Human Reproduction Update

Human Reproduction Update Advance Access originally published online on March 27, 2006
Human Reproduction Update 2006 12(4):333-340; doi:10.1093/humupd/dml001

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GnRH antagonists in ovarian stimulation for IVF

B.C. Tarlatzis^1,5, B.C. Fauser², E.M. Kolibianakis¹, K. Diedrich³, P. Devroey⁴ , On Behalf of the Brussels GnRH Antagonist Consensus Workshop Group

¹ Unit for Human Reproduction, 1st Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Thessaloniki, Greece, ² Department of Reproductive Medicine and Gynaecology, University Medical Centre, Utrecht, Netherlands, ³ Department of Gynecology and Obstetrics, Division of Gynaecological Endocrinology and Reproductive Medicine, University Clinic of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany and ⁴ Centre for Reproductive Medicine, Dutch-Speaking Brussels Free University, Brussels, Belgium

⁵ To whom correspondence should be addressed at: 1st Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Unit for Human Reproduction, Papageorgiou General Hospital, Nea Efkarpia Peripheral Road, Thessaloniki 54603, Greece. E-mail: tarlatzis{at}hol.gr

Submitted on December 21, 2005; accepted on January 13, 2006

	Abstract

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The present review describes, on the basis of the currently available evidence, the consensus reached by a group of experts on the use of gonadotropin-releasing hormone (GnRH) antagonists in ovarian stimulation for IVF. The single or multiple low-dose administration of GnRH antagonist during the late-follicular phase effectively prevents a premature rise in serum luteinizing hormone (LH) levels in most women. Although controversy remains, most comparative studies suggest a slight, not significant reduction in the probability of pregnancy after IVF using GnRH antagonist versus GnRH agonist co-treatment. Published meta-analyses suggest that this slight difference in pregnancy rates is not attributed to chance. Further studies applying varying treatment regimens and outcome measures are required. Data are not in favour of a need to modify the starting dose of gonadotropins. Data are not in favour of increasing gonadotropin dose at GnRH antagonist initiation. The addition of LH from the initiation of ovarian stimulation or from GnRH antagonist administration does not appear to be necessary. Replacement of human chorionic gonadotropin (HCG) by GnRH agonist for triggering final oocyte maturation is associated with a lower probability of pregnancy. The optimal timing for HCG administration needs to be explored further. GnRH antagonist initiation on day 6 of stimulation appears to be superior to flexible initiation by a follicle of 14–16 mm, although earlier GnRH antagonist administration is worth further evaluation. Luteal phase supplementation in GnRH antagonist protocols remains mandatory in IVF. Effects of GnRH antagonist co-treatment on the incidence of ovarian hyperstimulation syndrome remains uncertain, although a trend is present in favour of the GnRH antagonists. The role of GnRH antagonists in ovarian stimulation for IVF appears to be promising, although many questions regarding preferred dose regimens and effects on clinical outcomes remain.

Key words: GnRH antagonists / IVF / ovarian stimulation / pregnancy rates

	Introduction

TOP Abstract Introduction Molecular and cellular actions... GnRH antagonists in ovarian... Coda References

 
Gonadotropin-releasing hormone (GnRH) antagonists were introduced in recent years in ovarian stimulation for assisted reproductive technologies (ART) to inhibit a premature rise in luteinizing hormone (LH), a role served by GnRH agonists since 1984 (Porter et al., 1984). The uptake of GnRH antagonists in ART, however, has so far been lower than expected. This has stimulated an ongoing debate and resulted in numerous editorials in the literature (Felberbaum and Diedrich, 2003; Engel et al., 2005; Fauser and Devroey, 2005; Kolibianakis et al., 2005a).

In an attempt to optimize the existing stimulation protocols, several studies have explored various aspects of the use of GnRH antagonist in IVF. Such studies involved the optimal day GnRH antagonist administration should be initiated (Ludwig et al., 2002; Escudero et al., 2004; Mochtar et al., 2004), the effect of the starting dose of exogenous follicle-stimulating hormone (FSH) on pregnancy rates (Wikland et al., 2001; Out et al., 2004), the need to supplement the follicular phase with LH (Cedrin-Durnerin et al., 2004; Griesinger et al., 2005a) as well as the need to increase the gonadotropin dose at GnRH antagonist initiation (Aboulghar et al., 2004). In addition, interest has been focused on the effect of the timing of human chorionic gonadotropin (HCG) administration on the probability of pregnancy (Kolibianakis et al., 2004a), the replacement of HCG with GnRH agonist for triggering final oocyte maturation (Fauser et al., 2002; Humaidan et al., 2005; Kolibianakis et al., 2005b) as well as the possibility of direct effects of GnRH antagonists on extra-pituitary tissues (Weiss et al., 2001; Tarlatzis and Kolibianakis, 2002). Finally, alternative stimulation schemes such as the late initiation of FSH in the follicular phase (de Jong et al., 2000; Hohmann et al., 2003), the application of IVF in a modified natural cycle (Rongieres-Bertrand et al., 1999, Kolibianakis et al., 2004b) and the use of GnRH antagonists in ovarian stimulation for intrauterine insemination (IUI) (Ragni et al., 2001, 2004) have been explored.

The purpose of the present review was to describe, on the basis of the currently available evidence, the consensus reached by a group of experts on the use of GnRH antagonists in ovarian stimulation for IVF. Before the consensus meeting a systematic literature search was performed by each of the invited speakers on the specific subject of the presentation given.

	Molecular and cellular actions of GnRH antagonists

TOP Abstract Introduction Molecular and cellular actions... GnRH antagonists in ovarian... Coda References

 
The inhibition of a premature LH rise by GnRH agonists requires at least 7 days, as it is accompanied by an initial stimulation of GnRH receptors before gonadotroph desensitization is achieved. In contrast, GnRH antagonists compete directly with endogenous GnRH for receptor binding and therefore rapidly inhibit secretion of gonadotropin and steroid hormones (Klingmuller et al., 1993). This property conveys a potential advantage over GnRH agonists in the management of ovarian stimulation. However, because of the constant need to block out endogenous GnRH, much higher doses of antagonists are required (mg per day compared with <0.1 mg per day for GnRH agonists).

