than three embryos were to be transferred at 2-5 days after oocyte retrieval. Progesterone for luteal support was given according to the centres' routine practice.
Assessments
Prior to the start of rFSH in the ganirelix group and prior to the start of agonist treatment in the triptorelin group, an HCG test was performed to exclude pregnancy. If the onset of menses did not occur within 2 weeks after starting triptorelin treatment, an additional HCG test was performed. Just before the first injection with rFSH, a blood sample was taken for hormone assessments and ultrasound was performed. From day 6 of rFSH treatment until the day of HCG administration, the subject returned to the clinic at least every 2 days for ultrasound and blood sampling. Blood samples for hormone concentrations were taken before the scheduled GnRH analogue injection. Serum FSH, LH, oestradiol and progesterone concentrations were determined by a central laboratory using fluoroimmunoassays (Delfia®; Wallac OY, Finland). Detection limits of these assays were: FSH <1 IU/ml, LH <0.6 IU/ml, oestradiol <14 pg/ml, and progesterone <0.3 ng/ml. Local tolerance after s.c. administration of ganirelix and triptorelin was assessed 1, 4 and 24 h (just prior to the next injection) after injection. Pain, itching, bruising, swelling, and redness were scored by the subject as either none, mild, moderate, or severe on a diary card.
Statistical methods
This study was designed to show that treatment with ganirelix was not inferior to triptorelin in a long protocol in terms of the number of oocytes and ongoing pregnancy rates (ICH Expert Working Group , 1998) `Statistical Considerations in the Design of Clinical Trials' for more information on this subject). Main efficacy parameters included: number of oocytes, number of good quality embryos (grade I and II), ongoing pregnancy rates, and treatment failure, which was defined as not receiving HCG or receiving HCG too early because of premature luteinization. Subjects who did not have embryo transfer were considered discontinuations.
Data from the intent-to-treat (ITT, defined as all subjects randomized who received at least one dose of either ganirelix, triptorelin, or rFSH) group were used for efficacy analysis and data from the all-subjects-treated group (AST) were used for safety analysis. In the current trial the ITT group was identical to the AST group.
For the number of oocytes and good quality embryos, adjusted-for-centre treatment means and their differences were calculated, using a weighed average over the centres based on the Cochran-Whitehead method. For the ongoing pregnancy outcome, Cochran-Mantel-Haenszel weights were used (Whitehead et al., 1991). For the number of oocytes the treatment difference was compared with the equivalence margin of 3 oocytes. The point estimate of the difference of ganirelix and triptorelin in ongoing pregnancy rate was compared with a 5% margin. The analysis of safety data was performed by means of frequency distributions of the incidence of adverse events and local tolerance outcome.
The adjusted treatment differences of means (ATDM) and two-sided confidence intervals (95% CI) between ganirelix and triptorelin are presented for the main parameters only, i.e. the duration of ganirelix treatment, the duration of rFSH treatment, the total dose of rFSH and both the number of follicles 11 mm and the oestradiol concentrations on day 6 and on the day of HCG. Furthermore, ATDM and 95% CI are presented for the number of oocytes retrieved per attempt, the number of good quality embryos and the ongoing pregnancy rate per attempt.
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Results |
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The vast majority of subjects (97.9%) participating in this study was Caucasian. A similar percentage of subjects with primary infertility was observed in both treatment groups (71.8%). The mean duration of infertility for the subjects treated with either ganirelix or triptorelin was 4.3 and 4.1 years respectively. No relevant differences were found between the treatment groups for the cause of infertility, which was mainly male factor (60.2 and 63.1% respectively) and tubal factor (17.7 and 16.2% respectively). In total, 146 couples ICSI was performed in the ganirelix group and for 76 in the buserelin group.
Disposition and cancellations
A total of 337 subjects was treated (226 with ganirelix and 111 with triptorelin). The number of subjects per treatment stage is presented in Table I. A total of 11 subjects (4.9 %) in the ganirelix group and five subjects (4.5%) in the triptorelin group had a treatment failure in that they did not receive HCG or received HCG too early because of premature luteinization. Thirty-seven subjects did not have embryo transfer, 22 subjects (9.7%) in the ganirelix group and 15 subjects (13.5%) in the triptorelin group. Overall, the most frequently reported reasons for discontinuation were insufficient ovarian response [six subjects (2.7%) in the ganirelix group and one subject (0.9%) in the triptorelin group] and fertilization failure (six subjects in each group, i.e. 2.7 and 5.4% in the ganirelix and triptorelin groups respectively).
