Article Depot GnRH agonist versus the single dose GnRH antagonist regimen (cetrorelix, 3 mg) in patients undergoing assisted reproduction treatment

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1 RBMOnline - Vol 7. No Reproductive BioMedicine Online; on web 18 June 2003 Article Depot GnRH agonist versus the single dose GnRH antagonist regimen (cetrorelix, 3 mg) in patients undergoing assisted reproduction treatment Dr Roger Roulier trained in France where he qualified as an endocrinologist and gynaecologist. He has been involved in reproductive medicine since 1978 as clinician in the Public Hospital in Marseille. He is now head of the Reproductive Medicine Unit at the private Reproductive Medicine Institute in Marseille. His research interests include ovarian stimulation protocols and andrology. He participated in several registration studies in infertility and is a member of the French Societies of Endocrinology and Reproductive Medicine. Dr Roger Roulier Roger Roulier 1, Véronique Chabert-Orsini, Marie-Christine Sitri, Bernard Barry, P Terriou Institut de Médecine de la Reproduction (IMR), 6, rue Rocca, Marseille, France 1 Correspondence: r.roulier@imr-marseille.com Abstract The objective of this study was to compare, in a centre with previous experience of gonadotrophin-releasing hormone (GnRH) antagonist use, single administration of a GnRH antagonist [cetrorelix (Cetrotide ) 3 mg] with a single administration of a GnRH agonist [Decapeptyl Retard 3.75 mg] in patients undergoing assisted reproduction treatment (n = 307 and 364 respectively). GnRH agonist was administered on the first day of menses, while cetrorelix was administered when the largest follicle reached 14 mm. Ovarian stimulation was performed with recombinant human FSH (r-hfsh; IU/day). Human chorionic gonadotrophin (HCG, 10,000 IU) was administered when at least two follicles reached a mean diameter 18 mm. Over 90% of patients in both groups reached the criteria for HCG administration and underwent oocyte retrieval and embryo transfer. Duration of FSH therapy (9.95 versus days) and cumulative dose of r-hfsh (1604 versus 1980 IU) were significantly reduced (P < 0.01) in the cetrorelix 3 mg group. The number of oocytes retrieved was lower (8.5 versus 11.2; P < 0.01) with cetrorelix, but the number of embryos replaced was similar (2.2 versus 2.3; NS). The pregnancy rates per oocyte retrieval were the same, 24.5%, in the antagonist and agonist groups. This study indicates that although fewer oocytes are recovered, similar pregnancy rates can be achieved with a GnRH antagonist compared with a GnRH agonist. Additionally, a single dose of 3 mg cetrorelix was administered in 84% of patients, thus being simpler and more convenient for patients. Cetrorelix 3 mg may thus be proposed as a first choice for preventing both a premature LH surge and detrimental rises in LH during ovarian stimulation prior to assisted reproduction treatment. Keywords: assisted reproduction treatment, cetrorelix, Decapeptyl, GnRH agonist, GnRH antagonist Introduction Administration of a gonadotrophin releasing hormone (GnRH) analogue to prevent a premature LH surge is a standard part of modern protocols for assisted reproduction treatment. GnRH agonists have been used since the mid-1980s (Porter et al., 1984; Loumaye, 1990; Hughes et al., 1992), and a number of different agents and formulations are available. GnRH agonists do not provide immediate suppression of LH activity and treatment must therefore be started before the start of controlled ovarian stimulation and continued for 2 4 weeks (Ortmann et al., 2002). Treatment may involve daily injections, intranasal administration several times daily or the use of a long-acting depot formulation. GnRH antagonists have been introduced into clinical practice more recently. Unlike the GnRH agonists, GnRH antagonists provide immediate suppression of LH secretion, allowing treatment to be limited to the few days immediately before HCG administration (Reissmann et al., 2000; Chillik and Acosta, 2001; Huirne and Lambalk, 2001; Barri et al., 2002; Howles, 2002; Olivennes et al., 2002). Two GnRH antagonists, cetrorelix (Cetrotide ) and ganirelix (Orgalutran /Antagon ), are licensed for clinical use (Albano et al., 2000; European Orgalutran Study Group, 2000; Felberbaum et al., 2000; 185

