FAQs

Gonadotropin-releasing hormone antagonists

This document provides answers to some of the questions most commonly asked about using gonadotropin-releasing hormone (GnRH) antagonists in clinical practice.

Introduction to GnRH antagonists

How do GnRH antagonists work (what is their mode of action)?

GnRH antagonists have been specifically developed to prevent the premature luteinizing hormone (LH) surge that can occur during ovarian stimulation. They act as competitive inhibitors of the GnRH receptors on gonadotrophs; by blocking these receptors, they prevent endogenous GnRH from stimulating the release of gonadotropins (i.e. LH and follicle stimulating hormone, FSH). The more antagonist available, the more receptors are blocked. In contrast to GnRH agonists, antagonists inhibit gonadotropins almost immediately, and GnRH receptors are not downregulated.

Huirne et al. Hum Reprod 2007;22:2805–2813.

What are the advantages of GnRH antagonists over agonists?

There are three main benefits of using GnRH antagonist protocols over agonist protocols:

1. Avoidance of LH flare and hypo-estrogenic adverse events
The mode of action of the antagonists means that the inhibition of LH and FSH is immediate, without the LH flare that occurs with agonists. One of the main advantages of using GnRH antagonists is therefore that they avoid hypo-estrogenic adverse events such as weight gain, headaches, hot flushes, night sweats, mood swings, breast tenderness, abdominal pain, diarrhea and nausea (Fauser et al.1999; Tarlatzis et al. 2006).

2. Reduced risk of OHSS
One of the most important advantages of GnRH antagonists is that they reduce the risk of ovarian hyperstimulation syndrome (OHSS) (Kolibianakis et al. 2006; Heijnen et al. 2004; Al-Inany et al. 2006; Bodri et al. 2009). The incidence of severe OHSS and hospital admissions is significantly lower with GnRH antagonists than with agonists (Kolibianakis et al. 2006; Al-Inany et al. 2006; Lainas et al. 2010). Furthermore, the use of antagonist protocols allows GnRH agonists to be used to trigger final oocyte maturation, which also helps to avoid the early-stage OHSS associated with human chorionic gonadotropin (hCG) triggers.

3. Lower treatment burden
GnRH antagonists reduce treatment duration (European Orgalutran Study Group, Borm & Mannaerts 2000; European and Middle East Orgalutran Study Group 2001; Fluker et al. 2001; Albano et al. 2000; Al-Inany et al. 2006; Kolibianakis et al. 2006). Short GnRH antagonist protocols require fewer injections than standard GnRH agonist protocols: there are usually 14 fewer injections required with the GnRH antagonist protocol, compared with the GnRH agonist protocol (European Orgalutran Study Group, Borm & Mannaerts 2000). This helps to improve patients’ experience of in vitro fertilization (IVF) and is expected to increase the likelihood that patients will return for further treatment if the first cycle does not result in a live birth (Devroey et al. 2009).

Albano et al. Hum Reprod 2000;15:526–31.
Al-Inany et al. Cochrane Database Syst Rev 2006;3:CD001750.
Bodri et al. Fertil Steril. 2009;91:365-71.
Devroey et al. Hum Reprod 2009;24:764–74.
European Orgalutran Study Group, Borm & Mannaerts. Hum Reprod 2000;15:1490-8.
European and Middle East Orgalutran Study Group. Hum Reprod 2001;16:644–51.
Fauser et al. Hum Reprod 1999;14:2681-6.
Fluker et al. Fertil Steril 2001;75:38-45.
Heijnen et al. Hum Reprod 2004;19:1936–8.
Kolibianakis et al. Hum Reprod Update 2006:12:651-71.
Lainas et al. Hum Reprod 2010:25:683-9.
Tarlatzis et al. Hum Reprod Update 2006;12:333–40.

Are GnRH antagonists suitable for normal responders, or only for patients who are at high risk of OHSS?

The GnRH antagonist protocol is recommended for predicted normal responders as it lowers the risk of OHSS (Al-Inany et al. 2006; Kolibianakis et al. 2006). It is also better tolerated than the GnRH agonist protocol, and may increase the likelihood that patients will return for a second cycle if the first cycle does not result in a live birth (Devroey et al. 2009).

