Review
GnRH agonist triggering: recent developments

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Abstract

The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages, including virtually complete prevention of ovarian hyperstimulation syndrome (OHSS), the introduction of a surge of FSH in addition to the LH surge and finally the possibility to individualize luteal-phase supplementation based on ovarian response to stimulation. We maintain that the automatic HCG triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients.

Routinely, human chorionic gonadotrophin (HCG) is used to induce ovulation in fertility treatments. This approach deviates significantly from physiology and often results in insufficient hormonal support in early pregnancy and in ovarian hyperstimulation syndrome (OHSS). An alternative approach is to use a gonadotrophin-releasing hormone (GnRH) agonist which allows a more physiological trigger of ovulation and, most importantly, virtually eliminates the risk of OHSS. The current communication summarizes recent developments in the area and suggests future research efforts to enhance patients’ safety and comfort.

Introduction

With the introduction of the gonadotrophin-releasing hormone (GnRH) antagonist protocol and the subsequent possibility of using a bolus of GnRH agonist (GnRHa) for final oocyte maturation and ovarian hyperstimulation syndrome (OHSS) prevention, the authors of this paper founded a special interest group in 2009 ‘The Copenhagen GnRH Agonist Triggering Workshop Group’. The first meeting was held in Copenhagen, resulting in an extensive review (Humaidan et al., 2011), followed by several publications employing the GnRHa trigger concept. The purpose of most of the subsequent trials was to overcome the luteal-phase insufficiency previously reported post GnRHa trigger – despite supplementation with a standard luteal-phase support. A recent review focused on luteal-phase deficiency after ovarian stimulation in general, emphasizing the luteal phase after GnRHa trigger (Humaidan et al., 2012a). Following this publication, several studies were published on the subject. As the interest in GnRHa trigger is rapidly increasing, this review presents an update on the most recent literature and the continuing controversies regarding GnRHa trigger.

Section snippets

Physiology

LH homology, an extended half life and an easy manufacturing process turned human chorionic gonadotrophin (HCG) into an excellent molecule to be used for triggering of final oocyte maturation and ovulation during assisted reproduction treatment. Typically, one bolus of urinary HCG (5000–10,000 units) or recombinant HCG (250 μg) is administered approximately 36 h before oocyte retrieval in IVF cycles.

Unlike the physiological mid-cycle surge of LH and FSH, terminating 48 h after its onset, the

Dual trigger

‘Dual trigger’ is the concept in which the benefits of a bolus of a GnRHa in terms of release of endogenous LH and FSH from the pituitary are combined with the long acting LH activity of a small bolus of HCG, covering the early luteal-phase LH deficiency, previously described after GnRHa trigger (Shapiro et al., 2008). The dual trigger protocol is usually followed by a standard luteal-phase support. Shapiro et al. (2011) retrospectively reported the effect of dual trigger in high-risk OHSS

Modified luteal-phase support post GnRH agonist trigger with HCG

The basic premise behind this approach is to dissociate the ovulation trigger from the luteal support. While a bolus of GnRHa is responsible for an endogenous surge of LH and FSH, a low dose(s) of HCG after oocyte aspiration will replace the actions of early luteal LH to sustain implantation and luteal ovarian steroidogenesis. This approach was previously reported prospectively by Humaidan et al., 2006, Humaidan et al., 2010 and Humaidan (2009) in normo-responding as well as hyper-responding

Modified luteal-phase support post GnRH agonist trigger: intensive luteal oestradiol and progesterone

Babayof et al. (2006) were the first to report the use of intensive oestradiol and progesterone for luteal support in high-risk OHSS patients post GnRHa trigger. The reproductive outcome of this trial was disappointingly low. Subsequently, Engmann et al. (2008) used a similar approach in high-risk OHSS patients (n = 33) post GnRHa trigger, reporting the prevention of OHSS while maintaining good pregnancy rates. In contrast, the OHSS rate in the HCG trigger control group (n = 32) was 30%. These

OHSS

A recent report by ESHRE (de Mouzon et al., 2012) clearly reveals that OHSS is still one of the major complications of ovarian stimulation for IVF. A diagnosis of OHSS was reported in 26 of the 33 countries. In total, 2470 cases of OHSS were recorded in 2007, corresponding to an OHSS occurrence of 0.7% in all stimulated cycles (0.8% in 2006). A wide variation in the occurrence of OHSS was reported: UK (1.3%) and Russia (1.8%) having the highest rates, and Germany and Spain the lowest (0.3%).

OHSS and GnRHa trigger

Virtually complete elimination of OHSS is one of the major benefits of GnRHa trigger. The mechanism behind this phenomenon is the luteolysis induced by a bolus of GnRHa caused by the short half-life of endogenous LH as compared with HCG. Once the endogenous HCG production from the trophoblast reaches measurable serum concentrations around day 8 after ovulation (Bonduelle et al., 1988), it is too late to rescue the corpora luteae, which results in virtual elimination of the late-onset

Cochrane reviews and GnRHa trigger

A recent Cochrane review comparing GnRHa versus HCG for triggering of final oocyte maturation in IVF concluded that GnRHa as a trigger of final oocyte maturation should not be routinely used due to the significantly lower live birth rate (Youssef et al., 2011). Moreover, the section on implications for research stated: ‘In view of the poor reproductive outcomes following oocyte triggering with GnRH agonist we believe there is no indication for further research with GnRH agonists for oocyte

Predictive factors and how to handle patients at risk of OHSS

Predicting OHSS is difficult; there are, however, predictive factors which need to be taken into consideration when choosing the type of GnRH analogue, the FSH dose and the duration of stimulation as well as the choice of trigger method. Predictive factors for OHSS may be divided into primary and secondary risk factors. The most important primary risk factors are: high anti-Müllerian hormone, high antral follicle count, PCOS, isolated PCOS characteristics and a previous history of OHSS. In

GnRH agonist trigger: side-benefits

GnRHa trigger is the trigger method of choice for the oocyte donor due to several advantages over HCG trigger, among those: virtual elimination of OHSS, a reduced luteal ovarian volume leading to diminished abdominal distension and pain, and a short interval until withdrawal bleeding occurs; factors that substantially decrease the treatment burden of the oocyte donor (Cerrillo et al., 2009, Hernández et al., 2009). Moreover, GnRHa trigger should be considered in situations like repeated IVF

Conclusion

The fast development during the last 2 years underscores our initial statement that GnRHa is a viable alternative to HCG for triggering of final oocyte maturation. GnRHa trigger is safer, patient friendly and offers several physiological advantages over HCG trigger. Although the most optimal luteal-phase support after GnRHa trigger is still being explored, the time has come to question the automatic HCG trigger concept and to move forward with thoughtful consideration of the needs and comfort of

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Dr Shahar Kol graduated from the Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel. He earned his MD in 1983. He interned at the Rambam Medical Center, Haifa, where he completed his residency in Ob/Gyn. He worked as a fellow in reproductive endocrinology at the department of obstetrics and gynaecology, Baltimore School of Medicine, University of Maryland, Baltimore, USA for 2 years and won the Merck Senior Fellow award from the Endocrine Society in 1994. Currently, Dr Kol concentrates clinically on IVF, both at the Rambam Medical Center and at Elisha Hospital, a private hospital in Haifa.

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