Principles and Practice of Controlled Ovarian Stimulation in ART 1st ed.

11. GnRH Agonist Versus Antagonist in ART

Madhuri Patil 

(1)

IVF and Reproductive Medicine, Dr. Patil’s Fertility and Endoscopy Clinic, No.1, Uma Admiralty, First Floor, Above HDFC Bank, Bannerghatta Road, Bangalore, Karnataka, 560029, India

Madhuri Patil

Email: drmadhuripatil59@gmail.com

Abstract

Most protocols for ovarian stimulation using gonadotrophins incorporate GnRH-agonist and GnRH-antagonist co-treatment, to prevent a premature rise in LH in in vitro fertilization (IVF) cycles. Its use in IUI cycles is controversial, though the pregnancy rates may be slightly higher with the use of analogues. But one must remember that the use of GnRH agonist in IUI cycles is associated with a higher incidence of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. On the other hand the GnRH antagonist may not be cost effective as one knows that to achieve one extra pregnancy, the number needed to treat (NNT) is 20. Protocols using GnRH antagonists are effective in preventing a premature rise of LH and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol.

We know that for more than 20 years, GnRH agonists have been the “gold standard” protocol in ovarian stimulation but today with more and more clinics utilizing the GnRH antagonist has had several advantages like lower total dosages of gonadotrophins, less incidence of hyperstimulation syndrome, lower cost, lack of side effects, shorter duration of treatment, and more individualized and less aggressive protocol.

With the long protocol of GnRH agonist started either in the midluteal phase or in the early follicular phase of the preceding cycle, pituitary desensitization in 2 or 3 weeks of treatment can be achieved. The initial stimulatory effect (“flare up”) may lead to ovarian cyst formation. On the other hand, GnRH antagonists cause an immediate suppression of gonadotrophin secretion, without the initial stimulatory effect; hence, they can be given after starting gonadotrophin administration.

Thus, the GnRH-antagonist protocol is a handy protocol with good clinical outcome and a definite reduction in incidence of severe OHSS. It is the protocol of choice as the Cochrane review also has demonstrated no evidence of statistically significant differences in the rates of live births or ongoing pregnancies when comparing GnRH-agonist long protocols with GnRH-antagonist protocols.

Keywords

GnRH agonistGnRH antagonistOvarian stimulationPremature LH surgeLive-birth rates

11.1 Introduction

The role of endogenous luteinizing hormone (LH) levels during ovarian stimulation is very important. Both low and high baseline LH will affect the outcome of assisted reproductive techniques (ART) and should be taken into consideration when controlled ovarian stimulation (COS) is planned. It is important to prevent a premature LH surge during COS to be able to collect oocytes at oocyte retrieval and also prevent premature luteinization, which can affect the endometrial receptivity. For years GnRH agonists have been used in the long and short protocol to prevent premature LH surge. With the introduction of GnRH antagonist early in the twenty-first century to prevent premature LH surge, it has made the clinicians think about its efficacy compared to GnRH agonist. GnRH antagonist had several advantages like avoidance of an acute stimulation of endogenous gonadotrophins (GT), a dramatic reduction in the length of analogue treatment because of their ability to inhibit directly the premature LH surge, and a reduction in the gonadotrophin requirement used for ovarian stimulation.

With both GnRH agonist and antagonist present in our armamentarium for COS, we also need to know whether the probability of live birth per started cycle is dependent on the type of analogue used. The initial use showed that the probability of clinical pregnancy was shown to be significantly lower compared with GnRH agonists [1]. But today the GnRH antagonist in ART is the first-choice analogue instead of GnRH agonist after the meta-analysis published by Cochrane in 2002 [1] showed that there is no significant difference in the probability of clinical pregnancy and live births. Moreover, the lower incidence of ovarian hyperstimulation syndrome (OHSS) in a GnRH-antagonist cycle, where there is an option of using GnRH agonist for trigger, has made them the analogue of choice.

Apart from clinical pregnancy and live-birth rate, we also need to take into account certain secondary outcomes like duration of analogue treatment, FSH requirement, duration of FSH stimulation, number of cumulus-oocyte complexes (COCs) retrieved, incidence of premature LH rise, incidence of OHSS, and probably cost.

