Fig. 10.1
Structure of the native GnRH and GnRH antagonist
Fig. 10.2
Neuroendocrine axis. LH luteinizing hormone, FSH follicle stimulating hormone
GnRH antagonists suppress gonadotropin secretion by competing with GnRH for the receptors on the pituitary gonadotroph cell membranes. Administration of the GnRH antagonists produces immediate and transient suppression of the secretion of follicle-stimulating hormone (FSH) and LH. As a result of their mechanism of action, they lack the initial stimulatory ‘flare effect’ of the GnRH agonists (Fig. 10.3).
Fig. 10.3
Mechanism of action of GnRH antagonist—blocking of the pituitary receptors
The first GnRH antagonist was developed in 1972 by the replacement of the histidine residue at position number 2 of the native GnRH. The initial preparations of the GnRH antagonists had side effects such as an oedematous reaction caused by the release of histamine from the mast cells and depot formation after injection due to ‘gelling’ resulting in unreliable and unpredictable release [6]. The first-generation product was followed by subsequent generations, and the present (fourth) generation of GnRH antagonists, such as cetrorelix and ganirelix used in assisted reproduction, have been developed to overcome these side effects.
10.3 GnRH Antagonist in Ovarian Stimulation
10.3.1 Dose-Finding Studies
The fourth-generation GnRH antagonists (cetrorelix and ganirelix) were studied in Phase II studies to determine the most effective dose to prevent a premature LH surge but also avoiding over-suppression of the pituitary at the same time. Initial dose-finding studies of cetrorelix and ganirelix demonstrated that administration of 0.25 mg/day in the follicular phase was the minimal effective dose for suppression of serum LH levels and at the same time not compromising the implantation and pregnancy rates [7–10].
Initial studies to determine the minimal effective dose of GnRH antagonist administered as a single dose compared 5 mg versus 3 mg single dose of cetrorelix and 3 mg versus 2 mg single dose of cetrorelix administered on day 8 of the stimulation cycle where the gonadotropin stimulation was commenced on day 2 [11–13]. The results from these studies demonstrated that a single dose of 3 mg of cetrorelix was the minimal effective dose for successfully preventing LH surge in gonadotropin-stimulated cycles. The dose-finding studies therefore established that the GnRH antagonist could be administered either as 0.25 mg/daily in a multiple-dose protocol or as 3 mg in a single-dose protocol to effectively suppress the LH surge and maintain IVF results [14].
10.3.2 Fixed Versus Flexible Protocols
GnRH antagonists due to their mechanism of action by blockade of the pituitary gonadotrophs cause a rapid decrease in LH and FSH levels following administration. This property allows their use in the mid/late follicular phase as they do not require a prolonged desensitization period as with the GnRH agonists. GnRH antagonists can be administered either as a fixed or a flexibe protocol. In a fixed protocol, they are administered on day 6 of stimulation whereas in a flexible protocol the GnRH antagonist is administered when a lead follicle is present at least 5 days after stimulation. A randomized controlled trial (RCT) comparing the fixed versus flexible start of GnRH antagonist commencing ganirelix 0.25 mg/day either on day 6 of stimulation or when a lead follicle of ≥15 mm found the ongoing implantation rate to be significantly higher with the fixed compared to the flexible start (23.9 % versus 8.8 % respectively) [15]. A subsequent meta-analysis involving four RCTs showed no significant difference in the incidence of premature LH surge and pregnancy rates with the fixed and flexible protocols [16]. Another RCT comparing the fixed start on day 6 of stimulation versus an earlier flexible GnRH antagonist start when the LH levels were >10 IU/l, and/or follicle diameter >12 mm, and/or serum oestradiol (E2) levels >150 pmol/l showed no significant difference in the incidence of LH rise nor ongoing implantation or pregnancy rates [17]. Therefore, based on current evidence, the fixed and flexible protocols seem to be equally effective with most protocols employing GnRH antagonist start on day 6 of stimulation with the fixed and with the lead follicle at ≥14 mm with the flexible start.
