Review Gonadotrophin-releasing hormone antagonists for assisted conception: a Cochrane Review

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1 RBMOnline - Vol 14. No Reproductive BioMedicine Online; on web 27 March 2007 Review Gonadotrophin-releasing hormone antagonists for assisted conception: a Cochrane Review Dr Hesham Al-Inany obtained his MD in 1998 from Cairo University, Egypt. He is presently Assistant Professor at the Department of Obstetrics and Gynecology, Cairo University and IVF consultant in the Egyptian IVF-ET centre, Maadi, Cairo. Dr Al-Inany has been an Editor in the Cochrane Menstrual Disorders SubFertility Cochrane Group since 2002 and has been a member of the Editorial Board of the British Journal of Obstetrics and Gynecology since He has been author or co-author of more than 50 research papers in both national and international journals. Dr Hesham Al-Inany HG Al-Inany 1,3, AM Abou-Setta 2, M Aboulghar 1 1 Department of Obstetrics and Gynaecology, Faculty of Medicine, Cairo University, 8 Moustapha Hassanin Street, Manial, Cairo, Egypt; 2 Private Clinic, Cairo, Egypt 3 Correspondence: Tel: ; Fax: ; kaainih@link.net This paper is based on a Cochrane Review published in The Cochrane Library 2006, Issue 3 (see for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the review. Abstract Gonadotrophin-releasing hormone (GnRH) antagonists suppress gonadotrophin secretion resulting in dramatic reduction in treatment cycle duration. Assuming comparable clinical outcomes, these benefits may justify changing the standard long GnRH agonist protocol to GnRH antagonist regimens. To evaluate the evidence, databases (e.g. Cochrane Library, MEDLINE, EMBASE) were electronically searched, hand searches were performed, and manufacturers in the field were contacted. Twenty-seven randomized controlled trials (RCT) fulfilled inclusion criteria for comparison of GnRH antagonist with long GnRH agonist protocol. Clinical pregnancy rate and ongoing pregnancy/live-birth rate were significantly lower in the antagonist group (P = 0.009; OR = 0.83, 95% CI and P = 0.02; OR = 0.82, 95% CI respectively). Conversely, incidence of severe OHSS was significantly reduced with the antagonist protocol (P = 0.01; OR = 0.60, 95% CI ), and interventions to prevent OHSS were administered more frequently in the agonist group (P = 0.03; OR = 0.43, 95% CI ). Concluding, GnRH antagonist protocols are short, simple, with good clinical outcomes and significant reduction in severe OHSS incidence and gonadotrophin amount; however, the lower pregnancy rate compared with the GnRH agonist long protocol necessitates counselling subfertile couples before recommending change from GnRH agonist to antagonist. Keywords: agonist, antagonist, GnRH, IVF, meta-analysis Introduction 640 Induction of ovulation is one of the major advances in the treatment of subfertility in the second half of the twentieth century. One aspect of ovulation induction that requires attention is the occurrence of an LH surge, which may occur prematurely before the leading follicle reaches the optimum diameter for triggering ovulation by human chorionic gonadotrophin (HCG) injection. Such premature LH surge prevents effective induction of multiple follicular maturation for IVF in a significant number of women. Gonadotrophin-releasing hormone agonists (GnRHa) have played an important role in reducing the incidence of premature LH surges by reversibly blocking pituitary gonadotrophin secretion. As a result, the rate of cancellation of assisted conception cycles was decreased and pregnancy rates were increased (Hughes et al., 1992; Albano et al., 1996). However, the use of GnRHa is not without disadvantages. The prolonged protocol of GnRHa that proved to be the most efficacious (Daya et al., 1998) needs 2 3 weeks for desensitization, with relatively high costs due to increased requirement of gonadotrophin injections and increased need for hormonal and ultrasonographic measurements (Olivennes et al., 1994). Gonadotrophin-releasing hormone antagonists have emerged as an alternative in preventing premature LH surges. In comparison 2007 Published by Reproductive Healthcare Ltd, Duck End Farm, Dry Drayton, Cambridge CB3 8DB, UK

2 with the GnRHa, the pharmacological mechanism by which GnRH antagonists suppress the release of gonadotrophins is completely different. While the agonists act on chronic administration through down-regulation of receptors and desensitization of the gonadotrophic cells, the antagonists bind competitively to the receptors and thereby prevent endogenous GnRH from exerting its stimulatory effects on the pituitary cells. The competitive blockade of receptors leads to an immediate arrest of gonadotrophin secretion. This mechanism of action is dependent on the equilibrium between endogenous GnRH and the applied antagonist. This antagonistic effect is highly dosedependent, in contrast to the agonists (Felberbaum et al., 1995). While the first generation of GnRH antagonists showed