The other thing one needs to consider is the gonadotrophin used, as the use of GnRH analogues can suppress the LH levels to an extent that may affect the folliculogenesis and in turn the outcome of ART. At present, available evidence suggests that among women with normal ovulation or World Health Organization (WHO) II oligo-anovulation, low endogenous LH levels during ovarian stimulation for IVF using gonadotrophin-releasing hormone (GnRH) analogues are not associated with a decreased probability of ongoing pregnancy beyond 12 weeks [2] However, it cannot be excluded that LH supplementation during the follicular phase might be beneficial for pregnancy achievement, independently of any effect of endogenous LH levels. The type of downregulation (agonist or antagonist) did not seem to modify the effect of LH addition to FSH.

11.2 Differences Between GnRH Agonist and Antagonist

11.2.1 Endocrinological Profile Differences Between the Two GnRH Analogues

A progesterone rise during the late follicular phase has a negative predictive value for clinical outcome in both GnRH-agonist [35] and GnRH-antagonist protocols [67]. This is because high serum progesterone levels on the day of hCG administration induce both advanced endometrial histological maturation [8] and differential endometrial gene expression [910] which may have a negative effect on the implantation failure.

Though a previous meta-analysis failed to demonstrate any relationship between progesterone levels and clinical pregnancy rates [11], data from large prospective randomized studies like the Merit study [12] and a retrospective study of 4,000 cycles [6] consistently support that pregnancy rates are inversely related to progesterone levels on the day of hCG administration, when a threshold of 1.5 ng/ml is adopted.

Papanikolaou et al. [13] published that there was no difference in the incidence of progesterone rise, but in both protocols elevated progesterone results in a significant decrease in pregnancy rates. There was no difference observed in the live-birth rates between the two GnRH analogues (28.1 % with GnRH antagonist versus 24.5 % with GnRH agonist) with or without premature progesterone rise.

11.2.2 Advantages of GnRh Antagonists over GnRH Agonists

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11.2.3 Advantages of GnRH Agonists over GnRH Antagonist

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11.2.4 Duration of Analogue Treatment

The duration of analogue administration was significantly longer in the agonist group [23].

11.2.5 Use of Exogenous FSH in GnRH-Antagonist and GnRH-Agonist Co-treatment Cycles

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 [24]. However, a lower number of cumulus-oocyte complexes (COCs) were retrieved with the use of GnRH antagonists compared with GnRH agonists [1]. A higher starting dose of FSH in an agonist cycle may result in an increased number of COCs retrieved but it does not appear to be associated with higher pregnancy rates [2526]. In addition, the increase of gonadotrophin doses at GnRH-antagonist initiation did not appear to result in higher probability of pregnancy [27].

In a GnRH-antagonist cycle, it is possible to start FSH stimulation later in the follicular phase by extending the FSH window for multi-follicular development [2829] resulting in milder stimulation. This flexibility of starting FSH later in the follicular phase can also be used in modified natural cycle for IVF, in which the development of a single follicle is supported by addition of exogenous FSH latter in the cycle in combination with GnRH antagonist to control the endogenous LH production [30]. Addition of LH for ovarian stimulation does not increase the probability of pregnancy in either group.

11.2.6 Duration of FSH Stimulation

The duration of stimulation was significantly longer in the GnRH-agonist group.

11.2.7 LH Supplementation

The increased pregnancy loss observed with low LH levels in GnRH-agonist cycles [31] and decreased probability of pregnancy associated with low LH levels, observed using high GnRH-antagonist doses [32], as a result of abrupt suppression of endogenous LH by GnRH antagonist occur in the mid-follicular phase, at a critical stage for follicular development. It was thus assumed that LH supplementation might improve pregnancy outcome in both groups, where one could add LH or increase the dose of LH in the form of rec-LH or rec-hMG.

Kolibianakis et al. and Merviel et al. published that there was no indication that low endogenous LH levels after GnRH-antagonist initiation are associated with a decreased probability of pregnancy in IVF cycles [3334].

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 but can be used in GnRH-agonist cycles associated with low LH levels on day 2 of the cycle in a GnRH-agonist long protocol.

11.2.8 LH Surge/Rise

The likelihood of LH surges and LH rises was significantly higher with GnRH-antagonist than with GnRH-agonist treatment especially in the flexible GnRH-antagonist protocol.