Al-Inany et al. Cochrane Database Syst Rev 2006;3:CD001750.
Devroey et al. Hum Reprod 2009;24:764–74.
Kolibianakis et al. Hum Reprod Update 2006:12:651-71.

Pregnancy rates

Are the GnRH antagonists now at least 'non-inferior' to long downregulation cycles?

There has been a misconception that GnRH antagonists are not as successful as agonists. However, the Kolibianakis (2006) meta-analysis found that live birth rate was not dependent on the type of GnRH analog used (odds ratio 0.86, 95% confidence interval [CI] 0.72–1.02).

Kolibianakis et al. Hum Reprod Update 2006;12:651–71.

Why did the Cochrane database analysis conducted by Al-Inany et al. (2006) show a small but significant difference in pregnancy rate between GnRH agonists and antagonists?

The odds ratios and numbers needed to treat for benefit (NNTB) for live birth/ongoing pregnancy calculated by Al-Inany et al. (2006) were very similar to those of Kolibianakis et al. (2006). Al-Inany et al. calculated a p value of 0.02, suggesting a slight difference between the two treatments, a finding which differs from that of Kolibianakis et al. (2006). However, the Al-Inany et al. meta-analysis included only 15 randomized trials, compared to 22 in the Kolibianakis et al. analysis, and some of these 15 were relatively old studies. These used protocols that we now know to be suboptimal and thus no longer reflect outcomes seen in contemporary research or practice. Some of the studies cited by Al-Inany et al. also have not been published in full.

When retrospectively comparing outcomes with these two treatment types, it must be remembered that GnRH antagonists have historically been used more often in patients who were less likely to have a successful outcome, e.g. in older women and in those who had previous unsuccessful cycles (Griesinger et al. 2005). If this is not corrected for, the results are likely to give a misleading impression.

Al-Inany et al. Cochrane Database Syst Rev 2006;3:CD001750.
Griesinger et al. Hum Reprod 2005;15:2372–5.
Kolibianakis et al. Hum Reprod Update 2006;12:651–71.

Scheduling of GnRH antagonist protocols

What is the suggested protocol for oral contraceptive pill (OCP) cycle programming?

Start OCP with menses (Day 1-5). The OCP needs to be taken for at least 14 days, and a withdrawal bleed is expected within 48–72 h of cessation. recFSH stimulation can be started within 2–5 days of withdrawal of the OCP (Huirne et al. 2007).

Huirne et al. Hum Reprod 2007;22:2805–2813.

Is OCP cycle programming recommended?

Ovarian response to stimulation is variable in both agonist and antagonist cycles, which makes it difficult to predict hCG administration accurately, even after use of oral contraceptives.

Furthermore, in a recent, prospective, randomized trial, patients who were pretreated with OC had a reduced chance of establishing an ongoing pregnancy, compared with those who had not received pretreatment (Tavmergen et al. 2009). These findings are supported by those of a systematic review and meta-analysis of six randomized clinical trials (involving 1340 patients): ongoing pregnancy rate was significantly lower in patients with OC pretreatment, compared with those who had not received OC pretreatment (relative risk 0.80, 95% CI 0.66–0.97, p = 0.02) (Griesinger et al. 2010). All six trials used combined OC pills with 30 ΅g ethyl estradiol and 150 ΅g gestogen (either desogestrel or levonorgestrel), and duration of pill pretreatment ranged from 14 to 28 days. In this analysis, neither fertilization rates nor numbers of cumulus–oocyte complexes retrieved were significantly different between the groups.

It thus appears that OCP pretreatment negatively affects ongoing pregnancy rates, and should not be routinely used. OCP pretreatment is also associated with increased recFSH usage and a longer duration of recFSH stimulation (Huirne et al. 2006; Griesinger et al. 2010). Lastly, from the patient’s perspective, OCP pretreatment increases the perceived length of treatment, and thus negates one of the major advantages of GnRH antagonist over agonists: the reduction in treatment duration (Devroey et al. 2009).

