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SURVEY RESULTS:
Triggering of ovulation with GnRH-a in ART:
Worldwide feedback on an emerging new option with great potential

 

Dominique de Ziegler, Université Paris Descartes – Hôpital Cochin, Paris France
Zeev Shoham, Kaplan Medical enter, rehovot, Israel


    Introduction and background data


In the menstrual cycle, final oocyte maturation is controlled by an abrupt release of LH or 'LH surge', which itself is brought about by rising E2 levels. In controlled ovarian stimulation (COS), hCG (5,000-10,000 IU) has been used in replacement for LH surge, as occurrence the latter is unreliable due to the use of GnRH analogs (agonists or antagonists) and/or excessive hormone levels. Yet reverting to hCG is prone to cause unwonted effects notably, the release of vasoactive substances – primarily, VEGF – through direct effects on the small stimulated ovarian follicles. Production of VGEF and other vasoactive substances causes variable degrees of extravasation, resulting in 3rd space formation and in turn variable degrees of hemo-concentration. The phenomenon ranges form moderate, as seen in nearly all ART cycles – amounting to 1-3kg weight gain – to more serious forms encountered in case of frank ovarian hyperstimulation syndrome (OHSS) that require specific fluid management measures.
More than 20 years ago Gonen et al. reported that it is possible to trigger an endogenous surge of LH sufficient for induction ovulation with a single injection of GnRH-a (1), which was soon confirmed by others (2). This finding got ignored and forgotten however, as GnRH agonist (GnRH-a) became the primary mode of preventing premature lutenization, which indeed precluded using GnRH-a for inducing a LH surge.
But the GnRH trigger story has gotten later revived, as it became known that exogenous GnRH-a can induce a LH surge and ovulation while the patient already receives an antagonist protocol. GnRH-a can indeed revert the competitive inhibition of the anterior hypophysis exerted by the antagonists used in ART. In the past few years therefore mounting numbers of clinical indications were outlined for preferring triggering the final stages of oocyte maturation with GnRH-a rather than hCG. The primary indications for preferring the GnRH trigger option in antagonist protocols are for avoiding OHSS when the risk looms and/or differing embryo transfers when anomalies are found on the endometrium, including a premature P4 elevation.
Emerging newer reasons for the GnRH trigger option in antagonist protocols include systematic "freeze all" and differed transfers choices made for example after multiple ART failures. It is seen that in these cases possibly weaker embryos – having contributed to the prior ART failures – would best benefit from being transferred on prime quality endometrium, as achieved with E2 and progesterone treatments.
The GnRH trigger option in COS is bound however to encounter circumstances in which it may not be as effective as anticipated. Considering the novelty of the GnRH trigger option and the relative scarcity of published data on the efficacy of this procedure, it was felt appropriate to conduct a broad-spectrum survey of its use in order to better and more rapidly define the possible pitfalls that may be encountered.


   Unresolved questions

 

Actual use of GnRH trigger


While the potential advantages of GnRH trigger appear to be numerous, these are outlined by a still small number of publications. In ages of an instant diffusion of information through novel media collectively referred as the Internet it is important to determine with similar promptitude how widely this new option is used and share the feedback – positive and negative – that is encountered.


GnRH trigger and oocyte-embryo quality


Donor egg data concur to indicate that the antagonist and GnRH-trigger option secures oocytes harvests of similar size and quality as achieved with the classical hCG regimen. Large donor egg programs in Spain have indeed observed in dedicated RCTs that the GnRH-trigger and hCG options provided equivalent outcome (3) (4), a finding confirmed by others (5).


GnRH trigger and endometrial quality


Serious doubts were cast however on the quality of endometrial receptivity achieved following GnRH trigger (6). Numerous studies using luteal support with vaginal progesterone indeed showed markedly decreased implantation rates. For reasons that elude our understanding luteal support with IM progesterone does not encounter the decreased implantation rates seen with GnRH trigger and vaginal progesterone (7) (8). It remains to be determined whether similar differences exist between vaginal progesterone and the recently approved subcutaneous progesterone (9). Other options proposed to palliate to the implantation problems encountered following GnRH trigger included adding minimal amounts of hCG for luteal support (10). In light of the decreased implantation rates certain including our own group have opted for the systematic freezing/vitrification of embryos in case of GnRH trigger.
Irrespective of the final option retained for palliating the endometrial shortcomings encountered with the GnRH-trigger option, we believe that it is of general interest to know what is actually done by practitioners worldwide. How many users have opted for the 'freeze-all' or combined GnRH trigger? How many prefer the exogenous hCG options? The website-based survey reported here attempted to provide an answer to this question.


Failure rates


An other unresolved issue is to know whether certain patients are prone to fail to ovulate – leading to no-oocyte retrievals – following GnRH trigger treatments. The exact nature of this risk is unknown practically and therefore, ought to be precised. Logically, the survey investigated this issue.
Indication for GnRH trigger
The indications for GnRH trigger are likely to vary worldwide, considering the novelty of the issues – positive and negative – at stake. The survey attempted to delineate a trend for the circumstances leading practitioners to prescribe GnRH trigger in ART.


Practical advantages of GnRH trigger


The theoretical advantages for GnRH trigger are numerous.


    Survey objectives


The primary objective of the survey was to further define the context in which this novel procedure of ART is used worldwide.