allergic side-effects due to induced histamine release, which hampered the clinical development of these compounds, third generation GnRH antagonists such as ganirelix (NV Organon, Oss, The Netherlands) or cetrorelix (ASTA-Medica, Frankfurt am Main, Germany) have solved these problems and have recently been approved for clinical use (Olivennes et al., 1998). Applying GnRH antagonists for ovulation induction in assisted conception will result in a dramatic reduction in the duration of GnRH analogue treatment and reduce the amount of gonadotrophin needed for stimulation. Other potential benefits include a lower risk for developing severe ovarian hyperstimulation syndrome (OHSS) and avoiding oestrogen deprivation symptoms (e.g. hot flushes, sleep disturbances, headache) as frequently observed in the prestimulation phase of a long protocol. Whether the previously mentioned benefits justify a change in routine treatment from the standard long GnRHa protocol to the newly designed GnRH antagonist regimen depends on whether the clinical outcome using these protocols is equivalent. The first version of this Cochrane review aimed at determining the efficacy of the GnRH antagonist regimen and the standard long GnRHa protocol in patients undergoing controlled ovarian hyperstimulation for assisted reproduction techniques. Since its release in 2001, many studies have been conducted to address the same topic. It was found necessary to update the best available evidence comparing GnRH antagonist versus long agonist protocol. Materials and methods Objectives To update the current evidence regarding the efficacy of gonadotrophin-releasing hormone (GnRH) antagonists with the standard long protocol of GnRHa for ovarian stimulation in assisted conception. Criteria for considering studies for this review Types of studies Only randomized controlled studies were included in this review comparing different protocols of GnRH antagonists with GnRHa in assisted conception cycles. Types of participants These were subfertile couples undergoing ovulation induction as part of an assisted reproductive programme using GnRH antagonists for the prevention of premature LH surges. The following characteristics of the participants were considered: age of the woman; duration of subfertility; semen analysis results, ovulatory status confirmed with luteal progesterone or sonographic evidence of ovulation; and tubal patency. Types of intervention This included pituitary suppression with GnRH antagonist or GnRHa together with ovarian stimulation with recombinant or urinary human follicle stimulating hormone (hfsh) and/or human menopausal gonadotrophin (HMG) as part of an assisted reproduction technique. Types of outcome measures Primary outcomes 1. Pregnancy rate per woman, live-birth per woman. Secondary outcomes 1. Incidence of OHSS. 2. Spontaneous miscarriage rate. 3. Duration of GnRHa treatment. 4. Amount of gonadotrophins used. Search methods for identification of studies The review authors searched: 1. The Cochrane Menstrual Disorders and Subfertility Review Group specialized register of controlled trials was searched using the keywords: gonadotrophinreleasing hormone antagonists; gonadotrophin-releasing hormone agonists; controlled ovarian hyperstimulation. 2. MEDLINE database using the same keywords (MeSH words). 3. EMBASE database using the same keywords. 4. Hand searched the reference lists of included studies. 5. Abstracts of The American Society for Reproductive Medicine ( ) and European Society for Human Reproduction and Endocrinology ( ) meetings. 6. The review authors contacted pharmaceutical industries to discuss the possibility of prospective registration of trials. If important information was lacking from the original publications, the authors were contacted. Methods of review Included trials data were processed as described in the Cochrane Handbook. The review authors assessed the methodological quality of all selected studies and appropriateness for inclusion without consideration of their results. The methodological quality of each trial was assessed in terms of randomization Each trial was judged, and given a quality rating as adequate or inadequate: A = adequate, B = unclear, C = inadequate, D = not used. Randomization was considered to be proper when 641