The GnRH antagonists incorporate a number of amino acid substitutions in the NH₂ terminal domain (involved in receptor activation) combined with a D-amino acid substitution for Gly⁶ which enhances the ßII type bend necessary for receptor binding (Millar et al., 2004). These features of GnRH antagonists used in the clinic are shown in Figure 1. The presence (Cheng and Leung, 2005) and cellular effects of GnRH I, GnRH II and GnRH receptor in human ovarian, uterine and placental cells suggests that GnRH analogues may also exert direct actions in these tissues through disruption of autocrine or paracrine signalling of GnRH (Weiss et al., 2001; Tarlatzis and Kolibianakis, 2002).

View larger version (56K): [in this window] [in a new window]   Figure 1. Structure of clinically used GnRH antagonists (modified from Millar et al., 2004).

 

Recently, certain GnRH antagonists have been shown to act as agonists for some intracellular signalling pathways (Maudsley et al., 2004). Thus they are pure antagonists at the pituitary GnRH receptor (i.e. inhibit GnRH stimulation of G_q and downstream Ca²⁺, and protein kinase C signalling) but are full agonists in stimulating G_i and the inhibition of proliferation and apoptosis in peripheral reproductive cells (G_q and G_i are the alpha subunits of the heterotrimeric G-proteins which mediate the GnRH receptor activation of intracellular signalling). Other GnRH antagonists have little or no G_i activity. GnRH antagonists may therefore have additional effects (negative or positive) when used in IVF. Further laboratory studies and thorough comparative clinical trials with GnRH agonists are required to address this possibility.

A number of non-peptide orally-active GnRH antagonists are currently undergoing clinical trials (Papanikolaou et al., 2005). These compounds are pure antagonists of G_q and do not activate G_i (Lu and Millar, personal communication). This singular activity coupled with flexible dosing and ease of administration suggests considerable potential for utilization in IVF. It is interesting that one of these compounds (TAK-013, Takeda) has potent oral activity in inhibiting LH but has no effect on FSH when administered for 80 days (Hara et al., 2003).

	GnRH antagonists in ovarian stimulation for IVF

TOP Abstract Introduction Molecular and cellular actions... GnRH antagonists in ovarian... Coda References

 
The aim of using GnRH antagonists in IVF is the inhibition of a premature LH rise which could lead to premature luteinization, follicle maturation arrest and asynchrony of oocyte maturation. The use of GnRH antagonists in IVF is characterized both by advantages and disadvantages.

Advantages and disadvantages for the use of GnRH antagonists in IVF

Advantages

1. Prevention of premature LH increase is easier and takes less time. GnRH antagonists act within a few hours after their administration (Klingmuller et al., 1993) and thus they can be administered only when there is a risk for an LH surge. This is in contrast to GnRH agonists where pituitary down-regulation occurs only after 7–10 days.
   
2. GnRH antagonists are not associated with an acute stimulation of gonadotropins and steroid hormones, which occurs with GnRH agonist administration.
   
3. The initial stimulation by GnRH agonists can induce cyst formation, which is avoided with GnRH antagonists.
   
4. No hot flushes are observed with GnRH antagonists as their use does not result in profound hypo-estrogenaemia observed with GnRH agonists (Varney et al., 1993).
   
5. Inadvertent administration of the GnRH analogue in early pregnancy can be avoided as GnRH antagonist is administered in the mid-follicular phase.
   
6. Requirements for exogenous gonadotropins are reduced, rendering ovarian stimulation less costly.
   
7. Duration of ovarian stimulation protocols is shortened, improving patient discomfort.
   

Disadvantages

1. GnRH antagonist co-treatment represents a novel approach in ovarian stimulation for IVF and knowledge accumulation is necessary for its optimization.
   
2. GnRH antagonists offer less flexibility regarding cycle programming as compared with the long, but not with the short, GnRH agonist protocol.
   
3. Most comparative studies report a minor reduction in pregnancy rates per cycle with GnRH antagonists as compared with GnRH agonists.
   

It should be noted that for units that manage starting dates of cycles to gain an orderly daily volume of oocyte retrievals the use of GnRH agonists has been an advantage. With GnRH antagonist protocols, sufficient flexibility regarding the starting dates and the ability to achieve a daily volume control is still present, although this can be improved by using the oral contraceptive pill (OCP) (Hwang et al., 2004).

Important aspects of GnRH antagonist use in ovarian stimulation for IVF

Single versus multiple dose GnRH antagonist protocol
Two GnRH antagonist protocols were developed involving either multiple (Diedrich et al., 1994) or single administration (Olivennes et al., 1994). In the multiple dose protocol, the GnRH antagonist was administered continuously until the day of HCG administration, starting 5 days after stimulation with gonadotropins. The minimal dose shown to prevent the occurrence of a premature LH rise in the great majority of patients was shown to be 0.25 mg (Albano et al., 1997; The Ganirelix dose finding study group, 1998).

In the single dose protocol, a 3 mg dose of GnRH antagonist given on cycle day 7 during ovarian stimulation was shown to prevent a premature LH surge (Olivennes et al., 1998). In case of the need to delay HCG, low daily doses of GnRH antagonists could be added 4 days after the single antagonist dose.

Pros for the single dose GnRH antagonist protocol: Potential for fewer injections, although in 10% of cycles additional daily doses of GnRH antagonist are necessary (Olivennes et al., 2000).

Cons for the single dose: Besides inhibiting premature LH surge, the single dose protocol results in an excessive and potentially harmful suppression of endogenous LH. However, no significant difference in pregnancy rates was shown in a randomized-controlled trial (RCT) which compared the two antagonist protocols (Wilcox et al., 2005).

Fixed versus flexible antagonist administration
In all phase three comparative trials in which the daily GnRH antagonist protocol was used, initiation of GnRH antagonist was performed on day 6 of stimulation. However, this choice was not evidence-based and, in principle, GnRH antagonist administration should commence when there is follicular development and/or production of estradiol (E₂) by the developing follicles which might give rise to a premature elevation in pituitary LH release due to positive feedback mechanisms. Thus the idea of a flexible GnRH antagonist initiation is worth evaluating and might lead to even further simplification of this protocol.