11.2.9 Criteria for hCG Administration

There is a marked variation in the criteria used for triggering final oocyte maturation in IVF both in GnRH-agonist and GnRH-antagonist cycles [35]. 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 [35] in GnRH-antagonist cycle.

11.2.10 Cumulus-Oocyte Complex (COCs) Retrieved

Significantly more oocytes were retrieved in the agonist group compared with the GnRH-antagonist group.

11.2.11 Luteal Phase Supplementation

The existing evidence in GnRH-antagonist cycles suggests that luteal supplementation remains mandatory as is the case with GnRH agonists.

11.2.12 OHSS

The incidence of OHSS associated with hospital admission was significantly lower in the antagonist than in the agonist group. The incidence of grade I and II OHSS did not differ significantly between the two GnRH analogues but was in favor of GnRH-antagonist group, in which the incidence of OHSS was lower.

11.3 Comparative Efficacy of Various GnRH-Analogue Protocols in IVF

11.3.1 The Evidence

In the meta-analysis of randomized comparative trials between GnRH analogues, the absolute treatment effect of clinical pregnancy rate on an intention-to-treat basis was 5 % in favor of the GnRH agonists [36]. Later meta-analysis by Al-Inany et al. in 2011 [36] and another meta-analysis [37] did not show any significant difference in the live-birth rates, suggesting that both GnRH analogues result in comparable pregnancy rates.

The differences in reported outcome measurements could be the consequence of the large variation in the regimens of GnRH antagonist. It depends on whether we use the fixed or flexible protocol and when using the fixed protocol on what day we start the GnRH antagonist. Several studies today show a better outcome when antagonist is started as early as day 5 of stimulation.

The two phenomena that play an important role to facilitate optimal IVF results when GnRH analogues are used are:

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11.3.2 Long Versus Short or Ultrashort GnRH-Agonist Regimen

The long protocol (starting in the midluteal phase of the preceding cycle) gave the best IVF results with regard to oocyte yield and pregnancy rates [38]. It results in profound suppression of endogenous release of gonadotrophins during the early follicular phase, allowing the early antral follicles to grow coordinately in response to exogenous gonadotrophins to accomplish simultaneous maturation. Basically it results in extended widening of the FSH window, increased FSH requirement, and in the end more mature follicles and retrieved oocytes [38].

11.3.3 Fixed Versus Flexible GnRH-Antagonist Regimens

Fixed GnRH-antagonist regimens started the antagonist relatively late in the follicular phase, mostly stimulation day 6. Normally, the luteo-follicular transitory rise of endogenous FSH starts the stimulation of a cohort of follicles that vary in stage of development as there is a decrease in FSH concentration just before exogenous FSH is started. The start of exogenous FSH allows further development of a few leading large follicles and several smaller follicles [3944]. Further there is again a small fall in the level of FSH, when the antagonist is started. As the criteria for administration of hCG are based on the size of the leading largest follicles, there are several immature follicles at that time. Though the stimulation period will be shorter with less FSH required, the number of mature oocytes obtained is definitely less compared to GnRH-agonist long protocol [394245].

Thus, GnRH-antagonist regimens result in less synchronization of the follicular cohort as compared to a long GnRH-agonist cycle with lesser mature and more immature follicles.

Significantly lower ongoing pregnancy rates are seen in patients with elevated progesterone at initiation of stimulation in GnRH-antagonist cycle, which is more common in a flexible protocol when the antagonists are initiated only after the dominant follicle is 14 mm. The high estradiol levels when the antagonist is initiated late may result in premature LH rise with early rise in progesterone levels with luteinization. This may result in early closure of the implantation window [46] through earlier expression of progesterone receptors in the follicular phase and downregulation of estrogen receptors by the exposure to supraphysiological steroid hormone levels [4748].

We know that once the endometrium is primed by estradiol, the duration of progesterone exposure is the crucial point leading to a receptive endometrium. Thus, the fixed protocol has better pregnancy rates as compared to the flexible protocol due to better control of hormonal levels (estradiol, LH, and progesterone).

One study indicated that the stability of LH levels rather than absolute LH values is associated with clinical pregnancy, as no pregnancies occurred if the LH and progesterone levels changed too markedly (either increase or decrease) during GnRH-antagonist administration [44].