3 642 computer-generated random number tables, or dark-sealed envelopes were used. Quasi-randomization was considered to be an inadequate form of randomization, and therefore quasirandomized studies were excluded from this review. The studies were analysed for the following quality criteria and methodological details. Trial characteristics 1. Study design. 2. Method of randomization. 3. Multi-centre or single-centre design. 4. Presence or absence of blinding to treatment allocation. 5. Number of patients randomized, excluded or lost to follow-up. 6. Whether an intention-to-treat analysis was done. 7. The presence of a power calculation. 8. Duration, timing and location of the study. 9. Sources of any funding. Characteristics of the study participants 1. Cause and duration of pre-existing subfertility. 2. Age of the woman. 3. Body mass index (BMI). 4. Number of previous IVF-embryo transfer cycles. Interventions used 1. Method of ovarian stimulation. 2. Method of GnRH antagonist and agonist administration: timing, route, duration and dose. 3. Amount of gonadotrophin needed for stimulation. Outcomes 1. Success rate (pregnancy/woman, pregnancy/cycle) as determined by serum β-hcg and ultrasound examination for fetal heart activity. 2. Incidence of OHSS (detected by clinical grading of OHSS, laboratory investigations as haematocrit, haemoglobin, renal functions and imaging techniques as ovarian and abdominal ultrasound and chest X-ray). 3. Number of cycle cancellations. 4. Spontaneous miscarriage rate. 5. Duration of GnRH analogue treatment. 6. Amount of gonadotrophins used. Two authors (HA and AMAS) independently extracted data and assessed the quality of trials using forms designed according to Cochrane guidelines. Additional information on trial methodology and/or actual original trial data were sought from the authors of trials that appeared to meet the eligibility criteria but had aspects of methodology that were unclear, or where the data were in a form unsuitable for meta-analysis. Trial authors were contacted to request additional information and/or data, and a response was also received from the sponsoring pharmaceutical companies. The heterogeneity between the results of different studies was examined by inspecting the scatter in the data points and the overlap in their confidence intervals, and more formally by checking results of chi-squared tests. It was planned to look at the possible contribution of differences in trial design to any heterogeneity identified in this manner. If possible, the outcomes were pooled statistically. The dichotomous data results for each study were expressed as an odds ratio with 95% confidence intervals. These results were combined for meta-analysis with RevMan software (using the Peto-modified Mantel Haenszel method). Relative risk or absolute risk difference were presented where appropriate. Description of studies The characteristics of 27 trials included in the analysis can be found in the original Cochrane review. Twenty-seven RCT were identified to meet the inclusion criteria (original review included five only). Of the 27 included studies, 20 trials involved an unspecified population of infertile couples. The remaining trials were performed in specific infertile populations. These subgroups were poor responders (Inza et al., 2004; Cheung et al., 2005; Marci et al., 2005), polycystic ovary syndrome (Kim et al., 2004; Bahçeci et al., 2005), mild male factor or unexplained infertility (Zikopoulos et al., 2005) and tubal factor (Causio et al., 2004). Three types of antagonist protocols were identified, a single, long-acting administration, a fixed, daily administration and a flexible administration protocol. The single, long-acting protocol was utilized by two included studies (Olivennes et al., 2000; Lee et al., 2005). In the fixed protocol, GnRH antagonist was begun on day 6 of FSH treatment, regardless of follicle size. This protocol was used by seven included studies (Albano et al., 2000; Euro Orgalutran et al., 2000; Euro Midd East et al., 2001; North American et al., 2001; Cheung et al., 2005; Xavier et al., 2005; Zikopoulos et al., 2005). In the flexible protocol, GnRH antagonist is administered according to the follicle size, and not the cycle date, nor the day of FSH administration. This protocol was identified in 13 included studies (Franco et al., 2003; Hohmann et al., 2003; Londra et al., 2003; Brelik et al., 2004; Check et al., 2004; Kim et al., 2004; Loutradis et al., 2004; Badrawy et al., 2005; Bahçeci et al., 2005; Barmat et al., 2005; Lee et al., 2005; Marci et al., 2005; Rombauts et al., 2006). The type of antagonist administration was not clear in four included trials (Friedler et al., 2003; Causio et al., 2004; Inza et al., 2004; Kyono et al., 2005). In 13 included trials, the antagonist ceterolix was administered (Albano et al., 2000; Olivennes et al., 2000; Hohmann et al., 2003; Brelik et al., 2004; Kim et al., 2004; Loutradis et al., 2004; Bahçeci et al., 2005; Cheung et al., 2005; Kyono et al., 2005; Lee et al., 2005; Marci et al., 2005; Xavier et al., 2005; Zikopoulos et al., 2005). In another seven included trials, the antagonist ganirelix was administered (Euro Orgalutran et al., 2000; Euro Midd East et al., 2001; North American et al., 2001; Franco et al., 2003; Badrawy et al., 2005; Barmat et al., 2005). In six included trials, the type of antagonist used was unclear (Londra et al., 2003; Causio et al., 2004; Check et al., 2004; Freitas et al., 2004; Inza et al., 2004; Rombauts et al., 2006). Patients randomized to treatment with GnRH antagonist started ovarian stimulation with recfsh on day 2 or 3 of the menstrual cycle with a once daily subcutaneous injection.

