1 Department of Obstetrics and Gynecology, University Clinic of Schleswig-Holstein, Campus Luebeck, Luebeck and 2 Department of Obstetrics and Gynecology, Clinic Kempten-Oberallgaeu, Kempten, Germany
3 To whom correspondence should be addressed. Email: georg.griesinger{at}frauenklinik.uni-luebeck.de
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Abstract |
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Key words: assisted reproductive technology/GnRH antagonist/IVF/ovarian stimulation/registry
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Introduction |
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However, uptake of GnRH antagonists has been slow and the vast majority of ovarian stimulation cycles are still performed in GnRH agonist long protocols (FIVNAT, 2002; Deutsches IVF Register, 2003
). Meta-analyses on studies comparing GnRH agonist long protocols with GnRH antagonist protocols have yielded conflicting results as regards the likelihood of pregnancy achievement (Ludwig et al., 2001
; Al-Inany and Aboulghar, 2002
; Daya, 2005
). Still, the picture drawn suggests that GnRH antagonists are slightly less efficacious than GnRH agonists in long protocols. This has stimulated an ongoing debate on the place of GnRH antagonists in infertility treatment which in turn is likely to have influenced clinician's attitudes towards GnRH antagonist usage. Herein we describe GnRH antagonist utilization for ovarian stimulation in Germany from 2000 to 2003 and present data from the national IVF registry supporting the notion that GnRH antagonists are clinically used as a second choice treatment option. The implications of this development are discussed.
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Materials and methods |
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Data are presented descriptively. 2-Test for linear trend was used for statistical testing in contingency tables employing StatsDirect statistical software package, version 2.4.4.
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Results |
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Discussion |
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In this analysis we demonstrate patient selection in favour of GnRH agonist protocols for both age and cycle rank. It is well established that younger patients as well as patients in lower treatment ranks have a comparatively higher chance of achieving pregnancy than older patients or patients in higher treatment cycle ranks. The data from the German registry thus suggest that GnRH antagonists are comparatively more often used in cycles which have an unfavourable a priori prognosis. It appears likely that the majority of clinicians favour the well-established GnRH agonist long protocol as a first choice for ovarian stimulation, whereas for patients who failed to become pregnant, or patients of older age, GnRH antagonist protocols are more often employed. Inherent to this approach is a danger of a self-fulfilling prophecy as regards pregnancy rates in the perception of the clinician. Presumably, clinicians use other variables, such as body mass index, presence of polycystic ovaries, risk of ovarian hyperstimulation, presence of endometriosis, cycle irregularities etc., to primarily select for either GnRH agonist or GnRH antagonist protocols. Here we report only two variables, age and cycle rank, that could be unambiguously and completely retrieved from the registry. Since older patients are more prone to a decreased ovarian response to exogenous gonadotrophins, it may appear rational to clinicans to use GnRH antagonist protocols to avoid ovarian suppression at the stage of follicular recruitment. However, little evidence exists to support the notion that GnRH antagonists are superior in older patients or patients with a decreased ovarian response (Tarlatzis et al., 2003) as compared to GnRH agonist-based treatment regimen.
In the annual report from the Deutsches IVF Register (2003), clinical pregnancy achievement per embryo transfer is recorded as 25.75% for GnRH antagonist protocol cycles as compared to 30.52% for GnRH agonist long protocol cycles. The size of effect of an unfavourable patient selection on the pregnancy rate in the GnRH antagonist treatment cycles as suggested by the present analysis is difficult to estimate, but it has to be assumed that such an effect exists. In support of this assumption is a subanalysis in the registry report on women with tubal infertility, first treatment cycles, and age <35 years, where the pregnancy rate was 37.83 and 36.07% for the GnRH agonist long protocol and GnRH antagonist protocol respectively. However, when pooled data from an annual statistic are interupted, it must be taken into consideration that a comparatively small number of patients are treated in higher cycle ranks. Moreover, not all patients that are recorded as being treated in a higher cycle rank in the German registry necessarily have a poor prognosis, because patients have their treatment cycles chronologically counted, irrespective of pregnancy achievement or live birth in a previous cycle. Obviously, only comparative controlled trials allow a conclusion on the efficacy of the two protocols. Thus, we herein refrained from reporting pregnancy.