Four RCTs have so far been performed comparing a fixed (on day 6) versus a flexible (by a follicle diameter of 14–15 mm) protocol of GnRH antagonist administration (Al-Inany et al., 2005). Although currently the difference is not significant, all published studies show a lower pregnancy rate in the flexible as compared to the fixed protocol (odds ratio 0.70, 95% CI: 0.47–1.05; Figure 2).

View larger version (9K): [in this window] [in a new window]   Figure 2. Clinical pregnancy rate in fixed and flexible GnRH antagonist protocols (modified from Al-Inany et al., 2005).

 

However, the criteria on which the initiation of GnRH antagonist is based on as well as the first day on which patients should start evaluation, in order to examine if these criteria are satisfied, have not been assessed so far. Earlier initiation of GnRH antagonist needs to be further explored (Kolibianakis et al., 2003a, 2004c). Moreover, dose and timing of gonadotropin administration may have an impact on the optimal day of starting GnRH antagonist to inhibit the premature LH rise (Hohmann et al., 2003).

GnRH agonist versus HCG for triggering final oocyte maturation
GnRH agonist has been used to trigger final oocyte maturation in GnRH antagonist cycles (Felberbaum et al., 1995). Replacing HCG with GnRH agonist has been claimed to lead to a decreased risk of developing ovarian hyperstimulation syndrome (OHSS) in high risk patients (Kol, 2004). However, GnRH agonist administration induces an LH surge which is not identical to that occurring in the natural cycle, especially regarding its duration (Fauser et al., 2002; Beckers et al., 2003).

The existing literature suggests that a lower probability of pregnancy is to be expected when a single dose of GnRH agonist is used instead of HCG for triggering final oocyte maturation (Humaidan et al., 2005; Griesinger et al., 2005b; Kolibianakis et al., 2005b). Thus, if GnRH agonists are used instead of HCG in high-risk patients to prevent OHSS, the reduced probability of pregnancy that might be associated with their use has to be considered. However, it remains to be explored whether the dose of the GnRH agonist administered, the repeated administration of the agonist or the use of alternative luteal support schemes would improve the pregnancy outcome. On the other hand, alternative existing methods shown to reduce the risk of OHSS such as coasting or cryopreservation of all embryos and transfer of the thawed embryos in a subsequent cycle can also be applied (Delvigne and Rozenberg, 2002; Aboulghar and Mansour, 2003). A comparison between various methods used to prevent OHSS is currently lacking.

Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists
The use of OCP has been advocated as a mean for programming IVF cycles using GnRH antagonists (Fischl et al., 2001; Cedrin-Durnerin et al., 2004). In addition, it has been speculated that the use of OCP pretreatment may result in improved synchronization of the recruitable cohort of ovarian follicles. Its use in ovarian stimulation for IVF is associated with advantages and disadvantages.

Pros: Easier scheduling of the cycle which is not based in this case on the occurrence of menstruation but on the discontinuation of the OCP.

Cons:

1. Pretreatment with OCP has been associated with a longer duration of treatment (van Loenen et al., 2001).
   
2. An increased gonadotropin requirement has been observed with the use of OCP (Bendikson et al., 2003).
   
3. Administration of OCP might be emotionally disturbing, since OCP is mainly used to prevent conception.
   

No significant effect of OCP pretreatment on the probability of pregnancy in GnRH antagonist cycles was shown in a large RCT (Kolibianakis et al., 2006), suggesting that programming of IVF cycles with the use of OCP is feasible. The effect of the time interval from OCP discontinuation to initiation of stimulation on IVF outcome (van Heusden and Fauser, 2002) still needs to be assessed.

Use of exogenous FSH in GnRH antagonist co-treatment cycles
On a physiological basis, the required starting dose of FSH in GnRH antagonist cycles is lower compared to GnRH agonist, due to the presence of higher endogenous FSH levels during the inter-cycle phase (Fauser and van Heusden, 1997). However, a lower number of cumulus-oocyte complexes (COCs) was retrieved with the use of GnRH antagonists in phase III comparative trials with GnRH agonists (Al-Inany and Aboulghar, 2002). The concept of a higher starting FSH dose that might compensate for this difference has been tested so far in two RCTs. It was shown that a higher starting dose of FSH results in an increased number of COCs retrieved but it does not appear to be associated with higher pregnancy rates (Wikland et al., 2001; Out et al., 2004; Table I). In addition, the increase of gonadotropin doses at GnRH antagonist initiation did not appear to result in higher probability of pregnancy (Aboulghar et al., 2004).

View this table: [in this window] [in a new window]   Table I. Randomized-controlled trials evaluating the need for an increase in the starting dose of rec FSH in patients treated for IVF using GnRH antagonists

 

It has been shown that it is possible to start FSH stimulation later in the follicular phase by extending the FSH window for multifollicular development (Hohmann et al., 2001, 2003). This would lead to the development of milder stimulation protocols. In the same direction is the use of the modified natural cycle for IVF in which the development of a single follicle is supported by exogenous FSH in combination with GnRH antagonist to control the endogenous LH production (Rongieres-Bertrand et al., 1999). The application of the modified natural cycle in poor prognosis groups is debatable (Kolibianakis et al., 2004b; Elizur et al., 2005). In theory, the type of gonadotropin preparation used (recombinant versus urinary, containing LH or not) for ovarian stimulation is not expected to result in a different probability of pregnancy.

LH supplementation
An abrupt suppression of endogenous LH by GnRH antagonist occurs in the mid-follicular phase, at a critical stage for follicular development. In view of the decreased probability of pregnancy associated with low LH levels, which was observed using high GnRH antagonist doses (The Ganirelix dose finding group, 1998) and the increased pregnancy loss observed with low LH levels in GnRH agonist cycles (Westergaard et al., 2000), it was assumed that LH supplementation might improve pregnancy outcome in GnRH antagonist cycles. However, data from RCTs suggest that the addition of 75 IU of recombinant LH to recombinant FSH at GnRH antagonist initiation (Cedrin-Durnerin et al., 2004) or from initiation of stimulation (Griesinger et al., 2005a) does not appear to enhance pregnancy rates (Table II). Similarly, no improvement in pregnancy rates could be shown by increasing the dose of HMG by 75 IU at GnRH antagonist initiation (Aboulghar et al., 2004).

