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GnRH agonist versus GnRH antagonist in ovarian stimulation: an ongoing debate
Reproductive BioMedicine Online, 1, 26, pages 4 - 8
The availability of gonadotrophin-releasing hormone (GnRH) antagonists for ovarian stimulation protocols has generated many meta-analyses comparing it to GnRH agonist long protocols. These meta-analyses have yielded conflicting results for pregnancy rate, with a tendency toward a better outcome for GnRH agonists. Recently, a Cochrane review seems to have settled the conflicts by demonstrating no evidence of statistically significant differences in the rates of live births or ongoing pregnancies when comparing GnRH agonist long protocols with GnRH antagonist protocols. This paper disputes the equivalence of these two protocols as discussed in the latest meta-analysis and argue that the GnRH agonist still has a demonstrable superiority over GnRH antagonist protocols.
The availability of gonadotrophin-releasing hormone (GnRH) antagonist for ovarian stimulation protocols has generated many meta-analyses comparing it to GnRH agonist long protocols. These meta-analyses have yielded conflicting results for pregnancy rate, with a tendency towards a better outcome for GnRH agonists. Recently, a Cochrane review seems to have settled the conflicts by demonstrating no evidence of statistically significant differences in the rates of live births or ongoing pregnancies when comparing GnRH agonist long protocols with GnRH antagonist protocols. In this paper, we dispute the equivalence of these two protocols as discussed in the latest meta-analysis and argue that the GnRH agonist still has a demonstrable superiority over GnRH antagonist protocols.
Keywords: GnRH agonist, GnRH antagonist, IVF outcome, Pregnancy.
Ovarian stimulation is an important variable for the success of IVF-embryo transfer. The two most common protocols for ovarian stimulation incorporate GnRH agonist and antagonist co-treatment, mainly to prevent a premature rise in LH. Lately, an increasing number of publications have appeared in literature reinforcing the advantages in using GnRH antagonists over the agonists, including the lack of hypo-oestrogenism, the shorter treatment duration, the lower gonadotrophin requirement and a reduction in the incidence of severe ovarian hyperstimulation syndrome (Ludwig et al, 2001 and Al-Inany and Aboulghar, 2001). However, as the utilization of GnRH antagonists in ovarian stimulation protocols is increasing as a result of these advantages, the information on the most important outcome of assisted reproduction treatment, the pregnancy rate, is still unclear and with no sound evidence.
Multiple meta-analyses comparing GnRH agonist long protocols with GnRH antagonist protocols have yielded conflicting results for pregnancy rate (Ludwig et al, 2001, Al-Inany and Aboulghar, 2001, Al-Inany et al, 2006, and Kolibianakis et al, 2006). However, recently, and in contrast to their previous reports (Al-Inany and Aboulghar, 2001 and Al-Inany et al, 2006), Al-Inany et al. (2011) have demonstrated no evidence of statistically significant differences in the rates of live births or ongoing pregnancies when comparing GnRH agonist long protocols with GnRH antagonist protocols.
This recent Cochrane review ( Al-Inany et al., 2011 ), which was based on the best available evidence comparing GnRH antagonist versus the long agonist protocol for women undergoing ovarian-stimulation IVF or intracytoplasmic sperm injection (ICSI), has apparently settled the ongoing debate on the place of GnRH antagonists in infertility treatment (Griesinger et al, 2005 and Fauser and Devroey, 2005). However, the present paper argues that the equivalence of these two protocols is not as clear as it has been presented.
