ReviewGnRH agonist triggering: recent developments
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
References (36)
- et al.
Intensive luteal phase support after GnRH agonist trigger: it does help
Reprod. Biomed. Online
(2012) - et al.
Differential regulation of VEGF after final oocyte maturation with GnRH agonist versus hCG: a rationale for OHSS reduction
Fertil. Steril.
(2009) - et al.
The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study
Fertil. Steril.
(2008) - et al.
Reproductive biology and IVF: ovarian stimulation and luteal phase consequences
Trends Endocrinol. Metab.
(2003) - et al.
Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders
Fertil. Steril.
(2012) - et al.
No room for cancellation, coasting, or ovarian hyperstimulation syndrome in oocyte donation cycles
Fertil. Steril.
(2009) Luteal phase rescue in high-risk OHSS patients by GnRHa triggering in combination with low-dose HCG: a pilot study
Reprod. Biomed. Online
(2009)- et al.
Rescue of corpus luteum function with peri-ovulatory HCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist: a pilot study
Reprod. Biomed. Online
(2006) - et al.
1500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study
Fertil. Steril.
(2010) - et al.
The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives
Reprod. Biomed. Online
(2012)
Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist
Fertil. Steril.
Luteolysis induced by a gonadotropin-releasing hormone agonist is the key to prevention of ovarian hyperstimulation syndrome
Fertil. Steril.
LH (as hCG) and FSH surges for final oocyte maturation: sometimes it takes two to tango
Reprod. Biomed. Online
Intensive luteal-phase support with oestradiol and progesterone after GnRH-agonist triggering: does it help?
Reprod. Biomed. Online
Substituting HCG with GnRH agonist to trigger final follicular maturation – a retrospective comparison of three different ovarian stimulation protocols
Reprod. Biomed. Online
Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles
Fertil. Steril.
Gonadotropin-releasing hormone agonist combined with a reduced dose of human chorionic gonadotropin for final oocyte maturation in fresh autologous cycles of in vitro fertilization
Fertil. Steril.
Comparison of ‘triggers’ using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin
Fertil. Steril.
Cited by (0)
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.