The authors are aware of three independent meta-analyses that compare GnRH antagonist protocols to the established GnRH agonist treatment regimen. Al-Inany and Aboulghar (2002) pooled data from five prospective, randomized controlled trials and found an OR of 0.79 (95% CI 0.630.99) for clinical pregnancy rate per woman in favour of the GnRH agonist long protocol. This meta-analysis has recently been updated and confirmed the finding of a lower pregnancy rate in GnRH antagonist cycles (Aboulghar, 2004
). The meta-analysis by Ludwig et al. (2001)
reported a trend towards a lower clinical pregnancy rate per woman randomized (OR 0.85; 95% CI 0.701.03) with a confidence interval that crossed the unity. Another recent meta-analysis by Daya (2005)
including 5000 treatment cycles on an intention-to-treat basis found an OR of 0.87 (95% CI 0.770.99) for clinical pregnancy in GnRH antagonist cycles; however, this marginal effect statistically vanished when only ongoing pregnancies were considered.
Due to the economic pressure on the side of the patient and the competition between centres, reproductive medicine has become dominated by the outcome parameter pregnancy rate. Pregnancy achievement without consideration of side-effects of the treatment can no longer be considered the objective of assisted reproduction. For the reduction of multiple gestations, a clinical trend towards elective single embryo transfer exists, although this will be associated for some patients with a decreased likelihood of pregnancy achievement per cycle (or embryo transfer) and the necessity to undergo comparatively more treatment (or embryo transfer) cycles. For ovarian stimulation, no consensus exists as yet on the endpoint measure that defines success.
For ovarian stimulation we advocate the balance of benefits and drawbacks of individual stimulation regimens. GnRH antagonists have helped to overcome some major disadvantages of GnRH agonist-based stimulation protocols, especially of the long protocol, resulting in safe and patient-friendly ovarian stimulation that does not deserve the place of a second choice treatment option. With GnRH antagonists, LH surges can reliably be prevented; there is absence of the flare-up effect, thus treatment time is considerably shorter and ovarian cysts are rare; no symptoms due to hypoestrogenism occur; there is no inadvertent administration of the GnRH analogue in early pregnancy; gonadotrophin consumption is lower and ovarian stimulation is softer; a trend in favour of GnRH antagonists is present for the incidence of severe OHSS (Al-Inany and Aboulghar, 2002). Furthermore, in our clinical experience, chemical castration by means of a GnRH agonist long protocol is emotionally disturbing for women who try to conceive. To fit the organizational regimen of IVF units, GnRH antagonist cycles can also reliably be programmed with an oral contraceptive pill (Fischl et al., 2001
).
In conclusion, GnRH antagonists offer a number of clinical advantages, but are apparently often not employed as a first line treatment. The pregnancy rates achieved are reduced as compared to GnRH agonist long protocol cycles in both controlled studies and observational registry data. However, in registry reports the effect of an unfavourable patient selection for GnRH antagonists has to be taken into consideration. We advocate that GnRH antagonist protocols deserve optimization rather than second place.
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References |
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Al-Inany H and Aboulghar M (2002) GnRH antagonist in assisted reproduction: a Cochrane review. Hum Reprod 17, 874885.
Daya S (2005) GnRH-agonists versus antagonists in assisted reproductiona systematic review. Abstract Book of the 8th International Symposium on GnRH-analogues in Cancer and Human Reproduction, A100.
Deutsches IVF Register (2003) Annual report from the German IVF registry 2003 (http://www.deutsches-ivf-register.de).
Fischl F, Huber JC and Obruca A (2001) Zeitliche Optimierung der kontrollierten Hyperstimulation (KOH) in Kombination mit GnrH-Antagonisten und Ovulationshemmer in einem IVF-Programm. J Fertilität Reprod 11, 5051.
FIVNAT (2002) Annual report from the French IVF registry. Bilan provisoire 2002 (http://www.perso.wanadoo.fr/fivnat.fr).
Ludwig M, Katalinic A and Diedrich K (2001) Use of GnRH antagonists in ovarian stimulation for assisted reproductive technologies compared to the long protocol Meta-analysis. Arch Gynecol Obstet 265, 175182.[CrossRef][Medline]
Tarlatzis BC, Zepiridis L, Grimbizis G and Bontis J (2003) Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update 9, 6176.
Submitted on March 3, 2005; resubmitted on April 10, 2005; accepted on April 18, 2005.