View this table: [in this window] [in a new window]   Table II. Randomized-controlled trials evaluating the addition of LH in patients stimulated with rec FSH and GnRH antagonists for IVF

 

Moreover, no indication that low endogenous LH levels after GnRH antagonist initiation are associated with a decreased probability of pregnancy in IVF cycles was provided by both retrospective (Merviel et al., 2004) and prospective studies (Kolibianakis et al., 2004d). On the contrary, it was suggested that the lower the LH levels on day 8 of stimulation for IVF, the higher the probability of pregnancy (Kolibianakis et al., 2004d).

On the basis of the currently available data it appears that LH supplementation in ovarian stimulation for IVF using GnRH antagonist cycles is not necessary.

Criteria for HCG administration
There is a marked variation in the criteria used for triggering final oocyte maturation in IVF both in GnRH agonists and antagonist cycles (Kolibianakis et al., 2004a). Recent data indicate that the timing of HCG administration might be important for the probability of pregnancy. Prolongation of the follicular phase was shown to be associated with decreased pregnancy rates (Kolibianakis et al., 2004a). Further studies are necessary to explore the optimal timing of HCG administration. It should be noted that criteria for HCG administration should be strict, especially in clinical trials, in order to ensure that the follicular phase ends in the same way in all patients treated.

Luteal phase supplementation
An initial attempt to not support the luteal phase in GnRH antagonist cycles indicated that luteal supplementation was necessary (Albano et al., 1998; de Jong et al., 2000). Further support to this concept was offered by data showing that endometrial development during a non-supplemented luteal phase is abnormal (Kolibianakis et al., 2003c). In addition, extremely low pregnancy rates and continuously suppressed pituitary gonadotropin release were observed in an unsupported luteal phase after GnRH antagonist co-treatment during ovarian stimulation (Beckers et al., 2003). The existing evidence in GnRH antagonist cycles suggests that luteal supplementation remains mandatory as is the case with GnRH agonists.

Efficacy of GnRH antagonists in IVF

The evidence
In the meta-analysis of five phase III randomized comparative trials between GnRH analogues, the absolute treatment effect of clinical pregnancy rate on an intention-to-treat basis was 5% in favour of the GnRH agonists (Al-Inany and Aboulghar, 2002). In the published meta-analysis, the additional period of treatment required with GnRH agonists was 21 days and the number needed to treat (inverse of the absolute risk difference) was 20 (Al-Inany and Aboulghar, 2002). Based on those data, it is necessary to treat patients for an extra 420 days (20 x 21 days = 420 days) to obtain one additional pregnancy with GnRH agonists. Since then a further three trials have been reported (Hohmann et al., 2003; Vlaisavljevic et al., 2003; Cheung et al., 2005).

In a similar meta-analysis including these trials, the difference in pregnancy rate per cycle was 3.3% (95% CI –0.4, 6.9) in favour of GnRH agonists (J. Collins, personal communication). If this difference were significant, the number needed to treat would be 31, which means that it would take 31 cycles to get one more pregnancy using GnRH agonist compared to GnRH antagonists.

Advantages of GnRH antagonists from meta-analysis of phase III trials (Al-Inany and Aboulghar, 2002)

1. A shorter duration of stimulation is required with the use of GnRH antagonists.
   
2. Gonadotropin requirements are decreased as compared with GnRH agonists.
   
3. Considering OHSS incidence, the odds ratio is in favour of GnRH antagonists, however, it includes unity (0.51, 95% CI 0.22–1.18).
   

Cost studies on the use of GnRH agonists and antagonists are necessary for further assessment of the two analogues of GnRH in ART. For evaluation of GnRH antagonists the clinical end point of interest needs to be agreed and justified (Germond et al., 2004; Griesinger et al., 2004; Heijnen et al., 2004; Min et al., 2004; Tiitinen et al., 2004; Fauser et al., 2005). A pragmatic approach with broad relevance for clinical practice should probably adopt as primary outcome measure live birth rate (Arce et al., 2005).

GnRH antagonists in ovarian stimulation for IUI

The issue of ovarian stimulation in combination with IUI in unexplained infertility is still not solved (Hughes et al., 2000; Fauser et al., 2005). If ovarian stimulation in combination with IUI is performed, GnRH antagonists can be used for preventing the premature LH surge (Ragni et al., 2001, 2004; Gomez-Palomares et al., 2005). In addition, they may be helpful in cycle programming and avoidance of inseminations during weekends. However, the hypothesis that avoiding LH surge in this case is associated with a higher probability of pregnancy needs to be tested in prospective trials.

Recommended use of GnRH antagonists co-treatment during ovarian stimulation for IVF on the basis of the best estimate from the available data in the literature (Table III)

View this table: [in this window] [in a new window]   Table III. Modifications of the standard GnRH antagonist protocol

 

1. Currently, data are not in favour of a need to increase the starting dose of gonadotropins or to increase gonadotropin dose at antagonist initiation.
   
2. Clinical evidence generated so far suggests that OCP pretreatment can be used for planning IVF cycles.
   
3. Addition of LH from initiation of stimulation or from antagonist administration does not appear to be necessary.
   
4. Replacement of HCG by GnRH agonist for triggering final oocyte maturation is associated with lower probability of pregnancy.
   
5. The optimal timing for HCG administration needs to be further explored.
   
6. GnRH antagonist initiation on day 6 of stimulation appears to be superior to flexible initiation by a follicle of 14–16 mm, although earlier GnRH antagonist administration is worth further evaluation.
   
7. The role of GnRH antagonists in ovarian stimulation for IUI as well as their application in mild stimulation protocols for IVF appears to be promising.
   
8. Luteal phase supplementation is required following GnRH antagonist co-treatment protocols.
   

	Coda

TOP Abstract Introduction Molecular and cellular actions... GnRH antagonists in ovarian... Coda References

 

1. GnRH antagonist co-treatement during ovarian hyperstimulation for IVF is effective in preventing an undesirable premature rise in serum LH. The daily low-dose protocol should be preferred over a single high-dose regimen for theoretical reasons. In addition, much more clinical experience exists with this protocol.
   
2. There is a general resistance in the clinic to further explore the use of GnRH antagonist because of the reported lower pregnancy rates associated with their use (Fauser and Devroey, 2005). This is based, however, on a non-significant difference of 3.3% in the pregnancy rate per cycle in favour of GnRH agonists, in case more recently published studies are also included in the meta-analysis.
   