Devroey et al. Hum Reprod 2009;24:764–74.
Griesinger et al. Fertil Steril 2010;94:2382–4.
Huirne et al. Reprod Biomed Online 2006;13:235–45.
Tavmergen et al. Hum Reprod 2009;24(Suppl 1):O-211.

Can cycle programming be reliably introduced without OCPs?

There is some flexibility in scheduling the start day of ovarian stimulation. For example, pregnancy rates do not appear to be compromised when altering the start day of recFSH to day 2, 3, or 4 of menses (Huirne et al. 2007). The hCG trigger can also be delayed by 1 day (Tremellen & Lane 2010). However, waiting any longer is deleterious: in one study, the ongoing pregnancy rate was 35.6% when triggering on the day of three follicles > 17 mm, but only 25% when triggering 2 days later (Kolibianakis et al. 2004). Moving the day of hCG administration forward is also a common practice used to avoid weekend working, and does not appear to effect the live birth rate (Tremellen & Lane 2010). Nevertheless, the clinical implications of advancement and delay still require further investigation before a detrimental effect on outcome can be ruled out completely (Devroey et al. 2009; Tremellen & Lane 2010).

Devroey et al. Hum Reprod 2009;1;1–11.
Huirne et al. Hum Reprod 2007;22:2805–13.
Kolibianakis et al. Fertil Steril 2004;82:102–7.
Tremellen & Lane. Hum Reprod 2010;25:1219–24.

Timing and dosing

When planning to use a GnRH antagonist protocol, what is the recommended dose of recFSH and when should it be started?

An initial daily dose of 150 IU recFSH has been suggested for patients aged < 35 years (Devroey et al. 2009). A meta-analysis of 10 randomized controlled trials also suggests that 150 IU recFSH is the optimal starting dose in predicted normal responders younger aged < 39 years (Sterrenburg et al. 2010). Although this dose resulted in fewer retrieved oocytes, pregnancy rates were equal to those obtained with higher doses. A starting dose of 150 IU recFSH also produced a sufficient number of oocytes to enable cryopreservation of embryos for use in later cycles.

Devroey et al. Hum Reprod 2009;24:764–74.
Sterrenburg et al. Hum Reprod 2010 ePub ahead of print.

When should GnRH antagonist co-treatment be started?

The initial clinical trials with GnRH antagonists started treatment on Day 6 of recFSH administration (European Orgalutran Study Group, Borm & Mannaerts 2000; European and Middle East Orgalutran Study Group 2001). However, recent trials have switched to starting GnRH antagonists on Day 5 and have reported excellent pregnancy rates (The Corifollitropin Alfa Dose-finding Study Group 2008; Fernandez Sanchez & Koper 2009). Further randomized clinical trials are needed to establish the optimal starting day.

European Orgalutran Study Group, Borm & Mannaerts Hum Reprod 2000:15:1490–8.
European and Middle East Orgalutran Study Group Hum Reprod 2001;16:644–51.
Fernandez Sanchez & Koper. Hum Reprod 2009;24(Suppl 1):O–005.
The Corifollitropin Alfa Dose-finding Study Group. Hum Reprod 2008;23:2484–92.

When you administer the GnRH antagonist on Day 5, do you increase the daily IU of recFSH?

No. If you are measuring estradiol levels you may observe an estradiol dip at the start of GnRH antagonist administration; however, this does not appear to have any negative effect. Thus, there are no data to suggest that an increase in recFSH dose is necessary in normal responders (Aboulghar et al. 2004; Propst et al. 2006; Sterrenburg et al. 2010).

Aboulghar et al. Reprod Biomed Online 2004;8:524–7.
Propst et al. Fertil Steril 2006;86:58–63
Sterrenburg et al. Hum Reprod 2010 ePub ahead of print.

Why does the GnRH antagonist protocol recommend a fixed protocol, rather than a flexible protocol in normal responders?

No differences in premature LH rise or ongoing pregnancy rate have been found between the fixed 6-day protocol and the flexible protocol (Kolibianakis et al. 2010). However, the fixed protocol is recommended, because it is simple to follow and avoids increased antagonist consumption.