The conflicting results of the first series of meta-analyses, together with the reported higher prevalence of ovarian stimulation using GnRH agonists (FIVNAT, 2002 and Deutsches IVF Register, 2003), continue to fuel debates in the medical community. Several editorials have reported a low utilization of GnRH antagonists and their consideration only as a second treatment option in ovarian stimulation (Griesinger et al, 2005 and Fauser and Devroey, 2005) and have encouraged investigations into the factors responsible for the poor clinical acceptance. While some reports did associate the lower pregnancy rates observed during the GnRH antagonist cycles to ‘centres’ inexperience’, others have justified the lower success rates of antagonists to their use in patients with an unfavourable prognosisa priori, i.e. repeated failures and elderly or low responders. Therefore, according to the latest meta-analysis when these conditions are factored in, GnRH antagonist protocols and GnRH agonist protocols are equivalent ( Al-Inany et al., 2011 ). This paper argues that the latest meta-analysis has not settled the debate and show that GnRH agonist still has a demonstrable superiority over GnRH antagonist protocols. It also challenges the arguments that ‘physician or centre experiences’ and ‘the use in patients with different prognosisa priori’ justify the better performance of the GnRH agonists. In fact, after correcting for these factors, the GnRH agonist protocol still has a real advantage over the GnRH antagonist protocol.
Patients with a favourable prognosis
While studying IVF outcome in young patients (<35 years old) undergoing one of their first three IVF attempts (thus excluding cycles/patients with an unfavourable prognosis) ( Orvieto et al., 2006 ), a significantly higher clinical pregnancy rate was observed in those given the midluteal long GnRH agonist suppressive protocol (41.2%) than in those given the multidose GnRH antagonist protocol (25.3%). This was true despite the comparable number of retrieved oocytes in the two groups and the conclusive, objective evidence of longer treatment duration, more gonadotrophin ampoules used and higher peak oestradiol concentrations in the agonist group.
Patients with an unfavourable prognosis
When patients with repeated IVF failure were studied ( Orvieto et al., 2009 ), the superiority of the GnRH agonist protocol was maintained, showing a significantly higher clinical pregnancy rate, when compared with the antagonist protocol (20.8% versus 14.5%;P < 0.02).
Further, the choice of the GnRH analogues may influence endometrial receptivity. The analysis of 712 IVF cycles in patients undergoing ovarian stimulation with either GnRH agonist or antagonist and with the transfer of at least one top-quality embryo ( Orvieto et al., 2008a ), the GnRH agonist group showed a significantly higher endometrial thickness and higher pregnancy rate, suggestive of a higher endometrial receptivity, as compared with the GnRH antagonist group.
With regard to ‘centres’ inexperience’, this issue was approached by examining this study centre’s experience of 9 years in treating patients with a favourable prognosisa prioriwith the GnRH antagonist ovarian stimulation protocols ( Orvieto et al., 2010 ). Throughout the study period, while gaining experience, patients used a significantly lower number of gonadotrophin ampoules, had a significantly lower peak oestrogen concentration on day of human chorionic gonadotrophin (HCG) administration and had fewer oocytes retrieved; however, there was no improvement in pregnancy rates ( Orvieto et al., 2010 ). In other words, despite becoming accustomed to adopting GnRH antagonist in ovarian stimulation protocols, the pregnancy rates remained stable. More importantly, throughout the same study period, pregnancy rates were significantly higher in patients with a favourable prognosisa prioriundergoing the GnRH agonist as compared with the GnRH antagonist ovarian stimulation.
When trying to clarify the contribution of ‘physicians’ experience’ on IVF outcome in patients undergoing GnRH antagonist ovarian stimulation, it was found that in patients using the GnRH antagonist, but not the long suppressive GnRH agonist protocols, day of HCG trigger is crucial for IVF success ( Orvieto et al., 2007 ). To achieve the highest pregnancy rates, patients undergoing GnRH antagonist ovarian stimulation protocols should be triggered whenever the ratio of oestradiol concentration to number of follicles of >14 mm on the day of HCG administration is lower than 100 pg/ml/follicle ( Orvieto et al., 2008b ).