2 186 Olivennes et al., 2000a; Ludwig et al., 2001; Felberbaum and Diedrich, 2002). Cetrorelix may be administered by subcutaneous injection at a daily dose of 0.25 mg (Albano et al., 2000; Felberbaum et al., 2000) or as a single subcutaneous dose of 3 mg. The single injection prevents the occurrence of an LH surge for approximately 4 days (Olivennes et al., 2000b) over a wide range of body weights (Engel et al., 2003). These two regimens of administration have been shown to have equivalent efficacy, safety and tolerance (Ng and Ho, 2001; Olivennes et al., 2003). The single dose has the advantage of increased simplicity compared with the multiple dose regimen. The phase III registration trials carried out to date used a fixed day of stimulation for administering the single 3 mg dose of cetrorelix (Olivennes et al., 2000a). Recently, it has been reported that an individualized approach to the day of cetrorelix administration is both effective and safe (Ludwig et al., 2002a). While the capability of a GnRH antagonist to prevent premature LH surges is well documented, there is an ongoing discussion on the outcome of GnRH antagonists compared with GnRH agonist protocols (Bouchard and Fauser, 2000; Al- Inany and Aboulghar, 2001; Barri et al., 2002; Felberbaum and Diedrich, 2002; Olivennes et al., 2002). Most previous studies, (except that of Ludwig et al., 2002a) have reported that the use of a GnRH antagonist started on a fixed day, rather than in relation to ovarian response. The objectives of this study were prospectively to compare, in one centre with previous experience with GnRH antagonists, the performance of a single administration of a GnRH antagonist (cetrorelix 3 mg), administered on the basis of the size of the leading follicle (14 mm), with a single administration of a GnRH agonist depot (the standard protocol used in the centre) in patients undergoing assisted reproductive techniques. Stimulation characteristics, incidence of ovarian hyperstimulation syndrome (OHSS) and clinical pregnancy rates and live birth outcomes were recorded. Materials and methods This study was carried out in one centre. The study aimed at comparing a single dose regime of administration for cetrorelix (Cetrotide 3 mg; Serono, Geneva, Switzerland) using one dose of 3 mg administered subcutaneously on the basis of follicle size with a single dose of GnRH agonist depot administered intramuscularly (Decapeptyl Retard 3.75 mg; Ipsen Beaufour, Paris, France). Subjects All patients starting IVF/intracytoplasmic sperm injection (ICSI) between September 2000 and March 2001 in the study centre who were less than 39 years of age and had had fewer than three previous attempts were invited to participate in the study. A total of 671 patients were allocated to treatment, based on their year of birth; patients born in an even year received GnRH agonist depot and patients born in an odd year received cetrorelix 3 mg. Therefore, 307 patients were allocated to cetrorelix 3 mg and 364 patients to GnRH agonist depot. Study medication and regimen of administration The injection of GnRH agonist was given on day 1 of menses. After confirmation of down-regulation by vaginal ultrasonography, ovarian stimulation was started at a daily dose of IU r-hfsh (Gonal-F ; Serono, Geneva, Switzerland). For patients allocated to the GnRH antagonist study group, r-hfsh administration was started on day 2 or 3 of a spontaneous menstrual cycle at a daily dose of IU r-hfsh. The starting dose of FSH in both groups was determined based on the age of the patient (patients under 35 years received 150 IU/day in both groups) and on any previous stimulation results. A flexible approach to the day of cetrorelix 3 mg injection was employed based upon size of the leading follicle, which was measured as an average of two diameters by vaginal ultrasound between days 6 and 8. One injection of cetrorelix 3 mg was administered when the largest follicle had reached a diameter of 14 mm. If HCG criteria were not met by 96 h after the 3 mg injection, a daily dose of 0.25 mg cetrorelix was given, up to and including on the day of HCG administration. In both groups, the FSH dose could be adapted from day 6 of stimulation onwards, according to the patient s response as observed by ultrasound monitoring. Final follicular maturation was triggered with 10,000 IU HCG when at least two follicles reached a diameter of 18 mm. Oocyte retrieval, fertilization method (IVF and ICSI) and embryo transfer timing and method were performed according to the clinical centre s routine practice. Embryo quality scoring was performed according to a previously published method with grades ranging from S0 to S4 (Giorgetti et al., 1995). Luteal phase support was mandatory and was given by micronized vaginal progesterone (Utrogestan ). Pregnancies were confirmed by ultrasound for fetal heartbeat approximately 6 weeks after oocyte recovery. A clinical pregnancy was defined as the presence of a fetal heart and sac. Results were usually expressed as mean ± SD. For the comparison of means, the Wilcoxon rank sum test was used. For nominal data comparison, a Fisher s exact test was used. A P-value <0.05 