4 The GnRH antagonist was started on stimulation day 6 by daily s.c. administration up to and including the day of human chorionic gonadotrophin (HCG) administration in fixed protocol and depending on follicle size in flexible protocol. The GnRHa reference treatment was started in the midluteal phase (cycle days 21 24) by either daily intranasal or subcutaneous administration. Ovarian stimulation was started after 2 weeks if pituitary down-regulation was established (serum oestradiol concentration < 50 pg/ml). In both treatment groups, ovarian stimulation was started with a fixed daily dose of 150 or 225 IU recfsh or HMG for the first 5 stimulation days. Thereafter, the dose of gonadotrophin was adapted depending on the ovarian response as monitored via ultrasonography. Triggering of ovulation was induced with HCG (10,000 IU) if at least three follicles >17 mm were observed by ultrasonography. Methodological quality Randomization All trials had parallel design and proper randomization was carried out by fifteen studies, using interactive voice response systems (Albano et al., 2000; Euro Orgalutran et al., 2000; Euro Midd East et al., 2001; Rombauts et al., 2006), stratified randomization (North American et al., 2001), computergenerated random number tables (Hohmann et al., 2003; Loutradis et al., 2004; Bahçeci et al., 2005; Cheung et al., 2005; Prapas et al., 2005; Xavier et al., 2005) or sealed envelopes (Badrawy et al., 2005; Barmat et al., 2005; Zikopoulos et al., 2005). In addition, the mode of randomization is unclear from seven studies (Olivennes et al., 2000; Franco et al., 2003; Friedler r et al., 2003; Londra et al., 2003; Brelik et al., 2004; Causio et al., 2004; Check et al., 2004; Inza et al., 2004; Kim et al., 2004; Kyono et al., 2005; Lee et al., 2005; Marci et al., 2005). Blinding Furthermore, blinding was examined with regards to who was blinded in the trials. All levels were sought and categorized as follows: (i) double blind (neither the investigator, nor the participants knew of the allocation); (ii) single blind (the investigator only knew of the allocation); (iii) no blinding (both investigator and participant knew the allocated treatment); (iv) unclear. Since it was impossible to administer the different medication (i.e. long and antagonist) according to one standard protocol, almost all the studies were open-label (i.e. no blinding). One study (Cheung et al., 2005) blinded the clinicians and embryologists from the treatment allocation by using a nurse practitioner to administer the medications. A second study (El Sahwi, 2005) stated that it was blinded, but no further data was unavailable. Sample size calculations Sample size calculations were considered to be proper when the authors of the studies precalculated the number needed in each arm prior to starting the trial. This helps to prevent the occurrence of type II errors. None of the studies performed an a priori power calculation to determine the sample size needed. Five percentage point difference in pregnancy rate situated in the region of 20% would require over 1200 women in each treatment group to draw a conclusion on pregnancy rate (Olivennes et al., 2000). Thus, each trial was not designed to adequately test the null hypothesis of no difference in pregnancy rates between the new GnRH antagonist regimen and the long protocol of GnRHa endometrial thickness was not reported in any trial. Study participant follow-up Finally, the degree of study participant follow-up was evaluated. The optimum follow up would be to report on the number of single, healthy babies going home with their parents (e.g. single, live, take-home baby rate). If this was unavailable, other degrees of follow up were also desired including ongoing pregnancy rate (OPR). In 16 studies, some degree of follow up was described. Of these, none described the single, live, take-home baby rate or the take-home baby rate. Two studies described the live-birth rate (Albano et al., 2000; Barmat et al., 2005). In addition, 14 studies described the ongoing pregnancy rate (Euro Orgalutran et al., 2000 Olivennes et al., 2000;; Euro Midd East et al., 2001; North American et al., 2001; Hohmann et al., 2003; Check et al., 2004; Badrawy et al., 2005; Bahceci et al., 2005; Cheung et al., 2005; Marci et al., 2005; Zikopoulos et al., 2005; Rombauts et al., 2006). In six studies, no follow-up of the pregnant participants was evident (Franco et al., 2003; Friedler r et al., 2003; Londra et al., 2003; Loutradis et al., 2004; Kyono