Duration of treatment and total dose of rFSH
The median duration of the GnRH antagonist protocol was 17 days shorter in comparison to the long protocol of GnRH agonist (9 versus 26 days, restricted to subjects who had HCG). The median (range) duration of exposure to triptorelin was 26 (1641) days whereas subjects treated with ganirelix were exposed for 5 (210) days (ATDM and 95% CI: 20.6; 21.1 to 20.2). The median (range) total amount of rFSH administered was 1350 (9003900) and 1800 (10504050) IU (ATDM and 95% CI 369; 454 to 283). The median (range) duration of rFSH treatment was 9 (614) and 11 (716) days (ATDM and 95% CI: 1.7; 2.1 to 1.4) and the median daily dose was 150 and 178 IU/day in the ganirelix and triptorelin groups respectively.
Follicle growth
The mean number of follicles 11 mm on days 1, 6, 8 of stimulation, and on the day of HCG are presented in Figure 2
. On days 6 and 8, the mean number of follicles was higher in the ganirelix treated subjects as compared with the triptorelin-treated subjects [4.9 versus 2.5 (ATDM and 95% CI: 2.4; 1.7 to 3.0) and 8.0 versus 6.7 follicles respectively], whereas on the day of HCG a comparable number of follicles
11 mm was observed in each group (10.1 versus 10.7 follicles respectively; ATDM and 95% CI: 0.0, 0.9 to 0.9). The mean numbers of follicles
11,
15 and
17 mm recorded on the day of the last ultrasound before HCG injection are given in Table II
.
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Serum hormone concentrations
Median pre-dose serum hormone concentrations during treatment are presented in Table III. On the first day of rFSH treatment, LH, FSH and oestradiol concentrations were higher in the ganirelix group as compared to the triptorelin group (4.5 I versus 1.3 IU/ml, 5.8 versus 2.8 IU/ml, and 39.8 versus 16.6 pg/ml respectively).
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LH concentrations on the day of HCG of the two groups were comparable. FSH concentrations increased to 7.2 IU/ml in the ganirelix treatment group and to 8.2 IU/ml in the triptorelin treatment group, whereas oestradiol concentrations were higher in the triptorelin-treated subjects as compared to ganirelix-treated subjects (1090 versus 1370 pg/ml respectively; ATDM and 95% CI: 369, 561 to 177). The progesterone concentrations of the two treatment groups from day 1 of stimulation until the day of HCG were comparable.
Before oocyte retrieval, the LH concentrations were slightly higher (1.10 IU/l versus not detectable), the FSH concentrations were comparable (3.3 versus 3.4 IU/l), and the oestradiol and progesterone concentrations tended to be lower (512 versus 776 pg/ml and 5.1 versus 6.2 ng/ml respectively) in the ganirelix-treated subjects.
At embryo transfer, LH concentrations were below detection limits (<0.6 IU/ml) in the majority of subjects treated with either ganirelix (median <0.6, range <0.62.52 IU/ml) or triptorelin (median <0.6, range <0.6 to <0.6 IU/ml). FSH and progesterone concentrations of both treatment groups were comparable, whereas the oestradiol concentration was still slightly lower in the ganirelix-treated subjects.
The hormonal concentrations at week 2 after embryo transfer were higher for LH and FSH (1.25 IU/l versus not detectable and 2.2 IU/l versus not detectable), lower for oestradiol (54 versus 93 pg/ml) and comparable for progesterone (17.6 versus 17.0 ng/ml) in subjects treated with ganirelix.