Thus, fixed protocols where the antagonist is started on day 6 are better than flexible protocols, which allow higher LH, estradiol, and progesterone levels and are associated with lower pregnancy rates [49]. An earlier start (cycle day 4 or 5) of GnRH antagonists is associated with improved pregnancy rates [50]. So if we start GnRH antagonist on day 1 compared with day 6, there will be even further decrease in the exposure to LH and estradiol during the early follicular phase [51] and it would be beneficial in PCOS women. However, the pregnancy rates (52 % per embryo transfer) were not different in this small study. Additionally, this regimen will increase the cost due to the extended period of GnRH-antagonist administration.

11.3.4 Long GnRH-Agonist Versus Flexible GnRH-Antagonist Regimens

The GnRH-agonist long protocol is more favorable compared to flexible start antagonist protocols with respect to the number of dominant follicles on the day of hCG and number of oocytes retrieved [295253]. The incidence of asynchronous follicle development through absent suppression of early endogenous FSH secretion is seen only in the antagonist protocol. The low gonadotrophin levels prior to stimulation created by the long agonist protocol are of particularly favorable to IVF/ICSI yield and outcome.

11.3.5 Comparisons of GnRH-Antagonist Versus GnRH-Agonist Protocol in Poor Ovarian Responders Undergoing IVF

Poor ovarian response is defined as reduced follicle/oocyte production (<4) after controlled ovarian hyperstimulation (COH) for IVF [5455]. It may be associated with high cancelation rates, impaired fertilization rates, and lower embryo quality [56]. Therefore, the management of poor responders has been one of the most difficult challenges in ART with overall poor IVF success rates.

Various treatment regimens and interventions have been investigated in an effort to improve ovarian response and IVF outcome. These include the use of high doses of gonadotrophins [57], the change to a “flare-up” protocol with OC pretreatment [58], and the use of growth hormone or growth hormone-releasing factor [59] or aspirin [60] as adjunct therapies. However, most of these interventions have only limited success in poor responders. The availability of GnRH antagonists has offered an alternative protocol for poor responders [6162] as GnRH-agonist long protocol may cause over-suppression of endogenous gonadotrophin secretion at the stage of follicular recruitment [6163].

Although the results of the GnRH antagonist in COS protocols offer a number of potential advantages [64] compared with the conventional GnRH-agonist long protocol, the efficacy of GnRH antagonist and GnRH agonist in poor-responder IVF patients is still controversial.

As early as 2009 Nelson et al. [65] published that treatment with a GnRH-antagonist protocol reduced the burden of treatment in poor responders compared with a GnRH-agonist protocol [66] but did not influence either the proportion of cases achieving egg collection or pregnancy rates [65]. Later a Cochrane review [67] published in 2010 and a meta-analysis published in 2011 showed that the duration of stimulation was significantly lower in GnRH-antagonist protocols than GnRH-agonist long protocols in poor responder, and no improvements were found in the number of oocytes and mature oocytes retrieved, the cycle cancelation rate (CCR), and the clinical pregnancy rate (CPR) with the use of GnRH antagonist. GnRH antagonist resulted in an LH surge in 9 % of poor responders, which was a cause for concern [65].

In a recent retrospective study [68], patients with extremely low AMH concentrations had a moderate but reasonable chance of pregnancy (7.9 % per cycle started) when treated with a microdose agonist protocol, a daily gonadotrophin dose of 600 IU, and dehydroepiandrosterone supplementation.

11.3.6 Comparisons of GnRH-Antagonist Versus GnRH-Agonist Protocol in Hyperresponders Undergoing IVF

AMH and AFC are a good predictor of excessive ovarian response [69]. Thus, in women with a high AMH concentration and high AFC, an individualized (reduced) dose of FSH and use of GnRH antagonist with GnRH-agonist trigger can improve both safety and pregnancy outcomes.

The antagonist protocol eliminated the need for complete cryopreservation of embryos due to excessive response (P < 0.001), coupled with significant reductions in the incidence of hospitalizations owing to the development of OHSS (13.9 % in the agonist group versus 0.0 % in the antagonist group; P = 0.02) [376570].

The antagonist protocol, in high responders, was also associated with higher fresh-cycle clinical pregnancy rates (odds ratio 4.40, 95 % confidence interval 1.95–9.93; P < 0.001), required fewer days of FSH stimulation, and was associated with lower egg yields compared with the agonist protocol [65]; these patients with low egg yields achieved pregnancy rates comparable with those with normal or high egg yields [6571]. Patients with AMH serum concentrations >40 pmol/l still remain at risk of developing an excessive response and OHSS despite the use of a “mild” antagonist protocol with hCG trigger.