3. GnRH antagonist co-treatment results in shorter and more cost-effective ovarian stimulation protocols. Many further studies are required for its optimization. Several aspects of GnRH antagonist use need to be further explored, such as: potential pharmacological differences in existing compounds, direct effects of GnRH antagonists on extra pituitary tissues (such as corpus luteum, endometrium, ovary, embryo) and optimization of the currently used stimulation protocols (compounds, initiation, doses).
   
4. The possibility of a reduced incidence of OHSS following ovarian stimulation with GnRH antagonist co-treatment deserves further evaluation.
   
5. The impact of timing and dose of HCG for inducing final oocyte maturation on IVF outcomes deserves further studies.
   
6. Further research needs to be carried out on the value of assessing hormonal levels on day 2 of the cycle (Kolibianakis et al., 2004e), prior to initiation of stimulation, and on the importance of hormonal values present on the day of HCG administration (Bosch et al., 2003).
   
7. Finally, the use of GnRH antagonist co-treatment should be viewed in the context of a broader discussion regarding how to assess IVF outcomes (healthy children, term births, chances for success in relation to side effects, complications and cost).
   

	Notes

 
Organized by the ESHRE Special Interest Group "Reproductive Endocrinology". Participants of the Brussels GnRH antagonist consensus workshop: M Aboulghar, The Egyptian IVF-ET Center, Maadi and Cairo University, Department of Obstetrics & Gynecology, Cairo, Egypt; J Collins, Departments of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario and Obstetrics and Gynaecology, Dalhousie University, Halifax, Canada, PG Crosignani, Department of Obstetrics and Gynecology, University of Milano, Milano, Italy; P Devroey, Centre for Reproductive Medicine, Dutch-Speaking Brussels Free University, Laarbeeklaan 101, 1090 Brussels, Belgium; K Diedrich, Department of Gynecology and Obstetrics, Division of Gynaecological Endocrinology and Reproductive Medicine, University Clinic of Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany; BC Fauser, Department of Reproductive Medicine & Gynecology, University Medical Center, 3584 CX Utrecht, The Netherlands; G Griesinger, Department of Gynecology and Obstetrics, Division of Gynaecological Endocrinology and Reproductive Medicine, University Clinic of Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany; S Kol, Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel; EM Kolibianakis, 1st Department of Obstetrics and Gynaecology,

Aristotle University of Thessaloniki, Unit for Human Reproduction, Papageorgiou General Hospital, Nea Efkarpia Peripheral Road, Thessaloniki 54603, Greece; VN Lan, Tu Du Obstetrics and Gynecology Hospital, Ho Chi Minh City, Vietnam; W Ledger, Department of Obstetrics and Gynaecology, The University of Sheffield, Jessop Wing, Sheffield Teaching Hospitals, Tree Root Walk, Sheffield S10 2SF, UK; N Macklon, Department of Reproductive Medicine & Gynecology, University Medical Center, 3584 CX Utrecht, The Netherlands; R Millar, MRC Human Reproductive Sciences Unit, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ; F Olivennes: Unitéd de Medicine de la Reproduction, Hopital Cochin (F.O), 75014 Paris, France; LJF Rombauts, Monash IVF, Clayton, Australia Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia; D Shapiro, Reproductive Biology Associates, Atlanta, Georgia; C Simon, Instituto Valenciano de Infertilidad (IVI), Plaza Policia Local, 3, 46015 Valencia; A Tavaniotou, Centre for Reproductive Medicine, Dutch-Speaking Brussels Free University, Laarbeeklaan 101, 1090 Brussels, Belgium; BC Tarlatzis, 1st Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Unit for Human Reproduction, Papageorgiou General Hospital, Nea Efkarpia Peripheral Road, Thessaloniki 54603, Greece; H Tournaye, Centre for Reproductive Medicine, Dutch-Speaking Brussels Free University, Laarbeeklaan 101, 1090 Brussels, Belgium.

	References

TOP Abstract Introduction Molecular and cellular actions... GnRH antagonists in ovarian... Coda References

 

Aboulghar MA and Mansour RT (2003) Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures. Hum Reprod Update 9,275–289.[Abstract/Free Full Text]

Aboulghar MA, Mansour RT, Serour GI, Al-Inany HG, Amin YM and Aboulghar MM (2004) Increasing the dose of human menopausal gonadotropins on day of GnRH antagonist administration: randomized controlled trial. Reprod Biomed Online 8,524–527.[ISI][Medline]

Albano C, Smitz J, Camus M, Riethmuller-Winzen H, Van Steirteghem A and Devroey P (1997) Comparison of different doses of gonadotropin-releasing hormone antagonist Cetrorelix during controlled ovarian hyperstimulation. Fertil Steril 67,917–922.[CrossRef][ISI][Medline]

Albano C, Grimbizis G, Smitz J, Riethmuller-Winzen H, Reissmann T, Van Steirteghem A and Devroey P (1998) The luteal phase of nonsupplemented cycles after ovarian superovulation with human menopausal gonadotropin and the gonadotropin-releasing hormone antagonist Cetrorelix. Fertil Steril 70,357–359.[CrossRef][ISI][Medline]

Al-Inany H and Aboulghar M (2002) GnRH antagonist in assisted reproduction: a Cochrane review. Hum Reprod 17,874–885.[Abstract]

Al-Inany HG, Aboulghar M, Mansour R and Serour GI (2005) Optimizing GnRH antagonist administration: meta-analysis of fixed vs flexible protocol. Reprod Biomed Online 10,567–570.[Medline]

Arce JC, Nyboe Andersen A and Collins J (2005) Resolving methodological and clinical issues in the design of efficacy trials in assisted reproductive technologies: a mini-review. Hum Reprod 20,1757–1771.[Abstract/Free Full Text]

Beckers NG, Macklon NS, Eijkemans MJ, Ludwig M, Felberbaum RE, Diedrich K, Bustion S, Loumaye E and Fauser BC (2003) Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment. J Clin Endocrinol Metab 88,4186–4192.[Abstract/Free Full Text]

Bendikson K, Milki A, Speck-Zulak A and Westphal L (2003) Comparison of GnRH antagonist cycles with and without oral contraceptive pill pretreatment in poor responders. Fertil Steril 80(Suppl. 3), s188.

