Human Reproduction Update Advance Access originally published online on March 31, 2006
Human Reproduction Update 2006 12(3):328-329; doi:10.1093/humupd/dml008
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Letter to the Editor |
Reply: Agonist trigger in the context of OHSS prevention: primum non nocere
1 Department of Obstetrics and Gynecology, University Clinic of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany and 2 Centre of Reproductive Medicine, Dutch Speaking, Brussels Free University, Brussels, Belgium
3 To whom correspondence should be addressed at: Ratzeburger Allee 160, 23538 Luebeck. E-mail: georg.griesinger{at}frauenklinik.uniluebeck.de
We thank Dr Kol for his interest in our recent systematic review (Griesinger et al., 2005
) on GnRH agonist usage for triggering final oocyte maturation in IVF patients.
In his letter, Dr Kol scrutinizes the necessity to test GnRH agonist triggering in normal responders at all, although he acknowledges that a randomized controlled trial (RCT) in ovarian hyperstimulation syndrome (OHSS)-risk patients is unethical. Still, Dr Kol states that exploring GnRH agonist triggering in normal responder patients came unexpectedly to him. However, in an article Dr Kol co-authored, it is suggested that ‘the introduction of the GnRH agonist-induced triggering of ovulation in GnRH antagonist protocols would offer additional benefits to all patients, i.e. both high and normal responders, though the efficacy and safety of such new treatment regimen needs to be established in comparative, randomized studies’ (Itskovitz-Eldor et al., 2000). We certainly agree with Dr Kol on the latter, and we like to add that a protocol should have proven safe and efficacious, before it can be recommended for wider spread clinical use.
Following the proposals of Kol (Kol, 2003, 2004; Kol and Muchtar, 2005), GnRH agonist triggering could eradicate clinically significant OHSS. To put this broad claim into practice, however, also implies that a significant proportion of patients will have to be exposed to GnRH agonist triggering, simply because no reliable text exists to predict patients who will develop OHSS. In line with this, it was recently proposed (Orvieto, 2005) in Human Reproduction, based on Kol’s (2004) ideas, to trigger virtually all patients (‘normal’ and ‘high’ responders) with GnRH agonist in a first IVF cycle. This example vividly illustrates the necessity to review and evaluate the data on the clinical efficacy of GnRH agonist-triggering protocols from RCTs conducted in (assumable) normal responder populations. Besides that, a scientific and clinical interest into the effects of GnRH agonist triggering on other outcome parameters than OHSS incidence and clinical pregnancy justifies such an evaluation.
Next, Kol expresses concerns about selective reporting and possible bias in our review, which might deter practitioners to use GnRH agonist in the context of OHSS prevention. The review was conducted with the aim of collating evidence on the clinical efficacy of GnRH agonist triggering—as explicitly stated. Because OHSS (which also occurs in assumable normal responder populations) was either not reported or did not occur in the available studies, no conclusion on OHSS incidence in normal responder populations can be drawn from comparative studies assessed—as explicitly stated. However, the review indicated that a decreased likelihood of pregnancy achievement can be expected after GnRH agonist triggering in current protocols in (assumable) normal responders. Whether this is also the case in OHSS patients is unclear, but at least possible. To illustrate this, we cite clinical outcome from observational studies (such as the study by Bankowski et al., 2004, entitled ‘Triggering ovulation with leuprolide acetate is associated with lower pregnancy rates’) on GnRH agonist triggering in OHSS risk patients.
As we strived to keep the article unbiased by our personal opinion, we had to refrain from expressing an opinion, let alone give a recommendation for clinical practice, whether the protocol as suggested by Kol and Muchtar (2005), or the protocol evaluated by Bankowski et al. (2004), or the protocols evaluated by the studies summarized in the systematic review (Griesinger et al., 2005) are useful for clinical use in OHSS risk patients, when risks, financial, physical and psychological burden of overall treatment have to be balanced with the chance of success.
We are aware of two publications of Kol containing original data on the use of GnRH agonist for prevention of OHSS: in the paper by Itskovitz-Eldor et al., 2000, eight patients considered at OHSS risk were triggered with 0.2 mg Triptorelin subcutaneously and received luteal phase support with daily injections of 50 mg progesterone in oil and 2 mg estradiol orally. No patient conceived. In another article (Kol and Muchtar, 2005), six patients considered at OHSS risk were triggered with 0.2 mg Triptorelin subcutaneously and received luteal phase support with 600 mg micronized vaginal progesterone and 4 mg vaginal estradiol. One patient conceived.
This, together with the evidence summarized in our review (Griesinger et al., 2005) is, at least for us, suggestive of the fact that the current GnRH agonist-triggering protocols might need optimization for possible use in both normal responders and patients considered at risk of OHSS. At no point did we suggest that the concept of GnRH agonist triggering should be abandoned. Instead, suggestions are made in the article, how the existing GnRH agonist-triggering protocols could possibly be modified for future use. The claim of Kol that our review could indirectly contribute to patient morbidity and mortality seems to arise mostly from the authors’ misunderstanding of our article.
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References |
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 TOP References |
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Bankowski B, Bracero N, King J, Garcia J, Wallach E and Vlahos N (2004) Triggering ovulation with leuprolide acetate is associated with lower pregnancy rates. Abstracts of the 19th Annual Meeting of the ESHRE, Berlin, Germany, p. 295 [abstract i103].
Griesinger G, Diedrich K, Devroey P and Kolibianakis EM (2005) GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. Hum Reprod Update. Advance access published on October 27, 2005; doi:10.1093/humupd/dmi045.
Itskovitz-Eldor J, Kol S and Mannaerts B (2000) Use of a single bolus of GnRH agonist Triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report (short communication). Hum Reprod 15,1965–1968.
Kol S (2003) Prediction of ovarian hyperstimulation syndrome: why predict if we can prevent! Hum Reprod 18,1557–1558.
Kol S (2004) Luteolysis induced by a gonadotropin-releasing hormone agonist is the key to prevention of ovarian hyperstimulation syndrome. Fertil Steril 81,1–5.[ISI][Medline]
Kol S and Muchtar M (2005) Recombinant gonadotrophin-based, ovarian hyperstimulation syndrome-free stimulation of the high responder: suggested protocol for further research. Reprod Biomed Online 10,575–577.[Medline]
Orvieto R (2005) Can we eliminate severe ovarian hyperstimulation syndrome? Hum Reprod 20,320–322.
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