The use of GnRH-antagonist protocols as part of the AMH- and AFC-tailored treatment strategy may result in improvement of efficacy and safety in high responders.

Individualized COS protocols using the AMH also helped in reducing the cost of treatment as well as the cost involved in the clinical management of OHSS in high responders.

11.3.7 Early Initiation of GnRH-Antagonist (Day 1) Versus GnRH-Agonist in GnRH-agonist long protocol

Initiation of GnRH antagonist on day 1 of stimulation for IVF when compared with the long agonist protocol is associated with a more rapid follicular development [72], an earlier rise in E2 levels, and significantly higher levels of progesterone. This is accompanied by significantly lower LH levels in the early follicular phase and significantly higher LH levels in the late follicular phase in the antagonist group. The exposure to LH, E2, and progesterone in the early follicular phase was higher in the antagonist when compared with the GnRH agonist group but did not reach statistical significance.

11.3.8 GnRH Analogues in Oocyte Donation (OD) Cycles

OD cycles, both the short GnRH agonist and antagonist, appear to be similar in ovarian response and embryo quality and comparable in terms of recipients’ pregnancy and implantation rates. The GnRH-antagonist protocol could be the protocol of choice for ovarian stimulation in OD cycles, as the risk of OHSS could be reduced by the triggering of ovulation with a GnRH agonist [73].

11.3.9 Oral Contraceptive Pill Pretreatment in Ovarian Stimulation with GnRH Antagonists and Agonist

The use of OCP has been advocated for programming IVF cycles using GnRH antagonists [7475] and improved synchronization of the recruitable cohort of ovarian follicles as against a GnRH-agonist cycle, where it is used to prevent ovulation, which in turn will reduce the cyst formation after initiation of the agonist in a long protocol.

Estrogen or OC pretreatment offers a simple alternative to achieve gonadotrophin suppression during the early follicular phase [7677]. Gonadotrophin can be started 2 or 3 days [757881] after OC withdrawal in either flexible or fixed GnRH-antagonist protocols. OC pretreatment using GnRH antagonists with subsequent starting of FSH 2 or 3 days after the last OC intake is associated with deep suppression of LH and FSH levels and improved synchronization of the follicular cohort development compared with GnRH-antagonist-only protocols [8081]. Similarly, improvement of the synchronization of the follicular cohort was observed only if stimulation was started 3 days after estradiol pretreatment in GnRH-antagonist protocols in a general population [82] and in poor responders with optimal pregnancy rates [83]. This effect is not seen when FSH stimulation was started on day 5 after the last OCP [8485]. Apparently, timing the start of exogenous gonadotrophin administration after OCP pretreatment affects follicular development [86].

But it was also observed that pretreatment with OCP has been associated with a longer duration of treatment [87] and increased gonadotrophin requirement [88]. No significant effect of OCP pretreatment was noted on the probability of pregnancy in GnRH-antagonist cycles which was shown in a large RCT [85], suggesting that programming of IVF cycles with the use of OCP is feasible.

Some studies have shown a lower implantation rates after OC pretreatment [8081] or increased pregnancy loss compared with GnRH-antagonist-only regimens [85]. Similar luteal endometrial development was found in OC-pretreated flexible GnRH-antagonist protocol [8] or fixed day 6 antagonist protocol [89] in comparison to a GnRH-agonist long protocol or a short GnRH-agonist protocol [90].

11.4 GnRH Analogues in Ovarian Stimulation for IUI

LH surge is an absolute requirement for luteinization, final maturation of the oocyte, and follicle rupture. Premature LH surge occurs in 25–30 % of stimulated IUI cycles and may interfere with timing of IUI or result in cancelation of IUI cycle and more treatment failures with IUI [9192].

So we need to see whether use of GnRH agonist or antagonist in IUI cycles is cost effective and helps in improving the outcome.

Moreover when IUI is done with gonadotrophins, the response may vary, ranging from no response to hyperresponse (more than four follicles of >12 mm developed). Among hyperresponders, where follicular recruitment is excessive, a decision must be made to either cancel the cycle or allow the multiple follicles to mature and thus risk the incidence of multiple pregnancy and OHSS or convert it into an IVF cycle.