Bosch E, Valencia I, Escudero E, Crespo J, Simon C, Remohi J and Pellicer A (2003) Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome. Fertil Steril 80,1444–1449.[CrossRef][ISI][Medline]

Cedrin-Durnerin I, Grange-Dujardin D, Laffy A, Parneix I, Massin N, Galey J, Theron L, Wolf JP, Conord C, Clement P et al. (2004) Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study. Hum Reprod 19,1979–1984.[Abstract/Free Full Text]

Cheng CK and Leung PCK (2005) Molecular biology of gonadotropin-releasing hormone (GnRH)-1, GnRH-II, and their receptors in humans. Endocr Rev 26,283–306.[Abstract/Free Full Text]

Cheung LP, Lam PM, Lok IH, Chiu TT, Yeung SY, Tjer CC and Haines CJ (2005) GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial. Hum Reprod 20,616–621.[Abstract/Free Full Text]

de Jong D, Macklon NS and Fauser BC (2000) A pilot study involving minimal ovarian stimulation for in vitro fertilization: extending the ‘follicle-stimulating hormone window’ combined with the gonadotropin-releasing hormone antagonist cetrorelix. Fertil Steril 73,1051–1054.[CrossRef][ISI][Medline]

Delvigne A and Rozenberg S (2002) Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update 8,559–577.[Abstract/Free Full Text]

Diedrich K, Diedrich C, Santos E, Zoll C, al-Hasani S, Reissmann T, Krebs D and Klingmuller D (1994) Suppression of the endogenous luteinizing hormone surge by the gonadotropin-releasing hormone antagonist Cetrorelix during ovarian stimulation. Hum Reprod 9,788–791.[Abstract/Free Full Text]

Elizur SE, Aslan D, Shulman A, Weisz B, Bider D and Dor J (2005) Modified natural cycle using GnRH antagonist can be an optional treatment in poor responders undergoing IVF. J Assist Reprod Genet 22,75–79.[CrossRef][ISI][Medline]

Engel JB, Riethmuller-Winzen H and Diedrich K (2005) Extrapituitary effects of GnRH antagonists in assisted reproduction: a review. Reprod Biomed Online 10,230–234.[ISI][Medline]

Escudero E, Bosch E, Crespo J, Simon C, Remohi J and Pellicer A (2004) Comparison of two different starting multiple dose gonadotropin-releasing hormone antagonist protocols in a selected group of in vitro fertilization-embryo transfer patients. Fertil Steril 81,562–566.[CrossRef][ISI][Medline]

Fauser BC and Van Heusden AM (1997) Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr Rev 18,71–106.[Abstract/Free Full Text]

Fauser BC and Devroey P (2005) Why is the clinical acceptance of gonadotropin-releasing hormone antagonist co-treatment during ovarian hyperstimulation for in vitro fertilization so slow? Fertil Steril 83,1607–1611.[CrossRef][ISI][Medline]

Fauser BC, de Jong D, Olivennes F, Wramsby H, Tay C, Itskovitz-Eldor J and van Hooren HG (2002) Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab 87,709–715.[Abstract/Free Full Text]

Fauser BC, Devroey P and Macklon NS (2005) Multiple birth resulting from ovarian stimulation for subfertility treatment. Lancet 365,1807–1816.[CrossRef][ISI][Medline]

Felberbaum RE and Diedrich K (2003) Gonadotropin-releasing hormone antagonists: will they replace the agonists? Reprod Biomed Online 6,43–53.[Medline]

Felberbaum RE, Reissmann T, Kupker W, Bauer O, al Hasani S, Diedrich C and Diedrich K (1995) Preserved pituitary response under ovarian stimulation with HMG and GnRH antagonists (Cetrorelix) in women with tubal infertility. Eur J Obstet Gynecol Reprod Biol 61,151–155.[CrossRef][ISI][Medline]

Fischl F, Huber JC, Obruca A (2001) Zeitliche optimierung der kontrollierten hyperstimulation (koh) in kombination mit gnrh-antagonisten und ovulationshemmer in einem ivf-programm. J Fertilität Reproduktion 11,50–51.

Germond M, Urner F, Chanson A, Primi MP, Wirthner D and Senn A (2004) What is the most relevant standard of success in assisted reproduction?: the cumulated singleton/twin delivery rates per oocyte pick-up: the CUSIDERA and CUTWIDERA. Hum Reprod 19,2442–2444.[Abstract/Free Full Text]

Gomez-Palomares JL, Julia B, Acevedo-Martin B, Martinez-Burgos M, Hernandez ER and Ricciarelli E (2005) Timing ovulation for intrauterine insemination with a GnRH antagonist. Hum Reprod 20,368–372.[Abstract/Free Full Text]

Griesinger G, Dafopoulos K, Schultze-Mosgau A, Felberbaum R and Diedrich K (2004) What is the most relevant standard of success in assisted reproduction? Is BESST (birth emphasizing a successful singleton at term) truly the best? Hum Reprod 19,1239–1241.[Abstract/Free Full Text]

Griesinger G, Schultze-Mosgau A, Dafopoulos K, Schroeder A, Schroer A, von Otte S, Hornung D, Diedrich K and Felberbaum R (2005a) Recombinant luteinizing hormone supplementation to recombinant follicle-stimulating hormone induced ovarian hyperstimulation in the GnRH-antagonist multiple-dose protocol. Hum Reprod 20,1200–1206.[Abstract/Free Full Text]

Griesinger G, Diedrich K, Devroey P and Kolibianakis EM (2005b) GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. Hum Reprod Update 12,159–168.

Hara T, Araki H, Kusaka M, Harada M, Cho N, Suzuki N, Furuya S and Fukino M (2003) Suppression of a pituitary-ovarian axis by chronic oral administration of a novel nonpeptide gonadotropin-releasing hormone antagonist, TAK-013 in cynomolgus monkeys. J Clin Endocrinol Metab 88,1697–1704.[Abstract/Free Full Text]

Heijnen EM, Macklon NS and Fauser BC (2004) What is the most relevant standard of success in assisted reproduction? The next step to improving outcomes of IVF: consider the whole treatment. Hum Reprod 19,1936–1938.[Abstract/Free Full Text]

Hohmann FP, Laven JS, de Jong FH, Eijkemans MJ and Fauser BC (2001) Low-dose exogenous FSH initiated during the early, mid or late follicular phase can induce multiple dominant follicle development. Hum Reprod 16,846–854.[Abstract/Free Full Text]

Hohmann FP, Macklon NS and F1auser BC (2003) A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab 88,166–173.[Abstract/Free Full Text]

Hughes E, Collins J and Vandekerckhove P (2000) Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev, CD000057.