was considered as statistically significant. Results The main demographic characteristics of patients who received cetrorelix are presented in Table 1. The patient populations were comparable with regard to age, cause of infertility, and number of previous assisted reproduction treatments. The proportions of patients undergoing IVF or ICSI were also comparable, and were 51 and 49% and 50 and 50% in patients treated with cetrorelix and patients treated with GnRH agonist respectively. Patient treatment outcomes were found to be very similar, with more than 90% of patients in both groups reaching the criteria for HCG administration, and undergoing oocyte retrieval (Table 2). All oocyte retrievals were routine, with no evidence of premature luteinization. Embryo transfer was performed in 94.6 and 96.3% of patients who underwent oocyte retrieval, in the antagonist and the agonist groups respectively. The

3 Table 1. Demographics. Patients (n) Age (years) 34.1 ± ± 4.1 NS No. previous assisted NS reproduction cycles Values are mean ± SD unless otherwise stated. Table 2. Ovarian response and IVF. No. patients No. patients with oocyte retrieval (%) 278 (90.6) 330 (90.7) NS No. patients with embryo transfer (%) 263 (94.6) 318 (96.3) NS Duration of FSH stimulation (day) 9.95 ± ± 2.29 <0.01 Cumulative dose of FSH (IU) 1604 ± ± 655 <0.01 Serum oestradiol on day of HCG (pg/ml) 1004 ± ± 1021 <0.01 No. oocytes retrieved 8.5 ± ± 6.2 <0.01 No. mature oocytes 6.2 ± ± 4.6 <0.01 No. embryos obtained 4.1 ± ± 4.1 <0.01 Embryo score (%) S S S S S No. transferred embryos 2.2 ± ± 0.9 NS Values are mean ± SD unless otherwise stated. Table 3. Pregnancy and outcome. Clinical pregnancy (n) Clinical pregnancy rate/initiated cycle (%) NS Clinical pregnancy rate/opu (%) NS Spontaneous miscarriage rate (%) NS Ectopic pregnancy rate (%) NS Delivery rate (%) NS Singletons (n) NS Twins (n) NS percentages of patients receiving 225 IU FSH/day were similar in both groups (54.7 versus 52.5%, antagonist and agonist groups respectively). Duration of FSH therapy and cumulative dose of r-hfsh were both significantly reduced in the cetrorelix group when compared with the GnRH agonist group (Table 2). Eighty-four per cent of patients received an HCG injection within 96 h after injection of cetrorelix 3 mg and therefore did not require any additional administration of cetrorelix. By contrast, 27 patients (9%) received one additional injection of cetrorelix (0.25 mg), 12 received two injections (4%), and nine received three or more additional injections (3%). The numbers of oocytes retrieved and embryos obtained were somewhat lower with the antagonist than with the agonist (Table 2). However, the fertilization rates were comparable at 68 and 70%, in the antagonist and agonist groups respectively, and embryo scoring showed similar embryo quality, with 45.9 and 43.9% of high grade embryos (S3 and S4) in the agonist and the antagonist groups respectively. The numbers of transferred embryos were also comparable. Sixty-eight clinical pregnancies were reported in the antagonist group and 81 in the agonist group. These figures translate into pregnancy rates per initiated cycle of 22.1 and 22.2% and per OPU of 24.5 and 24.5% for the antagonist and 187

4 188 agonist groups respectively (NS) (Table 3). There was no difference in the rate of ectopic pregnancy and miscarriage. Overall, 51 and 62 births were reported in the antagonist and agonist groups, with the proportion of singleton pregnancies being similar at 40/51 and 48/62 respectively. In terms of adverse events, the proportion of patients who developed moderate or severe OHSS was found to be lower following GnRH antagonist treatment (three cases) than GnRH agonist treatment (14 cases), with an incidence of 0.9 and 3.8% respectively (P < 0.05). The numbers of severe OHSS cases requiring care were one and four respectively in the two groups. Discussion Prevention of a premature LH surge during stimulation of multiple follicular development is an important aspect of the assisted reproduction protocol. The use of GnRH agonists has been very successful in achieving this objective, and has been until recently the standard regimen for most assisted reproduction procedures. According to the French IVF registry (FIVNAT, 2000), the percentage of cycles using a GnRH long agonist protocol in 1999 was The recent availability of GnRH antagonists for preventing premature LH surge prior to assisted reproduction treatment has brought some clear advantages for patients. Immediate suppression of LH secretion allows the start of treatment only when a significant risk of premature surge is expected, i.e. during the last days of ovarian stimulation, hence minimizing the duration of GnRH analogue treatment