Here is then the role of GnRH analogues, and GnRH antagonists have the advantage over GnRH agonist as they could be added later in the cycle.

11.4.1 GnRH Agonists in Ovarian Stimulation for IUI

There seems to be no role for GnRH agonists in IUI programs as they increase cost as the dose of gonadotrophins is increased tremendously. Its use also increases the incidence of multiple pregnancies without increasing the probability of conception. Thus, the use of GnRH agonists with gonadotrophins should be carefully considered in an intrauterine insemination program [93].

11.4.2 GnRH Antagonists in Ovarian Stimulation for IUI

When GnRH antagonists are used for ovarian stimulation in combination with IUI [9496] (Ragni et al. 2001, 2004; Gomez-Palomares et al. 2005), there may be a small increase in probability of pregnancy and the number needed to treat is 20. In addition, they may be helpful in cycle programming and avoidance of inseminations during weekends.

Conversion of high-response gonadotrophin-IUI cycles to “rescue” IVF using a GnRH antagonist is a cost-effective strategy that produces better results than regular IVF with relatively minimal morbidity and shorter duration to achieve pregnancy. Implantation and ongoing clinical pregnancy rates tend to be higher than those from hyperresponder regular IVF patients.

Whether or not GnRH antagonists are going to play a role in mild ovarian hyperstimulation/IUI programs needs to be determined in future trials [93].

The GnRH antagonist resulted in more monofollicular development, less premature luteinization, and less cycle cancelation in IUI cycles of patients with PCOS; however, the cost of stimulation increased without an improvement in pregnancy rates [97].

Patients with a previous canceled cycle because of premature luteinization are candidates for this treatment.

11.5 Discussion

Ovarian stimulation is applied to restore mono-ovulatory cycles in anovulatory women (ovulation induction) or to induce the development of multiple dominant follicles for ART. Ovarian response is the endocrine and follicular reaction of the ovaries to stimulation. Achieving an appropriate ovarian response to exogenous gonadotrophins without much variation in hormonal milieu and preventing complications is most important during COS. To achieve adequate response without cycle cancelation and adverse effects, it is important to predict the patient’s ovarian response to medication and to individualize the starting dose and type of exogenous gonadotrophin and select the correct GnRH analogue.

Antimüllerian hormone (AMH) and antral follicle count (AFC) can predict response to COS and identify women who are at risk either for OHSS or poor response. Thus, AMH and AFC have the potential to determine the optimal treatment protocol for an individual undergoing ART. This knowledge could be used to address safety and efficacy issues associated with COS by varying the type of GnRH analogue used or the type and daily dose of gonadotrophin.

In women who are at risk of developing OHSS, one can adjust the stimulation strategy to incorporate GnRH antagonists [98] and can also completely eliminate the possibility of OHSS by adopting a GnRH-agonist trigger before oocyte retrieval [99]. This unique approach has tremendous benefits in women undergoing altruistic oocyte donation, eliminating completely the risk of IVF [73100]. For anticipated normal responders, one could continue to use GnRH-agonist protocols, due to higher ongoing pregnancy (28 randomized, controlled trials: odds ratio [OR] 0.87; 95 % confidence interval [CI], 0.77–1.00) and live births (9 randomized, controlled trials: OR 0.86; 95 % CI, 0.69–1.08) favoring agonist-based rather than antagonist-based strategies [98]. In potential poor responders, currently the use of flare strategy, because of its reduced treatment burden and ability to capitalize on endogenous luteinizing hormone (LH) activity, makes GnRH-agonist short protocol the treatment of choice. This is in accordance with recent studies supporting a beneficial role of LH in older women [101]. Today it is a great challenge to determine the optimal protocol in poor responders and to improve clinical outcomes, while minimizing treatment burden would be the ultimate goal of future prospective research.

The probability of live birth is not dependent on the type of GnRH analogue (GnRH agonists and GnRH antagonists) used for suppression of premature LH rise/surge. A significantly higher incidence of premature LH rise/surge in GnRH-antagonist cycles may be seen in a GnRH-antagonist flexible protocol, where the analogue is started only after the dominant follicle reaches 14 mm. Here if there are many developing follicles, there could be high estradiol levels resulting in rise of LH levels. Moreover, the timing of LH assessment in relation to antagonist administration is also very important. Ideally, antagonist administration should occur immediately after blood is collected for hormonal analysis [102].