Humaidan P, Ejdrup Bredkjaer H, Bungum L, Bungum M, Grondahl ML, Westergaard L and Yding Andersen C (2005) GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Hum Reprod 20,1213–1220.[Abstract/Free Full Text]

Hwang JL, Seow KM, Lin YH, Huang LW, Hsieh BC, Tsai YL, Wu GJ, Huang SC, Chen CY, Chen PH et al. (2004) Ovarian stimulation by concomitant administration of cetrorelix acetate and HMG following Diane-35 pre-treatment for patients with polycystic ovary syndrome: a prospective randomized study. Hum Reprod 19,1993–2000.[Abstract/Free Full Text]

Klingmuller D, Schepke M, Enzweiler C and Bidlingmaier F (1993) Hormonal responses to the new potent GnRH antagonist Cetrorelix. Acta Endocrinol (Copenh) 128,15–18.[Medline]

Kol S (2004) Luteolysis induced by a gonadotropin-releasing hormone agonist is the key to prevention of ovarian hyperstimulation syndrome. Fertil Steril 81,1–5.[ISI][Medline]

Kolibianakis EM, Albano C, Camus M, Tournaye H, Van Steirteghem AC and Devroey P (2003a) Initiation of gonadotropin-releasing hormone antagonist on day 1 as compared to day 6 of stimulation: effect on hormonal levels and follicular development in in vitro fertilization cycles. J Clin Endocrinol Metab 88,5632–5637.[Abstract/Free Full Text]

Kolibianakis EM, Albano C, Kahn J, Camus M, Tournaye H, Van Steirteghem AC and Devroey P (2003b) Exposure to high levels of luteinizing hormone and estradiol in the early follicular phase of gonadotropin-releasing hormone antagonist cycles is associated with a reduced chance of pregnancy. Fertil Steril 79,873–880.[CrossRef][ISI][Medline]

Kolibianakis EM, Bourgain C, Platteau P, Albano C, Van Steirteghem AC and Devroey P (2003b) Abnormal endometrial development occurs during the luteal phase of nonsupplemented donor cycles treated with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonists. Fertil Steril 80,464–466.[CrossRef][ISI][Medline]

Kolibianakis EM, Albano C, Camus M, Tournaye H, Van Steirteghem AC and Devroey P (2004a) Prolongation of the follicular phase in in vitro fertilization results in a lower ongoing pregnancy rate in cycles stimulated with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonists. Fertil Steril 82,102–107.[ISI][Medline]

Kolibianakis E, Zikopoulos K, Camus M, Tournaye H, Van Steirteghem A and Devroey P (2004b) Modified natural cycle for IVF does not offer a realistic chance of parenthood in poor responders with high day 3 FSH levels, as a last resort prior to oocyte donation. Hum Reprod 19,2545–2549.[Abstract/Free Full Text]

Kolibianakis EM, Zikopoulos K, Smith J, Camus M, Tournaye H, Van Steirteghem AC and Devroey P (2004c) Administration of gonadotropin-releasing hormone antagonist from day 1 of stimulation in in-vitro fertilization. Fertil Steril 82,223–226.[CrossRef][ISI][Medline]

Kolibianakis EM, Zikopoulos K, Schiettecatte J, Smith J, Tournaye H, Camus M, Van Steirteghem AC and Devroey P (2004d) Profound LH suppression after GnRH antagonist administration is associated with a significantly higher ongoing pregnancy rate in IVF. Hum Reprod 19,2490–2496.[Abstract/Free Full Text]

Kolibianakis EM, Zikopoulos K, Smith J, Camus M, Tournaye H, Van Steirteghem AC and Devroey P (2004e) Elevated progesterone at initiation of stimulation is associated with a lower ongoing pregnancy rate after IVF using GnRH antagonists. Hum Reprod 19,1525–1529.[Abstract/Free Full Text]

Kolibianakis EM, Tarlatzis BC and Devroey P (2005a) GnRH antagonists in IVF. Reprod Biomed Online 10,705–712.[ISI][Medline]

Kolibianakis EM, Schultze-Mosgau A, Schroer A, van Steirteghem A, Devroey P, Diedrich K and Griesinger G (2005b) A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. Hum Reprod 20,2887–2892.[Abstract/Free Full Text]

Kolibianakis EM, Papanikolaou EG, Camus M, Tournaye H, Van Steirteghem AC and Devroey P (2006) Effect of oral contraceptive pill pretreatment on ongoing pregnancy rates in patients stimulated with GnRH antagonists and recombinant FSH for IVF. A randomized controlled trial. Hum Reprod 21, 352–357.[Abstract/Free Full Text]

Ludwig M, Katalinic A, Banz C, Schroder AK, Loning M, Weiss JM and Dedrich K (2002) Tailoring the GnRH antagonist cetrorelix acetate to individual patients’ needs in ovarian stimulation for IVF: results of a prospective, randomized study. Hum Reprod 17,2842–2845.[Abstract/Free Full Text]

Maudsley S, Davidson L, Pawson AJ, Chan R, Lopez de Maturana R and Millar RP (2004) Gonadotropin-releasing hormone (GnRH) antagonists promote proapoptotic signalling in peripheral reproductive tumor cells by activating a G_ai-coupling state of the type I GnRH receptor. Cancer Res 64,7533–7544.[Abstract/Free Full Text]

Merviel P, Antoine JM, Mathieu E, Millot F, Mandelbaum J and Uzan S (2004) Luteinizing hormone concentrations after gonadotropin-releasing hormone antagonist administration do not influence pregnancy rates in in vitro fertilization-embryo transfer. Fertil Steril 82,119–125.[CrossRef][ISI][Medline]