Kolibianakis et al. Fertil Steril 2010; ePub ahead of print.

What is the best timing (hours of the day) for last antagonist dose and trigger administration?

Morning administration is best for both GnRH antagonists and hCG triggering. This increases the cost of the cycle slightly, but ensures avoidance of premature luteinization (Devroey et al. Hum Reprod 2009).

Devroey et al. Hum Reprod 2009;24:764–74.

Triggering methods

Using agonists as a trigger in antagonist cycles: what experience do we have and does this effect pregnancy rates?

The key advantage of using GnRH agonists to trigger final oocyte maturation - while using a GnRH antagonist protocol - is that it reduces the risk of OHSS (Kolibianakis et al. 2006; Heijnen et al. 2004; Al-Inany et al. 2006; Bodri et al. 2009). In some clinics, triggering with GnRH agonists is limited to patients at risk of OHSS (i.e. those with PCOS, polycystic ovarian morphology or previous high response to stimulation). However, other IVF clinics use it routinely for patients who are not undergoing embryo transfer, such as oocyte donors or fertility preservation patients (Acevedo et al. 2006; Bodri et al. 2008; Cerrillo et al. 2009). It is particularly useful for patients who travel long distances to attend an IVF clinic and where medical care can be hours away. Using GnRH agonist triggering is, therefore, considered to be a safety precaution.

However, using GnRH agonist triggering, compared with hCG triggering, may result in lower pregnancy rates (Griesinger et al. 2006). We know that this is not due to lower quality of oocytes and embryos: the live birth rates achieved with frozen-thawed embryos using this method of triggering are good (Griesinger et al. 2007a, 2007b). More recently, triggering combined with fresh embryo transfer has been more successful. One study found no difference in ongoing pregnancy rates between GnRH agonists and hCG triggering in patients with high risk of OHSS (Engmann et al. 2008). It is thus possible that the differences in outcomes between studies arise from differences in the provision of additional luteal support (Engmann et al. 2008).

Some studies have explored whether a bolus of 1500 IU hCG could rescue the luteal phase after GnRH agonist triggering. Reassuringly, no significant difference in delivery rate has been found between this method and 10,000 IU hCG triggering (Humaidan et al. 2006; Humaidan et al. 2009a and b). However, at this stage, we cannot be completely sure which protocol provides the best luteal phase support following GnRH agonist triggering, and further investigation is required (Humaidan et al. 2010).

Acevedo et al. Fertil Steril 2006;86:1682–7.
Al-Inany et al. Cochrane Database Syst Rev 2006;3:CD001750.
Bodri et al. Reprod Biomed Online 2008;17:237–43.
Bodri et al. Fertil Steril. 2009;91:365-71
Cerrillo et al. Fertil Steril 2009;91:1526–8.
Engmann et al. Fertil Steril. 2008;89:84–91.
Griesinger et al. Hum Reprod Update 2006;12:159–68
Griesinger et al. Hum Reprod 2007a;22:1348–52.
Griesinger et al. Fertil Steril 2007b;88:616–21.
Heijnen et al. Hum Reprod 2004;19:1936–38.
Humaidan et al. Reprod Biomed Online 2006;13:173–8.
Humaidan et al. Fertil Steril. 2009a;93:847–54.
Humaidan et al. Reprod Biomed Online 2009b;18:630–4.
Humaidan et al. Fertil Steril 2010;94:389–400.
Kolibianakis et al. Hum Reprod Update 2006:12:651-71.

What hormone levels should be tested on the day of hCG triggering?

If serum estradiol is &gt; 4000 pg/ml on the day of hCG administration, consider different strategies to avoid OHSS, such as coasting, cabergoline administration, or substituting hCG with a GnRH agonist bolus (Garcia-Velasco 2009).

If serum progesterone is &gt; 1.5 ng/mL, consider oocyte/embryo freezing to postpone embryo transfer (Bosch et al. 2010).

Garcia-Velasco. Reprod Biomed Online 2009;18:71–5.
Bosch et al. Hum Reprod 2010;25:2092–100.