It is important for us to remember that the endocrine environment in cycles which are downregulated with GnRH agonist is more controlled than cycles controlled by GnRH antagonists, and all follicular growth is dictated only by the exogenous gonadotrophins.

The application of GnRH antagonist in ovarian stimulation for IVF was associated with a significantly lower probability of OHSS associated with hospital admission.

Conclusion

The achievement of a simple, safe, and cost-effective treatment protocol in controlled ovarian hyperstimulation (COH) is of paramount importance to improve the quality of care in assisted reproduction. Both GnRH-agonist and GnRH-antagonist co-treatment during ovarian hyperstimulation for IVF are effective in preventing an undesirable premature rise in serum LH. When using GnRH antagonist, the daily low-dose protocol should be preferred over a single high-dose regimen. GnRH antagonist could produce a more physiological follicular selection than the long luteal GnRH-agonist protocol, recruiting a smaller number of follicles and thus reducing OHSS risk.

Initial publications suggested that OCP pretreatment in GnRH-antagonist cycles reduced the pregnancy rates, but the clinical evidence generated recently suggests that OCP pretreatment can be used for planning IVF cycles.

In patients treated with FSH and GnRH analogues for IVF, the addition of rLH does not increase live-birth rate or have any beneficial effect on secondary outcome variables. So addition of LH from initiation of stimulation or from antagonist administration does not appear to be necessary. There is also no need to increase the starting dose of gonadotrophins or to increase gonadotrophin dose at antagonist initiation.

Progesterone elevation (PE) on the day of hCG administration is associated with a decreased probability of pregnancy in fresh IVF cycles in women undergoing ovarian stimulation using GnRH analogues and gonadotrophins. On the other hand, a negative association between PE on the day of hCG administration in the fresh cycle and the probability of pregnancy after transfer of frozen-thawed embryos originating from that cycle does not seem to be present. GnRH-antagonist initiation on day 6 of stimulation appears to be superior to flexible initiation by a follicle of 14–16 mm, and probably initiation of GnRH antagonist earlier in the cycle if the estradiol levels are more than 200 pg/ml on day 4 of COS may prevent early rise of progesterone and therefore improve the pregnancy rates.

Today the evidence suggests that the choice of GnRH analogue for inhibiting the premature LH surge does not alter significantly the probability of live birth. But the OHSS rate in women receiving the antagonist is significantly lower compared with the agonist protocols as hCG can be replaced by GnRH agonist for triggering final oocyte maturation. This may be associated with lower probability of pregnancy if a fresh transfer is done not using the modified luteal phase support protocol where hCG is given in the dose of 1,500 IU on the day of oocyte retrieval. The pregnancy rates remain the same if all embryos are frozen and transferred in the subsequent cycle. GnRH-antagonist protocol may be used for patients at high risk of developing OHSS to make the clinic an OHSS-free one.

Luteal phase supplementation is required following both GnRH-agonist and GnRH-antagonist co-treatment protocols with gonadotrophins.

GnRH antagonists may have a role in ovarian stimulation for IUI as well as their application in mild stimulation protocols for IVF. Use of GnRH agonist does not improve the outcome in IUI cycles.

Today with the availability of new markers of ovarian reserve, the improvement in methodology for their measurement allows a scientific estimate of the pool of follicles that potentially respond to ovarian stimulation. This then has supported the use of individualization of COS in ART cycles (Fig. 11.1). Today most protocols are selected on values of AMH and AFC. This protocol enables the correct selection of the different GnRH analogues and the gonadotrophin dose. The benefits of a personalized therapy are reduction in the risk of poor response or hyperresponse thus reducing the incidence of cancelation of the cycle and at the same time optimizing the outcome of ART.

A319836_1_En_11_Fig1_HTML.gif

Fig. 11.1

Key points in selection of stimulation protocols to improve results in IVF. AFC antral follicle count, FSH follicle stimulating hormone, hMG human menopausal gonadotropin, hCG human chorionic gonadotropin, SC subcutaneous, LPS luteal phase support, sET single embryo transfer, OHSS ovarian hyperstimulation syndrome, DET double embryo transfer, AMH anti mullerian hormone

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