Indirect evidence for the superiority of the long GnRH agonist protocol
A careful reading of the literature may also provide more evidence of the relative advantage of the long GnRH agonist over the GnRH antagonist protocol. For example, when the IVI group ( Bosch et al., 2010 ) studied the influence of elevated serum progesterone concentrations during IVF/ICSI cycles on pregnancy rates, they reviewed the files of all patients who were treated at the Instituto Valenciano de Infertilidad during the period from January 2003 to December 2007, and who had their serum progesterone concentrations determined on the day of HCG administration. Analysing the 4032 eligible IVF/ICSI embryo-transfer cycles, they could demonstrate that increased circulating progesterone concentrations at the end of ovarian stimulation are related to poorer ongoing pregnancy rates, irrespective of the GnRH analogue used ( Bosch et al., 2010 ). However, stratification of their results according to the GnRH analogue used showed that, within each category, the ongoing pregnancy rate using the GnRH agonist was significantly higher. In patients with progesterone concentrations on HCG day ⩽1.5 ng/ml, the ongoing pregnancy rate in patients undergoing long GnRH agonist (n = 1177) was significantly higher compared with those undergoing GnRH antagonist (n = 2855; 38.4% versus 28.1%;P < 0.0001, respectively). The same trend was also observed in those with progesterone concentrations on HCG day >1.5 ng/ml.
Recently, many IVF programmes have encouraged the transfer of a single embryo in young women with good prognosis, in an attempt to reduce the incidence of multiple births. When searching for well-designed randomized controlled trials (RCT) that compared elective single-embryo transfer with double-embryo transfer, there was another indirect proof that GnRH agonist protocols were favoured. In fact, in a recent systematic review and meta-analysis of all the eligible RCT dealing with the aforementioned issue, all the chosen ovarian stimulation protocols were utilizing the long GnRH agonist ( Gelbaya et al., 2010 ).
The Cochrane review
In their recent comprehensive Cochrane review, by updating their previous Cochrane reviews (Al-Inany and Aboulghar, 2001 and Al-Inany et al, 2006), Al-Inany et al. (2011) achieved a contradictory conclusion. Of the 45 RCT (n = 7511) comparing the antagonist to the long agonist protocols that fulfilled their inclusion criteria, no evidence of a statistically significant difference was demonstrated in rates of live births (nine RCT; odds ratio 0.86, 95% CI 0.69–1.08) or ongoing pregnancies (28 RCT; odds ratio 0.88, 95% CI 0.77–1.00).
However, a closer analysis of their included studies reveals that some of the studies utilizing the long GnRH agonist protocol had an unacceptable pregnancy rate, such as zero ( Marci et al., 2005 ). Moreover, studies using the minimal stimulation approach, a strategy that does not utilize all the advantages of the long GnRH agonist protocol, were also included. Simply being a RCT does not justify its inclusion. Specifically, studies including patients with poor prognosisa priorior providing treatment of poor quality (low: 0–20% ongoing pregnancy rates) should be excluded.
Prompted by the aforementioned observations and weaknesses of the latest meta-analysis, this review reanalysed the data after excluding studies using the minimal stimulation approach and those resulting with unacceptable (<20%) pregnancy rates, which reflects either a selection of patients with unfavourable prognosisa priorior a centre’s inexperience with the long GnRH agonist protocol.
The results of the live birth and ongoing pregnancy rates are shown inTable 1 and Table 2(Albano et al, 2000, Badrawi et al, 2005, Bahceci et al, 2005, Barmat et al, 2005, Depalo et al, 2009, Engmann et al, 2008, European and Middle East Orgalutran Study Group, 2001, European Orgalutran Study Group, 2000, Firouzabadi et al, 2010, Fluker et al, 2001, Huirne et al, 2006, Kim et al, 2004, Kim et al, 2009, Kurzawa et al, 2008, Lainas et al, 2007, Lainas et al, 2010, Moshin et al, 2007, Rombauts et al, 2006, Tazegül et al, 2008, Tehraninejad et al, 2010, and Ye et al, 2009), respectively. The tables gather all the relevant studies identified by Al-Inany et al. (2011) , following the aforementioned exclusions. The re-analysis revealed significantly higher live birth and ongoing pregnancy rates in patients undergoing long GnRH agonist as compared with GnRH antagonist (32.5% versus 24.9%,P < 0.025; and 31.2% versus 26.0%,P < 0.001, respectively).