Oocyte numbers

Reduction in egg and embryo numbers with the antagonist protocol: how do we manage the psychological effect on patients?

There is a need for pretreatment counseling. The number of oocytes retrieved is likely to be less with GnRH antagonist protocol; however the number of good quality oocytes is the same in both protocols. The long downregulation protocol harvests more oocytes, but not more euploid embryos (Baart et al. 2007; Kyrou et al. 2010). To an extent, you play off safety against having larger numbers of embryos to freeze.

Baart et al. Hum Reprod 2007;22:980–88. Kyrou et al. Fertil Steril 2010 ePub ahead of print.

Corifollitropin alfa

What is corifollitropin alfa?

Corifollitropin alfa is a recombinant glycoprotein created from the fusion of the &szlig;-subunit of FSH with the carboxy-terminal part of the &szlig;-subunit of hCG (Fares et al. 1992). This carboxy-terminal peptide has a significant impact on the biological activity of corifollitropin alfa, increasing the half-life of the molecule from ~30 h to ~70 h (Duijkers et al. 2002).

Fares et al. Proc Natl Acad Sci USA 1992:89:4304–08.
Duijkers et al. Hum Reprod. 2002;17:1987–93.

What are the advantages of using corifollitropin alfa over recFSH for ovarian stimulation?

Corifollitropin alfa achieves outcomes comparable with currently available protocols, but with fewer injections and a simplified regimen: only a single injection of corifollitropin alfa is required, compared with daily doses of recFSH (Devroey et al. 2009). Corifollitropin alfa is therefore expected to reduce the treatment burden for patients undergoing IVF substantially. The safety profile of corifollitropin alfa is also similar to that of recFSH (Fauser et al. 2009).

Devroey et al. Hum Reprod. 2009;24:3063-72.
Fauser et al. Hum Reprod Update. 2009;3:309-21.

How can a single injection of corifollitropin alfa sustain multiple follicular development for an entire week?

Due to its pharmacokinetic profile, only one dose of corifollitropin alfa is necessary to initiate and maintain multiple follicular development. Its maximum serum concentration is reached within 2 to 3 days, unlike recFSH, which reaches its maximum concentration in only half a day (Duijkers et al. 2002). Furthermore, the elimination half-life of corifollitropin alfa is approximately two-fold longer than the elimination half-life of recFSH. Therefore, overall, the serum concentration of corifollitropin alfa remains above the required threshold for activity for a longer period of time, compared with recFSH.

Duijkers et al. Hum Reprod. 2002;17:1987–93.

How do the outcomes with corifollitropin alfa compare with those obtained using recFSH? What are the findings from the phase III trials?

Two pivotal phase III trials have evaluated corifollitropin alfa: Engage and Ensure. Both were double-blind randomized trials of similar design, differing only in corifollitropin alfa dose and body mass index (Devroey et al. 2009, Mannaerts et al. 2010).

Ongoing pregnancy rates were comparable between corifollitropin alfa and daily recFSH in the large Engage trial (1506 patients): 38.9% vs. 38.1%, respectively (Devroey et al. 2009). The estimated difference for corifollitropin alfa vs recFSH was 0.9% (95% CI -3.9 to 5.7), therefore slightly favoring corifollitropin alfa, although not significantly so.

The mean number of oocytes retrieved in both trials was significantly higher with corifollitropin alfa, compared with recFSH, over the entire ovarian stimulation period. In the ENGAGE trial, the estimated difference between treatments (using a 95% CI) was 1.2 oocytes more in the corifollitropin alfa treatment group, compared with the recFSH group (Devroey et al. 2009). In the Ensure study, the estimated difference was 2.5 more oocytes in the corifollitropin alfa treatment group, compared with the recFSH group (Mannaerts et al. 2010). (Equivalence margins for the difference in the number of oocytes retrieved were predefined to be -3 and +5 oocytes). The quality of oocytes (i.e. percentages of metaphase II [MII] oocytes), was comparable between treatments in both studies.

Devroey et al. Hum Reprod. 2009;24:3063-72.
Mannaerts et al. Reprod Biomed Online. 2010;21:66–76.