    Survey questions and answers


Use of the GnRH-trigger option
Of 123 ART centers reporting on a total 108,300 ART cases, the GnRH trigger option was selected in 5.2 to 36.1% of cases. The primary reason invoked for using the GnRH trigger option was the fear of OHSS in 76% of the cases, while it was used for a deliberate decision of differing embryo transfer (DET) in 8% of the cases.


Combined measure with GNRH trigger


In 43% of the cases, the responders indicated opting for systematic cryopreservation and DET each time GnRH trigger is used. In 26% of the cases, GnRH trigger is associated with small amounts of hCG, whereas as in 10% of the cases GnRH trigger is simply associated with luteal phase support using IM progesterone, as described by Engmann (7).


Suboptimal outcome following GnRH trigger


An 'empty follicle' syndrome or no-oocyte retrieval was encountered by 11% of practitioners who used GRH trigger, whereas suboptimal harvests were encountered by 23% of the users and 15% more encountered both. Nearly 50% of those who experienced an empty follicle or no-oocyte retrieval undertook to retrigger ovulation with hCG. A third of these reported a normal oocyte harvest, whereas it was suboptimal in the remaining 60% and 5% had no oocytes at all.


Offering DET in ART


An impressive 85% of the responding doctors indicated offering DET options to certain of their patients. Endometriosis was a criteria for DET in only 29% of those offering DET, whereas general uterine pathology and prior failed ART was indicated as criteria for DET in 77% and 46%, respectively.


Discussion


Our survey speaks for the widespread penetration of the GnRH trigger option in ART practices worldwide despite its relative recent description in antagonist protocols. This finding is quite remarkable considering the relatively small number of published data and the remaining doubts that linger on its impact on endometrial receptivity.
A striking finding of our survey is also the relatively high incidence of suboptimal outcome, which speaks for the fact that the limits of the GnRH trigger option ought to be better defined. Certain forms of pituitary dysfunctions such as possibly, partial hypothalamic disorders and/or profound pituitary suppression are likely responsible of these suboptimal outcomes. The fact that oocytes were retrieved in nearly all cases following retriggering with hCG speaks for the fact that the no-oocyte retrieval resulted from a failure of GnRH to trigger a LH surge in these cases. Further studies ought more precisely delineate the functional contraindication for GnRH trigger in order to curb these counter performances.


    Take home message


The results of this survey indicate that GnRH trigger is widely used worldwide and therefore has become part of the standard of care today. Hence, doctors are entitled to prescribe it just as patients may ask that this option is considered in their case. From the survey it appears that GnRH trigger is principally used for avoiding the risk of OHSS and also simply, for DET. Interestingly, DET is prescribed by a sizable fraction of groups – 46% of the practitioners – in cases of prior ART failures.
On broader terms, our survey speaks for the rapid worldwide diffusion of new treatment regimens, even when such treatment is still problematic and enigmatic as GnRH trigger remains. This pattern of rapid diffusion of new treatments probably follows the widespread instant diffusion of information in Internet times. The rapid diffusion of treatments speaks for the need to adapt our monitoring system accordingly, as is offered by website-based surveys of our type. Website-based surveys constitute indeed a proper adjustment to digital-age instant diffusion of medical practices, which allows to timely point at corrective measures when these are appropriate.

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     References

 

  1. Gonen Y, Balakier H, Powell W, Casper RF. Use of gonadotropin-releasing hormone agonist to trigger follicular maturation for in vitro fertilization. The Journal of clinical endocrinology and metabolism 1990;71:918-22.
  2. Itskovitz J, Boldes R, Levron J, Erlik Y, Kahana L, Brandes JM. Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertility and sterility 1991;56:213-20.
  3. Bodri D, Vernaeve V, Guillen JJ, Vidal R, Figueras F, Coll O. Comparison between a GnRH antagonist and a GnRH agonist flare-up protocol in oocyte donors: a randomized clinical trial. Hum Reprod 2006;21:2246-51.
  4. Galindo A, Bodri D, Guillen JJ, Colodron M, Vernaeve V, Coll O. Triggering with HCG or GnRH agonist in GnRH antagonist treated oocyte donation cycles: a randomised clinical trial. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 2009;25:60-6.
  5. Sismanoglu A, Tekin HI, Erden HF, Ciray NH, Ulug U, Bahceci M. Ovulation triggering with GnRH agonist vs. hCG in the same egg donor population undergoing donor oocyte cycles with GnRH antagonist: a prospective randomized cross-over trial. Journal of assisted reproduction and genetics 2009;26:251-6.
  6. Humaidan P, Bredkjaer HE, Bungum L, Bungum M, Grondahl ML, Westergaard L et al. GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Hum Reprod 2005;20:1213-20.
  7. Engmann L, Benadiva C. Agonist trigger: what is the best approach? Agonist trigger with aggressive luteal support. Fertility and sterility 2012;97:531-3.
  8. Benadiva C, Engmann L. Intensive luteal phase support after GnRH agonist trigger: it does help. Reproductive biomedicine online 2012;25:329-30.
  9. de Ziegler D, Sator M, Binelli D, Leuratti C, Cometti B, Bourgain C et al. A randomized trial comparing the endometrial effects of daily subcutaneous administration of 25 mg and 50 mg progesterone in aqueous preparation. Fertility and sterility 2013;100:860-6.
  10. Humaidan P, Kol S, Papanikolaou EG. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Human reproduction update 2011;17:510-24.