et al., 2005; Xavier et al., 2005). Randomization was done at time of recruitment of participants. None of the trials used double blinded treatment allocation as blinding was difficult to be conducted in such trials, because, in the GnRH long protocol, ovarian suppression is required before starting ovulation induction by gonadotrophins. In contrast, the GnRH antagonist is given after starting gonadotrophin stimulation. Results The included studies enrolled 3865 participants who were randomized although the sample size varied across the trials. In total, 2292 women were randomized to treatment with the GnRH antagonist and 1573 women were randomized to treatment with GnRHa. The analysis was done on the number of women randomized not on all participants treated. It was observed that in individual trials, women treated with the GnRH antagonist required significant less FSH/HMG and the duration of stimulation was significantly shorter in each trial. The individual trials showed no statistically significant differences between the agonist and antagonist regime regarding clinical pregnancy rate. After pooling the data from all included studies, the following was observed. Pregnancy per woman The clinical pregnancy rate was significantly lower in the antagonist group (P = 0.009). OR for clinical pregnancy per 643

5 woman randomized was 0.83 (95% CI ) in favour of the long GnRHa protocol (Figure 1). The chi-squared test for heterogeneity of treatment effect was not statistically significant. The absolute treatment effect (ATE) was calculated to be 4.7%. The number needed to treat to benefit (NNTB) was 21. This means that for every 21 subfertile couples undergoing IVF/ICSI programme, one additional successful pregnancy can be expected in the GnRHa treated group The ongoing pregnancy/live-birth rate showed the same significant lower pregnancy in the antagonist group (P = 0.02; OR 0.82, 95% CI ; Figure 2). Incidence of severe OHSS Using the Peto modified Mantel Haenszel method, data were combined across the studies showing statistically significant reduction in incidence of severe OHSS with antagonist protocol. The odds ratio was calculated (P = 0.01; OR 0.60, 95% CI ; Figure 3). In addition, interventions to prevent OHSS (e.g. coasting, cycle cancellation) were administered more frequently in the agonist group (P = 0.03; OR 0.43, 95% CI ; Figure 4). The chi-squared test for heterogeneity of treatment effect was not statistically significant. Risk difference was estimated to be 0.02 (95% CI 0.03 to 0.00). Spontaneous miscarriage rate There was no statistically significant difference between the two protocols regarding the incidence of multiple pregnancy and miscarriage rates were similar between the two groups [P = 0.29; OR 0.82, 95% CI (data not shown) and P = 0.90; OR 0.97, 95% CI (Figure 5)] respectively. Cycle characteristics The number of days of analogue treatment was longer in the agonist arm (P < ; WMD 20.90, 95% CI to 19.60; data not shown). So was the number of days of HMG treatment (P = ; WMD 1.62, 95% CI 1.81 to 1.43; Figure 6). Also, the number of HMG ampoules used was significantly different between the two groups [(P = ; WMD 1.37, 95% CI 1.85 to 0.89; Figure 7). On the day of oocyte retrieval, fewer oocytes were retrieved in the antagonist arm (P = ; WMD 1.07, 95% CI 1.52 to 0.61; Figure 8) and this appeared to lead to fewer embryos being available for transfer but this result was not significant (P = 0.71; WMD 0.02, 95% CI 0.09 to 0.14; Figure 9). Furthermore, the number of embryos transferred was similar (P = 0.70; WMD 0.01, 95% CI 0.06 to 0.04; Figure 10). Figure 1. From analysis of pregnancy outcome: clinical pregnancy rate. 644

6 Figure 2. From analysis of pregnancy outcome: ongoing pregnancy/live birth rate. Figure 3. From analysis of ovarian hyperstimulation: OHSS. Figure 4. From analysis of ovarian hyperstimulation: cycles cancelled, or coasting, due to high risk of OHSS. 645

7 Figure 5. From analysis of pregnancy outcome: miscarriage rate. Figure 6. From analysis of ovarian stimulation: days of HMG treatment. Figure 7. From analysis of ovarian stimulation: number of HMG ampoules. 646

8 Figure 8. From analysis of ovarian stimulation: number of oocytes retrieved. Figure 9. From analysis of pregnancy outcome: number of embryos obtained. Figure 10. From analysis of pregnancy outcome: number of embryos transferred. 647