|Study||GnRH antagonist||GnRH agonist|
|Albano et al. (2000)||34||198||19||95|
|Barmat et al. (2005)||13||40||17||40|
|Kim et al. (2009)||13||54||8||28|
|Kurzawa et al. (2008)||14||37||18||37|
|Ye et al. (2009)||35||109||39||111|
|Live birth rate (%) a||24.9||32.5|
a P < 0.025.
Values arenunless otherwise stated. Studies with unfavourable outcome included those using minimal stimulation and those providing treatment of poor quality (low: 0–20% ongoing pregnancy rate).
|Study||GnRH antagonist||GnRH agonist|
|Albano et al. (2000)||34||198||19||95|
|Badrawi et al. (2005)||11||50||13||50|
|Bahceci et al. (2005)||32||73||36||75|
|Barmat et al. (2005)||13||40||17||40|
|Depalo et al. (2009)||16||67||21||69|
|Engmann et al. (2008)||16||34||19||32|
|European and Middle East Orgalutran Study Group (2001)||70||236||37||119|
|European Orgalutran Study Group (2000)||94||486||61||244|
|Firouzabadi et al. (2010)||34||118||27||117|
|Fluker et al. (2001)||61||205||36||108|
|Huirne et al. (2006)||17||91||20||91|
|Kim et al. (2004)||7||21||7||20|
|Kurzawa et al. (2008)||20||37||21||37|
|Lainas et al. (2007)||12||26||25||52|
|Lainas et al. (2010)||47||110||50||110|
|Moshin et al. (2007)||8||25||8||24|
|Rombauts et al. (2006)||41||234||26||117|
|Tazegül et al. (2008)||8||48||10||48|
|Tehraninejad et al. (2010)||16||45||13||47|
|Ongoing pregnancy rate (%) a||26.0||31.2|
a P = 0.001.
Values arenunless otherwise stated. Studies with unfavourable outcome included those using minimal stimulation and those providing treatment of poor quality (low: 0–20% ongoing pregnancy rates).
In conclusion, the data presented in the most recent meta-analysis should not be considered as proof of equivalence between antagonist and agonist protocols, as evident by the recent survey on the use of GnRH agonist in IVF protocols ( www.IVF-worldwide.com ). This survey included reports from 273 centres worldwide and demonstrated that while out of 151,000 cycles/year, 134,494 (89.1%) used GnRH agonist, only 18,144 (12.0%) were reported using GnRH antagonist. Therefore, a proper, well-designed, RCT (for example, Devroey et al., 2009 ) is still required. In the meantime, the agonist protocol is still favoured over the antagonist protocol.
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a Department of Obstetrics and Gynecology, Barzilai Medical Center, Ashkelon, Israel
b Faculty of Health Science, Ben Gurion University of the Negev, Beer Sheva, Israel
c Department of Obstetrics and Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
Raoul Orvieto is a full professor at the Faculty of Health Sciences, Ben-Gurion University of the Negev and the Director of the Infertility and IVF unit and the male infertility centre at the Barzilai Medical Center, Israel. He has been author and co-author of more than 150 publications in national and international journals. His scientific interests include various aspects of ovarian stimulation, the role of gonadotrophin-releasing hormone (GnRH) analogues, and specifically GnRH agonist versus antagonist in ovarian stimulation for IVF and several aspects of ovarian hyperstimulation syndrome: pathophysiology, prediction, prevention and its relation to the inflammatory response.
© 2012 Reproductive Healthcare Ltd., Published by Elsevier B.V.