Clinical outcome
The total mean number of cumulus-oocyte complexes per attempt was 7.9 and 9.6 for the ganirelix and triptorelin groups respectively (Table IV). The ATDM was 1.3 oocytes with a 95% CI of 2.4 to 0.2. The estimated treatment difference and confidence limit were well within the equivalence margin of 3 oocytes as described. The mean number of cumulus-oocyte complexes per attempt for subjects who had IVF was 6.9 and 10.4 for the ganirelix and triptorelin group respectively. For subjects who had ICSI, the mean number of cumulus-oocyte complexes per attempt was 8.4 for the ganirelix treatment group and 10.3 for the triptorelin treatment group, whereas the number of metaphase II oocytes was 6.8 (81%) and 8.2 (80%) respectively. The mean fertilization rates of ganirelix- and triptorelin-treated subjects were comparable (64.0 and 64.9% respectively).
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Mean implantation rates were identical (22.9%). In total, two ectopic pregnancies were reported, both in the ganirelix group. Miscarriage rates per clinical pregnancy were 10.3% for the ganirelix group and 11.4% for the triptorelin group. Vital pregnancy rates per attempt were 32.3 and 37.8% and per transfer 35.8 and 41.7% for the ganirelix group and triptorelin groups respectively. The ongoing pregnancy rates per attempt were 31.0% in the ganirelix group and 33.9% in the triptorelin group (ATDM and 95% CI: 2.5, 13.0 to 8.0) (Table IV).
Safety and tolerance
A total of 51 subjects (22.6%) in the ganirelix group and 30 subjects (21.6%) in the triptorelin group experienced at least one adverse event. Serious adverse events were observed in 3.1% of the subjects in the ganirelix group versus 2.7% in the triptorelin group. None of the reported serious adverse events were drug-related and all subjects recovered.
Four subjects (1.8%) in the ganirelix group and one subject in the triptorelin group (0.9%) experienced signs and symptoms related to ovarian hyperstimulation syndrome (OHSS). One subject suffered from severe OHSS and was hospitalized; all other cases were of mild or moderate intensity.
At least one moderate or severe local reaction at 1 h after injection was reported by 26 subjects (11.9%) treated with ganirelix and by 26 subjects (24.1%) treated with triptorelin (Table VI). At 4 and 24 h after injection, these incidences were 5.1 and 4.6% in the ganirelix group and 16.2% and 9.5% in the triptorelin group. The most frequently reported local reactions at 1 h were redness (5.9 versus 10.2%) and pain (3.2 versus 10.2%). At 4 h after injection, most of these reactions had disappeared except for bruising (1.9 versus 10.5%). The tolerance index, which indicates the mean number of days with moderate or severe scoring per subject, was 0.2 for subjects treated with ganirelix and 0.84 for subjects treated with triptorelin.
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Discussion |
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At oocyte retrieval, the number of oocytes recovered tended to be lower in the antagonist group, whereas the percentages of metaphase II oocytes (in the ICSI-treated subjects), the fertilization rates and the number of good quality embryos were similar in both treatment groups. These findings are in good agreement with those of previous controlled European studies with GnRH antagonists (Albano et al., 2000; European Orgalutran study group, 2000). However, the overall implantation rates in the current study were higher in comparison to those trials. Furthermore, the implantation rates of the two treatment arms in the current study were identical (22.9%) with similar ongoing pregnancy rates per attempt (31.0 versus 33.9%). Differences between the current study and the previous controlled studies of GnRH antagonists might be explained by a slightly younger mean age (2 years) and a higher frequency of a male factor as the major cause of infertility in the subjects of the current study.
Ganirelix treatment was started on day 6 of rFSH stimulation. It was previously demonstrated that median serum LH concentrations tend to rise after 5 days of stimulation (Ganirelix dose-finding study group , 1998). From day 6 onwards, oestradiol concentrations become as high as in the late follicular phase of the normal menstrual cycle, i.e. the risk of a premature LH rise becomes imminent (Filicori et al., 1986). In the current study, a rise in LH accompanied by a rise in progesterone concentration during ganirelix treatment was observed in only one subject supporting the effectiveness in preventing premature LH surges by daily treatment with 0.25 mg ganirelix. Prior to the start of ganirelix treatment, LH rises were observed in seven subjects, which were effectively suppressed by treatment with ganirelix. All seven women underwent embryo transfer and three of them achieved an ongoing pregnancy indicating that early LH rises do not affect the clinical outcome. All three subjects who had an ongoing pregnancy also experienced a rise in progesterone (81.2, 37.8 and 37.3 ng/ml at embryo transfer).