from weeks to a few days. Furthermore, the cumulative dose of gonadotrophins and the incidence of OHSS are reduced when compared with GnRH agonist-treated cycles (for review, see Olivennes et al., 2002). The most contentious point regarding the systematic use of GnRH antagonists in assisted reproduction treatment programmes has been the clinical pregnancy rate compared with that with a GnRH agonist. This question has been triggered by an apparently small and statistically nonsignificant but consistent reduction in pregnancy rates with GnRH antagonists in the phase III trials (Albano et al., 2000; European Orgalutran Study Group, 2000; Felberbaum et al., 2000; Barri et al., 2002; Olivennes et al., 2000a et al.). One exception was the Middle East Orgalutran study, which found no apparent difference in pregnancy rates (European and Middle East Orgalutran Study Group, 2001). These differences were subsequently translated into a marginally statistically significant difference by means of a meta-analysis, i.e. overall odds ratio for clinical pregnancy per woman randomized was 0.79 (95% CI, 0.63, 0.99) (Al-Inany and Aboulghar, 2001). Several hypotheses have been proposed to interpret this observation, including a potential direct effect on ovarian function, or on the endometrium, as well as the absence of previous experience of the clinical centre with an antagonist the so-called learning curve process (Bouchard and Fauser 2000; Hernandez 2000). The present large prospective study brings a new and relevant contribution to address this important question, because it has been conducted in a centre with significant clinical experience in using GnRH antagonists, and where a routine assisted reproduction treatment population was enrolled. Furthermore, the single dose of antagonist was administered in a flexible manner, based upon follicle size ( 14 mm) rather than on a standard day of FSH stimulation (day 8). One other recent study (Ludwig et al., 2002a) has examined the utility of administering cetrorelix (either in the multiple or the single dose protocol) in a flexible manner. This study confirms once again that preventing a premature LH rise with a GnRH antagonist single dose protocol instead of a GnRH agonist (i) results in similar cancellation rates before oocyte retrieval, (ii) reduces the duration of FSH treatment and the cumulative dose of FSH, (iii) reduces the incidence of OHSS and (iv) reduces the oocyte yield. High quality embryo (S3 + S4) number is, however, similar. It is also noteworthy that no premature LH surge was recorded in the antagonist group. Of importance is the finding that the clinical pregnancy and delivery rates recorded in this large study were similar. These results show a different trend for pregnancy rates compared with a previously reported study also comparing cetrorelix 3 mg with a depot preparation of GnRH agonist, i.e. pregnancy rates of 22.6 and 28.2% respectively for cetrorelix and the GnRH agonist respectively (Olivennes et al., 2000a). In the latter, however, the study groups were much smaller (113 cetrorelix patients and 35 GnRH agonist patients). This study therefore supports the hypothesis that experience with GnRH antagonists is essential to obtain a pregnancy rate comparable to that obtained with GnRH agonist. It also further confirms that when a pregnancy is established, the probability of delivery is around 75% and is very similar to the delivery rate obtained in assisted reproduction treatment cycles cotreated with a GnRH agonist (Ludwig et al., 2002b). Finally, the single dose antagonist used in this study has the advantage of requiring only one injection in most patients, which increases patient comfort in relation to adverse effects such as hot flushes and weight increase, and can be beneficial for treatment compliance. Cetrorelix 3 mg may thus be proposed as a first choice for preventing both a premature LH surge and detrimental rises in LH during ovarian stimulation prior to assisted reproduction treatment. References Albano C, Felberbaum RE, Smitz J et al Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)-antagonist cetrotide and the LHRH-agonist buserelin. European Cetrotide Study Group. Human Reproduction 15, Al-Inany H, Aboulghar M 2001 Gonadotrophin-releasing hormone antagonists for assisted conception. Cochrane Database of Systematic Reviews (4), CD Barri PN, Martinez F, Coroleu B et al The role of GnRH antagonists in assisted reproduction. Reproductive BioMedicine Online 5 (suppl. 1), Bouchard P, Fauser BCJM 2000 Gonadotropin-releasing hormone antagonist: new tools vs. old habits. Fertility and Sterility 73, Chillik C, Acosta A 2001 The role of LHRH agonists and antagonists. 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