10.4 GnRH Antagonist Use in Unselected Patients
Reassuring data from the initial phase II and III studies resulted in a gradual increase in GnRH antagonist use in IVF programmes. There then followed several studies and RCTs comparing the efficacy of GnRH agonists versus GnRH antagonists for pituitary down-regulation in IVF. Early studies and meta-analyses, however, were in favour of GnRH agonists over antagonists in terms of live birth rates [16, 18]. These studies, however, favoured the use GnRH antagonists over agonists in terms of a shorter duration of treatment and lower incidence of ovarian hyperstimulation syndrome (OHSS). Given the earlier reservation of the GnRH anatgonists on the pregnancy rates, the GnRH agonists remained the predominantly used GnRH analogue for pituitary down-regulation in IVF [19]. However, with more confidence in the use of GnRH antagonists, recent studies and updated evidence have shown comparable pregnancy and live birth rates leading to their widespread use with the added benefit of patient compliance and a reduced risk of OHSS [20].
10.5 GnRH Antagonists in Selected Patient Groups
10.5.1 GnRH Antagonists for Hyper-Responders and Women with PCOS
With the embracing of individualization of COS in IVF, GnRH antagonist use has seen a high uptake in the recent past. A worldwide survey in 2010 involving 179,300 IVF cycles from 262 centres in 68 countries showed the use of GnRH antagonist-based protocols in 50 % of IVF cycles among women with polycystic ovarian syndrome (PCOS) [21]. The use of GnRH antagonists in this group of women is substantiated by a significantly lower risk of OHSS compared with GnRH agonist-based protocols [20]. A recent meta-analysis of studies comparing GnRH antagonist versus GnRH agonist protocols in women with PCOS involving nine RCTs from 2002 to 2013 showed comparable clinical pregnancy rates (CPR) between the two groups and a significantly lower incidence in severe OHSS in the GnRH antagonist group [22]. An added advantage with the use of GnRH antagonist-based protocols is the use of GnRH agonist trigger as a substitute for hCG in triggering of final oocyte maturation and potentially eliminating the risk of OHSS.
10.5.2 GnRH Antagonists for Poor Responders
A worldwide survey of GnRH analogue use in poor responders involving 124,700 IVF cycles from 196 centres in 45 countries showed that the GnRH antagonist protocol was used in 53 % of cycles [21]. Numerous studies and reviews on the ideal regimen for poor responders had suggested insufficient evidence in recommending a particular regimen for poor responders [23–25]. One of the recurring criticisms was the lack of a uniform evidence-based definition of poor ovarian response. A recent RCT comparing the GnRH agonist long regimen versus the GnRH agonist short regimen versus the GnRH antagonist regimen in previous poor responders demonstrated the GnRH agonist and the GnRH antagonist regimens as being most effective in terms of the number of oocytes retrieved [26]. This study was conducted to overcome the previously identified deficiencies in studies of poor ovarian response and defined a poor responder woman as someone who had a previous IVF cycle with ≤3 oocytes retrieved following gonadotropin stimulation with at least 300 IU of gonadotropin daily.
10.6 GnRH Agonist Trigger with GnRH Antagonist Protocols
The GnRH agonist trigger has been proposed as an alternative to the hCG trigger by virtue of inducing an endogenous rise in LH and FSH due to its initial flare effect [27, 28]. The GnRH agonist trigger can only be used with COS regimens where prior pituitary suppression has not been achieved with the GnRH agonist as the mechanism of action of the GnRH agonist in causing down-regulation and desensitization of the pituitary receptors precludes the use of the agonist trigger. On the other hand, the advent of the GnRH antagonist into COS regimens and the recent widespread uptake has enabled the use of the GnRH agonist trigger [7, 12, 21]. Due to the specific mode of action of the antagonist by competitive blockade of the pituitary receptors and a shorter half-life, the pituitary remains responsive to the GnRH agonist, thus enabling its use for triggering ovulation.
The Cochrane review comparing the GnRH agonist versus the hCG trigger in IVF demonstrated a significantly lower incidence of OHSS and a lower live birth rate with the GnRH agonist trigger [29]. It demonstrated significantly reduced live birth rates in fresh autologous cycles with the use of the GnRH agonist trigger, but there was no reduction in live birth rates in oocyte donor/recipient cycles. Following initial use of the GnRH agonist trigger, it was soon recognized of the need to modify the standard luteal support to obtain reliable reproductive outcomes [30]. Study groups have since endeavoured to fine tune the luteal phase support in IVF cycles using the GnRH agonist trigger to optimise clinical outcomes [31, 32]. Recent suggestions and developments in overcoming the luteal insufficiency with the GnRH agonist trigger are use of
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