The initial follicular growth was faster and, consequently, oestradiol concentrations were higher in the ganirelix group. These findings are consistent with those from other studies (Albano et al., 2000; European Orgalutran study group, 2000) and are thought to be related to the start of stimulation at day 2 to 3 of the menstrual cycle when follicular recruitment has already occurred and serum gonadotrophin concentrations are higher than after pituitary down-regulation. Finally, at the day of HCG, the ganirelix regimen resulted in a similar final cohort of follicles, though serum oestradiol concentrations were lower than those obtained with the GnRH agonist protocol in the current study. This may be partly explained by the shorter mean duration of treatment and the lower total dose of administered rFSH in subjects treated with ganirelix. In a recent study, the same differential pattern of follicular growth was observed using another GnRH antagonist, cetrorelix, and human menopausal gonadotrophin (HMG) (Albano et al., 2000
) in a similar ovarian stimulation protocol. Since HMG contains LH activity (75 IU FSH and 75 IU LH) it is therefore unlikely that the observed differences in follicle dynamics can be explained by the amount of LH activity in the circulation. In addition, the extent of pituitary LH suppression does not affect follicular growth as demonstrated in the dose-finding study of ganirelix (Ganirelix dose-finding study group , 1998
). In contrast, data from a recently published study suggest that low LH concentrations on day 8 of stimulation have a detrimental effect on pregnancy outcome in women downregulated with low doses of the GnRH agonist buserelin (Westergaard et al., 1999). If so, an additional advantage of antagonists over agonists would be that, due to their competitive mechanism of action, the degree of suppression can be tailored rapidly by adjusting the antagonist dose.
In previous studies using buserelin in a long protocol as a reference, the incidence of OHSS was clearly lower in the GnRH antagonist group than in the agonist group i.e. 1.1 versus 6.5% (Albano et al., 2000) and 2.4 versus 5.9% (European Orgalutran study group, 2000). This finding may be explained by the smaller cohort of growing follicles and the lower serum oestradiol concentrations in the GnRH antagonist-treated subjects during the late follicular phase, which are predictors of the syndrome (Navot et al., 1992
; Brinsden et al., 1995
). Although similar follicular growth patterns and similar oestradiol concentrations were found in the current study the incidence of OHSS was similar in both treatment groups, which can be explained by the overall low percentage of OHSS (1.8 versus 0.9% in the ganirelix- and triptorelin-treated subjects respectively). Furthermore, there is increasing evidence that treatment can be safely continued by using a single bolus injection of a GnRH agonist to induce final oocyte maturation (Imoedemhe et al., 1991
; Lewit et al., 1995
; Ben Arie et al., 1996
) if patients are at risk for developing OHSS while treated with FSH and ganirelix (Itskovitz et al., 2000
).
Local skin reactions upon administration of ganirelix are limited, which is in agreement with the minimal histamine-releasing properties of the third generation antagonists such as ganirelix (Rabinovici et al., 1992). Per treatment cycle the percentage of subjects with at least one local reaction of moderate or severe intensity at 1 h after administration was twice as low after ganirelix treatment as compared with triptorelin-treated subjects. Subjects treated with ganirelix reported especially pain, redness, and bruising less frequently. Furthermore, the tolerance index was lower in the ganirelix group as compared with the triptorelin group. Taking all safety data together, it can be concluded that including ganirelix in an ovarian stimulation protocol for IVF or ICSI is safe and well-tolerated.
In summary, it may be concluded that ganirelix offers a new treatment regimen in ovarian stimulation that is short, safe and well-tolerated, optimizing convenience for the patient.
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Notes |
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*The European and Middle East Ogalutran® Study Group: F.Fischl (Vienna, Wien, Austria), Aboulghar (Cairo, Egypt), Marès (Nimes, France), B.Nicollet (Bron, France), H.M.Behre (Münster, Germany), H.van der Ven (Bonn, Germany), A.Simon (Jerusalem, Israel), Z.Kilani (Amman, Jordan), P.N.Barri (Barcelona, Spain), M.Häberle (Baden, Switzerland), D.D.M.Braat (Nijmegen, The Netherlands) and N.Lambalk (Amsterdam, The Netherlands).
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References |
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Submitted on June 20, 2000; accepted on December 20, 2000.