Millar RP, Lu Z, Pawson AJ, Flanagan CA, Morgan K and Maudsley SR (2004) Gonadotropin-releasing hormone receptors. Endocr Rev 25,235–275.[Abstract/Free Full Text]

Min JK, Breheny SA, MacLachlan V and Healy DL (2004) What is the most relevant standard of success in assisted reproduction? The singleton, term gestation, live birth rate per cycle initiated: the BESST endpoint for assisted reproduction. Hum Reprod 19,3–7.[Abstract/Free Full Text]

Mochtar MH (2004) The effect of an individualized GnRH antagonist protocol on folliculogenesis in IVF/ICSI. Hum Reprod 19,1713–1718.[Abstract/Free Full Text]

Olivennes F, Fanchin R, Bouchard P, de Ziegler D, Taieb J, Selva J and Frydman R (1994) The single or dual administration of the gonadotropin-releasing hormone antagonist Cetrorelix in an in vitro fertilization-embryo transfer program. Fertil Steril 62,468–476.[ISI][Medline]

Olivennes F, Alvarez S, Bouchard P, Fanchin R, Salat-Baroux J and Frydman R (1998) The use of a GnRH antagonist (Cetrorelix) in a single dose protocol in IVF-embryo transfer: a dose finding study of 3 versus 2 mg. Hum Reprod 13,2411–2414.[Abstract/Free Full Text]

Olivennes F, Belaisch-Allart J, Emperaire JC, Dechaud H, Alvarez S, Moreau L, Nicollet B, Zorn JR, Bouchard P and Frydman R (2000) Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin). Fertil Steril 73,314–320.[CrossRef][ISI][Medline]

Out HJ, Rutherford A, Fleming R, Tay CC, Trew G, Ledger W and Cahill D (2004) A randomized, double-blind, multicentre clinical trial comparing starting doses of 150 and 200 IU of recombinant FSH in women treated with the GnRH antagonist ganirelix for assisted reproduction. Hum Reprod 19,90–95.[Abstract/Free Full Text]

Papanikolaou EG, Kolibianakis E and Devroey P (2005) Emerging drugs in assisted reproduction. Expert Opin Emerg Drugs 10,425–440.[Medline]

Porter RN, Smith W, Craft IL, Abdulwahid NA and Jacobs HS (1984) Induction of ovulation for in-vitro fertilisation using buserelin and gonadotropins. Lancet 2,1284–1285.[ISI][Medline]

Ragni G, Vegetti W, Baroni E, Colombo M, Arnoldi M, Lombroso G and Crosignani PG (2001) Comparison of luteal phase profile in gonadotropin stimulated cycles with or without a gonadotropin-releasing hormone antagonist. Hum Reprod 16,2258–2262.[Abstract/Free Full Text]

Ragni G, Alagna F, Brigante C, Riccaboni A, Colombo M, Somigliana E and Crosignani PG (2004) GnRH antagonists and mild ovarian stimulation for intrauterine insemination: a randomized study comparing different gonadotropin dosages. Hum Reprod 19,54–58.[Abstract/Free Full Text]

Rongieres-Bertrand C, Olivennes F, Righini C, Fanchin R, Taieb J, Hamamah S, Bouchard P and Frydman R (1999) Revival of the natural cycles in in-vitro fertilization with the use of a new gonadotrophin-releasing hormone antagonist (Cetrorelix): a pilot study with minimal stimulation. Hum Reprod 14,683–688.[Abstract/Free Full Text]

Tarlatzis BC and Kolibianakis EM (2002) Direct ovarian effects and safety aspects of GnRH agonists and antagonists. Reprod Biomed Online 5,8–13.[Medline]

The Ganirelix Dose-Finding Study Group (1998) A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotropin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). Hum Reprod 13,3023–3031.[Abstract/Free Full Text]

Tiitinen A, Hyden-Granskog C and Gissler M (2004) What is the most relevant standard of success in assisted reproduction?: the value of cryopreservation on cumulative pregnancy rates per single oocyte retrieval should not be forgotten. Hum Reprod 19,2439–2441.[Abstract/Free Full Text]

van Heusden AM and Fauser BC (2002) Residual ovarian activity during oral steroid contraception. Hum Reprod Update 8,345–358.[Abstract/Free Full Text]

van Loenen ACD, Huirne JAF, Schats R, Donnez J and Lambalk CB (2001) An open-label multicentre, randomized, parallel, controlled phase II study to assess the feasibility of a new programming regimen using an oral contraceptive prior to the administration of recombinant FSH and a GnRH-antagonist in patients undergoing ART (IVF-ICSI) treatment. Hum Reprod 16,144.

Varney NR, Syrop C, Kubu CS, Struchen M, Hahn S and Franzen K (1993) Neuropsychologic dysfunction in women following leuprolide acetate induction of hypoestrogenism. J Assist Reprod Genet 10,53–57.[CrossRef][ISI][Medline]

Vlaisavljevic V, Lovrec VG and Kovacic B (2003) Comparable effectiveness using flexible single-dose GnRH antagonist (cetrorelix) and single-dose long GnRH agonist (goserelin) protocol for IVF cycles – a prospective, randomized study. Reprod Biomed Online 7,301–308.[Medline]

Weiss JM, Oltmanns K, Gurke EM, Polack S, Eick F, Felberbaum R, Diedrich K and Ortmann O (2001) Actions of gonadotropin-releasing hormone antagonists on steroidogenesis in human granulosa lutein cells. Eur J Endocrinol 144,677–685.[Abstract]

Westergaard LG, Laursen SB and Andersen CY (2000) Increased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotropic women undergoing assisted reproduction. Hum Reprod 15,1003–1008.[Abstract/Free Full Text]

Wikland M, Bergh C, Borg K, Hillensjo T, Howles CM, Knutsson A, Nilsson L and Wood M (2001) A prospective, randomized comparison of two starting doses of recombinant FSH in combination with cetrorelix in women undergoing ovarian stimulation for IVF/ICSI. Hum Reprod 16,1676–1681.[Abstract/Free Full Text]

Wilcox J, Potter D, Moore M, Ferrande L and Kelly E (2005) Prospective, randomized trial comparing cetrorelix acetate and ganirelix acetate in a programmed, flexible protocol for premature luteinizing hormone surge prevention in assisted reproductive technologies. Fertil Steril 84,108–117.[Medline]

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