9 648 Discussion Over the last two decades, GnRHa have been used in ovarian stimulation protocols in assisted reproductive techniques in combination with gonadotrophins to prevent a premature LH surge. The concept of suppressing gonadotrophins by competitive receptor blockage rather than through pituitary desensitization with its inevitable flare-up is compelling. Controlling the endogenous LH surge by GnRH antagonists may increase the efficiency both in unstimulated and clomiphene citrate cycles (Rongières-Bertrand et al., 1999). The previous version of this systematic review included only five studies but all were large multicentre RCT. This updated version included 21 RCT and confirmed most of the findings in the previous version. The number of oocytes retrieved was consistently smaller in women treated with the GnRH antagonist, which was in good agreement with the smaller cohort of growing follicles, the lower amount of gonadotrophin used and the shorter duration of stimulation. There was a statistically significant reduction in pregnancy rate in GnRH antagonist group. This reduction occurred despite the transfer of an equivalent number of good quality embryos in both group being transferred. However, there was reduction in incidence of severe OHSS. This finding was not observed in the previous version of this systematic review. The increased number of participants has allowed this difference to be detected. It can be recognized that there was a consistent trend in favour of GnRHa whether in terms of oocytes retrieved or number of embryos obtained. These findings together with lower concentrations of serum oestradiol during ovarian stimulation with the antagonists may support the new finding that antagonist reduce the incidence of severe OHSS. The persistent lower pregnancy rate with antagonist may raise questions on the impact of GnRh antagonist on the endometrium and subsequently on implantation. Further controlled research, including examination of endometrium biopsies, may provide further insight into the possible effects of GnRH antagonists on endometrial development. Pretreatment with an oral contraceptive may be valuable in cycle programming which is of practical importance to physicians and it may also allow for oocyte synchronization which may subsequently improve the number of oocytes retrieved, number of embryos obtained and quality of embryos transferred. For clinical pregnancy per woman, the OR was 0.83 (95% CI ) in favour of the agonist. Therefore, for a typical antagonist-treated pregnancy rate (e.g. 20% CPR), then the expected CPR will be 17% (95% CI 15 19%) with the alternative treatment. In other words, there is an absolute difference of 3 (95% CI 5 to 1) percentage points. Therefore, the calculated NNTB will be 33 (95% CI ) treated women. It was not possible to evaluate the economic differences between the two protocols. It may be assumed that the significant reduction of severe OHSS, together with the reduction in the amount of gonadotrophins and the much shorter duration of GnRHa treatment, could have direct impact on reduction of the cost of the cycle in favour of the antagonist regimen. However, it should be noted that cost effectiveness should be estimated by cost per pregnancy rather than cost per cycle. One should also keep in mind the indirect costs, e.g. absence from work (both partners), productivity loss, other indirect costs due to differences in treatment duration. In conclusion, the GnRH antagonist protocol is a short and simple protocol with good clinical outcome with significant reduction in incidence of severe OHSS and amount of gonadotrophins, but the lower pregnancy rate compared with the GnRHa long protocol necessitates counselling subfertile couples before recommending change from GnRH agonist to antagonist. In addition, the impact of the GnRH antagonist on endometrium through its GnRH receptor should be further investigated and the value of using GnRH antagonists in polycystic ovarian syndrome should be further investigated in IVF embryo transfer cycles. Similarly, the GnRH antagonists use in preventing the LH surge in the intrauterine insemination cycles. Declaration Potential conflict of interest: Professor Aboulghar was an investigator in the European Middle-East Orgalutran trial which is an included study in the review. Acknowledgements The authors would like to thank all members of MDSG for their valuable support in this review. References Albano C, Felberbaum R, 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 cetrorelix and the LHRH-agonist buserelin. 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